Myocardial Metabolism Research Articles

1626-P: Activation of Cardiac Mitochondrial Akt1 Enhanced Myocardial Fatty Acid Utilization, Protected against Diabetic Cardiomyopathy, and Improved Whole Body Fat Distribution

Insulin stimulates Akt1 translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondria Akt1 led to mitochondrial dysfunction and cardiomyopathy. However, whether activation of mitochondrial Akt1 in cardiac muscle can protect against the development of diabetic cardiomyopathy is not known. To this end, we have generated an inducible heart-specific transgenic mouse harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). Long-term high fat-high fructose diet (HFFD) caused myocardial hypertrophy, fibrosis and ventricular dysfunction in control mice, but the impact of HFFD were attenuated in the CAMCAKT mice. After just two months on HFFD, expression of Col1a1 and Col3a1 in CAMCAKT mice were lower than controls (p<0.01). After five months on HFFD, ejection fraction in CA mice was 17 % higher than in controls while fractional shortening was 22% higher (p<0.05). This indicated that activation of mitochondrial Akt protected myocardium against the development of cardiomyopathy in diet-induced diabetes. Metabolically, cardiac mitochondrial Akt1 increased fatty acid uptake in the cardiac muscle, which resulted in redistribution of whole-body fatty acid metabolism. Dynamic PET scans revealed a 65% increase (p<0.001) in heart uptake of fatty acid reporter [18F]fluoro-4-thia-oleate in CAMCAKT mice. CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and expended 13% more energy, compared to controls (p<0.05). Interestingly, fatty liver was reduced in the CAMCAKT mice (p<0.05), suggesting that cardiac mitochondrial Akt modulated fat deposition in the liver by higher myocardial fatty acid metabolism. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, attenuated fatty liver, and induced whole body metabolism in this murine model of diet-induced diabetes. Disclosure A.Ta: None. Y.Chen: None. J.Li: None. E.Salem: None. P.H.Wang: Research Support; ViaCyte, Inc. Funding National Institutes of Health (R01HL096987); Ko Family Foundation

Shengxian decoction protects against chronic heart failure in a rat model via energy regulation mechanisms

BackgroundChronic heart failure (CHF) is actually a disease caused by an imbalanced energy metabolism between myocardial energy demand and supply, ultimately resulting in abnormal myocardial cell structure and function. Energy metabolism imbalance plays an important role in the pathological process of chronic heart failure (CHF). Improving myocardial energy metabolism is a new strategy for the treatment of CHF. Shengxian decoction (SXT), a well-known traditional Chinese medicine (TCM) formula, has good therapeutic effects on the cardiovascular system. However, the effects of SXT on the energy metabolism of CHF is unclear. In this study, we probed the regulating effects of SXT on energy metabolism in CHF rats using various research methods.MethodsHigh-performance liquid chromatography (HPLC) analysis was used to perform quality control of SXT preparations. Then, SD rats were randomly assigned into 6 groups: sham, model, positive control (trimetazidine) and high-, middle-, and low-dose SXT groups. Specific reagent kits were used to detect the expression levels of ALT and AST in rats’ serum. Echocardiography was used to evaluate cardiac function. H&E, Masson and TUNEL staining were performed to examine myocardial structure and myocardial apoptosis. Colorimetry was used to determine myocardial ATP levels in experimental rats. Transmission electron microscopy was used to observe the ultrastructure of myocardial mitochondria. ELISA was used to estimate CK, cTnI, and NT-proBNP levels, and LA、FFA、MDA、SOD levels. Finally, Western blotting was used to examine the protein expression of CPT-1, GLUT4, AMPK, p-AMPK, PGC-1α, NRF1, mtTFA and ATP5D in the myocardium.ResultsHPLC showed that our SXT preparation method was feasible. The results of ALT and AST tests indicate that SXT has no side effect on the liver function of rats. Treatment with SXT improved cardiac function and ventricular remodelling and inhibited cardiomyocyte apoptosis and oxidative stress levels induced by CHF. Moreover, CHF caused decrease ATP synthesis, which was accompanied by a reduction in ATP 5D protein levels, damage to mitochondrial structure, abnormal glucose and lipid metabolism, and changes in the expression of PGC-1α related signal pathway proteins, all of which were significantly alleviated by treatment with SXT.ConclusionSXT reverses CHF-induced cardiac dysfunction and maintains the integrity of myocardial structure by regulating energy metabolism. The beneficial effect of SXT on energy metabolism may be related to regulating the expression of the PGC-1α signalling pathway.

