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Background: In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation.Methods: We enrolled 15 patients with severe heart failure due to nonischemic cardiomyopathy and with no histologic evidence of active myocarditis. All had markedly reduced cardiac output and were receiving inotropes. The patients underwent implantation of left ventricular assist devices and were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling. Once regression of left ventricular enlargement had been achieved, the beta2-adrenergic-receptor agonist clenbuterol was administered to prevent myocardial atrophy.Results: Eleven of the 15 patients had sufficient myocardial recovery to undergo explantation of the left ventricular assist device a mean (+/-SD) of 320+/-186 days after implantation of the device. One patient died of intractable arrhythmias 24 hours after explantation; another died of carcinoma of the lung 27 months after explantation. The cumulative rate of freedom from recurrent heart failure among the surviving patients was 100% and 88.9% 1 and 4 years after explantation, respectively. The quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire score at 3 years was nearly normal. Fifty-nine months after explantation, the mean left ventricular ejection fraction was 64+/-12%, the mean left ventricular end-diastolic diameter was 59.4+/-12.1 mm, the mean left ventricular end-systolic diameter was 42.5+/-13.2 mm, and the mean maximal oxygen uptake with exercise was 26.3+/-6.0 ml per kilogram of body weight per minute.Conclusions: In this single-center study, we found that sustained reversal of severe heart failure secondary to nonischemic cardiomyopathy could be achieved in selected patients with the use of a left ventricular assist device and a specific pharmacologic regimen. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence of coexistence of aortic stenosis (AS) and transthyretin cardiac amyloidosis (CA). Not screening AS patients at the time of hospital/clinic visit for CA represents a lost opportunity., Methods: We surveyed studies that reported the prevalence of CA among AS patients. Studies that compared patients with aortic stenosis with cardiac amyloidosis (AS-CA) and AS alone were further analyzed, and meta-regression was performed., Results: We identified nine studies with 1,321 patients of AS, of which 131 patients had concomitant CA, with a prevalence of 11%. When compared to AS-alone, the patients with AS-CA were older, more likely to be males, had higher prevalence of carpal tunnel syndrome, right bundle branch block. On echocardiogram, patients with AS-CA had thicker interventricular septum, higher left ventricular mass index (LVMI), lower myocardial contraction fraction, and lower stroke volume index. Classical low-flow low-gradient (LFLG) physiology was more common among patients with AS-CA. Patients with AS-CA had higher all-cause mortality than patients with AS alone (33% vs. 22%, P = 0.02) in a follow-up period of at least 1 year., Conclusions: CA has a high prevalence in patients with AS and is associated with worse clinical, imaging, and biochemical parameters than patients with AS alone., Competing Interests: None of the authors have any conflict of interest to declare., (Copyright 2022, Arshad et al.)

Background: Gastrointestinal bleeding (GIB) is one of the most common bleeding complications associated with left ventricular assist devices (LVAD). Currently, there is no strong evidence or clear guidance for which secondary GIB prophylaxis strategy should be implemented after the discontinuation of aspirin., Methods: Our single-center study describes the outcomes of 26 LVAD patients who experienced a total of 49 GIB events: these individuals were either in Group-1 (lower INR target range) or Group-2 (lower INR target plus a hemostatic agent) as the secondary prophylaxis strategy. Each GIB event was considered an independent event. Outcomes assessed were bleeding reoccurrence rates, time to next GIB, acute GIB strategies, GIB-free days, thromboembolic events, survival, coagulation, and hematologic parameters., Results: GIB reoccurrence rates were not statistically different: Group-1, 9 (40.9%), versus Group-2, 15 (55.6%); p = 0.308. Danazol was utilized 81.5% of the time as the designated hemostatic agent. Additionally, no significant differences were observed with all of our secondary outcome measures for bleeding, ischemic events, or survival., Conclusion: While our study was not powered to assess the clinical outcomes related to survival and thromboembolic events, no discernable increased risk for ischemic events including pump thrombosis were observed. Our data suggest that a lower INR target range plus danazol does not confer any additional benefit over a lower INR target range only approach. The results of this report are hypothesis-generating and additional studies are warranted to elucidate the optimal antithrombotic strategy and role of hemostatic agents in reducing the risk of recurrent GIB events., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Cardiac remodeling is an adaptive, compensatory biological process following an initial insult to the myocardium that gradually becomes maladaptive and causes clinical deterioration and chronic heart failure (HF). This biological process involves several pathophysiological adaptations at the genetic, molecular, cellular, and tissue levels. A growing body of clinical and translational investigations demonstrated that cardiac remodeling and chronic HF does not invariably result in a static, end-stage phenotype but can be at least partially reversed. One of the paradigms which shed some additional light on the breadth and limits of myocardial elasticity and plasticity is long term mechanical circulatory support (MCS) in advanced HF pediatric and adult patients. MCS by providing (a) ventricular mechanical unloading and (b) effective hemodynamic support to the periphery results in functional, structural, cellular and molecular changes, known as cardiac reverse remodeling. Herein, we analyze