CAP Profiles

Bio

Academic Appointments

Administrative Appointments

  • Senior Associate Dean for Diversity and Faculty Development, School of Medicine (2005 - Present)
  • President, Western State Affiliation, American Heart Association (2004 - 2005)

Professional Education

  • MBBS, St Georges Hosp/London Univ, UK, Medicine (MD equivalent) (1978)
  • MRCP, London University, London, UK, Internal Medicine (1982)
  • Registrar, Hammersmith Hospital, London, UK, Cardiology Fellow (1984)
  • Fellow, Stanford University, Cardiology (1986)
  • MD, London University, London, UK, Cardiology (PhD equivalent) (1988)

Contact

Research & Scholarship

Current Research and Scholarly Interests

Prior to my expanded administrative role, my lab focused on understanding the mechanism mediating acute and chronic allograft failure, in particular on the role of microvascular injury in acute allograft failure and the mechanisms of mediating transplant coronary artery disease.

1. Role of microvascular injury in acute allograft failure. We observed decreased cardiac allograft function in patients to be significantly associated with loss of microvascular cell surface markers, consistent with altered biology of the vascular endothelium or injury, and with up-regulation of cytokines such as IL-6, IL-10, TGF-b, and TNF-a. Decreased cardiac allograft function, in particular diastolic dysfunction, was highly predictive of allograft vascular disease and poor outcome in long-term patients. To further characterize cellular and molecular mechanisms we developed quantitative methods to monitor allograft function and correlate it with cytokine expression in a rat heterotopic transplant model. We developed echocardiographic markers of systolic and diastolic function and found decreasing systolic and diastolic function highly correlated with up-regulation of IL-6 expression.

2. Mechanisms mediating allograft dysfunction. We observed the major risk factors for transplant atherosclerosis in patients to be metabolic (hyperglycemia, hypertriglyceridemia, and low HDL). To further study cellular and molecular mechanisms mediating this process, we recapitulated metabolic abnormalities in the rat heart transplant model and confirmed rapid development of transplant atherosclerosis.

My current focus is on clinical and translational research, expanding on my earlier laboratory-based research on the mechanisms of allograft failure and vasculopathy. I study the role of sub-clinical cytomegalovirus infection in the development of cardiac allograft vasculopathy (CAV), and the effect of antiviral agents in preventing CAV, work that has been supported by a program project grant from NIH. Translating my earlier work on gene expression profiling, I conduct clinical trials on the application of this technology for non-invasive diagnosis of transplant rejection. This work, recently published in the New England Journal of Medicine, showed that peripheral blood leukocyte gene expression can be used safely for monitoring rejection in heart transplant recipients, with a substantial decrease in the number of endomyocardial biopsies performed. On going studies in this area will include application of the technology to diagnose CAV; monitor level of immunosuppression in a patient to guide therapy; and individualization of immunosuppression. My current research, in collaboration with bio-X faculty, uses the new technologies of whole genome scans, to detect the appearance of donor DNA in the recipient’s blood as a novel, non-invasive marker of allograft damage due to acute rejection. Ongoing studies include confirmation studies of the utility, and then external validation in a randomized controlled trial.

Clinical Trials

  • Heartsbreath Test for Heart Transplant Rejection Recruiting

    The purpose of this study is to demonstrate and validate a breath test for detection of biomarkers of heart transplant rejection (Grade 2R heart transplant).

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  • Angiotensin Converting Enzyme (ACE) Inhibition and Cardiac Allograft Vasculopathy Not Recruiting

    Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure. Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation. Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Preliminary data suggest that angiotensin converting enzyme inhibitors retard the atherosclerotic plaque development that is the hallmark of cardiac allograft vasculopathy. Moreover, this class of drug appears to increase circulating endothelial progenitor cell number and has anti-inflammatory properties, both of which improve endothelial dysfunction, the key precursor to the development of cardiac allograft vasculopathy. The objective of this project is to investigate the role of an angiotensin converting enzyme inhibitor, ramipril, in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque volume in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function and mediators of endothelial function, including circulating endothelial progenitor cells, will be measured. Subjects will then be randomized in a double blind fashion to either ramipril or placebo. After 1 year, the above assessment will be repeated. The primary endpoint will be the development of cardiac allograft vasculopathy based on intravascular ultrasound-derived parameters. The second aim will be to assess the effect of ramipril on endothelial dysfunction early after transplantation. The final aim is to determine the impact of ramipril on coronary physiology early after transplantation.

    Stanford is currently not accepting patients for this trial. For more information, please contact William Fearon, (650) 725 - 2621.

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  • Clinical Trial of Pioglitazone for Prevention of Cardiac Allograft Vasculopathy After Heart Transplantation Not Recruiting

    The purpose of this study is to determine the benefit of using the FDA-approved insulin-sensitizing agent, Pioglitazone, on human heart transplant recipients. The objectives of this project are to (1) determine if pioglitazone effectively treats insulin resistance in heart transplant recipients, and (2) to determine whether pioglitazone therapy after heart transplantation impacts the development or progression of cardiac allograft vasculopathy (CAV), a form of chronic rejection after heart transplantation.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nicole Constantz, BSc, 650-724-4740.

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  • Genome Transplant Dynamics: Non-invasive Sequencing-based Diagnosis of Rejection Not Recruiting

    The purpose of this study is to determine whether shotgun sequencing technology, which can be used to detect donor DNA in recipient plasma, can be used as a rapid, accurate, non-invasive method to detect Acute Cellular Rejection (ACR) after heart transplantation. Currently, all heart transplant recipients undergo invasive heart biopsies to diagnose ACR. Thus, there is an ongoing need to monitor patients for the development of acute and chronic rejection, with the primary goal of non-invasive early detection and treatment to prevent organ damage.

    Stanford is currently not accepting patients for this trial. For more information, please contact Spectrum Child Health, 650-724-1175.

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  • IMAGE: A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection Not Recruiting

    This study is designed to evaluate the safety and efficacy of a leukocyte gene expression profiling method in the monitoring of asymptomatic heart transplant patients for acute rejection.

    Stanford is currently not accepting patients for this trial.

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Teaching

2019-20 Courses

Publications

All Publications

  • Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation INTERNATIONAL JOURNAL OF CARDIOLOGY Okada, K., Honda, Y., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Fearon, W. F. 2019; 290: 27–32

    View details for DOI 10.1016/j.ijcard.2019.04.018

    View details for Web of Science ID 000470826500005

  • Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation. International journal of cardiology Okada, K., Honda, Y., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Fearon, W. F. 2019

    Abstract

    BACKGROUND: Acute allograft rejection (AAR) plays an important role in patient and graft survival; therefore, more emphasis should be placed on its prediction. This study aimed to investigate baseline clinical and diagnostic variables associated with subsequent AAR during the first year post-transplant, especially focusing on early physiologic and anatomic measures.METHODS: This study enrolled 88 heart transplant patients who underwent fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) in the left anterior descending artery at baseline (within 8 weeks post-transplant). Cardiac index (CI), pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP), right atrial pressure and left ventricular ejection fraction were also evaluated. AAR was defined as acute cellular rejection of grade ≥2R and/or pathological antibody-mediated rejection of grade ≥pAMR2.RESULTS: During the first year post-transplant, 25.0% of patients experienced AAR. Patients with AAR during the first year showed higher rates of recipient obesity, lower rates of recipient-donor sex mismatch and rATG and tacrolimus uses, higher PCWP, mPAP and IMR, and lower CFR at baseline, compared with those without. In the multivariate analysis, only baseline IMR ≥ 16.0 was independently associated with AAR during the first year, demonstrating high negative predictive value (96.7%).CONCLUSIONS: Invasively assessing microvascular resistance (baseline IMR ≥ 16.0) in the early post-transplant period was an independent determinant of subsequent acute allograft rejection during the first year post-transplant, suggesting that early assessment of IMR may enhance patient risk stratification and target medical therapies to improve patient outcome.

    View details for PubMedID 30987835

  • Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. EBioMedicine Agbor-Enoh, S., Wang, Y., Tunc, I., Jang, M. K., Davis, A., De Vlaminck, I., Luikart, H., Shah, P. D., Timofte, I., Brown, A. W., Marishta, A., Bhatti, K., Gorham, S., Fideli, U., Wylie, J., Grimm, D., Goodwin, N., Yang, Y., Patel, K., Zhu, J., Iacono, A., Orens, J. B., Nathan, S. D., Marboe, C., Berry, G. J., Quake, S. R., Khush, K., Valantine, H. A. 2019

    Abstract

    BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.

    View details for PubMedID 30692045

  • De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans. Nature biotechnology Deuse, T., Hu, X., Agbor-Enoh, S., Koch, M., Spitzer, M. H., Gravina, A., Alawi, M., Marishta, A., Peters, B., Kosaloglu-Yalcin, Z., Yang, Y., Rajalingam, R., Wang, D., Nashan, B., Kiefmann, R., Reichenspurner, H., Valantine, H., Weissman, I. L., Schrepfer, S. 2019

    Abstract

    The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.

    View details for DOI 10.1038/s41587-019-0227-7

    View details for PubMedID 31427818

  • Association of Endothelin-1 with Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation. Journal of cardiac failure Parikh, R. V., Khush, K., Pargaonkar, V. S., Luikart, H., Grimm, D., Yu, M., Akada, K., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2018

    Abstract

    BACKGROUND: Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well-studied in humans.METHODS AND RESULTS: In 90 HT patients, plasma ET-1 was measured within 8 weeks of HT (baseline) via a competitive enzyme-linked immunosorbent assay. 3D volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined using the 75th percentile as a cutoff. Patients were followed beyond the first year post-HT for late death or re-transplantation. A receiver operative characteristic curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year [area under the curve=0.69 (0.57-0.82), p=0.007]. In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV [odds ratio (OR)=2.13, 95% confidence interval (CI): 1.15-3.94; p=0.01]; this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR=4.88, 95% CI: 1.69-14.10; p=0.003). Eighteen deaths occurred during a median follow-up period of 3.99 (2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression [hazard ratio (HR)=1.22, 95% CI: 0.72-2.05; p=0.44]. However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (p=0.047), and was independently associated with late mortality (HR=2.94, 95% CI: 1.12-7.72; p=0.02).CONCLUSIONS: Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

    View details for PubMedID 30543947

  • Usefulness of Asymmetric Dimethylarginine to Predict Outcomes After Heart Transplantation AMERICAN JOURNAL OF CARDIOLOGY Parikh, R., Khush, K., Luikart, H., Sakarovitch, C., Lee, J., Desai, M., Valantine, H., Yeung, A. C., Fearon, W. F. 2018; 122 (10): 1707–11

    Abstract

    Asymmetric dimethylarginine (ADMA) is a key mediator of vascular homeostasis and an independent predictor of the development of accelerated cardiac allograft vasculopathy after heart transplantation. However, its association with clinical outcomes in heart transplant recipients has not been described. Plasma levels of ADMA were assayed within 8 weeks following transplantation (baseline) using a competitive enzyme-linked immunosorbent assay. The primary end point was the composite of nonfatal myocardial infarction, percutaneous coronary intervention, retransplantation, or death at 5-year follow-up. Kaplan-Meier curves were generated to assess the association between baseline ADMA levels (stratified at 0.70 µM, a previously established cutoff) and cumulative event-free survival. Multivariate Cox regression was performed to adjust for other candidate predictors. In 69 heart transplant recipients at Stanford, the primary end point occurred in 11 patients (16%)-4 percutaneous coronary intervention, 1 retransplant, and 6 deaths-during 5-years follow-up. Patients with baseline ADMA ≥0.70 µM had lower cumulative 5-year event-free survival (77% vs 93%, p = 0.059). In multivariate Cox analysis, baseline ADMA was the only significant predictor of the primary end point (hazard ratio 1.33, 95% confidence interval 1.03 to 1.72 per 0.1 µM; p = 0.031). This association remained significant even after restricting the end point to death or retransplantation (hazard ratio 1.48, 95% confidence interval 1.12 to 1.97 per 0.1 µM; p = 0.006). In conclusion, elevated baseline plasma levels of ADMA independently predicted 5-year clinical outcomes after heart transplantation, suggesting that ADMA has potential prognostic value in the heart transplant arena.

    View details for PubMedID 30220417

  • Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Jackson, A. M., Tunc, I., Berry, G. J., Cochrane, A., Grimm, D., Davis, A., Shah, P., Brown, A. W., Wang, Y., Timofte, I., Shah, P., Gorham, S., Wylie, J., Goodwin, N., Jang, M., Marishta, A., Bhatti, K., Fideli, U., Yang, Y., Luikart, H., Cao, Z., Pirooznia, M., Zhu, J., Marboe, C., Iacono, A., Nathan, S. D., Orens, J., Valantine, H. A., Khush, K. 2018; 37 (7): 925–32

    Abstract

    Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

    View details for PubMedID 29500138

  • An Integrated Career Coaching and Time Banking System Promoting Flexibility, Wellness, and Success: A Pilot Program at Stanford University School of Medicine Academic Medicine Fassiotto, M., Simard, C., Sandborg, C., Valantine, H., Raymond, J. 2018

    View details for DOI 10.1097/ACM.0000000000002121

  • An Integrated Career Coaching and Time-Banking System Promoting Flexibility, Wellness, and Success: A Pilot Program at Stanford University School of Medicine. Academic medicine : journal of the Association of American Medical Colleges Fassiotto, M., Simard, C., Sandborg, C., Valantine, H., Raymond, J. 2018; 93 (6): 881–87

    Abstract

    Faculty in academic medicine experience multiple demands on their time at work and home, which can become a source of stress and dissatisfaction, compromising success. A taskforce convened to diagnose the state of work-life flexibility at Stanford University School of Medicine uncovered two major sources of conflict: work-life conflict, caused by juggling demands of career and home; and work-work conflict, caused by competing priorities of the research, teaching, and clinical missions combined with service and administrative tasks. Using human-centered design research principles, the 2013-2014 Academic Biomedical Career Customization (ABCC) pilot program incorporated two elements to mitigate work-life and work-work conflict: integrated career-life planning, coaching to create a customized plan to meet both career and life goals; and a time-banking system, recognizing behaviors that promote team success with benefits that mitigate work-life and work-work conflicts. A matched-sample pre-post evaluation survey found the two-part program increased perceptions of a culture of flexibility (P = .020), wellness (P = .013), understanding of professional development opportunities (P = .036), and institutional satisfaction (P = .020) among participants. In addition, analysis of research productivity indicated that over the two-year program, ABCC participants received 1.3 more awards, on average, compared with a matched set of nonparticipants, a funding difference of approximately $1.1 million per person. These results suggest it is possible to mitigate the effects of extreme time pressure on academic medicine faculty, even within existing institutional structures.

    View details for PubMedID 29298183

  • Pulled in Too Many Directions: The Causes and Consequences of Work-Work Conflict Sociological Perspectives Wynn, A. T., Fassiotto, M., Simard, C., Raymond, J. L., Valantine, H. 2018

    View details for DOI 10.1177/0731121418774568

  • Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. International journal of cardiology Kobayashi, Y., Kobayashi, Y., Yang, H. M., Bouajila, S., Luikart, H., Nishi, T., Choi, D. H., Schnittger, I., Valantine, H. A., Khush, K. K., Yeung, A. C., Haddad, F., Fearon, W. F. 2018; 260: 31–35

    Abstract

    Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting.A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year.The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively).Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation.

    View details for PubMedID 29622448

  • Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Tunc, I., De Vlaminck, I., Fideli, U., Davis, A., Cuttin, K., Bhatti, K., Marishta, A., Solomon, M. A., Jackson, A., Graninger, G., Harper, B., Luikart, H., Wylie, J., Wang, X., Berry, G., Marboe, C., Khush, K., Zhu, J., Valantine, H. 2017; 36 (9): 1004–12

    Abstract

    Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts.After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts.We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R2 > 0.99, p < 10-6), as well as across manual and automated platforms (slope = 0.80, R2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001).The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.

    View details for PubMedID 28624139

  • The effect of negative remodeling on fractional flow reserve after cardiac transplantation INTERNATIONAL JOURNAL OF CARDIOLOGY Fearon, W. F., Felix, R., Hirohata, A., Sakurai, R., Jose, P. O., Yamasaki, M., Nakamura, M., Fitzgerald, P. J., Valantine, H. A., Yock, P. G., Yeung, A. C. 2017; 241: 283–87

    Abstract

    Negative remodeling is a common occurrence early after cardiac transplantation. Its impact on the development of myocardial ischemia is not well documented. The aim of this study is to investigate the impact of negative remodeling on fractional flow reserve after cardiac transplantation.Thirty-four cardiac transplant recipients underwent intravascular ultrasound (IVUS) and fractional flow reserve (FFR) assessment soon after transplantation and one year later. Patients were divided into those with and without negative remodeling based on IVUS, and the impact on FFR was assessed. In the 19 patients with negative remodeling, there was no significant change in plaque volume (119.3±82.0 to 131.3±91.2mm3, p=0.21), but vessel volume (775.6±212.0 to 621.9±144.1mm3, p<0.0001) and lumen volume (656.3±169.1 to 490.7±132.0mm3, p<0.0001) decreased significantly and FFR likewise decreased significantly (0.88±0.06 to 0.84±0.07, p=0.04). In the 15 patients without negative remodeling, vessel volume did not change (711.7±217.6 to 745.7±198.5, p=0.28), but there was a significant increase in plaque volume (126.8±88.3 to 194.4±92.7, p<0.001) and a resultant significant decrease in FFR (0.89±0.05 to 0.85±0.05, p=0.01).Negative remodeling itself, without any change in plaque volume can cause a significant decrease in fractional flow reserve after cardiac transplantation and appears to be another possible mechanism for myocardial ischemia.

    View details for PubMedID 28413112

  • Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype PLOS COMPUTATIONAL BIOLOGY Sharon, E., Shi, H., Kharbanda, S., Koh, W., Martin, L. R., Khush, K. K., Valantine, H., Pritchard, J. K., De Vlaminck, I. 2017; 13 (8): e1005629

    Abstract

    Quantification of cell-free DNA (cfDNA) in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD) quantifies donor-derived cfDNA (dd-cfDNA) by taking advantage of single-nucleotide polymorphisms (SNPs) distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM) of identity-by-descent (IBD) states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD). These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application.

    View details for PubMedID 28771616

  • Designing a physician leadership development program based on effective models of physician education. Health care management review Hopkins, J., Fassiotto, M., Ku, M. C., Mammo, D., Valantine, H. 2017

    Abstract

    Because of modern challenges in quality, safety, patient centeredness, and cost, health care is evolving to adopt leadership practices of highly effective organizations. Traditional physician training includes little focus on developing leadership skills, which necessitates further training to achieve the potential of collaborative management.The aim of this study was to design a leadership program using established models for continuing medical education and to assess its impact on participants' knowledge, skills, attitudes, and performance.The program, delivered over 9 months, addressed leadership topics and was designed around a framework based on how physicians learn new clinical skills, using multiple experiential learning methods, including a leadership active learning project. The program was evaluated using Kirkpatrick's assessment levels: reaction to the program, learning, changes in behavior, and results. Four cohorts are evaluated (2008-2011).Reaction: The program was rated highly by participants (mean = 4.5 of 5). Learning: Significant improvements were reported in knowledge, skills, and attitudes surrounding leadership competencies. Behavior: The majority (80%-100%) of participants reported plans to use learned leadership skills in their work. Improved team leadership behaviors were shown by increased engagement of project team members.All participants completed a team project during the program, adding value to the institution.Results support the hypothesis that learning approaches known to be effective for other types of physician education are successful when applied to leadership development training. Across all four assessment levels, the program was effective in improving leadership competencies essential to meeting the complex needs of the changing health care system.Developing in-house programs that fit the framework established for continuing medical education can increase physician leadership competencies and add value to health care institutions. Active learning projects provide opportunities to practice leadership skills addressing real word problems.

    View details for DOI 10.1097/HMR.0000000000000146

    View details for PubMedID 28157830

  • Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. Journal of the American College of Cardiology Fearon, W. F., Okada, K., Kobashigawa, J. A., Kobayashi, Y., Luikart, H., Sana, S., Daun, T., Chmura, S. A., Sinha, S., Cohen, G., Honda, Y., Pham, M., Lewis, D. B., Bernstein, D., Yeung, A. C., Valantine, H. A., Khush, K. 2017; 69 (23): 2832–41

    Abstract

    Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT.This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT.In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year.Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm(3) vs. 177.3 ± 94.3 mm(3), respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group.Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363).

    View details for PubMedID 28595700

  • Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation. The American journal of cardiology Parikh, R. V., Khush, K. K., Luikart, H., Pargaonkar, V. S., Kobayashi, Y., Lee, J. H., Sinha, S., Cohen, G., Valantine, H. A., Yeung, A. C., Fearon, W. F. 2017

    Abstract

    Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.

    View details for PubMedID 28754566

  • Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation Lee, J. H., Okada, K., Khush, K., Kobayashi, Y., Sinha, S., Luikart, H., Valantine, H., Yeung, A. C., Honda, Y., Fearon, W. F. 2017; 135 (11): 1093–95

    View details for PubMedID 28289008

  • Reducing Implicit Gender Leadership Bias in Academic Medicine With an Educational Intervention. Academic medicine Girod, S., Fassiotto, M., Grewal, D., Ku, M. C., Sriram, N., Nosek, B. A., Valantine, H. 2016; 91 (8): 1143-1150

    Abstract

    One challenge academic health centers face is to advance female faculty to leadership positions and retain them there in numbers equal to men, especially given the equal representation of women and men among graduates of medicine and biological sciences over the last 10 years. The purpose of this study is to investigate the explicit and implicit biases favoring men as leaders, among both men and women faculty, and to assess whether these attitudes change following an educational intervention.The authors used a standardized, 20-minute educational intervention to educate faculty about implicit biases and strategies for overcoming them. Next, they assessed the effect of this intervention. From March 2012 through April 2013, 281 faculty members participated in the intervention across 13 of 18 clinical departments.The study assessed faculty members' perceptions of bias as well as their explicit and implicit attitudes toward gender and leadership. Results indicated that the intervention significantly changed all faculty members' perceptions of bias (P < .05 across all eight measures). Although, as expected, explicit biases did not change following the intervention, the intervention did have a small but significant positive effect on the implicit biases surrounding women and leadership of all participants regardless of age or gender (P = .008).These results suggest that providing education on bias and strategies for reducing it can serve as an important step toward reducing gender bias in academic medicine and, ultimately, promoting institutional change, specifically the promoting of women to higher ranks.

    View details for DOI 10.1097/ACM.0000000000001099

    View details for PubMedID 26826068

  • Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy. Journal of the American College of Cardiology Okada, K., Fearon, W. F., Luikart, H., Kitahara, H., Otagiri, K., Tanaka, S., Kimura, T., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Khush, K. K., Honda, Y. 2016; 68 (4): 382-392

    Abstract

    Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events.This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation.In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation.At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality.ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

    View details for DOI 10.1016/j.jacc.2016.05.028

    View details for PubMedID 27443435

  • Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma SCIENTIFIC REPORTS Burnham, P., Kim, M. S., Agbor-Enoh, S., Luikart, H., Valantine, H. A., Khush, K. K., De Vlaminck, I. 2016; 6

    Abstract

    Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA (p 10(-5), Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10(-5)) and microbial cfDNA (71.3x, p 10(-5)). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.

    View details for DOI 10.1038/srep27859

    View details for Web of Science ID 000377827700001

    View details for PubMedID 27297799

    View details for PubMedCentralID PMC4906518

  • Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation CIRCULATION Yang, H., Khush, K., Luikart, H., Okada, K., Lim, H., Kobayashi, Y., Honda, Y., Yeung, A. C., Valantine, H., Fearon, W. F. 2016; 133 (20): 1945-1950

    Abstract

    -The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation.-Seventy-four cardiac transplant recipients had fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary endpoint was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with an FFR<0.90 at baseline (42 vs 79%, p=0.01) or an IMR≥20 measured one year after heart transplantation (39 vs. 69%, p=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared to those patients with an increase in IMR (66 vs. 36%, p=0.03). FFR<0.90 at baseline (hazards ratio [HR] 0.13, 95% confidence interval [CI] 0.02-0.81, p=0.03), IMR ≥20 at 1 year (HR 3.93, 95% CI 1.08-14.27, p=0.04) and rejection during the first year (HR 6.00, 95% CI 1.56-23.09, p=0.009) were independent predictors of death/retransplantation, while IVUS parameters were not.-Invasive measures of coronary physiology (FFR and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation.

    View details for DOI 10.1161/CIRCULATIONAHA.115.018741

    View details for PubMedID 27143679

  • Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty JOURNAL OF WOMENS HEALTH Fassiotto, M., Hamel, E. O., Ku, M., Correll, S., Grewal, D., Lavori, P., Periyakoil, V. J., Reiss, A., Sandborg, C., Walton, G., Winkleby, M., Valantine, H. 2016; 25 (3): 292-298

    Abstract

    Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine.Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty.174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42).Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.

    View details for DOI 10.1089/jwh.2015.5380

    View details for Web of Science ID 000372173200014

  • Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation JACC-HEART FAILURE Okada, K., Kitahara, H., Yang, H., Tanaka, S., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Valantine, H. A., Fitzgerald, P. J., Khush, K. K., Honda, Y., Fearon, W. F. 2015; 3 (12): 942-952

    Abstract

    This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

    View details for DOI 10.1016/j.jchf.2015.07.013

    View details for Web of Science ID 000366949300002

  • Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation. JACC. Heart failure Okada, K., Kitahara, H., Yang, H., Tanaka, S., Kobayashi, Y., Kimura, T., Luikart, H., Yock, P. G., Yeung, A. C., Valantine, H. A., Fitzgerald, P. J., Khush, K. K., Honda, Y., Fearon, W. F. 2015; 3 (12): 942-952

    Abstract

    This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

    View details for DOI 10.1016/j.jchf.2015.07.013

    View details for PubMedID 26577615

  • Noninvasive monitoring of infection and rejection after lung transplantation. Proceedings of the National Academy of Sciences of the United States of America De Vlaminck, I., Martin, L., Kertesz, M., Patel, K., Kowarsky, M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Nicolls, M. R., Cornfield, D., Weill, D., Valantine, H., Khush, K. K., Quake, S. R. 2015; 112 (43): 13336-13341

    Abstract

    The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

    View details for DOI 10.1073/pnas.1517494112

    View details for PubMedID 26460048

  • Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study PLOS MEDICINE Vollmers, C., De Vlaminck, I., Valantine, H. A., Penland, L., Luikart, H., Strehl, C., Cohen, G., Khush, K. K., Quake, S. R. 2015; 12 (10)

    Abstract

    It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.If confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.