Riboflavin ameliorates pathological cardiac hypertrophy and fibrosis through the activation of short-chain acyl-CoA dehydrogenase

Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. FAD, a coenzyme of SCAD, participates in the electron transfer of SCAD-catalyzed fatty acid β-oxidation, which plays a crucial role in maintaining the balance of myocardial energy metabolism. Insufficient riboflavin intake can lead to symptoms similar to short-chain acyl-CoA dehydrogenase (SCAD) deficiency or flavin adenine dinucleotide (FAD) gene abnormality, which can be alleviated by riboflavin supplementation. However, whether riboflavin can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of riboflavin on pathological cardiac hypertrophy and fibrosis. In vitro experiments, riboflavin increased SCAD expression and the content of ATP, decreased the free fatty acids content and improved PE-induced cardiomyocytes hypertrophy and AngⅡ-induced cardiac fibroblasts proliferation by increasing the content of FAD, which were attenuated by knocking down the expression of SCAD using small interfering RNA. In vivo experiments, riboflavin significantly increased the expression of SCAD and the energy metabolism of the heart to improve TAC induced pathological myocardial hypertrophy and fibrosis in mice. The results demonstrate that riboflavin improves pathological cardiac hypertrophy and fibrosis by increasing the content of FAD to activate SCAD, which may be a new strategy for treating pathological cardiac hypertrophy and fibrosis.

Multi-omics approach for identification of molecular alterations of QiShenYiQi dripping pills in heart failure with preserved ejection fraction

Ethnopharmacological relevanceTraditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood. Aim of the studyThe objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF. Materials and methodsHFpEF mouse models established by feeding mice combined high-fat diet and Nω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG. ResultsComputational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG. ConclusionThis study provides mechanistic insights into the pathogenesis of HFpEF and molecular mechanisms of QSYQ in HFpEF. We also identified the regulatory role of PKG in myocardial stiffness, making it an ideal therapeutic target for myocardial remodeling.

MAGNESIUM: A BLOOD PRESSURE MODULATOR

Objective: Magnesium plays an important role at cardiac level as it affects myocardial metabolism, calcium homeostasis, tone and vascular peripherals resistances. Low serum magnesium levels are associated with an increased risk of coronary artery disease and arteriosclerosis. Design and method: We propose a case of a 57 y.o. male, non smoker hypertensive patient treated with sartans and potassium kanreonate. In the past medical history: biopsy-proven chronic gastropathy and revascularized ischemic heart disease. He arrived in ER for dizziness, nausea and severe hypertension. The patient presented psychomotor agitation, muscle pain and paraesthesia. Blood tests revealed hypocalcaemia, hypokalaemia, hypomagnesaemia. Electrolyte supplementation was performed with a significant improvement of clinical picture. Two months later, the patient is back to the ER for hypertensive crisis. So he is hospitalized in the Nephrology Unit to be studied. Results: Blood tests revealed: haemoglobin: 12.2 g/dl, serum creatinine: 0.6 mg/dL, serum potassium levels: 4 mEq/L, serum calcium levels: 9.1 mg/dL, and serum magnesium levels: 1.2 mg/dL. Abdominal echo resulted negative for acute lesions and the renal artery Doppler did not show stenosis. Plasma and urinary catecholamines were normal. During the hospitalization, due to severe symptoms, iv supplementation with Magnesium sulphate (1 fl IV/week) was performed with an increased of serum magnesium levels and progressive hemodynamic compensation. On the contrary, serum sodium and potassium levels and magnesuria were normal, rather than increased. The patient was discharged after performing genetic investigations for possible tubulopathy (in progress) and with a programmed outpatient follow-up in which we observed the normalization of blood pressure values with the same antihypertensive therapy, but with magnesium values rather normal. Conclusions: Blood pressure control is affected by serum magnesium levels .

