Abstract 289: Improved Disease Modeling Reveals 9p21 Risk Allele Regulates Connexins to Induce Arrhythmic Phenotypes

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the non-coding 9p21 gene locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI). In addition, SNP correlations with sudden and arrhythmic death, even after accounting for patient and family history for CAD and MI, suggest an altered cardiac remodeling response. However, little is known about a possible cardiac phenotype as studies have largely focused on its effect on CAD and have trouble describing regulation with non-coding loci. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs, we assessed cardiomyocyte (CM) function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. stiffening from 10 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype beat synchronously on soft matrices, R/R CMs cultured on dyna...