Bio

Clinical Focus


  • Cardiovascular Medicine
  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Assistant Professor of Medicine, Cardiovascular Medicine (2011 - Present)
  • Instructor, Cardiovascular Medicine, Stanford University (2008 - 2011)

Honors & Awards


  • Clinical Research Program Award, American Heart Association (2010)
  • Transplant Registry Early Career Award, International Society for Heart and Lung Transplantation (2010)
  • Career Development Award (K23), National Institutes of Health (2009)
  • Beginning Grant-in-Aid, American Heart Association (2008)
  • Fellow, American College of Cardiology (2008)
  • Postdoctoral Research Fellowship Award, American Heart Association (2006)
  • Julius R. Krevans Award for Clinical Excellence, University of California San Francisco (2001)
  • House Officer of the Year Award, San Francisco General Hospital (2001)

Professional Education


  • Board Certification: Advanced Heart Failure and Transplant Cardiology, American Board of Internal Medicine (2010)
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2006)
  • Fellowship:UCSF Dean's Office Postdoctoral Education (2006) CA
  • Residency:UCSF-Graduate Medical Education (2003) CA
  • Medical Education:Harvard Medical School - Children's Hospital (2000) MA
  • MAS, Univ of California San Francisco, Clinical Research (2008)
  • Fellowship, Univ of California San Francisco, Heart Transplant, Heart Failure, (2006)
  • Fellowship, Univ of California San Francisco, Echocardiography (Level III) (2006)
  • Fellowship, Univ of California San Francisco, General Cardiology (2005)
  • Residency, Univ of California San Francisco, Internal Medicine (2003)
  • MD, Harvard University, Medicine (2000)
  • BSc with Honors and Distinction, Stanford University, Biology (1995)

Research & Scholarship

Current Research and Scholarly Interests


Dr. Khush’s clinical research interests include the evaluation of donors and recipients for heart transplantation; mechanisms of adverse outcomes after heart transplantation, including coronary allograft vasculopathy and antibody-mediated rejection; the treatment of acute decompensated heart failure; and the cardiorenal syndrome.

Clinical Trials


  • 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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  • Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation Recruiting

    All people who have a heart transplant are at risk for developing cardiac allograft vasculopathy (CAV). CAV means narrowing of the heart transplant vessels, which is associated with poor heart transplant function. People who develop antibodies after transplant have a higher risk of developing CAV. Infections, high cholesterol, and rejection also increase the risk of developing CAV. People who develop CAV usually have to receive another transplant. The purpose of this research study is to see if a study drug called Rituximab prevents CAV. Rituximab destroys certain types of white blood cells called B cells. B cells are important cells in the immune system that help the body fight infection by producing substances called antibodies. B cells and the antibodies they produce are also involved in some kinds of rejection after organ transplantation. Rituximab decreases the number of B cells in the blood and other tissues. The goal of this study is to determine if decreasing B cells with Rituximab can prevent injury to the transplanted heart.

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  • Genome Transplant Dynamics: Non-invasive Sequencing-based Diagnosis of Rejection 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.

    View full details

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • 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

  • 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

  • Donor Predictors of Allograft Use and Recipient Outcomes After Heart Transplantation CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., John Nguyen, J., Zaroff, J. G., Goldstein, B. A. 2013; 6 (2): 300-309

    Abstract

    Despite a national organ-donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft nonuse, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.We studied a cohort of 1872 potential organ donors managed by the California Transplant Donor Network from 2001 to 2008. Forty-five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft nonuse included age >50 years, female sex, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay, left-ventricular dysfunction and regional wall motion abnormalities, and left-ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes mellitus was predictive of increased recipient mortality.Whereas there are many donor predictors of allograft discard in the current era, these characteristics seem to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.

    View details for DOI 10.1161/CIRCHEARTFAILURE.112.000165

    View details for Web of Science ID 000331381200026

  • Pregnancy-Related Human Leukocyte Antigen Sensitization Leading to Cardiac Allograft Vasculopathy and Graft Failure in a Heart Transplant Recipient: A Case Report TRANSPLANTATION PROCEEDINGS Ginwalla, M., Pando, M. J., Khush, K. K. 2013; 45 (2): 800-802

    Abstract

    In this report, we present a heart transplant recipient who developed cross-reactive paternal and donor-specific human leukocyte antigen (HLA) class II antibodies during pregnancy, leading to accelerated cardiac allograft vasculopathy and severe allograft dysfunction 17 years after transplantation. This resulted in acute heart failure and ventricular arrhythmias requiring repeat heart transplantation.

