Cardiac Metabolic Stress Research Articles

Cardiac Metabolic Stress During Ischemia and Reperfusion in Patients Undergoing Coronary Artery Bypass Surgery Using Either Calafiore or Modified Del Nido Cardioplegic Solutions

Objective: Calafiore and modified del Nido cardioplegic solutions are currently being used during coronary artery bypass surgery. This study aims to compare myocardial ischemic stress associated with both solutions by studying the changes in cardiac metabolites during cardioplegic ischemic arrest and early reperfusion.Methods: Biopsy specimens were taken from the left ventricles of 20 patients undergoing routine coronary artery bypass grafting using Calafiore or modified del Nido cardioplegic solutions. Biopsies were taken immediately after the beginning of extracorporeal circulation (basal biopsy), 30 min after application of the aortic cross‐clamp (ischemic biopsy), and 20 min following the removal of aortic cross‐clamp (reperfusion biopsy) and were analyzed for their amino acid and lactic acid contents using amino acid analyzer and appropriate kits. Peripheral blood samples were also collected for the determination of blood concentrations of cardiac proteins (CK‐MB and troponin I) using an immunofluorescence scanner.Results: Both CK‐MB and troponin I increased significantly 12 h postoperatively and were associated with an increase in myocardial lactic acid, but there were no significant differences in markers of myocardial injury between the two groups. Comparison of amino acid concentrations between the two groups according to sampling time showed that glutamic acid concentrations were significantly lower in the Calafiore cardioplegia group compared to the del Nido cardioplegia group, but there were no other significant differences in markers of metabolic stress (taurine and alanine/glutamate ratio) between the two groups. Moreover, there were no significant differences in changes in amino acid concentrations regardless of the type of cardioplegic solution used.Conclusions: Cardioplegic ischemic arrest and early reperfusion are associated with a rise in myocardial metabolic stress. Both Calafiore and modified del Nido cardioplegic solutions are effective in attenuating myocardial substrate derangements and confer equal myocardial protection during routine coronary artery bypass surgery.Trial Registration: ClinicalTrials.gov identifier: NCT06287372

Fructose Metabolism and Cardiac Metabolic Stress.

Cardiovascular disease is one of the leading causes of mortality in diabetes. High fructose consumption has been linked with the development of diabetes and cardiovascular disease. Serum and cardiac tissue fructose levels are elevated in diabetic patients, and cardiac production of fructose via the intracellular polyol pathway is upregulated. The question of whether direct myocardial fructose exposure and upregulated fructose metabolism have potential to induce cardiac fructose toxicity in metabolic stress settings arises. Unlike tightly-regulated glucose metabolism, fructose bypasses the rate-limiting glycolytic enzyme, phosphofructokinase, and proceeds through glycolysis in an unregulated manner. In vivo rodent studies have shown that high dietary fructose induces cardiac metabolic stress and functional disturbance. In vitro, studies have demonstrated that cardiomyocytes cultured in high fructose exhibit lipid accumulation, inflammation, hypertrophy and low viability. Intracellular fructose mediates post-translational modification of proteins, and this activity provides an important mechanistic pathway for fructose-related cardiomyocyte signaling and functional effect. Additionally, fructose has been shown to provide a fuel source for the stressed myocardium. Elucidating the mechanisms of fructose toxicity in the heart may have important implications for understanding cardiac pathology in metabolic stress settings.

Preventive effects of l-glutamine on gestational fructose-induced cardiac hypertrophy: involvement of pyruvate dehydrogenase kinase-4.