Positron Emission Tomography in Heart Failure: From Pathophysiology to Clinical Application.

Imaging modalities are increasingly being used to evaluate the underlying pathophysiology of heart failure. Positron emission tomography (PET) is a non-invasive imaging technique that uses radioactive tracers to visualize and measure biological processes in vivo. PET imaging of the heart uses different radiopharmaceuticals to provide information on myocardial metabolism, perfusion, inflammation, fibrosis, and sympathetic nervous system activity, which are all important contributors to the development and progression of heart failure. This narrative review provides an overview of the use of PET imaging in heart failure, highlighting the different PET tracers and modalities, and discussing fields of present and future clinical application.

Neocryptotanshinone ameliorates insufficient energy production in heart failure by targeting retinoid X receptor alpha

Retinoid X receptor alpha (RXRα) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRα drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRα. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component–target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRα. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRα. Meanwhile, the critical downstream target genes of RXRα/PPARα, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRα. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRα/PPARα pathway in mice with HF post-AMI.

Takotsubo syndrome is a coronary microvascular disease: experimental evidence.

Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Review on the protective mechanism of astragaloside IV against cardiovascular diseases.

Cardiovascular disease is a global health problem. Astragaloside IV (AS-IV) is a saponin compound extracted from the roots of the Chinese herb Astragalus. Over the past few decades, AS-IV has been shown to possess various pharmacological properties. It can protect the myocardium through antioxidative stress, anti-inflammatory effects, regulation of calcium homeostasis, improvement of myocardial energy metabolism, anti-apoptosis, anti-cardiomyocyte hypertrophy, anti-myocardial fibrosis, regulation of myocardial autophagy, and improvement of myocardial microcirculation. AS-IV exerts protective effects on blood vessels. For example, it can protect vascular endothelial cells through antioxidative stress and anti-inflammatory pathways, relax blood vessels, stabilize atherosclerotic plaques, and inhibit the proliferation and migration of vascular smooth muscle cells. Thus, the bioavailability of AS-IV is low. Toxicology indicates that AS-IV is safe, but should be used cautiously in pregnant women. In this paper, we review the mechanisms of AS-IV prevention and treatment of cardiovascular diseases in recent years to provide a reference for future research and drug development.

SYSTEMI - systemic organ communication in STEMI: design and rationale of a cohort study of patients with ST-segment elevation myocardial infarction

BackgroundST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking.MethodsSystemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150–200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism.DiscussionSYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy.Trial registrationTrial Registration Number: NCT03539133

Risk prediction model for major adverse cardiovascular events (MACE) during hospitalization in patients with coronary heart disease based on myocardial energy metabolic substrate.

The early attack of coronary heart disease (CHD) is very hidden, and clinical symptoms generally do not appear until cardiovascular events occur. Therefore, an innovative method is needed to judge the risk of cardiovascular events and guide clinical decision conveniently and sensitively. The purpose of this study is to find out the risk factors related to MACE during hospitalization. In order to develop and verify the prediction model of energy metabolism substrates, and establish a nomogram to predict the incidence of MACE during hospitalization and evaluate their performance. The data were collected from the medical record data of Guang'anmen Hospital. This review study was collected the comprehensive clinical data of 5,935 adult patients hospitalized in the cardiovascular department from 2016 to 2021. The outcome index was the MACE during hospitalization. According to the occurrence of MACE during hospitalization, these data were divided into MACE group (n = 2,603) and non-MACE group (n = 425). Logistic regression was used to screen risk factors, and establish the nomogram to predict the risk of MACE during hospitalization. Calibration curve, C index and decision curve were used to evaluate the prediction model, and drawn ROC curve to find the best boundary value of risk factors. The logistic regression model was used to establish a risk model. Univariate logistic regression model was mainly used to screen the factors significantly related to MACE during hospitalization in the training set (each variable is put into the model in turn). According to the factors with statistical significance in univariate logistic regression, five cardiac energy metabolism risk factors, including age, albumin(ALB), free fatty acid(FFA), glucose(GLU) and apolipoprotein A1(ApoA1), were finally input into the multivariate logistic regression model as the risk model, and their nomogram were drawn. The sample size of the training set was 2,120, the sample size of the validation set was 908. The C index of the training set is 0.655 [0.621,0.689], and the C index of the validation set was 0.674 [0.623,0.724]. The calibration curve and clinical decision curve show that the model performs well. The ROC curve was used to establish the best boundary value of the five risk factors, which could quantitatively present the changes of cardiac energy metabolism substrate, and finally achieved prediction of MACE during hospitalization conveniently and sensitively. Age, albumin, free fatty acid, glucose and apolipoprotein A1 are independent factors of CHD in MACE during hospitalization. The nomogram based on the above factors of myocardial energy metabolism substrate provides prognosis prediction accurately.