    View details for DOI 10.1016/j.transproceed.2012.10.038

    View details for Web of Science ID 000316772500058

    View details for PubMedID 23498823

  • Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors AMERICAN JOURNAL OF TRANSPLANTATION Khush, K. K., Pawlikowska, L., Menza, R. L., Goldstein, B. A., Hayden, V., Nguyen, J., Kim, H., Poon, A., Sapru, A., Matthay, M. A., Kwok, P. Y., Young, W. L., Baxter-Lowe, L. A., Zaroff, J. G. 2012; 12 (12): 3377-3386

    Abstract

    Prior studies have demonstrated associations between beta-adrenergic receptor (?AR) polymorphisms and left ventricular dysfunction-an important cause of allograft nonutilization for transplantation. We hypothesized that ?AR polymorphisms predispose donor hearts to LV dysfunction after brain death. A total of 1043 organ donors managed from 2001-2006 were initially studied. The following ?AR single nucleotide polymorphisms were genotyped: ?1AR 1165C/G (Arg389Gly), ?1AR 145A/G (Ser49Gly), ?2AR 46G/A (Gly16Arg) and ?2AR 79C/G (Gln27Glu). In multivariable regression analyses, the ?2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction <50%. The ?1AR1165 and ?2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 ?g/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between ?AR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. ?AR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts.

    View details for DOI 10.1111/j.1600-6143.2012.04266.x

    View details for Web of Science ID 000311854800022

    View details for PubMedID 22994654

  • The 4G/4G Genotype of the PAI-1 (Serpine-1) 4G/5G Polymorphism Is Associated With Decreased Lung Allograft Utilization AMERICAN JOURNAL OF TRANSPLANTATION Sapru, A., Zaroff, J. G., Pawlikowska, L., Liu, K. D., Khush, K. K., Baxter-Lowe, L. A., Hayden, V., Menza, R. L., Convery, M., Lo, V., Poon, A., Kim, H., Young, W. L., Kukreja, J., Matthay, M. A. 2012; 12 (7): 1848-1854

    Abstract

    Widespread thrombi are found among donor lungs rejected for transplantation. The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene impacts transcription and the 4G allele is associated with increased PAI-1 levels. We hypothesized that the 4G/4G genotype would be associated with decreased lung graft utilization, potentially because of worse oxygenation in the donor. We genotyped donors managed by the California Transplant Donor Network from 2001 to 2008 for the 4G/5G polymorphism in the PAI-1 gene. Non-Hispanic donors from 2001 to 2005 defined the discovery cohort (n = 519), whereas donors from 2006 to 2008 defined the validation cohort (n = 369). We found, that the odds of successful lung utilization among Non-Hispanic white donors were lower among donors with the 4G/4G genotype compared to those without this genotype in both the discovery (OR = 0.55, 95% CI = 0.3-0.9, p = 0.02) and validation (OR = 0.5, 95% CI = 0.3-0.9, p = 0.03) cohorts. This relationship was independent of age, gender, cause of death, drug use and history of smoking. Donors with the 4G/4G genotype also had a lower PaO2/FiO2 ratio (p = 0.03) and fewer donors with the 4G/4G genotype achieved the threshold PaO2/FiO2 ratio ? 300 (p = 0.05). These findings suggest a role for impaired fibrinolysis resulting in worse gas exchange and decreased donor utilization.

    View details for DOI 10.1111/j.1600-6143.2012.03996.x

    View details for Web of Science ID 000305789400023

    View details for PubMedID 22390401

  • Electrocardiographic Characteristics of Potential Organ Donors and Associations With Cardiac Allograft Use CIRCULATION-HEART FAILURE Khush, K. K., Menza, R., Nguyen, J., Goldstein, B. A., Zaroff, J. G., Drew, B. J. 2012; 5 (4): 475-483

    Abstract

    Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.A single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.

