Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.

BACKGROUND AND AIMS: Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. METHODS: Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. RESULTS: At the latest data cut-off, 211 (91.3%) of 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the week 156 and 180 visits, respectively. Sustained reductions from baseline to week 180 occurred in left ventricular outflow tract gradients (mean [standard deviation]: resting, -40.3 [32.7] mmHg; Valsalva, -55.3 [33.7] mmHg), NT-proBNP (median [interquartile range]: -562 [-1162.5, -209] ng/L), and EQ-5D-5L score (mean [standard deviation]: 0.09 [0.17]). Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (week 24) and 63.9% (week 180). At week 180, 74 (77.9%) of 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). CONCLUSIONS: Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Direct mitral regurgitation quantification in hypertrophic cardiomyopathy using 4D flow CMR jet tracking: evaluation in comparison to conventional CMR.

BACKGROUND: Quantitative evaluation of mitral regurgitation (MR) in hypertrophic cardiomyopathy (HCM) by cardiovascular magnetic resonance (CMR) relies on an indirect volumetric calculation. The aim of this study was to directly assess and quantify MR jets in patients with HCM using 4D flow CMR jet tracking in comparison to standard-of-care CMR indirect volumetric method. METHODS: This retrospective study included patients with HCM undergoing 4D flow CMR. By the indirect volumetric method from CMR, MR volume was quantified as left ventricular stroke volume minus forward aortic volume. By 4D flow CMR direct jet tracking, multiplanar reformatted planes were positioned in the peak velocity of the MR jet during systole to calculate through-plane regurgitant flow. MR severity was collected for agreement analysis from a clinical echocardiograms performed within 1 month of CMR. Inter-method and inter-observer agreement were assessed by intraclass correlation coefficient (ICC), Bland-Altman analysis, and Cohen's kappa. RESULTS: Thirty-seven patients with HCM were included. Direct jet tracking demonstrated good inter-method agreement of MR volume compared to the indirect volumetric method (ICC = 0.80, p = 0.004) and fair agreement of MR severity (kappa = 0.27, p = 0.03). Direct jet tracking showed higher agreement with echocardiography (kappa = 0.35, p = 0.04) than indirect volumetric method (kappa = 0.16, p = 0.35). Inter-observer reproducibility of indirect volumetric method components revealed the lowest reproducibility in end-systolic volume (ICC = 0.69, p = 0.15). Indirect volumetric method showed good agreement of MR volume (ICC = 0.80, p = 0.003) and fair agreement of MR severity (kappa = 0.38, p < 0.001). Direct jet tracking demonstrated (1) excellent inter-observer reproducibility of MR volume (ICC = 0.97, p < 0.001) and MR severity (kappa = 0.84, p < 0.001) and (2) excellent intra-observer reproducibility of MR volume (ICC = 0.98, p < 0.001) and MR severity (kappa = 0.88, p < 0.001). CONCLUSIONS: Quantifying MR and assessing MR severity by indirect volumetric method in HCM patients has limited inter-observer reproducibility. 4D flow CMR jet tracking is a potential alternative technique to directly quantify and assess MR severity with excellent inter- and intra-observer reproducibility and higher agreement with echocardiography in this population.

Fibrosis in Hypertrophic Cardiomyopathy Patients With and Without Sarcomere Gene Mutations.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) and an identified sarcomere mutation have worse outcomes than those without though the underlying mechanism is incompletely understood. The presence of replacement fibrosis measured by late gadolinium enhancement (LGE) and diffuse fibrosis measured by extracellular volume (ECV) using cardiac magnetic resonance imaging (CMR) are associated with ventricular arrhythmias and cardiac mortality. We aimed to associate these two forms of fibrosis with identified sarcomere mutations. METHODS AND RESULTS: Three hundred and thirty-six (336) patients with HCM underwent CMR at a single quaternary referral centre between January 2012 and February 2017. Genetic testing was performed in 73 of these patients, yielding an identified sarcomeric mutation in 29 (G+), no mutation in 39 (G-), and a variant of unknown significance (VUS) in five. LGE was more prevalent in G+ compared to G- patients (86 vs. 56%, OR 4.3, p=0.01) and was more extensive (7.5±5.5% of left ventricular [LV] mass vs. 3.0±3.0%, p<0.001). Global ECV from myocardial segments excluding LGE was similar among both groups (26.9±2.9 vs. 25.6±2.8%, p=0.46). However, in G+ patients ECV was greater in the hypertrophied regions of the basal anteroseptum (30.2±7.0 vs. 26.8±3.6%, p=0.004) and basal inferoseptum (28.1±4.3 vs. 26.2±2.9%, p=0.005). CONCLUSIONS: Genotyped HCM patients with an identified sarcomere mutation have greater LGE and greater regional, but not global, ECV than HCM patients without an identified mutation. This difference in fibrosis may contribute to worse outcomes in patients with an identified HCM mutation.

Appropriate Implantable Defibrillator Therapy in Adults With Hypertrophic Cardiomyopathy.

