Wheeler, Matthew T

Background: MARVEL-HCM is a US multicenter study assessing the safety and effectiveness of mavacamten in real-world academic and community practices. Mavacamten is a first-in-class cardiac myosin inhibitor (CMI) and the only CMI currently approved in over 50 countries for use in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Modest evidence exists describing the effectiveness and safety of mavacamten monotherapy. Aims: To describe the real-world outcomes of patients using mavacamten as monotherapy for oHCM. Methods: Patient-level data from medical records at 5 sites were analyzed to describe mavacamten monotherapy, defined as monotherapy at baseline or after background HCM therapy (beta-blockers [BB], calcium channel blockers [CCB], disopyramide) discontinuation within 12 weeks(wks) of mavacamten initiation and without reinitiation, up to 60 wks. A minimum of 12 wks follow-up was required for inclusion. Patient characteristics, echocardiographic data, and safety are reported at baseline and follow-up visits. Results: The monotherapy cohort comprised 13.4% (32/239) of patients: 24 were on mavacamten monotherapy at initiation, and 8 discontinued background therapy. Baseline characteristics included: NYHA Class II (46.9%) and III (53.1%), female (66%), hypertension (50%), and atrial fibrillation (AF) (18%) (Table 1). Median follow-up and duration of mavacamten monotherapy were 48 wks (range 12-60 wks) and 57 wks (range 14-60 wks), respectively. Resting left ventricular outflow tract gradient (LVOTg) was ≤ 30 mmHg in 93%, 91% and 100% of patients at Wk 24, 36, and 60. Valsalva LVOTg was ≤ 30 mmHg in 61%, 77% and 86% of patients at Wk 24, 36, and 60 (Fig 1). No patients were in NYHA Class III at wk 60, and ~50% of patients were NYHA Class I by wk 48 (Fig 2). Mean reduction in LVEF was 4.8% over 60 wks. One patient had LVEF < 50% at Wk 20, resulting in a dose reduction (10 to 7.5 mg). Safety events included 3 hospitalizations due to AF ablation (n=1), viral gastrointestinal illness (n=1) and heart failure (n=1). Demographic, clinical characteristics, and outcomes were similar across the mavacamten monotherapy cohort, mavacamten in combination with background HCM therapy (n=207), and the overall cohort of MARVEL-HCM (N=239). Conclusions: Mavacamten monotherapy was effective, safe, and consistent with the overall MARVEL cohort, as well as previously reported monotherapy cohorts from pivotal, long-term, and real-world evidence.

Background: Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States. Research Questions: This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM. Methods: In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks. Results: Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of <40% and 2% experienced an LVEF of <50%. Conclusions: This is the largest observational study to date demonstrating the effectiveness and safety of mavacamten with substantial sustained reductions in resting and Valsalva LVOTg, and progressive improvements in NYHA class without considerable changes in mean LVEF up to 72 weeks.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

Background: The study of hypertrophic cardiomyopathy (HCM) can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease. Methods: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered short hairpin ribonucleic acids and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell–derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics. Results: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio . Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell–derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil. Conclusions: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.