Abdallah G. Kfoury

Outcomes of Left Ventricular Assist Device Implantation as Destination Therapy in the Post-REMATCH Era Implications for Patient Selection

Background— The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial first demonstrated that implantation of left ventricular assist devices (LVADs) as destination therapy (DT) can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation. In the present study, we describe outcomes of DT in the post-REMATCH era in the United States. Methods and Results— The present study included 280 patients who underwent HeartMate XVE LVAD implantation between November 2001 and December 2005. A preoperative risk score for in-hospital mortality after LVAD implantation was established in 222 patients with complete data. All patients were followed up until death or December 2006. The 1-year survival after LVAD implantation was 56%. The in-hospital mortality after LVAD surgery was 27%. The main causes of death included sepsis, right heart failure, and multiorgan failure. The most important determinants of in-hospital mortality were poor nutrition, hematological abnormalities, markers of end-organ or right ventricular dysfunction, and lack of inotropic support. Stratification of DT candidates into low (n=65), medium (n=111), high (n=28), and very high (n=18) risk on the basis of the risk score calculated from these predictors corresponded with 1-year survival rates of 81%, 62%, 28%, and 11%, respectively. Conclusions— Appropriate selection of candidates and timing of LVAD implantation are critical for improved outcomes of DT. Patients with advanced heart failure who are referred for DT before major complications of heart failure develop have the best chance of achieving an excellent 1-year survival with LVAD therapy.

Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation

BACKGROUND Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Risk factors predictive of right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation.

Report from a consensus conference on antibody-mediated rejection in heart transplantation

BACKGROUND The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. METHODS The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. RESULTS A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. CONCLUSIONS The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.

Pulsatility and the Risk of Nonsurgical Bleeding in Patients Supported With the Continuous-Flow Left Ventricular Assist Device HeartMate II

Background—Bleeding is an important cause of morbidity and mortality in patients with continuous-flow left ventricular assist devices (LVADs). Reduced pulsatility has been implicated as a contributing cause. The aim of this study was to assess the effects of different degrees of pulsatility on the incidence of nonsurgical bleeding. Methods and Results—The Utah Transplantation Affiliated Hospitals (U.T.A.H.) heart failure and transplant program databases were queried for patients with end-stage heart failure who required support with the continuous-flow LVAD HeartMate II (Thoratec Corp, Pleasanton, CA) between 2004 and 2012. Pulsatility was evaluated by means of the LVAD parameter pulsatility index (PI) and by the echocardiographic assessment of aortic valve opening during the first 3 months of LVAD support. PI was analyzed as a continuous variable and also stratified according to tertiles of all the PI measurements during the study period (low PI: <4.6, intermediate PI: 4.6–5.2, and high PI: >5.2). Major nonsurgical bleeding associated with a decrease in hemoglobin ≥2 g/dL (in the absence of hemolysis) was the primary end point. A total of 134 patients (median age of 60 [interquartile range: 49–68] years, 78% men) were included. Major bleeding occurred in 33 (25%) patients (70% gastrointestinal, 21% epistaxis, 3% genitourinary, and 6% intracranial). In multivariable analysis, PI examined either as a categorical variable, low versus high PI (hazard ratio, 4.06; 95% confidence interval, 1.35–12.21; P=0.04), or as a continuous variable (hazard ratio, 0.60; 95% confidence interval, 0.40–0.92; P=0.02) was associated with an increased risk of bleeding. Conclusions—Reduced pulsatility in patients supported with the continuous-flow LVAD HeartMate II is associated with an increased risk of nonsurgical bleeding, as evaluated by PI.

Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized, Multicenter Trial

In an open‐label, 24‐month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced‐dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard‐dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12‐month composite incidence of biopsy‐proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow‐up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: –7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24‐month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12‐month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced‐dose cyclosporine offers similar efficacy to MMF with standard‐dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Relation of Heart Failure Hospitalization to Exposure to Fine Particulate Air Pollution