    View details for DOI 10.1161/CIRCHEARTFAILURE.112.968388

    View details for Web of Science ID 000313578100018

    View details for PubMedID 22615333

  • Relation of Improvement in Estimated Glomerular Filtration Rate With Atorvastatin to Reductions in Hospitalizations for Heart Failure (from the Treating to New Targets [TNT] Study) AMERICAN JOURNAL OF CARDIOLOGY Ho, J. E., Waters, D. D., Kean, A., Wilson, D. J., DeMicco, D. A., Breazna, A., Wun, C., Deedwania, P. C., Khush, K. K. 2012; 109 (12): 1761-1766

    Abstract

    Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

    View details for DOI 10.1016/j.amjcard.2012.02.019

    View details for Web of Science ID 000305729200014

    View details for PubMedID 22459310

  • Influence of donor and recipient sex mismatch on heart transplant outcomes: Analysis of the International Society for Heart and Lung Transplantation Registry JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Kubo, J. T., Desai, M. 2012; 31 (5): 459-466

    Abstract

    Prior studies have presented contradictory results after analyzing associations between donor and recipient sex on survival after heart transplantation and causes of death such as acute rejection (AR) and cardiac allograft vasculopathy (CAV). We used the International Society for Heart and Lung Transplantation (ISHLT) Registry, the largest repository of heart transplant outcomes worldwide, to comprehensively address these questions.We studied 60,584 adult recipients of heart transplants performed between 1990 and 2008. Outcomes of interest were overall survival, death-censored allograft survival, AR, and CAV, which were studied using regression models. To assess whether donor/recipient sex mismatch affected outcomes, the experience of male recipients with female vs male donors was compared with that of female recipients with female vs male donors through inclusion of an interaction term between donor and recipient sex.Significant differences were observed between male and female recipients in overall survival and death-censored allograft survival for female vs male donors. Male recipients of female allografts had a 10% increase in adjusted mortality relative to male recipients of male allografts, whereas female recipients of female allografts had a 10% decrease in adjusted mortality relative to female recipients of male allografts (p < 0.0001). Findings were similar for death-censored allograft survival. Differences in the effect of donor sex on AR or CAV between male and female recipients were not significant.Analysis of the ISHLT data set has demonstrated a strong association between donor/recipient sex mismatch and reduced survival after heart transplantation.

    View details for DOI 10.1016/j.healun.2012.02.005

    View details for Web of Science ID 000302756700005

    View details for PubMedID 22418079

  • 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

  • Single-nucleotide polymorphisms in the beta-adrenergic receptor genes are associated with lung allograft utilization JOURNAL OF HEART AND LUNG TRANSPLANTATION Sapru, A., Pawlikowska, L., Liu, K. D., Khush, K. K., Ann-Baxter-Lowe, L., Hayden, V., Menza, R. L., Convery, M., Poon, A., Landeck, M., Zaroff, J. G., Matthay, M. A. 2011; 30 (2): 211-217

    Abstract

    Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of ?-adrenergic receptors (?ARs). Single-nucleotide polymorphisms (SNPs) in ?AR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in ?AR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.Nine hundred fifty-one organ donors were genotyped for 4 amino-acid-coding SNPs in the ?AR genes. Lung allograft utilization was compared among donors stratified by genotypes.Utilization of donor lung allografts was 55% vs 35% (p = 0.02) among donors with GG vs AA/AG genotypes of the Ser49Gly SNP, 39% vs 32% (p = 0.04) with GG vs AA/AG genotype of Gly16Arg SNP and 37% vs 32% (p = 0.1) with CC vs GC/GG genotype of the Arg389Gly SNP. In the combined analysis, donors carrying 0 or 1 associated genotype had a utilization rate of 33%, whereas donors carrying 2 or 3 associated genotypes had utilization rates of 44% and 58%, respectively (p = 0.008). There was a stepwise decrease in chest radiograph infiltrates and an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO(2)/FIO(2)) with an increasing number of these associated genotypes.Genetic variants in the ?AR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests that ?AR agonists may have a role in donor management.

