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Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics., Objectives: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM., Methods: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints., Results: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better V E /Vco 2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO 2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04)., Conclusions: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study., Competing Interests: Funding Support and Author Disclosures Imbria Pharmaceuticals contributed significant funding to this study. Dr Neubauer acknowledges support from the Oxford NIHR Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. Dr Valkovic is supported by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (#221805/Z/20/Z), and also acknowledges the support from the Oxford BHF Centre of Research Excellence and from the Slovak Grant Agencies VEGA (#2/0004/23) and APVV (#21-0299). Dr Samat was supported by a doctoral scholarship funded by the Ministry of Higher Education Malaysia and National University of Malaysia. Dr Maron has served on the steering committee for SEQUOIA-HCM; and has received consultant/advisor fees from Cytokinetics, Imbria, and Edgewise. Dr Mahmod has served as an investigator for SEQUOIA-HCM, FOREST-HCM (Cytokinetics), and EMPA-VISION (Boehringer Ingelheim). Dr Massera has received consulting fees from Sanofi, Tenaya Therapeutics, and Chiesi Pharmaceuticals. Dr Cresci has served on the data monitoring committee for the SEQUOIA-HCM, MAPLE-HCM, and ACACIA-HCM trials (Cytokinetics). Dr Martinez has served on the steering committee for ACACIA-HCM; and has received consultant/advisor fees from Cytokinetics and BMS. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and has received consultancy/advisory fees from Cytokinetics, BMS, Eidos/BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. Dr Adler is currently the chief medical officer and head of research at Lexeo Therapeutics; has equity holdings in Lexeo Therapeutics, Rocket Pharmaceuticals, and Papillion Therapeutics; and has served on advisory boards for Cytokinetics and Kiniksa Pharmaeuticals. Dr Wever-Pinzon has received speaker fees from Bristol Myers Squibb. Dr Lewis has received research support and/or served as a consultant for the National Institutes of Health, American Reagent, Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Cardiage, Cytokinetics, Edwards, Imbria, Lilly, Merck, Novartis, NXT, Pfizer, and Rivus. Drs Chamberlin and Patel are salaried employees of Imbria Pharmaceuticals. Dr Yavari has served as a consultant for Imbria Pharmaceuticals; and is an employee of Weatherden Ltd. Dr Dehbi has received consulting fees from Imbria Pharmaceuticals. Dr Sarwar has received consulting fees from Imbria Pharmaceuticals and Ultromics. Dr Udelson has served as a member of the data and safety monitoring committee for the trial and has received consulting fees from Imbria Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: The 2018 U.S. heart allocation system offers an accelerated pathway for heart transplantation to the most urgent patients., Objectives: This study sought to determine whether the new allocation system resulted in lower likelihood of candidate recovery., Methods: Adult patients waitlisted for heart transplantation with temporary mechanical circulatory support at the time of initial listing between 2010 and 2020 in the United Network for Organ Sharing registry were included. Competing events of heart transplantation, waitlist death or delisting for deteriorating condition, and delisting for improved condition (candidate recovery) were analyzed in the new vs old heart allocation system., Results: A total of 688 patients were waitlisted with venoarterial extracorporeal membrane oxygenation or a surgical nondischargeable biventricular assist device (status 1 or old 1A). Overall, 2,237 patients were waitlisted with an intra-aortic balloon pump, a percutaneous left ventricular assist device (LVAD), or a surgical nondischargeable LVAD (status 2 or old 1A). Patients waitlisted with venoarterial extracorporeal membrane oxygenation or a nondischargeable biventricular assist device had significantly shorter median waitlist times (5 vs 31 days), higher incidence for cardiac transplantation (81.5% vs 43.0%), and lower incidence of candidate recovery (1.5% vs 7.9%) in the new vs old heart allocation system (all P < 0.05). Patients waitlisted with an intra-aortic balloon pump or percutaneous or a nondischargeable LVAD also had significantly shorter median waitlist times (8 vs 35 days), higher incidence of transplantation (88.9% vs 64.9%), and lower incidence of candidate recovery (0.2% vs 1.6%) in the new vs old heart allocation system (all P < 0.05)., Conclusions: Current practice of the new allocation system may not offer select temporary mechanical circulatory support patients the opportunity and adequate time to recover to the point of waitlist removal. Further research will determine which patients would benefit from urgent transplantation vs recovery strategy., Competing Interests: Funding Support and Author Disclosures Dr Topkara has been supported by NIH K08 HL146964. Dr Sayer has received consulting fees from Abbott Laboratories. Dr Clerkin has been supported by NIH K23 HL148528. Dr Wever-Pinzon has been supported by NIH K23 HL150322. Dr Burkhoff has received institutional educational grant support from Abiomed; and has received consulting fees from CardioDyme Inc and from Abbott Laboratories unrelated to mechanical circulatory assist. Dr Uriel has received consulting fees from Leviticus and LiveMetric. Dr Drakos is supported by the American Heart Association Heart Failure Strategically Focused Research Network (16SFRN29020000), NIH R01 HL135121, NIH R01 HL132067, Merit Review Award I01 CX0002291 (U.S. Department of Veterans Affairs), and Nora Eccles Treadwell Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM., Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM., Methods: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6., Results: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009)., Conclusions: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Small-scale studies focused mainly on nonischemic cardiomyopathy (NICM) have shown that a subset of left ventricular assist device (LVAD) patients can achieve significant improvement of their native heart function, but the impact of ischemic cardiomyopathy (ICM) has not been specifically investigated. Many patients with acute myocardial infarction are discharged from their index hospitalization without heart failure (HF), only to return much later with overt HF syndrome, mainly caused by chronic remodeling of the noninfarcted region of the myocardium., Objectives: This study sought to prospectively investigate the effect of ICM HF etiology on LVAD-associated improvement of cardiac structure and function using NICM as control., Methods: Consecutive patients (n = 154) with documented chronic and dilated cardiomyopathy (ICM, n = 61; NICM, n = 93) requiring durable support with continuous-flow LVAD were prospectively evaluated with serial echocardiograms and right heart catheterizations., Results: In patients supported with LVAD for at least 6 months, we found that 5% of subjects with ICM and 21% of subjects with NICM achieved left ventricular ejection fraction ≥40% (p = 0.034). LV end-diastolic and end-systolic volumes and diastolic function were significantly and similarly improved in patients with ICM and NICM., Conclusions: LVAD-associated unloading for 6 months resulted in a substantial improvement in myocardial structure, and systolic and diastolic function in 1 in 20 ICM and 1 in 5 NICM patients. These specific incidence and timeline findings may provide guidance in clinical practice and research design for sequencing and prioritizing advanced HF and heart transplantation therapeutic options in patients with ICM and NICM., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