Gestational fructose exposure has detrimental health consequences on both the maternal and fetus or offspring in the early or later life, contributing to epidemic rise in cardiometabolic syndrome including cardiac events. l-Glutamine has been shown to mitigate cardiac metabolic stress. However, the effect of l-glutamine on cardiac hypertrophy induced by gestational fructose exposure is not known. We therefore hypothesized that l-glutamine would prevent gestational fructose-induced cardiac hypertrophy, possibly by suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Pregnant Wistar rats were allotted into the control, l-glutamine, gestational fructose exposure, and gestational fructose exposure plus l-glutamine groups (6 rats in each group). The groups received distilled water (vehicle, per os), 1 g/kg body weight l-glutamine (per os), 10% fructose (w/v) and 10% fructose (w/v) plus 1 g/kg l-glutamine (per os), respectively, daily for 19 days. Data from this study showed that gestational fructose-enriched drink caused cardiac hypertrophy with correspondent body weight gain, glucose dysregulation, increased cardiac PDK-4, triglyceride, glycogen, lactate, and uric acid production. On the other hand, defective glutathione-dependent antioxidant barrier was also observed in pregnant rats taking fructose-enriched drink. However, the gestational fructose-induced cardiac hypertrophy and its correlates were attenuated by l-glutamine. The present results demonstrate that gestational fructose-enriched drink induces cardiac hypertrophy that is accompanied by increased PDK-4. The findings also suggest that the inhibitory effect of l-glutamine on PDK-4 prevents the development of cardiac hypertrophy, thereby implying that PDK-4 may be a potential novel therapeutic intervention for cardiac hypertrophy especially in pregnancy.

Myocardial glycogen dynamics: new perspectives on disease mechanisms.

Cardiac glycogen regulation involves a complex interplay between multiple signalling pathways, allosteric activation of enzymes, and sequestration for autophagic degradation. Signalling pathways appear to converge on glycogen regulatory enzymes via insulin (glycogen synthase kinase 3β, protein phosphatase 1, allosteric action of glucose-6-phosphate), β-adrenergic (phosphorylase kinase protein phosphatase 1 inhibitor), and 5' adenosine monophosphate-activated protein kinase (allosteric action of glucose-6-phosphate, direct glycogen binding, insulin receptor). While cytosolic glycogen synthesis and breakdown are relatively well understood, recent findings relating to phagic glycogen degradation highlight a new area of investigation in the heart. It has been recently demonstrated that a specific glycophagy pathway is operational in the myocardium. Proteins involved in recruiting glycogen to the forming phagosome have been identified. Starch-binding domain-containing protein 1 is involved in binding glycogen and mediating membrane anchorage via interaction with a homologue of the phagosomal protein light-chain 3. Specifically, it has been shown that starch-binding domain-containing protein 1 and light-chain 3 have discrete phagosomal immunolocalization patterns in cardiomyocytes, indicating that autophagic trafficking of glycogen and protein cargo in cardiomyocytes can occur via distinct pathways. There is strong evidence from glycogen storage diseases that phagic/lysosomal glycogen breakdown is important for maintaining normal cardiac glycogen levels and does not simply constitute a redundant 'alternative' breakdown route for glycogen. Advancing understanding of glycogen handling in the heart is an important priority with relevance not only to genetic glycogen storage diseases but also to cardiac metabolic stress disorders such as diabetes and ischaemia.

Myocardial autophagic energy stress responses--macroautophagy, mitophagy, and glycophagy.

An understanding of the role of autophagic processes in the management of cardiac metabolic stress responses is advancing rapidly and progressing beyond a conceptualization of the autophagosome as a simple cell recycling depot. The importance of autophagy dysregulation in diabetic cardiomyopathy and in ischemic heart disease - both conditions comprising the majority of cardiac disease burden - has now become apparent. New findings have revealed that specific autophagic processes may operate in the cardiomyocyte, specialized for selective recognition and management of mitochondria and glycogen particles in addition to protein macromolecular structures. Thus mitophagy, glycophagy, and macroautophagy regulatory pathways have become the focus of intensive experimental effort, and delineating the signaling pathways involved in these processes offers potential for targeted therapeutic intervention. Chronically elevated macroautophagic activity in the diabetic myocardium is generally observed in association with structural and functional cardiomyopathy; yet there are also numerous reports of detrimental effect of autophagy suppression in diabetes. Autophagy induction has been identified as a key component of protective mechanisms that can be recruited to support the ischemic heart, but in this setting benefit may be mitigated by adverse downstream autophagic consequences. Recent report of glycophagy upregulation in diabetic cardiomyopathy opens up a novel area of investigation. Similarly, a role for glycogen management in ischemia protection through glycophagy initiation is an exciting prospect under investigation.

