title: Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.
  
  
  RESULTS
  Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH-), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (-) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (epsilon(sys)) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal epsilon(sys) and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea.
  
  
  CONCLUSIONS
  Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.
authors.affiliation: Cardiovascular Division, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. cho@partners.org
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Christian
authors.initials: C
authors.lastname: Carlsen
authors.forename: Jens Jakob
authors.initials: JJ
authors.lastname: Thune
authors.forename: Ole
authors.initials: O
authors.lastname: Havndrup
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
authors.forename: Faranak
authors.initials: F
authors.lastname: Farrohi
authors.forename: Jose
authors.initials: J
authors.lastname: Rivero
authors.forename: Allison L
authors.initials: AL
authors.lastname: Cirino
authors.forename: Paal Skytt
authors.initials: PS
authors.lastname: Andersen
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maron
authors.forename: E John
authors.initials: EJ
authors.lastname: Orav
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D015331:Cohort Studies; D003971:Diastole; D015150:Echocardiography, Doppler; D005260:Female; D005838:Genotype; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012518:Sarcomeres / Q000235:genetics*; D013599:Systole; D014335:Tropomyosin / Q000235:genetics; D019210:Troponin I / Q000235:genetics; D020107:Troponin T / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D014335:Tropomyosin; D019210:Troponin I; D020107:Troponin T; D024723:Ventricular Myosins; D000099163:Myosin Binding Protein C; C545568:TNNT2 protein, human