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Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD has been associated with many cardiac abnormalities including the arrhythmogenic remodeling in clinical evaluations. In our current study, we hypothesized that  Pkd2  gene mutation results in structural and functional defects in the myocardium. The structural and functional changes of  Pkd2  mutant hearts were analyzed in the myocardial-specific  Pkd2  knockout (KO) mouse. We further assessed a potential role of TGF-b 1  signaling in the pathology of  Pkd2 -KO hearts. Hearts from age-matched 6-month-old  MyH6 • Pkd2   wt / wt   (control or wild-type) and  MyH6 • Pkd2   flox / flox   (mutant or  Pkd2 -KO) mice were used to study differential heart structure and function. Cardiac histology was used to study structure, and the “isolated working heart” system was adapted to mount and perfuse mouse heart to measure different cardiac parameters. We found that macrophage1 (M1) and macrophage 2 (M2) infiltration, transforming growth factor (TGF-b 1 ) and TGF-b 1  receptor expressions were significantly higher in  Pkd2 -KO, compared to wild-type hearts. The increase in the extracellular matrix in  Pkd2 -KO myocardium led to cardiac hypertrophy, interstitial and conduction system fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Left ventricular (LV) expansion or compliance and LV filling were impaired in fibrotic  Pkd2 -KO hearts, resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic  Pkd2 -KO hearts, resulted in systolic dysfunction. Compared to wild-type hearts,  Pkd2 -KO hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion,  Pkd2 -KO mice had systolic and diastolic dysfunction with arrhythmogenic hearts.

Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions