William Hiesinger

All Publications

• Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Tashima, Y., Shad, R., Cheng, P., Wirka, R., Churovich, S., Nakamura, K., Yokoyama, N., Cui, J. Z., Iosef, C., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2020: ATVBAHA120314670

  Abstract

  OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF (transforming growth factor)-beta-responsive genes correlated with SMC modulation in mouse and human data sets.CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

  View details for DOI 10.1161/ATVBAHA.120.314670

  View details for PubMedID 32698686

• Donors after circulatory death heart trial. Future cardiology Shudo, Y., Benjamin-Addy, R., Koyano, T. K., Hiesinger, W., MacArthur, J. W., Woo, Y. J. 2020

  Abstract

  Orthotopic heart transplantation is the gold standard treatment for end-stage heart failure. However, the persistent shortage of available donor organs has resulted in an ever-increasing waitlist and longer waiting periods for transplantation. On the contrary, increasing the number of heart transplants by preserving extended criteria donors and donation after circulatory deathhearts with the Organ Care System (OCS) Heart System has the potential to provide the goldstandard, life-saving treatment to patients with end-stage heart failure. The objective of the Donation After Circulatory Death Heart Trial is to evaluate the effectiveness of the OCS Heart System to preserve and assess hearts donated after circulatory death for transplantation to increase the pool of donor hearts available for transplantation, which can potentially provide patients with end-stage heart failure with the life-saving treatment. Clinical Trial Registration: NCT03831048 (ClinicalTrials.gov).

  View details for DOI 10.2217/fca-2020-0070

  View details for PubMedID 32628044

• Open-Chest Ablation of Incessant Ventricular Tachycardia During Left Ventricular Assist Device Implantation. JACC. Clinical electrophysiology Shah, R. L., Hiesinger, W., Badhwar, N. 2020; 6 (7): 901–2

  View details for DOI 10.1016/j.jacep.2020.03.012

  View details for PubMedID 32703578

• Novel Methods for Donor and Recipient Size Matching in Heart Transplantation Miller, R. J., Hedman, K., Vrotec, B., Ingelsson, E., Heidenreich, P., Hiesinger, W., Oyer, P., Teuteberg, J., Haddad, F. ELSEVIER SCIENCE INC. 2020: S50

  View details for Web of Science ID 000522637200100

• Severe Primary Graft Dysfunction: Impact of the New UNOS Heart Allocation System Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Tremblay-Gravel, M., Alexander, K. M., Kawana, M., Hiesinger, W., Teuteberg, J. J., Khush, K. K. ELSEVIER SCIENCE INC. 2020: S173–S174

  View details for Web of Science ID 000522637201101

• Thoracotomy Approach is Associated with Less Right Ventricular Failure and Shorter Length of Stay: An Intermacs Analysis of Nearly 1000 Implants via Thoracotomy Lampert, B. C., Teuteberg, J. J., Mokadam, N. A., Myers, S., Hiesinger, W., Woo, Y., Kirklin, J. K., Whitson, B. A. ELSEVIER SCIENCE INC. 2020: S121–S122

  View details for Web of Science ID 000522637200275

• Take the First Available Heart: Use of Higher-Risk Donors in Recipients with Pre-Transplant Mechanical Circulatory Support Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Feng, K. Y., Hiesinger, W., Teuteberg, J. J., Khush, K. K. ELSEVIER SCIENCE INC. 2020: S42

  View details for Web of Science ID 000522637200080

• To SIPAT or Not to SIPAT: The Stanford Integrated Psychosocial Assessment for Transplant Moayedi, Y., Yang, W. A., Mueller, B., Fan, C. S., Purewal, S., Ramirez, N., Han, J., Henricksen, E. J., Lee, R., Duclos, S., Lyapin, A., Wainwright, R., Hiesinger, W., Ross, H. J., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2020: S39–S40

  View details for Web of Science ID 000522637200073

• More Money and More Miles: The Hidden Costs of Donor Procurement with the New Heart Allocation System Lampert, B. C., Ravichandran, A. K., Teuteberg, J. J., Patel, C., Shah, P., Hiesinger, W., Campbell, D. A., Slivnick, J., Hasan, A. K., Salerno, C., Thomas, J., Seasor, E., Schroder, J. N., Ganapathi, A. M., Whitson, B. A., Mokadam, N. A. ELSEVIER SCIENCE INC. 2020: S175

  View details for Web of Science ID 000522637201104

• Moving towards an Induction-Free Era: Short-Term Renal and Infectious Outcomes Moayedi, Y., Henricksen, E. J., Lafreniere-Roula, M., Fan, C. S., Multani, A., Puing, A., Couture-Cosette, A., Quintero, O., Han, J., Feng, K. Y., Lee, R., Duclos, S., Lyapin, A., Purewal, S., Subramanian, A., Ross, H. J., Hiesinger, W., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2020: S274–S275

  View details for Web of Science ID 000522637202019

• More Frequent Hospitalizations and Worse Quality of Life with Late Right Heart Failure Compared to Early Right Heart Failure after Left Ventricular Assist as Destination Therapy Teuteberg, J., Hiesinger, W., Cowger, J. A., Rich, J., Najjar, S. S., Jacoski, M., Markham, D., Rogers, J. ELSEVIER SCIENCE INC. 2020: S91–S92

  View details for Web of Science ID 000522637200201

• A Decade of Single Center HeartWare (TM) HVAD (TM) Experience Guenther, S. P., Fong, R., Abovwe, N., Shad, R., MacArthur, J. W., Teuteberg, J., Woo, Y., Shudo, Y., Hiesinger, W. ELSEVIER SCIENCE INC. 2020: S339

  View details for Web of Science ID 000522637202190

• Use of direct oral anticoagulants after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Henricksen, E. J., Tremblay-Gravel, M., Moayedi, Y., Yang, W., Lee, R., Ross, H. J., Hiesinger, W., Teuteberg, J. J., Khush, K. K. 2020

  View details for DOI 10.1016/j.healun.2019.12.007

  View details for PubMedID 32007373

• Use of patient-specific computational models for optimization of aortic insufficiency after implantation of left ventricular assist device. The Journal of thoracic and cardiovascular surgery Kasinpila, P., Kong, S., Fong, R., Shad, R., Kaiser, A. D., Marsden, A. L., Woo, Y. J., Hiesinger, W. 2020

  Abstract

  Aortic incompetence (AI) is observed to be accelerated in the continuous-flow left ventricular assist device (LVAD) population and is related to increased mortality. Using computational fluid dynamics (CFD), we investigated the hemodynamic conditions related to the orientation of the LVAD outflow in these patients.We identified 10 patients with new aortic regurgitation, and 20 who did not, after LVAD implantation between 2009 and 2018. Three-dimensional models of patients' aortas were created from their computed tomography scans. The geometry of the LVAD outflow graft in relation to the aorta was quantified using azimuth angles (AA), polar angles (PAs), and distance from aortic root. The models were used to run CFD simulations, which calculated the pressures and wall shear stress (rWSS) exerted on the aortic root.The AA and PA were found to be similar. However, for combinations of high values of AA and low values of PA, there were no patients with AI. The distance from aortic root to the outflow graft was also smaller in patients who developed AI (3.39 ± 0.7 vs 4.07 ± 0.77 cm, P = .04). There was no significant difference in aortic root pressures in the 2 groups. The rWSS was greater in AI patients (4.60 ± 5.70 vs 2.37 ± 1.20 dyne/cm2, P < .001). Qualitatively, we observed a trend of greater perturbations, regions of high rWSS, and flow eddies in the AI group.Using CFD simulations, we demonstrated that patients who developed de novo AI have greater rWSS at the aortic root, and their outflow grafts were placed closer to the aortic roots than those patients without de novo AI.