    View details for DOI 10.1016/j.healun.2010.08.011

    View details for Web of Science ID 000286545200015

    View details for PubMedID 20869266

  • 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

  • Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: Analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database AMERICAN HEART JOURNAL Khush, K. K., Tasissa, G., Butler, J., McGlothlin, D., De Marco, T. 2009; 157 (6): 1026-1034

    Abstract

    Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressure > or = 25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > or = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure.This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality.Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P < .001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups.Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

    View details for DOI 10.1016/j.ahj.2009.02.022

    View details for Web of Science ID 000266669500010

    View details for PubMedID 19464413

  • 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

  • Association of African American race with elevated pulmonary artery Diastolic pressure: Data from the heart and soul study JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Kush, K. K., Shah, S. J., Ristow, B., De Marco, T., Whooley, M. A., Schiller, N. B. 2007; 20 (11): 1307-1313

    Abstract

    Whether increased severity of heart failure in African Americans is a result of differences in cardiac physiology is uncertain. The end-diastolic pulmonary regurgitation (EDPR) gradient is associated with abnormal cardiac physiology. We hypothesized that African American race is associated with an elevated EDPR gradient that may partially predispose African Americans to heart failure.The Heart and Soul Study prospectively assessed the EDPR gradient in 480 patients with coronary disease. We used multivariable linear regression to investigate the independent association of African American race with EDPR gradient.Compared with 393 non-African Americans, the 87 African Americans had similar indices of left ventricular systolic and diastolic function, left ventricular mass index, mitral regurgitation, peak tricuspid regurgitation gradient, and pulmonary velocity time integral. However, the EDPR gradient was significantly higher in African Americans (4.2 +/- 3.3 mm Hg) than in Caucasians (3.1 +/- 2.5 mm Hg) or other racial groups (3.5 +/- 2.7 mm Hg) (P = .008). In a multivariable model, African American race was a significant predictor of elevated EDPR gradient (beta coefficient 0.75, P = .03).African American race is independently associated with an elevated EDPR gradient in patients with coronary artery disease.

    View details for DOI 10.1016/j.ccho.2007.03.011

    View details for Web of Science ID 000251062300012

    View details for PubMedID 17588717

  • Donor cardiac troponin I levels do not predict recipient survival after cardiac transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Khush, K. K., Menza, R. L., Babcock, W. D., Zaroff, J. G. 2007; 26 (10): 1048-1053

    Abstract

    Serum levels of cardiac troponin I (cTnI) are frequently measured in the evaluation of potential heart donors. However, the utility of cTnI levels for predicting recipient outcomes remains controversial. This study was performed to determine whether donor cardiac cTnI levels exceeding 1.0 microg/liter are associated with adverse recipient outcomes.All donors managed by the California Transplant Donor Network between January 2001 and July 2002 with consent for donor evaluation and at least 1 measured cTnI level were included in the study if 1-year recipient mortality data were available. Each study subject was classified as having elevated cTnI if any level exceeded 1.0 microg/liter. Donor variables, recipient risk of 30-day and 1-year mortality, and recipient need for mechanical circulatory support were compared between the 2 groups.A total of 263 potential donors were evaluated, and 98 had elevated cTnI levels. Of these potential donors, 139 were accepted for transplantation. The cTnI levels were normal in 96 and elevated in 43. Most donors (77%) with elevated cTnI levels had levels of less than 10 microg/liter. Donor cardiopulmonary resuscitation was associated with cTnI elevations. Donors with elevated cTnI levels did not require higher doses of inotropic drugs before transplantation and had similar hemodynamic profiles compared with donors with normal cTnI levels. Although there was a trend towards longer post-transplant hospitalization in recipients of grafts from donors with elevated cTnI levels (17 days vs 15 days, p = 0.044), there was no significant difference in the recipient need for mechanical circulatory support or 30-day and 1-year mortality between the 2 groups.In this study, a modestly elevated donor cTnI was not associated with a higher risk of recipient mortality or need for post-transplant mechanical circulatory support. A potential donor heart should not be discarded solely because the troponin level is elevated.

    View details for DOI 10.1016/j.healun.2007.07.026

    View details for Web of Science ID 000250268900013

    View details for PubMedID 17919626

  • Effect of high-dose atorvastatin on hospitalizations for heart failure - Subgroup analysis of the treating to new targets (TNT) study CIRCULATION Khush, K. K., Waters, D. D., Bittner, V., Deedwania, P. C., Kastelein, J. J., Lewis, S. J., Wenger, N. K. 2007; 115 (5): 576-583

