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Background: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients., Objectives: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM., Methods: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout., Results: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms., Conclusions: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM., Competing Interests: Funding Support and Author Disclosures The REDWOOD-HCM study was funded by Cytokinetics, Incorporated. Dr Maron has received consultant/advisor fees from Imbria and Takeda; and has received steering committee fees for REDWOOD-HCM from Cytokinetics, Incorporated. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, and Ionis; and has received research grants from Ionis, Akcea, Pfizer, Ultromics, and Wheeler Foundation. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, and Tenaya; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Saberi has received consultant/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consultant/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer and Alnylam; has received consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, BridgeBio, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, BridgeBio, and Alnylam. Dr Lakdawala has received consultant/advisor fees from Tenaya, Pfizer, Bristol Myers Squibb, Cytokinetics, and Sarepta; and has received a research grant from Pfizer. Dr Rader has received Speakers Bureau fees from Bristol Myers Squibb and Medtronic; and has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, ReCor, and Medtronic. Dr Turer has received consultant/advisor fees from Cytokinetics. Dr Coats has received consultant/advisor fees from Cytokinetics. Dr Fifer has received consultant/advisor fees from Cytokinetics; and has received research grants from Bristol Myers Squibb and Novartis. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Solomon has received consultant/advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health; and has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Kramer has received consultant/advisor fees from Cytokinetics, and Bristol Myers Squibb; and has received research grants from Cytokinetics and Bristol Myers Squibb. Dr Wong has received Speakers Bureau fees from Projects in Knowledge, PCM Scientific; and has served as an unpaid consultant/advisor for Bristol Myers Squibb and Cytokinetics. Drs Heitner, Kupfer, Malik, Meng, and Wohltman are employees of Cytokinetics Incorporated; and holds stock in Cytokinetics Incorporated. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to examine the frequency and hemodynamic correlates of shortness of breath when bending forward, a symptom we have termed "bendopnea.", Background: Many heart failure patients describe bendopnea such as when putting on their shoes. This symptom has not previously been characterized., Methods: We conducted a prospective study of 102 subjects with systolic heart failure referred for right-heart catheterization. Time to onset of bendopnea was measured prior to catheterization. Forty-six subjects also underwent hemodynamic assessment when sitting and bending. Hemodynamic profiles were assigned on the basis of whether pulmonary capillary wedge pressure (PCWP) was ≥ 22 mm Hg and cardiac index (CI) was ≤ 2.2 l/min/m(2)., Results: Bendopnea was present in 29 of 102 (28%) subjects with median (25th, 75th percentiles) time to onset of 8 (7, 11) seconds. Subjects with bendopnea had higher supine right atrial pressure (RAP) (p = 0.001) and PCWP (p = 0.0004) than those without bendopnea but similar CI (p = 0.2). RAP and PCWP increased comparably in subjects with and without bendopnea when bending, but CI did not change. In those with, versus without, bendopnea, there was more than a 3-fold higher frequency of a supine hemodynamic profile consisting of elevated PCWP with low CI (55% vs. 16%, respectively, p < 0.001) but no association with a profile of elevated PCWP with normal CI (p = 0.95)., Conclusions: Bendopnea is mediated via a further increase in filling pressures during bending when filling pressures are already high, particularly if CI is reduced. Awareness of bendopnea should improve noninvasive assessment of hemodynamics in subjects with heart failure., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Dyspnea and the resulting functional impairment are a common complication in hypertrophic cardiomyopathy (HCM). The relationship between physician-perceived functional status, patient-perceived health status, and objective exercise test results has not been evaluated in this condition., Purpose: To evaluate the correlation between the Kansas City Cardiomyopathy Questionnaire (KCCQ) and (1) physician's perceived (NYHA class) and (2) objective measurement (cardiopulmonary exercise test) of functional capacity in patients with HCM., Methods: In 24 outpatients with HCM at a single, referral center, the KCCQ instrument was administered and cardiopulmonary exercise testing (CPX) was performed. Severity of symptoms as determined by physician (NYHA classification) and patient (KCCQ instrument) was obtained before exercise test results were known. Pearson correlation was used to assess the independent correlation between KCCQ score and the various exercise parameters; Spearman correlation was used to assess correlation between KCCQ score and NYHA class., Results: KCCQ results demonstrated moderate reductions in all domains, with greatest reduction in quality-of-life domain. CPX testing showed reduction in peak oxygen consumption (mean absolute VO2 20.5 ± 7.8 ml/kg/min and percent predicted VO2 76.8 ± 4.1 %). There were negative correlations between NYHA class and all KCCQ components except the self-efficacy score. The strongest correlations were between NYHA class and the overall summary score (r = -0.623, p = 0.001) as well as the physical limitation score (r = -0.604, p = 0.002). Similarly, there were statistically significant positive correlations between the KCCQ components and percent predicted peak VO2. The strongest correlation was between percent predicted peak VO2 and the physical limitation score (r = 0.474, p = 0.019), but there was also correlation between percent predicted peak VO2 and the quality-of-life score (r = 0.456, p = 0.025), the functional status score (r = 0.455, p = 0.025), and the clinical summary score (r = 0.444, p = 0.030)., Conclusions: The multiple domains of the KCCQ provide data on patient-perceived health status, which correlate with physician-perceived and objective measurement of functional capacity in HCM. Additional studies are needed to evaluate the sensitivity of the KCCQ to changes in functional capacity over time or in response to therapies for this condition.

