Familial aggregation of sinus node dysfunction indicating pacemaker implantation: A nation-wide cohort study

Abstract

Abstract Background Rare genetically inherited forms of sinus node dysfunction (SND) have been described but the significance of a family history of SND and the associated prognosis remains unknown. Purpose To investigate the risk of SND indicating pacemaker implantation and mortality in first-degree relatives to patients who received a pacemaker because of SND, and to assess the effect of age of onset on disease risk. Methods This was a nationwide retrospective register-based cohort study including all Danish citizens born after 1954. SND was defined to be present when a first pacemaker was implanted on this indication. To establish family structures, we retrieved data from the Danish civil registration registry which contains information on parental links and merged them with the Danish Pacemaker and ICD registry which contains information on all pacemaker implanted because of SND in Denmark. Using Poisson regression, we compared the rates of SND and the risk of all-cause mortality in first-degree relatives of SND patients with the rates in the general population between January 1st 1982 and August 31st 2022. Analyses were adjusted for selected diagnosis- and procedure codes from the Danish National Patient Registry, including hypertension, diabetes mellitus, heart failure, coronary artery disease, atrial fibrillation or flutter, valvular heart disease, stroke, and cardiac surgery. Results We included 6,027,090 individuals among whom 2,477 first pacemakers were implanted due to SND in the time period. The adjusted rate ratio (RR) of SND was 2.9 (95% CI 2.4-3.6), p<0.001, for individuals having any father, mother or sibling with SND compared with the general population. This risk was increased in first-degree relatives across all ages of SND onset in the index person but substantially higher if SND onset in the index person occurred ≤50 years (adjusted RR=7.1 (95% CI 3.5-14.3), p<0.001). Comparable risks of SND were observed for first-degree relatives to mothers, fathers and siblings with SND as well as for men and women. Overall, mortality was similar between individuals having any father, mother or sibling with SND and the general population (adjusted RR=1.02 (0.97-1.08), p=0.45). However, there was a trend towards an increased mortality among first-degree relatives to index persons with an early onset. Conclusions First-degree relatives to SND patients are at increased risk of SND with risk being inversely associated with age of onset in the index person. Overall, mortality in first-degree relatives was comparable to the general population, suggesting a benign prognosis in the vast majority of cases with genetically inherited SND.Table 1Figure 1