    View details for DOI 10.1371/journal.pmed.1001890

    View details for Web of Science ID 000364466600008

    View details for PubMedID 26466143

    View details for PubMedCentralID PMC4605651

  • Gene expression profiling to study racial differences after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Deng, M. C., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Hiller, D., Yee, J., Valantine, H. A. 2015; 34 (7): 970-977

    Abstract

    The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.

    View details for DOI 10.1016/j.healun.2015.01.987

    View details for Web of Science ID 000356998800014

    View details for PubMedID 25840504

    View details for PubMedCentralID PMC4475410

  • Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty. Journal of women's health (2002) Fassiotto, M., Hamel, E. O., Ku, M., Correll, S., Grewal, D., Lavori, P., Periyakoil, V. J., Reiss, A., Sandborg, C., Walton, G., Winkleby, M., Valantine, H. 2015

    Abstract

    Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine.Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty.174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42).Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.

    View details for PubMedID 26555562

  • Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection SCIENCE TRANSLATIONAL MEDICINE De Vlaminck, I., Valantine, H. A., Snyder, T. M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Bernstein, D., Weisshaar, D., Quake, S. R., Khush, K. K. 2014; 6 (241)

    Abstract

    Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

    View details for DOI 10.1126/scitranslmed.3007803

    View details for Web of Science ID 000338711700003

  • Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Science translational medicine De Vlaminck, I., Valantine, H. A., Snyder, T. M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Bernstein, D., Weisshaar, D., Quake, S. R., Khush, K. K. 2014; 6 (241): 241ra77-?

    Abstract

    Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

    View details for DOI 10.1126/scitranslmed.3007803

    View details for PubMedID 24944192

  • The gender gap in academic medicine: comparing results from a multifaceted intervention for stanford faculty to peer and national cohorts. Academic medicine Valantine, H. A., Grewal, D., Ku, M. C., Moseley, J., Shih, M., Stevenson, D., Pizzo, P. A. 2014; 89 (6): 904-911

    Abstract

    To assess whether the proportion of women faculty, especially at the full professor rank, increased from 2004 to 2010 at Stanford University School of Medicine after a multifaceted intervention.The authors surveyed gender composition and faculty satisfaction five to seven years after initiating a multifaceted intervention to expand recruitment and development of women faculty. The authors assessed pre/post relative change and rates of increase in women faculty at each rank, and faculty satisfaction; and differences in pre/post change and estimated rate of increase between Stanford and comparator cohorts (nationally and at peer institutions).Post intervention, women faculty increased by 74% (234 to 408), with assistant, associate, and full professors increasing by 66% (108 to 179), 87% (74 to 138), and 75% (52 to 91), respectively. Nationally and at peer institutions, women faculty increased by about 30% (30,230 to 39,200 and 4,370 to 5,754, respectively), with lower percentages at each rank compared with Stanford. Estimated difference (95% CI) in annual rate of increase was larger for Stanford versus the national cohort: combined ranks 0.36 (0.17 to 0.56), P = .001; full professor 0.40 (0.18 to 0.62), P = .001; and versus the peer cohort: combined ranks 0.29 (0.07 to 0.51), P = .02; full professor 0.37 (0.14 to 0.60), P = .003. Stanford women faculty satisfaction increased from 48% (2003) to 71% (2008).Increased satisfaction and proportion of women faculty, especially full professors, suggest that the intervention may ameliorate the gender gap in academic medicine.

    View details for DOI 10.1097/ACM.0000000000000245

    View details for PubMedID 24871242

  • Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients. Transplantation Deng, M. C., Elashoff, B., Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Starling, R. C., Cappola, T. P., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Bogaev, R. C., Shahzad, K., Hiller, D., Yee, J., Valantine, H. A. 2014; 97 (6): 708-714

    Abstract

    Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death.Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥ 34), and score variability were studied in multivariate Cox regression models to predict future clinical events.Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3).The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.

    View details for DOI 10.1097/01.TP.0000443897.29951.cf

    View details for PubMedID 24637869

    View details for PubMedCentralID PMC3983476

  • Identification of Common Blood Gene Signatures for the Diagnosis of Renal and Cardiac Acute Allograft Rejection PLOS ONE Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

    Abstract

    To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

    View details for DOI 10.1371/journal.pone.0082153

    View details for Web of Science ID 000328735700038

    View details for PubMedID 24358149

    View details for PubMedCentralID PMC3864873

  • Temporal response of the human virome to immunosuppression and antiviral therapy. Cell De Vlaminck, I., Khush, K. K., Strehl, C., Kohli, B., Luikart, H., Neff, N. F., Okamoto, J., Snyder, T. M., Cornfield, D. N., Nicolls, M. R., Weill, D., Bernstein, D., Valantine, H. A., Quake, S. R. 2013; 155 (5): 1178-1187

    Abstract

    There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.

    View details for DOI 10.1016/j.cell.2013.10.034

    View details for PubMedID 24267896

  • Changing the Culture of Academic Medicine to Eliminate the Gender Leadership Gap: 50/50 by 2020 ACADEMIC MEDICINE Valantine, H., Sandborg, C. I. 2013; 88 (10): 1411–13

    Abstract

    Central to the daily struggles that successful working women face is the misalignment of the current work culture and the values of the workforce. In addition to contributing to work-life integration conflicts, this disconnect perpetuates the gender leadership gap. The dearth of women at the highest ranks of academic medicine not only sends a clear message to women that they must choose between career advancement and their personal life but also represents a loss of talent for academic health centers as they fail to recruit and retain the best and the brightest. To close the gender leadership gap and to meet the needs of the next generation of physicians, scientists, and educators, the authors argue that the culture of academic medicine must change to one in which flexibility and work-life integration are core parts of the definition of success. Faculty must see flexibility policies, such as tenure clock extensions and parental leaves, as career advancing rather than career limiting. To achieve these goals, the authors describe the Stanford University School of Medicine Academic Biomedical Career Customization (ABCC) model. This framework includes individualized career plans, which span a faculty member's career, with options to flex up or down in research, patient care, administration, and teaching, and mentoring discussions, which ensure that faculty take full advantage of the existing policies designed to make career customization possible. The authors argue that with vision, determination, and focus, the academic medicine community can eliminate the gender leadership gap to achieve 50/50 by 2020.

    View details for PubMedID 23969359

  • Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients. Transplantation proceedings Vrtovec, B., Haddad, F., Pham, M., Deuse, T., Fearon, W. F., Schrepfer, S., Leon, S., Vu, T., Valantine, H., Hunt, S. A. 2013; 45 (6): 2406-2409

    Abstract

    We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients.Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9)cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence.At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively).G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

    View details for DOI 10.1016/j.transproceed.2013.01.106

    View details for PubMedID 23953556

  • Transdisciplinary translational science and the case of preterm birth JOURNAL OF PERINATOLOGY Stevenson, D. K., Shaw, G. M., Wise, P. H., Norton, M. E., Druzin, M. L., Valantine, H. A., McFarland, D. A. 2013; 33 (4): 251-258

    Abstract

    Medical researchers have called for new forms of translational science that can solve complex medical problems. Mainstream science has made complementary calls for heterogeneous teams of collaborators who conduct transdisciplinary research so as to solve complex social problems. Is transdisciplinary translational science what the medical community needs? What challenges must the medical community overcome to successfully implement this new form of translational science? This article makes several contributions. First, it clarifies the concept of transdisciplinary research and distinguishes it from other forms of collaboration. Second, it presents an example of a complex medical problem and a concrete effort to solve it through transdisciplinary collaboration: for example, the problem of preterm birth and the March of Dimes effort to form a transdisciplinary research center that synthesizes knowledge on it. The presentation of this example grounds discussion on new medical research models and reveals potential means by which they can be judged and evaluated. Third, this article identifies the challenges to forming transdisciplines and the practices that overcome them. Departments, universities and disciplines tend to form intellectual silos and adopt reductionist approaches. Forming a more integrated (or 'constructionist'), problem-based science reflective of transdisciplinary research requires the adoption of novel practices to overcome these obstacles.

    View details for DOI 10.1038/jp.2012.133

    View details for PubMedID 23079774

  • Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection. PloS one Li, L., Khush, K., Hsieh, S., Ying, L., Luikart, H., Sigdel, T., Roedder, S., Yang, A., Valantine, H., Sarwal, M. M. 2013; 8 (12)

    Abstract

    To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

    View details for DOI 10.1371/journal.pone.0082153

    View details for PubMedID 24358149

  • Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions CLINICAL TRANSPLANTATION Epailly, E., Albanell, J., Andreassen, A., Bara, C., Campistol, J. M., Delgado, J. F., Eisen, H., Fiane, A. E., Mohacsi, P., Schubert, S., Sebbag, L., Turazza, F. M., Valantine, H., Zuckermann, A., Potena, L. 2011; 25 (5): E475-E486

    Abstract

    Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.

    View details for DOI 10.1111/j.1399-0012.2011.01476.x

    View details for Web of Science ID 000296262300002

    View details for PubMedID 21592231

  • Decisions, Decisions: How Program Diversity Influences Residency Program Choice JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Ku, M. C., Li, Y. E., Prober, C., Valantine, H., Girod, S. C. 2011; 213 (2): 294-305

    Abstract

    Recent studies suggest that students' feelings of fit with a residency program substantially influence students' ranking of the program. As diversity issues become increasingly focal concerns, we investigate how perception of gender and racial diversity of a program influences students' rankings of the program. We focus on students pursuing surgical specialties and ask whether diversity concerns are more prominent among applicants to surgical programs than among applicants to nonsurgical programs.We invited all interviewees at all residency programs at the Stanford University School of Medicine to participate in our study in the spring of 2009. Nineteen residency programs, amounting to 1,657 residency interviewees, participated. Sixty-eight percent (n = 1,132) responded to the survey.Women and under-represented minority applicants differ in their assessments from male and non-under-represented minority applicants because women applying to surgical programs and under-represented minority students are less likely than others to perceive their prospective programs as diverse. However, perceived program diversity is an important factor that positively influences the program ranking decision for women and minorities pursuing surgical training.Surgical training programs that promote gender and racial diversity will likely be more successful in attracting women and minority students because women and minorities are especially sensitive to program diversity in both their perceptions and rankings of programs. Promoting women and minorities within programs and connecting women and minority applicants to outreach programs and mentors is pertinent to the recruitment of these traditionally under-represented groups to surgical programs.

    View details for DOI 10.1016/j.jamcollsurg.2011.04.026

    View details for Web of Science ID 000293843300015

    View details for PubMedID 21641834

  • Impact of Donor-Transmitted Atherosclerosis on Early Cardiac Allograft Vasculopathy: New Findings by Three-Dimensional Intravascular Ultrasound Analysis TRANSPLANTATION Yamasaki, M., Sakurai, R., Hirohata, A., Honda, Y., Bonneau, H. N., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Fearon, W. F. 2011; 91 (12): 1406-1411

    Abstract

    The influence of donor-transmitted coronary atherosclerosis (DA) on plaque progression during the first year after cardiac transplantation (Tx) is unknown.Serial 3-dimensional intravascular ultrasound (IVUS) studies were performed within 8 weeks (baseline; BL) and at 1 year after Tx in 38 recipients. On the basis of maximum intimal thickness (MIT) at BL, recipients were divided into DA group (DA+; MIT≥0.5 mm, n=23) or non-DA group (DA-; MIT<0.5 mm, n=15). Plaque, lumen, and vessel volume indexes were calculated by volume/measured length (mm/mm) in the left anterior descending artery. Univariate and multivariate regression analyses were attempted to reveal clinical predictors of change in coronary dimensions.During the first year after Tx, plaque volume index increased significantly in DA+ group, but did not change in DA- Group (DA+, 3.0±1.5 to 4.1±1.5 mm/mm, P<0.0001: DA-, 1.2±0.4 to 1.3±0.5 mm/mm, P=0.53). In both groups vessel volume index decreased significantly (DA+, 16.3±3.6 to 14.6±3.3 mm/mm, P=0.003: DA-, 13.5±4.1 to 12.0±3.3 mm/mm, P=0.01), as did lumen volume index (DA+, 13.2±3.1 to 10.5±2.7 mm/mm, P<0.0001: DA-, 12.2±3.7 to 10.7±3.0 mm/mm, P=0.004). Univariate and multivariate regression analyses revealed that DA was one of the strongest predictors for plaque progression.DA was associated with significant plaque progression during the first year after Tx, and in conjunction with negative remodeling, may be an important determinant of cardiac allograft vasculopathy.

    View details for DOI 10.1097/TP.0b013e31821ab91b

    View details for PubMedID 21512436

  • Identification and Classification of Acute Cardiac Rejection by Intragraft Transcriptional Profiling CIRCULATION Holweg, C. T., Potena, L., Luikart, H., Yu, T., Berry, G. J., Cooke, J. P., Valantine, H. A., Mocarski, E. S. 2011; 123 (20): 2236-U154

    Abstract

    Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation.Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings.The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.

    View details for DOI 10.1161/CIRCULATIONAHA.109.913921

    View details for Web of Science ID 000290852200018

    View details for PubMedID 21555702

    View details for PubMedCentralID PMC3115694

  • Universal noninvasive detection of solid organ transplant rejection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Snyder, T. M., Khush, K. K., Valantine, H. A., Quake, S. R. 2011; 108 (15): 6229-6234

    Abstract

    It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.

    View details for DOI 10.1073/pnas.1013924108

    View details for Web of Science ID 000289413600060

    View details for PubMedID 21444804

    View details for PubMedCentralID PMC3076856

  • Academic Couples: Implications for Medical School Faculty Recruitment and Retention JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Girod, S., Gilmartin, S. K., Valantine, H., Schiebinger, L. 2011; 212 (3): 310-319

    Abstract

    Academic couples constitute 36% of the US professoriate. Universities are in the midst of a major transition in hiring practices to support these and other faculty with working partners. However, less is known about academic couples among medical school faculty and surgical specialties specifically. This study was designed to address this gap.In 2006-2007, the Michelle R Clayman Institute for Gender Research at Stanford University designed and administered the "Managing Academic Careers Survey" to nearly 30,000 full-time faculty across all academic fields at leading research universities nationwide. This study included 2,475 medical school faculty survey respondents at 12 participating institutions. Main outcomes measures were academic partner status; number of journal articles/chapters during career; and applications to other academic position(s) in last 5 years.A total of 73.3% of medical school faculty respondents were in dual-career partnerships (where both partners actively pursue employment) and 32.2% had an academic partner. Sixty-nine percent of academic partners were also in medical schools. Women faculty were more likely than men to have an academic partner. Among surgery faculty, 40% of women had an academic partner, as compared with 29.3% of men. In fully adjusted regression models, faculty with academic partners had higher publication counts than other faculty, and had higher odds of applying to other academic positions.Academic couples constitute one-third of all medical school faculty. They represent a productive and potentially mobile component of the medical faculty workforce. Because women had a higher rate of academic partnering, dual-career academic hiring policies are especially important for recruitment and retention of female faculty in surgical specialties.

    View details for DOI 10.1016/j.jamcollsurg.2010.11.005

    View details for Web of Science ID 000289427400006

    View details for PubMedID 21296007

  • Gene-Expression Profiling after Cardiac Transplantation REPLY NEW ENGLAND JOURNAL OF MEDICINE Pham, M. X., Valantine, H. A. 2010; 363 (14): 1374-1374

    View details for Web of Science ID 000282271500022

  • Differentially Expressed RNA from Public Microarray Data Identifies Serum Protein Biomarkers for Cross-Organ Transplant Rejection and Other Conditions PLOS COMPUTATIONAL BIOLOGY Chen, R., Sigdel, T. K., Li, L., Kambham, N., Dudley, J. T., Hsieh, S., Klassen, R. B., Chen, A., Caohuu, T., Morgan, A. A., Valantine, H. A., Khush, K. K., Sarwal, M. M., Butte, A. J. 2010; 6 (9)

    Abstract

    Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO), contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR) across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.

    View details for DOI 10.1371/journal.pcbi.1000940

    View details for Web of Science ID 000282372600010

    View details for PubMedID 20885780

    View details for PubMedCentralID PMC2944782

  • Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation NEW ENGLAND JOURNAL OF MEDICINE Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Starling, R. C., Deng, M. C., Cappola, T. P., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Bogaev, R. C., Elashoff, B., Baron, H., Yee, J., Valantine, H. A. 2010; 362 (20): 1890-1900

    Abstract

    Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy.We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation.During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001).Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

    View details for DOI 10.1056/NEJMoa0912965

    View details for Web of Science ID 000277815600007

    View details for PubMedID 20413602

  • Changing trends in infectious disease in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Deuse, T., Pham, M., Khazanie, P., Rosso, F., Luikart, H., Valantine, H., Leon, S., Vu, T. A., Hunt, S. A., Oyer, P., Montoya, J. G. 2010; 29 (3): 306-315

    Abstract

    During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation.Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil.The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred.The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.

    View details for DOI 10.1016/j.healun.2009.08.018

    View details for PubMedID 19853478

  • Right Ventricular Dysfunction Predicts Poor Outcome Following Hemodynamically Compromising Rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Fisher, P., Pham, M., Berry, G., Weisshaar, D., Kuppahally, S., Vrtovec, B., Deuse, T., Virani, S., Fearon, W., Valantine, H., Hunt, S. 2009; 28 (4): 312-319

    Abstract

    Hemodynamically compromising rejection (HCR) is a major cause of mortality and morbidity after heart transplantation. Right ventricular (RV) function is a strong predictor of outcome in patients with heart failure and myocarditis. The objective of the current study is to determine whether RV dysfunction predicts event-free survival in patients with HCR.Medical records of 548 heart transplant patients followed at Stanford University between January 1998 and January 2007 were reviewed. HCR was defined as a rejection episode requiring hospitalization for heart failure. Univariate and multivariate analyses were performed to identify risk factors for death or retransplantation at 1 year.HCR occurred in 71 patients (12.9%). Death or retransplantation at 1 year occurred in 28 patients (39%). Univariate analysis identified non-cellular rejection (odds ratio [OR] = 3.20, p = 0.021), the need for inotropic support (OR = 4.80, p = 0.007), RV dysfunction (OR = 4.63, p = 0.006), left ventricular ejection fraction (OR = 0.941, p = 0.031) and acute renal failure (OR = 3.82, p = 0.010) as predictors of death or retransplantation at 1 year. Multivariate analysis identified RV dysfunction (OR = 4.80, p = 0.007) and the need for inotropic support (OR = 5.00, p = 0.009) as predictors of death or retransplantation at 1 year.In the modern era of immunosuppression, HCR remains a major complication after heart transplantation. RV dysfunction was identified as a novel risk factor for death or retransplantation following HCR.

    View details for DOI 10.1016/j.healun.2008.12.023

    View details for PubMedID 19332256

  • New developments in immunosuppressive therapy for heart transplantation EXPERT OPINION ON EMERGING DRUGS Khush, K. K., Valantine, H. A. 2009; 14 (1): 1-21

    Abstract

    Heart transplantation is a well-established therapeutic option for many patients with end-stage heart disease. A major challenge in heart transplantation today is providing effective immunosuppression to prevent graft rejection while minimizing the many adverse effects of currently available therapies.To systematically review current immunosuppressive treatment strategies after heart transplantation and to review emerging drugs in various stages of development.A comprehensive literature review was performed using the online PubMed and Pharmaprojects databases.This article gives an overview of the immunosuppressive agents in current use, with a detailed review of emerging drugs with novel therapeutic targets.

    View details for DOI 10.1517/14728210902791605

    View details for Web of Science ID 000264685900001

    View details for PubMedID 19265486

  • Twenty-year survivors of heart transplantation at Stanford University AMERICAN JOURNAL OF TRANSPLANTATION Deuse, T., Haddad, F., Pham, M., Hunt, S., Valantine, H., BATES, M. J., Mallidi, H. R., Oyer, P. E., Robbins, R. C., Reitz, B. A. 2008; 8 (9): 1769-1774

    Abstract

    Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 +/- 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 +/- 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.

    View details for DOI 10.1111/j.1600-6143.2008.02310.x

    View details for Web of Science ID 000258401700004

    View details for PubMedID 18557718

  • Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation AMERICAN HEART JOURNAL Sinha, S. S., Pham, M. X., Vagelos, R. H., Perlroth, M. G., Hunt, S. A., Lee, D. P., Valantine, H. A., Yeung, A. C., Fearon, W. F. 2008; 155 (5)

    Abstract

    Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown.Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18).At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation.Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.

    View details for DOI 10.1016/j.ahj.2008.02.004

    View details for PubMedID 18440337

  • Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: Modulation by sirolimus TRANSPLANTATION Potena, L., Fearon, W. F., Sydow, K., Holweg, C., Luikart, H., Chin, C., Weisshaar, D., Mocarski, E. S., Lewis, D. B., Valantine, H. A., Cooke, J. P. 2008; 85 (6): 827-833

    Abstract

    Cardiac allograft vasculopathy (CAV) is a major cause of death after heart transplantation (HT). The reduced bioavailability of endothelium-derived nitric oxide may play a role in endothelial vasodilator dysfunction and thus in the structural changes characterizing CAV. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. It was hypothesized that ADMA concentrations may influence CAV progression during the first postoperative year.Thirty-two consecutive HT recipients underwent intravascular ultrasound evaluation at month 1 and year 1 after HT. Immunosuppression included mycophenolate mofetil (MMF, n=16) and sirolimus (n=16). Change in intimal volume greater than the median and vascular remodeling were major outcome measures.Plasma ADMA levels were associated with subsequent development of intimal hyperplasia (risk ratio [95% confidence interval] =2.72 [1.06-6.94]; P=0.038), and plasma ADMA levels greater than 0.70 micromol/L most accurately identified patients who would have developed intimal hyperplasia. However, ADMA levels did not correlate with negative coronary remodeling. Treatment with sirolimus, as compared with MMF, was associated with significantly lower ADMA levels (0.65+/-0.12 vs. 0.77+/-0.10 micromol/L; P<0.01) and less intimal hyperplasia (risk ratio [95% confidence interval] = 0.08 [0.01-0.56]; P=0.01).Elevated plasma ADMA is associated with coronary intimal hyperplasia, supporting the importance of nitric oxide synthase inhibition in CAV pathogenesis. Treatment with sirolimus (rather than MMF) is associated with lower ADMA levels and reduced risk of accelerated CAV.

    View details for DOI 10.1097/TP.0b013e318166a3a4

    View details for PubMedID 18360263

  • Multidisciplinary insights on clinical guidance for the use of proliferation signal inhibitors in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Zuckermann, A., Manito, N., Epailly, E., Fiane, A., Bara, C., Delgado, J. F., Lehmkuhl, H., Ross, H., Eisen, H., Chapman, J., Valantine, H. 2008; 27 (2): 141-149

    Abstract

    Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

    View details for DOI 10.1016/j.healun.2007.08.014

    View details for Web of Science ID 000253258800001

    View details for PubMedID 18267219

  • Cardiac allograft vasculopathy and insulin resistance - Hope for new therapeutic targets ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Potena, L., Valantine, H. A. 2007; 36 (4): 965-?

    Abstract

    Cardiac allograft vasculopathy (CAV) is a major cause of death in patients surviving more than 1 year after heart transplantation. An important cluster of CAV risk factors occurs as a consequence of insulin resistance and manifests as part of the metabolic syndrome. This article summarizes the pathologic features of CAV and reviews the contribution of the major components of insulin resistance in CAV development and progression. It focuses on the few studies that have analyzed the impact of the individual metabolic abnormalities and inflammation and on therapeutic strategies to minimize the clinical manifestation of insulin resistance after heart transplantation.

    View details for DOI 10.1016/.j.ecl.2007.07.012

    View details for Web of Science ID 000251518300008

    View details for PubMedID 17983931

    View details for PubMedCentralID PMC3785936

  • Proliferation signal inhibitors in transplantation: Questions at the cutting edge of everolimus therapy TRANSPLANTATION PROCEEDINGS Chapman, J. R., Valantine, H., Albanell, J., Arns, W. A., Campistol, J. M., Eisen, H., Frigerio, M., Lehmkuhl, H., Marcen, R., Morris, R., Nashan, B., Pascual, J., Pohanka, E., SEGOVIA, J., Zuckermann, A. 2007; 39 (10): 2937-2950

    Abstract

    While advances in immunosuppressive therapy have allowed dramatic improvements in the control of acute allograft rejection, there is still a need to improve long-term graft and patient survival rates following renal and heart transplantation. Among the recognized threats to long-term organ survival are chronic allograft dysfunction in the form of chronic allograft nephropathy and cardiac allograft vasculopathy, with long-term patient morbidity and mortality further compromised by higher than normal rates of posttransplant cardiovascular disease, infection, and malignancy. A growing body of evidence finds that the selection and dosing of immunosuppressive therapies can have great influence on long-term transplantation outcomes. Early evidence suggests that the proliferation signal inhibitors (PSIs), everolimus and sirolimus, might offer effective immunosuppressive activity together with antiproliferative effects that may address some of the unmet needs in the long-term therapeutic management of the posttransplant patient. This review summarizes the emerging evidence for employing PSI-based immunosuppression to seek a balance between the goals of maximizing graft and patient survival, while minimizing the risks of adverse events and long-term complications. Based on the proceedings of an international gathering of nephrologists, cardiologists and surgeons at the inaugural PSI Forum meeting "Proliferation signal inhibitors in transplantation: questions at the cutting edge," this paper aims to provide both an evidence base and practical guidance for transplant physicians seeking to optimize their use of PSI treatment and highlights avenues of ongoing research into the clinical potential of this class of immunosuppressive therapy.