    Abstract

    Statins reduce the rate of major cardiovascular events in high-risk patients, but their potential benefit as treatment for heart failure (HF) is less clear.Patients (n=10,001) with stable coronary disease were randomized to treatment with atorvastatin 80 or 10 mg/d and followed up for a median of 4.9 years. A history of HF was present in 7.8% of patients. A known ejection fraction <30% and advanced HF were exclusion criteria for the study. A predefined secondary end point of the study was hospitalization for HF. The incidence of hospitalization for HF was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The treatment effect of the higher dose was more marked in patients with a history of HF: 17.3% versus 10.6% in the 10- and 80-mg arms, respectively (hazard ratio, 0.59; 95% confidence interval, 0.4 to 0.88; P=0.009). Among patients without a history of HF, the rates of hospitalization for HF were much lower: 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34). Only one third of patients hospitalized for HF had evidence of preceding angina or myocardial infarction during the study period. Blood pressure was almost identical during follow-up in the treatment groups.Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF. In a post hoc analysis, this benefit was observed only in patients with a history of HF. The mechanism accounting for this benefit is unlikely to be due primarily to a reduction in interim coronary events or differences in blood pressure.

    View details for DOI 10.1161/CIRCULATIONAHA.106.625574

    View details for Web of Science ID 000244000800009

    View details for PubMedID 17261662

  • Effects of statin therapy on the development and progression of heart failure: Mechanisms and clinical trials JOURNAL OF CARDIAC FAILURE Khush, K. K., Waters, D. D. 2006; 12 (8): 664-674

    Abstract

    Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction.This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF.Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.

    View details for DOI 10.1016/j.cardfail.2006.05.003

    View details for Web of Science ID 000241534400013

    View details for PubMedID 17045188

  • Nesiritide acutely increases pulmonary and systemic levels of nitric oxide in patients with pulmonary hypertension JOURNAL OF CARDIAC FAILURE Khush, K. K., De Marco, T., Vakharia, K. T., Harmon, C., Fineman, J. R., Chatterjee, K., Michaels, A. D. 2006; 12 (7): 507-513

    Abstract

    Pulmonary hypertension (PH) is characterized by decreased pulmonary vascular expression of nitric oxide (NOx), a vasodilator that increases levels of smooth muscle cyclic guanosine monophosphate (cGMP). This study investigated mechanisms by which the vasodilator B-type natriuretic peptide (BNP) affects the systemic and pulmonary vasculature in PH patients.Twenty PH patients with mean pulmonary artery (PA) pressure > 25 mm Hg were enrolled. Ten had precapillary (pulmonary capillary wedge pressure [PCWP] < or = 15 mm Hg) and 10 had postcapillary (PCWP > 15 mm Hg) PH. Right heart catheterization was performed before and 30 minutes after intravenous nesiritide infusion. NOx and cGMP levels from the PA and systemic (AO) arteries were obtained before and after nesiritide infusion. The postcapillary PH patients demonstrated significantly reduced pulmonary vascular resistance after nesiritide; there was no change in the precapillary PH cohort. NOx levels increased significantly in both AO (P < .0001) and PA (P = .0093), as did cGMP levels (P < .0001). There was a higher increase in NOx levels from the pulmonary arteries in precapillary PH patients compared to postcapillary PH patients (P = .020).In PH patients, nesiritide infusion significantly increases NOx levels, suggesting a novel mechanism for its vasodilatory effects. These responses may differ between pre- and postcapillary PH patients.

    View details for DOI 10.1016/j.cardfail.2006.05.004

    View details for Web of Science ID 000240708700003

    View details for PubMedID 16952783

  • Obese patients have lower B-type and atrial natriuretic peptide levels compared with nonobese. Congestive heart failure (Greenwich, Conn.) Khush, K. K., Gerber, I. L., Mckeown, B., Marcus, G., Vessey, J., Foster, E., Chatterjee, K., Michaels, A. D. 2006; 12 (2): 85-90

    Abstract

    Obesity is a risk factor for the development of heart failure, but the causal mechanism remains unclear. Impaired production or enhanced clearance of natriuretic peptides, which regulate sodium balance and sympathetic activation, may play an important role. The authors investigated the relationship of plasma B-type natriuretic peptide and atrial natriuretic peptide levels to body mass index in 100 patients referred for left heart catheterization. Hemodynamic and echocardiographic data were obtained for all study participants. Atrial natriuretic peptide and B-type natriuretic peptide levels were compared in obese (body mass index > or = 30 kg/m2) and nonobese (body mass index < 30 kg/m2) subjects. Multivariate regression analyses were performed, adjusting for clinical and hemodynamic covariates. Obese patients had significantly lower B-type natriuretic peptide (p = 0.03) and atrial natriuretic peptide (p = 0.04) levels compared with nonobese. Multivariate analysis revealed lower B-type natriuretic peptide (p = 0.095) and atrial natriuretic peptide (p = 0.007) levels in obese patients while controlling for age, sex, left ventricular end-diastolic pressure, and left ventricular ejection fraction. Low levels of circulating natriuretic peptides are thus associated with obesity and may contribute to the development of heart failure.

