Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression.

Abstract

OBJECTIVES:

The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers.

BACKGROUND:

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 that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence.

METHODS:

In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) 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 (LV) end-diastolic diameter improved toward 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, 2 in each treatment group.

CONCLUSIONS:

Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982).

• Authors: Carolyn Y Ho, Neal K Lakdawala, Allison L Cirino, Steven E Lipshultz, Elizabeth Sparks, Siddique A Abbasi, Raymond Y Kwong, Elliott M Antman, Christopher Semsarian, Arantxa González, Begoña López, Javier Diez, E John Orav, Steven D Colan, Christine E Seidman
• Journal: JACC. Heart failure (JACC Heart Fail) Vol. 3 Issue 2 Pg. 180-8 (Feb 2015) ISSN: 2213-1787 [Electronic] United States
• PMID: 25543971 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Carrier Proteins
• Troponin I
• myosin-binding protein C
• Diltiazem

Topics

• Adolescent
• Adult
• Calcium Channel Blockers (therapeutic use)
• Cardiomyopathy, Hypertrophic (genetics, prevention & control)
• Carrier Proteins (genetics)
• Child
• Child, Preschool
• Diastole
• Diltiazem (therapeutic use)
• Double-Blind Method
• Echocardiography
• Female
• Genetic Predisposition to Disease
• Heart Ventricles (diagnostic imaging, pathology)
• Heterozygote
• Humans
• Magnetic Resonance Imaging, Cine
• Male
• Mutation
• Pilot Projects
• Sarcomeres (genetics)
• Troponin I (blood)
• Young Adult