A minimally invasive swine model of chronic kidney disease-associated heart failure

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 ¼ 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 ¼ 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, P ¼ 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 ¼ 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, P ¼ 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, P ¼ 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.