Prevalence and cardiac risk of Familial ST-depression Syndrome: A study of 12 million electrocardiograms

BACKGROUND: Familial ST depression syndrome (Fam-STD) is a recently identified inherited cardiac disease characterized by a distinct electrocardiographic phenotype and occurrence of arrhythmias and heart failure.

OBJECTIVE: We aimed to investigate the electrocardiographic prevalence of the Fam-STD and its association with cardiac events in a large, nationwide cohort.

METHODS: We used a Danish nationwide electrocardiogram (ECG) database containing 11,952,430 ECGs from 2,485,987 unique individuals. We excluded ECGs from children <15 years and ECGs with likely secondary causes of ST-segment deviations. The Fam-STD phenotype prevalence was assessed according to the original (Fam-STD-2018) and revised (Fam-STD-2022 probands/relatives) proposed diagnostic criteria. Through linkage with national registries, we evaluated the risk of a composite cardiac end point (new-onset atrial fibrillation, ventricular arrhythmias, heart failure, cardiac device implantation) and all-cause mortality by Cox proportional hazards models.

RESULTS: A total of 6,352,104 ECGs (1,890,184 individuals; 55% female; 3.4 ECGs per individual) remained after application of the exclusion criteria. We found 56 (3/100,000) individuals fulfilling Fam-STD-2018, 173 (9/100,000) fulfilling Fam-STD-2022 probands, and 4975 (263/100,000) fulfilling Fam-STD-2022 relatives criteria. During a mean follow-up of 2.4 ± 3.4 years, we observed increased risks of the composite cardiac end point (hazard ratio, 4.4 [confidence interval, 1.2-15.9], 3.6 [2-6.5], 2.21 [2-2.5]) and all-cause mortality (hazard ratio, 6.2 [confidence interval, 3.6-10.6], 3.1 [1.7-1.9], 1.8 [1.7-1.9]) for Fam-STD-2018, Fam-STD-2022 probands, and Fam-STD-2022 relatives, respectively, compared with matched controls without ST deviation.

CONCLUSION: The Fam-STD proband electrocardiographic phenotype is rare and has a prevalence in Denmark of 3-9/100,000, fairly similar to estimates of other inherited arrhythmia syndromes. The increased risk of cardiac events and mortality highlights the importance of early identification to allow preventive interventions.