Genotype-Negative Patients With Familial Hypertrophic Cardiomyopathy: Traveling to the "Middle Earth".

BACKGROUND

A substantial proportion of hypertrophic cardiomyopathy (HCM) patients and negative genetic testing (Sarc-) have a positive family history of HCM (FH), suggesting a stronger genetic component.

OBJECTIVES

The purpose of this study was to assess whether Sarc-/FH+ patients differ from Sarc-/FH- and gene-positive (Sarc+) patients in terms of phenotype and prognosis.

METHODS

Six hundred fifty-four HCM patients underwent comprehensive clinical assessment and genetic testing, followed for a median of 6 years. The 3 groups (Sarc-/FH-, Sarc-/FH+, Sarc+) were compared for major arrhythmic events, heart failure, all-cause death, atrial fibrillation, and stroke.

RESULTS

Of the 654 patients, 182 were Sarc-/FH- (28%), 101 were Sarc-/FH+ (15%), and 371 were Sarc+ (57%). Sarc-/FH+ were similar to Sarc+: they were younger, with higher HCM risk sudden cardiac death and lower prevalence of obstruction (age 43 [IQR: 23-53] years vs 39 [IQR: 23-52] years; P = 0.235; 19% obstructive vs 18%; P = 0.763) compared to Sarc-/FH-. However, Sarc-/FH+ were akin to Sarc-/FH- due to the lower prevalence of female sex, higher burden of cardiovascular risk factors, and less prevalent late gadolinium enhancement at cardiac magnetic resonance imaging (for female prevalence 26% vs 27%; P = 0.829; for late gadolinium enhancement in 50% vs 53%; P = 0.541), compared to Sarc+. There were no significant outcome differences, except for the incidence of stroke (2.7% for Sarc-/FH-, 1% for Sarc-/FH+, 5.9% for Sarc+, P = 0.046).

CONCLUSIONS

Sarc-/FH+ represented 15% of our HCM cohort and exhibited intermediate clinical features between Sarc-/FH- and Sarc+, suggesting an interplay of monogenic/oligogenic disease with environmental factors. This population provides a unique opportunity for gene discovery and an understanding of nongenetic modifiers of HCM, deserving of dedicated investigation.