TY - JOUR
T1 - Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions
AU - Amirrad, Farideh
AU - Pala, Rajasekharreddy
AU - Shamloo, Kiumars
AU - Muntean, Brian S.
AU - Nauli, Surya M.
N1 - Publisher Copyright:
Copyright © 2021 Amirrad, Pala, Shamloo, Muntean and Nauli.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - cardiac function
KW - cardiovascular
KW - fibrosis
KW - inflammation
KW - polycystic kidney disease
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U2 - 10.3389/fcvm.2021.772961
DO - 10.3389/fcvm.2021.772961
M3 - Article
AN - SCOPUS:85135723826
SN - 2297-055X
VL - 8
JO - Frontiers in Cardiovascular Medicine
JF - Frontiers in Cardiovascular Medicine
M1 - 772961
ER -