Diabetes and chronic kidney disease synergistically contribute to left ventricular diastolic dysfunction and coronary microvascular disease in swine

Background Chronic kidney disease (CKD) and diabetes (DM) are common causes of cardiovascular disease (CVD), and contribute to the development of left ventricular diastolic dysfunction (LVDD) and coronary microvascular dysfunction (CMD). Purpose To investigate if CKD and DM contribute synergistically to the development of CMD and LVDD by increasing myocardial interstitial fibrosis in a swine model. Methods CKD was induced by renal microembolization at 10-12 weeks of age in 8 wild type (WT) and 6 DM (INSC94Y) swine, while 6 WT and 5 DM swine served as control. LVDD was assessed using pressure volume loops and coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in the left anterior descending coronary artery. Afterwards, myocardium and kidney tissues were histologically examined for interstitial fibrosis. Results DM was confirmed by increased blood glucose values in the DM and DMCKD (figure 1-A). Renal embolization resulted in renal fibrosis in the WTCKD and DMCKD (figure 1-B), which was accompanied by a trend towards proteinuria, i.e., elevated protein/creatinine ratios (figure 1-C). LVDD was evidenced by an increase in the slope of the end-diastolic pressure volume relationship (EDPVR) in WTCKD, DM and DMCKD as compared to WT, with the largest increase in DMCKD (figure 1-D). WTCKD and DMCKD animals showed higher interstitial fibrosis levels in the LV (figure 1-E). CFR tended to be decreased in WTCKD, DM and DMCKD swine compared to WT (figure 1-F). Conclusions Renal embolization resulted in proteinuria and renal fibrosis, particularly in DM animals. DM and CKD also caused myocardial interstitial fibrosis, which impaired left ventricular diastolic function. The effects tended to be larger in DMCKD as compared to DM or WTCKD. Moreover, CFR tended to be decreased, suggestive of CMD, with the largest effect in DMCKD. In conclusion, DM and CKD contributed synergistically to LVDD and CMD.