The role of (18F)-fluoro-D-glucose positron emission tomography/computed tomography in the surveillance of abnormal myocardial energy metabolism and cardiac dysfunction in a rat model of cardiopulmonary resuscitation.

To investigate the feasibility and usefulness of 2-deoxy-2-(18F)-fluoro-D-glucose positron emission tomography/computed tomography [(18F)-FDG PET/CT] as a novel examination in the surveillance of abnormal myocardial energy metabolism and cardiac dysfunction after cardiopulmonary resuscitation (CPR). Thirteen male Sprague-Dawley rats were randomly divided into a sham group (n = 4), CPR group (n = 4), and trimetazidine (TMZ) + CPR group (n = 5). The expression levels of the myocardial injury marker cardiac troponin I (CTNI) in serum were tested at 6 hours after CPR or TMZ + CPR. The ejection fraction and fraction shortening were evaluated by echocardiography. (18F)-FDG PET/CT was used to measure the FDG uptake and the standardized uptake value (SUV) after CPR or TMZ + CPR for 6 hours. The intermediary carbohydrate metabolites of glycolysis including phosphoenolpyruvate, 3-phospho-D-glycerate, and the lactate/pyruvate ratio were detected through the multiple reaction monitoring approach. Simultaneously, the authors also tested the expression levels of the total adenosine triphosphate (ATP) and the key intermediate products of glucose ovidation as alpha ketoglutarate, citrate, and succinate in the myocardium. The authors found that the aerobic oxidation of glucose was reduced, and the anaerobic glycolysis was significantly enhanced in the myocardium in the early stage of CPR. Meanwhile, the myocardial injury marker CTNI was upregulated considerably (P = 0.014, P = 0.021), and the left ventricular function of the animal heart also markedly deteriorated with the downregulation of ATP after CPR. In contrast, myocardial injury and cardiac function were greatly improved with the increase of ATP in the CPR + TMZ group. In addition, aerobic glucose oxidation metabolites were significantly increased (P < 0.05) and anaerobic glycolysis metabolites were significantly decreased (P < 0.05) after CPR in the myocardium. Surprisingly, (18F)-FDG PET/CT could track the above changes by detecting the FDG uptake value and the SUV. Glucose metabolism is an essential factor for myocardial self-repair after CPR. (18F) FDG PET/CT, as a non-invasive technology, can monitor myocardial energy metabolism and cardiac function by tracking changes in glucose metabolism after CPR.

Dependence of cardiomyocyte force, velocity, and power generation on ATP concentration

