Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Early Postoperative Aortic Root Thrombus After Heartmate 3.

As a bridge to heart transplantation or destination treatment, implantation of the Heartmate 3 (HM3) left ventricular assist device is a viable option for patients with end-stage congestive heart failure. The recent Momentum 3 trial has shown favorable outcomes compared with Heartmate 2. We report the first case of aortic root thrombus occurring early after HM3 implantation as a bridge to heart transplantation. Our case suggests that bridging with an Impella 5.0 preceding HM3 implantation could potentially predispose patients to aortic root thrombus after HM3 implantation, due to Impella-related injury to the aortic valve and aortic root stasis after durable LVAD support.

Cardiorespiratory Fitness (Peak Oxygen Uptake): Safe and Effective Measure for Cardiovascular Screening Before Kidney Transplant.

BACKGROUND: Significant heterogeneity exists in practice patterns and algorithms used for cardiac screening before kidney transplant. Cardiorespiratory fitness, as measured by peak oxygen uptake (VO2peak), is an established validated predictor of future cardiovascular morbidity and mortality in both healthy and diseased populations. The literature supports its use among asymptomatic patients in abrogating the need for further cardiac testing. METHODS AND RESULTS: We outlined a pre-renal transplant screening algorithm to incorporate VO2peak testing among a population of asymptomatic high-risk patients (with diabetes mellitus and/or >50 years of age). Only those with VO2peak <17 mL/kg per minute (equivalent to <5 metabolic equivalents) underwent further noninvasive cardiac screening tests. We conducted a retrospective study of the a priori dichotomization of the VO2peak <17 versus ≥17 mL/kg per minute to determine negative and positive predictive value of future cardiac events and all-cause mortality. We report a high (>90%) negative predictive value, indicating that VO2peak ≥17 mL/kg per minute is effective to rule out future cardiac events and all-cause mortality. However, lower VO2peak had low positive predictive value and should not be used as a reliable metric to predict future cardiac events and/or mortality. In addition, a simple mathematical calculation documented a cost savings of ≈$272 600 in the cardiac screening among our study cohort of 637 patients undergoing evaluation for kidney and/or pancreas transplant. CONCLUSIONS: We conclude that incorporating an objective measure of cardiorespiratory fitness with VO2peak is safe and allows for a cost savings in the cardiovascular screening protocol among higher-risk phenotype (with diabetes mellitus and >50 years of age) being evaluated for kidney transplant.

Histologic remission of cardiac amyloidosis: a case report.

The main determinant of survival in amyloid light chain amyloidosis is cardiac involvement. The rate of change in wall thickness may be a strong predictor of survival. After treatment, some hematologic responders have had documented regression of wall thickness by echocardiography with resolution of heart failure symptoms. Herein, we demonstrate a case of treated immunoglobulin light chain cardiac amyloidosis with echocardiographic wall thinning and cardiac biopsies demonstrating complete histologic remission. This observation suggests a mechanism of treatment response and that with appropriately timed treatment, cardiac deposition of amyloid fibrils can be completely reversed.

Antibody-mediated rejection in heart transplantation: case presentation with a review of current international guidelines.

Antibody-mediated rejection (AMR) (humoral rejection) of cardiac allografts remains difficult to diagnose and treat. Interest in AMR of cardiac allografts has increased over the last decade as it has become apparent that untreated humoral rejection threatens graft and patient survival. An international and multidisciplinary consensus group has formulated guidelines for the diagnosis and treatment of AMR and established that identification of circulating or donor-specific antibodies is not required and that asymptomatic AMR, that is, biopsy-proven AMR without cardiac dysfunction is a real entity with worsened prognosis. Strict criteria for the diagnosis of cardiac AMR have not been firmly established, although the diagnosis relies heavily on tissue pathological findings. Therapy remains largely empirical. We review an unfortunate experience with one of our patients and summarize recommended criteria for the diagnosis of AMR and potential treatment schemes with a focus on current limitations and the need for future research and innovation.

Natural history of left ventricular mechanics in transplanted hearts: relationships with clinical variables and genetic expression profiles of allograft rejection.