and synthesize the advances in our understanding of the biology of MCS-mediated reverse remodeling and myocardial recovery. The MCS investigational setting offers access to human tissue, providing an unparalleled opportunity in cardiovascular medicine to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures. These human tissue findings have triggered and effectively fueled a "bedside to bench and back" approach through a variety of knockout, inhibition or overexpression mechanistic investigations in vitro and in vivo using small animal models. These follow-up translational and basic science studies leveraging human tissue findings have unveiled mechanistic myocardial recovery pathways which are currently undergoing further testing for potential therapeutic drug development. Essentially, the field is advancing by extending the lessons learned from the MCS cardiac recovery investigational setting to develop therapies applicable to the greater, not end-stage, HF population. This review article focuses on the biological aspects of the MCS-mediated myocardial recovery and together with its companion review article, focused on the clinical aspects, they aim to provide a useful framework for clinicians and investigators., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Post-translational modification of the myofilament protein troponin I by phosphorylation is known to trigger functional changes that support enhanced contraction and relaxation of the heart. We report for the first time that human troponin I can also be modified by SUMOylation at lysine 177. Functionally, TnI SUMOylation is not a factor in the development of passive and maximal force generation in response to calcium, however this modification seems to act indirectly by preventing SUMOylation of other myofilament proteins to alter calcium sensitivity and cooperativity of myofilaments. Utilising a novel, custom SUMO site-specific antibody that recognises only the SUMOylated form of troponin I, we verify that this modification occurs in human heart and that it is upregulated during disease., (© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes 1 . Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer 2 . Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background Experiments measuring the contractile properties of human myocardium are important for translational research but complicated by the logistical difficulties of acquiring specimens. Accordingly, many groups perform contractile assays using samples that are acquired from patients at one institution and shipped to another institution for experiments. This necessitates freezing the samples and performing subsequent assays using chemically permeabilized preparations. It is unknown how prior freezing affects the contractile function of these preparations. Methods and Results To examine the effects of freezing we measured the contractile function of never-frozen and previously frozen myocardial samples. Samples of left ventricular tissue were obtained from 7 patients who were having a ventricular assist device implanted. Half of each sample was chemically permeabilized and used immediately for contractile assays. The other half of the sample was snap frozen in liquid nitrogen and maintained at -180 °C for at least 6 months before being thawed and tested in a second series of experiments. Maximum isometric force measured in pCa 4.5 solution, passive force measured in pCa 9.0 solution, and Hill coefficients were not influenced by prior freezing ( P =0.07, P =0.14, and P =0.27 respectively). pCa 50 in never-frozen samples (6.11±0.04) was statistically greater ( P <0.001) than that measured after prior freezing (5.99±0.04) but the magnitude of the effect was only ≈0.1 pCa units. Conclusions We conclude that prior freezing has minimal impact on the contractile properties that can be measured using chemically permeabilized human myocardium.

Purpose of Review: Progression of heart failure (HF) and its unpredictable and volatile nature, often requires advanced therapies including heart transplant. Mechanical circulatory support plays an integral part in the advanced treatment options. This technology can be deployed in several ways, particularly in the preparation and patient optimization for heart transplants. This article discusses the use of temporary and durable devices and their deployment strategies in the pre and posttransplant period., Recent Findings: Recently temporary mechanical support devices have allowed us to improve survival to transplant as well as posttransplant. Early implementation of temporary devices both for stabilization of advanced HF patients being considered for transplant as well as those with posttransplant primary graft dysfunction (although utilization of extracorporeal membrane oxygenation has repeatedly shown to be associated with worse outcomes compared to the other devices discussed), is reflective of the degree of disease progression in these patients. The outcomes of patients supported with durable devices have significantly improved with advancing technology. HeartMate 3 device has not only been shown to improve survival as well as the quality of life but in comparison to its predecessor, has been shown to decrease the morbidity associated with this technology., Summary: Both temporary and durable devices are now associated with improved survival and allow us to transplant patients in a more stable and safer manner with fewer adverse events. Based on the new United Network of Organ Sharing allocation system, it allows us to upgrade those who do not have the luxury of time to wait for a transplant. Primary graft dysfunction now also can be assisted with those devices, which is reflected in improved survival of posttransplant patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation., Methods: Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months., Results: Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P <0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years., Conclusions: In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.