    View details for DOI 10.1016/j.transproceed.2007.09.008

    View details for Web of Science ID 000252037900001

    View details for PubMedID 18089298

  • Determinants of lumen loss between years 1 and 2 after cardiac transplantation TRANSPLANTATION Sakurai, R., Yamasaki, M., Nakamura, M., Hirohata, A., Honda, Y., Bonneau, H. N., Luikart, H., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Valantine, H. A., Fearon, W. F. 2007; 84 (9): 1097-1102

    Abstract

    We previously reported that negative remodeling, not plaque progression, correlated with lumen loss during the first year after cardiac transplantation and that cytomegalovirus antibody seropositivity correlated with increased negative remodeling and greater lumen loss. Whether these findings persist between years 1 and 2 after transplantation is unknown.Serial 3-dimensional intravascular ultrasound analysis in the left anterior descending coronary artery was performed in 30 cardiac transplant recipients at year 1 and 2 after transplantation. Vessel, lumen, and plaque area were determined at 0.5-mm axial intervals in the first 50 mm of the left anterior descending coronary artery, and volumes were computed using Simpson's method. Univariate and multivariate regression analyses were performed to identify clinical predictors of change in coronary dimensions.Although mean vessel area did not change (13.6+/-3.4 to 13.4+/-3.3 mm/mm(3), P=0.45), mean plaque area increased (3.4+/-2.3 to 3.8+/-2.2 mm/mm(3), P=0.012), resulting in significant mean lumen area loss (10.3+/-2.5 to 9.6+/-2.3 mm/mm(3), P=0.016). However, the degree of luminal change strongly correlated with the degree of change in vessel size (R=0.81, P<0.0001), but not with change in plaque amount (R=-0.19, P=0.32). In fact, in 57% of the patients who demonstrated lumen loss, negative remodeling contributed more to lumen loss than did plaque progression. Diabetes at 2 years was the only significant independent clinical predictor of plaque progression and lumen loss.Despite significant plaque progression, negative remodeling correlated with coronary lumen loss between years 1 and 2 after cardiac transplantation.

    View details for DOI 10.1097/01.tp.0000285987.27033.65

    View details for PubMedID 17998863

  • Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S. S., Valantine, H. A., Weisshaar, D., Parekh, H., Hung, Y. Y., Haddad, F., Fowler, M., Vagelos, R., Perlroth, M. G., Robbins, R. C., Hunt, S. A. 2007; 7 (10): 2388-2395

    Abstract

    The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

    View details for DOI 10.1111/j.1600-6143.2007.01930.x

    View details for Web of Science ID 000249167000022

    View details for PubMedID 17845572

  • Molecular testing for long-term rejection surveillance in heart transplant recipients: Design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial JOURNAL OF HEART AND LUNG TRANSPLANTATION Pham, M. X., Deng, M. C., Kfoury, A. G., Teuteberg, J. J., Starling, R. C., Valantine, H. 2007; 26 (8): 808-814

    Abstract

    Acute rejection continues to occur beyond the first year after cardiac transplantation, but the optimal strategy for detecting rejection during this late period is still controversial. Gene expression profiling (GEP), with its high negative predictive value for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB).The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multicenter, non-blinded, randomized clinical trial designed to test the hypothesis that a primarily non-invasive rejection surveillance strategy utilizing GEP testing is not inferior to an invasive EMB-based strategy with respect to cardiac allograft dysfunction, rejection with hemodynamic compromise (HDC) and all-cause mortality.A total of 199 heart transplant recipients in their second through fifth post-transplant years have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008.The IMAGE study is the first randomized, controlled comparison of two rejection surveillance strategies measuring outcomes in heart transplant recipients who are beyond their first year post-transplant. The move away from routine histologic evaluation for allograft rejection represents an important paradigm shift in cardiac transplantation, and the results of this study have important implications for the future management of heart transplant patients.

    View details for DOI 10.1016/j.healun.2007.05.017

    View details for Web of Science ID 000248992200005

    View details for PubMedID 17692784

  • Cytomegalovirus-associated allograft rejection in heart transplant patients CURRENT OPINION IN INFECTIOUS DISEASES Potena, L., Valantine, H. A. 2007; 20 (4): 425-431

    Abstract

    Modern antiviral strategies are effective in controlling the clinical syndromes associated with acute cytomegalovirus infection in heart transplant recipients. Despite this effectiveness, subclinical cytomegalovirus infection is a common finding in these patients and its impact on long-term graft outcome is currently underestimated.Recent studies provide evidence implicating subclinical cytomegalovirus infection in the pathogenesis of allograft rejection and cardiac allograft vasculopathy. In this process, cytomegalovirus interacts with local inflammatory pathways, and systemic immune-regulation mechanisms, which may lead to graft damage, even in the absence of cytomegalovirus replication within the graft. Consequently, in addition to pharmacologic strategies that inhibit viral replication, immune-based therapies that abrogate host immune response may provide an effective tool to prevent the indirect impact of cytomegalovirus on graft function.Current evidence suggests that subclinical cytomegalovirus infection plays an important role in the pathogenesis of long-term graft dysfunction in heart transplant recipients and in other solid organ transplant recipients. Pending the availability of definitive data from randomized trials, we propose that the use of pharmacologic and immune-based approaches, directed at complete suppression of cytomegalovirus infection, represents the best strategy for prevention of cytomegalovirus-induced rejection, cardiac allograft vasculopathy and chronic allograft damage.

    View details for Web of Science ID 000248074100013

    View details for PubMedID 17609604

  • Changes in coronary anatomy and physiology after heart transplantation AMERICAN JOURNAL OF CARDIOLOGY Hirohata, A., Nakamura, M., Waseda, K., Honda, Y., Lee, D. P., Vagelos, R. H., Hunt, S. A., Valantine, H. A., Yock, P. G., Fitzgerald, P. J., Yeung, A. C., Fearon, W. F. 2007; 99 (11): 1603-1607

    Abstract

    Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial and microvascular coronary systems. The timing of the development of abnormalities in these 2 compartments and the correlation between changes in physiology and anatomy are undefined. The invasive evaluation of coronary artery anatomy and physiology with intravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance (IMR) was performed in the left anterior descending coronary artery during 151 angiographic evaluations of asymptomatic heart transplant recipients from 0 to >5 years after heart transplantation (HT). There was no angiographic evidence of significant CAV, but during the first year after HT, fractional flow reserve decreased significantly (0.89 +/- 0.06 vs 0.85 +/- 0.07, p = 0.001), and percentage plaque volume derived by intravascular ultrasound increased significantly (15.6 +/- 7.7% to 22.5 +/- 12.3%, p = 0.0002), resulting in a significant inverse correlation between epicardial physiology and anatomy (r = -0.58, p <0.0001). The IMR was lower in these patients compared with those > or =2 years after HT (24.1 +/- 14.3 vs 29.4 +/- 18.8 units, p = 0.05), suggesting later spread of CAV to the microvasculature. As the IMR increased, fractional flow reserve increased (0.86 +/- 0.06 to 0.90 +/- 0.06, p = 0.0035 comparing recipients with IMRs < or =20 to those with IMRs > or =40), despite no difference in percentage plaque volume (21.0 +/- 11.2% vs 20.5 +/- 10.5%, p = NS). In conclusion, early after HT, anatomic and physiologic evidence of epicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV may be less, because of increased microvascular dysfunction.

    View details for DOI 10.1016/j.amjcard.2007.01.039

    View details for PubMedID 17531589

  • Is there a role for proliferation signal/mTOR inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology JOURNAL OF HEART AND LUNG TRANSPLANTATION Valantine, H. 2007; 26 (6): 557-564

    Abstract

    With the development of new immunosuppressive agents, the majority of transplant recipients are surviving for over a decade, and malignancy has become a major burden on long-term survival. Reducing the incidence of post-transplant malignancies is especially important in heart transplantation where the risk of malignancies is higher than in other organ transplants. Everolimus and sirolimus, the proliferation signal inhibitors (PSIs) or mammalian target-of-rapamycin (mTOR) inhibitors, now provide new strategies for immunosuppression because of their proven efficacy that translates to a reduction in doses of calcineurin inhibitors needed to prevent acute rejection. In addition, the anti-proliferative effects of this class of drugs raise the possibility that they may be effective for reducing the risk of malignancies after solid-organ transplantation. Despite the paucity of direct clinical evidence for this effect in heart transplant patients, observations from renal transplant recipients suggest that the anti-proliferative actions of PSIs/mTOR inhibitors may also protect against malignancies in heart transplant recipients. This potential for an anti-cancer effect is further supported by the emerging data on the use of PSIs/mTOR inhibitors in non-transplant oncology patients. Reviewed in this article are the incidence rates of malignancies after solid-organ transplantation, and the evidence for anti-cancer effects of PSIs/mTOR inhibitors in renal transplant recipients and in non-transplant patients. Also discussed are the implications of these observational data for future studies on the reduction of malignancies after heart transplantation.

    View details for DOI 10.1016/j.healun.2007.03.010

    View details for Web of Science ID 000247222200001

    View details for PubMedID 17543777

  • Frequent occult infection with cytomegalovirus in cardiac transplant recipients despite antiviral prophylaxis JOURNAL OF CLINICAL MICROBIOLOGY Potena, L., Holweg, C. T., Vana, M. L., Bashyam, L., Rajamani, J., McCormick, A. L., Cooke, J. P., Valantine, H. A., Mocarski, E. S. 2007; 45 (6): 1804-1810

    Abstract

    Despite antiviral prophylaxis, a high percentage (over 90%) of heart transplant patients experience active cytomegalovirus (CMV) infection, diagnosed by detection of viral DNA in peripheral blood polymorphonuclear leukocytes within the first few months posttransplantation. Viral DNA was detected in mononuclear cells prior to detection in granulocytes from CMV-seropositive recipients (R+) receiving a heart from a CMV-seropositive donor (D+). Based on assessment of systemic infection in leukocyte populations, both R+ subgroups (R+/D- and R+/D+) experienced a greater infection burden than the R-/D+ subgroup, which was aggressively treated because of a higher risk of acute CMV disease. Despite widespread systemic infection in all at-risk patient subgroups, CMV DNA was rarely (< 3% of patients) detected in transplanted heart biopsy specimens. The R+ patients more frequently exceeded the 75th percentile of the CMV DNA copy number distribution in leukocytes (110 copies/10(5) polymorphonuclear leukocytes) than the R-/D+ subgroup. Therefore, active systemic CMV infection involving leukocytes is common in heart transplant recipients receiving prophylaxis to reduce acute disease. Infection of the transplanted organ is rare, suggesting that chronic vascular disease attributed to CMV may be driven by the consequences of systemic infection.

    View details for DOI 10.1128/JCM.01362-06

    View details for Web of Science ID 000247286500022

    View details for PubMedID 17409205

    View details for PubMedCentralID PMC1933112

  • Interplay between systemic inflammation and markers of insulin resistance in cardiovascular prognosis after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Biadi, O., Potena, L., Fearon, W. F., Luikart, H. I., Yeung, A., Ferrara, R., Hunt, S. A., Mocarski, E. S., Valantine, H. A. 2007; 26 (4): 324-330

    Abstract

    Metabolic and immuno-inflammatory risk factors contribute to cardiac allograft vasculopathy (CAV) pathogenesis. Although systemic inflammation, as detected by C-reactive protein (CRP), predicts CAV development, the relationship between CRP and markers of metabolic abnormalities remains unexplored.CRP and the entire metabolic panel were evaluated in 98 consecutive heart transplant recipients at the time of annual coronary angiography, 5.8 years after transplant (range, 1-12 years). A ratio of triglycerides (TG) to high-density lipoproteins (HDL) of 3.0 or more was considered a marker of insulin resistance. CAV prevalence was defined by angiography, and subsequent prognosis was evaluated as incidence of major cardiac adverse events.CRP was higher in the 34 patients with angiographic CAV than in those without CAV (1.10 +/- 0.20 vs 0.50 +/- 0.05 mg/dl, p < 0.001). Patients with insulin resistance had higher CRP concentrations (p = 0.023) and higher CAV prevalence (p = 0.005). High CRP and a TG/HDL of 3.0 or more were independently associated with an increased likelihood of CAV (odds ratio, > or = 3.9; p = 0.02) and predicted an increased risk of major cardiac adverse events. The combination of high CRP and a TG/HDL of 3.0 or more identified a subgroup of patients having a 4-fold increased risk for CAV and a 3-fold increased risk for major cardiac adverse events compared with patients with low CRP and normal values for metabolic indicators.Both CRP and insulin resistance, as estimated by TG/HDL, appear to be strong, synergic risk factors for CAV and for major cardiac adverse events. These findings support the hypothesis that in heart transplant recipients, systemic inflammation may be an important mediator of graft vascular injury associated with metabolic syndrome.

    View details for DOI 10.1016/j.healun.2007.01.020

    View details for PubMedID 17403472

  • Changes in coronary arterial dimensions early after cardiac transplantation TRANSPLANTATION Fearon, W. F., Potena, L., Hirohata, A., Sakurai, R., Yamasaki, M., Luikart, H., Lee, J., Vana, M. L., Cooke, J. P., Mocarski, E. S., Yeung, A. C., Valantine, H. A. 2007; 83 (6): 700-705

    Abstract

    Significant changes in coronary artery structure, including intimal thickening and vessel remodeling, occur early after cardiac transplantation. The degree to which these changes compromise coronary lumen dimensions, and the clinical factors that affect these changes, remain controversial.Thirty-eight adult cardiac transplant recipients underwent coronary angiography and volumetric intravascular ultrasound (IVUS) evaluation of the left anterior descending artery within 8 weeks of transplantation and at 1 year. Clinical parameters including donor and recipient characteristics, rejection episodes, and serology were prospectively recorded. Two-dimensional IVUS measurements and vessel, lumen and plaque volume were calculated at both time points and compared. Multivariate regression analysis was performed to reveal clinical predictors of change in coronary dimensions.During the first year after transplantation, significant decreases in vessel size (negative remodeling) and lumen size were observed with significant increases in plaque burden based on IVUS analyses. Loss of lumen volume correlated significantly with the degree of negative remodeling (R=0.82, P<0.0001), but not with changes in plaque burden (R=0.08, P=0.64). Patients with the greatest increase in plaque volume had significantly less negative remodeling (R=0.53, P=0.0006). Transplant recipient cytomegalovirus (CMV) antibody seropositivity and lack of aggressive prophylaxis against CMV infection/reactivation were significant independent predictors of greater negative remodeling (P<0.01 and P=0.03, respectively) and greater lumen loss (P=0.02 and P=0.03, respectively).Negative remodeling is primarily responsible for coronary artery lumen loss during the first year after cardiac transplantation. CMV seropositivity and lack of aggressive CMV prophylaxis correlate with increased negative remodeling, resulting in greater lumen loss.

    View details for DOI 10.1097/01.tp.0000256335.84363.9b

    View details for PubMedID 17414701

  • Pulmonary nocardiosis in a heart transplant patient: Case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Hunt, S. A., Perlroth, M., Valantine, H., Doyle, R., Montoya, J. 2007; 26 (1): 93-97

    Abstract

    Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections.

    View details for DOI 10.1016/j.healun.2006.11.002

    View details for PubMedID 17234524

  • Peripheral blood leukocyte counts in cytomegalovirus infected heart transplant patients: Impact of acute disease versus subclinical infection TRANSPLANTATION Cooke, M. E., Potena, L., Luikart, H., Valantine, H. A. 2006; 82 (11): 1419-1424

    Abstract

    Cytomegalovirus (CMV)-associated leucopenia in heart transplant patients is poorly characterized.We conducted a retrospective analysis of timing, degree, and type of leukopenia in four groups of patients: cases (n=20); controls (n=20); subclinical early infection (n=21), and subclinical late infection (n=22). In the cases, white blood cells (WBC) count at diagnosis was compared to prediagnosis; and cases were compared to controls. Subclinical cases (early and late) were identified by measurement of CMV DNA in peripheral blood mononucleocytes, and WBC was compared to those of the cases and controls.First, in human heart transplant recipients the total leukocyte count decreased prior to the time of diagnosis of CMV disease: cases: 5.4+/-2.1 x 10/microL vs. 3.7+/-2.1x10/muL (P<0.01); subclinical early: 8.1+/-4.1 x 10/microL vs. 6.9+/-1.6 x 10/microL (P<0.01). Second, the leukocyte populations most reduced during CMV disease are the neutrophils: 4.4 x 10/microL (78%) to 2.5 x 10/microL (69%) (P<0.05), and monocytes 0.6 x 10/microL (11%) to 0.3 x 10/microL (7.5%) (P<0.05). Third, the reduction in leukocyte count that occurs during CMV disease appears to be independent of immunosuppressive therapy (using cyclosporine A, mycophenolate mofetil, or azathioprine and prednisone). Finally, subclinical CMV infection in stable long-term heart transplant patients without disease is unassociated with a reduction in the leukocyte count.Aside from implications for early diagnosis, CMV-associated decrease in monocytes is important because viral infections like Epstein-Barr virus cause monocytosis. The absence of leucopenia in subclinical late infections is a new important finding.

    View details for DOI 10.1097/01.tp.0000242139.13197.7f

    View details for Web of Science ID 000242948600009

    View details for PubMedID 17164711

  • Molecular testing in the management of cardiac transplant recipients: Initial clinical experience JOURNAL OF HEART AND LUNG TRANSPLANTATION Starling, R. C., Pham, M., Valantine, H., Miller, L., Eisen, H., Rodriguez, E. R., Taylor, D. O., Yamani, M. H., Kobashigawa, J., McCurry, K., Marboe, C., Mehra, M. R., Zuckerman, A., Deng, M. C. 2006; 25 (12): 1389-1395

    View details for DOI 10.1016/j.healun.2006.10.002

    View details for Web of Science ID 000243206400001

    View details for PubMedID 17178330

  • Giant coronary aneurysms in heart transplantation: an unusual presentation of cardiac allograft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Perez, M., Fleischmann, D., Valantine, H., Hunt, S. A. 2006; 25 (11): 1367-1370

    Abstract

    Cardiac allograft vasculopathy is a leading cause of death during long-term follow-up of heart transplant recipients. We report 2 cases of cardiac allograft vasculopathy associated with giant coronary aneurysms. To our knowledge, these are the first reported cases of spontaneous giant coronary aneurysms in heart transplant recipients.

    View details for DOI 10.1016/j.healun.2006.07.006

    View details for Web of Science ID 000242222100015

    View details for PubMedID 17097503

  • T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease CIRCULATION Tu, W., Potena, L., Stepick-Biek, P., Liu, L., Dionis, K. Y., Luikart, H., Fearon, W. F., Holmes, T. H., Chin, C., Cooke, J. P., Valantine, H. A., Mocarski, E. S., Lewis, D. B. 2006; 114 (15): 1608-1615

    Abstract

    Asymptomatic cytomegalovirus (CMV) replication is frequent after cardiac transplantation in recipients with pretransplantation CMV infection. How subclinical viral replication influences cardiac allograft disease remains poorly understood, as does the importance of T-cell immunity in controlling such replication.Thirty-nine cardiac recipients who were pretransplantation CMV antibody positive were longitudinally studied for circulating CMV-specific CD4 and CD8 T-cell responses, CMV viral load in blood neutrophils, and allograft rejection during the first posttransplantation year. Nineteen of these recipients were also analyzed for changes of coronary artery intimal, lumen, and whole-vessel area. All recipients received early prophylactic therapy with ganciclovir. No recipients developed overt CMV disease. Those with detectable levels of CMV-specific CD4 T cells in the first month after transplantation were significantly protected from high mean and peak posttransplantation viral load (P<0.05), acute rejection (P<0.005), and loss of allograft coronary artery lumen (P<0.05) and of whole-vessel area (P<0.05) compared with those who lacked this immune response. The losses of lumen and vessel area were both significantly correlated with the time after transplantation at which a CD4 T-cell response was first detected (P<0.05) and with the cumulative graft rejection score (P<0.05).The early control of subclinical CMV replication after transplantation by T-cell immunity may limit cardiac allograft rejection and vascular disease. Interventions to increase T-cell immunity might be clinically useful in limiting these adverse viral effects.

    View details for DOI 10.1161/CIRCULATIONAHA.105.607549

    View details for PubMedID 17015794

  • Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection TRANSPLANTATION Potena, L., Holweg, C. T., Chin, C., Luikart, H., Weisshaar, D., Narasimhan, B., Fearon, W. F., Lewis, D. B., Cooke, J. P., Mocarski, E. S., Valantine, H. A. 2006; 82 (3): 398-405

    Abstract

    Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes.This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n = 21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n = 45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R-/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. RESULTS.: CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73 +/- 10% vs. 94 +/- 4%; P = 0.038), and an independent reduced relative risk for acute rejection graded > or =3A (relative risk [95% CI] = 0.55 [0.26-0.96]; P = 0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=-21 +/- 13% vs. -10+/-14%; P = 0.05); and vessel shrinkage (vessel volume change = -15 +/- 11% vs. -3 +/- 18%; P = 0.03).Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.

    View details for DOI 10.1097/01.tp.0000229039.87735.76

    View details for PubMedID 16906040

  • Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic investigation for transplant arteriopathy II (PITA II) study JOURNAL OF HEART AND LUNG TRANSPLANTATION Fearon, W. F., Hirohata, A., Nakamura, M., Luikart, H., Lee, D. P., Vagelos, R. H., Hunt, S. A., Valantine, H. A., Fitzgerald, P. J., Yock, P. G., Yeung, A. C. 2006; 25 (7): 765-771

    Abstract

    Investigating changes in coronary physiology that occur after cardiac transplantation has been challenging. Simultaneous and independent assessment of the epicardial artery by measuring fractional flow reserve (FFR) and of the microvasculature by calculating the index of microvascular resistance (IMR) with a single coronary pressure wire may be useful.Twenty-five asymptomatic patients with normal coronary angiograms underwent FFR, thermodilution-derived IMR and coronary flow reserve (CFR) and intravascular ultrasound (IVUS) evaluation soon after cardiac transplantation and 1 year later.FFR significantly worsened (0.90 +/- 0.05 at baseline to 0.85 +/- 0.06 at 1 year, p = 0.004). FFR correlated strongly with percent plaque volume as measured by IVUS (r = -0.58, p < 0.0001). IMR improved significantly (29.2 +/- 15.9 at baseline to 19.3 +/- 7.6 units at 1 year, p = 0.007). CFR increased, but not significantly (2.6 +/- 1.4 at baseline to 3.2 +/- 1.2 at 1 year, p = not significant). Diabetes and donor heart ischemic time independently predicted baseline IMR. Treatment with rapamycin independently predicted FFR at 1 year.New coronary physiologic measures, FFR and IMR, show that epicardial artery physiology worsens and correlates with anatomic changes, whereas microvascular physiology improves during the first year after cardiac transplantation. CFR, the traditional method for evaluating coronary circulatory physiology, did not identify these changes.

    View details for DOI 10.1016/j.healun.2006.03.003

    View details for PubMedID 16818118

  • Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S., Al-Khaldi, A., Weisshaar, D., Valantine, H. A., Oyer, P., Robbins, R. C., Hunt, S. A. 2006; 6 (5): 986-992

    Abstract

    Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in the incidence of post-surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)-based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post-surgical wound complication (52% vs. 28%, p=0.019) and deep surgical wound complication (35% vs. 13%, p=0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p=0.035) and large pericardial effusions (p=0.033) requiring intervention. Logistic regression analysis showed sirolimus (p=0.027) and longer cardiac bypass time (OR=1.011; p=0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post-surgical wound healing complications as well as symptomatic pleural and pericardial effusions.

    View details for DOI 10.1111/j.1600-6143.2006.01282.x

    View details for Web of Science ID 000236860700015

    View details for PubMedID 16611334

  • Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: Reanalysis of the multicenter trial AMERICAN JOURNAL OF TRANSPLANTATION Kobashigawa, J. A., Tobis, J. M., MENTZER, R. M., Valantine, H. A., Bourge, R. C., Mehra, M. R., Smart, F. W., Miller, L. W., Tanaka, K., Li, H. Y., Gjertson, D. W., Gordon, R. D. 2006; 6 (5): 993-997

    Abstract

    The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. Results: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). Conclusion: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

    View details for DOI 10.1111/j.1600-6143.2006.01297.x

    View details for Web of Science ID 000236860700016

    View details for PubMedID 16611335

  • Validation of a screening protocol for identifying low-risk candidates with type 1 diabetes mellitus for kidney with or without pancreas transplantation 35th Annual Meeting of the American-Society-of-Nephrology Ma, I. W., Valantine, H. A., Shibata, A., Waskerwitz, J., Dafoe, D. C., Alfrey, E. J., Tan, J. C., MILLAN, M., Busque, S., Scandling, J. D. WILEY-BLACKWELL PUBLISHING, INC. 2006: 139–46

    Abstract

    Certain clinical risk factors are associated with significant coronary artery disease in kidney transplant candidates with diabetes mellitus. We sought to validate the use of a clinical algorithm in predicting post-transplantation mortality in patients with type 1 diabetes. We also examined the prevalence of significant coronary lesions in high-risk transplant candidates.All patients with type 1 diabetes evaluated between 1991 and 2001 for kidney with/without pancreas transplantation were classified as high-risk based on the presence of any of the following risk factors: age >or=45 yr, smoking history >or=5 pack years, diabetes duration >or=25 yr or any ST-T segment abnormalities on electrocardiogram. Remaining patients were considered low risk. All high-risk candidates were advised to undergo coronary angiography. The primary outcome of interest was all-cause mortality post-transplantation.Eighty-four high-risk and 42 low-risk patients were identified. Significant coronary artery stenosis was detected in 31 high-risk candidates. Mean arterial pressure was a significant predictor of coronary stenosis (odds ratio 1.68; 95% confidence interval 1.14-2.46), adjusted for age, sex and duration of diabetes. In 75 candidates who underwent transplantation with median follow-up of 47 months, the use of clinical risk factors predicted all eight deaths. No deaths occurred in low-risk patients. A significant mortality difference was noted between the two risk groups (p = 0.03).This clinical algorithm can identify patients with type 1 diabetes at risk for mortality after kidney with/without pancreas transplant. Patients without clinical risk factors can safely undergo transplantation without further cardiac evaluation.