  View details for DOI 10.1016/j.jtcvs.2020.04.164

  View details for PubMedID 32653292

• Impact of Surgical Approach in Double Lung Transplantation: Median Sternotomy vs Clamshell Thoracotomy. Transplantation proceedings Shudo, Y., Rinewalt, D., Lingala, B., Kim, F. Y., He, H., Boyd, J. H., Lee, A. M., Hiesinger, W., Currie, M. E., MacArthur, J. W., Woo, Y. J. 2020

  Abstract

  Double lung transplantation (DLT) remains the gold standard for end-stage lung disease. Although DLT was historically performed via clamshell thoracotomy, recently the median sternotomy has emerged as a viable alternative. As the ideal surgical approach remains unclear, the aim of our study was to compare the short- and long-term outcomes of these 2 surgical approaches in DLT.We retrospectively reviewed 192 consecutive adult patients who underwent primary DLT at our institution between 2012 and 2017 (sternotomy, n = 147; clamshell, n = 45). The impact of each surgical approach on post-transplant morbidity was investigated, and the overall survival probability analyses were performed.There were no significant differences in recipients' baseline and donors' characteristics and bilateral allograft ischemic time. Freedom from primary graft dysfunction, acute rejection episodes, postoperative prolonged ventilator support, tracheostomy, postoperative stroke, and airway dehiscence were comparable between these 2 groups. The duration of cardiopulmonary bypass and operative time were significantly longer in the clamshell thoracotomy group. Postoperative extracorporeal membrane oxygenation usage tended to be more frequent in the clamshell thoracotomy group than the median sternotomy group, despite no statistical significance. Length of hospital and intensive care unit stay were not influenced by the type of incision. There was no significant difference in overall survival between these 2 procedure groups (P = .61, log-rank test).The median sternotomy approach in DLT decreases operative time and more importantly leads to a shorter duration of cardiopulmonary bypass. The type of surgical approach did not show any statistically significant impact on adult DLT recipients' morbidity and survival.

  View details for DOI 10.1016/j.transproceed.2019.10.018

  View details for PubMedID 31911057

• OUTCOMES OF PATIENTS WITH INFECTION RELATED TO VENTRICULAR ASSIST DEVICE AFTER HEART TRANSPLANTATION Moayedi, Y., Multani, A., Bunce, P., Tremblay-Gravel, M., Gomez, C., Garvert, D., Duclos, S., Hiesinger, W., Ross, H., Khush, K., Montoya, J., Teuteberg, J. WILEY. 2019: 55

  View details for Web of Science ID 000491488701171

• "Cheese Wire" Fenestration of Dissection Intimal Flap to Facilitate Thoracic Endovascular Aortic Repair in Chronic Dissection. Journal of vascular and interventional radiology : JVIR Iwakoshi, S., Watkins, C. A., Ogawa, Y., Fischbein, M., Lee, A., Lee, J. T., Hiesinger, W., Dake, M. D. 2019

  Abstract

  Thoracic endovascular aortic repair (TEVAR) for aneurysmal chronic dissection is often complicated by retrograde filling of the false lumen and dissected distal landing zone. A "cheese wire"-style fenestration of the dissection intimal flap can create a landing zone facilitating TEVAR. This technique successfully aided TEVAR in 3 patients with an average age of 57.3 years. Complications included type III endoleak requiring relining and renal artery occlusion requiring stent placement. Average duration of clinical follow-up was 19 ± 4 months. Imaging follow-up was 8 ± 10 months. All patients have survived for more than 1 year without aneurysm enlargement.

  View details for DOI 10.1016/j.jvir.2019.06.004

  View details for PubMedID 31542270

• Outcomes of patients with infection related to a ventricular assist device after Heart Transplantation. Clinical transplantation Moayedi, Y., Multani, A., Bunce, P. E., Henricksen, E., Lee, R., Yang, W., Gomez, C. A., Garvert, D. W., Tremblay-Gravel, M., Duclos, S., Hiesinger, W., Ross, H. J., Khush, K. K., Montoya, J. G., Teuteberg, J. J. 2019: e13692

  Abstract

  BACKGROUND: Despite significant advances in durable mechanical support survival, infectious complications remain the most common adverse event after ventricular assist device (VAD) implantation and the leading cause of early death after transplantation. In this study, we aim to describe our local infectious epidemiology and review short term survival and infectious incidence rates in the post transplantation period and assess risk factors for infectious episodes after transplantation.METHODS: Retrospective single-center study of all consecutive adult heart transplant patients from 2008-2017. Survival data was estimated and summarized using the Kaplan-Meier method. We quantified and evaluated the difference in the incidence rate between patients with and without infection using a Fine-Gray model. The outcome of interest is the time to first infection diagnosis with post-transplant death as the competing event.RESULTS: Among 282 heart transplantations, 74 (26.5%) underwent LVAD implantation. Twenty-one patients (28.3%) developed an infection while supported by an LVAD. When compared to patients supported by an LVAD without a preceding infection, BMI was significantly greater (31.2 vs. 27.8 kg/m2, p=0.03). Median follow-up post transplantation was 3.01 years. Significant risk factors for the competing risk regression for infection after heart transplantation include LVAD infection (HR 1.94, [95% CI] 1.11-3.39, p=0.020) and recipient COPD (HR 2.14, [95% CI] 1.39-3.32, p=0.001) when adjusted for recipient age, gender, hypertension, diabetes mellitus and body mass index.CONCLUSIONS: Patients with LVAD-related infection had a significantly increased risk of infectious complications after heart transplantation. Further research on the avoidance of induction agents and reduced maintenance immunosuppression in this patient population is warranted This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13692

  View details for PubMedID 31403741

• A modified implantation technique for temporary right ventricular assist device: Enabling ambulation and less invasive decannulation. Journal of cardiac surgery Rinewalt, D., Shudo, Y., MacArthur, J. W., Woo, Y. J., Hiesinger, W. 2019

  Abstract

  This report describes our unique temporary right ventricular assist device (RVAD) implantation technique, which enables early mobilization even during biventricular support and subsequent less invasive RVAD removal without needing resternotomy upon recovery.

  View details for DOI 10.1111/jocs.14193

  View details for PubMedID 31389624

• Risk of reoperative valve surgery for endocarditis associated with drug use. The Journal of thoracic and cardiovascular surgery Mori, M., Bin Mahmood, S. U., Schranz, A. J., Sultan, I., Axtell, A. L., Sarsour, N., Hiesinger, W., Boskovski, M. T., Hirji, S., Kaneko, T., Woo, J., Tang, P., Jassar, A. S., Atluri, P., Whitson, B. A., Gleason, T., Geirsson, A. 2019

  Abstract

  BACKGROUND: We aimed to quantify incidence and operative risks associated with reoperative valve surgeries (RVS) in patients with drug-associated infective endocarditis in a multi-center setting.METHODS: We formed a registry of patients with drug-associated infective endocarditis who underwent valve surgeries at 8 US centers between 2011 and 2017. Outcomes of first-time valve surgery (FVS) and RVS were compared. Multivariable logistic regression models related RVS to 30-day mortality. Poisson regression models were fitted to evaluate temporal trends in overall case volume and proportions of patients undergoing RVS.RESULTS: The cohort consisted of 925 patients with drug-associated infective endocarditis who underwent a valve surgery, of which 652 were FVS and 273 were RVS. Patients undergoing FVS had fewer comorbidities than those undergoing RVS. Overall case volume increased from 108 in 2012 to 229 cases in 2017 (P<.001). The proportion of redo valve cases increased from 19% in 2012 to 28% in 2017 (P<.001). The 30-day mortality in RVS was higher compared with FVS (8.1% vs 4.8%; P=.049). An increase in unadjusted mortality rates were observed as the number of prior cardiac surgeries increased, from 4.8% in FVS to 11.8% in ≥3 RVS. Multivariable model demonstrated that RVS was associated with an increased risk of 30-day mortality (odds ratio, 2.22; 95% confidence interval, 1.22-4.06; P=.010).CONCLUSIONS: An increasing proportion of valve surgery for drug-associated infective endocarditis is for RVS. Despite being young and harboring few comorbidities, the RVS cohort is still susceptible to increased risk of 30-day mortality compared with those undergoing FVS.

