Emerging Medical Treatment for Hypertrophic Cardiomyopathy

Argirò, Alessia; Zampieri, Mattia; Berteotti, Martina; Marchi, Alberto; Tassetti, Luigi; Zocchi, Chiara; Iannone, Luisa; Bacchi, Beatrice; Cappelli, Francesco; Stefàno, Pierluigi; Marchionni, Niccolò; Olivotto, Iacopo

doi:10.3390/jcm10050951

Cited by 22 publications

(26 citation statements)

References 65 publications

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“…In addition, the efficacy of mavacamten in both nonobstructive HCM and as an alternative to SRT in severe LVOTO cases is being currently tested in the phase II MAVERICK‐HCM [74] and phase III VALOR‐HCM (NCT04349072) clinical trials, respectively. The safety, tolerability and clinical dose of CK‐274, another small molecule with a mechanism of action comparable to that of mavacamten, is currently being assayed in a phase II RCT for the treatment of obstructive HCM (REDWOOD‐HCM, NCT04219826) [61].…”

Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%

“…Most of the currently available pharmacological treatments are focussed on relieving symptoms in obstructive HCM [14,61,62]. For that, drugs with negative inotropic* (reduction of the force of contraction) and chronotropic* (decrease in the heart rate) effects are used.…”

Section: Treatmentmentioning

confidence: 99%

“…When neither of these treatments prove effectiveness, administration of the antiarrhythmic drug disopyramide is recommended. Albeit the combination of these drugs reduces disabling symptoms in 50-65% of the patients, only 25% benefit in the long term [61,63].…”

Section: Treatmentmentioning

confidence: 99%

“…If pharmacological treatment of obstructive HCM does not relieve symptoms, invasive surgical procedures can be considered [14,61,62]. Septal reduction therapy or SRT* (either by septal myectomy* or alcohol septal ablation, ASA*) is the most effective practice in the treatment of LVOTO.…”

Section: Treatmentmentioning

confidence: 99%

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The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Suay-Corredera

Alegre-Cebollada

2022

FEBS Letters

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Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart. HCM is mainly caused by variants in genes encoding proteins of the sarcomere, the basic contractile unit of cardiomyocytes. The most frequently mutated among them is MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key regulator of sarcomere contraction. In this review, we summarize clinical and genetic aspects of HCM and provide updated information on the function of the healthy and HCM sarcomere, as well as on emerging therapeutic options targeting sarcomere mechanical activity. Building on what is known about cMyBP-C activity, we examine different pathogenicity drivers by which MYBPC3 variants can cause disease, focussing on protein haploinsufficiency as a common pathomechanism also in nontruncating variants. Finally, we discuss recent evidence correlating altered cMyBP-C mechanical properties with HCM development.

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Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

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The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Suay-Corredera

Alegre-Cebollada

2022

FEBS Letters

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“…The clinical presentation of HCM varies widely [ 1 , 3 , 7 , 8 ]: some patients are asymptomatic [ 1 , 7 , 13 ], while others manifest symptomatic left ventricular outflow tract obstruction (LVOTO) [ 7 , 8 ], atrial fibrillation (AF) [ 3 , 8 ], sudden cardiac death (SCD) [ 3 , 7 , 13 , 14 ], or heart failure (HF) [ 1 , 3 , 10 , 11 ]. Pathophysiologic features of HCM include cardiomyocyte hypertrophy [ 15 , 16 ], cardiomyocyte disarray [ 16 , 17 ], myocardial remodeling [ 18 , 19 ], fibrosis [ 3 , 20 , 21 ], myocardial hypercontractility [ 22 , 23 ], impaired myocardial relaxation [ 20 , 24 ], myocardial stiffness [ 17 , 20 ], diastolic dysfunction [ 13 , 14 , 17 ], coronary microvascular dysfunction [ 25 , 26 ], and myocardial ischemia [ 25 , 27 ], but the underlying molecular mechanisms are poorly understood. Molecular determinants of the disease presentations are also still not known.…”

Section: Introductionmentioning

confidence: 99%

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Glavaški

Velicki

2021

Life

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with a prevalence of 1 in 500 people and varying clinical presentations. Although there is much research on HCM, underlying molecular mechanisms are poorly understood, and research on the molecular mechanisms of its specific clinical presentations is scarce. Our aim was to explore the molecular mechanisms shared by HCM and its clinical presentations through the automated extraction of molecular mechanisms. Molecular mechanisms were congregated by a query of the INDRA database, which aggregates knowledge from pathway databases and combines it with molecular mechanisms extracted from abstracts and open-access full articles by multiple machine-reading systems. The molecular mechanisms were extracted from 230,072 articles on HCM and 19 HCM clinical presentations, and their intersections were found. Shared molecular mechanisms of HCM and its clinical presentations were represented as networks; the most important elements in the intersections’ networks were found, centrality scores for each element of each network calculated, networks with reduced level of noise generated, and cooperatively working elements detected in each intersection network. The identified shared molecular mechanisms represent possible mechanisms underlying different HCM clinical presentations. Applied methodology produced results consistent with the information in the scientific literature.

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Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy

Tian,

Li,

et al. 2023

JAMA Cardiol

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ImportanceMavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking.ObjectiveTo evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM.Design, Setting, and ParticipantsThis phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks.InterventionsPatients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks.Main Outcomes and MeasuresThe primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis.ResultsA total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, −70.3 mm Hg; 95% CI, −89.6 to −50.9 mm Hg; 1-sided P &lt; .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, −55.0 mm Hg; 95% CI, −69.1 to −40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, −30.8 g/m2; 95% CI, −41.6 to −20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%.ConclusionsMavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients.Trial RegistrationClinicalTrials.gov Identifier: NCT05174416

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Emerging Medical Treatment for Hypertrophic Cardiomyopathy

Cited by 22 publications

References 65 publications

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy

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