OBJECTIVES: The aim of this study was to explore the temporal evolution of left ventricular (LV) mechanics in relation to clinical variables and genetic expression profiles implicated in cardiac allograft function. BACKGROUND: Considerable uncertainty exists regarding the range and determinants of variability in LV systolic performance in transplanted hearts (TXH). METHODS: Fifty-one patients (mean age 53 ± 12 years; 37 men) underwent serial assessment of echocardiograms, cardiac catheterization, gene expression profiles, and endomyocardial biopsy data within 2 weeks and at 3, 6, 12, and 24 months after transplantation. Two-dimensional speckle-tracking data were compared between patients with TXH and 37 controls (including 12 post-coronary artery bypass patients). Post-transplantation mortality and hospitalizations were recorded with a median follow-up period of 944 days. RESULTS: Global longitudinal strain (LS) and radial strain remained attenuated in patients with TXH at all time points (p < 0.001 and p = 0.005), independent of clinical rejection episodes. Failure to improve global LS at 3 months (≥ 1 SD) was associated with higher incidence of death and cardiac events (hazard ratio: 5.92; 95% confidence interval: 1.96 to 17.91; p = 0.049). Multivariate analysis revealed gene expression score as the only independent predictor of global LS (R(2) = 0.53, p = 0.005), with SEMA7A gene expression having the highest correlation with global LS (r = -0.84, p < 0.001). CONCLUSIONS: Speckle tracking-derived LV strains are helpful in estimating the burden of LV dysfunction in patients with TXH that evolves independent of biopsy-detected cellular rejection. Failure to improve global LS at 3 months after transplantation is associated with a higher incidence of death and cardiac events. Serial changes in LV mechanics correlate with peripheral blood gene expression profiles and may affect the clinical assessment of long-term prognosis in patients with TXH.

Successive circulatory support stages: a triple bridge to recovery from fulminant myocarditis.

Fulminant myocarditis with rapid onset of symptoms and hemodynamic compromise is a rare indication for mechanical support. Because of the potentially reversible nature of this illness, advanced mechanical circulatory support is warranted to achieve recovery or as a bridge to transplantation. Circulatory device options currently available allow for a phased implementation of support modalities in a manner that reduces costs and patient risk. We present a patient with fulminant myocarditis where extracorporeal membrane oxygenation (ECMO) support escalated to short-term Levitronix CentriMag (Levitronix, Waltham, MA) biventricular assist devices (BiVADs). These in turn were exchanged, without major surgery, to long-term paracorporeal VADs (Thoratec, Pleasanton, CA). After rehabilitation and nearly total recovery, the patient was weaned from mechanical circulatory support after 104 cumulative days.

Recrudescent tobacco exposure following heart transplantation: clinical profiles and relationship with athero-thrombosis risk markers.

To identify tobacco recidivism among 86 heart transplant recipients who were smokers but demonstrated compliance with a smoking cessation program pre-transplant, we used a questionnaire and randomly tested urine for nicotine and its by-products. In 36 patients, we also evaluated circulating levels of HS-CRP, homocysteine and MPV. Twenty-eight (32.5%) of 86 patients met our definition for tobacco exposure. In this cohort, 28 (32.5%) of 86 patients met our definition for tobacco exposure. Of these 28, 12 patients self-reported tobacco use and demonstrated biochemical verification; 14 patients demonstrated only biochemical evidence of significant tobacco exposure; 2 patients self-reported tobacco use but did not demonstrate biochemical positivity. Smoking cessation within 6 months of transplantation (r = 0.52) and time post-transplantation (r = 0.43) were independent predictors for recidivism of tobacco use, p < 0.01. No differences in HS-CRP, homocysteine and MPV levels were noted among the groups. Our investigation demonstrates a high rate of tobacco recidivism among heart transplant recipients, yet few admit to it. The adverse effects of tobacco do not appear to be directly modulated by an effect on athero-thrombotic risk markers.

Obesity and suppressed B-type natriuretic peptide levels in heart failure.

OBJECTIVES: This investigation evaluated the relationship between obesity and B-type natriuretic peptide (BNP) in heart failure. BACKGROUND: Obesity is a major risk factor for the development of heart failure, but the precise mechanisms remain uncertain. Physiologically, natriuretic peptides and lipolysis are closely linked. METHODS: A total of 318 patients with heart failure were evaluated between June 2001 and June 2002. Levels of BNP were compared in obese (body mass index [BMI] > or =30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with respect to New York Heart Association functional class and lean body weight-adjusted peak aerobic oxygen consumption. In a subset of 36 patients, plasma levels of tumor necrosis factor-alpha, interleukin-6, and soluble intercellular adhesion molecule-1 were measured. RESULTS: The population's BMI was 29.4 +/- 6.6 kg/m(2); 24% were lean (BMI <25 kg/m(2)), 31% overweight (BMI > or =25 to 29.9 kg/m(2)), and 45% obese (BMI > or =30 kg/m(2)). Obese patients were younger, more often African American, and more likely to have a history of antecedent hypertension, but less likely to have coronary artery disease and with only a trend toward diabetes mellitus. Levels of BNP were significantly lower in obese than in nonobese subjects (205 +/- 22 and 335 +/- 39 pg/ml, respectively; p = 0.0007), despite a similar severity of heart failure and cytokine levels. Multivariate regression analysis identified BMI as an independent negative correlate of BNP level. There were no differences in emergency department visits, heart failure hospitalization, or death between the obese and nonobese patients at 12-month follow-up. CONCLUSIONS: Our investigation indicates that a state of reduced natriuretic peptide level exists in the obese individual with heart failure.

