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Published on: August 8, 2022
Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized
Carolyn Y Ho1, Neal K Lakdawala1, Allison L Cirino1
1Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Diltiazem is safe for hypertrophic cardiomyopathy (HCM) mutation carriers and may improve early left ventricular remodeling. This early intervention strategy shows promise for preventing disease progression in at-risk individuals.
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- Hypertrophic cardiomyopathy (HCM) stems from sarcomere mutations, leading to left ventricular hypertrophy (LVH), heart failure, and sudden death.
- Early diagnosis of HCM is challenging, though subtle phenotypes exist before LVH onset.
- Animal studies suggest altered calcium handling precedes LVH, and early diltiazem treatment may prevent disease emergence.
Purpose of the Study:
- To evaluate the safety, feasibility, and disease-modifying effects of diltiazem in individuals with at-risk hypertrophic cardiomyopathy (HCM) gene mutations.
- To assess diltiazem's impact on early left ventricular (LV) remodeling in preclinical HCM.
Main Methods:
- A pilot, double-blind, placebo-controlled trial involving 38 sarcomere mutation carriers without LVH.
- Participants received diltiazem (360 mg/day or 5 mg/kg/day) or placebo for 12-42 months (median 25 months).
- Evaluations included ECG, echocardiography, cardiac MRI, and serum biomarkers.
Main Results:
- Diltiazem was safe, with no serious adverse events and no significant differences in heart rate or blood pressure between groups.
- The diltiazem group showed improved LV end-diastolic diameter z-scores (+0.6) compared to controls (-0.5; p < 0.001).
- In MYBPC3 carriers, diltiazem improved LV wall thickness, mass, diastolic filling, and troponin I levels; 4 participants developed overt HCM (2 per group).
Conclusions:
- Pre-clinical diltiazem administration is safe and may positively influence early LV remodeling in HCM.
- This therapeutic strategy warrants further investigation for preventing HCM progression.
- Diltiazem may represent a novel approach to disease modification in at-risk HCM mutation carriers.
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).
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