  View details for DOI 10.1016/j.jtcvs.2019.06.055

  View details for PubMedID 31420136

• Predicting Transfusions During Left Ventricular Assist Device Implant: Peri-Operative Transfusions with LVAD Implantation. Seminars in thoracic and cardiovascular surgery Miller, R. J., Gregory, A. J., Kent, W., Banerjee, D., Hiesinger, W., Clarke, B. 2019

  Abstract

  OBJECTIVE: Perioperative bleeding and transfusion cause morbidity and mortality in patients receiving left ventricular assist devices (LVADs). We assessed factors associated with transfusions within 30 days of durable LVAD implantation and the clinical outcomes associated with transfusions.METHODS: A retrospective cohort study of patients undergoing initial durable LVAD implantation between 2014 and 2016 was performed. Rates of packed red blood cell (PRBC) or other blood product transfusions (platelets or fresh frozen plasma [FFP]) were asssessed. Ordinal multivariable regression analysis was performed to determine factors independently associated with transfusion.RESULTS: Analysis included 156 patients, mean age 54.6 years and 74.4% male, who received a mean of 11.7 units of PRBC and 10.0 units of other products within 30-days. Pre-implant mechanical ventilation, dialysis, higher INR, previous sternotomy, higher model for end-stage liver disease score and lower hemoglobin were associated with increased PRBC transfusion rates. Higher pre-operative central venous pressure (CVP), mechanical ventilation, concomitant surgical procedures, previous sternotomy, and lower hemoglobin were associated with increased PRBC transfusion rates within 48 hours of implant (adjusted OR 1.46, p=0.013 per 5mmHg). There were no significant associations with ferritin (adjusted OR 1.00, p=0.236) or transferrin saturation (adjusted OR 1.17, p=0.068) . Transfusions were associated with an increase in ventilation duration, intensive care unit length of stay, re-operation for bleeding and all-cause mortality.CONCLUSIONS: In patients undergoing LVAD implantation, peri-operative blood product exposure is common and associated with increased morbidity and mortality. Elevated CVP and anemia are potentially modifiable factors associated with increased early PRBC transfusion rates.

  View details for DOI 10.1053/j.semtcvs.2019.05.015

  View details for PubMedID 31128255

• Comprehensive Analysis of Differential Expressed Genes Related with Myocardial Reverse Remodeling Following HeartWare Ventricular Assist Device Implantation Shudo, Y., Jaatinen, K. J., NIshiga, M., Chen, I. Y., Greene, C. L., Koyano, T. K., Fong, R. W., Boyd, J. H., Lee, A. M., Hiesinger, W., Woo, J. ELSEVIER SCIENCE INC. 2019: S244

  View details for DOI 10.1016/j.healun.2019.01.603

  View details for Web of Science ID 000461365101285

• Improving Nutrition Practices for Critically Ill Postoperative Heart Transplant and Ventricular Assist Device Implant Patients Modir, R., Rao, V., Teuteberg, J., Banerjee, D., Oyer, P., Tulu, Z., Hadhazy, E., Hiesinger, W., Jimenez, S., Tu, L., Hill, C. ELSEVIER SCIENCE INC. 2019: S217

  View details for DOI 10.1016/j.healun.2019.01.530

  View details for Web of Science ID 000461365101214

• The Gift That Keeps on Giving? The Impact of Donor Coronary Atherosclerosis on the Development of Coronary Allograft Vasculopathy by IVUS Moayedi, Y., Fan, C. S., Miller, R. J., Tremblay-Gravel, M., Kawana, M., Luikart, H. I., D'Emilio, N., Gordon, J., Parizo, J. T., Oro, G., Wainwright, R., Hiesinger, W., Manlhiot, C., Ross, H. J., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2019: S218–S219

  View details for DOI 10.1016/j.healun.2019.01.533

  View details for Web of Science ID 000461365101217

• Directly to a DOAC? Safety of Alternatives to Warfarin for Anticoagulation in Heart Transplantation Tremblay-Gravel, M., Alexander, K. M., Czobor, P., Lee, R., Foroutan, F., Yang, W. A., Hayes, A., Hiesinger, W., Ross, H. J., Khush, K. K., Teuteberg, J. J., Moayedi, Y. ELSEVIER SCIENCE INC. 2019: S389

  View details for DOI 10.1016/j.healun.2019.01.991

  View details for Web of Science ID 000461365102327

• Impact of Surgical Approach in Double Lung Transplantation: Median Sternotomy Decreases Operative and Cardiopulmonary Bypass Time Compared to Clamshell Thoracotomy Shudo, Y., Rinewalt, D., Lingala, B., Kim, F. Y., He, H., Boyd, J. H., Lee, A. M., Hiesinger, W., Currie, M. E., MacArthur, J. W., Woo, J. ELSEVIER SCIENCE INC. 2019: S414

  View details for DOI 10.1016/j.healun.2019.01.1054

  View details for Web of Science ID 000461365103045

• Contemporary Use of Glycoprotein IIb/IIIa Inhibitors in Patients with Left Ventricular Assist Devices Duclos, S., Matsuda, K., Jimenez, S., Wheeler, M., Sallam, K., Hiesinger, W., Banerjee, D. ELSEVIER SCIENCE INC. 2019: S423–S424

  View details for DOI 10.1016/j.healun.2019.01.1079

  View details for Web of Science ID 000461365103068

• Impact of Concomitant Valvular Surgery on Patients Undergoing LVAD Implantation Mulumba, K. Y., Kasinpila, P., Fong, R., Kong, S., Hecker, L., Nissan, R., Banerjee, D., Teuteberg, J., Shudo, Y., Woo, Y., Hiesinger, W. ELSEVIER SCIENCE INC. 2019: S72–S73

  View details for DOI 10.1016/j.healun.2019.01.164

  View details for Web of Science ID 000461365100155

• Evaluation of Risk Factors for Heart-Lung Transplant Recipient Outcome: An Analysis of the United Network for Organ Sharing Database. Circulation Shudo, Y., Wang, H., Lingala, B., He, H., Kim, F. Y., Hiesinger, W., Lee, A. M., Boyd, J. H., Currie, M., Woo, Y. J. 2019; 140 (15): 1261–72

  Abstract

  Heart-lung transplantation (HLTx) is an effective treatment for patients with advanced cardiopulmonary failure. However, no large multicenter study has focused on the relationship between donor and recipient risk factors and post-HLTx outcomes. Thus, we investigated this issue using data from the United Network for Organ Sharing database.All adult patients (age ≥18 years) registered in the United Network for Organ Sharing database who underwent HLTx between 1987 and 2017 were included (n=997). We stratified the cohort by patients who were alive without retransplant at 1 year (n=664) and patients who died or underwent retransplant within 1 year of HLTx (n=333). The primary outcome was the influence of donor and recipient characteristics on 1-year post-HLTx recipient death or retransplant. Kaplan-Meier curves were created to assess overall freedom from death or retransplant. To obtain a better effect estimation on hazard and survival time, the parametric Accelerated Failure Time model was chosen to perform time-to-event modeling analyses.Overall graft survival at 1-year post-HLTx was 66.6%. Of donors, 53% were male, and the mean age was 28.2 years. Univariable analysis showed advanced donor age, recipient male sex, recipient creatinine, recipient history of prior cardiac or lung surgery, recipient extracorporeal membrane oxygenation support, transplant year, and transplant center volume were associated with 1-year post-HLTx death or retransplant. On multivariable analysis, advanced donor age (hazard ratio [HR], 1.017; P=0.0007), recipient male sex (HR, 1.701; P=0.0002), recipient extracorporeal membrane oxygenation support (HR, 4.854; P<0.0001), transplant year (HR, 0.962; P<0.0001), and transplantation at low-volume (HR, 1.694) and medium-volume centers (HR, 1.455) in comparison with high-volume centers (P=0.0007) remained as significant predictors of death or retransplant. These predictors were incorporated into an equation capable of estimating the preliminary probability of graft survival at 1-year post-HLTx on the basis of preoperative factors alone.HLTx outcomes may be improved by considering the strong influence of donor age, recipient sex, recipient hemodynamic status, and transplant center volume. Marginal donors and recipients without significant factors contributing to poor post-HLTx outcomes may still be considered for transplantation, potentially with less impact on the risk of early postoperative death or retransplant.