Theoretical analysis and computer modeling of myocardial energy metabolism under physiological and heart failure conditions predicts that cytoplasmic ATP and ADP levels both fall roughly in proportion to reductions in total adenine nucleotide pool observed in heart failure. Assessing sub-maximal force and velocity in loaded myocardial muscle at MgATP levels in the range of 2 to 8 mM, Beard et al. ( Biophys. J. 2022. 121: 3213–3223) observed effects of MgATP on myocardial power generation that suggest that although maximal force and velocity are not substantially sensitive to differences in [MgATP] that occur in the normal versus failing myocardium, maximal power generation, which occurs at submaximal force and velocity, is sensitive to [MgATP]. Previously developed computational models are not able to reproduce the observed dependence on MgATP. The goals of the present study are to construct and analyze a computational model of muscle dynamics to analyze data on the dependence of maximal force, velocity, and power generation on [MgATP] in order to determine a potential mechanism to explain the MgATP-dependent phenomena. Model development and identification was guided by dynamic measurements on permeabilized mouse trabecular fibers. The data include force-velocity relation and time constant of tension development. The mathematical model used to simulate cardiomyocyte crossbridge mechanics was based on the previous crossbridge and calcium models from Tewari et al. (J Mol Cell Cardiol, 2016. 96: 11-25) and Campbell et al. (Biophys J, 2018. 115: 543-553). The developed model includes strain- and metabolite-dependent transition between attachment states, and ATP-dependent destabilization of the super-relaxed (SRX) myosin state. Model-based analysis of force and velocity dyanmics is consistent with the hypothesis that ATP assocition with the myosin protein influence the kinetics and thermodynamics of transitions between the SRX and disorded (DRX) states. Funding: Department of Veterans Affairs Merit Review Award I01BX000740 (A.J.B.) and National Heart, Lung, and Blood Institute grant R01 HL154624 (A.J.B., D.A.B.) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mild hypoxia as therapy for post-ischemic mitochondrial injury

Introduction: Mitochondrial injury occurs following cellular ischemia in the setting of myocardial infarction, stroke, and cardiac arrest (CA). Effective strategies for reducing injury are limited. Hypoxia has shown benefit in reversing mitochondrial mediated neurodegenerative disease but is little studied in the setting of post-ischemic injury and is regarded as potentially harmful. In this study, we investigated the effects of mild hypoxia on global post-ischemic injury following CA. We hypothesized that brief mild hypoxia following CA would improve mitochondrial function resulting in improved cellular metabolism and physiological recovery. Methods and Results: Anesthetized C57BL6 mice underwent brief asystolic CA (12 min) followed bycardiopulmonary resuscitation(CPR). One hour following successful CPR, mice were randomized to receive a brief episode (6 hours) of normoxia (21% O2) or hypoxia (10% O2) in an environmental chamber. Post intervention, the mice were returned to room air (21% O2). Mild hypoxia improved cardiac mitochondrial complex 1 respiration in the heart by 28% and ATP-related oxygen consumption by 49% (n=3, P&lt;0.05 vs normoxia, respectively) compared to normoxia treated mice. Hypoxia was further associated with improved glucose oxidation in heart as evidenced by decreases in pyruvate dehydrogenase kinase 4 (PDK4) gene and protein expression (n=4, P&lt;0.05 vs normoxia, respectively) as well as decreases in pyruvate dehydrogenase phosphorylation (n=4, P&lt;0.05, respectively) in heart. Hypoxia decreased lactate dehydrogenase (LDH) expression and lactate concentration in heart compared to normoxia treated controls (n=4, P&lt;0.05 vs normoxia, respectively). ROS production in heart by 20% (n=6, P&lt;0.05) was also decreased by mild hypoxia when compared to normoxia post CA. These changes were associated with improved recovery of myocardial function, neurological recovery, and 10-day survival following CA (n=13, P&lt;0.05 vs normoxia, respectively). Conclusion: Brief mild hypoxia treatment following global ischemic injury paradoxically improved recovery of myocardial mitochondrial respiration and metabolism and was associated with improved physiological recovery and survival. Post-ischemia hypoxia is a potential therapeutic strategy for mitochondrial ischemic injury and requires further study. No financial disclosures. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Roles of Increase Fatty Acid Utilization in the Pathological Pathway of Heart Failure in Diabetes

This paper reviews the molecular mechanism that led diabetic patients to its major complication heart failure. While AGEs, RAAS, impaired Ca2+ handling, and ER stress also contribute to the progress of diabetic cardiomyopathy, this review emphasizes on the effect of increasing fatty acid (FA) uptake and utilization since it interconnects with other crucial causes of diabetic cardiomyopathy such as lipotoxicity, mitochondrial dysfunction, and myocardial apoptosis. The review started with the root of increasing myocardial FA metabolism, which is the overactivation of a transcription factor called peroxisome proliferator-activated receptor (PPAR). Then, the paper detailedly reviews the molecular mechanism of how increasing FA oxidation and impaired glucose oxidation leads to lipid accumulation, apoptosis, and cardiac inefficiency, which ultimately causes contractile dysfunction, left ventricular hypertrophy, and heart failure.