    View details for PubMedID 16596042

  • The history of the coronary care unit CANADIAN JOURNAL OF CARDIOLOGY Khush, K. K., Rapaport, E., Waters, D. 2005; 21 (12): 1041-1045

    Abstract

    The first coronary care units were established in the early 1960s in an attempt to reduce mortality from acute myocardial infarction. Pioneering cardiologists recognized the threat of death due to malignant arrhythmias in the postinfarction setting, and developed techniques for successful external defibrillation. The ability to abort sudden death led to continuous monitoring of the cardiac rhythm and an organized system of cardiopulmonary resuscitation, incorporating external defibrillation with cardiac drugs and specialized equipment. Arrhythmia monitoring and cardiopulmonary resuscitation could be performed by trained nursing staff, which eliminated delays in treatment and significantly reduced mortality. These early triumphs in aborting sudden death led to the development of techniques to treat cardiogenic shock, limit infarct size and initiate prehospital coronary care, all of which laid the foundation for the current era of interventional cardiology.

    View details for Web of Science ID 000232871000009

    View details for PubMedID 16234887

  • A full house: complications from an uncorrected patent ductus arteriosus. Current cardiology reports Khush, K. K., Randhawa, R., Israel, E. 2005; 7 (4): 310-313

    Abstract

    True aneurysms of the pulmonary artery are rare, and are most often due to pulmonary hypertension arising from congenital heart defects. We report the case of a 40-year-old man with an uncorrected patent ductus arteriosus who presented with pulmonary infarction and pneumonia, and subsequently died of cardiac arrest. Autopsy revealed a large pulmonary artery aneurysm, in situ pulmonary artery thrombosis complicated by pulmonary infarction, pulmonary artery dissection, and cardiac tamponade. Although each of these complications is rare in and of itself, this case demonstrates the entire spectrum of complications from a single uncorrected congenital cardiac anomaly.

    View details for PubMedID 15987630

  • Age and aneurysm position predict patterns of left ventricular dysfunction after subarachnoid hemorrhage JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Khush, K., Kopelnik, A., Tung, P., Banki, N., Dae, M., Lawton, M., Smith, W., Drew, B., Foster, E., Zaroff, J. 2005; 18 (2): 168-174

    Abstract

    Cardiac injury, including left ventricular dysfunction, frequently occurs in patients with subarachnoid hemorrhage. Patterns of left ventricular dysfunction often do not follow coronary artery distributions, and may correlate with myocardial sympathetic innervation. Left ventricular dysfunction of the anterior and anteroseptal walls that spares the apex is unusual for patients with myocardial infarction and may represent a neurally mediated pattern of injury. We performed serial echocardiography on 225 patients with subarachnoid hemorrhage and classified those with regional wall-motion abnormalities as following either an apex-sparing (AS) or apex-affected (AA) pattern. Wall-motion abnormalities were found in 61 of 225 patients studied (27%). The AS pattern was found in 49% of these patients. Younger age and anterior aneurysm position were independent predictors of this AS pattern. Both patterns of wall-motion abnormalities appear to be transient, reversible phenomena. The AS pattern may represent a unique form of neurally mediated cardiac injury.

    View details for DOI 10.1016/j.echo.2004.08.045

    View details for Web of Science ID 000226972000011

    View details for PubMedID 15682055

  • Lessons prom the PROVE-IT trial - Higher dose of potent statin better for high-risk patients CLEVELAND CLINIC JOURNAL OF MEDICINE Khush, K. K., Waters, D. 2004; 71 (8): 609-616

    Abstract

    The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE-IT/TIMI-22) showed that in patients with acute coronary syndromes, aggressive lipid-lowering using atorvastatin 80 mg/day provided greater protection against death or major cardiovascular events than did moderate lipid-lowering using pravastatin 40 mg/day. Lowering the low-density lipoprotein cholesterol level to approximately 62 mg/dL with atorvastatin resulted in a 16% reduction in cardiovascular end points.

    View details for Web of Science ID 000223379600003

    View details for PubMedID 15449756

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