Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy.
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.
Ho
Carolyn Y
CY
Cardiovascular Division, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. cho@partners.org
Carlsen
Christian
C
Thune
Jens Jakob
JJ
Havndrup
Ole
O
Bundgaard
Henning
H
Farrohi
Faranak
F
Rivero
Jose
J
Cirino
Allison L
AL
Andersen
Paal Skytt
PS
Christiansen
Michael
M
Maron
Barry J
BJ
Orav
E John
EJ
Køber
Lars
L
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
D002352:Carrier Proteins; D014335:Tropomyosin; D019210:Troponin I; D020107:Troponin T; D024723:Ventricular Myosins; D000099163:Myosin Binding Protein C; C545568:TNNT2 protein, human