Key result
High-fat-salt-sugar diet and streptozotocin successfully replicate metabolic syndrome and HFpEF features in rats.
Why the study?
The complexity of HFpEF makes developing a comprehensive preclinical model challenging, hindering elucidation of disease mechanisms and development of new drugs.
A combination of a high-fat-salt-sugar diet and streptozotocin in spontaneously hypertensive rats successfully replicates the metabolic syndrome-related HFpEF phenotype, providing a useful preclinical model.
Offers a preclinical HFpEF model for metabolic syndrome research; leaves open clinical translation pending validation.
Background Heart failure with preserved ejection fraction (HFpEF) represents a syndrome involving multiple pathophysiologic disorders and clinical phenotypes. This complexity makes it challenging to develop 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 produced a rat model of the MetS-related HFpEF phenotype and explored the molecular mechanisms underpinning the observed pathological changes. Methods A rat model of the MetS-related HFpEF phenotype was created by feeding spontaneously hypertensive rats a high-fat-salt-sugar diet and administering streptozotocin 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 cardiac anomalies, such as left ventricular (LV) remodeling and diastolic impairment, and left atrial dilation. Additionally, inflammation, myocardial hypertrophy, and fibrosis were observed in LV myocardial tissue, which may be associated with diverse cellular and molecular signaling cascades. First, the inflammatory response might be related to the overexpression of inflammatory regulators (growth differentiation factor 15 (GDF-15), intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial cell adhesion molecule-1 (VCAM-1)). Secondly, phosphorylated glycogen synthase kinase 3 β (GSK-3β) may stimulate cardiac hypertrophy, which was regulated by activated -RAC-alpha serine/threonine-protein kinase (AKT). Finally, the transforming growth factor- β 1 (TGF- β 1)/Smads pathway might regulate collagen production and fibroblast activation, promoting myocardial fibrosis. 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 develop effective treatment strategies.
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Shi et al. (2023) studied Heart failure with preserved ejection fraction (HFpEF) and metabolic syndrome (n=30). High-fat-salt-sugar diet and streptozotocin vs. Normal maintenance diet (WKY and SHR controls) was evaluated on Development of metabolic syndrome and HFpEF-related structural and functional cardiac abnormalities. A rat model induced by a high-fat-salt-sugar diet and streptozotocin successfully replicated the clinical features of metabolic syndrome and HFpEF-related structural and functional cardiac abnormalities.
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