Vascular Rarefaction and Perivascular Fibrosis Contribute to the Development of Left Ventricular Diastolic Dysfunction in HFpEF

Abstract

Coronary microvascular dysfunction (CMD) develops in patients with heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure), but the nature of the underlying pathomechanisms behind this prevalent disease remain poorly understood. The hypothesis tested was that coronary microvascular rarefaction contributes to left ventricle (LV) diastolic function in HFpEF. The obese ZSF1 rat model of human HFpEF was employed and using transthoracic echocardiography it was found that 18-week-old male obese ZSF1 rats exhibited a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities) and increased DT (E wave deceleration time) with no change in ejection fraction, indicating diastolic dysfunction. In isolated myocardial papillary muscle preparations, the isometric force generation and myocardial relaxation kinetics were found to be similar in lean and obese ZSF1 rats, indicating no significant differences in contractility. Coronary arteriolar and capillary trees were labeled using Tomato Lectin (Lycopersicon esculentum) DyLight®594 and were imaged by fluorescent confocal microscopy to generate image stacks for 3D reconstruction. Unbiased automated tracing of the microvasculature was done using VesselLucida360 software (MBF) followed by a morphometric analysis (VesselLucida Explorer). It was found that total vessel length and the number of vessel's branching nodes were reduced in the obese ZSF1 rats, whereas the total vessel's volumes were increased, when compared to ZSF1 lean controls. These changes in the coronary microvasculature were accompanied by enhanced perivascular fibrosis within obese ZSF1 rats, as assessed by Masson's trichrome staining for collagen. From these results, it was concluded that vascular rarefaction and perivascular fibrosis both play a mechanistic role in the development of LV diastolic dysfunction in the obese ZSF1 rat model of human HFpEF.