Risk factor burden drives adverse outcomes in gene-negative hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) has traditionally been viewed as a monogenic disease. Increasing evidence, however, suggests that gene-elusive HCM constitutes a distinct subgroup. A clearer understanding of its natural history is essential to support tailored management strategies. Purpose To characterise clinical and epidemiological profile of patients with gene-elusive HCM. Methods Over 10 years, 842 patients with HCM underwent genetic testing according to established referral criteria. Of these, 637 with longitudinal follow-up were included in the Natural History of HCM registry (NatHCM). The present analysis focuses on patients with negative genetic test (HCMG-). Results A total of 322 HCM patients from 302 families were included. Mean age at first assessment was 53.5 ± 13.1 years (IQR 44.5–62). Mean duration of follow-up (FU) from diagnosis to last assessment was 8.1 ± 5.9 years. Overall, 236 patients (73.3%) were men, while women were older at first assessment (58.1 ± 14.4 vs 51.8 ± 12.2 years). Ethnicity was recorded as Caucasian in 151 patients (46.9%), Asian in 69 (21.4%), Black in 59 (18.3%), and other ethnic backgrounds in 43 (13.3%). The most common reason for referral was presence of symptoms (62.4%). At diagnosis, 68% of patients had at least one cardiovascular risk factor (CRF): hypertension, dyslipidaemia, diabetes mellitus, or obesity (BMI>30). By the end of follow-up, 82% of the cohort had at least one CRF, and 52.4% had two or more. During follow-up, 61 patients (19.6%) experienced at least one cardiovascular event, with a median time to first event of 5 years. Symptomatic arrhythmias were the most frequent first event (34.4%), predominantly fast atrial fibrillation (14/21). Cerebrovascular accidents (CVA) accounted for 17 patients (27.9%), heart failure for 10 (16.4%), and acute coronary syndromes for 9 (14.8%). Cardiovascular events prior to first appointment were documented in 48 patients (15%). Patients with cardiovascular events were older (57.1 ± 13.3 vs 52.6 ± 12.9 years) and had a higher prevalence of CRFs, particularly hypertension (28.0% vs 7.2%; p<0.001). They demonstrated a more advanced structural phenotype, with greater maximal wall thickness on CMR (20.3 ± 3.3 vs 17.2 ± 3.5 mm; p=0.001) and larger left atrial diameter (43.2 ± 6.5 vs 41.2 ± 5.9 mm; p=0.024). Interestingly, no events occurred among patients without cardiovascular risk factors (0/43). 26 patients died during follow-up (8%), of whom 30% (8/26) had a cardiovascular cause of death. Conclusions Gene-elusive HCM is associated with a substantial risk of adverse events, driven primarily by cardiovascular risk-factor burden. Patients without risk factors had no events, whereas those with multiple risk factors developed mainly CVA, atrial fibrillation, and heart failure. These findings indicate that standard treatment thresholds may be insufficient, and more intensive risk-factor management is warranted in HCMG-.