Patricia A. Uber

International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.

The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update

Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

Chronic Heart Failure: Contemporary Diagnosis and Management

Chronic heart failure (CHF) remains the only cardiovascular disease with an increasing hospitalization burden and an ongoing drain on health care expenditures. The prevalence of CHF increases with advancing life span, with diastolic heart failure predominating in the elderly population. Primary prevention of coronary artery disease and risk factor management via aggressive blood pressure control are central in preventing new occurrences of left ventricular dysfunction. Optimal therapy for CHF involves identification and correction of potentially reversible precipitants, target-dose titration of medical therapy, and management of hospitalizations for decompensation. The etiological phenotype, absolute decrease in left ventricular ejection fraction and a widening of QRS duration on electrocardiography, is commonly used to identify patients at increased risk of progression of heart failure and sudden death who may benefit from prophylactic implantable cardioverter-defibrillator placement with or without cardiac resynchronization therapy. Patients who transition to advanced stages of disease despite optimal traditional medical and device therapy may be candidates for hemodynamically directed approaches such as a left ventricular assist device; in selected cases, listing for cardiac transplant may be warranted.

The vexing problem of thrombosis in long-term mechanical circulatory support

Durable left ventricular assist devices (LVADs) have not only enhanced longevity but also conferred sustained improvements in quality of life, symptom control, and functional capacity in patients with medically refractory advanced heart failure. Problems with device-related infection, bleeding, neurologic events, right-sided heart failure, and device malfunction have dominated the clinical care of patients living on mechanical support. Even as adoption of durable LVADs accelerated globally, we began to encounter a growing dilemma of pump malfunction caused by thrombosis. In early 2011, clinicians began to notice a spike in the incidence of pump thrombosis with the HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. By 2012, the problem of thrombosis in LVADs began to consume most of the scientific direction as centers and collaborative groups began to dissect this nascent phenomenon. In this perspective, we describe the magnitude and implications of pump thrombosis, discuss secular and management trends in this unique population, attempt to dissect the problem at its root, offer guidance on surveillance and therapeutic principles, and outline issues that deserve our immediate and collaborative attention.

Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival

OBJECTIVES We sought to evaluate the relative effects of low doses of pravastatin (20 mg/day) and simvastatin (10 mg/day) on indices of cardiac allograft rejection. We further examined the relative efficacy and safety of these two drugs on lipid-lowering in heart transplantation. BACKGROUND The immunomodulatory effects of hydroxy methyl glutaryl-coenzyme A reductase inhibitors have been increasingly recognized. Previous studies have demonstrated an ameliorative influence of pravastatin on hemodynamically compromising rejection after heart transplantation. A recent observational trial suggested that simvastatin 20 mg/day was associated with trends to lower survival and more adverse effects than pravastatin 40 mg/day. METHODS In a 12-month prospective, open-label study, 50 heart transplant recipients received either open-label pravastatin 20 mg daily (n = 24) or simvastatin 10 mg daily (n = 26) within four weeks of transplantation. Indices of allograft rejection including treated rejection, rejection with hemodynamic compromise, noncellular rejection, and mean one-year biopsy score were compared between the two cohorts, as well as with a statin-naive control population (n = 37). Lipid levels, safety, and post-transplant outcomes were also assessed as secondary end points. RESULTS We found no significant differences in any allograft rejection parameter between the two groups. However, total low-density lipoprotein (LDL), but not high-density lipoprotein cholesterol or triglycerides, were lower in the simvastatin arm (-23% vs. -11%, p = 0.02). No cases of rhabdomyolysis or myositis occurred in either group. Survival at one year was similar in both treatment groups (91% for patients on pravastatin and 92% for patients on simvastatin). Both groups had better survival compared with the statin-naive control group (80%, p = 0.04). CONCLUSIONS Simvastatin (10 mg/day) and pravastatin (20 mg/day) are associated with similar beneficial effects on cardiac allograft rejection and one-year survival. At these doses, simvastatin decreases LDL cholesterol more so than pravastatin with no increase in adverse effects in heart transplantation.

Heart failure therapy at a crossroad: are there limits to the neurohormonal model?

The advent of neurohormonal blockade in heart failure (HF) has been an overwhelming success, but current evidence points to a ceiling effect as newer neurohormonal targets are exploited in an incremental manner. This has lead us to question whether the neurohormonal model of HF can be sustained by simply stacking multiple neurohormonal or cytokine blockers together as treatment. A unifying theme in some of these disparate trials relates to either a lack of efficacy or, more importantly, adversity resulting in regression of already achieved benefits. It is our contention that the available evidence has uncovered the remarkable complexity of interaction within the context of the neurohormonal construct. As we stand at a crossroad in HF and begin to fervently pursue non-neurohormonal therapeutic targets, we must also direct attention at navigating the multifaceted labyrinth of the neurohormonal model that has led to the current imbroglio.