INTRODUCTION: Implantable cardioverter-defibrillators (ICDs) are effective at terminating the ventricular arrhythmias that cause sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, identifying patients at risk for SCD remains an ongoing challenge. METHODS AND RESULTS: We retrospectively studied all adult patients with HCM treated with ICDs at our referral center from 2000 to 2013 to determine the risk factor profile, rates of appropriate ICD therapy, and complications associated with ICD implantation and discharge. Over a mean follow-up period of 5.2 ± 4.5 years, ICDs provided appropriate therapy to 25 of 135 patients (2.6%/year for primary prevention, 9.8%/year for secondary prevention). Established risk factors for SCD were equally prevalent among patients who received appropriate therapy and those who did not. There were similar rates of appropriate therapy for primary prevention patients with each risk factor. Patients with multiple risk factors had similar rates of appropriate therapy to patients with a single risk factor. Patients who underwent implantation at a younger age were more likely to experience appropriate therapy. Inappropriate therapy occurred in 27 of 135 patients (20%). CONCLUSIONS: These data indicate that the rate of appropriate ICD therapy for primary prevention in a contemporary adult HCM population is lower than previously reported. The frequency of appropriate therapy was equally modest regardless of the nature and number of risk factors that led to ICD implantation, and patients with multiple risk factors for SCD did not have an increased rate of appropriate therapy.

4D flow MRI and T1 -Mapping: Assessment of altered cardiac hemodynamics and extracellular volume fraction in hypertrophic cardiomyopathy.

PURPOSE: Hypertrophic cardiomyopathy (HCM) is associated with altered hemodynamics in the left ventricular outflow tract (LVOT) and myocardial tissue abnormalities such as fibrosis. The aim of this study was to quantify changes in LVOT 3D hemodynamics and myocardial extracellular volume fraction (ECV, measure of fibrosis) and to investigate relationships between elevated flow metrics and left ventricular (LV) tissue abnormalities. MATERIALS AND METHODS: Cardiac magnetic resonance imaging (MRI) including 4D flow (field strength = 1.5T, resolution = 2.1-4.0 × 2.1-4.0 × 2.5-3.2 mm(3) ; venc = 150-250 cm/s; TE/TR/FA = 2.2-2.5msec/4.6-4.9msec/15°) for the in vivo assessment of 3D blood flow velocities with full coverage of the LVOT was applied in 35 patients with HCM (54 ± 15 years) and 10 age-matched healthy controls (45 ± 14 years). In addition, pre- and postcontrast myocardial T1 -mapping (resolution = 2.3 × 1.8 mm, slice thickness = 8 mm, TE/TR-FA = 1.0-1.1msec/2.0-2.2msec/35°) of the LV (basal, mid-ventricular, apical short axis) was performed in a subgroup of 23 HCM patients. Analysis included the segmentation of the LVOT and quantification of peak systolic LVOT pressure gradients and rate of viscous energy loss EL ' as well as left ventricular ECV. RESULTS: HCM patients demonstrated significantly elevated peak systolic LVOT pressure gradients (21 ± 16 mmHg vs. 9 ± 2 mmHg) and energy loss EL ' (3.8 ± 2.5 mW vs. 1.5 ± 0.7 mW, P < 0.005) compared to controls. There was a significant relationship between increased LV fibrosis (ECV) with both elevated pressure gradients (R(2) = 0.44, P < 0.001) and energy loss EL ' (R(2) = 0.46, P < 0.001). CONCLUSIONS: The integration of 4D-flow and T1 -mapping-MRI allowed for the evaluation of tissue and flow abnormalities in HCM patients. Our findings suggest a mechanistic link between abnormal LVOT flow, increased LV loading, and adverse myocardial remodeling in HCM.

The Clinical Impact of SARS-CoV-2 on Hypertrophic Cardiomyopathy.

BACKGROUND: This study aims to understand and describe the clinical impact of SARS-CoV-2 (COVID-19) infection in patients with Hypertrophic Cardiomyopathy (HCM). METHODS: A data repository of over 6.6 million patients in a large metropolitan (Chicago IL) healthcare system was queried to identify adults with a history of HCM and COVID-19 infection between 2019 and 2021. Propensity score-matched analysis was performed based on age, sex, BMI, and elements of the cardiovascular history, including tobacco use, hypertension, hyperlipidemia, myocardial injury, and heart failure. RESULTS: Individuals with HCM and COVID-19 infection had more total hospitalizations (41.6 v 23 per 100 persons, p < 0.01), more heart-failure-related hospitalizations (24.2 v 8.7 per 100-persons, p < 0.01), more non-ST elevation myocardial injury (NSTEMI) hospitalizations (8.6 v 4.6 per 100-persons, p < 0.01), and increased mortality (10.8 v 5 per 100-persons, p < 0.01) compared to HCM patients without a history of COVID-19 infection. Patients with HCM and COVID-19 were also noted to have a higher peak CRP when compared to those without prior COVID-19 (Inter-quartile range of 9.0-106.9 v 1.8-21.3, p < 0.01). CONCLUSIONS: In patients with HCM, COVID-19 infection is associated with increased incidence of myocardial injury, increased number of total and heart-failure specific hospitalizations, and increased mortality.

