Abstract: FR-PO394
Characterization of Cardiac Phenotype in Mouse CKD Models
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Wong, Dickson WL, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Yesilyurt, Burcu, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Zhang, Li, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Klinkhammer, Barbara Mara, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Moellmann, Julia, Department of Internal Medicine I-Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Droste, Patrick, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Hohl, Mathias, Klinik für Innere Medizin III, IMED, Universität des Saarlandes, Homburg, Germany
- Lehrke, Michael, Department of Internal Medicine I-Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Boor, Peter, Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
Group or Team Name
- Laboratory of Nephropathology.
Background
Cardiovascular disease (CVD) constitutes ~40-50% of mortality of chronic kidney disease (CKD) patients. Heart injury was described as left ventricular (LV) diastolic dysfunction, cardiac hypertrophy and fibrosis. While CKD rat models partially develop such cardiac phenotype, this is more challenging in mouse models. In this study, we aim to comprehensively examine various cardiac pathologies in two CKD mouse models.
Methods
The Col4a3-/- (Alport) mice, and wild-type (wt) mice on 6- or 12-weeks of mixed adenine diet (0.2% adenine + Western diet + 1.8% P) were examined for LV contractility using Millar-catheter, plasma Troponin I and BNP, and echocardiography (ECHO, Simpson’s method). Heart histology, CD31 (endothelial cell) and CD45 (immune cell) were assessed.
Results
Compared to wt mice, the 8-week-old Alport mice developed CKD with histological kidney injury and fibrosis. Alport mice had decreased stroke volume, cardiac output and ejection fraction in ECHO and reduced LV relaxation in Millar-catheter measurement. The mice also showed higher plasma troponin I and BNP, reduced CD31/myocyte area ratio and increased myocardial CD45+ cells. Compared to the control diet, mice with mixed adenine diet at both time points showed higher serum cholesterol and phosphate and reduced calcium and histological signs of kidney injury, fibrosis and tubular atrophy. In the heart, mice with mixed adenine diet showed reduced LV contractility (ejection + relaxation phase), increased plasma Troponin I and BNP, and at 12 weeks, LV wall thickening and reduced stroke volume/cardiac output. The mice also showed increased cardiac infiltration of CD45+ cells and reduced CD31 expression. No overt cardiointerstitial fibrosis was observed in all models.
Conclusion
Alport mice, and mice fed with mixed adenine diet showed signs of CVD with LV dysfunction, elevated plasma cardiac injury marker, myocardial capillary rarefaction and microinflammation, while no overt fibrosis was observed. Alport mice have short lifespans thus limits the therapeutic time frame. The mixed adenine diet model further accelerates the cardiac injury onset compared to other CKD mouse models, with a good survival rate and similar physiology to CKD-CVD patients. Thus, the mixed adenine diet model with both kidney and heart injury has the potential for CKD-related CVD studies.
Funding
- Government Support – Non-U.S.