Video_3.MP4

Abstract

Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD patients have been associated with the arrhythmogenic remodeling in some clinical evaluations. We hypothesized that Pkd2 mutation resulted in structural and functional defects in the PKD myocardium. The structural and functional changes of PKD hearts were analyzed in the myocardiac-specific Pkd2 knockout mouse. We further assessed a potential role of TGF-1 signaling in the pathology of PKD hearts. Hearts from age-matched 6-month-old MyH6•Pkd2wt/wt (wild-type) and MyH6•Pkd2flox/flox (Pkd2) 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 have direct measurements of different cardiac parameters. We found that the Pkd2 myocardium was infiltrated by M1 and M2 inflammatory cells. Expression of transforming growth factor (TGF-1) and TGF-1 receptor was significantly up-regulated in Pkd2, compared to wild-type hearts. The increase in extracellular matrix in Pkd2 myocardium led to cardiac hypertrophy and fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Impairment in left ventricular (LV) expansion or compliance and LV filling in fibrotic Pkd2 hearts resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic Pkd2 hearts resulted in systolic dysfunction. Compared to wild-type hearts, Pkd2 hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion, hearts from Pkd2 mice are characterized with hypertrophy, interstitial and conduction system fibrosis with upregulated TGF-1 and its receptor. Evaluation of heart function in Pkd2 mouse indicates systolic and diastolic dysfunction with arrhythmogenic hearts.