Faculty Bibliography

BACKGROUND:We present the case of a 74-year-old woman diagnosed with obstructive hypertrophic cardiomyopathy. CASE SUMMARY/METHODS:Amyloidosis was initially considered because she was genotype positive in the transthyretin gene. However, because of 2 negative 99m technetium pyrophosphate radionuclide scans, this diagnosis was considered unlikely, and endomyocardial biopsy was deferred. She had an adverse response to all attempted medical therapies for her left ventricular outflow tract obstruction and ultimately underwent surgical myectomy. Surgical pathology revealed transthyretin (TTR) amyloidosis. DISCUSSION/CONCLUSIONS:This case highlights the limitations of diagnostic testing and reinforces the consideration of more invasive procedures to determine the true underlying cause of disease. This helps clinicians provide the most advanced level of treatment available. TAKE-HOME MESSAGES/CONCLUSIONS:TTR amyloidosis can mimic hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. 99m Technetium pyrophosphate scans are useful to investigate the presence of TTR amyloid, but if suspicion persists despite negative testing, it is reasonable to perform an endomyocardial biopsy.

BACKGROUND:The clinical benefits of mavacamten in patients with obstructive hypertrophic cardiomyopathy previously treated with advanced therapies are not established. METHODS:Clinical and echocardiographic outcomes of patients treated with mavacamten for left ventricular outflow obstruction for at least 8 weeks were assessed based on prior treatment with one or more advanced therapies: disopyramide, septal myectomy, alcohol septal ablation, dual-chamber ventricular pacing with short atrioventricular delay; we also evaluated patients with left ventricular outflow obstruction that emerged as major driver of symptoms after aortic valve replacement. RESULTS:=0.31). CONCLUSIONS:Mavacamten is a safe and effective treatment for symptomatic left ventricular outflow obstruction in patients with obstructive hypertrophic cardiomyopathy resistant to previous advanced pharmacologic therapy, surgery, or alcohol septal ablation or who develop manifest left ventricular outflow obstruction after aortic valve replacement.

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.