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  • Taking into account the heart s high metabolic demand it


    Taking into account the heart's high metabolic demand, it comes as no surprise that cardiovascular diseases involve marked changes in myocardial metabolism. Many studies have assessed the metabolic changes that take place in the heart during the progression to heart failure, assessing animal models of cardiac hypertrophy and failure, as well as patients with heart failure. Though the results have not always been consistent, the consensus is that fatty Gilteritinib use is decreased in almost all models of hypertrophy and heart failure, and this is most often accompanied with an increase in glycolysis and glucose oxidation. Patients with idiopathic dilated cardiomyopathy, who exhibited systolic dysfunction, showed decreases in markers of fatty acid utilization and evidence for increased glucose use [121,122]. Similarly left ventricular hypertrophy, induced by aortic banding or by myocardial infarction, is associated with decreased fatty acid oxidation and increased glucose use [123,124]. It is important to note that the progression to heart failure is a slow, complex process and, for this reason, the metabolic changes observed in cardiac hypertrophy and heart failure will vary depending on aetiology, progression, and severity and stage of disease. In pathologic hypertrophy, hypoxia induces HIF-1α expression [125], which plays an important role in reprogramming myocardial metabolism. The initial metabolic reprogramming, which involves an adaptive increase in glucose uptake and glycolysis, is likely to be due to the hypoxia that results from the mismatch between oxygen supply and demand [126]. The transition to heart failure involves changes in metabolic targets involved in glycolysis and PDH flux in patients at the later stages of hypertrophy [86]. Additionally, the transition to heart failure has also been associated with changes in fatty acid oxidation markers, namely PPARα targets [127]. Diabetes is a growing concern worldwide and a systemic metabolic disease, which has been recognised as an independent risk factor for the development of heart failure, with a significant decrease in survival rate following MI compared to non-diabetic patients [[128], [129], [130]]. Diabetic cardiomyopathy (DCM) is a specific pathology associated with diabetes mellitus, which is characterised by structural and functional cardiac changes, including fibrosis, ventricular dilation and diastolic dysfunction [131]. In diabetes mellitus, energy metabolism is greatly re-shaped, due to a dysregulation of glucose metabolism and fatty acid metabolism. From a metabolic perspective, type 2 diabetes is characterised by increased cardiac fatty acid oxidation and an inability to use glucose due to insulin resistance [132], and as a consequence, cardiac metabolic flexibility is impaired [59]. It is likely that early in obesity, prior to type 2 diabetes, the changes in substrate use relate to substrate availability, namely the increase in circulating fatty acids and triglycerides. This, however, leads to an adaptation of the cardiac metabolic machinery in response to changing conditions, leading to decreased glucose use as a result of increased fatty acid use via the Randle cycle [129,133]. The resulting hyperglycaemia and hyperlipidaemia, together with insulin resistance, lead to changes in the expression and translocation of GLUT4 and FAT/CD36, with increased translocation of FAT/CD36 towards the sarcolemma and decreased sarcolemmal GLUT4 [134]. Increased fatty acid uptake is associated with increased fatty acid oxidation, activation of PPARα and its fatty acid metabolism target genes and increased lipid storage. These fatty acid metabolic changes ultimately result in a decreased ability to use glucose, and an associated loss of diastolic function, which has been observed in rodent models of obesity with insulin resistance [135], diabetes [136] and in patients with type 2 diabetes with no concomitant cardiovascular symptoms [137].
    HIF signalling in cardiovascular diseases