AUTHOR=Shi Yujiao , Liu Chunqiu , Yang Chenguang , Qiao Wenbo , Liu Yongcheng , Liu Siyu , Dong GuoJu 

TITLE=A rat model of metabolic syndrome-related heart failure with preserved ejection fraction phenotype: pathological alterations and possible molecular mechanisms

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1208370

DOI=10.3389/fcvm.2023.1208370

ISSN=2297-055X

ABSTRACT=Background: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with multiple pathophysiologic disorders and clinical phenotypes. This complexity limits the development of a comprehensive preclinical model, which presents an obstacle to elucidating disease mechanisms and developing new drugs. Metabolic syndrome (MetS) is a major phenotype of HFpEF. Thus, we aimed to establish a rat model of the MetS-related HFpEF phenotype and explore the molecular mechanisms underlying the pathological changes in the rats. 
Methods: A rat model of the MetS-related HFpEF phenotype by feeding spontaneously hypertensive rats (SHR) a high-fat-salt-sugar diet and injecting STZ solution intraperitoneally. Subsequently, pathological changes in the rat heart and their possible molecular mechanisms were explored.
Results: The HFpEF rats demonstrated primary features of MetS, such as hypertension, hyperglycemia, hyperlipidemia, insulin resistance and structural and functional cardiac abnormalities, including left ventricular (LV) remodeling, left atrial enlargement, and LV diastolic dysfunction. Additionally, inflammation, myocardial hypertrophy, and fibrosis were observed in LV myocardial tissue, which may be associated with diverse cellular and molecular signaling cascades. These molecular mechanisms may involve the overexpression of inflammatory regulators (growth differentiation factor 15 (GDF-15) and cell adhesion molecules (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)), activation of the RAC-alpha serine/threonine-protein kinase (AKT)/glycogen synthase kinase 3β (GSK-3β) pathway, and activation of the transforming growth factor-β1 (TGF-β1)/Smad pathway, respectively.
Conclusion: The HFpEF rat replicates the pathology and clinical presentation of human HFpEF with MetS and may be a reliable preclinical model that helps elucidate HFpEF pathogenesis and explore therapeutic interventions.