B-type natriuretic peptide in heart transplantation: an important marker of allograft performance.

The successful management of a cardiac allograft recipient centers around detection of allograft dysfunction early and preferably in a noninvasive manner. Up to this point, echocardiography or right heart catherization with endomyocardial biopsy are the only definitive methods available to diagnose allograft dysfunction. However, these methods do not reflect early structural changes and neurohormonal aberrations involved in allograft dysfunction. B-type natriuretic peptide (BNP) reflects ventricular wall stress and pressure and early studies have intimated potential usefulness of this marker in heart transplantation. Recent studies utilizing point-of-care BNP assay in heart transplant recipients have demonstrated elevated BNP levels at baseline compared with controls. Furthermore, the two most significant correlates of BNP levels are central hemodynamic perturbations despite preserved systolic function and presence of right sided cardiac dysfunction. Initial investigations have demonstrated BNP levels to serve as prognostic marker for cardiac related events and to track responses to therapeutic interventions. Further studies are needed to further assess the utility of BNP as surrogate marker for cardiac function and adaptation.

Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity-quality paradox.

BACKGROUND: Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators' attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a "prognostically relevant" threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free. METHODS: We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass. RESULTS: Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 +/- 0.27 mm, vs Group 2, 0.94 +/- 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up. CONCLUSIONS: These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.

Usefulness of B-type natriuretic peptide levels in predicting hemodynamic perturbations after heart transplantation despite preserved left ventricular systolic function.

The aim of this prospective study was to evaluate the association of peripheral B-type natriuretic peptide (BNP) levels with clinical symptoms and central hemodynamic and echocardiographic measures in cardiac transplantation. BNP reflects ventricular wall stress and correlates with severity of heart failure. No previous investigation has comprehensively assessed the rapid bedside BNP assay for predicting hemodynamic measures of cardiac allograft function in heart transplantation. We evaluated BNP levels using a rapid point-of-care assay in 87 stable cardiac transplant recipients who had 237 consecutive measurements along with endomyocardial biopsy, right-sided cardiac catheterization, and echocardiography. Using median tendencies, 2 groups were identified: the low BNP group (n = 116, BNP <150 pg/ml) and the high BNP group (n = 121, BNP >/=150 pg/ml). The high BNP group had increased right atrial pressures, higher pulmonary artery systolic pressures, pulmonary capillary wedge pressures, and lower cardiac index. Besides hemodynamic variables, the presence of right ventricular dysfunction (p = 0.05) and significant tricuspid regurgitation (p = 0.003) were associated with higher BNP levels. Independent predictors of BNP levels on multivariate analysis included elevated pulmonary capillary wedge pressure, lower cardiac index, and symptoms of dyspnea and fatigue. This initial investigation establishes the accuracy of a point-of-care BNP assay in predicting cardiopulmonary hemodynamic aberrations despite preserved left ventricular systolic function in heart transplant recipients. Rapid bedside BNP analysis may provide a noninvasive surrogate method for the comprehensive assessment of cardiac allograft function and hemodynamics in heart transplantation.

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.

Difficult cases in heart failure: the challenge of neurocognitive dysfunction in severe heart failure.

Often ignored, neurocognitive dysfunction in chronic heart failure represents a daunting morbidity progressing to loss of self-reliance. Although the precise mechanisms arbitrating the development of this disorder remain elusive, microembolization and cerebral hypoperfusion are implicated. Other causes of cognitive decline may include prior cardiac surgery, chronic hypertension, sleep disordered breathing, hyperhomocysteinemia, dementia of aging, and more traditional causes such as Alzheimer's disease. The discovery of neurocognitive defects in heart failure must prompt a well-constructed diagnostic evaluation to search for the underlying causes since this process may be at least partially reversible in many cases.

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.