Published Online
on June 19, 2009

A more recent version of this article appeared on August 1, 2009

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Original Article

Echocardiographic Strain Imaging to Assess Early and Late Consequences of Sarcomere Mutations in Hypertrophic Cardiomyopathy

Carolyn Y. Ho^1,7; Christian Carlsen²; Jens Jakob Thune³; Ole Havndrup²; Henning Bundgaard²; Faranak Farrohi¹; Jose Rivero¹; Allison L. Cirino¹; Paal Skytt Andersen⁴; Michael Christiansen⁴; Barry J. Maron⁵; E.John Orav⁶ and Lars Køber²

¹ Brigham and Women's Hospital, Boston, MA;
² Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
³ Brigham and Women's Hospital, Boston, MA & Copenhagen Univ. Hospital, Copenhagen, Denmark;
⁴ Statens Serum Institut, Copenhagen, Denmark;
⁵ Minneapolis Heart Institute Foundation, Minneapolis, MN;
⁶ Brigham and Women's Hospital & Harvard Medical School, Boston, MA

⁷ E-mail: cho{at}partners.org

Background—Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Prior 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.

Methods and 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+) HCM subjects, and 38 mutation (-) normal control relatives. All subjects had normal LV ejection fraction (EF). In preclinical HCM, global and regional peak systolic strain (_sys) and longitudinal systolic strain rate (SSR) 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 _sys and SSR 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 function. 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 EF. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathologic remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

Key Words: cardiomyopathy • contractility • echocardiography • genetics • hypertrophy