Free fatty acid receptor 4 in cardiac myocytes ameliorates ischemic cardiomyopathy.

Aims: Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would also attenuate cardiac ischemic injury. Methods and Results: Using a mouse model of ischemia-reperfusion (I/R), we found that mice with systemic deletion of Ffar4 (Ffar4KO) demonstrated impaired recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. In the Ffar4KO infarcted myocardium, gene ontology (GO) analyses revealed augmentation of glycosaminoglycan synthesis, neutrophil activation, cadherin binding, extracellular matrix, rho signaling, and oxylipin synthesis, but impaired glycolytic and fatty acid metabolism, cardiac repolarization, and phosphodiesterase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated impaired AMPK signaling and augmented cellular senescence in the Ffar4KO infarcted myocardium. Interestingly, phosphodiesterase 6c (PDE6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 prevented systolic dysfunction post-I/R, defining a cardioprotective role of Ffa4 in cardiac myocytes. Conclusions: Our results demonstrate that Ffar4 in cardiac myocytes attenuates systolic dysfunction post-I/R, potentially by attenuating oxidative stress, preserving mitochondrial function, and modulation of cGMP signaling.

Atrial Myopathy Quantified by Speckle-tracking Echocardiography in Mice.

BACKGROUND: Emerging evidence suggests that atrial myopathy may be the underlying pathophysiology that explains adverse cardiovascular outcomes in heart failure (HF) and atrial fibrillation. Lower left atrial (LA) function (strain) is a key biomarker of atrial myopathy, but murine LA strain has not been described, thus limiting translational investigation. Therefore, the objective of this study was to characterize LA function by speckle-tracking echocardiography in mouse models of atrial myopathy. METHODS: We used 3 models of atrial myopathy in wild-type male and female C57Bl6/J mice: (1) aged 16 to 17 months, (2) Ang II (angiotensin II) infusion, and (3) high-fat diet+Nω-nitro-L-arginine methyl ester (HF with preserved ejection fraction, HFpEF). LA reservoir, conduit, and contractile strain were measured using speckle-tracking echocardiography from a modified parasternal long-axis window. Left ventricular systolic and diastolic function, and global longitudinal strain were also measured. Transesophageal rapid atrial pacing was used to induce atrial fibrillation. RESULTS: LA reservoir, conduit, and contractile strain were significantly reduced in aged, Ang II and HFpEF mice compared with young controls. There were no sex-based interactions. Left ventricular diastolic function and global longitudinal strain were lower in aged, Ang II and HFpEF, but left ventricular ejection fraction was unchanged. Atrial fibrillation inducibility was low in young mice (5%), moderately higher in aged mice (20%), and high in Ang II (75%) and HFpEF (83%) mice. CONCLUSIONS: Using speckle-tracking echocardiography, we observed reduced LA function in established mouse models of atrial myopathy with concurrent atrial fibrillation inducibility, thus providing the field with a timely and clinically relevant platform for understanding the pathophysiology and discovery of novel treatment targets for atrial myopathy.

FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

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.