Abstract 4144528: The Polygenic Mechanisms of Dilated Cardiomyopathy Contribute to The Development of Tachycardia-Associated Cardiomyopathy in Patients With Atrial Tachyarrhythmias

Background Longstanding tachycardia can lead to reversible left ventricular (LV) systolic dysfunction called tachycardia-associated cardiomyopathy (TAC). It is unknown if there is a genetic predisposition to the development of TAC or whether there is overlap between the genetic pathways of TAC and dilated cardiomyopathy (DCM). Research Questions Is there a genetic predisposition towards the development of TAC in individuals with arrhythmia? If so, do these genetic pathways overlap with those of DCM? Methods/Approach The study is a single-center case control study performed at the Montreal Heart Institute (MHI). Inclusion criteria for TAC cases are shown in Table 1. All cases underwent array genotyping and exome sequencing. Previously genotyped controls with arrhythmia but no documented LV dysfunction were included from the MHI Biobank. Following imputation using the TOPMed imputation server, a polygenic score for DCM (PGS DCM ; PGS000666) was calculated for cases and controls. The rate of (likely) pathogenic variants in known cardiomyopathy genes was reported in cases. Results/Data (descriptive and inferential statistics) The study included 107 cases and 878 controls. Case characteristics are shown in Table 1. The average PGS DCM for cases was significantly higher than that of controls (p-value <10 -10 ; Figure 1). Logistic regression with correction for age, sex, and ancestry (principal components) showed a strong association of PGS DCM with TAC (OR 1.99, 95% CI 1.54-2.58; p-value <10 -6 ). Notably, among patients with atrial tachyarrhythmias, those with a PGS DCM above the 95 th percentile had a 3.53-fold increased risk of TAC (p-value 4.5 -4 ). Exome sequencing in TAC cases identified only 2/107 (2%) carriers of (likely) pathogenic variants (in cardiomyopathy genes TNNT2 and MYH7 ). Conclusions Pathogenic variants account for a small minority of TAC cases. In contrast, a significant association between PGS DCM and TAC is suggestive of a shared polygenic pathway between TAC and DCM.