    View details for DOI 10.1111/j.1399-0012.2005.00461.x

    View details for Web of Science ID 000237095200001

    View details for PubMedID 16640517

  • Recurrence of iron deposition in the cardiac allograft in a patient with non-HFE hemochromatosis JOURNAL OF HEART AND LUNG TRANSPLANTATION Kuppahally, S. S., Hunt, S. A., Valantine, H. A., Berry, G. J. 2006; 25 (1): 144-147

    Abstract

    We report the case of a 36-year-old woman with a diagnosis of idiopathic dilated cardiomyopathy who underwent cardiac transplantation. The results of her initial iron studies were normal, but hemochromatosis was suspected after microscopy of the explanted heart revealed iron deposition. By 6 months post-transplantation, iron deposition was detected in her surveillance endomyocardial biopsy specimens and studies then confirmed the existence of non-HFE hemochromatosis. The patient has been stable on treatment with regular phlebotomies and a low vitamin C diet.

    View details for DOI 10.1016/j.healun.2005.08.002

    View details for Web of Science ID 000234610200025

    View details for PubMedID 16399547

  • Everolimus (certican) in heart transplantation: Optimizing renal function through minimizing cyclosporine exposure TRANSPLANTATION PROCEEDINGS Lehmkuhl, H., Ross, H., Eisen, H., Valantine, H. 2005; 37 (10): 4145-4149

    Abstract

    The proliferation signal inhibitor everolimus is efficacious for reducing the incidence of acute rejection and cardiac allograft vasculopathy (CAV) in heart transplantation; and it has the potential to facilitate cyclosporine (CsA) minimization in this setting. Reducing CsA dose in heart transplantation is dependent on everolimus trough blood levels of 3 to 8 ng/mL being achieved. Physicians experienced in the use of everolimus aim for CsA trough blood levels of 175 to 200 ng/mL in everolimus-treated patients during the initial 3 months following heart transplantation. Modeling data from the heart pivotal study suggest that CsA trough blood levels of 100 ng/mL at 6 months posttransplant could be targeted without loss of efficacy, and antibody induction therapy may assist with this approach. Target CsA trough blood levels for maintenance patients could possibly be reduced from the current 80 to 100 ng/mL to 50 to 80 ng/mL. Maintenance patients with renal dysfunction or CAV may benefit from conversion to everolimus and subsequent reduction in CsA trough blood levels (eg, by 50%). Initial experience of everolimus with reduced CsA trough blood levels in heart transplantation is favorable, but there is scope for further study.

    View details for DOI 10.1016/j.transproceed.2005.10.005

    View details for Web of Science ID 000234412900002

    View details for PubMedID 16387066

  • Use of the implantable cardioverter-defibrillator in long-term survivors of orthotopic heart transplantation HEART RHYTHM Ptaszek, L. M., Wang, P. J., Hunt, S. A., Valantine, H., Perlroth, M., Al-Ahmad, A. 2005; 2 (9): 931-933

    Abstract

    Orthotopic heart transplantation is considered an effective treatment for patients with refractory heart failure. The long-term survival of orthotopic heart transplantation recipients has increased over the last several decades, but many long-term survivors of orthotopic heart transplantation develop graft atherosclerosis and associated left ventricular dysfunction. The risk of sudden cardiac death in long-term survivors of orthotopic heart transplantation with these complications is believed to be high. There are no data on the usefulness of implantable cardioverter-defibrillators (ICDs) in this population; therefore, we report our early experience with ICD placement in such patients.The purpose of this study was to examine the use of ICDs in adults who are long-term survivors of heart transplantation.We retrospectively reviewed all adult patients who underwent orthotopic heart transplantation at Stanford University Hospital (Stanford, CA, USA) from 1980 to 2004. All patients who received an ICD after transplant were included in this study. We reviewed demographic data, medical history, ejection fraction, presence of graft atherosclerosis, indication for ICD placement, and any device therapy delivered.Of the 925 patients who had orthotopic heart transplantation during this time period, 493 patients were alive at the beginning of the year 2000. Of these patients, 10 ( approximately 2%) had subsequent placement of an ICD. All 10 patients were male. The average age at orthotopic heart transplantation was 37.8 years. The average age at ICD placement was 50.5 years. The average time from orthotopic heart transplantation to ICD placement was 14.6 years. The average ejection fraction at the time of implant was 46.5%. Five of the 10 patients had a low ejection fraction (within this subgroup, the average ejection fraction was 31%, range 15%-45%) and graft atherosclerosis. ICDs were placed because of symptomatic episodes of ventricular tachycardia (3 patients), low ejection fraction and severe graft atherosclerosis without symptoms (3 patients), and after thorough evaluation for otherwise unexplained syncope (4 patients). The average follow-up after device implantation was 13 months. Complications related to ICD placement were an infected ICD system requiring explant in one patient and a lead fracture in another patient. Three patients had subsequent appropriate shocks for ventricular arrhythmias, and one patient underwent a second orthotopic heart transplantation. One patient died of malignancy.Use of the ICD in long-term survivors of orthotopic heart transplantation should be considered in appropriately selected patients. Further data are needed regarding ICD use in this population.

    View details for DOI 10.1016/j.hrthm.2005.06.018

    View details for Web of Science ID 000231986200008

    View details for PubMedID 16171746

  • Induction therapy for pediatric and adult heart transplantation: Comparison between OKT3 and daclizumab TRANSPLANTATION Chin, C., Pittson, S., Luikart, H., Bernstein, D., Robbins, R., Reitz, B., Oyer, P., Valantine, H. 2005; 80 (4): 477-481

    Abstract

    Induction therapy can reduce morbidity and early mortality in pediatric and adult heart transplant recipients. Monoclonal and polyclonal agents are most widely used; they nonspecifically deplete the T-cell pool and are thus associated with drug-induced side effects. The cytokine release syndrome is one of the most problematic events associated with induction. Daclizumab, a highly humanized, specific interleukin-2 receptor blocker, may be efficacious to the monoclonal agent, OKT3. Due to its specific action and properties, the safety profile of this agent may be superior to OKT3.Forty subjects received daclizumab and their clinical outcomes were compared against a historical group of 40 subjects who received OKT3. Three- and six-month outcome measures included survival, rejection history, steroid burden, and complications.Mortality was low between the groups with equivalent 6-month survival. No differences in rejection profile or time to the first significant rejection event were detected; no subject had severe acute rejection within the first 180 days. Steroid requirement for maintenance immunosuppression and treatment of rejection was also similar between the groups. Six-month prevalence for complications were significantly different; 55% of OKT3-treated subjects having at least one event compared to 33% of daclizumab-treated subjects (P=0.04). The likelihood of complications occurred within the first month after transplantation.Daclizumab induction therapy is as efficacious as OKT3 in the prevention of early acute rejection after heart transplantation among pediatric and adult subjects. Complications related to the induction agent are significantly lower in the humanized product.

    View details for DOI 10.1097/01.tp.0000168153.50774.30

    View details for Web of Science ID 000231566800008

    View details for PubMedID 16123721

  • Multicenter intravascular ultrasound validation study among heart transplant recipients - Outcomes after five years JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kobashigawa, J. A., Tobis, J. M., Starling, R. C., Tuzcu, E. M., Smith, A. L., Valantine, H. A., Yeung, A. C., Mehra, M. R., Anzai, H., Oeser, B. T., Abeywickrama, K. H., Murphy, J., Cretin, N. 2005; 45 (9): 1532-1537

    Abstract

    We sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation.Cardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome.First-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2).Group 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004).This multicenter study suggests that progression of intimal thickening >/=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

    View details for DOI 10.1016/j.jacc.2005.02.035

    View details for Web of Science ID 000228776600025

    View details for PubMedID 15862430

  • Improving outcomes in heart transplantation: The potential of proliferation signal inhibitors TRANSPLANTATION PROCEEDINGS Eisen, H., Kobashigawa, J., Starling, R. C., Valantine, H., Mancini, D. 2005; 37 (4): 4S-17S

    Abstract

    Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P < .05). Sirolimus and everolimus were also associated with a lower rate of cytomegalovirus infection. As with other immunosuppressants, these agents are associated with adverse events (eg, hyperlipidemia), but they can be managed. Coadministration with calcineurin inhibitors (CNIs) can exacerbate CNI-related nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.

    View details for DOI 10.1016/j.transproceed.2005.02.118

    View details for Web of Science ID 000229592900002

    View details for PubMedID 15809102

  • Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Eisen, H. J., Kobashigawa, J., Keogh, A., Bourge, R., Renlund, D., Mentzer, R., Alderman, E., Valantine, H., Dureau, G., Mancini, D., Mamelok, R., Gordon, R., Wang, W. D., Mehra, M., Constanzo, M. R., Hummel, M., Johnson, J. 2005; 24 (5): 517-525

    Abstract

    This study reports the 36-month results of a randomized, double-blind, active-controlled trial of mycophenolate mofetil (MMF) vs azathioprine (AZA) in heart transplant patients.Patients were randomized at the time of transplant to receive MMF (1,500 mg twice a day, N = 327) or AZA (1.5 to 3 mg/kg in 4 daily doses, N = 323) in addition to cyclosporine and corticosteroids; 289 patients in each group received study drug. Data were analyzed in all randomized patients (enrolled) and in patients who received study medications (treated). Clinical and graft assessments continued for 36 months.For the co-primary end-point, 53 of 289 (18.3%) AZA-treated patients either died or received another transplant compared with 34 of 289 (11.8%) MMF-treated patients (p < 0.01). Time to re-transplantation or patient death was significantly shorter for AZA- than MMF-treated patients (p = 0.029). In patients undergoing intravascular ultrasound, the change in mean maximal intimal thickness was less for the MMF group than for the AZA group (0.06 +/- 0.03 mm vs 0.13 +/- 0.03 mm, respectively; p = 0.056). No significant differences between treatments were observed in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia and leukopenia were more common in the AZA group, whereas diarrhea, esophagitis, Herpes simplex, Herpes zoster and cytomegalovirus (CMV) tissue invasion were more common in MMF-treated patients.MMF reduces mortality and graft loss up to 36 months after transplantation.

    View details for DOI 10.1016/j.healun.2005.02.002

    View details for Web of Science ID 000229250300002

    View details for PubMedID 15896747

  • From clinical trials to clinical practice: An overview of Certican((R)) (everolimus) in heart transplantation Meeting on Certican in Heart Transplantation Valantine, H., Zuckermann, A. ELSEVIER SCIENCE INC. 2005: S185–S190

    Abstract

    Cardiac allograft vasculopathy (CAV) is the primary cause of late morbidity and mortality in heart transplant patients and remains a major challenge to further improvements in long-term graft survival in this population. Clearly, there is a need for immunosuppressive regimens that reduce the risk of CAV. Certican (everolimus) is a proliferation signal inhibitor developed for the prevention of acute and chronic rejection after solid-organ transplantation. Pre-clinical studies suggest that everolimus prevents vascular remodeling and neointimal proliferation, which are key components of CAV. In a pivotal trial in heart transplantation, everolimus at 1.5 or 3.0 mg plus standard-dose cyclosporine (CsA; Neoral) and corticosteroids demonstrated superior efficacy to azathioprine (AZA) by decreasing the incidence of biopsy-proven acute rejection (BPAR) and the composite end-point, efficacy failure. Importantly, in this trial, everolimus was also associated with a significant reduction in both the incidence and severity of CAV in recipients of heart transplants. Furthermore, cytomegalovirus (CMV) infection rates were significantly lower with everolimus than with AZA. The study suggests that everolimus has the ability to target the primary causes of chronic allograft dysfunction by reducing acute rejection and CMV infection, and preventing CAV. Moreover, these findings indicate that use of everolimus as part of the primary immunosuppression regimen, could provide a major benefit for heart transplant patients, offering a real hope of alleviating CAV in the long term. Few large-scale trials have been conducted in heart transplant patients, so their value must therefore be maximized with findings being effectively translated into clinical practice.

    View details for DOI 10.1016/j.healun.2005.01.013

    View details for Web of Science ID 000228015300002

    View details for PubMedID 15774320

  • Certican (Everolimus) in heart transplantation: from clinical trial to clinical experience. Proceedings of a meeting, Vienna, Austria, September 9, 2004. journal of heart and lung transplantation 2005; 24 (4): S183-211

    View details for PubMedID 15774319

  • Prevention of cardiac allograft vasculopathy with Certican((R)) (everolimus): The Stanford University experience within the Certican Phase III clinical trial Meeting on Certican in Heart Transplantation Valantine, H. ELSEVIER SCIENCE INC. 2005: S191–S195

    Abstract

    A large Phase III clinical trial with the novel proliferation signal inhibitor, Certican (everolimus), has shown this agent to be associated with lower rates of acute rejection, cardiac allograft vasculopathy (CAV) and cytomegalovirus (CMV) infection when compared with azathioprine (AZA) at 12 months post-transplant. Given that CAV is the main risk factor for mortality after the first year post-transplant, and that acute rejection and CMV infection play a key role in the development of this disease, the findings suggest that everolimus has an important role as part of the primary immunosuppression of this population. Consideration of the presentation and outcome of patients from Stanford University who were enrolled in the pivotal trial with everolimus in heart transplantation has highlighted the efficacy of everolimus in this setting. Analysis of the angiographic outcome data of these patients demonstrates that the efficacy of everolimus observed in the large, multicenter trial involving heart transplant patients was replicated in the findings of a single center. This finding is important for the interpretation of clinical trial data, offering reassurance that data from large trials are applicable to an individual center. The results from Stanford also reveal an important difference between everolimus and AZA with regard to intimal thickening and the incidence of abnormal left ventricular ejection fraction (LVEF), suggesting that everolimus may improve left ventricular function. Because abnormal LVEF has been associated with greater risk of vascular rejection and allograft vascular disease, use of everolimus could well improve long-term outcomes in heart transplant recipients.

    View details for DOI 10.1016/j.healun.2005.01.012

    View details for Web of Science ID 000228015300003

    View details for PubMedID 15774321

  • Cardiac allograft vasculopathy after heart transplantation: Risk factors and management JOURNAL OF HEART AND LUNG TRANSPLANTATION Valantine, H. 2004; 23 (5): S187-S193

    Abstract

    Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.

    View details for DOI 10.1016/j.healun.2004.03.009

    View details for Web of Science ID 000221593400002

    View details for PubMedID 15093804

  • Glucose intolerance, as reflected by hemoglobin A(1c) level, is associated with the incidence and severity of transplant coronary artery disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kato, T., Chan, M. C., Gao, S. Z., Schroeder, J. S., Yokota, M., Murohara, T., Iwase, M., Noda, A., Hunt, S. A., Valantine, H. A. 2004; 43 (6): 1034-1041

    Abstract

    The possible effect of plasma hemoglobin A(1c) (HbA(1c)) on the development of transplant coronary artery disease (TxCAD) was investigated.Glucose intolerance is implicated as a risk factor for TxCAD. However, a relationship between HbA(1c) and TxCAD has not been demonstrated.Plasma HbA(1c) was measured in 151 adult patients undergoing routine annual coronary angiography at a mean period of 4.1 years after heart transplantation. Intracoronary ultrasound (ICUS) was also performed in 42 patients. Transplant CAD was graded by angiography as none, mild (stenosis in any vessel < or =30%), moderate (31% to 69%), or severe (> or =70%) and was defined by ICUS as a mean intimal thickness (MIT) > or =0.3 mm in any coronary artery segment. The association between TxCAD and established risk factors was examined.Plasma HbA(1c) increased with the angiographic grade of TxCAD (5.6%, 5.8%, 6.4%, and 6.2% for none, mild, moderate, and severe disease, respectively; p < 0.05 for none vs. moderate or severe) and correlated with disease severity (r = 0.24, p < 0.05). The HbA(1c) level was higher in patients with MIT > or =0.3 mm than in those with MIT <0.3 mm (6.4% vs. 5.7%, p < 0.05). Multivariate logistic regression analysis identified HbA(1c) as an independent predictor of TxCAD, as detected by angiography or ICUS (odds ratios 1.9 and 2.4, 95% confidence intervals 1.5 to 6.3 [p = 0.010] and 1.3 to 4.2 [p < 0.005], respectively).Persistent glucose intolerance, as reflected by plasma HbA(1c), is associated with the occurrence of TxCAD and may play an important role in its pathogenesis.

    View details for DOI 10.1016/j.jacc.2003.08.063

    View details for Web of Science ID 000220212400018

    View details for PubMedID 15028363

  • Cytomegalovirus infection impairs the nitric oxide synthase pathway - Role of asymmetric dimethylarginine in transplant arteriosclerosis CIRCULATION Weis, M., Kledal, T. N., LIN, K. Y., Panchal, S. N., Gao, S. Z., Valantine, H. A., Mocarski, E. S., Cooke, J. P. 2004; 109 (4): 500-505

    Abstract

    We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV.Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion.CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway.

    View details for DOI 10.1161/01.CIR.0000109692.16004.AF

    View details for Web of Science ID 000188669400011

    View details for PubMedID 14732750

  • The role of viruses in cardiac allograft vasculopathy AMERICAN JOURNAL OF TRANSPLANTATION Valantine, H. A. 2004; 4 (2): 169-177

    Abstract

    Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

    View details for DOI 10.1046/j.1600-6143.2003.00316.x

    View details for Web of Science ID 000188644100004

    View details for PubMedID 14974936

  • Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience JOURNAL OF HEART AND LUNG TRANSPLANTATION Shiba, N., Chan, M. C., Kwok, B. W., Valantine, H. A., Robbins, R. C., Hunt, S. A. 2004; 23 (2): 155-164

    Abstract

    Truly long term survival post heart transplantation has become increasingly frequent over the past two decades.We analyzed multiple clinical outcomes in the cohort of 140 patients in the Stanford database who underwent heart transplantation after the introduction of cyclosporine-based immunosuppression in 1980 and survived >10 years after transplantation.We found generally excellent functional status in these patients, but a high incidence of hypertension, renal dysfunction, and graft CAD as well as malignancy.With continued improvement in post-transplant survival rates, providing complex care for such long-term recipients as these will assume increasing clinical importance in the everyday practice of transplant medicine and these data highlight the problems to be anticipated.

    View details for DOI 10.1016/S1053-2498(03)00147-5

    View details for Web of Science ID 000188759100001

    View details for PubMedID 14761762

  • The impact of brain death on survival after heart transplantation: Time is of the essence TRANSPLANTATION Cantin, B., Kwok, B. W., Chan, M. C., Valantine, H. A., Oyer, P. E., Robbins, R. C., Hunt, S. A. 2003; 76 (9): 1275-1279

    Abstract

    It has been suggested that the modality of brain death and time from brain death until harvest impact survival and rejection after heart transplantation.Donor files from 475 adult heart-transplant recipients were examined. From these files, a total management time (time from incident leading to brain death until aortic cross clamp) was determined, and the cause of brain death was noted. Recipient characteristics, details of postoperative course, as well as survival were obtained from the Stanford University Medical Center Heart Transplantation Database.Two hundred and thirty (48.4%) donors sustained traumatic injuries, 112 (23.6%) suffered a subarachnoid hemorrhage, and 102 (21.4%) died of a gunshot wound to the head. The modality of brain death did not influence medium and long-term survival. A management time longer than 72 hours was associated with poorer outcome of the heart-transplant recipients. There were significantly more treated rejection episodes in recipients whose donor sustained traumatic injuries.Modality of brain death does not impact survival but appears to influence rejection. Increased management time is associated with adverse survival trends in heart-transplant recipients.

    View details for DOI 10.1097/01.TP.0000093445.50624.5A

    View details for Web of Science ID 000186653100001

    View details for PubMedID 14627902

  • Longer-term risks associated with 10-year survival after heart transplantation in the cyclosporine era JOURNAL OF HEART AND LUNG TRANSPLANTATION Shiba, N., Chan, M. C., Valantine, H. A., Gao, S. Z., Robbins, R. C., Hunt, S. A. 2003; 22 (10): 1098-1106

    Abstract

    Long-term survival after heart transplantation is common in the cyclosporine era. However, there are few data documenting pre-transplant/peri-operative factors predictive of truly long-term survival (>10 years). The purpose of this study is to identify factors associated with 10-year survival after heart transplantation.Our study population included 197 adults who survived >6 months and died <10 years after heart transplant (medium-term group) and 140 adults who survived >10 years after heart transplant (long-term group) between December 1980 and May 2001. A comparison was done between the two groups and we used multivariate analysis to identify which factors predicted 10-year survival.The long-term group had younger recipient and donor age, lower recipient body mass index at transplant, shorter waiting time and lower percentages of ischemic etiology/male recipient/non-white recipient. Kaplan-Meier plots of freedom from graft coronary artery disease and malignancy showed later onset patterns in the long-term group compared with the medium-term group. Multivariate analysis showed that white recipient, younger recipient and lower recipient body mass index at heart transplant were factors significantly associated with 10-year survival.Several pre-transplant/peri-operative factors were associated with survival beyond 10 years after heart transplantation. Stratified/tailored strategies based on these factors may be helpful to attain longer-term survival of recipients with higher risks.

    View details for DOI 10.1016/S1053-2498(02)01192-0

    View details for Web of Science ID 000185764400004

    View details for PubMedID 14550819

  • Cardiac allograft vasculopathy: Central role of endothelial injury leading to transplant "atheroma" TRANSPLANTATION Valantine, H. A. 2003; 76 (6): 891-899

    Abstract

    Endothelial injury plays a central role in the pathophysiologic mechanisms underlying cardiac allograft vasculopathy (CAV). Although the accelerated course of CAV and its localization to the allograft support an important role for the alloimmune response, there is considerable evidence implicating lipoprotein abnormalities, metabolic disturbances, viral infections, and systemic inflammation in the process. This multifactorial basis for CAV may be put into a pathophysiologic context in which endothelial cell injury is the triggering event that initiates and drives the proliferative and fibrotic processes characteristic of CAV. In the transplant setting, endothelial cell injury is induced by multiple factors, including brain death, ischemia-reperfusion, alloimmune responses, and viral infections. Once initiated, propagation of the proliferative processes that ultimately lead to vascular occlusion is enhanced by the abnormal metabolic environment of elevated lipoproteins and insulin resistance encountered in most patients. This review examines the evidence for the role of potential triggers of endothelial injury in the pathophysiology of CAV and discusses the central role of the nitric oxide pathway in the disease process.

    View details for DOI 10.1097/01.TP.0000080981.90718.EB

    View details for Web of Science ID 000185637900002

    View details for PubMedID 14508350

  • Post-operative conversion from cyclosporine to tacrolimus in heart transplantation: A single-center experience JOURNAL OF HEART AND LUNG TRANSPLANTATION Cantin, B., Kwok, B. W., Shiba, N., Valantine, H. A., Hunt, S. A., Chan, M. C. 2003; 22 (7): 723-730

    Abstract

    Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients.Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed.During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation.Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.

    View details for DOI 10.1016/S1053-2498(02)00647-2

    View details for Web of Science ID 000184235800003

    View details for PubMedID 12873539

  • Preferential involvement of larger vessels in a rat model of diabetes induced graft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Cantin, B., Zhu, D., Wen, P. Z., Panchal, S. N., Gwathmey, J. K., Reaven, G. M., Valantine, H. A. 2002; 21 (9): 1040-1043

    Abstract

    Using previously described models of diabetes-induced transplant coronary artery atherosclerosis (TxCAD), we quantitatively assessed TxCAD using computer-assisted morphometric measurements. More than 95% of the evaluated vessels were intramyocardial vessels. The first and last tertile of the vessel size distribution were evaluated for the presence of TxCAD. Severe TxCAD, defined as a luminal occlusion > or =75%, was more prevalent in the larger vessels. We observed a differential involvement based on vessel size in diabetes-induced TxCAD.

    View details for Web of Science ID 000177942400013

    View details for PubMedID 12231376

  • Conversion of cyclosporine to tacrolimus for refractory or persistent myocardial rejection 2nd International Congress on Immunosuppression Chan, M. C., Kwok, B. W., Shiba, N., Cantin, B., Valantine, H. A., Hunt, S. A. ELSEVIER SCIENCE INC. 2002: 1850–52

    View details for Web of Science ID 000177369700202

    View details for PubMedID 12176601

  • Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection CLINICAL TRANSPLANTATION Cantin, B., Giannetti, N., Parekh, H., Panchal, S. N., Kwok, B. W., Najem, R., Woodman, K., Hunt, S. A., Valantine, H. A. 2002; 16 (3): 196-201

    Abstract

    When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation.Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart.There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose.There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.

    View details for Web of Science ID 000176236300008

    View details for PubMedID 12010143

  • Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin JOURNAL OF HEART AND LUNG TRANSPLANTATION Cantin, B., Zhu, D., Wen, P., Panchal, S. N., Dai, X., Gwathmey, J. K., Reaven, G. M., Valantine, H. A. 2002; 21 (6): 637-643

    Abstract

    Induction of diabetes in rat heterotopic heart transplantation models leads to an accelerated form of severe transplant coronary artery disease (TxCAD). We undertook this study to determine whether treatment of diabetes with metformin would favorably affect TxCAD.Heterotopic abdominal heart transplantation was performed in rat isograft and allograft models. After transplantation, diabetes was induced with streptozotocin. Fifty percent of the animals received metformin at 500 mg/kg twice daily. We quantitatively assessed TxCAD using histologic sections of harvested hearts at 30 and 60 days with computer-assisted morphometry. We compared vessels in the first tertile of the area distribution with vessels in the last tertile.Fasting glucose levels in metformin-treated animals were 161 +/- 45 mg/dl compared with 400 +/- 120 mg/dl (p < 0.05) in untreated rats. Treatment with metformin led to decreased diabetes-induced TxCAD in the larger vessels. This effect was sustained during the study course in the isografts but not in the allografts. Treatment with metformin did not prevent progression of TxCAD in the smaller vessels at 60 days.Metformin reduced luminal occlusion and severe TxCAD in the larger vessels but did not alter the course of TxCAD in the smaller vessels. These results may have therapeutic implications for patients.

