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A minimally invasive swine model of chronic kidney disease-associated heart failure
Spyros A Mavropoulos1, Tadao Aikawa1, Renata Mazurek1
1Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, New York, United States.
Insights
This study developed a swine model for cardiorenal syndrome type 4 (CRS4) by inducing chronic kidney disease (CKD) through renal embolization. The model shows cardiac diastolic dysfunction, aiding research into CKD-related heart failure.
Area of Science:
- Nephrology
- Cardiology
- Animal Models
Background:
- Chronic kidney disease (CKD) significantly increases cardiac mortality, often due to unelucidated reno-cardiac interactions known as cardiorenal syndrome type 4 (CRS4).
- Developing reliable animal models is crucial for understanding CRS4 mechanisms and testing interventions.
Purpose of the Study:
- To establish and characterize a large animal model of CRS4 in swine exhibiting cardiac diastolic dysfunction.
- To investigate reno-cardiac interactions in the context of induced renal dysfunction.
Main Methods:
- Yorkshire pigs underwent staged renal artery embolization using autologous clot to induce chronic kidney disease.
- Physiological parameters (aortic pressure, GFR, serum creatinine) and cardiac function (echocardiogram, LV pressure-volume loops) were monitored.
- Histopathological analyses of cardiac and renal tissues were performed postmortem.
Main Results:
- Renal embolization led to increased serum creatinine, elevated aortic pressure, and reduced GFR, confirming induced CKD.
- The model demonstrated diastolic dysfunction, characterized by increased left ventricular stiffness, without significant changes in ejection fraction.
- Histological examination revealed cardiac fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction consistent with heart failure.
Conclusions:
- Serial, titrated renal embolization effectively creates a swine model of advanced CKD with cardiac abnormalities mirroring CRS4.
- This model provides a valuable platform for studying the mechanisms of heart failure in CKD and for preclinical testing.
Abstract:
Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine (n = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, P = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, P = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, P < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, P = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, P = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, P = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.NEW & NOTEWORTHY Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.