  View details for DOI 10.1161/CIRCULATIONAHA.119.040682

  View details for PubMedID 31589491

• Successful Repair of Type A Aortic Dissection in an Octogenarian With Double Aortic Arch. The Annals of thoracic surgery Zeigler, S. M., Hiesinger, W. 2019; 107 (1): e19–e21

  Abstract

  An 80-year-old woman was transferred to our institution with a subacute type A aortic dissection and a previously undiagnosed double aortic arch. The patient underwent successful repair with aortic valve resuspension, ascending aortic replacement, and repair of the proximal right-sided arch. This is the first reported case of a type A dissection associated with a double aortic arch in the United States.

  View details for PubMedID 30558737

• Transplant Outcomes in Destination Therapy Left Ventricular Assist Device Patients. ASAIO journal (American Society for Artificial Internal Organs : 1992) Miller, R. J., Moayedi, Y., Sharma, A., Haddad, F., Hiesinger, W., Banerjee, D. 2019

  Abstract

  Left ventricular assist devices (LVAD) can be implanted as either a bridge to transplantation (BTT) or destination therapy (DT). This definition is fluid, as some DT patients undergo transplantation. This study compared posttransplant outcomes between BTT and DT LVAD patients. We performed a retrospective analysis of LVAD patients who underwent cardiac transplantation from 2010 to 2016. Outcomes including mortality, rejection, infection, and overall readmission were assessed with univariable Cox analyses. This cohort included 92 LVAD patients underwent transplantation: 57 BTT, mean age 52 years, and 79% male. The DT group had a longer LVAD support time (median support 406 versus 161 days, p < 0.001) with no significant difference in 1-year survival (BTT 86% and DT 92%, p = 0.52) or survival time (HR 0.89, 95% confidence interval [CI] 0.33-2.41, p = 0.82). Rates of nonfatal adverse events were also similar between BTT and DT patients. In our cohort, DT patients had similar long-term survival and rates of adverse events as compared with BTT, despite a longer time to transplant. This study suggests that transplant outcomes are acceptable for patients initially labeled DT and that a longer duration of LVAD support may not adversely affect posttransplant outcomes.

  View details for DOI 10.1097/MAT.0000000000001016

  View details for PubMedID 31192848

• The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32

  Abstract

  BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 ± 13 years, with 79% male; 49% had INTERMACS profiles ≤2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

  View details for PubMedID 30539717

• Planned Concomitant Left and Right Ventricular Assist Device Insertion to Avoid Long-term Biventricular Mechanical Support: Bridge to Right Ventricular Recovery. The heart surgery forum Salna, M., Shudo, Y., Teuteberg, J. J., Banerjee, D., Ha, R. V., Woo, Y. J., Hiesinger, W. 2018; 21 (5): E412–E414

  Abstract

  INTRODUCTION: The planned use of a temporary right ventricular assist device (RVAD) at the time of left ventricular assist device (LVAD) implantation may prevent the need for a permanent biventricular assist device (BiVAD). Herein we describe our RVAD weaning protocol that was effectively employed in 4 patients to prevent the need for permanent BiVAD.METHODS: Four patients in refractory cardiogenic shock underwent planned RVAD insertion during LVAD implantation due to severely depressed right ventricular function with dilation preoperatively. A standardized RVAD weaning protocol was employed in these 4 patients in preparation for decannulation.RESULTS: Temporary RVADs were successfully placed in all 4 patients at the time of LVAD implantation. All patients survived to RVAD decannulation and discharge and were alive at the time of most recent follow-up (range, 528-742 days post-RVAD decannulation).CONCLUSION: Planned implantation of a temporary RVAD in high risk patients may avoid the need for biventricular mechanical support in the future.

  View details for PubMedID 30311895

• Right ventricular load adaptability metrics in patients undergoing left ventricular assist device implantation. The Journal of thoracic and cardiovascular surgery Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. 2018

  Abstract

  OBJECTIVE: Several right load adaptability metrics have been proposed as predictors of right heart failure (RHF) following left ventricular assist device implantation. This study sought to validate and compare the prognostic value of these indices.METHODS: This retrospective study included 194 patients undergoing continuous-flow left ventricular assist device implantation. The primary end point was unplanned right atrial assist device (RVAD) need within 30days after left ventricular assist device implantation; the secondary end points included clinical RHF syndrome without RVAD need and the composite of RHF or RVAD need. Load adaptability indices or interventricular ratios were divided into surrogates of ventriculoarterial coupling (RV area change:end-systolic area), indices reflecting adaptation proportionality (Dandel's index=tricuspid regurgitation velocity-time integral normalized for average RV radius in diastole or systole), and simple ratios (eg, pulse pressure:right atrial pressure or right arterial pressure:pulmonary arterial wedge pressure).RESULTS: Mean age was 55±13years with 77% of men. RHF occurred in 75 patients with 30 patients requiring RVAD implantation. Among right heart metrics, right arterial pressure (normalized odd ratio, 1.62; 95% confidence interval, 1.15-2.38), right arterial pressure:pulmonary arterial wedge pressure (normalized odds ratio, 1.59; 95% confidence interval, 1.08-2.32) and pulse pressure:right arterial pressure<2.0 (normalized odds ratio, 2.56; 95% confidence interval, 1.16-5.56) were associated with RVAD need (all P values<.02). These 3 metrics significantly added incremental prognostic value to the Interagency Registry for Mechanically Assisted Circulatory Support classification score in a similar range, whereas only RAP was incremental to the Michigan score. Correlates of RHF not requiring RVAD included RV end-systolic area index and the Dandel indices, which provided similar incremental value to the Interagency Registry for Mechanically Assisted Circulatory Support, Michigan, and European Registry for Patients with Mechanical Circulatory Support scores.CONCLUSIONS: Although associated with outcome, right load adaptability indices do not appear to provide strong incremental value when compared with simple metrics.

