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Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction.

ABSTRACT: Melatonin has been shown to inhibit myocardial infarction-induced apoptosis, its function in heart failure with preserved ejection fraction (HFpEF) has not been investigated. This study aimed to investigate whether melatonin attenuates obesity-related HFpEF. Male mice were fed a high-fat diet (HFD) from weaning to 6 months of age to induce HFpEF. The mice were orally administered melatonin (50?mg/kg) by 3 weeks. Diastolic function was significantly improved by melatonin supplementation in mice fed an HFD. Melatonin attenuated obesity-induced myocardial oxidative stress and apoptosis and promoted the secretion of C1q/tumour necrosis factor-related protein 3 (CTRP3) by adipose tissue. And depletion of circulating CTRP3 largely abolished melatonin-mediated cardio-protection. Melatonin-mediated secretion of adipocyte-derived CTRP3 activated NF-E2-related factor 2 (Nrf2), which were largely abrogated by knocking down CTRP3 in adipocytes or Nrf2 in cardiomyocytes. Nrf2 activation was mediated by miR-200a, and a miR-200a antagomir offset the effects of melatonin-conditioned medium on Nrf2 expression. Our results indicate that melatonin can be used to treat and prevent obesity-related HFpEF.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6076208 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction.

Liu Yuan Y Li Li-Na LN Guo Sen S Zhao Xiao-Yan XY Liu Yu-Zhou YZ Liang Cui C Tu Sheng S Wang Dan D Li Ling L Dong Jian-Zeng JZ Gao Lu L Yang Hai-Bo HB

Redox biology 20180711

Melatonin has been shown to inhibit myocardial infarction-induced apoptosis, its function in heart failure with preserved ejection fraction (HFpEF) has not been investigated. This study aimed to investigate whether melatonin attenuates obesity-related HFpEF. Male mice were fed a high-fat diet (HFD) from weaning to 6 months of age to induce HFpEF. The mice were orally administered melatonin (50 mg/kg) by 3 weeks. Diastolic function was significantly improved by melatonin supplementation in mice f ...[more]

PMID: 30031269

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Project description:Background Depressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is unclear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF. Methods and Results We studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF-free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF-free participants (P<0.001 and P=0.59, respectively). Among HF-free participants, Center for Epidemiologic Studies Depression Scale score was not associated with cardiac structure and function after adjusting for demographics and comorbidities (all P>0.05). Over 5.5-year follow-up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04-1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96-1.08]; P=0.54), independent of echocardiographic measures, NT-proBNP (N-terminal pro-B-type natriuretic peptide), troponin, and hs-CRP (high-sensitivity C-reactive protein) (HR [95% CI], 1.06 [1.00-1.12]; P=0.04). Conclusions Worse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF.

Project description:AimsThe diagnostic and treatment of patients with heart failure with preserved ejection fraction (HFpEF) are both hampered by an incomplete understanding of the pathophysiology of the disease. Novel imaging tools to adequately identify these patients from individuals with a normal cardiac function and respectively patients with HF with reduced EF are warranted. Computing multilayer myocardial strain with feature tracking is a fast and accurate method to assess cardiac deformation. Our purpose was to assess the HFpEF diagnostic ability of multilayer strain parameters and compare their sensitivity and specificity with other established parameters.Methods and resultsWe included 20 patients with a diagnosis of HFpEF and, respectively, 20 matched controls. We assessed using feature-tracking cardiac magnetic resonance longitudinal and circumferential myocardial strain at three distinct layers of the myocardium: subendocardial (Endo-), mid-myocardial (Myo-), and subepicardial (Epi-). Comparatively, we additionally assessed various others clinical, imaging, and biochemical parameters with a putative role in HFpEF diagnostic: left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM), interventricular septum (IVS) wall thickness and free wall thickness, left atrial volume and strain, septal and lateral mitral annular early diastolic velocity (e`), E/e´ ratio, and plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Global longitudinal strain (GLS) is significantly impaired at Endo (-20.8 ± 4.0 vs. -23.2 ± 3.4, P = 0.046), Myo- (-18.0 ± 3.0 vs. -21.0 ± 2.5, P = 0.002), and Epi- (-12.2 ± 2.0 vs. -16.2 ± 2.5, P < 0.001) levels. Compared with any other imaging parameter, an Epi-GLS lower than 13% shows the highest ability to detect patients with HFpEF [area under the curve (AUC) = 0.90 (0.81-1), P < 0.001] and in tandem with NT-proBNP can diagnose with maximal sensibility (93%) and specificity (100%), patients with HFpEF from normal, composed variable [AUC = 0.98 (0.95-1), P < 0.001]. In a logistic regression model, a composite predictive variable taking into account both GLS Epi and NT-proBNP values in each individual subject reached a sensitivity of 89% and a specificity of 100% with an AUC of 0.98 (0.95-1), P < 0.001, to detect HFpEF.ConclusionsEpi-GLS is a promising new imaging parameter to be considered in the clinical assessment of HFpEF patients. Given its excellent specificity, in tandem with a highly sensitive parameter such as NT-proBNP, Epi-GLS holds the potential to greatly improve the current diagnostic algorithms.

Project description:ObjectivePulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.ConclusionsOur data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Dataset Information

Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction.

Publications

Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction.

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