Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome

Abstract

Background— The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Methods and Results— Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. Conclusions— The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

“…The vascular endothelium is a critical player in the pathogenesis and progression of coronary artery disease [1], hypertension [2], diabetic cardiomyopathy [3], stroke and heart failure [4]. Vascular remodeling is a process responsible for the complex, dynamic interactions between different cell types, including endothelial cells, mesenchymal smooth muscle-type cells and fibroblast cells [5, 6], of which changes of endothelial cell are necessary and essential for the remodeling process.…”

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

“…Their efficacy relates to a restored pressure-natriuresis relationship in the presence of renal microvascular inflammation 55 . Administration of diuretics can be guided by use of implantable hemodynamic monitors that either directly and continuously measure diastolic LV pressures or provide surrogates of pressure 45 .…”

“…HFpEF promotes renal dysfunction by 1) an elevated central venous pressure, which results from pulmonary hypertension and right ventricular dysfunction; 2) inability to raise cardiac output following arterial vasodilation because of chronotropic incompetence and fixed LV stroke volume 119 ; 3) systemic inflammation, endothelial dysfunction and low NO bioavailability, which reduces renal blood flow 55,120 and sodium excretion 44 . Renal dysfunction promotes HFpEF by worsening systemic inflammation, endothelial dysfunction and NO bioavailability partially because of renal-specific mediators such as high levels of fibroblast growth factor 23, phosphorus, parathyroid hormone or uremic toxins and low levels of vitamin D or erythropoietin 118 .…”

An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

“…Chronic kidney disease is highly prevalent and constitutes a major determinant of outcome in HFpEF, the common link may be ED and inflammation. The interactive role of renal and cardiac disturbances has been recognized in HFpEF models . Finally, the AT may be an important contributor to HFpEF .…”