  View details for PubMedID 30482529

• Transplant Outcomes in Destination Therapy vs Bridge to Transplant LVAD Patients Miller, R. J., Moyaedi, Y., Sharma, A., Zarafshar, S., Varr, B., Haddad, F., Hiesinger, W., Banerjee, D. ELSEVIER SCIENCE INC. 2018: S434–S435

  View details for Web of Science ID 000430727300515

• RIGHT VENTRICULAR LOAD ADAPTABILITY IN PATIENTS UNDERGOING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Wheeler, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1624

  View details for DOI 10.1016/S0735-1097(18)32165-X

  View details for Web of Science ID 000429659703274

• Prolonged veno-arterial extracorporeal life support for cardiac failure. The International journal of artificial organs Guenther, S. P., Shudo, Y., Hiesinger, W., Banerjee, D. 2018: 391398818777359

  Abstract

  In intractable cardiogenic shock, extracorporeal life support frequently is the last treatment option. Outcomes of prolonged veno-arterial extracorporeal life support for cardiac failure are poorly defined.We retrospectively analyzed 10 patients (4 females, age = 36 ± 16 years) who underwent prolonged extracorporeal life support (≥7 days) from December 2015 to March 2017 for cardiogenic shock. The primary endpoint was survival to hospital discharge.Etiologies included ischemic cardiomyopathy with non ST-segment elevation myocardial infarction (n = 1), dilated (n = 3), hypertrophic (n = 1), postpartum cardiomyopathy (n = 1), and others (n = 4). Heart failure was left or biventricular in 80.0% (left ventricular ejection fraction = 15.6 ± 5.5%). Among the 10 patients, 80.0% underwent femoral and 20.0% central cannulation, 40.0% required changes in the cannulation strategy, and 80.0% underwent left ventricular venting. No technical malfunctions occurred, but 50.0% required circuit exchanges for thrombus formation. 80.0% suffered from infections. 60.0% could be decannulated after 717 ± 830 (168-2301) h of support, and survival to hospital discharge was 40.0%. Longest follow-up available is 160 ± 175 (12-409) days after discharge, with 30.0% alive and in satisfying functional condition.Prolonged veno-arterial extracorporeal life support for cardiac failure is feasible with low technical complication rates. Survival rates are acceptable, yet inferior to short-term support. We observed a shift from initial shock-related complications to infections during prolonged support. Since recovery and thus weaning is rather unlikely after a prolonged need for extracorporeal life support, this form of support should be limited to centers offering the full spectrum of interdisciplinary cardiac care including ventricular assist device implantation and transplantation.

  View details for PubMedID 29896993

• Injectable Bioengineered Hydrogel Therapy in the Treatment of Ischemic Cardiomyopathy. Current treatment options in cardiovascular medicine MacArthur, J. W., Steele, A. N., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. J. 2017; 19 (4): 30-?

  Abstract

  Over the past two decades, the field of cardiovascular medicine has seen the rapid development of multiple different modalities for the treatment of ischemic myocardial disease. Most research efforts have focused on strategies aimed at coronary revascularization, with significant technological advances made in percutaneous coronary interventions as well as coronary artery bypass graft surgery. However, recent research efforts have shifted towards ways to address the downstream effects of myocardial infarction on both cellular and molecular levels. To this end, the broad application of injectable hydrogel therapy after myocardial infarction has stimulated tremendous interest. In this article, we will review what hydrogels are, how they can be bioengineered in unique ways to optimize therapeutic potential, and how they can be used as part of a treatment strategy after myocardial infarction.

  View details for DOI 10.1007/s11936-017-0530-x

  View details for PubMedID 28337717

• Operative technique and pitfalls in donor heart procurement. Asian cardiovascular & thoracic annals Shudo, Y., Hiesinger, W., Oyer, P. E., Woo, Y. J. 2017; 25 (1): 80-82

  Abstract

  We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

  View details for DOI 10.1177/0218492316678716

  View details for PubMedID 28074702

• An innovative biologic system for photon-powered myocardium in the ischemic heart. Science advances Cohen, J. E., Goldstone, A. B., Paulsen, M. J., Shudo, Y., Steele, A. N., Edwards, B. B., Patel, J. B., MacArthur, J. W., Hopkins, M. S., Burnett, C. E., Jaatinen, K. J., Thakore, A. D., Farry, J. M., Truong, V. N., Bourdillon, A. T., Stapleton, L. M., Eskandari, A., Fairman, A. S., Hiesinger, W., Esipova, T. V., Patrick, W. L., Ji, K., Shizuru, J. A., Woo, Y. J. 2017; 3 (6): e1603078

  Abstract

  Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

  View details for PubMedID 28630913

• Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. Journal of vascular surgery Edwards, B. B., Fairman, A. S., Cohen, J. E., Macarthur, J. W., Goldstone, A. B., Woo, J. B., Hiesinger, W., Woo, Y. J. 2016; 64 (4): 1093-1099

  Abstract

  Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion.Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers.Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03).Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

  View details for DOI 10.1016/j.jvs.2015.06.140

  View details for PubMedID 26372192

• Cell transplantation in heart failure: where do we stand in 2016? EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY MacArthur, J. W., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. 2016; 50 (3): 396–99

  View details for PubMedID 27587719

• Hybrid coronary revascularization: Ready for prime time, but who should star? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2016; 151 (4): 1090–91

  View details for DOI 10.1016/j.jtcvs.2015.12.015

  View details for Web of Science ID 000372436900056

  View details for PubMedID 26809426

• Building a better bridge: Remodeling, recovery, and a better understanding of the biologic foundation of mechanical circulatory support JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2015; 150 (5): 1342–43

  View details for DOI 10.1016/j.jtcvs.2015.09.042

  View details for Web of Science ID 000365038900062

  View details for PubMedID 26546204

• A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy TISSUE ENGINEERING PART A Shudo, Y., Cohen, J. E., MacArthur, J. W., Goldstone, A. B., Otsuru, S., Trubelja, A., Patel, J., Edwards, B. B., Hung, G., Fairman, A. S., Brusalis, C., Hiesinger, W., Atluri, P., Hiraoka, A., Miyagawa, S., Sawa, Y., Woo, Y. J. 2015; 21 (19-20): 2515-2525

  Abstract

  There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 × 10(7) cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.

  View details for DOI 10.1089/ten.tea.2014.0155

  View details for PubMedID 26154752

• A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement ANNALS OF THORACIC SURGERY Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., MacArthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1991

  Abstract

  We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

  View details for DOI 10.1016/j.athoracsur.2014.12.076

  View details for Web of Science ID 000357521600028

  View details for PubMedID 25865766

• A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement. Annals of thoracic surgery Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., Macarthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1990

  Abstract

  We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

  View details for DOI 10.1016/j.athoracsur.2014.12.076

  View details for PubMedID 25865766

• Ventricular assist device implantation in the elderly. Annals of cardiothoracic surgery Hiesinger, W., Boyd, J. H., Woo, Y. J. 2014; 3 (6): 570-572

  Abstract

  Dramatic advances in ventricular assist device (VAD) design and patient management have made mechanical circulatory support an attractive therapeutic option for the growing pool of elderly heart failure patients.A literature review of all relevant studies was performed. No time or language restrictions were imposed, and references of the selected studies were checked for additional relevant citations.In concordance with the universal trend in mechanical circulatory support, continuous flow devices appear to have particular benefits in the elderly. In addition, the literature suggests that early intervention before the development of cardiogenic shock, important in all patients, is particularly paramount in older patients.The ongoing refinement of patient selection, surgical technique, and post-operative care will continue to improve surgical outcomes, and absolute age may become a less pivotal criterion for mechanical circulatory support. However, clear guidelines for the use of mechanical circulatory support in the elderly remain undefined.

