Diltiazem Treatment for Pre-Clinical Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers

Abstract

Background Hypertrophic cardiomyopathy (HCM) is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate alterations in intracellular calcium handling before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Objectives To assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk HCM mutation carriers. Methods In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean age 15.8 years) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular end diastolic diameter improved towards normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. −0.5; P<0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group, but increased in controls (−0.02 vs. +0.15; P=0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, two in each treatment group. Conclusions Preclinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration.

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

“…Identification of HCM leads to lifestyle modifications, periodic SCD risk stratification, and close clinical follow-up, with the opportunity to implant an ICD for primary prevention and timely referral for septal reduction therapy. In the future, early disease identification might lead to novel therapies to prevent hypertrophy 32 or delay progression to advanced disease stages. 33 In this study, the clinical phenotypes of FG+ carriers showed substantial variation.…”

“…The main advantage of genetic testing in relatives is reassurance in case the mutation is absent. However, the identification of FG+/Ph− subjects currently has limited therapeutic and prognostic consequences because at present, no therapy is available to retard or prevent the development of HCM, 32,33 and clinical manifestation cannot be predicted. 35 Moreover, a FG+/Ph− status may have psychological and socioeconomic implications.…”

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

“…A pilot trial investigated whether oral diltiazem attenuated disease progression in patients with preclinical HCM and an identified genetic mutation. 95 . LV end-diastolic diameter improved towards normal in the diltiazem group but decreased further in controls…”

Role of risk stratification and genetics in sudden cardiac death

“…Hypertrophic cardiomyopathy is a major cause of SCD in the adult population and young athletes, and it has been suggested that intracellular calcium handling in the heart is altered before development of LVH; in addition progression of LVH development can be attenuated by preclinical use of diltiazem (Ho et al 2015). Sudden cardiac death in heart failure with reduced EF has been well-studied, and the potential role of implantable devices and pharmacological agents to prevent SCD in heart failure patients with preserved EF have been reported (Vaduganathan et al 2016).…”