Glucose as an agent of post-translational modification in diabetes — New cardiac epigenetic insights

Diabetes elicits cardiac metabolic stress involving impaired glucose uptake and metabolic substrate shifts. Diabetic cardiac pathology is well documented in human patients and experimental animal models to be characterized by diastolic dysfunction, but the underlying mechanisms are not well understood. Signaling disturbances involved in cardiac insulin resistance are linked to glucose handling abnormalities. Both reversible (e.g. O-GlcNAc) and irreversible (e.g. AGEs) glucose-modifications of cardiomyocyte extracellular and intracellular proteins are implicated in structural and functional alterations underlying pathology in the diabetic heart. This review highlights some aspects of the epigenetic roles played by glucose (and related hexose sugars) in mediating diabetic cardiac pathology with specific consideration for the mechanisms impinging on post-translational modifications which have key signaling and mechanical impacts.

Myocardial glycophagy — A specific glycogen handling response to metabolic stress is accentuated in the female heart

Cardiac metabolic stress is a hallmark of many cardiac pathologies, including diabetes. Cardiac glycogen mis-handling is a frequent manifestation of various cardiopathologies. Diabetic females have a higher risk of heart disease than males, yet sex disparities in cardiac metabolic stress settings are not well understood. Oestrogen acts on key glycogen regulatory proteins. The goal of this study was to evaluate sex-specific metabolic stress-triggered cardiac glycogen handling responses. Male and female adult C57Bl/6J mice were fasted for 48h. Cardiac glycogen content, particle size, regulatory enzymes, signalling intermediates and autophagic processes were evaluated. Female hearts exhibited 51% lower basal glycogen content than males associated with lower AMP-activated-kinase (AMPK) activity (35% decrease in pAMPK:AMPK). With fasting, glycogen accumulated in female hearts linked with decreased particle size and upregulation of Akt and AMPK signalling, activation of glycogen synthase and inactivation of glycogen phosphorylase. Fasting did not alter glycogen content or regulatory proteins in male hearts. Expression of glycogen autophagy marker, starch-binding-protein-domain-1 (STBD1), was 63% lower in female hearts than males and increased by 69% with fasting in females only. Macro-autophagy markers, p62 and LC3BII:I ratio, increased with fasting in male and female hearts. This study identifies glycogen autophagy (‘glycophagy’) as a potentially important component of the response to cardiac metabolic stress. Glycogen autophagy occurs in association with a marked and selective accumulation of glycogen in the female myocardium. Our findings suggest that sex-specific differences in glycogen handling may have cardiopathologic consequences in various settings, including diabetic cardiomyopathy.

Product of Heart Rate and First Heart Sound Amplitude as an Index of Myocardial Metabolic Stress During Graded Exercise

The double product (DP) breakpoint of heart rate (HR) and systolic blood pressure has been identified as coincident with anaerobic threshold (AT), but there are no simple methods for measuring cardiac metabolic stress (CMS) during an exercise test. It was hypothesized that the DP of HR and the amplitude of the first heart sound (AHS1) (DP-AHS1) would reflect CMS, and thus, the breakpoint in the DP-AHS1 (DPBP-AHS1) could be an alternative method for determining AT. Subjects (age range, 18-73 years) were recruited to perform a graded exercise test on a cycle ergometer with continuous monitoring of DP-AHS1, with left ventricular pressure (LVP; experiment 1, Ex1), plasma catecholamine and blood lactate (experiment 2, Ex2) and gas exchange (experiment 3, Ex3). Ex1: in all subjects there was a strong correlation between AHS1 and LVdP/dtmax (r=0.94-0.98), and between the DP-AHS1 and the triple product of HR, LVdP/dtmax, and max LVP (r=0.98-0.99). Ex2: DP-AHS1 was strongly correlated with adrenaline (r=0.97-1.00) and lactate (r=0.96-1.00) levels in all subjects. Ex3: there was a strong correlation between DPBP-AHS1, AT and maximum oxygen consumption. The present simple measure of DP-AHS1 can reflect plasma adrenaline and lactate levels during graded exercise testing. Further, DPBP-AHS1 is a surrogate marker of AT and a good index of functional aerobic capacity.