Background: Ventricular assist devices provide improved outcomes for patients with advanced heart failure, but their benefit in the severely obese is not well documented., Methods: Patients enrolled in the HeartWare ADVANCE trial (n=382) were divided into 2 body mass index (BMI) groups. Patients with severe obesity (>35 kg/m 2 ) were compared with a control group with BMI ≤35 kg/m 2 . The association of BMI with survival was tested using Kaplan-Meier analysis and major adverse events were compared., Results: At implantation, 48 (13%) of patients were severely obese. There was no difference in survival through 2 years of support between severely obese patients and the control group. Severely obese patients were at higher risk of driveline infection (P = .01) and acute renal dysfunction (P = .002). Both groups experienced similar improvements in quality of life. Functional capacity improved in both severely obese and control patients, although severely obese patients had smaller improvements than controls in their 6-minute walk scores., Conclusions: Despite an increased risk of adverse events, severe obesity was not associated with reduced survival or quality of life. A better understanding of the risks and benefits of left ventricular assist device therapy in obese patients will help in the shared decision-making of the patient selection process., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: While clinical experience with left ventricular assist devices (LVAD) continues to grow and evolve, little is known regarding the ongoing use of certain medications in this population. We sought to evaluate the utility of digoxin in LVAD recipients and its association with outcomes., Methods: A total of 505 patients who underwent continuous-flow LVAD implantation at 5 centers from 2007-2015 were included. Patients were divided into 4 groups: not on digoxin at any time (ND; n = 257), received digoxin pre implant (PreD; n = 144), received digoxin pre and post implant (ContD; n = 55), and received digoxin only post implant (PostD; n = 49). Survival and all-cause readmission were compared between the 4 groups., Results: There was no difference in survival at 1 year nor at 3 years between groups (ND = 88%, 66%, respectively; PreD = 85%, 66%; ContD = 86%, 57%; PostD = 90%, 51%; p = 0.7). Readmission per 100 days also was not different between groups (ND = 0.5, PreD = 0.6, ContD = 0.5, PostD = 0.7; p = 0.1)., Conclusions: In this large, multicenter cohort, use of digoxin was not associated with any significant benefit in regard to mortality or hospitalization in patients supported with a continuous-flow LVAD. Importantly, its discontinuation post implant did not worsen all-cause hospitalization or survival., Competing Interests: Henri Roukoz is a consultant for Boston Scientific. Jennifer Cowger serves on a steering committee for Medtronic, receives research-related travel support from Abbott, and receives institutional clinical trial research support from Medtronic and Abbott. Mark S. Slaughter has a research grant from Heartware Inc., and serves on an advisory board for Oregon Heart (no compensation). Rakesh Gopinathannair is a consultant and serves on speakers’ bureaus for Abbott Medical, American Heart Association, Pfizer, Bristol Myers Squibb, and Zoll Medical, and serves on an advisory board for HealthTrust PG. Ashwin Ravichandran serves on speakers’ bureaus and receives institutional clinical trial research support and research-related travel support from Abbott and Medtronic. All other authors report that they have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Hemorrhagic or thrombotic events are common complications in heart failure patients with continuous-flow left ventricular assist device (CF-LVAD) support. Aim of this study is to investigate the effect of change in antiplatelet therapy after thrombotic or hemorrhagic events in patients with CF-LVAD support. A total of 231 CF-LVAD patients were included in this study. Patients with CF-LVAD were categorized into three groups: (1) high antiplatelet regimen as control group (aspirin [ASA] 325 mg; n = 115), (2) low antiplatelet regimen (ASA 81 mg; n = 82), started after hemorrhagic complications, and (3) double antiplatelet therapy (ASA/clopidogrel; n = 34) started after thrombotic complications. In our analysis, indications for low antiplatelet therapy were gastrointestinal (GI) bleeding (36%), hemorrhagic stroke (8%), and epistaxis (9%). Freedom from major bleeding events after changing therapy was comparable at 1 year for all three groups respectively 96%, 97%, and 91% (log rank = 0.421). Major indications for double antiplatelet therapy were pump thrombosis (15%) and coronary artery stent placement (2.5%). Freedom from thrombotic events after changing therapy was comparable at 1 year for groups 1, 2, and 3, respectively, 97%, 98%, and 91% (log rank = 0.317). Logistic regression shows that Heartmate II patients required more antiplatelet therapy changes compared with HeartWare (odds ratio [OR]: 3.611, 95% confidence interval [CI]: 1.8-6.9; p = 0.0001). HeartMate II required more adjustment of antiplatelet therapy during follow-up. Reducing or increasing antithrombotic therapies in response to major thrombotic hemorrhagic events in CF-LVAD patients is a safe strategy to avoid recurrences.