There is a long history of investigation into the metabolism of the failing heart. Congestive heart failure is marked both by severe disruptions in myocardial energy supply and an inability of the heart to efficiently uptake and oxidize fuels. Despite the many advancements in our understanding, there are still even more outstanding questions in the field. Metabolomics has the power to assist our understanding of the metabolic derangements which accompany myocardial dysfunction. Metabolomic investigations in animal models of heart failure have already highlighted several novel, potentially important pathways of substrate selection and toxicity. Metabolomic biomarker studies in humans, already successfully applied to other forms of cardiovascular disease, have the potential to improve diagnosis and patient care. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism"., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose of Review: Profound abnormalities in myocardial energy metabolism occur in heart failure and correlate with clinical symptoms and survival. Available comprehensive human metabolic data come from small studies, enrolling patients across heart failure causes, at different disease stages, and using different methodologies, and is often contradictory. Remaining fundamental gaps in knowledge include whether observed shifts in cardiac substrate utilization are adaptive or maladaptive, causal or an epiphenomenon of heart failure., Recent Findings: Recent studies have characterized the temporal changes in myocardial substrate metabolism involved in progression of heart failure, the role of insulin resistance, and the mechanisms of mitochondrial dysfunction in heart failure. The concept of metabolic inflexibility has been proposed to explain the lack of energetic and mechanical reserve in the failing heart., Summary: Despite current therapies, which provide substantial benefits to patients, heart failure remains a progressive disease, and new approaches to treatment are necessary. Developing metabolic interventions would be facilitated by systems-level integration of current knowledge on myocardial metabolic control. Although preliminary evidence suggests that metabolic modulators inducing a shift towards carbohydrate utilization seem generally beneficial in the failing heart, such interventions should be matched to the stage of metabolic deregulation in the progression of heart failure.

Intravenous diuretics are the cornerstone of management for patients hospitalized for heart failure. Physiologic data suggest that intermittent high-dose furosemide promotes neurohormonal activation, which a slow continuous infusion might remediate. However, the limited clinical data comparing dosing schemes are confounded. This study was a randomized, open-label, single-center trial of twice-daily bolus injection versus continuous infusion furosemide in patients hospitalized with heart failure and volume overload. The primary outcome was change in creatinine from admission to hospital day 3 or discharge. Twenty-one patients were randomized to bolus injection and 20 patients to continuous infusion. Baseline characteristics were balanced between study arms except for gender, with a mean age of 60 +/- 15 years, a mean ejection fraction of 35 +/- 19%, and a mean creatinine level of 1.9 +/- 1.2 mg/dl. The mean doses of furosemide were similar between arms over the first 48 hours (162 +/- 48 and 162 +/- 52 mg/24 hours). None of the outcomes differed significantly between bolus and continuous dosing from admission to hospital day 3 or discharge (mean change in creatinine -0.02 vs 0.13 mg/dl, p = 0.18; urine output 5,113 vs 4,894 ml, p = 0.78; length of stay 8.8 vs 9.9 days, p = 0.69). All patients survived to discharge. In conclusion, there were no substantial differences between bolus injection and continuous infusion of equal doses of furosemide for the treatment of patients hospitalized with heart failure. Given the high prevalence of heart failure hospitalization and the disparate results of small studies regarding optimal dosing of loop diuretics to treat these patients, larger multicenter blinded studies are needed.

Despite significant advancements in the treatment of heart failure over the past 2 decades, this patient population is still subject to considerably high morbidity and mortality rates. In recent years, the field of device therapy as adjunctive treatment to the medical management of congestive heart failure has grown in the wake of the large number of randomized trials that have demonstrated the safety and efficacy of these devices. The implantable defibrillator currently represents the standard of care in certain segments of the heart failure population, even in those without a prior arrhythmic event. Biventricular pacing systems appear to have a role in heart failure patients with prolongation of their QRS duration in improving ventricular performance and symptoms, if not mortality. Last, the shortage of organs available for orthotopic transplant has heightened interest in using ventricular-assist devices as destination therapy, and although there is evidence for the feasibility for this approach at the current time, there is a next generation of devices that appear even more promising.