    View details for Web of Science ID 000176074500004

    View details for PubMedID 12057696

  • Detection of early atherosclerosis with radiolabeled monocyte chemoattractant protein-1 in prediabeteic Zucker rats 43rd Annual Meeting of the Society-for-Pediatric-Radiology Blankenberg, F. G., Wen, P. Z., Dai, M., Zhu, D. N., Panchal, S. N., Tait, J. F., Post, A. M., Strauss, H. W., Valantine, H. A. SPRINGER. 2001: 827–35

    Abstract

    Migration of monocytes into the arterial wall is an early finding of atherosclerosis. Monocytes are attracted to sites of vascular endothelial cell injury, the initiating event in the development of atheromatous disease, by a chemokine known as monocyte chemoattractant protein-1 (MCP-1). Injured vascular endothelial and smooth muscle cells selectively secrete MCP-1.This study was performed to determine if radiolabeled MCP-1 would co-localize at sites of monocyte/macrophage concentration in an experimental model of transplant-induced vasculopathy in diabetic animals.Hearts from 3-month-old male Zucker rats, heterozygote (Lean) or homozygote (Fat) for the diabetes-associated gene fa, were transplanted into the abdomens of genetically matched recipients. Lean and Fat animals were then fed normal or high-fat diets for 90 days.At 90 days significant increases (P < 0.013) of MCP-1 graft uptake were seen at imaging and confirmed on scintillation gamma well counting studies in Lean (n = 5) and Fat (n = 12) animals, regardless of diet, 400 % and 40 %, above control values, respectively. MCP-1 uptake of native and grafted hearts correlated with increased numbers of perivascular macrophages (P < 0.02), as seen by immunostaining with an antibody specific for macrophages (ED 2).Radiolabeled MCP-1 can detect abnormally increased numbers of perivascular mononuclear cells in native and grafted hearts in prediabetic rats. MCP-1 may be useful in the screening of diabetic children for early atherosclerotic disease.

    View details for Web of Science ID 000172685800001

    View details for PubMedID 11727015

  • Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation - A comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone TRANSPLANTATION Valantine, H. A., Luikart, H., Doyle, R., Theodore, J., Hunt, S., Oyer, P., Robbins, R., Berry, G., Reitz, B. 2001; 72 (10): 1647-1652

    Abstract

    Cytomegalovirus (CMV) disease was previously shown to be unaltered by a 28-day course of ganciclovir compared with placebo in seronegative recipients of hearts from seropositive donors (D+/R-). This study tests the hypothesis that a combination of ganciclovir plus CMV hyperimmune globulin (CMVIG) is more effective than ganciclovir alone for preventing acute CMV illness and its long-term sequelae.The study population receiving CMVIG (n=80) included 27 heart transplant recipients (D+/R-) and 53 heart-lung and lung transplant recipients (R+ and/or D+). Each group was matched with historical controls who underwent transplantation within the preceding 2-3 years. Outcome measures compared were as follows: 3-year incidence of CMV disease; fungal infection; acute rejection; survival; rates and severity of transplant coronary artery disease (in heart patients) defined by intimal thickness (ultrasound) and coronary artery stenosis (angiographic); and incidence and death from obliterative bronchiolitis defined by pathological criteria on endobronchial biopsy specimens (in heart-lung/lung patients).Patients treated with CMVIG had a higher disease-free incidence of CMV, lower rejection incidence, and higher survival rate compared with the patients treated with ganciclovir alone. The coronary artery intimal thickness and the prevalence of intimal thickening were lower in the patients receiving CMVIG. Heart-lung and lung transplant patients treated with CMVIG had lower incidences of obliterative bronchiolitis and death from obliterative bronchiolitis and longer survival compared with the patients treated with ganciclovir alone.CMVIG plus ganciclovir seems to be more effective that ganciclovir alone for preventing the sequelae of CMV infection. A prospective randomized study is required to confirm these observations.

    View details for Web of Science ID 000172614200012

    View details for PubMedID 11726825

  • Transplant coronary artery disease - A novel model independent of cellular alloimmune response CIRCULATION Cantin, B., Wen, P. Z., Zhu, D. N., Dai, M., Panchal, S. N., Billingham, M. E., Gwathmey, J. K., Valantine, H. A. 2001; 104 (21): 2615-2619

    Abstract

    Allograft coronary atherosclerosis (TxCAD) is the leading cause of death after the first year after transplantation. TxCAD is believed to be a form of chronic rejection of the cardiac allografts. This study was undertaken to determine whether TxCAD could develop in the absence of a cellular alloimmune response.Inbred lean Zucker rats (>26 generations) served as donors and recipients of the cardiac grafts. Donor hearts were explanted at 60 or 90 days. Explanted hearts were processed for coronary artery histological analysis. Cytokine expression was determined by reverse transcription-polymerase chain reaction, and the presence of T cells within the explanted hearts was evaluated by immunohistochemistry. Forty-six transplantations were made, and TxCAD developed in all but one of the transplanted hearts. Overall, one third of the vessels examined were affected by TxCAD, and in roughly half of these vessels, the disease was severe. Native hearts were free of atherosclerosis. Interleukin-2 was absent from the transplanted hearts, and T cells were present in minimal amounts (<1 per low-power field).TxCAD developed in the absence of a cellular alloimmune response in these genetically similar donors and recipients. The observed TxCAD was significant and comparable to what is found in rat allografting models.

    View details for Web of Science ID 000172307200020

    View details for PubMedID 11714659

  • Detection and treatment of coronary artery disease in liver transplant candidates LIVER TRANSPLANTATION Keeffe, B. G., Valantine, H., Keeffe, E. B. 2001; 7 (9): 755-761

    Abstract

    Patients with end-stage liver disease and coronary artery disease (CAD) being considered for orthotopic liver transplantation (OLT) present a difficult dilemma. The availability of multiple screening tests and newer treatment options for CAD prompted this review. Recent data suggest that the prevalence of CAD in patients with cirrhosis is much greater than previously believed and likely mirrors or exceeds the prevalence rate in the healthy population. The morbidity and mortality of patients with CAD who undergo OLT without treatment are unacceptably high, making identification of patients with CAD before OLT an important consideration. Patients with documented CAD or major clinical predictors of CAD should undergo cardiac catheterization before OLT. Those with advanced CAD not amenable to interventional therapy or with poor cardiac function are not candidates for OLT. Dobutamine stress echocardiogram appears to be an excellent means of screening patients with intermediate or minor clinical predictors of CAD before OLT. Patients found to have mild or moderate CAD should be aggressively treated medically and, if necessary and feasible based on hepatic reserve, by percutaneous or, less likely, surgical intervention pre-OLT to correct obstructive coronary lesions. Prospective studies regarding optimal screening strategies for the presence of CAD and the indications, timing, and outcomes of interventional therapy in patients with advanced cirrhosis are lacking and much needed.

    View details for Web of Science ID 000170987400001

    View details for PubMedID 11552207

  • Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease CLINICAL TRANSPLANTATION Giannetti, N., Herity, N. A., Alimollah, A., Gao, S. Z., Schroeder, J. S., Yeung, A. C., Hunt, S. A., Valantine, H. A. 2001; 15 (4): 247-252

    Abstract

    Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease.Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months.For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001).Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

    View details for Web of Science ID 000170338600005

    View details for PubMedID 11683818

  • Severe tricuspid regurgitation after heart transplantation 72nd Annual Scientific Session of the American-Heart-Association Chan, M. C., Giannetti, N., Kato, T., Kornbluth, M., Oyer, P., Valantine, H. A., Robbins, R. C., Hunt, S. A. ELSEVIER SCIENCE INC. 2001: 709–17

    Abstract

    Tricuspid regurgitation (TR) is common after heart transplantation. However, the incidence of severe TR and the incidence of symptoms after echocardiographic diagnosis of severe TR have not been documented. The purpose of this study is to determine the incidence of severe TR and its clinical significance in the heart transplant population.We reviewed echocardiograms (echo) of all heart transplant patients coming for regular echocardiographic follow-up between 1990 and 1995. We reviewed the charts of all patients who had echo diagnosis of severe TR.A total of 336 patients had echo follow-up during this time period. The number of months post-heart transplant to last echo was 54 +/- 50 (range, 1 to 265 months). Ninety patients had moderate TR and 23 patients had severe TR. Mean time from heart transplantation to diagnosis of severe TR was 43 +/- 38 months (range, 1 to 132). Using Cutler-Ederer analysis, at 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, 17 had charts available for review. The mean number of prior endomyocardial biopsies was 28 +/- 21 (range, 3 to 88). These patients were followed for 35 +/- 18 months after diagnosis. During this period, they developed significant heart failure and peripheral edema. Six patients eventually underwent tricuspid valve replacement.Moderate to severe TR commonly occurs following heart transplantation. Severe TR is associated with significant morbidity.

    View details for Web of Science ID 000169835400002

    View details for PubMedID 11448795

  • Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease - A prospective study CIRCULATION Valantine, H., Rickenbacker, P., Kemna, M., Hunt, S., CHEN, Y. D., Reaven, G., Stinson, E. B. 2001; 103 (17): 2144-2152

    Abstract

    This study examines the hypothesis that metabolic abnormalities of dysmetabolic syndrome are risk factors for transplant coronary artery disease (TxCAD).Sixty-six patients without overt diabetes, 2 to 4 years after surgery, underwent intracoronary ultrasound (ICUS), measurement of plasma glucose and insulin after oral glucose (75 g), and fasting lipid and lipoproteins. TxCAD incidence by angiography or autopsy was prospectively determined during subsequent follow-up (8 years). Coronary artery intimal thickness (IT) and subsequent outcomes were compared in patients stratified as having "high" versus "low" plasma glucose (>8.9 mmol/L) and insulin (>760 pmol/L) 2 hours after glucose challenge; and "abnormal" versus "normal" fasting lipid and lipoprotein concentrations as defined by the National Cholesterol EducationPatients with high glucose or insulin concentrations had greater IT: 0.38+/-0.05 versus 0.22+/-0.02 mm, P0.3 mm than with IT

    View details for Web of Science ID 000168583700005

    View details for PubMedID 11331254

  • Impact of type 1 diabetes on microvascular vs. macrovascular involvement with TXCAD: is there a difference in models of the disease? journal of heart and lung transplantation Valantine, H., Zhu, D., Wen, P., Panchal, S. N., Dai, X. 2001; 20 (2): 186-187

    View details for PubMedID 11250312

  • Neoral use in the cardiac transplant recipient Conference on Neoral Absorption Profiling: Advances in Neoral Management in the Solid Organ Transplant Recipient Valantine, H. ELSEVIER SCIENCE INC. 2000: 27S–44S

    Abstract

    CyA is the core immunosuppressant of choice for the majority of transplant patients. The introduction of Neoral, a new microemulsion formulation of CyA. and more recently a range of adjunctive immunosuppressants have further enhanced the efficacy and tolerability of CyA-based immunosuppression. In the first year following transplantation the major causes of morbidity and death are graft failure, acute rejection, and systemic infection. Patients with deteriorated pulmonary circulation before transplantation are at increased risk of early postoperative death. Risk factors for early acute rejection include female donor sex, young donor age, and multiple HLA-DR mismatches. The principal cause of death in the long term is graft vasculopathy which accounted for 40% of all deaths. Risk factors that have been hypothesized to play a role in the pathogenesis of graft vasculopathy include hyperlipidemia, recipient age and gender, donor age, the number of HLA AB and DR mismatches, and CMV infection. Strategies proposed to reduce the risk of graft vasculopathy include aggressive use of lipid-lowering agents, avoidance of low CyA doses, and the use of adjunctive rapamycin or RAD therapy. Rejection surveillance therefore relies on routine serial endomyocardial biopsy. Recent research suggests that a more accurate assessment of the state of the graft can be obtained by considering the results across a number of biopsy samples obtained from different parts of the heart, rather than basing clinical judgment on the worst single result obtained. New molecular markers such as granzyme A mRNA are likely to improve the power of histology to diagnose and predict rejection. Neoral pharmacokinetics give greater bioavailability and less intrapatient variability than Sandimmune. In the keynote OLN 351 study comparing Neoral with Sandimmune in de novo heart transplant recipients, fewer Neoral patients needed antilymphocyte therapy to treat rejection, fewer female patients had rejection episodes in the Neoral group, the tolerability of the two formulations was equivalent, and there was a lower incidence of infections in the Neoral group. The clinical impact of Neoral in comparison with Sandimmune in de novo heart transplant patients has been investigated in a number of additional trials, including long-term studies, which have confirmed that Neoral is associated with: Lower CyA doses than Sandimmune. Equal or greater antirejection efficacy than Sandimmune. Comparable tolerability to Sandimmune. During the administration of intravenous CyA as an induction therapy in the days immediately following transplantation, there is evidence to suggest that a 6-hour infusion given twice daily, which mimics the pharmacokinetic profile of oral dosing, may be clinically more effective than a continuous 24-hour infusion. Milligram-for-milligram dose conversion from Sandimmune to Neoral is feasible. Following conversion, a reduction in the CyA dose may be required in the majority of patients to maintain target levels. In pediatric patients, the rate of elimination of CyA is greater and bioavailability increases with increasing age. Younger patients (less than 8 years of age) may be managed more effectively with a 3-times-daily, rather than a twice-daily dosing schedule. A number of studies have compared the clinical effects of Sandimmune and Neoral in maintenance therapy for cardiac transplant patients. As with de novo patients, these studies have found the new formulation of CyA to be associated with lower rates of acute rejection, lower therapeutic doses, and comparable tolerability. Milligram-to-milligram conversion from the old to the new CyA formulation is generally well tolerated, although in a minority of patients there is a significant increase in CyA levels. These may be associated with a transient increase in side effects which resolve on dose reduction. There is a dose-sparing effect with Neoral. Routine monitoring of both CyA and serum creatinine levels are adv

    View details for Web of Science ID 000087340300005

    View details for PubMedID 10814748

  • Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis - A post hoc analysis of a randomized, placebo-controlled study CIRCULATION Valantine, H. A., Gao, S. Z., Menon, S. G., Renlund, D. G., Hunt, S. A., Oyer, P., Stinson, E. B., Brown, B. W., Merigan, T. C., Schroeder, J. S. 1999; 100 (1): 61-66

    Abstract

    Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD.One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS).TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

    View details for Web of Science ID 000081279300013

    View details for PubMedID 10393682

  • Role of CMV in transplant coronary artery disease and survival after heart transplantation. Transplant infectious disease Valantine, H. A. 1999; 1: 25-30

    Abstract

    The development of arteriosclerosis after heart transplantation plays a major role in decreased graft and patient survival. Although several pathogenic mechanisms have been proposed for the development of posttransplant coronary artery disease (CAD), a significant amount of accumulating evidence suggests that cytomegalovirus is a critical factor in this disease. Because post-transplant CAD is often a silent disease and early detection escapes conventional angiography, physicians must maintain close surveillance of heart transplant patients and institute prophylaxis in high-risk groups. In addition to targeting conventional risk factors, prophylaxis against CMV disease should decrease the incidence of the disease.

    View details for PubMedID 11565583

  • A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients TRANSPLANTATION Kobashigawa, J., Miller, L., Renlund, D., Mentzer, R., Alderman, E., Bourge, R., Costanzo, M., Eisen, H., Dureau, G., Ratkovec, R., Hummel, M., Ipe, D., Johnson, J., Keogh, A., Mamelok, R., Mancini, D., Smart, F., Valantine, H. 1998; 66 (4): 507-515

    Abstract

    After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation.In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients).Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025).Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

    View details for Web of Science ID 000075718800016

    View details for PubMedID 9734496

  • Diabetes and dyslipidemia - A new model for transplant coronary artery disease CIRCULATION Hoang, K., Chen, I., Reaven, G., Zhang, L. N., Ross, H., Billingham, M., Valantine, H. 1998; 97 (21): 2160-2168

    Abstract

    Clinical observations suggest that transplant coronary artery disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic heart transplantation in the presence of diabetes and dyslipidemia to further study their role in TxCAD development.Major histocompatibility complex-mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts). Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transplantation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (+F). Allograft transplants were divided into four groups: (1) +DM/+F; (2) +DM/-F; (3) -DM/+F; and (4) -DM/-F. Isograft transplants (Lewis to Lewis, +DM/+/-F) were controls. All animals received daily cyclosporine (5 mg/kg). Grafts surviving > 30 days were evaluated for TxCAD on histological sections and graded 0 to 5 for intimal thickness. All streptozotocin-treated animals were diabetic within 2 weeks, with fourfold increases in plasma glucose concentrations versus nondiabetics. Severe TxCAD was observed in diabetic allografts only. The mean grade of TxCAD in diabetic allografts was 3.2 +/- 0.5 versus 1.1 +/- 0.4 in diabetic isografts (P < 0.03) and zero TxCAD in nondiabetic allografts (P < or = 0.0001). Fructose feeding resulted in a 1.5-fold higher triglyceride and a 1.3-fold higher cholesterol level versus the regular diet (-F) but showed no independent contribution to the development of TxCAD.These findings suggest that metabolic derangements associated with diabetes play an important role in TxCAD development in heterotopic ACI-to-Lewis rat heart transplantation. In this model of TxCAD in major histocompatibility complex-mismatched, diabetic, and dyslipidemic rats, immunologic and metabolic mechanisms that contribute to TxCAD can be further delineated and approaches to its prevention assessed.

    View details for Web of Science ID 000073959900012

    View details for PubMedID 9626177

  • Scedosporium apiospermum (Pseudallescheria boydii) infection in a heart transplant recipient: A case of mistaken identity JOURNAL OF HEART AND LUNG TRANSPLANTATION Lopez, F. A., Crowley, R. S., Wastila, L., Valantine, H. A., Remington, J. S. 1998; 17 (3): 321-324

    Abstract

    We report a case of fatal central nervous system infection with Scedosporium apiospermum (Pseudallescheria boydii) in a heart transplant recipient. This ubiquitous fungus is known to cause mycetoma and localized infections in patients with otherwise normal conditions. Disseminated infections occur rarely and are seen primarily in patients who are receiving immunosuppressive medications or who have neutropenia. Often life-threatening when infection is disseminated and involves the central nervous system, this diagnosis is difficult to make rapidly because S. apiospermum (P. boydii) mimics Aspergillus spp. and Fusarium spp., both clinically and histopathologically. Imidazoles such as miconazole, but not amphotericin B, are considered the therapeutic compounds of choice. Improved diagnostic and treatment options are needed to optimize management of infections with S. apiospermum (P. boydii).

    View details for Web of Science ID 000072988500013

    View details for PubMedID 9563611

  • Importance of decreased heart rate in predicting transplant coronary artery disease CLINICAL TRANSPLANTATION Gullestad, L., Ross, H., Myers, J., Hoang, K., Hunt, S., Stinson, E. B., Valentine, H. A. 1997; 11 (6): 628-632

    Abstract

    Studies in animals and humans have demonstrated that an increased heart rate is a predictor for the development of coronary atherosclerosis and overall cardiovascular mortality. In contrast, we have previously reported that the need for pacemaker implantation because of bradycardia in heart transplant recipients is associated with an increased prevalence of transplant coronary artery disease (TxCAD). Hence, the relevance of changes in heart rate to the development of TxCAD remains unclear. Intra-coronary ultrasound examinations (ICUS) were therefore analyzed in 130 heart transplant recipients (age 50 +/- 11 yr) studied at annual evaluations (3.7 +/- 3.0 yr after transplantation). Quantitative ultrasound measurements were obtained by calculating mean coronary artery intimal thickness (MIT) obtained by examination of the left anterior descending artery. The presence of TxCAD was defined as MIT > 0.3 mm. Resting heart rates (HR) were recorded with the patients in the supine position during routine echocardiography. Based on HR recordings, two groups were defined: group 1, HR below; or group 2, HR above the median. TxCAD was detected in 40% of the ICUS studies overall. The prevalence of TxCAD was higher in group 1 (49%) compared with group 2 (33%), p < 0.05. There was no significant difference in donor ischemic time or donor gender, recipient age, gender, body weight, CMV status, creatinine, total cholesterol, use of lipid lowering drugs or diltiazem. Donor age and use of beta-blockers were higher in group 1 compared with group 2 (29 +/- 10 vs. 25 +/- 9 yr, and 15% vs. 5%, for donor age and beta-blocker use, respectively). By multivariate regression analysis only donor age and years after transplantation were independently correlated with TxCAD. After excluding patients taking beta-blockers and diltiazem, the prevalence of CAD was still higher in group 1 (50%) vs. group 2 (34%). In conclusion, transplant coronary artery disease is more prevalent in patients with lower, rather than higher, heart rates. The reason for this is unclear, but may reflect impaired blood flow to the sinoatrial node.

    View details for Web of Science ID A1997YK49400019

    View details for PubMedID 9408698

  • Individualizing immunosuppression for heart transplantation: Strategies for the next decade TRANSPLANTATION PROCEEDINGS Valantine, H. A. 1997; 29 (8A): 5S-8S

    View details for Web of Science ID 000071123700001

    View details for PubMedID 9414666

  • Heart transplantation in patients over 54 years of age - Mortality, morbidity and quality of life XVIIth Congress of the European-Society-of-Cardiology Rickenbacher, P. R., Lewis, N. P., Valantine, H. A., Luikart, H., Stinson, E. B., Hunt, S. A. W B SAUNDERS CO LTD. 1997: 870–78

    Abstract

    As a consequence of recent advances in heart transplantation, upper age limits for the procedure have been liberalized in many centres. It was the purpose of this study to compare post-transplant mortality, morbidity and quality of life in a consecutive series of 72 patients > 54 years (mean age, 57.6 +/- 2.7 years) with a control group of 72 adult patients < or = 54 years (mean age, 42.4 +/- 9.5 years) transplanted at one centre between 1985 and 1991.Patients were followed for 41 +/- 27 months post-transplant. Actuarial 1-, 5- and 7-year survival rates were 78 +/- 5%, vs 81 +/- 5%, 52 +/- 7% vs 66 +/- 6% and 46 +/- 8% vs 63 +/- 6% in patients > 54 years and < or = 54 years, respectively (P = ns). Causes of death were not significantly different between the groups. Patients > 54 years experienced significantly fewer rejection episodes after the 6th month post-transplant (0.5 +/- 0.9 vs 0.9 +/- 1.0, P < 0.04), and incidence and treatment of rejection episodes as well as incidence of infection was comparable between the groups. Non-lymphoid malignancies, mainly skin cancer, occurred more often in the older age group (27% vs 13%, P < 0.05). Quality of life, as assessed by the Nottingham Health Profile, was better in 5/6 dimensions of social functioning in older patients and the difference reached statistical significance for the dimensions of emotional reactions (P = 0.005) and sleep (P = 0.0005).In conclusion, carefully selected patients > 54 years can undergo heart transplantation with mortality and morbidity comparable to younger patients. Quality of life post-transplant seems even to be slightly better in the older age group.

    View details for Web of Science ID A1997WX06100025

    View details for PubMedID 9152659

  • Methotrexate or total lymphoid radiation for treatment of persistent or recurrent allograft cellular rejection: A comparative study JOURNAL OF HEART AND LUNG TRANSPLANTATION Ross, H. J., Gullestad, L., Pak, J., Slauson, S., Valantine, H. A., Hunt, S. A. 1997; 16 (2): 179-189

    Abstract

    Methotrexate and total lymphoid irradiation (TLI) have been used successfully for treatment of recurrent and persistent rejection in orthotopic heart transplant recipients; however, there has been no comparison of these two modalities.We retrospectively compared the efficacy of methotrexate (n = 29) versus TLI (n = 28) in heart transplant recipients with recurrent or persistent rejection. All patients received induction therapy (rabbit anti-thymocyte globulin or OKT3) and standard triple immunosuppressive therapy. Methotrexate (7.5 mg to 22.5 mg per wk) or TLI (80 cGy x 10 fractions) was used for the treatment of recurrent or persistent rejection on the basis of clinical indications. Average biopsy scores (International Society of Heart and Lung Transplantation biopsy score/total number of biopsies performed) calculated over 3-month periods, daily maintenance prednisone dose before and after methotrexate or TLI treatment, and actuarial survival and freedom from angiographic coronary artery disease and infection were compared. To control for the general decrease in prednisone with increased time from transplantation, a control group matched for time from transplantation was selected.Recipient sex and age at transplant, donor age, and donor ischemic time were similar in both groups. Days after transplantation to start of therapy was longer in patients receiving methotrexate; however, this did not reach statistical significance. Patients receiving TLI had received more cumulative corticosteroids and OKT3 before the start of TLI therapy (p < 0.001). There were no differences in actuarial freedom from infection or coronary artery disease between the two groups and between the treatment groups and the control group. Actuarial survival was reduced in patients receiving TLI 3 years after transplantation (p < 0.05). Maintenance prednisone doses from 3 months before until 9 months after therapy (mg/kg) were not different between patients receiving TLI and methotrexate and were significantly greater than the prednisone doses in the control group. Four months after treatment initiation, the prednisone dose was significantly reduced in both treatment groups compared with the pretherapy dose (methotrexate 0.28 +/- 0.16 to 0.22 +/- 0.13, p = 0.05; TLI 0.36 +/- 0.16 to 0.22 +/- .07, p < 0.001). The average biopsy score was significantly reduced by both methotrexate and TLI therapy (methotrexate 1.8 +/- 0.7 to 0.83 +/- 0.9, p = 0.0001; TLI 2.1 +/- 0.8 to 1.0 +/- 0.9, p = 0.0001).Methotrexate and TLI are both effective for the treatment of recurrent or persistent rejection after heart transplantation, reducing average biopsy scores and daily maintenance prednisone doses. There was a reduction in actuarial survival rates in patients treated with TLI, possibly reflecting the greater rejection therapy received before TLI initiation. Because both agents are effective, the choice of methotrexate or TLI may be based on clinical indications, as well as other issues, such as cost, compliance, and availability.