Objectives: Wide QRS duration and ventricular pacing are common in recipients of continuous-flow left ventricular assist devices (CF-LVADs) but their impact on outcomes remains unclear. We assessed the clinical and arrhythmic outcomes of CF-LVAD patients with wide QRS or right ventricular (RV) pacing at baseline, compared with those with narrow QRS and those with continued cardiac resynchronization therapy (CRT)., Methods and Results: A total of 520 patients (57 ± 13 years) with an implantable cardioverter-defibrillator (ICD) (n = 240) or CRT-defibrillator (n = 280) who underwent CF-LVAD implantation at 5 centers in 2007-2015 were studied. Patients were divided into 3 groups: ICD-N (QRS ≤120 ms; n = 134), ICD-W (QRS >120 ms; n = 106), and CRT (n = 280). Mortality, hospitalization, and ventricular arrhythmia (VA) incidence were compared among the groups. Baseline QRS duration was different among the groups (100 ± 13 [ICD-N] vs 155 ± 26 [ICD-W] vs 159 ± 29 ms [CRT]; P < .0001). In the ICD-W group, 37 (35%) had >80% RV pacing at baseline. Median biventricular pacing in the CRT group was 96%. Over 523 days of CF-LVAD support, Kaplan-Meier analysis showed no difference in survival among groups (log rank P = .9). According to multivariate Cox regression, wide QRS duration and RV pacing were not associated with survival. QRS narrowed during CF-LVAD support in the ICD-W and CRT groups but was not associated with improved survival (P = .9). No differences were noted among the groups in hospitalizations (P = .9), VA (P = .2), or ICD shocks (P = .06)., Conclusions: In this large CF-LVAD cohort, a wide QRS duration, high percentage of RV pacing at baseline, and changes in QRS duration after LVAD implantation were not associated with survival. Continued CRT after CF-LVAD implantation also was not associated with improved survival or HF hospitalizations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to prospectively evaluate the impact of blood pressure management on stroke rates in patients receiving the HeartWare HVAD System., Background: The ENDURANCE trial demonstrated noninferiority of the HeartWare HVAD System versus control (HeartMate II) in patients with advanced heart failure ineligible for heart transplantation. However, stroke was more common in HVAD subjects. Post hoc analyses demonstrated increased mean arterial blood pressure as a significant independent risk factor for stroke., Methods: The ENDURANCE Supplemental Trial was a prospective, multicenter evaluation of 465 patients with advanced heart failure ineligible for transplantation, randomized 2:1 to HVAD (n = 308) or control (n = 157). The primary endpoint was the 12-month incidence of transient ischemic attack or stroke with residual deficit 24 weeks post-event. Secondary endpoints included the composite of freedom from death, disabling stroke, and need for device replacement or urgent transplantation, as well as comparisons of stroke or transient ischemic attack rates in HVAD cohorts in ENDURANCE Supplemental and ENDURANCE., Results: The enhanced blood pressure protocol significantly reduced mean arterial blood pressure. The primary endpoint was not achieved (14.7% with HVAD vs. 12.1% with control, noninferiority [margin 6%] p = 0.14). However, the secondary composite endpoint demonstrated superiority of HVAD (76.1%) versus control (66.9%) (p = 0.04). The incidence of stroke in HVAD subjects was reduced 24.2% in ENDURANCE Supplemental compared with ENDURANCE (p = 0.10), and hemorrhagic cerebrovascular accident was reduced by 50.5% (p = 0.02)., Conclusions: The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of HVAD versus control regarding the pre-specified primary endpoint. However, the trial confirmed that BP management is associated with reduced stroke rates in HVAD subjects. HVAD subjects, relative to control subjects, more commonly achieved the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation). (A Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System [ENDURANCE SUPPLEMENTAL TRIAL] [DT2]; NCT01966458)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with heart failure continue cardiac resynchronization therapy (CRT) after continuous flow left ventricular assist device (CF-LVAD) implant. We report the first multicenter study to assess the impact of CRT on clinical outcomes in CF-LVAD patients., Methods and Results: Analysis was performed on 488 patients (58±13 years, 81% male) with an implantable cardioverter defibrillator (ICD) (n=223) or CRT-D (n=265) who underwent CF-LVAD implantation at 5 centers from 2007 to 2015. Effects of CRT on mortality, hospitalizations, and ventricular arrhythmia incidence were compared against CF-LVAD patients with an ICD alone. Baseline differences were noted between the 2 groups in age (60±12 versus 55±14, P <0.001) and QRS duration (159±29 versus 126±34, P =0.001). Median biventricular pacing in the CRT group was 96%. During a median follow-up of 478 days, Kaplan-Meier analysis showed no difference in survival between groups (log rank P =0.28). Multivariate Cox regression demonstrated no survival benefit with type of device (ICD versus CRT-D; P =0.16), whereas use of amiodarone was associated with increased mortality (hazard ratio 1.77, 95% confidence interval 1.1-2.8, P =0.01). No differences were noted between CRT and ICD groups in all-cause ( P =0.06) and heart failure ( P =0.9) hospitalizations, ventricular arrhythmia incidence (43% versus 39%, P =0.3), or ICD shocks (35% versus 29%, P =0.2). During follow-up, 69 (26%) patients underwent pulse generator replacement in the CRT-D group compared with 36 (15.5%) in the ICD group ( P =0.003)., Conclusions: In this large, multicenter CF-LVAD cohort, continued CRT was not associated with improved survival, hospitalizations, incidence of ventricular arrhythmia and ICD therapies, and was related to a significantly higher number of pulse generator changes., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Mechanical circulatory support with a left ventricular assist device (LVAD) is an established treatment for patients with advanced heart failure. We compared a newer LVAD design (a small intrapericardial centrifugal-flow device) against existing technology (a commercially available axial-flow device) in patients with advanced heart failure who were ineligible for heart transplantation., Methods: We conducted a multicenter randomized trial involving 446 patients who were assigned, in a 2:1 ratio, to the study (centrifugal-flow) device or the control (axial-flow) device. Adults who met contemporary criteria for LVAD implantation for permanent use were eligible to participate in the trial. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The trial was powered to show noninferiority with a margin of 15 percentage points., Results: The intention-to treat-population included 297 participants assigned to the study device and 148 participants assigned to the control device. The primary end point was achieved in 164 patients in the study group and 85 patients in the control group. The analysis of the primary end point showed noninferiority of the study device relative to the control device (estimated success rates, 55.4% and 59.1%, respectively, calculated by the Weibull model; absolute difference, 3.7 percentage points; 95% upper confidence limit, 12.56 percentage points; P=0.01 for noninferiority). More patients in the control group than in the study group had device malfunction or device failure requiring replacement (16.2% vs. 8.8%), and more patients in the study group had strokes (29.7% vs. 12.1%). Quality of life and functional capacity improved to a similar degree in the two groups., Conclusions: In this trial involving patients with advanced heart failure who were ineligible for heart transplantation, a small, intrapericardial, centrifugal-flow LVAD was found to be noninferior to an axial-flow LVAD with respect to survival free from disabling stroke or device removal for malfunction or failure. (Funded by HeartWare; ENDURANCE ClinicalTrials.gov number, NCT01166347 .).

