title: Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression.
abstract: OBJECTIVE
  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.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: cho@partners.org.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neal K
authors.initials: NK
authors.lastname: Lakdawala
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Cirino
authors.affiliation: Department of Pediatrics, Wayne State University School of Medicine, and Department of Cardiology, Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.affiliation: Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sparks
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Siddique A
authors.initials: SA
authors.lastname: Abbasi
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Kwong
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute; Sydney Medical School, University of Sydney and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: 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.
authors.forename: Javier
authors.initials: J
authors.lastname: Diez
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: E John
authors.initials: EJ
authors.lastname: Orav
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts; Howard Hughes Medical Institute, New York, New York.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000293:Adolescent; D000328:Adult; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003971:Diastole; D004110:Diltiazem / Q000627:therapeutic use*; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D009154:Mutation; D010865:Pilot Projects; D012518:Sarcomeres / Q000235:genetics*; D019210:Troponin I / Q000097:blood; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004110:Diltiazem; D019210:Troponin I; D000099163:Myosin Binding Protein C
keywords: cardiomyopathy; genetics; hypertrophy; translational research; treatment; trials