    View details for Web of Science ID A1997WL96500004

    View details for PubMedID 9059929

  • Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis XVI International Congress of the Transplantation-Society Reichenspurner, H., Gamberg, P., Nitschke, M., Valantine, H., Hunt, S., Oyer, P. E., Reitz, B. A. ELSEVIER SCIENCE INC. 1997: 627–28

    View details for Web of Science ID A1997WM12700260

    View details for PubMedID 9123449

  • Volume-mediated pulmonary responses in liver transplant candidates CLINICAL TRANSPLANTATION Kuo, P. C., Schroeder, R. A., Vagelos, R. H., Valantine, H., Garcia, G., Alfrey, E. J., Haddow, G., Dafoe, D. C. 1996; 10 (6): 521-527

    Abstract

    Pulmonary hypertension, defined as mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg, is a recognized complication of hepatic dysfunction with portal hypertension and is considered a relative contraindication to liver transplantation. To characterize pulmonary hemodynamic responses in OLT candidates without pre-existing primary pulmonary hypertension, 22 consecutive patients referred for OLT at the Stanford University Hospital underwent prospective right heart catheterization with pressure determinations at baseline and following infusion of 11 crystalloid over 10 min. In addition, EKG, chest X-ray and transthoracic echocardiograms were performed as a part of the routine evaluation. Eleven non-cirrhotic patients served as controls. At baseline, 1/22 (4.5%) OLT patients had pulmonary hypertension while 9/22 (41%) developed pulmonary hypertension following volume infusion (p < 0.0001). In contrast, 0/11 controls manifested elevated pulmonary pressures at baseline or following volume challenge. OLT candidates were found to have significant increases in mean pulmonary pressure and capillary wedge pressure (PCWP) compared to controls, suggesting intravascular volume overload or left ventricular dysfunction as potential causes. OLT candidates who manifested volume-dependent pulmonary hypertension (a) had a 2-fold higher baseline PCWP, (b) currently smoked, and (c) had previously undergone portosystemic shunts. Aggregate analysis of EKG, echo and CXR for determination of volume-mediated pulmonary hypertension revealed a sensitivity of 25%, specificity of 75% and a positive predictive value of 40%. Preoperative identification of patients with a predisposition to manifesting elevated pulmonary pressures in the context of rapid volume infusion offers the potential for improved risk stratification and optimized clinical management.

    View details for Web of Science ID A1996WC09400009

    View details for PubMedID 8996773

  • Early Doppler echocardiographic dysfunction is associated with an increased mortality after orthotopic cardiac transplantation. Circulation Ross, H. J., Gullestad, L., Hunt, S. A., TOVEY, D. A., PURYEAR, J. B., McMillan, A., Stinson, E. B., Valantine, H. A. 1996; 94 (9): II289-93

    Abstract

    Doppler echocardiographic (DE) diastolic dysfunction has been correlated with rejection after orthotopic cardiac transplantation (Tx). However, the relationship of early diastolic dysfunction to late outcome is unknown. The purpose of this study was to assess the correlation between early DE diastolic dysfunction and outcome after heart Tx.Of 133 patients undergoing heart Tx between October 1990 and April 1994, 83 were identified with > or = 4 routine DE performed during the first 6 months. Assessment of diastolic function included measurement of isovolumic relaxation time (IVRT), pressure half-time (PHT), and peak early mitral inflow velocity (M1). Diastolic dysfunction was defined as a decrease of 15% from baseline (IVRT and PHT) or an increase of 20% (M1). A mean dysfunction score (MDS) was calculated for each patient (number of episodes of dysfunction by Doppler total number of echocardiograms performed). The population diastole MDS was determined and two groups established (group 1, MDS < mean; group 2, MDS > mean). Actuarial survival, rejection, and transplant coronary artery disease (TxCAD) were compared between groups. Actuarial survival was significantly reduced in patients with greater early diastolic dysfunction (P < .05). There were 17 deaths overall: 5 in group 1 (mean, 786 days) and 12 in group 2 (mean, 384 days). There were no significant differences in treated rejection episodes, actuarial freedom from rejection or TxCAD, immunosuppression, sex, donor age, donor ischemic time, or cytomegalovirus between the two groups.Diastolic dysfunction within 6 months of transplant was associated with an increased late mortality.

    View details for PubMedID 8901762

  • Early Doppler echocardiographic: Dysfunction is associated with an increased mortality after orthotopic cardiac transplantation CIRCULATION Ross, H. J., Gullestad, L., Hunt, S. A., TOVEY, D. A., PURYEAR, J. B., McMillan, A., Stinson, E. B., Valantine, H. A. 1996; 94 (9): 289-293

    View details for Web of Science ID A1996VP69000053

  • Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle CIRCULATION Lewis, N. P., Tsao, P. S., Rickenbacher, P. R., Xue, C., Johns, R. A., Haywood, G. A., VONDERLEYEN, H., Trindade, P. T., Cooke, J. P., Hunt, S. A., Billingham, M. E., Valantine, H. A., Fowler, M. B. 1996; 93 (4): 720-729

    Abstract

    The mechanisms underlying cardiac contractile dysfunction after transplantation remain poorly defined. Previous work has revealed that inducible nitric oxide synthase (iNOS) is expressed in the rat heterotopic cardiac allograft during rejection; resultant overproduction of nitric oxide (NO) might cause cardiac contractile dysfunction via the negative inotropic and cytotoxic actions of NO. In this investigation, we tested the hypothesis that induction of iNOS may occur and be associated with cardiac allograft contractile dysfunction in humans.We prospectively studied 16 patients in the first year after cardiac transplantation at the time of serial surveillance endomyocardial biopsy. Clinical data, the results of biopsy histology, and echocardiographic and Doppler evaluation of left ventricular systolic and diastolic function were recorded. Total RNA was extracted from biopsy specimens, and mRNA for beta-actin, detected by reverse transcription-polymerase chain reaction (RT-PCR) using human specific primers, was used as a constitutive gene control; iNOS mRNA was similarly detected by RT-PCR using human specific primers. iNOS protein was detected in biopsy frozen sections by immunofluorescence. Myocardial cGMP was measured by radioimmunoassay, and serum nitrogen oxide levels (NOx = NO2 + NO3) were measured by chemiluminescence. iNOS mRNA was detected in allograft myocardium at some point in each patient and in 59 of 123 biopsies (48%) overall. In individual patients, iNOS mRNA expression was episodic and time dependent; the frequency of expression was highest during the first 180 days after transplant (P = .0006). iNOS protein associated with iNOS mRNA was detected by immunofluorescence in cardiac myocytes. iNOS mRNA expression was not related to the ISHLT histological grade of rejection or to serum levels of NOx but was associated with increased levels of myocardial cGMP (P = .01) and with both systolic (P = .024) and diastolic (P = .006) left ventricular contractile dysfunction measured by echocardiography and Doppler.These data support a relation between iNOS mRNA expression and contractile dysfunction in the human cardiac allograft.

    View details for Web of Science ID A1996TV05300015

    View details for PubMedID 8641001

  • Coronary artery intimal thickening in the transplanted heart - An in vivo intracoronary ultrasound study of immunologic and metabolic risk factors TRANSPLANTATION Rickenbacher, P. R., Kemna, M. S., Pinto, F. J., Hunt, S. A., Alderman, E. L., Schroeder, J. S., Stinson, E. B., Popp, R. L., Chen, I., Reaven, G., Valantine, H. A. 1996; 61 (1): 46-53

    Abstract

    This study examined the hypothesis that immunologic factors are the major correlates of coronary artery intimal thickening and luminal stenosis. The study population included 116 adult heart transplant recipients with a mean age of 44.7 +/- 12.0 years (89 men and 27 women) undergoing annual coronary angiography and intracoronary ultrasound 3.4 +/- 2.7 (range, 1.0-14.6) years after transplantation. Mean intimal thickness was obtained from several distinct sites along the left anterior descending and/or left circumflex coronary artery by intracoronary ultrasound. Coronary artery stenosis defined by angiography was classified as mild (< 30% luminal stenosis), moderate (> or = 30-70% luminal stenosis), or severe (> 70% luminal stenosis or diffuse pruning of distal vessels). Prevalence of any transplant coronary artery disease (TxCAD) was 85% by intracoronary ultrasound and 15% by angiography. By multiple regression analysis, only average fasting plasma triglyceride level (P < 0.006) and average weight (P < 0.007) were significantly correlated with severity of intimal thickening (R = 0.54, P < 0.0001). Donor age (P < 0.006) and average fasting plasma triglyceride level (P < 0.009) were significantly correlated with stenosis by angiography. Correlation of multiple immunologic and metabolic factors with intimal thickness by univariate analysis suggests a multifactorial etiology for TxCAD. Among the multiple univariate correlates of TxCAD, higher fasting plasma triglyceride levels and body weight are the only independent correlates of TxCAD. The absence of acute rejection as an independent predictor of intimal thickening suggests that mechanisms beyond those mediating typical cellular rejection should be targeted for advancing our understanding of Tx-CAD.

    View details for Web of Science ID A1996TQ20100011

    View details for PubMedID 8560573

  • Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation 14th Annual Meeting of the American-Society-of-Transplant-Physicians Wagner, J. A., Ross, H., Hunt, S., Gamberg, P., Valantine, H., Merigan, T. C., Stinson, E. B. WILLIAMS & WILKINS. 1995: 1473–77

    Abstract

    Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.

    View details for Web of Science ID A1995TN23000018

    View details for PubMedID 8545877

  • The relationship of granzyme A and perforin expression to cardiac allograft rejection and dysfunction 14th Annual Meeting of the American-Society-of-Transplant-Physicians Alpert, S., Lewis, N. P., Ross, H., Fowler, M., Valantine, H. A. WILLIAMS & WILKINS. 1995: 1478–85

    Abstract

    The mechanisms underlying contractile dysfunction following heart transplantation are poorly defined. To investigate the role of cytotoxic T cells (CTL) in cardiac transplant rejection, and during episodic contractile dysfunction, we performed a prospective study analyzing the expression of granzyme A and perforin, two functional markers of activated CTL. Sixteen consecutive patients were analyzed during the first year posttransplantation. All patients received induction therapy with OKT-3 and received standard three-drug immunosuppression therapy. Rejection status was monitored using routine surveillance endomyocardial biopsy and graded according to the ISHLT scale. Granzyme A and perforin mRNA were detected by reverse transcription PCR at the time of each routine biopsy. A total of 64/123 biopsies were positive for granzyme expression, while 38/123 samples were positive for perforin expression. LV function was monitored using M-mode derived fractional shortening and Doppler assessment of diastolic function (isovolumic relaxation time [IVRT] and pressure half-time [P1/2]). As expected, the presence of granzyme A message was associated with rejection score (ANOVA, P = 0.001). In addition, granzyme A expression was correlated with a decrease in diastolic function (chi 2 = 6.4, P < 0.02), but was not associated with systolic function. The presence of perforin message was not correlated with functional changes or with rejection grade, but was associated with granzyme expression (chi 2 = 9.11, P = 0.0025). These studies suggest that the presence of granzyme A message may be an important predictor of graft function.

    View details for Web of Science ID A1995TN23000019

    View details for PubMedID 8545878

  • PROGNOSTIC IMPORTANCE OF INTIMAL THICKNESS AS MEASURED BY INTRACORONARY ULTRASOUND AFTER CARDIAC TRANSPLANTATION CIRCULATION Rickenbacher, P. R., Pinto, F. J., Lewis, N. P., Hunt, S. A., Alderman, E. L., Schroeder, J. S., Stinson, E. B., Brown, B. W., Valantine, H. A. 1995; 92 (12): 3445-3452

    Abstract

    Although intracoronary ultrasound (ICUS) has been validated for the early detection of transplant coronary artery disease (TxCAD), the prognostic importance of findings detected by this new imaging technique is unknown.This study examined the relation of clinical outcome in 145 heart transplant recipients (mean age, 45.1 +/- 11.1 years) with the amount of intimal thickness measured by ICUS during routine annual coronary angiography 1 to 10 years (mean, 3.1 +/- 2.2 years) after transplantation. From published autopsy data, a mean intimal thickness of > 0.3 mm was considered significant. During a mean follow-up time of 48.2 +/- 10.2 months, 23 deaths (12 cardiac) occurred, and 6 patients required retransplantation. Angiographic TxCAD developed in 22 of 125 patients (17.6%) in the subgroup with normal angiograms at the time of ICUS and a follow-up annual angiographic study. In the total population and the subgroup, mean intimal thicknesses of > 0.3 and < or = 0.3 mm, respectively, were associated with significantly inferior 4-year actuarial overall survival (73% versus 96%, P = .005; 72% versus 92%, P = .05), cardiac survival (79% versus 96%, P = .005; 80% versus 98%, P = .04), and freedom from cardiac death and retransplantation (74% versus 98%, P < .0001; 70% versus 96%, P = .001). In addition, ICUS predicted freedom from development of subsequent angiographic TxCAD in the subgroup that was initially normal (26% versus 72%, P = .02). A mean intimal thickness by ICUS of > 0.3 mm was associated with inferior clinical outcome regardless of the presence of angiographic TxCAD and predicted the development of subsequent angiographic TxCAD. Despite significantly longer duration after transplantation, higher rejection incidence, and lower average daily cyclosporine dose, none of these covariates were independent risk factors for outcome.These findings confirm the prognostic importance of mean intimal thickening of > 0.3 mm in heart transplant recipients and suggest that these patients should be candidates for early interventional strategies.

    View details for Web of Science ID A1995TJ65500018

    View details for PubMedID 8521566

  • Role of lipids in allograft vascular disease: A multicenter study of intimal thickening detected by intravascular ultrasound 2nd International Symposium on Allograft Coronary Disease - A Basic Science and Clinical Review Valantine, H. A. ELSEVIER SCIENCE INC. 1995: S234–S237

    View details for Web of Science ID A1995TN11900022

    View details for PubMedID 8719492

  • Incidence and progression of transplant coronary artery disease over 1 year: Results of a multicenter trial with use of intravascular ultrasound 2nd International Symposium on Allograft Coronary Disease - A Basic Science and Clinical Review Yeung, A. C., Davis, S. F., Hauptman, P. J., Kobashigawa, J. A., Miller, L. W., Valantine, H. A., Ventura, H. O., Wiedermann, J., Wilensky, R. ELSEVIER SCIENCE INC. 1995: S215–S220

    View details for Web of Science ID A1995TN11900019

    View details for PubMedID 8719489

  • MAGNETIC-RESONANCE IMAGING-DERIVED PARAMETER OF PORTAL FLOW PREDICTS VOLUME-MEDIATED PULMONARY-HYPERTENSION IN LIVER-TRANSPLANTATION CANDIDATES 52nd Annual Meeting of the Central-Surgical-Association Kuo, P. C., Alfrey, E. J., Li, K., Vagelos, R., Valantine, H., Garcia, G., Dafoe, D. C. MOSBY-ELSEVIER. 1995: 685–92

    Abstract

    Pulmonary hypertension is a source of perioperative mortality after orthotopic liver transplantation (OLT). The purpose of this study is to (1) characterize the pulmonary hemodynamic response in OLT candidates, and (2) determine whether portal flow index (PFI), a magnetic resonance imaging (MRI)-derived parameter, is a useful predictor of the pulmonary hemodynamic response.Twenty-five consecutive OLT candidates underwent right heart catheterization with pressure measurements at baseline and after infusion of 1 L of crystalloid. MRI, chest roentgenography, electrocardiography, and echocardiography were also performed as routine screening techniques. Sixteen patients in intensive care unit with normal liver function served as controls.After volume infusion, pulmonary hypertension (mean pulmonary artery pressure greater than 25 mm Hg) developed in 9 of 25 OLT candidates with elevations in both pulmonary capillary wedge and mean pulmonary pressures. In contrast, 0 of 16 controls experienced pulmonary hypertension (p < 0.01). Although routine modalities did not predict this hemodynamic response, PFI had a 94% specificity and 78% sensitivity.OLT candidates exhibit volume-induced pulmonary hypertension with responses suggestive of left ventricular dysfunction. The significance of this observation is unknown, but the MRI-derived parameter, PFI, may serve as a screening technique to limit catheterization to a select group of OLT candidates.

    View details for Web of Science ID A1995RY29700016

    View details for PubMedID 7570323

  • PREVENTION AND TREATMENT OF CYTOMEGALOVIRUS DISEASE IN THORACIC ORGAN TRANSPLANT PATIENTS - EVIDENCE FOR A BENEFICIAL EFFECT OF HYPERIMMUNE GLOBULIN 1st Annual Symposium on Controversies in Transplant Infection Valantine, H. A. APPLETON & LANGE. 1995: 49–57

    View details for Web of Science ID A1995TD34800016

    View details for PubMedID 7482821

  • CORRELATION OF DONOR CHARACTERISTICS WITH TRANSPLANT CORONARY-ARTERY DISEASE AS ASSESSED BY INTRACORONARY ULTRASOUND AND CORONARY ANGIOGRAPHY AMERICAN JOURNAL OF CARDIOLOGY RICHENBACHER, P. R., Pinto, F. J., Lewis, N. P., Hunt, S. A., Gamberg, P., Alderman, E. L., Schroeder, J. S., Valantine, H. A. 1995; 76 (5): 340-345

    Abstract

    The mechanisms responsible for transplant coronary artery disease (CAD) and its predisposing factors remain incompletely understood. The influence of donor characteristics as predisposing factors has not been studied systematically. We examined the correlation of donor demographic, clinical, and immunologic parameters with transplant CAD assessed by both intracoronary ultrasound (ICUS) and coronary angiography in 116 heart transplant recipients (age 44.7 +/- 12.0 years) studied 3.4 years (range 1.0 to 14.6) after transplantation. Quantitative ultrasound data were obtained by calculating mean intimal thickness from several distinct coronary sites. Coronary angiograms were categorized visually as normal or showing any transplant CAD. By multivariate regression analysis, donor undersize of > 20% of recipient weight (p < 0.02) and duration after transplantation (p < 0.005) were independently correlated with the amount of ICUS intimal thickness (r = 0.36, p = 0.0007), and older donor age with angiographic evidence for the disease (r = 0.34, p < 0.006). In a subgroup analysis of the 39 patients studied 1 year after transplantation, white donor race (p < 0.05), fewer human leukocyte antigen-DR mismatches (p < 0.002), shorter ischemic time (p < 0.04), and donor smoking history (p < 0.02) were independent predictors for severity of ICUS intimal thickening (r = 0.92, p = 0.0009); higher donor age (p < 0.006) and higher arterial partial pressure of oxygen (p < 0.003) were independent predictors for angiographic disease (r = 0.67, p < 0.002). In conclusion, donor characteristics may contribute to the probably multifactorial pathogenesis of transplant CAD.

    View details for Web of Science ID A1995RN75900005

    View details for PubMedID 7639157

  • CLINICAL OUTCOME OF INTERVAL CADAVERIC RENAL-TRANSPLANTATION IN CARDIAC ALLOGRAFT RECIPIENTS CLINICAL TRANSPLANTATION Kuo, P. C., Luikart, H., BUSSEHENRY, S., Hunt, S. A., Valantine, H. A., Stinson, E. B., Oyer, P. E., Scandling, J. D., Alfrey, E. J., Dafoe, D. C. 1995; 9 (2): 92-97

    Abstract

    The introduction of cyclosporine into widespread clinical use has resulted in improved patient survival following cardiac transplantation. As a result of increased numbers of cardiac transplants, the inherent nephrotoxicity of cyclosporine, and prolonged patient survival, cardiac transplant recipients commonly present with renal dysfunction. In the subgroup who ultimately develop end-stage renal disease (ESRD), therapeutic options include renal transplantation. However, the clinical course associated with this treatment modality is unknown. From 1980 to 1993, 430 cardiac transplants were performed with cyclosporine-based immunosuppression at the Standard University Medical Center. Fourteen (3.3%) patients developed ESRD, requiring chronic dialysis or renal transplantation. The cause of ESRD was cyclosporine nephropathy (13/14; 93%) and glomerulonephritis (1/14; 7%). The average time interval to the development of ESRD was 82 +/- 42 months. Nine patients underwent renal transplantation. During the period of followup (38 +/- 27 months; range 6-89 months) after renal transplantation, cardiac function remained stable. There were no episodes of primary nonfunction of the renal allograft. Patient and renal allograft survival was 89% at both 1 and 3 years after renal transplant. Average serum creatinine was 1.3 +/- 0.6 mg/dl at 1 year and 1.6 +/- 0.8 mg/dl at 3 years post-transplant. The incidence of infectious complications was not statistically different when compared to that of the heart transplant controls and that of a group of cadaveric renal transplant controls (n = 20). Surprisingly, the incidence of renal allograft rejection in the heart transplant patients was 10-fold less than that of the renal transplant controls (0.006 +/- 0.02/patient-year vs. 0.062 +/- 0.05/patient-year; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995QV67600006

    View details for PubMedID 7599409

  • CARDIAC ALLOGRAFT VASCULAR-DISEASE - RELATIONSHIP TO MICROVASCULAR CELL-SURFACE MARKERS AND INFLAMMATORY CELL PHENOTYPES ON ENDOMYOCARDIAL BIOPSY CIRCULATION Deng, M. C., Bell, S., Huie, P., Pinto, F., Hunt, S. A., Stinson, E. B., Sibley, R., Hall, B. M., Valantine, H. A. 1995; 91 (6): 1647-1654

    Abstract

    Cardiac allograft vascular disease is characterized by accelerated and diffuse intimal proliferation involving both the microvasculature and epicardial vessels. Because in vivo documentation of this complication is now possible with intracoronary ultrasound imaging, we can examine the relationship of intimal proliferation to markers of immunity and endothelial activation. We hypothesize that alterations of microvascular cell surface markers likely mirror changes in the epicardial vessels that may be important in the pathophysiology of intimal proliferation.Forty-three heart transplant patients were examined by intracoronary ultrasound more than 1 year after transplantation, and these images were analyzed to obtain mean intimal thickness and intimal thickness class (I through IV), calculated from the mean thickness and circumferential involvement. Right ventricular endomyocardial biopsies obtained at the time of intracoronary ultrasound were examined by immunohistochemistry to detect microvascular expression of histocompatibility leukocyte antigen (HLA) classes I and II (HLA ABC, DR, DP, and DQ); endothelial-specific antigen detected by the monoclonal antibody E 1.5; intercellular adhesion molecules (ICAM-1); CD4+ and CD8+ lymphocytes and macrophages (CD 14+). Microvascular antigen expression was graded 1 through 5 on the basis of the diffuseness of positive staining. The number of each inflammatory cell phenotype present per high-power field was counted. By ANOVA, scores for HLA DR, HLA DQ, and E1.5 expression were lower in intimal thickness classes II, III, and IV compared with class I. This inverse relationship was significant by linear regression analysis of mean intimal thickness. Inflammatory cells were not significantly correlated with intimal thickening. Rejection incidence was higher, and time since transplantation longer, in intimal thickness classes II, III, and IV compared with class I.Transplant coronary artery intimal proliferation is associated with alteration of microvascular endothelial cell surface markers. These changes in cell surface antigen expression could provide the substrate for coronary artery intimal proliferation and narrowing.

    View details for Web of Science ID A1995QL45800006

    View details for PubMedID 7882470

  • Distribution and morphologic features of coronary artery disease in cardiac allografts: an intracoronary ultrasound study. Journal of the American Society of Echocardiography Chenzbraun, A., Pinto, F. J., Alderman, E. L., Botas, J., Oesterle, S. N., Schroeder, J. S., Valantine, H., Popp, R. L. 1995; 8 (1): 1-8

    Abstract

    The longitudinal distribution and circumferential pattern of coronary intimal proliferation were studied with intravascular ultrasonography in 135 patients after heart transplantation. Eighty-seven (64%) of 135 patients had significant intimal thickening, with most lesions (63%) concentric and free of fibrosis or calcification. Both diffuse and nonuniform longitudinal patterns of intimal thickening were found.

    View details for PubMedID 7710741

  • INCIDENCE AND SEVERITY OF TRANSPLANT CORONARY-ARTERY DISEASE EARLY AND UP TO 15 YEARS AFTER TRANSPLANTATION AS DETECTED BY INTRAVASCULAR ULTRASOUND JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rickenbacher, P. R., Pinto, F. J., Chenzbraun, A., Botas, J., Lewis, N. P., Alderman, E. L., Valantine, H. A., Hunt, S. A., Schroeder, J. S., Popp, R. L., Yeung, A. C. 1995; 25 (1): 171-177

    Abstract

    The purpose of this study was to quantify the severity of transplant coronary artery disease and to assess lesion characteristics early and up to 15 years after heart transplantation by using intracoronary ultrasound.Intravascular ultrasound has the ability to measure the components of the arterial wall and has been shown to be a sensitive method for detection of transplant coronary artery disease.A total of 304 intracoronary ultrasound studies were performed in 174 heart transplant recipients at baseline and up to 15 (mean 3.3 +/- 0.2) years after transplantation. Mean intimal thickness and an intimal index were calculated, and lesion characteristics (eccentricity, calcification) were assessed for all coronary sites imaged (mean 3.0 +/- 0.1 sites/study). The Stanford classification was used to grade lesion severity.Compared with findings in patients studied at baseline (< 2 months after transplantation, n = 50), mean intimal thickness (0.09 +/- 0.02 vs. 0.16 +/- 0.02 mm, p < 0.01), intimal index (0.07 +/- 0.01 vs. 0.14 +/- 0.02, p < 0.01) and mean severity class (1.5 +/- 0.2 vs. 2.3 +/- 0.2, p < 0.01) were significantly higher at year 1 (n = 52) after transplantation. Thereafter, all three variables further increased over time and reached highest values between years 5 and 15. Calcification of lesions was detected in 2% to 12% of studies up to 5 years after transplantation, with a significant increase to 24% at years 6 to 10 (p < 0.05).Severity of transplant coronary artery disease appeared to progress with time after transplantation in this cross-sectional study. This characteristic was most prominent during the 1st 2 years after transplantation, whereas calcification of plaques occurred to a significant extent only later in the process. These data may serve as a reference for comparison of intravascular ultrasound findings in other studies of patients with transplant coronary artery disease.

