Key result
Systemic deletion of Ffar4 in male mice worsened diastolic function and microvascular rarefaction in HFpEF secondary to metabolic syndrome by altering the inflammatory oxylipin balance.
Why the study?
Systemic nonresolving inflammation associated with metabolic syndrome may drive HFpEF remodeling, leading to the hypothesis that Ffar4 attenuates remodeling in HFpEF secondary to metabolic syndrome.
Ffar4 regulates the proinflammatory/proresolving oxylipin balance to resolve inflammation and attenuate ventricular remodeling in a mouse model of HFpEF secondary to metabolic syndrome.
Answers are grounded in this paper and cite their sources.
FFAR4 agonism merits exploration in metabolic HFpEF; animal findings leave open human translation.
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.
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Zhang et al. (2023) studied Heart failure with preserved ejection fraction secondary to metabolic syndrome (HFpEF-MetS). Systemic deletion of Ffar4 (Ffar4KO) vs. Wild-type (WT) mice was evaluated on Diastolic function, microvascular rarefaction, and ventricular remodeling. Systemic deletion of Ffar4 in male mice worsened diastolic function and microvascular rarefaction in HFpEF secondary to metabolic syndrome by altering the inflammatory oxylipin balance.
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