Prevalence and clinical implications of double sarcomere mutations in patients with hypertrophic cardiomyopathy

Background

Hypertrophic cardiomyopathy (HCM) is a hereditary myocardial disorder, with an autosomal-dominant inheritance pattern. Patients with homozygous or compound heterozygous sarcomere gene mutations often present with a more severe clinical profile, characterized by earlier disease onset, and a higher risk of heart failure and sudden cardiac death (SCD). However, there is conflicting evidence on the precise prognostic predictive value of double mutations.

Aims

To evaluate the prevalence and clinical implications of carrying double sarcomeric mutations in a contemporary cohort of HCM.

Methods

We conducted a single-center retrospective study including consecutive HCM patients that had undergone genetic testing. Patients were classified as genotype-negative, single sarcomere mutation carries or double sarcomere mutation carriers. For the latter, homozygous and compound heterozygous were considered. For genotype categorization, positive cases were considered whenever likely pathogenic or pathogenic (LP/P) variants were present, as per the ACMG recommendations. The primary outcome was a composite of appropriate implantable cardioverter-defibrillator (ICD) shocks, heart transplantation or all-cause death. Event-free survival was assessed by using Cox regression models and Kaplan–Meier curves.

Results

Of a total of 550 patients with HCM, 323 (58.7%) had been genotyped. Of these, 14 had double mutations, 189 single mutations, and 120 were genotype-negative. Patients with double mutations were younger at diagnosis (41 vs. 57 vs. 63 years; p<0.001), more often presenting with a positive family history of HCM (35.7 vs. 19.3 vs. 6.7%; p=0.001) and of SCD (28.6 vs. 9.7 vs. 3.4%; p=0.002). Moreover, they also presented with higher disease burden: e.g., NYHA (III-IV 21.4 vs. 19.7 vs. 13.3%; p=0.001), NT-proBNP (3684 vs. 1000 vs. 453 pg/mL; p=0.005), burnout (42.9 vs. 9.0 vs. 5.0%; p<0.001) and ICD for secondary-prevention of SCD (28.6 vs. 6.3 vs. 1.7%; p<0.001).

Over a median follow-up of 3.9 [1.9-8.9] years, the primary composite endpoint occurred in 35 patients, of whom 12 had received a heart transplant and 15 died. In the multivariate analysis, adjusted for a family history of SCD, atrial fibrillation, NYHA NT-proBNP and LVEF, a positive genotype was associated with a higher risk of the primary endpoint (HR 5.94 per mutation; 95% CI 1.40-25.21; p=0.016). Moreover, a significantly higher event rate was observed in double-mutation carriers (log rank p=0.003) (central figure).

Conclusion

In a contemporary cohort of HCM, approximately 1 in every 25 patients had double gene mutations, whom presented with a more severe phenotype and worse clinical outcomes. Whether double mutations should be used for individualized risk stratification and to guide management decisions should be further investigated in larger cohort studies.For image description, please refer to the figure legend and surrounding text.