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Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality. The current mechanistic paradigm supports a comorbidity-driven systemic proinflammatory state that evokes microvascular and myocardial dysfunction. Crucially, diabetes and obesity are frequently prevalent in HFpEF patients; as such, we review the involvement of a metabolic-inflammatory circuit in disease pathogenesis.Experimental models of diastolic dysfunction and genuine models of HFpEF have facilitated discovery of underlying drivers of HFpEF, where metabolic derangement and systemic inflammation appear to be central components of disease pathophysiology. Despite a shared phenotype among these models, molecular signatures differ depending on type and combination of comorbidities present. Inflammation, oxidative stress, hypertension, and metabolic derangements have been positioned as therapeutic targets to suppress the metabolic-inflammatory circuit in HFpEF. However, the stratification of unique patient phenogroups within the collective HFpEF subgroup argues for specific interventions for distinct phenogroups.

AIMS Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. METHODS AND RESULTS Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6 ± 1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated ischaemia/reperfusion injury (IRI), hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7 ± 2.5% vs control 34.1 ± 1.5%, P = 0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6 ± 6.5% vs vehicle control 54.1 ± 4.9%, P = 0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9 ± 3.0% vs vehicle control 58.2 ± 3.8%, P

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30&ndash, 40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 &plusmn, 8.6 vs. mdivi-1 50.5 &plusmn, 11.4, p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 &plusmn, 0.4 vs. mdivi-1 59.6 &plusmn, 0.6, p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.

Acute myocardial infarction (AMI) and the heart failure (HF) that often results are among the leading causes of death and disability in the world. As such, novel strategies are required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury (IRI), in order to reduce myocardial infarct (MI) size and prevent the onset of HF. The endogenous cardioprotective strategy of remote ischemic conditioning (RIC), in which cycles of brief ischemia and reperfusion are applied to a tissue or organ away from the heart, has been reported in experimental studies to reduce MI size in animal models of acute IRI. In the clinical setting, RIC can be induced by simply inflating and deflating a cuff placed on the upper arm or thigh to induce brief cycles of ischemia and reperfusion, a strategy which has been shown to reduce MI size in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). The results of the ongoing CONDI2/ERIC-PPCI trial are eagerly awaited, and will provide definitive answers with regards to the cardioprotective effect and clinical outcome benefits of RIC in STEMI.