Cardiac Metabolism in Sepsis

The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.

Function and Mechanism of Trimetazidine in Myocardial Infarction-Induced Myocardial Energy Metabolism Disorder Through the SIRT1–AMPK Pathway

Myocardial energy metabolism (MEM) is an important factor of myocardial injury. Trimetazidine (TMZ) provides protection against myocardial ischemia/reperfusion injury. The current study set out to evaluate the effect and mechanism of TMZ on MEM disorder induced by myocardial infarction (MI). Firstly, a MI mouse model was established by coronary artery ligation, which was then treated with different concentrations of TMZ (5, 10, and 20 mg kg–1 day–1). The results suggested that TMZ reduced the heart/weight ratio in a concentration-dependent manner. TMZ also reduced the levels of Bax and cleaved caspase-3 and promoted Bcl-2 expression. In addition, TMZ augmented adenosine triphosphate (ATP) production and superoxide dismutase (SOD) activity induced by MI and decreased the levels of lipid peroxide (LPO), free fatty acids (FFA), and nitric oxide (NO) in a concentration-dependent manner (all P < 0.05). Furthermore, an H2O2-induced cell injury model was established and treated with different concentrations of TMZ (1, 5, and 10 μM). The results showed that SIRT1 overexpression promoted ATP production and reactive oxygen species (ROS) activity and reduced the levels of LPO, FFA, and NO in H9C2 cardiomyocytes treated with H2O2 and TMZ. Silencing SIRT1 suppressed ATP production and ROS activity and increased the levels of LPO, FFA, and NO (all P < 0.05). TMZ activated the SIRT1–AMPK pathway by increasing SIRT1 expression and AMPK phosphorylation. In conclusion, TMZ inhibited MI-induced myocardial apoptosis and MEM disorder by activating the SIRT1–AMPK pathway.

Barth Syndrome-Related Cardiomyopathy is Associated with a Reduction in Myocardial Glucose Oxidation

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS (doxycycline-inducible Taz knockdown (TazKD) mice). In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared to their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired prior to the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.

IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.

Perturbations in myocardial energy metabolism in the ischemic heart

As an organ that must continuously pump oxygenated blood throughout the body, the heart has an enormous metabolic demand, which is primarily met via oxidative metabolism of fatty acids and carbohydrates. Because of its high metabolic demand, during times of reduced oxygen supply such as ischemia, the heart becomes highly susceptible to injury, and if flow is not re-established, myocardial tissue is lost and can result in death (myocardial infarction). Of interest, both myocardial ischemia and reperfusion are associated with a number of perturbations in energy metabolism that contribute to the pathology of ischemic heart disease. This includes marked elevations in glycolysis to counteract the reduction in oxidative metabolism, whereas fatty acids predominate as the primary fuel source for residual oxidative metabolism. During the early stages of cardiac recovery after successful reperfusion of the ischemic heart, fatty acid oxidation rates also rapidly recover at the expense of low glucose oxidation rates. These metabolic perturbations increase myocardial acidosis due to glycolysis being uncoupled from glucose oxidation, which impairs cardiac efficiency. As such, therapeutic approaches to stimulate glucose oxidation or inhibit fatty acid oxidation have the potential to correct dysregulated myocardial energy metabolism during ischemia and reperfusion, which improves cardiac efficiency and may lead to improved clinical outcomes in people with ischemic heart disease. L