Cardiopulmonary disease has been associated with particulate matter (PM) air pollution. There is evidence that exposure to elevated PM concentrations increases risk of acute ischemic heart disease events, alters cardiac autonomic function, and increases risk of arrhythmias. It is plausible, therefore, that PM exposure may exacerbate heart failure (HF). A case-crossover study design was used to explore associations between fine PM (PM(2.5): particles with an aerodynamic diameter < or =2.5 microm) and 2,628 HF hospitalizations. Patients lived on Utahs Wasatch Front and were drawn from those hospitalized at Intermountain Healthcare facilities with a primary diagnosis of HF. A 14-day lagged cumulative moving average of 10 microg/m(3) PM(2.5) was associated with a 13.1% (95% confidence interval 1.3 to 26.2) increase in HF admissions. The strongest PM(2.5)-HF associations were for elderly patients who had previously been admitted for HF and who required only a short period of hospitalization. HF hospitalizations are associated with lagged cumulative exposure to PM(2.5) of approximately 2 weeks. In conclusion, particulate air pollution may play a role in precipitating acute cardiac decompensation in otherwise well-managed patients with HF, perhaps through effects of PM on myocardial ischemia, cardiac autonomic function, and/or arrhythmic effects.

Red cell distribution width, C-reactive protein, the complete blood count, and mortality in patients with coronary disease and a normal comparison population.

BACKGROUND Red cell distribution width (RDW) is associated with morbidity and mortality in coronary artery disease (CAD), but the connection of RDW with chronic inflammation is equivocal. METHODS In 1,489 patients with CAD and 8.4-15.2 years of follow-up all-cause mortality and RDW were studied using Cox regression. RDW and its associations with inflammation, liver function, renal function, and body mass were assessed. A population of 449 normal (No-CAD) patients also was evaluated. RESULTS RDW predicted all-cause mortality in a step-wise manner (HR=1.37 per quintile; 95% CI=1.29, 1.46; p-trend<0.001). A significant but meaningless correlation between RDW and high-sensitivity C-reactive protein (hsCRP) was identified (r=0.181; p<0.001). With full adjustment, RDW remained significant (p-trend<0.001) and the strongest predictor of mortality among all factors included in the model. RDW also strongly predicted all-cause mortality in the normal control population (HR=1.33 per quintile, CI=1.15, 1.55; p-trend<0.001), but hsCRP did not predict mortality among normal controls. CONCLUSIONS RDW was associated with mortality in patients with CAD and may provide clinically useful prognostication. Although RDW was correlated with hsCRP, they were independent predictors of mortality. RDW has been incorporated into risk prediction tool using data from basic chemistries available at: http://intermountainhealthcare.org/IMRS.

Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery.

OBJECTIVES This study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function. BACKGROUND The magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown. METHODS Eighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies. RESULTS After 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥ 40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m(2), p < 0.01, and 92 vs. 60 ml/m(2), p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m(2), p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading. CONCLUSIONS Continuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression.

Cardiovascular Mortality Among Heart Transplant Recipients With Asymptomatic Antibody-Mediated or Stable Mixed Cellular and Antibody-Mediated Rejection

BACKGROUND Little has been reported on the clinical significance of asymptomatic antibody-mediated rejection (AMR) alone or mixed rejection (MR), defined as concurrent cellular rejection (CR) and AMR in heart transplantation. In this study, we examined whether a differential impact on cardiovascular mortality (CVM) existed when comparing asymptomatic AMR, to stable MR or CR. METHODS The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program pathology database of all heart transplant recipients between 1985 and 2004 was queried. Patients were classified as cellular, antibody-mediated, or mixed rejectors based on their predominant pattern of rejection type in the first three months post-transplant. Kaplan-Meier survival curves were fit to each of the three groups and analyses were adjusted for age at the time of transplant, gender, and underlying primary cardiac disease. RESULTS Eight hundred and sixty nine heart transplant recipients qualified for analysis. Over the study period, patients with asymptomatic AMR or stable MR patterns had significantly worse CVM when compared to patients with stable CR pattern (AMR, 21.2%; MR, 18.0%; CR, 12.6%; AMR vs. CR, p = 0.009; MR vs. CR, p = 0.001). In contrast, CVM was comparable in patients with asymptomatic AMR or stable MR patterns (p = 0.9). CONCLUSIONS Asymptomatic or subclinical AMR and MR are clinically relevant, should be recognized, and deserve consideration for therapeutic intervention in hopes of avoiding adverse outcomes.