Mapping the Unseen: In Vivo CEST-MRI of Creatine Reveals Improved Cardiac Energetics in Subjects with Obesity Following Bariatric Surgery.

Obesity is associated with derangement of cardiac metabolism and the development of subclinical cardiovascular disease. This prospective study examined the impact of bariatric surgery on cardiac function and metabolism. Subjects with obesity underwent cardiac magnetic resonance imaging (CMR) at Massachusetts General Hospital before and after bariatric surgery between 2019 and 2021. The imaging protocol included Cine for global cardiac function assessment and creatine chemical exchange saturation transfer (CEST) CMR for myocardial creatine mapping. Thirteen subjects were enrolled, and 6 subjects [mean BMI 40.5 ± 2.6] had completed the second CMR (i.e. post-surgery), with a median follow-up of 10 months. The median age was 46.5 years, 67% were female, and 16.67% had diabetes. Bariatric surgery led to significant weight loss, with achieved mean BMI of 31.0 ± 2.0. Additionally, bariatric surgery resulted in significant reduction in left ventricular (LV) mass, LV mass index, and epicardial adipose tissue (EAT) volume. This was accompanied by slight improvement in LV ejection fraction compared to baseline. Following bariatric surgery, there was a significant increase in creatine CEST contrast. Subjects with obesity had significantly lower CEST contrast compared to subjects with normal BMI (n = 10), but this contrast was normalized after the surgery, and statistically similar to non-obese cohort, indicating an improvement in myocardial energetics. CEST-CMR has the ability to identify and characterize myocardial metabolism in vivo non-invasively. These results demonstrate that in addition to reducing BMI, bariatric surgery may favorably affect cardiac function and metabolism.

Influence of Isolated Resistance Exercise on Cardiac Remodeling, Myocardial Oxidative Stress, and Metabolism in Infarcted Rats.

Exercise is an important therapeutic strategy for preventing and treating myocardial infarction (MI)-induced cardiac remodeling and heart failure. However, the myocardial effects of resistance exercise on infarcted hearts are not completely established. In this study, we investigated the effects of resistance exercise on structural, functional, and molecular cardiac alterations in infarcted rats. Three months after MI induction or simulated surgery, Wistar rats were assigned into three groups: Sham (n = 14); MI (n = 9); and exercised MI (MI-Ex, n = 13). Exercised rats performed, 3 times a week for 12 weeks, four climbs on a ladder with progressive loads. Cardiac structure and left ventricle (LV) function were analyzed by echocardiogram. Myocyte diameters were evaluated in hematoxylin- and eosin-stained histological sections as the smallest distance between borders drawn across the nucleus. Myocardial energy metabolism, lipid hydroperoxide, malondialdehyde, protein carbonylation, and antioxidant enzyme activities were evaluated by spectrophotometry. Gene expressions of NADPH oxidase subunits were evaluated by RT-PCR. Statistical analyses were performed using ANOVA and Tukey or Kruskal-Wallis and Dunn's test. Mortality did not differ between the MI-Ex and MI groups. MI had dilated left atrium and LV, with LV systolic dysfunction. Exercise increased the maximum load-carrying capacity, with no changes in cardiac structure or LV function. Myocyte diameters were lower in MI than in Sham and MI-Ex. Lactate dehydrogenase and creatine kinase activity were lower in MI than in Sham. Citrate synthase and catalase activity were lower in MI and MI-Ex than in Sham. Lipid hydroperoxide concentration was lower in MI-Ex than in MI. Nox2 and p22phox gene expressions were higher in MI-Ex than in Sham. Gene expression of Nox4 was higher in MI and MI-Ex than in Sham, and p47phox was lower in MI than in Sham. Late resistance exercise was safe in infarcted rats. Resistance exercise improved maximum load-carrying capacity, reduced myocardial oxidative stress, and preserved myocardial metabolism, with no changes in cardiac structure or left ventricle function in infarcted rats.