Gene Expression Profiles and B-Type Natriuretic Peptide Elevation in Heart Transplantation More Than a Hemodynamic Marker

Background— B-type natriuretic peptide (BNP) is chronically elevated in heart transplantation and reflects diastolic dysfunction, cardiac allograft vasculopathy, and poor late outcome. This investigation studied peripheral gene expression signatures of elevated BNP concentrations in clinically quiescent heart transplant recipients in an effort to elucidate molecular correlates beyond hemodynamic perturbations. Methods and Results— We performed gene microarray analysis in peripheral blood mononuclear cells of 28 heart transplant recipients with clinical quiescence (absence of dyspnea or fatigue; normal left ventricular ejection fraction [EF >55%]; ISHLT biopsy score 0 or 1A; and normal hemodynamics [RAP <7 mm Hg, PCWP ≤15 mm Hg, and CI ≥2.5 L/min per m2]). BNP levels were performed using the Triage B-type Natriuretic Peptide test (Biosite Diagnostics Inc, San Diego, Calif) and median BNP concentration was 165 pg/mL. Seventy-eight probes (of 7370) mapped to 54 unique genes were significantly correlated with BNP concentrations (P<0.001). Of these, the strongest correlated genes (P<0.0001) were in the domains of gelsolin (actin cytoskeleton), matrix metallopeptidases (collagen degradation), platelet function, and immune activity (human leukocyte antigen system, heat shock protein, mast cell, and B-cell lineage). Conclusions— In the clinically quiescent heart transplant recipient, an elevated BNP concentration is associated with molecular patterns that point to ongoing active cardiac structural remodeling, vascular injury, inflammation, and alloimmune processes. Thus, these findings allude to the notion that BNP elevation is not merely a hemodynamic marker but should be considered reflective of integrated processes that determine the balance between active cardiac allograft injury and repair.

Anything but a biopsy: noninvasive monitoring for cardiac allograft rejection

Endomyocardial biopsy has stood the test of time as a surveillance technique; however, the expense, resources required, invasive nature, and low but definite risks have motivated investigators to pursue less invasive techniques. The search for noninvasive surveillance techniques for cardiac rejection have centered on measurements of cardiac function, intragraft electrical events, peripheral proteomic markers of graft micronecrosis, immune activation, and nonimmune accompaniments of rejection. Although several investigations allude to a reasonable negative predictive value of such monitoring, the specificity of these techniques remains poor. Until well-constructed studies not only define the predictive values of noninvasive techniques but also appropriately evaluate the clinical safety of any such approach, invasive endomyocardial biopsy will remain the gold standard.

Generic drug immunosuppression in thoracic transplantation: an ISHLT educational advisory.

c he 1990s ushered in approval of several novel immuosuppressant drugs, including mycophenolate mofetil, acrolimus, cyclosporine microemulsion, everolimus and irolimus, with consequent improvement in clinical utcomes. Subsequently, the transplant community has een challenged with the development and introducion of generic immunosuppression drugs. These drugs epresent a narrow therapeutic index and are thus lassified as critical-dose agents. Sengai Gibon, a Japaese zen monk, wrote “Whether for life, whether for eath—(it depends on) the right spoon-measure.” The urpose of this educational advisory is to provide an nternational perspective on regulatory and clinical oncerns with generic immunosuppression medicaions in thoracic transplantation.

Allosensitization in heart transplantation: implications and management strategies.

The detection of anti-human leukocyte antigen (HLA) donor-specific antibodies has been associated with a variety of clinical syndromes that determine short-term and long-term outcomes of cardiac transplant recipients, including an increased incidence of early and more severe allograft rejection and cardiac allograft vasculopathy. Recent surveys indicate marked heterogeneity in clinical protocols for detection and management of sensitization in heart transplantation. The commonly performed complement-dependent cytotoxicity assay is insensitive compared with newer methods such as flow cytometry for antibody screening. The imperative exists to create strategies that can decrease the level of sensitization and increase the likelihood for a negative crossmatch. In this effort, several strategies have been suggested, including administration of intravenous immunoglobulin, apheresis, and combination therapies using potent immunosuppression, particularly with cyclophosphamide. The future of managing allosensitization may be in induction of a chimeric state to allow graft tolerance.