Faculty Bibliography

BACKGROUND: The hydrodynamic cause of systolic anterior motion of the mitral valve (SAM) is unresolved. OBJECTIVES: This study hypothesized that echocardiographic vector flow mapping, a new echocardiographic technique, would provide insights into the cause of early SAM in obstructive hypertrophic cardiomyopathy (HCM). METHODS: We analyzed the spatial relationship of left ventricular (LV) flow and the mitral valve leaflets (MVL) on 3-chamber vector flow mapping frames, and performed mitral valve measurements on 2-dimensional frames in patients with obstructive and nonobstructive HCM and in normal patients. RESULTS: We compared 82 patients (22 obstructive HCM, 23 nonobstructive HCM, and 37 normal) by measuring 164 LV pre- and post-SAM velocity vector flow maps, 82 maximum isovolumic vortices, and 328 2-dimensional frames. We observed color flow and velocity vector flow posterior to the MVL impacting them in the early systolic frames of 95% of obstructive HCM, 22% of nonobstructive HCM, and 11% of normal patients (p < 0.001). In both pre- and post-SAM frames, we measured a high angle of attack >60 degrees of local vector flow onto the posterior surface of the leaflets whether the flow was ejection (59%) or the early systolic isovolumic vortex (41%). Ricochet of vector flow, rebounding off the leaflet into the cul-de-sac, was noted in 82% of the obstructed HCM, 9% of nonobstructive HCM, and none (0%) of the control patients (p < 0.001). Flow velocities in the LV outflow tract on the pre-SAM frame 1 and 2 mm from the tip of the anterior leaflet were low: 39 and 43 cm/s, respectively. CONCLUSIONS: Early systolic flow impacts the posterior surfaces of protruding MVL initiating SAM in obstructive HCM.

BACKGROUND:Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES/OBJECTIVE:This study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study. METHODS:Obstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study. Participants received aficamten 5 mg once daily titrated ≤20 mg based on site-read echocardiographic assessments of Valsalva left ventricular outflow tract gradient and left ventricular ejection fraction. RESULTS:; P = 0.0008), lateral E/e' (-2.2 ± 6.1; P = 0.02), and cardiac biomarkers (P ≤ 0.0031). Aficamten was well tolerated with 2 (4.3%) asymptomatic and transient instances of left ventricular ejection fraction <50% (range: 47%-49%), neither resulting in drug discontinuation, and no new-onset atrial fibrillation. CONCLUSIONS:Aficamten treatment over 48 weeks was well tolerated and associated with substantial and durable relief of obstruction and symptom burden, lower cardiac biomarker levels, and cardiac phenotypic changes, which may indicate favorable cardiac remodeling. (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).

BACKGROUND:Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction. OBJECTIVES/OBJECTIVE:This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten. METHODS:Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group). RESULTS:Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean -27.0 ± 3.6, Valsalva: Δ least squares mean -39.2 ± 5.0, both P < 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; P < 0.0001; Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score: 12.3 ± 3.3 [P < 0.001]), and reduced N-terminal pro-B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; P < 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal. CONCLUSIONS:In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disopyramide. (Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Aficamten in Adults With HCM [FOREST-HCM]; NCT04848506).

Hypertrophic cardiomyopathy is a common but underrecognized cardiac disorder characterized by a heterogenous phenotype that includes increased left ventricular thickness, outflow obstruction, diastolic dysfunction, and arrhythmia. Hypertrophic cardiomyopathy is often heritable and associated with pathogenic variants in sarcomeric genes. While not curable, an integrated approach involving medical, interventional, and surgical care can have a considerable impact on disease burden, quality of life, and mortality. This review provides a practical overview of important topics in hypertrophic cardiomyopathy, including evaluation of differential diagnosis, imaging, provocation of left ventricular outflow obstruction, treatment of obstructive and nonobstructive hypertrophic cardiomyopathy with negative inotropic therapy and myosin inhibition, as well as surgical and interventional approaches to septal reduction and mitral valve intervention.

BACKGROUND:Disopyramide is used to treat heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM) with known medium-term efficacy and safety, while long-term outcomes are unknown. METHODS AND RESULTS/RESULTS:=0.51). Ventricular tachyarrhythmias and left ventricular systolic dysfunction were uncommon (n=3 and n=1) and were not attributed to disopyramide. Death on disopyramide was exceedingly rare (n=3 [5%]) and non-HCM-related occurring at age ≥90 years. CONCLUSIONS:In patients with obstructive HCM, disopyramide is safe and effective at relieving heart failure symptoms from outflow obstruction in a subgroup of patients who were maintained on disopyramide for >5 years.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. OBJECTIVES/OBJECTIVE:The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. METHODS:In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate <0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling. RESULTS:The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings. CONCLUSIONS:The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.

BACKGROUND:Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects. OBJECTIVES/OBJECTIVE:We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506). METHODS:Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal. RESULTS:Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups. CONCLUSIONS:In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).