Shashank Desai

Detection of Cardiac Allograft Rejection and Response to Immunosuppressive Therapy With Peripheral Blood Gene Expression

Background—Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. Methods and Results—We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). Conclusions—These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.

Combined orthotopic heart and liver transplantation: The need for exception status listing1

Through May 2004, 33 combined orthotopic heart‐liver transplants (OHT/OLT) have been performed nationwide. No published data exist to date regarding outcomes of patients awaiting such transplants, although progression of two organ disease processes may contribute to premature death for waiting patients. Retrospective data were collected on patients listed for combined OHT/OLT from both an individual tertiary care transplant center and the national UNOS registry to delineate listing criteria and evaluate patient outcomes in both the pre‐ and post‐MELD eras. All patients who survived to transplantation or died on the waiting list were included in the analysis. Results show that 29.6% of patients registered nationally and 42% of patients listed institutionally survived to transplantation. Survival to transplantation was associated with less severe liver disease, though patients with MELD scores ranging from 19 to 26 had significantly higher wait list mortality than expected when compared to single‐organ liver transplants. Following combined orthotopic heart‐liver transplantation, 80% and 70% of patients survive 1 and 3 years, respectively. In conclusion, combined OHT/OLT is a successful therapy, but current organ allocation policies may not ensure expeditious transplantation in critically ill patients with dual vital organ failure. Providing exception status listing to these patients would ensure more expeditious transplantation and potentially contribute to improved survival. (Liver Transpl 2004;10:1539–1544.)

Pulsatile hemodynamic effects of candesartan in patients with chronic heart failure: The CHARM Program

Abnormal large artery function and increased pulsatile load are exacerbated by excess angiotensin‐II acting through the AT1 receptor and contribute to the pathogenesis and progression of chronic heart failure (CHF).

The use of percutaneous ECMO support as a 'bridge to bridge' in heart failure patients: a case report.

A 65-year-old male with a known history of ischemic cardiomyopathy was admitted to the intensive care unit in cardiogenic shock. Cardiac catheterization revealed bi-ventricular hypokinesis, with an estimated ejection fraction of 15%. Despite moderate inotropic support, the patient’s liver enzymes, international normalization ratio (INR), and creatinine became grossly elevated, indicating multi-organ injury from hypoperfusion. Due to the patient’s state of shock and probable bleeding complications, a full sternotomy and emergent biventricular assist device insertion was deemed very high risk. In order to achieve hemodynamic stability, a decision was made for extracorporeal membrane oxygenation (ECMO) support. ECMO support was quickly initiated by percutaneous cannulation of the femoral vein and artery. The ECMO circuit was comprised of a Centrimag blood pump and Quadrox-D Safeline-coated membrane oxygenator. With successful perfusion and organ resuscitation, abnormal liver function tests, INR, and creatinine all returned to normal in less than one week. With normal organ function, especially the liver, the patient successfully underwent an implantable left ventricular assist device, HeartMate II LVAD, without requiring mechanical right heart support. Prior to ECMO, the patient was at very high risk of needing biventricular support. Thus, the temporary use of ECMO allowed for a safer and more durable bridge to transplantation. The use of percutaneous ECMO has many advantages, including improving the patient condition and allowing for time to evaluate fully the LVAD patient.

Clinical Outcomes of Advanced Heart Failure Patients with Cardiogenic Shock Treated with Temporary Circulatory Support Before Durable LVAD Implant.

Temporary circulatory support (TCS) is used to improve hemodynamics in patients with cardiogenic shock as a bridge to durable ventricular assist device (dVAD). Data from dVAD recipients with or without TCS (extracorporeal membranous oxygenation [ECMO], n = 14; TandemHeart [TH], n = 26) were evaluated. Clinical characteristics and hemodynamics were analyzed for patients before and after TCS and compared with profile 1 (n = 29) or profile 2–3 (n = 269) patients without TCS before dVAD. Extracorporeal membranous oxygenation patients had the highest use of preoperative mechanical ventilation, vasopressors, and the highest HeartMate II risk score before dVAD (p < 0.01). Patients receiving TCS before dVAD implant had hemodynamics comparable with patients in Profiles 2–3 and superior to that of Profile 1 patients without TCS. Operative survival after dVAD was lower in patients receiving ECMO (57%) compared with Profile 1 patients receiving TH (88%), Profile 1 without TCS (82%), or Profile 2–3 patients (97%; all p < 0.01). Despite improved clinical stability with TCS, patients bridged to a dVAD have event-free survival that parallels patients in profile 1 without TCS. Our data suggest that patients requiring TCS before dVAD implant should be still classified Interagency Registry for Mechanically Assisted Circulatory Support profile 1.

Changes in lipoprotein(a) concentration after orthotopic heart transplantation

BACKGROUND Elevated concentrations of lipoprotein(a) have been considered an important risk factor in the development of premature cardiovascular disease and have been proposed as a risk factor in the development of accelerated cardiac allograft vasculopathy after orthotopic heart transplantation. METHODS We prospectively measured lipoprotein(a), fasting cholesterol, and triglyceride concentrations before (n = 38), 6 months (n = 38), and 1 year (n = 21) after orthotopic heart transplantation. The mean age of the patients was 52 +/- 2 years. Eighty-seven percent of the patients were men, 82% were white, and 61% had ischemic cardiomyopathy. RESULTS Mean lipoprotein(a) concentration was lower 6 months after transplantation than it was before the operation (23 +/- 3 mg/dL vs 17 +/- 3 mg/dL; P =.014) and remained low 1 year after transplantation (23 +/- 3 mg/dL vs 18 +/- 4 mg/dL; P = not significant). In contrast, mean cholesterol concentration was higher 6 months after transplantation (171 +/- 8 mg/dL vs 221 +/- 8 mg/dL; P <.001) and 1 year (171 +/- 8 mg/dL vs 205 +/- 10 mg/dL; P <.01) than it was before transplantation. Triglyceride concentration was higher 1 year after transplantation than it was before the operation (146 +/- 13 mg/dL vs 184 +/- 20 mg/dL; P =.017). CONCLUSIONS Lipoprotein(a) concentrations decrease during the 6 months after transplantation and stay low for at least 1 year after the operation. Additional studies are needed to ascertain the effect these changes in lipoprotein(a) concentration on the development of cardiac allograft vasculopathy.

De Novo Ampullary Neuroendocrine Tumor in an Orthotopic Heart Transplant Recipient

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Antithrombotic Strategies and Device Thrombosis

Despite improvements in left ventricular assist device (LVAD) technology, bleeding and thrombotic complications are major concerns that adversely influence morbidity and mortality. Current antithrombotic therapy recommendations for LVAD thrombosis prophylaxis are largely derived from clinical device trials that implement a one-size-fits-all strategy. Objective serial laboratory-based assessment of thrombogenicity is needed to balance the risk of bleeding and thrombotic complications. Finally, the newest-generation device, the HeartMate 3, has been associated with lower levels of shear and reduced hemolysis that may mitigate thrombotic event occurrences.