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Original Articles

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

Carolyn Y. Ho, MD; Christian Carlsen, MD; Jens Jakob Thune, MD, PhD; Ole Havndrup, MD, PhD; Henning Bundgaard, MD, PhD; Faranak Farrohi, BS; Jose Rivero, MD; Allison L. Cirino, MS, CGC; Paal Skytt Andersen, MS, PhD; Michael Christiansen, MD; Barry J. Maron, MD; E. John Orav, PhD and Lars Køber, MD, DSci

From the Cardiovascular Division (C.Y.H., J.J.T., F.F., J.R., A.L.C.), Brigham and Women’s Hospital, Boston, Mass; Department of Cardiology (C.C., J.J.T., O.H., H.B., L.K.), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Biochemistry (P.S.A., M.C.), Statens Serum Institut, Copenhagen, Denmark; Minneapolis Heart Institute Foundation (B.J.M.), Minneapolis, Minn; and Brigham and Women’s Hospital (E.J.O.), Harvard Medical School, Boston, Mass.

Correspondence to Carolyn Y. Ho, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail cho{at}partners.org

Received March 2, 2009; accepted June 19, 2009.

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.

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+) 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 (_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 _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.

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

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