title: The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers: Findings From the HCMNet Study.
abstract: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression.
  
  
  
  (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers.
  
  
  
  This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH-), and healthy related control individuals (G-/LVH-) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016.
  
  
  
  The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT.
  
  
  
  Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts.
  
  
  
  Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH- (20 [10] years), and 42 G-/LVH- (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E' velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH-, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than -1.85 or the combination of an LV end-diastolic dimension z score of -1.85 or higher and a septal E' velocity z score less than -0.52 as having 74% accuracy in discriminating G+/LVH- participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition.
  
  
  
  G+/LVH- individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G- controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree-based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.affiliation: Division of Cardiology, Department of Medicine, New York University Langone Medical Center, New York, New York.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Sherrid
authors.affiliation: Department of Pediatrics, Washington University School of Medicine in St Louis, Missouri.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Canter
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: John L
authors.initials: JL
authors.lastname: Jefferies
authors.affiliation: Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murphy
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Cirino
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora.
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
authors.affiliation: Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Bluemke
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: New England Research Institutes, Watertown, Massachusetts.
authors.forename: Ling
authors.initials: L
authors.lastname: Shi
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Sleeper
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts14Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: E John
authors.initials: EJ
authors.lastname: Orav
mesh_terms: D000293:Adolescent; D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000000981:diagnostic imaging* / Q000503:physiopathology; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies; D012518:Sarcomeres / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology*; D055815:Young Adult