Abstract Body (Do not enter title and authors here): 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.