Background: Although common among families with hypertrophic cardiomyopathy (HCM), the clinical course and outcome of relatives with sarcomere mutations judged to be disease causing, but without left ventricular hypertrophy (LVH), is largely unresolved.
Objective: To determine the clinical features and natural history of genotype positive (+) –LVH negative (−) HCM.
Methods: Prospective analysis of G+LVH- individuals followed at 4 international referral centers for HCM. Participants were ≥12 years old at first evaluation and carried a pathogenic/likely pathogenic sarcomere variant considered to cause HCM in their family.
Results: Two-hundred and three individuals were identified from 158 HCM families. Age at first evaluation was 32±11 years and 147 (72%) were <40 years; 61% were female. Initially, each patient showed normal LV thickness and cavity dimensions with preserved systolic function. Maximal LV wall thickness was 9±2mm.
Over follow-up of 6±2 years, no adverse cardiovascular events such as death, heart failure, or cardiac symptoms occurred among the 203 patients; 182 (90%) remained without LVH, including 37 (20%) ≥50 years of age (including 5% ≥60 years, range to 69). Twenty-one patients (10%) converted to clinically evident HCM with LVH (maximum wall thickness ≥13mm range to 17mm) at 35±15 years of age (range 7 to 62 years). Of the 21 patients who developed LVH, 8 (38%) were >40 years old; rate of conversion was 0.3%/year, and similar across all age groups (p=0.76). 12-lead ECGs were abnormal in 10 patients (48%) at the time LV thickness was normal. Multivariate analysis showed pathologic Q waves to be an independent predictor for development of LVH (HR 2.1, 95% CI: 1.3–5.1, p=0.01).
Conclusions: G+LVH- patients demonstrated exceedingly low risk for mortality, morbidity, and HCM-related complications. Phenotypic conversion to HCM was uncommon, often preceded (4-years) by abnormal ECG patterns, with a large proportion of patients remaining free of LVH at relatively advanced ages, implying that many gene carriers may not develop HCM during their lifetime.