Sarcomeric hypertrophic cardiomyopathy is associated with a worse prognosis requiring vigilant surveillance, whereas nonsarcomeric disease is linked to modifiable comorbidities.
Does sarcomeric genotype compared to nonsarcomeric genotype affect disease trajectory, comorbidities, and mortality in patients with hypertrophic cardiomyopathy?
Genotype in HCM can refine risk stratification, with sarcomeric HCM requiring more vigilant surveillance for arrhythmias and systolic dysfunction.
Absolute Event Rate: 0% vs 0%
BACKGROUND: Sarcomere gene variants are a key cause of hypertrophic cardiomyopathy (HCM), and have been associated with worse prognosis. However, it is unclear how comorbidities influence clinical trajectories, the timing of events, and causes of death in sarcomeric and nonsarcomeric HCM. METHODS: We conducted a multicenter longitudinal cohort study of genotyped patients with HCM in the Sarcomeric Human Cardiomyopathy registry (SHaRe). Patients were classified as sarcomeric HCM (pathogenic/likely pathogenic sarcomere variant) or nonsarcomeric HCM (genetically elusive). The influence of genetic classification and comorbidities on the sequence of cardiovascular events were assessed in time-varying Cox proportional hazards models. RESULTS: Among 6120 patients (40% women; 87% probands; 50% sarcomeric HCM), followed for a median of 5.3 years, sarcomeric HCM (n=3082) was associated with a younger age at diagnosis (median 38.1 versus 54.3 years; P<0.001), a higher proportion of women and less obesity, hypertension, and left ventricular (LV) obstruction. After age standardization, sarcomeric HCM was associated with a higher burden of atrial fibrillation (age-standardized incidence ASI ratio, 1.28 CI, 1.16-1.40), LV systolic dysfunction (ASI ratio, 1.31 CI, 1.15-1.48), and ventricular arrhythmias (ASI ratio, 1.37 CI, 1.17-1.52) than nonsarcomeric HCM. All-cause mortality was similar (10.4% versus 9.4%; P=0.20); however, patients with sarcomeric HCM died younger (mean 7.8 years; P<0.001), with model-based survival-analysis estimating 3.5 life-years lost between ages 44 and 85. Sarcomeric HCM was also associated with higher HCM-related mortality (hazard ratio HR, 1.61 CI, 1.18-2.20). Temporal analysis identified atrial fibrillation as the strongest disease-modifier, increasing the risk of LV systolic dysfunction (HR, 2.54 CI 2.07-3.11), ventricular arrhythmias (HR, 3.13 CI, 2.36-4.20), and mortality (HR, 1.94 CI, 1.64-2.31) in both groups. Genotype-interaction analyses demonstrated a larger impact of atrial fibrillation and LV systolic dysfunction on adverse outcomes in sarcomeric versus nonsarcomeric HCM, with effect ratios up to 1.98 for severe heart failure and 2.01 for mortality (both P<0.01). CONCLUSIONS: Genotype can refine risk stratification and inform clinical management in HCM. Sarcomeric HCM is associated with worse prognosis and may benefit from more vigilant surveillance for arrhythmias and systolic dysfunction, with a lower threshold for advanced therapies. Comorbidities, including hypertension and obesity, may be modifiable risk factors for patients with nonsarcomeric HCM.
“The cumulative burden and progressive nature of HCM emphasizes that patients require careful long-term follow-up and underscores the need to develop disease-modifying therapies that may avert the onset of serious comorbidities.”
Vissing et al. (Mon,) reported a other. Sarcomeric hypertrophic cardiomyopathy is associated with a worse prognosis requiring vigilant surveillance, whereas nonsarcomeric disease is linked to modifiable comorbidities.