Low-carbohydrate diets containing plant-derived fat but not animal-derived fat ameliorate heart failure.

Cardiovascular disease (CVD) is a global health burden in the world. Although low-carbohydrate diets (LCDs) have beneficial effects on CVD risk, their preventive effects remain elusive. We investigated whether LCDs ameliorate heart failure (HF) using a murine model of pressure overload. LCD with plant-derived fat (LCD-P) ameliorated HF progression, whereas LCD with animal-derived fat (LCD-A) aggravated inflammation and cardiac dysfunction. In the hearts of LCD-P-fed mice but not LCD-A, fatty acid oxidation-related genes were highly expressed, and peroxisome proliferator-activated receptor α (PPARα), which regulates lipid metabolism and inflammation, was activated. Loss- and gain-of-function experiments indicated the critical roles of PPARα in preventing HF progression. Stearic acid, which was more abundant in the serum and heart of LCD-P-fed mice, activated PPARα in cultured cardiomyocytes. We highlight the importance of fat sources substituted for reduced carbohydrates in LCDs and suggest that the LCD-P-stearic acid-PPARα pathway as a therapeutic target for HF.

The effect of immunosuppressive therapy on cardiac involvements in anti-mitochondrial antibody-positive myositis.

AIMS: Anti-mitochondrial antibody (AMA)-positive myositis is frequently associated with various cardiac involvements, such as arrhythmia and left ventricular (LV) dysfunction. However, the efficacy of immunosuppressive therapy in these complications remains unknown. This study aimed to investigate the cardiac response to immunosuppressive therapy in patients with AMA-positive myositis. METHODS AND RESULTS: The clinical data of 15 AMA-positive myositis patients with cardiac involvement were retrospectively collected at our centre. To evaluate the effects of immunosuppressive therapy, echocardiographic and laboratory data of patients who received glucocorticoid therapy with additional immunosuppressants (n = 6) and those who did not (n = 6) were compared. Also, the characteristics of patients with or without >5% LV ejection fraction (LVEF) decline during the follow-up period (n = 5 vs. n = 7) were compared. Thirteen patients (87%) had arrhythmias, and eight patients (53%) had LV wall motion abnormalities. Although arrhythmias decreased after treatment, reduced LVEF and LV wall motion abnormalities persisted. Further investigation revealed an increased LV end-systolic dimension and reduced LVEF in patients without additional immunosuppressive therapy, while those in patients with additional immunosuppressive therapy were maintained. Six of seven patients (86%) without LVEF decline received additional immunosuppressive therapy, whereas no patients with LVEF decline had additional immunosuppressive therapy. CONCLUSIONS: Cardiac involvement in AMA-positive myositis may worsen even with glucocorticoid monotherapy, and there might be some associations between the change of LV function and additional immunosuppressive therapy.

CXCR7 ameliorates myocardial infarction as a ß-arrestin-biased receptor.

Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through ß-arrestin as a biased receptor. As several ß-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a ß-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited ß-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a ß-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.

Omega-3 fatty acid prevents the development of heart failure by changing fatty acid composition in the heart.

Some clinical trials showed that omega-3 fatty acid (FA) reduced cardiovascular events, but it remains unknown whether omega-3 FA supplementation changes the composition of FAs and their metabolites in the heart and how the changes, if any, exert beneficial effects on cardiac structure and function. To clarify these issues, we supplied omega-3 FA to mice exposed to pressure overload, and examined cardiac structure and function by echocardiography and a proportion of FAs and their metabolites by gas chromatography and liquid chromatography-tandem mass spectrometry, respectively. Pressure overload induced cardiac hypertrophy and dysfunction, and reduced concentration of all FAs' components and increased free form arachidonic acid and its metabolites, precursors of pro-inflammatory mediators in the heart. Omega-3 FA supplementation increased both total and free form of eicosapentaenoic acid, a precursor of pro-resolution mediators and reduced free form arachidonic acid in the heart. Omega-3 FA supplementation suppressed expressions of pro-inflammatory cytokines and the infiltration of inflammatory cells into the heart and ameliorated cardiac dysfunction and fibrosis. These results suggest that omega-3 FA-induced changes of FAs composition in the heart have beneficial effects on cardiac function via regulating inflammation.

Variable Cardiac Responses to Immunosuppressive Therapy in Anti-Mitochondrial Antibody-Positive Myositis.

We describe a case of anti-mitochondrial antibody-positive myositis associated with cardiovascular involvement. An electrophysiological study (EPS) showed binodal dysfunction, and cardiac magnetic resonance (CMR) imaging revealed left ventricular dysfunction with diffuse, patchy T2 high-intensity areas and late gadolinium enhancement indicative of inflammation and fibrosis. The left ventricular dysfunction was successfully treated with immunosuppressive therapy as documented by CMR. Persistence of conduction system dysfunction was confirmed by EPS, and a pacemaker was implanted. CMR and EPS concisely documented the variable cardiac response to treatment in anti-mitochondrial antibody-positive myositis. We demonstrate the utility of cardiac investigations in this rare disorder.