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.

BACKGROUND: Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES: The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). METHODS: After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. RESULTS: Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. CONCLUSIONS: Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias.

BACKGROUND: Many cardiomyopathy-associated FLNC pathogenic variants are heterozygous truncations, and FLNC pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood. METHODS AND RESULTS: We describe an individual with biallelic FLNC pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with FLNC variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The FLNC truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous FLNC disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, FLNC-null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. FLNC null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. FLNC null engineered heart tissues had impaired function after low-dose bortezomib. CONCLUSIONS: FLNC pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM Baseline Characteristics and Study Design.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

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 VE/Vco2 (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 VO2 (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.

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

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.

Vigorous Exercise in Patients With Hypertrophic Cardiomyopathy.

Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. Exposures: Amount and intensity of physical activity. Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category. Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

4D flow MRI left atrial kinetic energy in hypertrophic cardiomyopathy is associated with mitral regurgitation and left ventricular outflow tract obstruction.

To noninvasively assess left atrial (LA) kinetic energy (KE) in hypertrophic cardiomyopathy (HCM) patients using 4D flow MRI and evaluate coupling associations with mitral regurgitation (MR) and left ventricular outflow tract (LVOT) obstruction. Twenty-nine retrospectively identified patients with HCM underwent 4D flow MRI. MRI-estimated peak LVOT pressure gradient (∆PMRI) was used to classify patients into non-obstructive and obstructive HCM. Time-resolved volumetric LA kinetic energy (KELA) was computed throughout systole. Average systolic (KELA-avg) and peak systolic (KELA-peak) KELA were compared between non-obstructive and obstructive HCM groups, and associations to MR severity and LVOT ∆PMRI were tested.The study included 15 patients with non-obstructive HCM (58.6 [45.9, 65.2] years, 7 females) and 14 patients with obstructive HCM (51.9 [47.6, 62.6] years, 6 females). Obstructive HCM patients demonstrated significantly elevated instantaneous KELA over all systolic time-points compared to non-obstructive HCM (P < 0.05). Obstructive HCM patients also demonstrated higher KELA-avg (14.8 [10.6, 20.4] J/m3 vs. 33.4 [23.9, 61.3] J/m3, P < 0.001) and KELA-peak (22.1 [15.9, 28.7] J/m3 vs. 57.2 [44.5, 121.4] J/m3, P < 0.001) than non-obstructive HCM. MR severity was significantly correlated with KELA-avg (rho = 0.81, P < 0.001) and KELA-peak (rho = 0.79, P < 0.001). LVOT ∆PMRI was strongly correlated with KELA metrics in obstructive HCM (KELA-avg: rho = 0.86, P < 0.001; KELA-peak: rho = 0.85, P < 0.001).In HCM patients, left atrial kinetic energy, by 4D flow MRI, is associated with MR severity and the degree of LVOT obstruction.

Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). OBJECTIVES: The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures. METHODS: Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory. RESULTS: More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m2 vs 41 ± 14 mL/m2; mean change from baseline of -7.5 mL/m2 [95% CI: -9.0 to -6.1 mL/m2] vs -0.09 mL/m2 [95% CI: -1.6 to 1.5 mL/m2]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04). CONCLUSIONS: Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).

Predictors of Major Atrial Fibrillation Endpoints in the National Heart, Lung, and Blood Institute HCMR.

OBJECTIVES: This study sought to identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy. BACKGROUND: Atrial fibrillation (AF) is a common morbidity associated with hypertrophic cardiomyopathy (HCM). The HCMR (Hypertrophic Cardiomyopathy Registry) trial is a prospective natural history study of 2,755 patients with HCM with comprehensive phenotyping. METHODS: All patients received yearly telephone follow-up. Major AF endpoints were defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF. Penalized regression via elastic-net methodology identified the most important predictors of major AF endpoints from 46 variables. This was applied to 10 datasets, and the variables were ranked. Predictors that appeared in all 10 sets were then used in a Cox model for competing risks and analyzed as time to first event. RESULTS: Data from 2,631 (95.5%) patients were available for analysis after exclusions. A total of 127 major AF endpoints events occurred in 96 patients over 33.3 ± 12.4 months. In the final model, age, body mass index (BMI), left atrial (LA) volume index, LA contractile percent (active contraction), moderate or severe mitral regurgitation (MR), and history of arrhythmia the most important. BMI, LA volume index, and LA contractile percent were age-dependent. Obesity was a stronger risk factor in younger patients. Increased LA volume, reduced LA contractile percent, and moderate or severe MR put middle-aged and older adult patients at increased risk. CONCLUSIONS: The major predictors of major AF endpoints in HCM include older age, high BMI, moderate or severe MR, history of arrhythmia, increased LA volume, and reduced LA contractile percent. Prospective testing of a risk score based on these parameters may be warranted.