Rare and common variant drivers of ischemic cardiomyopathy

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Abstract Background Ischemic cardiomyopathy (ICM) is a severe consequence of coronary artery disease (CAD), but develops in only a minority of CAD patients. The influence of genetic factors, particularly those linked to myocardial dysfunction, on the progression of CAD to ICM remains unclear. Purpose To determine whether rare and common genetic variants predisposing to dilated cardiomyopathy (DCM) contribute to the development of ICM. Methods We studied participants from the UK Biobank (UKB), Mass General Brigham Biobank (MGBB), and All of Us (AoU). DCM rare variants (RV) were ascertained from whole-genome sequencing data and a DCM polygenic risk score (PRS) was computed from a recent genome-wide association analysis of DCM (PGS004951). ICM and left ventricular (LV) dysfunction were identified by electronic phenotyping using ICD codes. First, we used logistic regression to assess whether cases specifically classified as ICM were enriched for DCM RVs and a high DCM PRS. Next, among individuals with CAD, we applied Cox proportional hazards models to examine the associations of DCM RVs and the DCM PRS with broader, incident LV dysfunction. Finally, leveraging cardiac magnetic resonance imaging (CMR) data from UKB participants with CAD but no prior heart failure or cardiomyopathy, we investigated the relationship between DCM RVs, DCM PRS, and subclinical changes in LV ejection fraction (LVEF). Results Among 721,401 study participants (434,783 from UKB, 43,717 from MGBB, and 242,901 from AoU), 4,313 (0.6%) carried a DCM RV, including 3,578 with TTN truncating variants. Both rare and common genetic risk for DCM were strongly associated with ICM across the three cohorts, with meta-analyzed ORs of 3.28 [95% CI, 2.36 to 4.54] for DCM RV and 1.68 [95% CI, 1.51 to 1.86] for participants in the top quintile of the DCM PRS compared to those in the bottom quintile (Figure 1). Among patients with CAD, carriers of a DCM RV (meta-analyzed HR, 3.17 [95% CI, 2.07 to 4.87]) and individuals with a high DCM PRS (meta-analyzed HR 1.47, Q5 versus Q1, [95% CI, 1.28 to 1.69]) had consistently increased risk of developing LV dysfunction in the UKB (669 incident events with a median of 8.33 years) and MGBB (1,596 incident events with a median period of 7.57 years), even after adjusting for traditional cardiovascular risk factors (Figure 2). In a subset of UKB participants with baseline CAD, no clinical heart failure, and available CMR data (N=952), LVEF was significantly lower in TTN variant carriers compared to non-carriers (46% vs. 54% with β=-10.90 [95% CI, -17.92 to -3.88]. Similarly, each SD increment in the DCM PRS was associated with lower LVEF (β=-0.94 [95% CI, -1.35 to -0.53]). Conclusions Both rare and common genetic variants associated with DCM are linked to an increased risk of subclinical and clinical ICM. Genetic factors may contribute to the development of ICM in CAD patients, and may aid in assessing the progression of ischemic heart disease.Figure 1 Figure 2

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