Abstract

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-b1 signaling in the pathology of Pkd2-KO hearts. Hearts from age-matched 6-month-old MyH6•Pkd2wt/wt (control or wild-type) and MyH6•Pkd2flox/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-b1) and TGF-b1 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.

Highlights

  • Autosomal dominant polycystic kidney disease (PKD) is the most common hereditary renal disorder that affects 1 in 800 live births

  • The MyH6Pkd2 mutantwt/wt mice were used as control or wild-type (WT), and MyH6Pkd2 mutantflox/flox was designated as mutant (Pkd2-KO)

  • The Pkd2-KO Hearts Were Characterized With Hypertrophy, Cardiac Fibrosis, and Fibrotic Conduction System

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Summary

INTRODUCTION

Autosomal dominant polycystic kidney disease (PKD) is the most common hereditary renal disorder that affects 1 in 800 live births. Cardiovascular manifestations in PKD include hypertension [7, 8], left ventricular hypertrophy [7, 9], valvular heart disease [10], intracranial and extracranial aneurysms [11], and atrial fibrillation [11]. Left ventricular hypertrophy (LVH) is another cardiovascular complication commonly measured in clinical studies using echocardiography in PKD patients [9, 20]. The presence of LVH affects clinical outcomes, with increased risk of atrial or ventricular arrhythmia [21], systolic and diastolic dysfunction [22, 23], congestive heart failure [24], cardiovascular mortality [21], and sudden cardiac death [21]. We studied fibrosis and fibrotic pathways in the cardiac tissues of Pkd mutant mouse model, and the effect of Pkd gene mutation on cardiac function was studied using an isolated working heart apparatus

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