  View details for DOI 10.3978/j.issn.2225-319X.2014.09.07

  View details for PubMedID 25512896

• Bioengineered Stromal Cell- Derived Factor-1 alpha Analogue Delivered as an Angiogenic Therapy Significantly Restores Viscoelastic Material Properties of Infarcted Cardiac Muscle JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Trubelja, A., MacArthur, J. W., Sarver, J. J., Cohen, J. E., Hung, G., Shudo, Y., Fairman, A. S., Patel, J., Edwards, B. B., Damrauer, S. M., Hiesinger, W., Atluri, P., Woo, Y. J. 2014; 136 (8)

  Abstract

  Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

  View details for DOI 10.1115/1.4027731

  View details for Web of Science ID 000338507000012

• A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circulation. Heart failure Cohen, J. E., Purcell, B. P., Macarthur, J. W., Mu, A., Shudo, Y., Patel, J. B., Brusalis, C. M., Trubelja, A., Fairman, A. S., Edwards, B. B., Davis, M. S., Hung, G., Hiesinger, W., Atluri, P., Margulies, K. B., Burdick, J. A., Woo, Y. J. 2014; 7 (4): 619-626

  Abstract

  Neuregulin-1β (NRG) is a member of the epidermal growth factor family possessing a critical role in cardiomyocyte development and proliferation. Systemic administration of NRG demonstrated efficacy in cardiomyopathy animal models, leading to clinical trials using daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to encapsulate NRG in a hydrogel to be directly delivered to the myocardium, accomplishing sustained localized NRG delivery.NRG was encapsulated in hydrogel, and release over 14 days was confirmed by ELISA in vitro. Sprague-Dawley rats were used for cardiomyocyte isolation. Cells were stimulated by PBS, NRG, hydrogel, or NRG-hydrogel (NRG-HG) and evaluated for proliferation. Cardiomyocytes demonstrated EdU (5-ethynyl-2'-deoxyuridine) and phosphorylated histone H3 positivity in the NRG-HG group only. For in vivo studies, 2-month-old mice (n=60) underwent left anterior descending coronary artery ligation and were randomized to the 4 treatment groups mentioned. Only NRG-HG-treated mice demonstrated phosphorylated histone H3 and Ki67 positivity along with decreased caspase-3 activity compared with all controls. NRG was detected in myocardium 6 days after injection without evidence of off-target exposure in NRG-HG animals. At 2 weeks, the NRG-HG group exhibited enhanced left ventricular ejection fraction, decreased left ventricular area, and augmented borderzone thickness.Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity, decreases apoptosis, and greatly enhances left ventricular function in a model of ischemic cardiomyopathy. This novel approach to NRG administration avoids off-target exposure and represents a clinically translatable strategy in myocardial regenerative therapeutics.

  View details for DOI 10.1161/CIRCHEARTFAILURE.113.001273

  View details for PubMedID 24902740

• Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1a analog in a translational ovine myocardial infarction model. Circulation research Macarthur, J. W., Cohen, J. E., McGarvey, J. R., Shudo, Y., Patel, J. B., Trubelja, A., Fairman, A. S., Edwards, B. B., Hung, G., Hiesinger, W., Goldstone, A. B., Atluri, P., Wilensky, R. L., Pilla, J. J., Gorman, J. H., Gorman, R. C., Woo, Y. J. 2014; 114 (4): 650-659

  Abstract

  After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

  View details for DOI 10.1161/CIRCRESAHA.114.302884

  View details for PubMedID 24366171

• Therapeutic potential of Rb phosphorylation in atherosclerosis CELL CYCLE Hiesinger, W., Cohen, J. E., Atluri, P. 2014; 13 (3): 352

  View details for DOI 10.4161/cc.27551

  View details for Web of Science ID 000332833400010

  View details for PubMedID 24346501

  View details for PubMedCentralID PMC3956530

• Sustained release of engineered stromal cell-derived factor 1-a from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation Macarthur, J. W., Purcell, B. P., Shudo, Y., Cohen, J. E., Fairman, A., Trubelja, A., Patel, J., Hsiao, P., Yang, E., Lloyd, K., Hiesinger, W., Atluri, P., Burdick, J. A., Woo, Y. J. 2013; 128 (11): S79-86

  Abstract

  Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000343

  View details for PubMedID 24030424

• Predicting Right Ventricular Failure in the Modern, Continuous Flow Left Ventricular Assist Device Era 59th Annual Meeting of the Southern-Thoracic-Surgical-Association (STSA) Atluri, P., Goldstone, A. B., Fairman, A. S., MacArthur, J. W., Shudo, Y., Cohen, J. E., Acker, A. L., Hiesinger, W., Howard, J. L., Acker, M. A., Woo, Y. J. ELSEVIER SCIENCE INC. 2013: 857–64

  Abstract

  In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support.We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs.Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools.We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era.

  View details for DOI 10.1016/j.athoracsur.2013.03.099

  View details for Web of Science ID 000323940200026

  View details for PubMedID 23791165

• Rapid onset of fulminant myocarditis portends a favourable prognosis and the ability to bridge mechanical circulatory support to recovery EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Atluri, P., Ullery, B. W., MacArthur, J. W., Goldstone, A. B., Fairman, A. S., Hiesinger, W., Acker, M. A., Woo, Y. J. 2013; 43 (2): 379-382

  Abstract

  Fulminant myocarditis with cardiogenic shock is fatal without mechanical circulatory support. Once haemodynamic stability has been established with a ventricular assist device (VAD), the decision to wait for myocardial recovery as opposed to listing for an orthotopic heart transplant (OHT) can be difficult. We have undertaken this study to establish the criteria for determining the need for heart transplantation following VAD implant for fulminant myocarditis.A total of 442 VADs were implanted between 1993 and 2011. Twenty-four VADs were implanted for fulminant myocarditis with refractory cardiogenic shock. We retrospectively analysed the variables and the pathology for this cohort. Patients who had a full recovery of myocardial function and subsequent VAD explant (Explant) were compared with those bridged to OHT. There was one acute death.There was no difference in the past medical history between the groups. Explant patients had a more acute onset of heart failure with a median of 7 days between the onset of symptoms and VAD implant, when compared with 22 days for OHT (P = 0.01). A rapid recovery in myocardial function was seen in the Explant group, with recovery of myocardial function (ejection fraction = 53 ± 24%) in 14 ± 7 days. Myocardial function was sustained for 5 years following the VAD explant. The female gender favoured myocardial recovery and VAD explantability. Two patients had giant cell myocarditis, neither of whom had a recovery of function, and they were bridged to heart transplant with a VAD.Fulminant myocarditis is a fatal condition without mechanical support. The rapid onset of symptoms is associated with a complete recovery of myocardial function and VAD explant. The absence of rapid recovery of myocardial function should prompt listing for a heart transplant.

  View details for DOI 10.1093/ejcts/ezs242

  View details for Web of Science ID 000313829300031

  View details for PubMedID 22564805

• Mathematically engineered stromal cell-derived factor-1 alpha stem cell cytokine analog enhances mechanical properties of infarcted myocardium JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY MacArthur, J. W., Trubelja, A., Shudo, Y., Hsiao, P., Fairman, A. S., Yang, E., Hiesinger, W., Sarver, J. J., Atluri, P., Woo, Y. J. 2013; 145 (1): 278-284

  Abstract

  The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilatation, loss of contractile function, abnormal stress patterns, and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell-derived factor-1α analog (ESA), improves mechanical properties of the heart after infarction.Male rats (n = 54) underwent either sham surgery (n = 17) with no coronary artery ligation or ligation of the left anterior descending artery (n = 37). The rats in the myocardial infarction group were then randomized to receive either saline (0.1 mL, n = 18) or ESA (6 μg/kg, n = 19) injected into the myocardium at 4 predetermined spots around the border zone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks, the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated using custom image acquisition software, Digi-Velpo, and analyzed in MATLAB.Compared with the saline control group at 4 weeks, the ESA-injected hearts had a greater ejection fraction (71.8% ± 9.0% vs 55.3% ± 12.6%, P = .0004), smaller end-diastolic left ventricular internal dimension (0.686 ± 0.110 cm vs 0.763 ± 0.160 cm, P = .04), greater cardiac output (36 ± 11.6 mL/min vs 26.9 ± 7.3 mL/min, P = .05), and a lower tensile modulus (251 ± 56 kPa vs 301 ± 81 kPa, P = .04). The tensile modulus for the sham group was 195 ± 56 kPa, indicating ESA injection results in a less stiff ventricle.Direct injection of ESA alters the biomechanical response to myocardial infarction, improving the mechanical properties in the postinfarct heart.

  View details for DOI 10.1016/j.jtcvs.2012.09.080

  View details for Web of Science ID 000312386300047

  View details for PubMedID 23244259

• Re-Engineered Stromal Cell-Derived Factor-1 alpha and the Future of Translatable Angiogenic Polypeptide Design TRENDS IN CARDIOVASCULAR MEDICINE Hiesinger, W., Goldstone, A. B., Woo, Y. J. 2012; 22 (6): 139-144

  Abstract

  Smaller engineered analogs of angiogenic cytokines may provide translational advantages, including enhanced stability and function, ease of synthesis, lower cost, and, most important, the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the stromal cell-derived factor-1α (SDF) molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low-molecular-weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than that of recombinant human SDF both in vitro and in a murine model of ischemic heart failure.

  View details for Web of Science ID 000311065900001

  View details for PubMedID 22902182

• Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1 alpha angiogenic therapy for acute myocardial infarction in a murine model 37th Annual Meeting of the Western-Thoracic-Surgical-Association Hiesinger, W., Brukman, M. J., McCormick, R. C., Fitzpatrick, J. R., Frederick, J. R., Yang, E. C., Muenzer, J. R., Marotta, N. A., Berry, M. F., Atluri, P., Woo, Y. J. MOSBY-ELSEVIER. 2012: 962–66

  Abstract

  Ventricular remodeling after myocardial infarction begins with massive extracellular matrix deposition and resultant fibrosis. This loss of functional tissue and stiffening of myocardial elastic and contractile elements starts the vicious cycle of mechanical inefficiency, adverse remodeling, and eventual heart failure. We hypothesized that stromal cell-derived factor 1α (SDF-1α) therapy to microrevascularize ischemic myocardium would rescue salvageable peri-infarct tissue and subsequently improve myocardial elasticity.Immediately after left anterior descending coronary artery ligation, mice were randomly assigned to receive peri-infarct injection of either saline solution or SDF-1α. After 6 weeks, animals were killed and samples were taken from the peri-infarct border zone and the infarct scar, as well as from the left ventricle of noninfarcted control mice. Determination of tissues' elastic moduli was carried out by mechanical testing in an atomic force microscope.SDF-1α-treated peri-infarct tissue most closely approximated the elasticity of normal ventricle and was significantly more elastic than saline-treated peri-infarct myocardium (109 ± 22.9 kPa vs 295 ± 42.3 kPa; P < .0001). Myocardial scar, the strength of which depends on matrix deposition from vasculature at the peri-infarct edge, was stiffer in SDF-1α-treated animals than in controls (804 ± 102.2 kPa vs 144 ± 27.5 kPa; P < .0001).Direct quantification of myocardial elastic properties demonstrates the ability of SDF-1α to re-engineer evolving myocardial infarct and peri-infarct tissues. By increasing elasticity of the ischemic and dysfunctional peri-infarct border zone and bolstering the weak, aneurysm-prone scar, SDF-1α therapy may confer a mechanical advantage to resist adverse remodeling after infarction.

  View details for DOI 10.1016/j.jtcvs.2011.12.028

  View details for Web of Science ID 000301609200036

  View details for PubMedID 22264415

• Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy JOURNAL OF APPLIED PHYSIOLOGY Hiesinger, W., Vinogradov, S. A., Atluri, P., Fitzpatrick, J. R., Frederick, J. R., Levit, R. D., McCormick, R. C., Muenzer, J. R., Yang, E. C., Marotta, N. A., MacArthur, J. W., Wilson, D. F., Woo, Y. J. 2011; 110 (5): 1460-1465

  Abstract

  This study evaluates a therapy for infarct modulation and acute myocardial rescue and utilizes a novel technique to measure local myocardial oxygenation in vivo. Bone marrow-derived endothelial progenitor cells (EPCs) were targeted to the heart with peri-infarct intramyocardial injection of the potent EPC chemokine stromal cell-derived factor 1α (SDF). Myocardial oxygen pressure was assessed using a noninvasive, real-time optical technique for measuring oxygen pressures within microvasculature based on the oxygen-dependent quenching of the phosphorescence of Oxyphor G3. Myocardial infarction was induced in male Wistar rats (n = 15) through left anterior descending coronary artery ligation. At the time of infarction, animals were randomized into two groups: saline control (n = 8) and treatment with SDF (n = 7). After 48 h, the animals underwent repeat thoracotomy and 20 μl of the phosphor Oxyphor G3 was injected into three areas (peri-infarct myocardium, myocardial scar, and remote left hindlimb muscle). Measurements of the oxygen distribution within the tissue were then made in vivo by applying the end of a light guide to the beating heart. Compared with controls, animals in the SDF group exhibited a significantly decreased percentage of hypoxic (defined as oxygen pressure ≤ 15.0 Torr) peri-infarct myocardium (9.7 ± 6.7% vs. 21.8 ± 11.9%, P = 0.017). The peak oxygen pressures in the peri-infarct region of the animals in the SDF group were significantly higher than the saline controls (39.5 ± 36.7 vs. 9.2 ± 8.6 Torr, P = 0.02). This strategy for targeting EPCs to vulnerable peri-infarct myocardium via the potent chemokine SDF-1α significantly decreased the degree of hypoxia in peri-infarct myocardium as measured in vivo by phosphorescence quenching. This effect could potentially mitigate the vicious cycle of myocyte death, myocardial fibrosis, progressive ventricular dilatation, and eventual heart failure seen after acute myocardial infarction.

  View details for DOI 10.1152/japplphysiol.01138.2010

  View details for Web of Science ID 000290472400043

  View details for PubMedID 21292844

  View details for PubMedCentralID PMC3098666

• Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-alpha (SDF) Generates a Supra-Efficient Angiogenic Polypeptide Analog Hiesinger, W., Perez-Aguilar, J., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Muenzer, J. R., Levit, R. D., Yuan, L., MacArthur, J. W., Saven, J. G., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231600703

• Acute Myocardial Rescue with Endogenous Endothelial Progenitor Cell Therapy HEART LUNG AND CIRCULATION Atluri, P., Panlilio, C. M., Liao, G. P., Hiesinger, W., Harris, D. A., McCormick, R. C., Cohen, J. E., Jin, T., Feng, W., Levit, R. D., Dong, N., Woo, Y. J. 2010; 19 (11): 644-654

  Abstract

  Post-myocardial infarction heart failure is a major health concern with limited therapy. Molecular revascularisation utilising granulocyte-macrophage colony stimulating factor (GMCSF) mediated endothelial progenitor cell (EPC) upregulation and stromal cell derived factor-1α (SDF) mediated myocardial EPC chemokinesis, may prevent myocardial loss and adverse remodelling. Vasculogenesis, viability, and haemodynamic improvements following therapy were investigated.Lewis rats (n=91) underwent LAD ligation and received either intramyocardial SDF and subcutaneous GMCSF or saline injections at the time of infarction. Molecular and haemodynamic assessments were performed at pre-determined time points following ligation.SDF/GMCSF therapy upregulated EPC density as shown by flow cytometry (0.12±0.02% vs. 0.06±0.01% circulating lymphocytes, p=0.005), 48hours following infarction. A marked increase in perfusion was evident eight weeks after therapy, utilising confocal angiography (5.02±1.7×10(-2)μm(3)blood/μm(3)myocardial tissue vs. 2.03±0.710(-2)μm(3)blood/μm(3)myocardial tissue, p=0.00004). Planimetric analysis demonstrated preservation of wall thickness (0.98±0.09mm vs. 0.67±0.06mm, p=0.003) and ventricular diameter (7.81±0.99mm vs. 9.41±1.1mm, p=0.03). Improved haemodynamic function was evidenced by echocardiography and PV analysis (ejection fraction: 56.4±18.1% vs. 25.3±15.6%, p=0.001; pre-load adjusted maximal power: 6.6±2.6mW/μl(2) vs. 2.7±1.4mW/μl(2), p=0.01).Neovasculogenic therapy with GMCSF-mediated EPC upregulation and SDF-mediated EPC chemokinesis maybe an effective therapy for infarct modulation and preservation of myocardial function following acute myocardial infarction.