Background: Heart transplantation remains the gold standard therapy for end-stage heart failure patients; however, volumes are limited because of donor organ shortage. With the increasing availability of more durable continuous flow left ventricular assist devices (CFLVADs), the matrix of the heart transplantation waiting list and that of donor allocation have seen substantial changes. We aimed to evaluate the impact of the stated reasons for status 1A at time of transplantation on post-transplantation survival in CFVAD patients., Methods: The United Network of Organ Sharing (UNOS) thoracic organ transplantation database was queried between 2006 and 2013 to identify patients aged 18 years or older who underwent heart transplantation as UNOS status 1A. We further assessed the data to identify reasons for status 1A at time of transplantation in CFVAD patients. We also computed post-transplantation survival of patients supported with CFLVAD who were status 1A at the time of transplantation., Results: A total of 15,779 patients underwent heart transplantation during the study time period, of whom 8,429 were Status 1A, and 3,913 had CFLVAD at time of transplantation. Of all status 1A patients, 2,737 had CFLVAD at time of transplantation, of which 52% (1,413) had device complications (thrombosis, infection, malfunction, and other) and 48% (1,314) were on 30-day grace status 1A. Post-transplantation survival (at 3 years) of CFLVAD patients who received a transplant on 30-day grace status 1A was similar to patients who underwent transplantation on status 1B (84% versus 85%, p = 0.5), both of which were significantly better than status 1A patients because of device complications (84% and 85% versus 78%, p = 0.01) (Fig 1)., Conclusions: CFLVAD patients who underwent transplantation as Status 1B or on the 30-day grace Status 1A have similar post-transplantation survival. These data suggest that there needs to be an objective organ allocation system for recipients of heart transplant that prioritize patients with CFVAD complications and patients not eligible for CFVAD for transplantation over 30-day grace period patients., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Donor to recipient undersizing can result in diminished graft survival. The United Network for Organ Sharing database was retrospectively queried from January 2008 to December 2013 to identify adult patients who underwent heart transplantation. This population was divided into those without and with a left ventricular assist device (LVAD) at the time of transplant. Both groups were further subdivided into three groups: donor:recipient body mass index (BMI) ratio <0.8 (undersized), ≥0.8 and ≤1.2 (matched), and >1.2 (oversized). Kaplan-Meier analysis was used to compare graft survival. Cox regression analysis was used to identify factors affecting graft survival time. There was no difference in mean graft survival between undersized, matched, and oversized groups in patients without an LVAD (p = 0.634). Mean graft survival was significantly worse for undersized patients with an LVAD when compared with matched and oversized patients (p = 0.032). Cox regression revealed age, creatinine, waitlist time, United Network for Organ Sharing status, BMI ratio, and total bilirubin as significant factors affecting graft survival time. A donor to recipient BMI ratio of ≥1.2 results in significantly improved long-term graft survival for patients with an LVAD at the time of heart transplantation compared with patients with a BMI ratio of <1.2. An oversized organ should be considered for patients supported with an LVAD.