Background: The number of centers with left ventricular assist device (LVAD) research programs focused on cardiac recovery is very small. Therefore, this phenomenon has been reported in real-world multi-center registries as a rare event., Objectives: This study evaluated the incidence of cardiac recovery with an a priori LVAD implantation strategy of bridge-to-recovery (BTR) and constructed a recovery predictive model., Methods: The study included LVAD recipients registered in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Cardiac recovery was evaluated in BTR and non-BTR patients. A weighted score was derived and externally validated in patients of the Utah Cardiac Recovery (UCAR) program., Results: Of 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). The incidence of recovery was 11.2% (n = 14) in BTR compared with 1.2% (n = 178) in non-BTR patients (p < 0.0001). Independent predictors of recovery included: age <50 years, non-ischemic cardiomyopathy, time from cardiac diagnosis <2 years, absence of ICD, creatinine ≤1.2 mg/dl, and LVEDD <6.5 cm (c-index: 0.85; p < 0.0001). A weighted score termed I-CARS, effectively stratified patients based on their probability of recovery. I-CARS was validated in the UCAR cohort (n = 190) with good performance (AUC: 0.94; 95% CI: 0.91 to 0.98). One-year survival after LVAD explantation, available in INTERMACS for 21 (11%) patients, was 86%., Conclusions: The incidence of cardiac recovery is higher in patients implanted with an a priori BTR strategy. We developed a simple tool to help identify patients in whom recovery is feasible. In BTR patients with favorable characteristics, I-CARS suggests a 24% probability of successful LVAD explantation. Large-scale studies to better address post-explantation outcomes are warranted., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

Background: In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied., Objectives: The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy., Methods: We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors., Results: Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm(2) to 1,011 ± 68 μm(2) (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm(2)). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system., Conclusions: Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

Objectives: This study aimed to evaluate the diagnostic accuracy of coronary computed tomography angiography (CCTA) for detecting cardiac allograft vasculopathy (CAV) in comparison with conventional coronary angiography (CCAG) alone or with intravascular ultrasound (IVUS)., Background: CAV limits long-term survival after heart transplantation, and screening for CAV is performed on annual basis. CCTA is currently not recommended for CAV screening due to the limited accuracy reported by early studies. Technological advances, however, might have resulted in improved test performance and might justify re-evaluation of this recommendation., Methods: A systematic review of Medline, Cochrane, and Embase for all prospective trials assessing CAV using CCTA was performed using a standard approach for meta-analysis for diagnostic test and a bivariate analysis., Results: Thirteen studies evaluating 615 patients (mean age 52 years, 83% male) and 9,481 segments fulfilled inclusion criteria. Patient-based analyses comparing CCTA versus CCAG for the detection of any CAV (> luminal irregularities) and significant CAV (stenosis ≥50%), showed mean weighted sensitivities of 97% and 94%, specificities of 81% and 92%, a negative predictive value (NPV) of 97% and 99%, a positive predictive value (PPV) of 78% and 67%, and diagnostic accuracies of 88% and 94%, respectively. There was a strong trend toward improved sensitivity (97% vs. 91%, p = 0.06) and NPV (99% vs. 97%, p = 0.06) to detect significant CAV with 64-slice compared with 16-slice CCTA. A patient-based analysis of 64-slice CCTA versus IVUS showed a mean weighted sensitivity and specificity of 81% and 75% to detect CAV (intimal thickening >0.5 mm), whereas the PPV and NPV were 93% and 50%, respectively., Conclusions: CCTA using currently available technology is a reliable noninvasive imaging alternative to coronary angiography with an excellent sensitivity, specificity, and NPV for the detection of CAV., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

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., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

The shape of Doppler velocity tracings in obstructive hypertrophic cardiomyopathy offers insights into its pathophysiology. Inflection points are the points on a curve where its shape changes from concave to convex, or vice versa. These dynamic systolic abnormalities are caused: 1) by the amplifying nature of the obstruction; and 2) by the adverse effect of the sudden imposition of afterload in midsystole. The midsystolic drop in left ventricular ejection velocities and the premature termination of longitudinal shortening are compelling evidence of the deleterious mechanical effect of obstruction on the ventricle. This dynamic systolic dysfunction, demonstrated on the Doppler curves, may contribute to heart failure symptoms and adverse outcome. In outflow obstruction, these abnormalities normalize after abolition of gradient. Therefore, their detection in an individual patient confirms obstruction as a therapeutic target. more...