  View details for DOI 10.1016/j.hlc.2010.06.1056

  View details for Web of Science ID 000283908600002

  View details for PubMedID 20719564

  View details for PubMedCentralID PMC3235678

• Spliced stromal cell-derived factor-1 alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Frederick, J. R., Atluri, P., McCormick, R. C., Marotta, N., Muenzer, J. R., Woo, Y. J. 2010; 140 (5): 1174-1180

  Abstract

  Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI.EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis.EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats.A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α.

  View details for DOI 10.1016/j.jtcvs.2010.08.012

  View details for Web of Science ID 000283057600043

  View details for PubMedID 20951261

• Stromal Cell-Derived Factor-1 alpha Activation of Tissue-Engineered Endothelial Progenitor Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis 82nd National Conference and Exhibitions and Annual Scientific Session of the American-Heart-Association Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Harris, D. A., Kim, A., Muenzer, J. R., Marotta, N., Smith, M. J., Cohen, J. E., Hiesinger, W., Atluri, P., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S107–S117

  Abstract

  Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction.Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure-volume conductance, and Doppler flow.Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.

  View details for DOI 10.1161/C1RCULATIONAHA.109.930404

  View details for Web of Science ID 000282294800017

  View details for PubMedID 20837901

• Rapid Onset of Fulminant Myocarditis Portends a Favorable Prognosis and Ability To Bridge Mechanical Support to Recovery Atluri, P., Ullery, B. W., Howard, J. L., Hiesinger, W., Filzpatrick, J., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: S51

  View details for DOI 10.1016/j.cardfail.2010.06.176

  View details for Web of Science ID 000281501800162

• Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Fitzpatrick, J. R., Frederick, J. R., Hiesinger, W., Hsu, V. M., McCormick, R. C., Kozin, E. D., Laporte, C. M., O'Hara, M. L., Howell, E., Dougherty, D., Cohen, J. E., Southerland, K. W., Howard, J. L., Paulson, C., Acker, M. A., Morris, R. J., Woo, Y. J. 2009; 137 (4): 971-977

  Abstract

  It is generally accepted that patients who require biventricular assist device support have poorer outcomes than those requiring isolated left ventricular assist device support. However, it is unknown how the timing of biventricular assist device insertion affects outcomes. We hypothesized that planned biventricular assist device insertion improves survival compared with delayed conversion of left ventricular assist device support to biventricular assist device support.We reviewed and compared outcomes of 266 patients undergoing left ventricular assist device or biventricular assist device placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided patients receiving biventricular assist devices into planned biventricular assist device (P-BiVAD) and delayed biventricular assist device (D-BiVAD) groups based on the timing of right ventricular assist device insertion. We defined the D-BiVAD group as any failure of isolated left ventricular assist device support.Of 266 patients who received left ventricular assist devices, 99 (37%) required biventricular assist device support. We compared preoperative characteristics, successful bridging to transplantation, survival to hospital discharge, and Kaplan-Meier 1-year survival between the P-BiVAD (n = 71) and D-BiVAD (n = 28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. Left ventricular assist device (n = 167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD group outcomes. Furthermore, patients in the P-BiVAD group had superior survival to discharge than patients in the D-BiVAD group (51% vs 29%, P < .05). One-year and long-term Kaplan-Meier survival distribution confirmed this finding. There was also a trend toward improved bridging to transplantation in the P-BiVAD (n = 55) versus D-BiVAD (n = 22) groups (65% vs 45%, P = .10).When patients at high risk for failure of isolated left ventricular assist device support are identified, proceeding directly to biventricular assist device implantation is advised because early institution of biventricular support results in dramatic improvement in survival.

  View details for DOI 10.1016/j.jtcvs.2008.09.021

  View details for Web of Science ID 000264562000028

  View details for PubMedID 19327526

  View details for PubMedCentralID PMC3232461

• Off-pump, minimally invasive and robotic coronary revascularization yield improved outcomes over traditional on-pump CABG INTERNATIONAL JOURNAL OF MEDICAL ROBOTICS AND COMPUTER ASSISTED SURGERY Atluri, P., Kozin, E. D., Hiesinger, W., Woo, Y. J. 2009; 5 (1): 1-12

  Abstract

  Coronary artery disease is a global health concern, with increasing morbidity and mortality. Surgical coronary artery bypass grafting has been performed on cardiopulmonary bypass for nearly four decades, with excellent long-term durability. Beating-heart coronary surgery has been increasing in frequency in an attempt to decrease cardiopulmonary bypass-related morbidity. Furthermore, with increasing expertise and technology, minimally invasive and robotic techniques have been developed to enhance post-operative recovery, patient satisfaction and cosmesis. Several clinical trials have demonstrated decreased morbidity and more rapid recovery following off-pump, minimally invasive and robotic procedures when compared to on-pump coronary artery bypass grafts (CABGs). An equivalent extent of revascularization and medium-term anastomotic patency has been demonstrated among all approaches. Furthermore, for a large number of patients who do not have anatomy amenable to traditional coronary revascularization, adjunctive molecular therapies may provide alternative myocardial micro-revascularization.

  View details for DOI 10.1002/rcs.230

  View details for Web of Science ID 000263998300001

  View details for PubMedID 19117020

• Cardiac retransplantation is an efficacious therapy for primary cardiac allograft failure JOURNAL OF CARDIOTHORACIC SURGERY Atluri, P., Hiesinger, W., Gorman, R. C., Pochettino, A., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. J. 2008; 3

  Abstract

  Although orthotopic heart transplantation has been an effective treatment for end-stage heart failure, the incidence of allograft failure has increased, necessitating treatment options. Cardiac retransplantation remains the only viable long-term solution for end-stage cardiac allograft failure. Given the limited number of available donor hearts, the long term results of this treatment option need to be evaluated.709 heart transplants were performed over a 20 year period at our institution. Repeat cardiac transplantation was performed in 15 patients (2.1%). A retrospective analysis was performed to determine the efficacy of cardiac retransplantation. Variables investigated included: 1 yr and 5 yr survival, length of hospitalization, post-operative complications, allograft failure, recipient and donor demographics, renal function, allograft ischemic time, UNOS listing status, blood group, allograft rejection, and hemodynamic function.Etiology of primary graft failure included transplant arteriopathy (n = 10), acute rejection (n = 3), hyperacute rejection (n = 1), and a post-transplant diagnosis of metastatic melanoma in the donor (n = 1). Mean age at retransplantation was 45.5 +/- 9.7 years. 1 and 5 year survival for retransplantation were 86.6% and 71.4% respectively, as compared to 90.9% and 79.1% for primary transplantation. Mean ejection fraction was 67.3 +/- 12.2% at a mean follow-up of 32.6 +/- 18.5 mos post-retransplant; follow-up biopsy demonstrated either ISHLT grade 1A or 0 rejection (77.5 +/- 95.7 mos post-transplant).Cardiac retransplantation is an efficacious treatment strategy for cardiac allograft failure.

  View details for DOI 10.1186/1749-8090-3-26

  View details for Web of Science ID 000262855000001

  View details for PubMedID 18462494

  View details for PubMedCentralID PMC2432055

• Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression CELLULAR & MOLECULAR BIOLOGY LETTERS Atluri, P., Morine, K. J., Liao, G. P., Panlilio, C. M., Berry, M. F., Hsu, V. M., Hiesinger, W., Cohen, J. E., Woo, Y. J. 2007; 12 (1): 127-138

  Abstract

  Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy.Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750+/-133500 vs. 901600+/-143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0+/-4.6 vs. 1.0+/-1.2 ng/ml, n=5, p=0.006) and western blot (1579400+/-477733 vs. 943000+/-157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.

  View details for DOI 10.2478/s11658-006-0058-7

  View details for Web of Science ID 000244632300011

  View details for PubMedID 17119870