Beyond the genotype: prevalence, phenotypic expression and prognosis in hypertrophic cardiomyopathy

Background

Genetic testing plays a pivotal role in the management of hypertrophic cardiomyopathy (HCM), however its clinical impact in real-world populations remains heterogeneous and uncertain.

Purpose

To characterize the genetic profile of a real-world HCM cohort and assess its correlation with phenotypic expression and disease-related outcomes.

Methods

Single-centre retrospective study of patients (pts) followed in our cardiomyopathies’ clinic with HCM diagnosis and available genetic testing. Pts with syndromic or infiltrative phenocopies were excluded. Disease-related outcomes included cardiovascular (CV) mortality, CV hospitalizations or urgent visits, device implantation or therapies, arrhythmias (ventricular arrhythmias and atrial fibrillation/flutter) and advanced heart failure. Data were collected through comprehensive medical record review.

Results

101 pts were included, predominantly male (54.5%), mean age 60 ± 18 years. 43.6% carried pathogenic/likely pathogenic (P/LP) variants, while the remaining had either no identifiable genetic variants (29.7%) or had variants of uncertain significance (VUS; 26.7%). Among genotype-positive (GP) pts, sarcomere variants predominated (86.4%).

Pts were diagnosed mainly through routine/familial cascade screening (58.4%), however, genotype-negative (GN) pts were diagnosed significantly later in adulthood (52 ± 18 vs 40 ± 21 years; p<0.001) and more often due to symptoms onset (35.6% in GN vs 36.4% in GP, p=0.006). No differences regarding family history of sudden cardiac death were found (p=0.59).

Asymmetric septal HCM was the predominant morphology (n=77, 76.2%). GN pts exhibited higher prevalence of left ventricle outflow tract obstruction (LVOTO) (28.1% in GN vs 11.6% in GP, p=0.046) and systolic anterior motion of the mitral valve/subvalvular apparatus (29.8% in GN vs 14% in GP, p<0.50). No group differences were observed in LV ejection fraction (65 ± 5%; p=0.99) or diastolic function parameters.

GP pts had more frequently late gadolinium enhancement (LGE) >15% extension (53.3% in GP vs 24.6% in GN, p=0.016) and broader intramyocardial LGE beyond septal segments (54.3% in GP vs 20.8% in GN, p=0.017).

Biomarkers including N-terminal pro-B-type natriuretic peptide (549, IQR 1127 pg/mL, p=0.64) and high sensitivity Troponin I (7, IQR 9 ng/L, p=0.44) were comparable between groups.

At a median follow-up of 6 (IQR 9) years, no significant differences were observed in the composite endpoint of disease-related outcomes (log-rank p=0.179) – figure 1.

Conclusions

In our real-world cohort, while GP pts showed a more extensive myocardial fibrosis, GN pts demonstrated a higher burden of late diagnosis and obstructive physiology. Despite these genotype–phenotype differences, disease-related outcomes were similar, underscoring the limitations of current risk models and the need for deeper understanding and integration of genetic testing.For image description, please refer to the figure legend and surrounding text.