Abstract Body: The average American consumes 50% more salt than the AHA’s recommendations. It is known that high salt intake is associated with hypertension and an increased risk of cardiac disease and stroke; still, the exact mechanisms by which these cardiovascular complications arise remain unclear. Salt is primarily excreted by the kidneys, yet the interplay between renal and cardiovascular complications is poorly understood. Cardiac complications are the main cause of mortality in the genetic kidney disease Autosomal Polycystic Kidney Disease (ADPKD), typified by mutations in either polycystin 1 or polycystin 2 (PKD2) genes. Interestingly, ADPKD patients with rapidly progressing disease have the highest salt intake. We investigated a potential link between a high salt diet, genes causative for ADPKD, and cardiac dysfunction. We hypothesized that a high salt diet would exacerbate cardiac dysfunction before renal cyst development, utilizing pre-cystic cardiomyocyte-specific PC2 knock-out (KO) and Cre control mouse models. Male and female mice were placed on either a 4% sodium chow diet or a normal 0.4% sodium chow diet for 3 weeks. Echocardiography revealed that male Cre mice on a high salt diet had a significant increase in left ventricular mass, localized to the anterior wall region in diastole. Strain analysis showed declining global radial and longitudinal strain between high salt and normal diet Cre mice, with further reductions observed in cardiac PC2 KO high salt mice. Protein analysis showed increased fibrotic (aSMA) and inflammatory and hypertrophic (NFAT and CREB) markers in PC2 KO mice fed high salt compared to chow controls. Collectively, these results demonstrate that a high salt diet exacerbates cardiac dysfunction before renal cyst development in ADPKD. Such new insights on the interactions between dietary sodium and polycystin genes may inform strategies to mitigate cardiovascular complications associated with ADPKD and advance our understanding of the role of polycystins in the heart.