Background: There is a paucity of data on the use of induction immunosuppression in patients with active infections undergoing orthotopic heart transplantation (OHT). We hypothesized that induction immunosuppression in patients with ventricular assist device (VAD) undergoing OHT with localized active driveline infection (DLI) does not lead to worse outcomes., Materials and Methods: We retrospectively analyzed our database for bridge-to-transplant VAD patients who underwent OHT and received induction therapy. Patients were stratified into those with and without active DLI at the time of OHT and followed up till death or at least 30 months after OHT. Posttransplant length of stay (LOS), frequency of infections, and mortality were compared between the two groups., Results: Thirty-eight patients (30 males) with mean age of 57.5 ± 13 years with VAD underwent OHT during the study period. Twelve had active DLI. Mean follow-up was 46.4 ± 23.1 months. In the DLI versus non-DLI group, there was no difference in mortality (17 vs. 23%, p = NS), LOS (16.3 ± 5.4 vs. 17.2 ± 13.7, p = NS), postoperative renal function, incidence of hyperacute or late rejection or infection either in the first month (25 vs. 23%, p = NS) or during entire follow-up (92 vs. 88%, p = NS). No patient in the DLI group had infections attributable to the same organism responsible for pretransplant DLI., Conclusion: In patients with active DLI, induction immunosuppression after OHT did not increase LOS, infections, or mortality after at least 30 months of follow-up and therefore it appears to be a safe and feasible therapeutic option., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) trial was a multicenter, prospective trial of the HeartWare Ventricular Assist Device (HVAD). The performance of the HVAD in various demographic sub-groups was evaluated., Methods: Baseline characteristics, adverse events, and survival were compared for men vs. women and whites vs. non-whites in the combined ADVANCE BTT and continued access protocol trial. Of 332 patients enrolled in these trials, 236 were men and 96 women, with 228 whites and 104 non-whites., Results: At baseline, women had a smaller body surface area (1.8 ± 0.2 vs. 2.1 ± 0.3 m2, p < 0.0001), less hypertension (50.0% vs. 61.9%, p = 0.05), and less ischemic cardiomyopathy (15.6% vs. 45.3%, p < 0.0001). Differences in Kaplan-Meier survival were not significant at 180 days (men, 91.8%; women, 91.7%) and 1 year (men, 85.3%; women, 85.1%) despite adjustment for baseline differences. Men had a lower incidence of early right heart failure and renal and respiratory dysfunction, and a shorter length of stay. In the analysis by race, non-whites were younger than whites and had less ischemic heart failure, more hypertension, and lower creatinine levels at baseline. Non-whites had lower rates of arrhythmia, bleeding requiring rehospitalization, and device malfunctions than whites. Survival was high in non-whites and whites, at 94.1% vs. 90.4% at 180 days and 89.2% vs. 82.8% at 1 year, respectively, despite adjustment for baseline differences., Conclusions: Although heart failure etiology differed between men and women and between whites and non-whites, sex and race were not factors that affected survival in patients receiving the HVAD as BTT, which was high in all sub-groups., (Copyright © 2015. Published by Elsevier Inc.)

Background: Implantable cardioverter-defibrillators (ICDs) can improve survival in left ventricular assist device (LVAD) recipients. However, the impact of cardiac resynchronization therapy (CRT-D) on outcomes in continuous-flow left ventricular assist device (CF-LVAD) patients is not known. We sought to determine if CRT-D improved clinical outcomes in CF-LVAD patients compared with ICDs alone., Methods and Results: Sixty-one consecutive CF-LVAD patients with an ICD or CRT-D were evaluated. Impacts of CRT-D on mortality, all-cause hospitalization, and incidence of atrial (AA) and ventricular (VA) arrhythmias after LVAD implantation was compared with patients with ICD alone. Of the 61 LVAD patients, 31 (age 59.8 ± 16 years, 84% male) had CRT-D and 30 (age 57.2 ± 13 years, 74% male) had ICD. Before LVAD implantation, no significant differences were noted between the groups in demographic and clinical characteristics, LVAD indications, and incidence of AA and VA. Over 682 ± 45 days of LVAD support, 8 patients (25.8%) died in the CRT-D arm versus 5 (16.7%) in the ICD arm (P = .35). No differences were noted between the CRT-D and ICD groups in all-cause (96.8 vs 93.3%; P = .63) and HF (19.4 vs 26.7%; P = .78) hospitalizations, left ventricular (LV) end-diastolic diameter (6.4 ± 1.5 vs 6.2 ± 1.1 cm, P = .47), and incidence of AA (35.4% vs 33.3%; P = .80), VA (29% vs 26.6%; P = .86), and ICD shocks (22.6% vs 16.7%; P = .93). Beta-blocker and antiarrhythmic drug use after LVAD implantation was similar in both groups., Conclusions: In patients with refractory HF who received CF-LVADs, CRT-D, compared with ICD, did not significantly improve mortality, all-cause hospitalization, LV dimensions, and incidence of AA and VA., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Left ventricular assist device (LVAD) thrombosis is a life-threatening complication that remains a major clinical problem. Consensus diagnostic criteria do not exist. We investigated whether hematologic, echocardiographic, or pump parameters reliably change during LVAD thrombosis., Methods: A retrospective analysis of 20 consecutive cases of continuous-flow LVAD thrombosis (Thoratec HeartMate II n = 16, HeartWare HVAD n = 4) was performed. Hematologic markers (lactate dehydrogenase, plasma-free hemoglobin, hemoglobin, creatinine), echocardiographic parameters (left ventricular end-systolic and end-diastolic diameter, mitral regurgitation, aortic insufficiency, inflow-cannula velocity), and pump characteristics (speed, power, estimated flow, pulsatility index) were analyzed with one-way repeated measures ANOVA with Tukey post-test or paired Student t-tests., Results: Lactate dehydrogenase and plasma-free hemoglobin were significantly (p < 0.05) elevated at admission for LVAD thrombosis. Hemoglobin and creatinine were not significantly different at admission but changed significantly after admission. Left ventricular end-systolic and end-diastolic diameter, mitral regurgitation, aortic insufficiency, inflow-cannula velocity, LVAD speed, power consumption, estimated flow, and pulsatility index were not significantly different at admission for LVAD thrombosis., Conclusion: Hematological markers of hemolysis, but not echocardiographic or pump parameters, reliably changed during LVAD thrombosis. Markers of hemolysis are the best early predictors of LVAD thrombosis., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: A post-approval (PA) study for destination therapy (DT) was required by the Food and Drug Administration (FDA) to determine whether results with the HeartMate (HM) II (Thoratec, Pleasanton, California) left ventricular assist device (LVAD) in a commercial setting were comparable to results during the DT multicenter pivotal clinical trial., Background: New device technology developed in the clinical research setting requires validation in a real-world setting., Methods: The PA study was a prospective evaluation of the first 247 HM II patients identified pre-operatively as eligible for DT in the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) registry. Patients were enrolled from January to September 2010 at 61 U.S. centers and followed for 2 years. A historical comparison group included patients (n = 133 at 34 centers) enrolled in the primary data cohort in the DT pivotal trial (TR). Survival rates and adverse events for the PA group were obtained from the INTERMACS registry., Results: Baseline characteristics were similar for PA versus TR. Forty-five percent of PA patients were in INTERMACS profiles 1 to 2 and 28% were in profile 3. Adverse events in the PA group were similar or lower than those in the TR group, including improvements in device-related infection (0.22 vs. 0.47) and post-operative bleeding requiring surgery (0.09 vs. 0.23) events per patient-year. Kaplan-Meier survival at 2 years was 62% (PA group) versus 58% (TR group). PA group survival at 1 and 2 years was 82 ± 5% and 69 ± 6% for INTERMACS profiles 4 to 7 (n = 63) versus 72 ± 3% and 60 ± 4% for profiles 1 to 3 (n = 184). The median length of stay after surgery was reduced by 6 days in the PA group versus the TR group., Conclusions: Results in a commercial patient care setting for the DT population supported the original pivotal clinical trial findings regarding the efficacy and risk profile of the HM II LVAD. Survival was best in patients who were not inotrope-dependent (INTERMACS profiles 4 to 7)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Previous United Network for Organ Sharing (UNOS) analysis has shown an increase in posttransplant mortality with pretransplant pulsatile-flow left ventricular assist device (LVAD). Recent studies evaluating continuous-flow LVAD demonstrated improved durability, excellent survival, and improved quality of life. This study investigates the association of preheart transplant continuous-flow LVAD placement and posttransplant mortality using the UNOS database. Heart transplant patients listed after April 2004 (N = 48,090) during the era of HeartMate (HM) II LVAD usage were investigated. Patients with UNOS 1A and 1B status with (n = 1,435) and without HMII (n = 16,379) placement before the heart transplantation were evaluated. Preliminary descriptive statistics suggested an extensive heterogeneity in patient characteristics between HMII LVAD recipients and nonrecipients. Propensity scores (1:2) were used to match HMII LVAD recipients and nonrecipients characteristics and donor characteristics. This resulted in a final sample of 2,265 patients (758 with HMII pretransplant placement and 1,507 without HMII pretransplant placement). The Kaplan-Meier curves were evaluated for the differences in postheart transplant mortality in patients with and without HMII pretransplant placement. A time-dependent Cox regression model was used to study the hazard ratios (HRs) for the association between HMII pretransplant placement and posttransplant survival. The mean age of the study group was 51.9 years old (standard deviation: 12.3). HeartMate II pretransplant placement was associated with no statistically significant difference in the risk of 30 days (HR = 1.23, 95% confidence interval [CI]: 0.79-1.95, p = 0.36) and 1 year posttransplant mortality (HR = 1.31, 95% CI: 0.85-2.01, p = 0.22) compared with non-HMII recipients. The use of HMII LVAD before heart transplantation, however, was associated with a statistically significant 64% lower risk (HR = 0.36, 95% CI: 0.16-0.77, p = 0.01) of mortality among heart transplant patients who survived beyond the first year of transplantation. Continuous-flow LVAD pretransplant placement is associated with improved long-term (>1 year) survival after heart transplantation.

