Abstract Body (Do not enter title and authors here): Introduction:
The role of genotype in sudden cardiac death (SCD) risk stratification in hypertrophic cardiomyopathy (HCM) patients is unclear. Whether family history of SCD (FHxSCD) is independently associated with SCD after correction for genotype has never been investigated.
Methods:
This observational cohort study included HCM patients who had genetic testing at Toronto General Hospital or Tufts Medical Center. FHxSCD was defined as unexplained SCD before the age of 40 or due to HCM in a first-degree family member. SARC+ was defined as the identification of a (likely) pathogenic variant in a sarcomeric gene. The combined SCD outcome included SCD, resuscitated cardiac arrest (rCA), or appropriate ICD therapy.
Results:
The study included 3258 patients [2142 (65.7%) male, 896 (27.5%) SARC+]. Over a median follow-up of 5 years (IQR 1.9–9.6), 114 (3.5%) experienced a SCD outcome (10 SCD, 27 rCA, and 77 ICD therapies).
Both FHxSCD and SARC+ were independently associated with SCD, with hazard ratios of 1.97 [1.26-3.10, P = 0.003] and 1.73 [1.15-2.59, P = 0.008], respectively (Fig. 1). Among patients with FHxSCD but no other risk markers, the cumulative proportion of SCD was 7.8% and 9.8% at 5 and 10 years in SARC+ patients, but only 2.6% and 4.6% in SARC- patients (Fig. 2).

Adding genotype to the HCM SCD risk calculator resulted in a net reclassification index of 0.162 (0.046–0.285). Compared with the original model and using a 6%/5-year cutoff, the new model identified 8 more patients with events as high-risk but also an additional 4 patients without events.

Conclusion:
In our cohort, both FHxSCD and genotype were independently associated with SCD outcomes. In patients with FHxSCD as the sole risk marker, the risk of SCD is significant (>6%/5 years) in SARC+ patients but not in SARC- patients. Adding genotype to the HCM SCD risk calculator improves its ability to discriminate between patients at high and low risk.