J. Eduardo Rame

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Unexpected Abrupt Increase in Left Ventricular Assist Device Thrombosis

BACKGROUND We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study. METHODS We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis. RESULTS A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis. CONCLUSIONS The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device

BACKGROUND Pump thrombosis remains an uncommon but potentially catastrophic complication of durable continuous-flow left ventricular assist devices (LVAD). A perceived increase in the incidence of pump thrombosis in the HeartMate II (HMII) LVAD (Thoratec, Pleasanton, CA) by clinicians prompted this analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. METHODS Between 2006 and June 2013, 8,988 United States patients aged older than 18 years received a durable LVAD. Of these, 6,910 adult patients from 132 institutions who received a HMII LVAD were entered in the INTERMACS database and constitute the study group for this analysis. RESULTS Overall survival (with censoring at transplant or explant for recovery) with the HMII LVAD was 80% at 1 year and 69% at 2 years and was not significantly different when stratified by era of implant. Freedom from device exchange or death due to thrombosis decreased from 99% at 6 months in 2009 to 94% in 2012 (p < 0.0001). Multivariable hazard function analysis showed risk factors for pump thrombosis included later implant year (p < 0.0001), younger age (p < 0.0001), higher creatinine (p = 0.002), larger body mass index (p = 0.004), white race (p = 0.0004), left ventricular ejection fraction above 20% (p = 0.02), and higher lactate dehydrogenase level at 1 month (p < 0.0001). Survival (p < 0.0001) and freedom from infection (p = 0.008) and cerebrovascular accident (p < 0.0001) were lower after pump exchange than after primary implant. CONCLUSIONS Pump exchange or death due to pump thrombosis increased during 2011 and 2012, but the magnitude of the increase remained relatively small. Survival remains high (80% at 1 year) with the HMII LVAD. Risk factor analysis suggests that a number of patient-related factors contribute to the risk of thrombosis. Markedly elevated lactate dehydrogenase in the first month is a predictor of pump thrombosis. This analysis could not examine the potential role of technical factors during implant, such as sub-optimal pump or graft positioning, changes in patient management paradigms with pump speed settings, improved recognition and change in the threshold for pump exchange, or design or production changes with the pump, as contributors to the risk of pump thrombosis.

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Background—Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results—We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ⩽22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017). Conclusions—ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Corin Gene Minor Allele Defined by 2 Missense Mutations Is Common in Blacks and Associated With High Blood Pressure and Hypertension

Background— The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. Method and Results— This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in ≈12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7±20.7 versus 129.4±17.4 mm Hg; P=0.029) and adjusted (132.5±1.6 versus 128.9±0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8±1.9 versus 121.4±0.7 mm Hg; P=0.03). Conclusions— The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.

Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload

Corin activates pro–A-type naturetic peptide and pro–B-type naturetic peptide into biologically active molecules. We recently identified a minor allele in the corin gene defined by 2 highly linked single nucleotide polymorphisms (T555I and Q568P), which was associated with hypertension in blacks. Because of the direct antihypertrophic effects of the natriuretic peptide system, we hypothesized that the minor corin I555(P568) allele would be associated with an enhanced hypertrophic response to pressure overload. The relationship between systolic blood pressure and indexed left ventricular mass, derived from cardiac MRI, was analyzed in the Dallas Heart Study as a function of corin allele status. The Multi-Ethnic Study of Atherosclerosis was used as a validation cohort. All of the analyses were limited to self-identified blacks without treatment for hypertension. In addition, we genotyped 2114 markers highly informative for African ancestry in the Dallas Heart Study and derived a covariate representing African ancestry for multivariate models. In adjusted analysis, the corin I555(P568) allele was an independent predictor of left-ventricular mass in subjects with elevated systolic blood pressure. Linear spline regression analysis confirmed a significant interaction (P=0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure >120 mm Hg, and this nonlinear interaction was replicated in the Multi-Ethnic Study of Atherosclerosis. In the Dallas Heart Study, the corin I555(P568) allele was also associated with an increased odds for prevalent left ventricular hypertrophy in the presence of untreated hypertension. These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension.

Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary Left Ventricular Assist Devices

Background— Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results— In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions— In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.

Background— The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se. Methods and Results— We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic &bgr;-hydroxybutyryl-CoA, in association with increased myocardial utilization of &bgr;-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of &bgr;-hydroxybutyrate and acetoacetate. Conclusions— These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.

Left Ventricular Hypertrophy, Subclinical Atherosclerosis, and Inflammation

To elucidate mechanisms by which left ventricular (LV) hypertrophy (LVH) increases the risk of atherosclerotic heart disease, we sought to determine whether LVH is independently associated with coronary artery calcium (CAC) and serum C-reactive protein (CRP) levels in the general population. The Dallas Heart Study is a population-based sample in which 2633 individuals underwent cardiac MRI to measure LV structure, electron beam CT to measure CAC, and measurement of plasma CRP. We used univariate and multivariable analyses to determine whether LV mass and markers of concentric LV hypertrophy or dilation were associated with CAC and CRP. Increasing quartiles of LV mass indexed to fat-free mass, LV wall thickness, and concentricity, but not LV volume, were associated with CAC in both men and women (P<0.001). After adjustment for traditional cardiovascular risk factors and statin use, LV wall thickness and concentricity remained associated with CAC in linear regression (P<0.001 for each). These associations were particularly robust in blacks. LV wall thickness and concentricity were also associated with elevated CRP levels (P=0.001 for both) in gender-stratified univariate analyses, although these associations did not persist in multivariable analysis. In conclusion, concentric LVH is an independent risk factor for subclinical atherosclerosis. LVH is also associated with an inflammatory state as reflected in elevated CRP levels, although this relationship appears to be mediated by comorbid conditions. These data likely explain in part why individuals with LVH are at increased risk for myocardial infarction.