Genotype-driven differences in the phenotype and prognosis of patients with hypertrophic cardiomyopathy
A Martins, C Esteves, A Vazao, J Pereira, M Amado, M Cabral, C Domingues, C Ruivo, D DuraoAbstract
Introduction
Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant disease commonly caused by pathogenic variants in sarcomere protein genes, although many patients remain genotype-negative or carry variants of uncertain significance (VUS). Despite decades of research, genotype-phenotype correlations remain incompletely understood.
Objectives
To evaluate the influence of genotype on clinical and imaging phenotypes and short-term prognosis in HCM patients followed at a regional Cardiomyopathy Clinic.
Methods
Retrospective, single-center study of patients diagnosed with HCM between 2018 and 2024. Those with uncontrolled hypertension, significant valvular disease, or lacking genetic testing were excluded. Patients were classified into two groups: genotype-negative or VUS (Group 1) and pathogenic (P) or likely pathogenic (LP) (Group 2). Group comparisons and regression analyses identified variables associated with P/LP variants (Table 1).
Results
Among 145 enrolled patients (61 ± 13 years; 64% male), genetic testing identified P/LP variants in 56 (39%) (Group 2), VUS in 27 (19%), and no detectable mutations in 62 (43%). P/LP carriers more frequently exhibited a midventricular phenotype (82 vs 66%, p=0.038) and had lower rates of overweight (52 vs 69%, p=0.043), hypertension (52 vs 70%, p=0.030), and dyslipidemia (57 vs 76%, p=0.015). This subgroup also had a higher prevalence of family history of HCM (30 vs 6%, p<0.001) and a normal ECG (25 vs 4%, p<0.001). Echocardiography demonstrated greater interventricular septal thickness (17.9 vs 17.4 mm, p=0.046) and left atrial volume index (53.6 vs 50.8 ml/m², p=0.007) in P/LP carriers. hs-TnI levels were likewise higher in this group (17.8 vs 11.3 pg/mL, p=0.032). The median follow-up was 46 months (IQR 35), with no differences between groups in the occurrence of extended MACE (cardiovascular mortality, myocardial infarction, stroke and heart failure hospitalizations) or new-onset AV/IV conduction disturbances or atrial fibrillation. ROC analysis defined cut-offs for continuous variables. In multivariate logistic regression family history of HCM, a normal ECG and hs-TnI ≥ 13.2 pg/ml remained independently associated with P/LP variants.
Conclusions
In this HCM cohort, higher hs-TnI, a normal ECG, and family history of the disease were associated with P/LP variants, while no differences were observed in follow-up outcomes. The small sample size limits conclusions regarding individual gene effects.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.