    View details for Web of Science ID A1995QL24900032

    View details for PubMedID 7798497

  • FEASIBILITY OF SERIAL INTRACORONARY ULTRASOUND IMAGING FOR ASSESSMENT OF PROGRESSION OF INTIMAL PROLIFERATION IN CARDIAC TRANSPLANT RECIPIENTS CIRCULATION Pinto, F. J., Chenzbraun, A., Botas, J., Valantine, H. A., STGOAR, F. G., Alderman, E. L., Oesterle, S. N., Schroeder, J. S., Popp, R. L. 1994; 90 (5): 2348-2355

    Abstract

    Serial quantitative coronary angiography is used to assess progression of coronary disease; however, pathology studies have demonstrated angiographic insensitivity for determining atheroma. Intracoronary ultrasound (ICUS) can define and measure the components of the arterial wall and offers the potential for precise quantitative assessment of disease progression on serial examinations. The present study was done to test the feasibility of serially assessing intimal proliferation at the same coronary site with ICUS imaging in cardiac transplant recipients.ICUS imaging was done with a 30-MHz, 5F or 4.3F ultrasound imaging catheter at the time of angiography in 70 cardiac allografts (3.8 sites per patient) initially and 1 year later. Mean intimal thickness (IT), luminal area (LA), and total area (TA) of lumen plus intima and an index of intimal thickness (II = TA - LA/TA) were measured at each site. Additionally, vessels were graded using a scale incorporating criteria of intimal thickness and circumferential involvement. Side-by-side comparisons of paired angiograms were performed both to verify the similarity of ICUS imaging site and to detect new angiographic abnormalities. At least one site could be assessed serially by ICUS in 100% of patients, but only 189 of the original 263 coronary sites (72%) (2.7 sites per patient) could be matched satisfactorily on the second study. Thirty-nine patients (56%) had mild IT and 31 patients (44%) had moderate or severe IT on the initial study. Both groups showed the same IT progression the following year (delta = 0.05 +/- 0.13 versus 0.07 +/- 0.15 mm; P = NS). Twenty-seven of the 70 patients (39%) showed progression by ICUS. The 23 patients with ICUS progression and angiographically normal vessels had the same progression in intimal thickening as the 4 patients with ICUS progression but showing angiographic disease (delta = 0.17 +/- 0.13 versus 0.22 +/- 0.10 mm; P = NS).Replication of the intracoronary imaging site by judgment of two observers at an initial study and at a second study 1 year later was possible in at least one vessel site in 100% of the 70 patients and in 72% (189 of 263) of the original imaging sites (2.7 sites per patient). Serial ICUS demonstrates progression of intimal thickening at specific sites in only some cardiac transplant patients. Progression of intimal proliferation can occur in individuals in the presence or absence of initially increased intimal thickening or of angiographic disease at the time of the initial studies. Angiography is insensitive for recognizing early intimal thickening of the coronary vessels.

    View details for Web of Science ID A1994PR28600025

    View details for PubMedID 7955193

  • CYTOKINES AS POTENTIAL MEDIATORS OF ACUTE ALLOGRAFT DIASTOLIC DYSFUNCTION IN CYCLOSPORINE-TREATED PATIENTS - A PILOT-STUDY USING IN-SITU HYBRIDIZATION 3rd International Congress on Cyclosporine Valantine, H., Johnson, F., Dong, C., Lewis, N., Tovey, D., Huie, P., Pratt, R., STINSON, E., Hunt, S., Sibley, R. ELSEVIER SCIENCE INC. 1994: 2852–53

    View details for Web of Science ID A1994PM60300142

    View details for PubMedID 7940898

  • IMPACT OF CYCLOSPORINE DOSE ON LONG-TERM OUTCOME AFTER HEART-TRANSPLANTATION 3rd International Congress on Cyclosporine Valantine, H., Hunt, S., Gamberg, P., Miller, J., Luikart, H. ELSEVIER SCIENCE INC. 1994: 2710–12

    View details for Web of Science ID A1994PM60300089

    View details for PubMedID 7940848

  • Cytokine gene expression in human cardiac allograft recipients. Transplant immunology Wu, C. J., Kurbegov, D., Lattin, B., Burchard, E., Finkle, C., Valantine, H., Billingham, M. E., Starnes, V. A., CLAYBERGER, C. 1994; 2 (3): 199-207

    Abstract

    The long-term success of heart transplantation for end-stage heart disease has been hindered by the problems associated with acute and chronic graft rejection, opportunistic infections and potentially fatal complications of intensive immunosuppression. A more complete understanding of the biology of transplant rejection should provide the basis for the development of improved methods for controlling and monitoring rejection. Cytokines, the soluble factors which regulate the immune response, are central to the rejection process. The objective of this study was to analyse cytokine mRNA transcripts in 99 biopsy samples and 89 blood samples from 65 and 35 Stanford Medical Center cardiac transplant recipients, respectively, gathered between January 1990 and January 1992. Following RNA extraction and conversion to cDNA, samples were amplified with cytokine-specific primers for interleukins (IL) 1 to 8, TNF-beta (tumour necrosis factor-beta) and IFN-gamma (interferon-gamma) and were analysed by gel electrophoresis and Southern blot hybridization. Our results demonstrate that despite chronic immunosuppressive therapy, the peripheral blood of transplant recipients expressed a higher combined percentage of different cytokine transcripts than did peripheral blood obtained from normal volunteers. In transplant patients, detection of cytokine transcripts for IL-1 alpha, IL-1 beta and IL-2 increased with time after transplantation. Intragraft IL-7 gene expression was significantly increased in biopsies diagnosed with mild (grade 1) rejection when compared to those with no evidence of rejection or with moderate to severe rejection. Implications of these results in light of possible mechanisms of rejection and of new approaches to immunotherapy are discussed.

    View details for PubMedID 8000848

  • CARDIAC TRANSPLANTATION - THE STANFORD EXPERIENCE IN THE CYCLOSPORINE ERA JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Sarris, G. E., Moore, K. A., Schroeder, J. S., Hunt, S. A., Fowler, M. B., VALANTINE, H. B., Vagelos, R. H., Billingham, M. E., Oyer, P. E., Stinson, E. B., Reitz, B. A., Shumway, N. E. 1994; 108 (2): 240-252

    Abstract

    We analyzed our experience with 496 patients who underwent primary cardiac transplantation since the introduction of cyclosporine immunosuppression (Dec. 16, 1980, to Jan. 7, 1993). There were 388 male and 108 female patients. Mean recipient age was 40 +/- 16 years (range 0.1 to 70 years, median 44 years). Recipient diagnoses included coronary disease in 188, idiopathic cardiomyopathy in 196, viral cardiomyopathy in 35, and congenital heart disease in 28 patients. Donor age was 25 +/- 10 years (range 1 to 53 years, median 24 years). Graft ischemic time was 148 +/- 57 minutes (range 38 to 495 minutes, median 149 minutes). Operative mortality (hospital death) rate was 7.9% +/- 1.3% (70% confidence intervals). Multivariate logistic regression analysis revealed that (higher) pulmonary vascular resistance and gender (female) were the only independent predictors of hospital death (p < 0.05). Actuarial survival estimates for all patients at 1, 5, and 10 years are 82% +/- 1.7% (83% +/- 1.8% adult, 77% +/- 5.2% pediatric), 61% +/- 2.5% (65% +/- 2.5% adult, 64% +/- 6.6% pediatric), and 41% +/- 3.7% (40% +/- 4% adult, 54% +/- 8.6% pediatric), respectively. For 232 patients treated with triple-drug immunosuppression and induction with OKT3 since 1987, survival estimates at 1 and 5 years are 82% +/- 2.6% and 67% +/- 3.7%, respectively. Causes of death for the entire group were rejection in 29 (14% of deaths), infection in 69 (34%), graft coronary disease in 36 (18%), nonspecific graft failure in 6 (3%), malignancy in 19 (10%), stroke in 6 (3%), pulmonary hypertension in 6 (3%), and other causes in 30 (15%) patients. Actuarial freedom from rejection at 3 months, 1 year, and 5 years was 21% +/- 1.9%, 14% +/- 1.7%, and 7.2% +/- 1.5%, respectively (+/- 1 standard error of the mean). Estimates of freedom from rejection-related death at 1, 5, and 10 years were 96% +/- 1%, 93% +/- 1.4%, and 93% +/- 1.4%, respectively. Actuarial freedom from any infection at 3 months and at 1 and 5 years was 40% +/- 2.3%, 27% +/- 2.1%, and 15% +/- 2.0% and from infection-related death, 95% +/- 1.0%, 93% +/- 1.2%, and 85% +/- 1.9%, respectively. Actuarial freedom from (angiographic or autopsy proved) graft coronary artery disease at 1, 5, and 10 years was 95% +/- 1.2%, 73% +/- 2.7%, and 65% +/- 3.6% and from coronary disease-related death or retransplantation 98% +/- 0.7%, 84% +/- 2.2%, and 66% +/- 4.3%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1994PB11400006

    View details for PubMedID 8041172

  • METABOLIC RISK-FACTORS FOR ATHEROSCLEROSIS IN HEART-TRANSPLANT RECIPIENTS AMERICAN HEART JOURNAL Kemna, M. S., Valantine, H. A., Hunt, S. A., Schroeder, J. S., CHEN, Y. D., Reaven, G. M. 1994; 128 (1): 68-72

    Abstract

    Development of coronary artery disease (CAD) in the cardiac allograft limits long-term survival after heart transplantation. Previous studies, focusing on lipoprotein metabolism, have paid little attention to changes in glucose and insulin metabolism that increase the risk of CAD in these patients. To address this issue, plasma glucose and insulin responses to an oral glucose load and lipid and lipoprotein concentrations were measured in male normal volunteers (n = 40) and cardiac transplant recipients with pretransplant diagnoses of either idiopathic cardiomyopathy (n = 24) or ischemic heart disease (n = 28), matched for age and body mass index. Patients with a pretransplant diagnosis of ischemic heart disease had higher plasma glucose and insulin concentrations in response to oral glucose as well as higher fasting plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol concentrations than did the control group (p < 0.005 to p < 0.001). In addition, high-density lipoprotein cholesterol concentrations were lower and the ratio of cholesterol to high-density lipoprotein cholesterol higher than control values in those with a pretransplant diagnosis of ischemic heart disease (p < 0.001). Values for almost all variables were intermediate in patients with a pretransplant diagnosis of idiopathic cardiomyopathy and in most instances were significantly different from both. Thus, male cardiac transplant recipients are dyslipidemic, relatively glucose intolerant, and hyperinsulinemic compared to normal volunteers. These changes, observed in patients with a pretransplant diagnosis of either ischemic heart disease or idiopathic cardiomyopathy, emphasize the important role of immunosuppression in the development of metabolic risk factors for CAD in these individuals.

    View details for Web of Science ID A1994NV84000010

    View details for PubMedID 8017286

  • EXERCISE ECHOCARDIOGRAPHY IN HEAT TRANSPLANT RECIPIENTS - A COMPARISON WITH ANGIOGRAPHY AND INTRACORONARY ULTRASONOGRAPHY JOURNAL OF HEART AND LUNG TRANSPLANTATION COLLINGS, C. A., Pinto, F. J., Valantine, H. A., Popylisen, S., Puryear, J. V., Schnittger, I. 1994; 13 (4): 604-613

    Abstract

    Transplant coronary artery disease is the leading cause of allograft failure in heart transplant recipients surviving beyond 1 year. Coronary angiography still remains the major technique for surveillance of these patients, with recent use of intracoronary ultrasonography to detect the early stages of intimal thickening. We evaluated exercise echocardiography to screen for the presence or absence of angiographic evidence of transplant coronary artery disease in any vessel, defined as follows: absent; stenosis 39% or less = mild; stenosis 40% to 69% = moderate; or stenosis > or = 70%, or more = severe. Fifty-one consecutive heart transplant recipients undergoing routine annual evaluation were included in the study. Of thirty-seven patients with no coronary artery disease, thirty-two had a normal and five had an abnormal exercise echocardiogram. Fourteen patients (27%) had transplant coronary artery disease by angiographic criteria; six had mild, six had moderate, and two had severe stenosis. One patient with mild and the two patients with severe transplant coronary artery disease had abnormal exercise echocardiograms. None of the patients with moderate disease had an abnormal exercise echocardiogram (false negative). Of forty-three patients with no or mild stenosis, 19 patients had moderate to severe intimal proliferation as seen with intracoronary ultrasonography. Of eight patients with moderate or severe stenosis, four were tested with intracoronary ultrasonography and all had moderate to severe intimal proliferation. Six patients had a "false positive" exercise echocardiogram, and of four who were tested with intracoronary ultrasonography, two had mild and two had moderate to severe intimal thickening. In summary, exercise echocardiography correctly excluded the presence of transplant coronary artery disease in 86% of patients but was associated with a high false negative rate for detection of moderate coronary stenosis. A false positive exercise echocardiogram was associated with intimal proliferation by intracoronary ultrasonography in several patients and suggests that coronary angiography may underestimate significant coronary artery disease.

    View details for Web of Science ID A1994PA31000005

    View details for PubMedID 7947876

  • RECOVERY OF THE RIGHT VENTRICLE AFTER SINGLE-LUNG TRANSPLANTATION IN PULMONARY-HYPERTENSION AMERICAN JOURNAL OF CARDIOLOGY Kramer, M. R., Valantine, H. A., Marshall, S. E., Starnes, V. A., Theodore, J. 1994; 73 (7): 494-500

    Abstract

    Single-lung transplantation has been successfully performed in patients with pulmonary fibrosis and emphysema. In contrast, patients with end-stage pulmonary hypertension (either primary or secondary to Eisenmenger's syndrome) have conventionally been offered heart-lung transplantation. The rationale underlying this approach is that chronic pulmonary hypertension results in irreversible right ventricular dilatation and failure. Recovery of the right ventricle has previously been reported after thromboendarterectomy for chronic large-vessel pulmonary embolism, correction of atrial septal defect or mitral valve replacement. The evolution of right ventricular morphology and function after lung transplantation has not been previously described. This study examines the reversibility of right ventricle dysfunction following normalization of pulmonary artery pressure after single-lung transplantation in 4 patients with pulmonary hypertension. Cardiac function was assessed using electrocardiography, echocardiography and radionuclide angiography. Pulmonary hemodynamic measurements, including pulmonary artery pressure and pulmonary vascular resistance, decreased in all patients after single-lung transplantation. Electrocardiographic changes observed were leftward shift in the QRS axis, and a decrease in P-wave amplitude and in right ventricular force. Echocardiographic examination revealed decreased right atrial, right ventricular and tricuspid valve annular dimensions, normalization of septal motion, and decreased tricuspid regurgitation. Thus, improved pulmonary hemodynamics after single-lung transplantation for pulmonary vascular disease results in reversal of right heart dilatation and dysfunction, and improved myocardial performance. The extent of right ventricular dysfunction beyond which recovery is unlikely to occur has yet to be determined.

    View details for Web of Science ID A1994NA80600012

    View details for PubMedID 8141091

  • INFLUENCE OF GRAFT-REJECTION ON INCIDENCE OF ACCELERATED GRAFT CORONARY-ARTERY DISEASE - A NEW APPROACH TO ANALYSIS JOURNAL OF HEART AND LUNG TRANSPLANTATION Gao, S. Z., Schroeder, J. S., Hunt, S. A., Valantine, H. A., Hill, I. R., Stinson, E. B. 1993; 12 (6): 1029-1035

    Abstract

    Conflicting data exist on the role of graft rejection as a risk factor for later development of accelerated graft coronary artery disease. We analyzed 126 consecutive heart transplant recipients treated with cyclosporine-based immunosuppressive regimens and devised an arbitrary method to incorporate the number, duration, and severity of myocardial rejection episodes during the first postoperative year, resulting in a rejection score for each patient. We then correlated the later incidence (mean follow-up, 4 years) of angiographic accelerated graft coronary artery disease with this rejection score and with its components: number, duration, and severity of rejection; number and duration of untreated rejection; and incidence and duration of delayed rejection therapy. Accelerated graft coronary artery disease developed in 60 patients (48%). The rejection score was 96.7 for patients in the "no accelerated graft coronary artery disease" group and 110.4 for those in the "accelerated graft coronary artery disease" group (p = NS). No significant difference was noted between patients with and without disease in any of the other seven rejection parameters analyzed, and no significant difference in time to occurrence of disease was noted between groups divided at the median rejection score. Donor age was older and fasting triglyceride blood level was higher in patients with accelerated graft coronary artery disease than in those without disease. All other clinical characteristics, including HLA mismatches, ischemic time, blood pressure, lipid profile, and drug therapy, did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993MP52100021

    View details for PubMedID 8312304

  • INTRACORONARY ULTRASOUND IMAGING IN HEART-TRANSPLANT RECIPIENTS - THE STANFORD EXPERIENCE INTERNATIONAL CONF ON CARDIAC ALLOGRAFT VASCULAR DISEASE : A BASIC SCIENCE AND CLINICAL REVIEW Valantine, H., Pinto, F. J., STGOAR, F. G., Alderman, E. L., Popp, R. L. MOSBY-YEAR BOOK INC. 1992: S60–S64

    View details for Web of Science ID A1992HZ31100014

    View details for PubMedID 1623002

  • INTRACORONARY ULTRASOUND IN CARDIAC TRANSPLANT RECIPIENTS - INVIVO EVIDENCE OF ANGIOGRAPHICALLY SILENT INTIMAL THICKENING CIRCULATION STGOAR, F. G., Pinto, F. J., Alderman, E. L., Valantine, H. A., Schroeder, J. S., Gao, S. Z., Stinson, E. B., Popp, R. L. 1992; 85 (3): 979-987

    Abstract

    Accelerated coronary atherosclerosis is a major factor limiting allograft longevity in cardiac transplant recipients. Histopathology studies have demonstrated the insensitivity of coronary angiography for detecting early atheromatous disease in this patient population. Intracoronary ultrasound is a new imaging technique that provides characterization of vessel wall morphology. The purpose of this study was to compare in vivo intracoronary ultrasound with angiography in cardiac transplant recipients.The left anterior descending coronary artery was studied with intracoronary ultrasound in 80 cardiac transplant recipients at the time of routine screening coronary angiography 2 weeks to 13 years after transplantation. A mean and index of intimal thickening were obtained at four coronary sites. Intimal proliferation was classified as minimal, mild, moderate, or severe according to thickness and degree of vessel circumference involved. Twenty patients were studied within 1 month of transplantation and had no angiographic evidence of coronary disease. An intimal layer was visualized by ultrasound in only 13 of these 20 presumably normal hearts. The 60 patients studied 1 year or more after transplantation all had at least minimal intimal thickening. Twenty-one patients (35%) showed minimal or mild, 17 (28%) moderate, and 21 (35%) severe thickening. Forty-two of these 60 patients had angiographically normal coronary arteries, 21 (50%) of whom had either moderate or severe thickening. All 18 patients with angiographic evidence of coronary disease had moderate or severe intimal thickening, but there was no statistically significant difference in intimal thickness or index when compared with the patients with moderate or severe proliferation and normal angiograms (thickness, 0.53 +/- 0.35 mm versus 0.64 +/- 0.30 mm, p = NS; index, 0.28 +/- 0.10 versus 0.34 +/- 0.10, p = NS).The majority of patients 1 or more years after cardiac transplantation have ultrasound evidence of intimal thickening not apparent by angiography. Intracoronary ultrasound offers early detection and quantitation of transplant coronary disease and provides characterization of vessel wall morphology, which may prove to be a prognostic marker of disease.

    View details for Web of Science ID A1992HG54100013

    View details for PubMedID 1537134

  • COST CONTAINMENT - COADMINISTRATION OF DILTIAZEM WITH CYCLOSPORINE AFTER HEART-TRANSPLANTATION JOURNAL OF HEART AND LUNG TRANSPLANTATION Valantine, H., Keogh, A., McIntosh, N., Hunt, S., Oyer, P., Schroeder, J. 1992; 11 (1): 1-8

    Abstract

    Coadministration of diltiazem with cyclosporine (CsA) has been reported to alter the metabolism of CsA, resulting in increased blood concentration with potential nephrotoxicity if dosage is not adjusted. This report analyzes the cost saving resulting from use of diltiazem and CsA together and examines the impact on renal function. Sixty-nine heart transplant recipients (59 men, 10 women) were randomized to diltiazem (n = 32) or to no calcium blocker (n = 37). Age range was 18 to 58 years. All patients received CsA (titrated to a 12-hour trough serum level of 100 to 200 ng/ml), azathioprine, and prednisone. Diltiazem was begun at 30 mg three times daily increasing to 60 mg three times daily at 1 month, as tolerated. Renal function was assessed by serial measurements of serum creatinine. Parameters before and after starting diltiazem were compared by paired t-tests, and differences between group means by analysis of variance. CsA doses and levels were comparable at baseline in both groups. At 12 months, CsA dose requirement was 2.5 +/- 1.0 versus 5.9 +/- 3.2 mg/kg/day (diltiazem group versus no calcium blocker group; p less than or equal to 0.001) to achieve similar serum levels (96 +/- 51 versus 123 +/- 96 ng/ml; p = NS). This represents a 48% reduction in dose cost of CsA. The average cost of CsA for 2 to 4 months of therapy in a patient weighing 70 kg was reduced from $12,122 in the no calcium blocker group to $6,356 in the diltiazem group.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992HC24900001

    View details for PubMedID 1540597

  • NITROGLYCERIN-INDUCED CORONARY VASODILATION IN CARDIAC TRANSPLANT RECIPIENTS - EVALUATION WITH INVIVO INTRACORONARY ULTRASOUND CIRCULATION Pinto, F. J., STGOAR, F. G., Fischell, T. A., Stadius, M. L., Valantine, H. A., Alderman, E. L., Popp, R. L. 1992; 85 (1): 69-77

    Abstract

    Coronary artery vasomotion is altered after cardiac transplantation. The impact of accelerated transplant coronary atherosclerosis and myocardial rejection on vasomotion is not well understood. Intravascular ultrasound is a new imaging method with the ability to study real-time changes in coronary artery dimensions.Epicardial coronary artery response to nitroglycerin was studied in 32 cardiac transplant recipients (age, 47 +/- 11 years) 3 weeks to 10 years after transplantation with intracoronary ultrasound. Cross-sectional luminal area and diameter were measured at a fixed position in the left anterior descending artery immediately before and every 30 seconds for 5 minutes after 0.4 mg of sublingual nitroglycerin. Cross-sectional area increased from a baseline of 13.1 +/- 3.9 mm2 to 15.8 +/- 3.9 mm2 at maximal vasodilation; luminal diameter increased from 4.0 +/- 0.6 mm to 4.5 +/- 0.6 mm. This increase reached statistical significance (p less than 0.001) at 1.5 minutes after administration of nitroglycerin; mean maximum increase occurred at 4.5 minutes (24% for cross-sectional area and 11% for luminal diameter). Patients with biopsy-proven mild or moderate concurrent rejection had a significantly blunted vasodilatory response versus the nonrejection group (9% versus 27% for cross-sectional area, p less than 0.04), although a vasodilatory effect was still present. Nitroglycerin response was well preserved in patients up to 10 years after transplantation; however, there was a trend toward a decreased response in patients studied immediately after transplantation (21% versus 29%, p = 0.37). Coronary intimal thickness, as measured by ultrasound, had no impact on the vasodilatory response (R = 0.23, p = 0.34).Vasodilatory response to nitroglycerin in cardiac transplant recipients is attenuated during episodes of cardiac rejection. This response is preserved in long-term survivors and is independent of the degree of intimal thickening. Intravascular ultrasound provides a new method to document real-time epicardial coronary vasomotion.

    View details for Web of Science ID A1992GY58200009

    View details for PubMedID 1728486

  • SENSITIVITY AND SPECIFICITY OF DIASTOLIC INDEXES FOR REJECTION SURVEILLANCE - TEMPORAL CORRELATION WITH ENDOMYOCARDIAL BIOPSY 10TH ANNUAL MEETING AND SCIENTIFIC SESSIONS OF THE INTERNATIONAL SOC FOR HEART TRANSPLANTATION Valantine, H. A., YEOH, T. K., Gibbons, R., McCarthy, P., Stinson, E. B., Billingham, M. E., Popp, R. L. MOSBY-YEAR BOOK INC. 1991: 757–65

    Abstract

    Although acute diastolic dysfunction is an early sequela of the rejecting heart, reported sensitivities and specificities have varied widely when Doppler echocardiography is used for rejection surveillance. This study examines the temporal relationship between changes in Doppler echocardiographic indexes of diastolic function and sequential endomyocardial biopsies to identify possible factors accounting for false-positive and false-negative results. A total of 114 Doppler echocardiographic studies and biopsies were performed weekly in 39 patients aged 14 to 59 years during the initial 3 months after heart transplantation. All Doppler examinations were within 24 hours of biopsy and were analyzed in a blinded fashion. Onset of restrictive physiology, defined as a 15% decrease in either isovolumic relaxation time or pressure half-time, was determined by analysis of the Doppler mitral flow velocity curve.

