Author + information
- Received July 12, 2014
- Revision received August 18, 2014
- Accepted August 22, 2014
- Published online February 1, 2015.
- Carolyn Y. Ho, MD∗∗ (, )
- Neal K. Lakdawala, MD∗,
- Allison L. Cirino, MS∗,
- Steven E. Lipshultz, MD†,
- Elizabeth Sparks, RNP‡,
- Siddique A. Abbasi, MD∗,
- Raymond Y. Kwong, MD∗,
- Elliott M. Antman, MD∗,
- Christopher Semsarian, MBBS, PhD§,
- Arantxa González, PhD‖,
- Begoña López, PhD‖,
- Javier Diez, MD, PhD‖,¶,
- E. John Orav, PhD#,
- Steven D. Colan, MD∗∗ and
- Christine E. Seidman, MD∗,††
- ∗Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- †Department of Pediatrics, Wayne State University School of Medicine, and Department of Cardiology, Children’s Hospital of Michigan, Detroit, Michigan
- ‡Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
- §Agnes Ginges Centre for Molecular Cardiology, Centenary Institute; Sydney Medical School, University of Sydney and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
- ‖Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
- ¶Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain
- #Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- ∗∗Boston Children’s Hospital, Boston, Massachusetts
- ††Howard Hughes Medical Institute, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Carolyn Y. Ho, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
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).
The National Institutes of Health (K23 HL078901 to Dr. Ho) funded this study but was not involved with study design or analysis. Additional support was provided to Dr. Ho by the Arthur L. Lenahan Sr. Family Foundation. Additional support to Drs. González, López, and Diez was provided by the Ministry of Economy and Competitiveness, Spain (RIC and Ramon y Cajal Program); and the European Union (HOMAGE and EU-MASCARA projects). Dr. Seidman is a founder of FCES and owns stock in Myokardia Inc., a startup company that is developing therapeutics that target the sarcomere. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received July 12, 2014.
- Revision received August 18, 2014.
- Accepted August 22, 2014.
- American College of Cardiology Foundation