Cardiomyopathy
Electrocardiographic Features of Sarcomere Mutation Carriers With and Without Clinically Overt Hypertrophic Cardiomyopathy

https://doi.org/10.1016/j.amjcard.2011.07.019Get rights and content

In hypertrophic cardiomyopathy (HC), electrocardiographic (ECG) changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when left ventricular (LV) wall thickness is still normal. However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECGs in a genotyped HC population to characterize ECG findings in mutation carriers (G+) with and without echocardiographic LV hypertrophy (LVH), and to evaluate the accuracy of ECG findings to differentiate at-risk mutation carriers from genetically unaffected relatives during family screening. The ECG and echocardiographic findings were analyzed from 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98% specificity) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects, and 3% of controls (p <0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (odds ratio 8.4, p = 0.007). Myocardial scar or perfusion abnormalities were not detected on cardiac magnetic resonance imaging in G+/LVH− subjects, irrespective of the ECG features. In overt HC, 75% had Q waves and/or repolarization changes, but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, owing to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.

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Methods

Genotyped HC probands and relatives identified by research protocols or through clinical evaluation were studied. Research subjects were recruited from 3 institutions: Brigham and Women's Hospital (n = 106), the Minneapolis Heart Institute Foundation (n = 57), and Copenhagen University Hospital (n = 50). Genetic status was previously determined in the family proband by direct DNA sequencing of 8 sarcomere genes, including myosin-binding protein C (MYBPC3), β-myosin heavy chain (MYH7), cardiac

Results

A total of 213 subjects from 60 different families were evaluated, including 76 G+/LVH− subjects, 57 overt (G+/LVH+) HC, and 80 genotype-negative (G−) healthy relatives who served as the normal controls. The clinical and echocardiographic characteristics are summarized in Table 2. Reflecting the age-dependent penetrance of LVH, the overt HC cohort was nearly 2 decades older than the G+/LVH− cohort. Pediatric subjects (<18 years) constituted 42% of the G+/LVH− cohort compared to 33% and 4% of

Discussion

Q waves and repolarization abnormalities are the most distinguishing ECG manifestations of sarcomere mutations in both early (G+/LVH−) and overt (G+/LVH+) HC. Despite the key role that increased LV wall thickness plays in the diagnosis of the disease, isolated ECG voltage criteria for LVH are neither sensitive nor specific markers of HC. Voltage criteria without accompanying repolarization abnormalities are frequently absent in sarcomere mutation carriers, including those with clinically overt

Acknowledgment

We are indebted to Calum A. MacRae, MBCHB, PhD for his careful reading of our manuscript and insightful comments.

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    This work was supported by grant K23 HL078901 from the National Institutes of Health, Bethesda, Maryland (to C.Y.H.), Hearst Foundation, New York, New York (to B.J.M.), and the American College of Cardiology/Merck Research Foundation, Washington, DC (to N.K.L.).

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