    View details for Web of Science ID A1991GJ15600018

    View details for PubMedID 1958683

  • FREQUENCY AND MECHANISM OF BRADYCARDIA IN CARDIAC TRANSPLANT RECIPIENTS AND NEED FOR PACEMAKERS AMERICAN JOURNAL OF CARDIOLOGY Dibiase, A., Tse, T. M., Schnittger, I., Wexler, L., Stinson, E. B., Valantine, H. A. 1991; 67 (16): 1385-1389

    Abstract

    Orthotopic cardiac transplantation is occasionally complicated by unexplained bradyarrhythmias. Sinus node injury as a consequence of operation or acute rejection has anecdotally been linked to the development of bradycardia early after transplantation. These arrhythmias are empirically managed by pacemaker implantation, the indications for which remain poorly defined. This retrospective study examined the 20-year experience of our institution with bradyarrhythmias after transplantation to determine the predisposing factors and indications for pacemaker implantation. Forty-one of 556 patients in our cardiac transplant program (7.4%) received permanent pacemakers between 1969 and 1989. The predominant rhythm disturbances were junctional rhythm (46%), sinus arrest (27%) and sinus bradycardia (17%). Most patients were asymptomatic (61%), and presented in the early post-transplant period (73%). Four possible predisposing factors were evaluated: (1) graft ischemic time, (2) rejection history, (3) use of bradycardia-inducing drugs, and (4) anatomy of blood supply to the sinoatrial (SA) node. No significant differences existed between patients with and without pacemakers with regard to the first 3 variables. However, after transplantation angiograms showed that prevalence of abnormal SA nodal arteries was greater in patients with than without pacemakers (p less than 0.02). Pacemaker follow-up at 3, 6 and 12 months showed persistent bradycardia (60 to 90 beats/min) in 88, 75 and 50% of patients, respectively. The most common pacemaker complication (15%) was lead displacement at time of biopsy. These results suggest that disruption of the SA nodal blood supply may be an important predisposing factor in the development of bradycardias.

    View details for Web of Science ID A1991FR02000014

    View details for PubMedID 2042569

  • CHANGES IN CARDIAC MORPHOLOGY AND FUNCTION FOLLOWING SINGLE-LUNG TRANSPLANTATION TRANSPLANTATION PROCEEDINGS YEOH, T. K., Kramer, M. R., Marshall, S., Theodore, J., Gibbons, R., Valantine, H. A., Starnes, V. A. 1991; 23 (1): 1226-1227

    View details for Web of Science ID A1991EV39100126

    View details for PubMedID 1989195

  • LEFT-VENTRICULAR DIASTOLIC FUNCTION - DOPPLER ECHOCARDIOGRAPHIC CHANGES SOON AFTER CARDIAC TRANSPLANTATION CIRCULATION STGOAR, F. G., Gibbons, R., Schnittger, I., Valantine, H. A., Popp, R. L. 1990; 82 (3): 872-878

    Abstract

    In acute cardiac rejection, left ventricular diastolic function is altered, and a restrictive ventricular filling pattern occurs. Doppler echocardiographic indexes of mitral inflow have been proposed as sensitive markers of the rejection process. As rejection progresses, the restrictive ventricular filling pattern is reflected by a shortening of isovolumic relaxation time and mitral valve pressure half-time and by an increase in early transmitral filling velocity. Diastolic function is also compromised in the nonrejecting cardiac transplant recipient during the early postoperative period. This study examined the progression in Doppler-derived mitral filling indexes in 25 recent cardiac transplant recipients who demonstrated no histological evidence of transplant rejection. Isovolumic relaxation time, mitral valve pressure half-time, and early transmitral filling velocity were measured at postoperative weeks 1, 2, 4, and 6 on the day that surveillance right ventricular endomyocardial biopsies were performed. The initial indexes were comparable to previously described restrictive parameters and over the 6-week study period evolved into a nonrestrictive filling pattern. This evolution reflects a progressive improvement in postoperative diastolic function and a decrease in left heart filling pressures. None of the evaluated clinical characteristics, including preoperative pulmonary pressures, total ischemic time of the transplanted heart, cardiopulmonary bypass time, and age of the donor heart, correlated with this process. Given the increasing use of Doppler echocardiography as a means of screening for transplant rejection, it is important to have a thorough understanding of normal postoperative changes in left ventricular diastolic function.

    View details for Web of Science ID A1990DY27700018

    View details for PubMedID 2394008

  • Variability of Doppler echocardiographic indexes of left ventricular filling in transplant recipients and in normal subjects. Journal of the American Society of Echocardiography Valantine, H. A., Hatle, L. K., Appleton, C. P., Gibbons, R., Popp, R. L. 1990; 3 (4): 276-284

    Abstract

    This study examines the reproducibility and variability of pulsed wave Doppler versus continuous wave Doppler ultrasound indexes of left ventricular filling in cardiac allograft recipients and in normal subjects. The following indexes were studied: isovolumic relaxation time, pressure half-time, peak early mitral flow velocity, and peak mitral flow velocity after atrial systole. Intraobserver and interobserver variability were assessed by regression analysis. Individual components of variance (subject, reader, beat, day, and tracing) were estimated in a subset of five patients and five normal subjects, and estimated total variance defined for each group. Temporal (day-to-day) variability for 95% confidence was estimated for these patients and for normal subjects. Temporal variability in the group from which the subsets were drawn was measured from absolute and percent change in values on two occasions. Estimated and observed 95% confidence limits were compared. Intersubject variability was the largest component of variance in both transplant recipients and in normal subjects. For all indexes in transplant recipients (in the absence of rejection) and normal subjects, observed absolute mean differences (+/- 2 standard deviations) between values from recordings taken on two different days were larger than the 95% confidence limits estimated from the components of variance analysis. The observed 95% limits for transplant recipients versus normal subjects were as follows: isovolumic relaxation time, 20 msec versus 6 msec; pressure half-time, 16 msec versus 9 msec; peak early mitral flow velocity, 32 cm per second versus 17 cm per second; and peak mitral flow velocity after atrial systole, 28 cm per second versus 10 cm per second.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for PubMedID 2206544

  • SERIAL MEASUREMENT OF INTEGRATED ULTRASONIC BACKSCATTER IN HUMAN CARDIAC ALLOGRAFTS FOR THE RECOGNITION OF ACUTE REJECTION CIRCULATION Masuyama, T., Valantine, H. A., Gibbons, R., Schnittger, I., Popp, R. L. 1990; 81 (3): 829-839

    Abstract

    Cyclic variation of integrated ultrasonic backscatter (IB) was noninvasively measured in the septum and left ventricular posterior wall using a quantitative IB imaging system to assess the alterations in the acoustic properties of myocardium associated with acute cardiac allograft rejection. The study population consisted of 23 cardiac allograft recipients and 18 normal subjects. In each cardiac allograft recipient, one to eight (mean, four) IB studies were performed, each within 24 hours of right ventricular endomyocardial biopsy performed for rejection surveillance. The magnitude of the cyclic variation of IB in the posterior wall was 5.9 +/- 0.9 dB in normal subjects and 6.2 +/- 1.3 dB in the cardiac allograft recipients without previous or current histological evidence of acute rejection (n = 17, p = NS vs. normal subjects). The magnitude of cyclic variation of IB in the septum was 4.8 +/- 1.1 dB in normal subjects and 3.8 +/- 2.0 dB in the cardiac allograft recipients (n = 15, p = NS vs. normal subjects). A significant decrease in the septal IB measure was observed in cardiac allograft recipients with left ventricular hypertrophy (wall thickness of at least 13 mm) (2.6 +/- 1.7 dB, n = 8, p less than 0.05 vs. normal subjects). IB studies were done before and during moderate acute rejection in 11 recipients (14 episodes). During moderate acute cardiac rejection, the magnitude of the cyclic variation in IB decreased from 6.7 +/- 1.3 to 5.1 +/- 1.4 dB in the posterior wall (n = 14, p less than 0.05) and from 4.2 +/- 2.1 dB to 2.9 +/- 1.8 dB in the septum (n = 12, p less than 0.05). These data suggest 1) the magnitude of the cyclic variation in IB of the septum is different in cardiac allografts with cardiac hypertrophy and normal subjects, possibly reflecting regionally depressed myocardial contractile performance and 2) acute cardiac rejection in humans is accompanied by an alteration in the acoustic properties of the myocardium. This change is detectable by serial measurement of the magnitude of the cyclic variation in IB, both in the septum and in the posterior wall.

    View details for Web of Science ID A1990CT01400012

    View details for PubMedID 2306834

  • CARDIAC TRANSPLANTATION IN PATIENTS WITH PREEXISTING NEOPLASTIC DISEASES AMERICAN JOURNAL OF CARDIOLOGY Edwards, B. S., Hunt, S. A., Fowler, M. B., Valantine, H. A., Stinson, E. B., Schroeder, J. S. 1990; 65 (7): 501-504

    Abstract

    Cardiac transplantation has traditionally been reserved for individuals with end-stage congestive heart failure (CHF) in whom there is no history of other life-threatening systemic disorders. In most transplant centers, patients with a history of malignancy and severe heart failure have not been considered acceptable candidates for cardiac transplantation. In the last 4 years at Stanford University Medical Center, 8 cardiac transplants have been performed in 7 patients with a history of neoplastic disease. Six of these patients had already received treatment for lymphoproliferative disorders and in 1 case, a patient underwent a transplant after treatment for adenocarcinoma of the colon. Six of the 7 patients were discharged from the hospital and in that group, the 1-year posttransplant survival rate was 71%. This was comparable to an overall 1-year survival rate of 80% for patients undergoing a cardiac transplant at our center during the same period of time. At follow-up averaging over 2 years, there has been 1 case of recurrent neoplasia. One patient with evidence of radiation-induced pulmonary damage died of respiratory failure 2 days after transplantation. One patient required retransplantation because of intractable rejection and subsequently died from infectious complications. Immunosuppressive therapy in these patients has not been associated with an increased risk for neoplastic recurrence or for the development of posttransplant lymphoproliferative disorders. The current study demonstrates that in a carefully selected group, previously treated neoplastic disease should not represent a contraindication to cardiac transplantation.

    View details for Web of Science ID A1990CN83200019

    View details for PubMedID 2305689

  • Long-term management and results in heart transplant recipients. Cardiology clinics Valantine, H. A. 1990; 8 (1): 141-148

    Abstract

    This article reviews the evolution of therapeutic strategies for maintenance immunosuppression, and presents current approaches to prevention, treatment, and surveillance of acute rejection. Other major complications influencing mortality and morbidity are discussed; these include infection, cyclosporine nephrotoxicity, malignancy, and bone disease.

    View details for PubMedID 2407355

  • Prevalence of accelerated coronary artery disease in heart transplant survivors. Comparison of cyclosporine and azathioprine regimens. Circulation Gao, S. Z., Schroeder, J. S., Alderman, E. L., Hunt, S. A., Valantine, H. A., WIEDERHOLD, V., Stinson, E. B. 1989; 80 (5): III100-5

    Abstract

    Rapid development of diffuse, occlusive coronary artery disease in the cardiac allograft has emerged as a major limiting factor for long-term survival after transplantation. Prior multivariate analyses have failed to identify any strong predictors of this disease. We retrospectively reviewed serial annual coronary angiograms to assess the prevalence of transplant coronary artery disease. A total of 103 patients treated initially with azathioprine-based therapy were compared with a later cohort of 78 patients for whom cyclosporine was the basis of immunosuppressive therapy. The percent of patients free of angiographically visible transplant coronary artery disease at 1 year was 89% for the azathioprine group versus 86% for the cyclosporine group. At 3 years, 74% of the azathioprine group versus 63% of the cyclosporine group were free of visible disease (p = NS). By the fifth postoperative year, 58% of azathioprine-treated and 50% of cyclosporine-treated patients were free of transplant coronary artery disease (p = NS). The mean number of rejection episodes in the first year after transplantation was 2.0 for cyclosporine patients versus 2.5 for azathioprine patients. The azathioprine and cyclosporine patients were compared with respect to a variety of baseline and clinical follow-up measurements that might influence the development of coronary artery disease. Patients in the cyclosporine group had higher blood pressure (135/94 versus 123/85 mm Hg, p less than 0.001) and were receiving lower maintenance prednisone doses. This study demonstrates that improved cyclosporine immunosuppression does not decrease the time-related prevalence of transplant coronary artery disease.

    View details for PubMedID 2805287

  • PREVALENCE OF ACCELERATED CORONARY-ARTERY DISEASE IN HEART-TRANSPLANT SURVIVORS - COMPARISON OF CYCLOSPORINE AND AZATHIOPRINE REGIMENS CIRCULATION Gao, S. Z., Schroeder, J. S., Alderman, E. L., Hunt, S. A., Valantine, H. A., WIEDERHOLD, V., Stinson, E. B. 1989; 80 (5): 100-105

    View details for Web of Science ID A1989CB17700017

  • RECURRENCE OF AMYLOID IN A CARDIAC ALLOGRAFT 4 MONTHS AFTER TRANSPLANTATION JOURNAL OF HEART TRANSPLANTATION Valantine, H. A., Billingham, M. E. 1989; 8 (4): 337-341

    View details for Web of Science ID A1989AJ45600010

    View details for PubMedID 2671318

  • FREQUENCY OF FAMILIAL NATURE OF DILATED CARDIOMYOPATHY AND USEFULNESS OF CARDIAC TRANSPLANTATION IN THIS SUBSET AMERICAN JOURNAL OF CARDIOLOGY Valantine, H. A., Hunt, S. A., Fowler, M. B., Billingham, M. E., Schroeder, J. S. 1989; 63 (13): 959-963

    Abstract

    A familial etiology was identified on the basis of family history in 16 (8.75%) of 184 patients undergoing cardiac transplantation at Stanford for endstage dilated cardiomyopathy (DC). These 16 patients, from 11 families, included 5 sibling pairs. To help determine optimal management of such patients, their case histories and posttransplant courses were reviewed. Mean age of patients at presentation was 23 +/- 15 years. In sibling pairs, duration of symptoms from onset to diagnosis was 14 +/- 5 weeks for the first sibling, but only 4 +/- 2 weeks for the second. Progressive cardiac enlargement was documented radiographically in siblings of transplant recipients in 2 families before the onset of symptoms. The posttransplant course with regard to rejection incidence, infectious complications, coronary artery disease and malignancy was similar to that of the 168 patients with nonfamilial DC. Actuarial survival at 5 years after transplantation was 80%. Thirteen patients (including all sibling pairs) are alive 1 to 11 years after transplantation. Sepsis was the cause of death in 3 patients, occurring during the early postoperative period in 2 and following retransplantation for graft atherosclerosis 7 years after the initial transplant in the third patient. Thus, diagnosis of DC in childhood or adolescence mandates evaluation and surveillance of family members, because this disease can progress rapidly. The favorable results of cardiac transplantation for familial DC suggest that it should be promptly considered for such patients with end-stage disease.

    View details for Web of Science ID A1989U107900014

    View details for PubMedID 2648793

  • INCREASING PERICARDIAL-EFFUSION IN CARDIAC TRANSPLANT RECIPIENTS CIRCULATION Valantine, H. A., Hunt, S. A., Gibbons, R., Billingham, M. E., Stinson, E. B., Popp, R. L. 1989; 79 (3): 603-609

    Abstract

    Although pericardial effusion after cardiac surgery is frequent and usually benign, its etiology and prognosis after cardiac transplantation are unknown. During 1 year (1985-1986), 12 of our current transplant population (total, 189) developed moderate or large pericardial effusions confirmed by two-dimensional echocardiography. These effusions occurred within 1 month of transplantation in 10 patients and at 3 months and 4.5 years in the other two. Pericardiocentesis was performed because of clinical evidence of increasing effusions in eight patients, with demonstrable hemodynamic compromise secondary to tamponade in five. Pericardial fluid was sterile in all but one. Endomyocardial biopsy at the time of increasing effusion revealed moderate acute rejection in five patients, mild rejection in three, and no rejection in four. All three patients with mild rejection had moderate acute rejection on subsequent biopsy performed within 7 days. In two of the four with no rejection, repeat biopsy within 5 days showed moderate acute rejection; in a third, moderate rejection was present on biopsy performed 14 days later. Legionella dumoffii was isolated from the pericardial fluid of the fourth patient, whose subsequent biopsies never showed rejection. Three of the 12 patients developed progressive ventricular dysfunction sufficiently severe to require retransplantation. One patient died suddenly 12 months after transplantation, and autopsy examination revealed severe coronary artery disease. Two died of sepsis within 3 months of transplantation. Intense inflammatory infiltrates and thickening of the pericardium and epicardium were characteristically present in explanted and autopsy hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989T597000015

    View details for PubMedID 2645065

  • INCREASED BETA-RECEPTOR DENSITY AND IMPROVED HEMODYNAMIC-RESPONSE TO CATECHOLAMINE STIMULATION DURING LONG-TERM METOPROLOL THERAPY IN HEART-FAILURE FROM DILATED CARDIOMYOPATHY CIRCULATION HEILBRUNN, S. M., Shah, P., Bristow, M. R., Valantine, H. A., Ginsburg, R., Fowler, M. B. 1989; 79 (3): 483-490

    Abstract

    Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.

    View details for Web of Science ID A1989T597000002

    View details for PubMedID 2537158

  • A HEMODYNAMIC AND DOPPLER ECHOCARDIOGRAPHIC STUDY OF VENTRICULAR-FUNCTION IN LONG-TERM CARDIAC ALLOGRAFT RECIPIENTS - ETIOLOGY AND PROGNOSIS OF RESTRICTIVE-CONSTRICTIVE PHYSIOLOGY CIRCULATION Valantine, H. A., Appleton, C. P., Hatle, L. K., Hunt, S. A., Billingham, M. E., Shumway, N. E., Stinson, E. B., Popp, R. L. 1989; 79 (1): 66-75

    Abstract

    Conventional hemodynamic measurements and Doppler echocardiography were used to assess ventricular physiology of the human cardiac allograft and to examine the influence of pertinent clinical factors on chronic myocardial performance. Sixty-four patients (18-55 years old; mean, 39 years) undergoing routine annual hemodynamic assessment were studied. Blood-flow velocity properties across the mitral, tricuspid, and aortic valves were analyzed from Doppler ultrasound recordings. Ten of these patients had elevated diastolic pressures associated with a sharp early diastolic dip followed by an exaggerated and abrupt rise in pressure, consistent with restrictive-constrictive ventricular physiology. Left ventricular dP/dt and stroke volume were lower in these patients compared with the other 54 patients. Doppler echocardiographic indexes of left ventricular filling and ejection in these 10 patients differed significantly. Isovolumic relaxation time and pressure half-time were shorter, peak early mitral and tricuspid flow velocities were higher, and mean aortic flow velocity and acceleration were lower. A higher rejection incidence was the only demonstrable clinical factor associated with impaired ventricular function. Doppler echocardiography may, therefore, noninvasively identify patients with hemodynamic evidence of restrictive-constrictive physiology. This abnormality occurs in approximately 15% of allograft recipients, is associated with impaired systolic performance, and may be related to rejection incidence.

    View details for Web of Science ID A1989R718300009

    View details for PubMedID 2642757

  • CARDIAC TRANSPLANTATION INTENSIVE CARE MEDICINE Valantine, H. A., Schroeder, J. S. 1989; 15 (5): 283-289

    Abstract

    Cardiac transplantation is now an accepted therapeutic option for patients with end-stage myocardial failure. Provided donor and recipient are appropriately selected and adequately matched, expected survival rates at one and five years are 85% and 65%, respectively. Two major challenges are encountered in clinical heart transplantation. The first is monitoring immunosuppression for adequate prevention of acute rejection and surveillance for side effects. The endomyocardial biopsy remains the gold standard for rejection surveillance, but since it is an invasive procedure which can only be performed at arbitrary time intervals, the search for non-invasive methods continues. The approach to immunosuppression currently practised by most centers is that of combination drug therapy, which allows low doses with decreased potential for side effects. At Stanford, immunosuppression is usually initiated with OKT3, corticosteroids, and cyclosporine, and maintained with a combination of steroids, cyclosporine, and azathioprine. The most frequently encountered complications include bacterial and opportunistic infections, cyclosporine nephrotoxicity, and malignancy. The second challenge is accelerated coronary disease, which has emerged as the major factor limiting long-term survival. It is usually clinically silent and often presents with sudden death, acute myocardial infarction, or progressive unexplained graft failure. Coronary arteriography is currently the only method for premorbid diagnosis, and retransplantation the only effective therapy.

    View details for Web of Science ID A1989AL50400001

    View details for PubMedID 2671079

  • Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation Valantine, H. A., Fowler, M. B., Hunt, S. A., NAASZ, C., Hatle, L. K., Billingham, M. E., Stinson, E. B., Popp, R. L. 1987; 76 (5): V86-92

    Abstract

    Changes in left ventricular filling and ejection as potential markers of cardiac allograft rejection were evaluated by serial Doppler echocardiography performed in 23 normal volunteers and within 24 hr of endomyocardial biopsy in 22 patients aged 14 to 53 years (mean 37). Peak aortic velocity, left ventricular ejection time index (ETI), isovolumic relaxation time (IVRT), mitral valve pressure half-time (PHT), peak early mitral flow velocity (M1), and velocity following donor atrial systole (M2) were measured without prior knowledge of endomyocardial biopsy findings. Biopsy specimens were graded histologically as: no rejection, mild rejection (cellular infiltrate), and moderate rejection (myocyte necrosis). A total of 120 biopsy-correlated Doppler echocardiographic studies were performed during 16 weeks after cardiac transplantation. Heart rate and mean arterial pressure were significantly higher in transplant recipients than in normal subjects. IVRT and PHT were significantly longer, while M1 and M2 were similar. Peak aortic velocity was higher in normal subjects than in transplant recipients, while ejection time was similar. Rejection of increasing severity was associated with a progressive shortening of IVRT and PHT and with an increase in M1 (p less than .0005 for all comparisons). Peak aortic velocity and ejection time index did not change significantly with rejection. These data indicate that acute cardiac rejection is accompanied by alteration in left ventricular filling dynamics detectable by Doppler echocardiography, without measureable changes in systolic function. These changes may provide noninvasive markers for surveillance of rejection.

    View details for PubMedID 3311461

  • CARDIAC TRANSPLANTATION IN CHILDREN AND ADOLESCENTS CIRCULATION Starnes, V. A., Stinson, E. B., Oyer, P. E., Valantine, H., Baldwin, J. C., Hunt, S. A., Shumway, N. E. 1987; 76 (5): 43-49

    View details for Web of Science ID A1987L004500008

  • CHANGES IN DOPPLER ECHOCARDIOGRAPHIC INDEXES OF LEFT-VENTRICULAR FUNCTION AS POTENTIAL MARKERS OF ACUTE CARDIAC REJECTION CIRCULATION Valantine, H. A., Fowler, M. B., Hunt, S. A., NAASZ, C., Hatle, L. K., Billingham, M. E., Stinson, E. B., Popp, R. L. 1987; 76 (5): 86-92

    View details for Web of Science ID A1987L004500016

  • Cardiac sarcoidosis: response to steroids and transplantation. journal of heart transplantation Valantine, H. A., Tazelaar, H. D., Macoviak, J., MULLIN, A. V., Hunt, S. A., Fowler, M. B., Billingham, M. E., Schroeder, J. S. 1987; 6 (4): 244-250

    Abstract

    From 1976 to 1986, six cases of cardiac sarcoidosis have been documented by myocardial biopsy in three of five instances; on examination of the explanted heart after transplantation in two, and at autopsy in one patient. Right ventricular end-diastolic pressure was elevated in all four patients with right ventricular involvement with sarcoidosis. Of three patients treated with steroids, improvement in ventricular function and decrease in arrhythmia occurred in two, whereas failure to respond led to transplantation in the other patient. Two further patients have undergone heart transplantation, one for resistant ventricular arrhythmia and the other for congestive heart failure. No recurrence of sarcoidosis has occurred in the grafts. Because two of five patients had sarcoidosis diagnosed on gross examination, a negative endomyocardial biopsy does not exclude the diagnosis of myocardial sarcoidosis, which should therefore be pursued in the setting of unexplained heart failure, conduction abnormalities, and ventricular arrhythmia, particularly when right ventricular end-diastolic pressure is raised. Steroids may result in improvement in some patients even in the presence of severe morphological damage. Heart transplantation may be performed without increased risk of recurrence of sarcoidosis.

    View details for PubMedID 3312535

  • INFLUENCE OF RECIPIENT ATRIAL CONTRACTION ON LEFT-VENTRICULAR FILLING DYNAMICS OF THE TRANSPLANTED HEART ASSESSED BY DOPPLER ECHOCARDIOGRAPHY AMERICAN JOURNAL OF CARDIOLOGY Valantine, H. A., Appleton, C. P., Hatle, L. K., Hunt, S. A., Stinson, E. B., Popp, R. L. 1987; 59 (12): 1159-1163

    Abstract

    Recipient atrial remnants retain electrical and mechanical activity after orthotopic cardiac transplantation. This study investigated the influence of recipient atrial contraction timing on Doppler ultrasound mitral flow velocity curves, isovolumic relaxation time, peak early mitral flow velocity (M1), mitral valve pressure half-time and peak mitral flow velocity due to atrial systole (M2). Clearly identifiable recipient atrial electrical activity (P waves) was present in 7 of 10 patients studied early postoperatively 2 to 6 months (mean 2.5) (early group) and in 20 of 24 patients seen 1 to 11 years (mean 3) after transplantation (late group). Median age and gender distribution were similar in both groups. For analysis of its influence on isovolumic relaxation time, pressure half-time and M1, recipient atrial contraction was classified by its position in the cardiac cycle as early systole, late systole or diastole. For analysis of M2, it was classified as early diastole, late diastole or systole. Compared with its occurrence in diastole, recipient atrial contraction in late systole was associated with a shorter isovolumic relaxation time, shorter pressure half-time and higher M1. In early systole it was associated with a longer pressure half-time and lower M1 than in diastole; isovolumic relaxation time was unchanged. Recipient atrial contraction in early diastole resulted in a lower M2 than in systole, whereas simultaneous contraction of recipient and donor atria in late diastole resulted in an increase in M2. These results indicate that the timing of recipient atrial contraction and relaxation significantly influences left ventricular filling dynamics.

    View details for Web of Science ID A1987H365700028

    View details for PubMedID 3554953

  • DOPPLER ECHOCARDIOGRAPHIC INDEXES OF DIASTOLIC FUNCTION AS MARKERS OF ACUTE CARDIAC REJECTION TRANSPLANTATION PROCEEDINGS Valantine, H., Fowler, M., Hatle, L., Hunt, S., Billingham, M., STINSON, E., Popp, R. 1987; 19 (1): 2556-2559

    View details for Web of Science ID A1987G101500265

    View details for PubMedID 3547937