Opinion Statement: Heart failure is a progressive disorder characterized by adverse left ventricular remodeling. Until recently, this has been thought to be an irreversible process. Mechanical unloading with a left ventricular assist device (LVAD), particularly if combined with neurohormonal blockade with heart failure medications, can lead to a reversal of the heart failure phenotype, a process called "reverse remodeling." Reverse remodeling refers to the regression of pathologic myocardial hypertrophy and improvement in LV chamber size that can occur in response to treatment. Myocardial recovery is the sustained normalization of structural, molecular, and hemodynamic changes sufficient to allow explant of the LVAD. Despite the fact that reverse remodeling is commonly seen in LVAD patients in clinical practice, myocardial recovery sufficient to allow device explantation is still rare. Previous experience suggests that young patients with short duration of heart failure and less myocardial fibrosis may be more likely to recover. Alternatively, it may just be that clinicians make a greater effort to recover these subgroups. A combined approach of mechanical unloading with LVADs and pharmacological management, together with regular testing of underlying myocardial function with the pump reduced to a speed at which it is not contributing, can increase the frequency of sustained recovery from heart failure. The goal is to achieve optimal unloading of the myocardium, combined with pharmacologic therapy aimed at promoting reverse remodeling. Myocardial recovery must be considered as a therapeutic target. Clinical variables such as pump speed and blood pressure must be optimized to promote maximal unloading, leading to reverse remodeling and myocardial recovery. Frequent echocardiographic and hemodynamic evaluation of underlying myocardial function must be performed. The combination of LVAD therapy with optimal neurohormonal blockade appears promising as an approach to myocardial recovery. In addition, there is a growing body of translational research which, when combined with LVADs, may further promote more durable recovery. Strategies to thicken the myocardium to enhance the durability of recovery prior to explantation, such as clenbuterol (which induces "physiological hypertrophy"), or intermittently reducing the pump speed to increase myocardial load may be beneficial. Emergence of cardiac stem cells and alternative biologic agents, when added to current therapies, may have a complementary role in promoting and maintaining myocardial recovery. This review will summarize both current strategies and emerging therapies.

Objectives: The objective of the study is to determine cardiac autonomic control in patients undergoing assessment for and/or LVAD therapy., Methods: Heart rate variability (HRV) was measured in 17 explanted LVAD, 17 implanted LVAD and 23 NYHA III-IV classified chronic heart failure (CHF) patients and ten healthy matched controls under three conditions: supine free breathing, standing and supine controlled breathing. Five measures of HRV were assessed: mean R-R interval (mR-R), high frequency (HF) and low frequency (LF) spectral power, LF in normalised units (LFnu), and LF to HF (LF:HF) ratio., Results: Repeat measures ANOVA showed significant (p < 0.05) differences in HRV between all three conditions within groups. Lower values were observed in CHF for LF(in log natural units) compared with explanted patients (-1.4 [95% CI -2.6 to -0.7], p = 0.04) and controls (-2.1 [-3.5 to -0.7], p = 0.001) and for LF:HF compared with implanted patients under paced breathing conditions (z = -2.7, p = 0.007) and controls in standing (z = -2.9, p = 0.004) and paced breathing conditions (z = -2.3, p = 0.02). However, no significant differences were seen between explanted, implanted and control groups under any condition., Conclusions: Patients implanted with an LVAD and explanted from a LVAD following myocardial recovery demonstrate a more normal dynamic response to autonomic stimuli and have a lower HRV risk profile compared to CHF patients., (© 2013.)

Aims: Dilated cardiomyopathy (DCM) patients have abundant levels of norepinephrine secondary to failure of the norepinephrine transporter uptake mechanism. Little is known about the effects of an LV assist device (LVAD) on cardiac sympathetic innervations and norepinephrine transporter dysfunction. This study examines the effects of continuous-flow HeartMate II LVAD on cardiac sympathetic innervations using [(123)I]metaiodobenzylguanidine ([(123)I]MIBG) nuclear imaging., Methods and Results: After injecting 431 ± 21 MBq of [(123)I]MIBG, planar scintigraphy was performed at 15 min and 4 h in 14 consecutive non-diabetic non-ischaemic DCM patients. Scans were executed early post-LVAD implantation (T1) and prior to either device explantation for myocardial recovery or transplant listing (T2). [(123)I]MIBG measured parameters included early and delayed heart-mediastinum (H/M) ratios and washout rate (W/O). Catecholamine levels were measured using liquid chromatography-mass spectrometry. Following 208.4 ± 85.5 days of LVAD support, both early and delayed H/M ratios increased by 42.1% (P < 0.001) and 54.7% (P < 0.001), respectively. The W/O rate decreased by 46% (P = 0.003). Plasma norepinephrine, epinephrine, and dopamine decreased significantly in correlation with [(123)I]MIBG parameters. Ten patients had recovered and had their device explanted as they had demonstrated a higher percentage change in delayed H/M ratio, W/O rate, and norepinephrine levels. Linear regression analysis revealed a strong correlation between percentage changes in both norepinephrine and epinephrine and myocardial recovery., Conclusion: Combination therapy with LVAD and drug resulted in enhancement of [(123)I]MIBG uptake in DCM patients.