Microvascular myocardial perfusion changes in a translational model of heart failure with preserved ejection fraction

• Grant number: 22/00849-5
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2022
• End date: August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Minna Moreira Dias Romano
• Grantee: Minna Moreira Dias Romano
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Marcus Vinicius Simões

Abstract

The pathophysiological mechanisms of heart failure with preserved ejection fraction (HFpEF) are still poorly understood. We hypothesize that a translational model of HFpEF in rats can be induced by arterial hypertension, obesity, and aging. Objectives: To investigate, in a translational model of HFpEF: (1) the presence, magnitude, and temporal evolution of coronary microvascular perfusion alterations and their correlations with the development of cardiac remodeling and myocardial dysfunction; (2) confirm the development of HFpEF with the proposed experimental model by detecting: (a) structural and functional cardiac abnormalities by the echocardiograph, (b) increased LV filling pressure, (c) pulmonary congestion and (d) reduced functional capacity during exercise; (3) confirm the presence of tissue and biochemical alterations associated with the HFpEF phenotype: endothelial inflammatory activation, increased oxidative stress and endothelial dysfunction, NO synthesis deficit, reduced cGMP and PKG activity and (4) correlate the presence and magnitude of myocardial function and perfusion alterations with tissue and biochemical repercussions. Methods: 36 10-week-old Wistar-Kyoto rats will be studied, divided into the following groups: Control group (CG-12); Hypertensive group (SHR), and Hypertensive and obese (SHR+OBS-12) with cafeteria diet inducing obesity through 40 weeks. Non-invasive analyzes of blood pressure, weight control, fasting glucose, glucose tolerance test, and physical capacity will be performed sequentially over the study period. Cardiological imaging exams with high similarity to those applied to humans will be used: echocardiography and myocardial perfusion scintigraphy with Sestamibi-99mTc (mini-SPECT) at rest and under stress with dipyridamole. At the end of the protocol, pulsatile intraventricular blood pressure measurement by cardiac catheterization (PVE) will be performed, followed by euthanasia and collection of blood, tissues/organs such as heart, liver, and lung for biochemical analysis of inflammatory markers and endothelial and tissue function. (AU)