Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death (SCD) in young people. The 2020 AHA/ACC and 2014 ESC HCM guidelines rely on previously identified risk factors to help in the SCD risk stratification. The ESC guidelines recommend the incorporation of the 5-year HCM risk-SCD calculator in the decision making. The AHA/ACC guidelines emphasize the importance of shared decision-making and recommend the consideration of primary prophylactic ICD implantation in patients with one or more SCD risk factors. Genetic results are not directly integrated into the SCD risk stratification methods, although the incidence of malignant arrhythmia is reported to be higher in patients with variants in genes encoding sarcomeric proteins. The aim of this study is to validate current SCD risk prediction methods in a German patient cohort and to investigate the benefit of integrating genetic findings into the mathematical 5-year ESC HCM risk-SCD calculator.

In a longitudinal, single center study, HCM patients ≥18 years of age, without prior SCD/-equivalent events were recruited. The primary end point was defined as SCD or SCD equivalent event within 5 years of baseline evaluation. 5-year SCD-risk estimates and recommendations for ICD implantations, as defined by the ESC and AHA/ACC guidelines, were analyzed for the study cohort. Known multivariate cox proportional hazards analyses were used to integrate genetic findings as an additive SCD risk predictor variable to the ESC HCM risk-SCD calculator. The performances of the SCD risk stratification methods were compared using ROC analysis.

283 patients were included into the cohort and followed for in median 5.77 years (2.92; 8.85). A disease-causing variant was found in 138 (48,8%) patients. 14 (5%) patients reached the SCD endpoint within 5 years after baseline evaluation (5-year incidence 4.9%). The ESC HCM risk-SCD model showed an area-under-the-curve (AUC) of 0.74 (95% CI, 0.68-0.79) with a sensitivity of 0.29 (95% CI, 0.08-0.58) and specificity of 0.89 (95% CI, 0.85-0.92) for risk estimates ≥6%. In comparison, the AHA/ACC HCM SCD risk stratification model showed an AUC of 0.60 (95% CI, 0.54-0.65) with a sensitivity of 0.64 (95% CI, 0.35-0.87) and specificity of 0.55 (95% CI, 0.49-0.61). The genetic findings of all patients were integrated into the modified ESC HCM risk-SCD model. The modified SCD risk model revealed an AUC of 0.76 (95% CI, 0.71-0.81) with a sensitivity of 0.86 (95% CI, 0.57-0.98) and specificity of 0.68 (95% CI, 0.62-0.74) for calculated risk estimates ≥6%. Following guideline recommendations, the number-needed-to-treat (NNT) to prevent 1 SCD event by prophylactic ICD-implantation equals 13 for the ESC model, 28 for the AHA/ACC model and 9 for the modified, genotype-including ESC model. Kaplan-Meier survival analysis shows significantly lower SCD event-free survival for patients with identified disease-causing variants (p<0.05).

The study confirms that the currently recommended SCD risk prediction models provide useful prognostic information that can help in clinical decision making regarding SCD risk stratification. The integration of genetic findings into the current SCD risk stratification methods could be beneficial in identifying a sub-population of HCM patients that do not present with the typical risk-factors for electrical vulnerability and thus could potentially improve current risk stratification methods.