Dynamic evolution and mechanism of myocardial glucose metabolism in different functional phenotypes of diabetic cardiomyopathy — a study based on 18 F-FDG microPET myocardial metabolic imaging

PurposeTo use 18 F-FDG microPET dynamic imaging to preliminarily identify the changes of myocardial glucose metabolism corresponding to different functional phenotypes of diabetic cardiomyopathy (DCM) in mice and elucidate their relationships.MethodsLeft ventricular function was measured by echocardiography in C57BL/KsJ-db/db (db/db) mice and their controls at 8, 12, 16, and 20 weeks of age to divide DCM stages and functional phenotypes. Myocardial histopathology was used to verify the staging accuracy and list-mode microPET dynamic imaging was conducted. The myocardial metabolic rate of glucose (MRglu) and the glucose uptake rate constant (Ki) were derived via Patlak graphical analysis, and the differences in myocardial glucose metabolism levels in different DCM stages were compared. The key proteins involved in myocardial glucose metabolism signaling pathway were analyzed by Western blotting to elucidate the underlying mechanism of abnormal glucose metabolism in DCM.ResultsCompared with the controls, the ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (E/e’) of db/db mice was significantly increased from the age of 12 weeks, while the left ventricular ejection fraction (LVEF) was significantly decreased from the age of 16 weeks (all P < 0.05). Based on the staging criteria, 8 and 12 weeks (8/12w) db/db mice were in DCM stage 1 (diastolic dysfunction with normal LVEF), and 16 and 20 weeks (16/20w) db/db mice were in DCM stage 2/3 (diastolic and systolic dysfunction). The degree of myocardial fibrosis, glycogen deposition and ultrastructural damage in 16/20w db/db mice were more obvious than those in 8/12w group. The myocardial MRglu, Ki of db/db mice in 8/12w group or 16/20w group were significantly lower than those in the control group (all P < 0.05), while the myocardial standard uptake value (SUV) was not significantly reduced in the 8/12w group compared with the control group (P > 0.05). MRglu and SUV were moderately negatively correlated with the E/e’ ratio (r=-0.539 and − 0.512, P = 0.007 and 0.011), which were not significantly correlated with LVEF (P > 0.05). Meanwhile, Ki was not significantly correlated with LVEF or E/e’ ratio. The decreased expression of glucose transporter (GLUT) -4 in db/db mice preceded GLUT-1 and was accompanied by decreased phosphorylated AMP-activated protein kinase (p-AMPK) expression. Myocardial MRglu, Ki and SUV were significantly positively correlated with the expression of GLUT-4 (MRglu: r = 0.537; Ki: r = 0.818; SUV: r = 0.491; P = 0.000 ~ 0.046), but there was no significant correlation with GLUT-1 expression (P = 0.238 ~ 0.780).ConclusionsDuring the progression of DCM, with the changes of left ventricular functional phenotype, abnormal and dynamic changes of myocardial glucose metabolism can occur in the early stage.

STUDY THE IN HOSPITAL MORTALITY AND MORBIDITY IN PATIENTS OF ACUTE MYOCARDIAL INFARCTION WITH RESPECT TO SERUM MAGNESIUM LEVELS

Magnesium improves myocardial metabolism, reduces platelet aggregation, decreases systemic vascular resistance, dilates coronary arteries, guards against catecholamine induced myocardial necrosis, and stabilizes cell membranes. Ventricular tachyarrhythmia, sudden cardiac death and re-infarction are frequently results of hypomagnesaemia in the early post-acute myocardial infarction (AMI) period. In this prospective observational study, all patients presenting in the emergency with Acute onset anginal chest pain and associated symptoms were screened for AMI by obtaining an Electrocardiogram and Biochemical Markers. For those diagnosed to have ST elevation myocardial Infarction were subjected to detailed clinical history and examination. Serum Magnesium levels and Electrolyte would be obtained within 6 hours of the admission. Patients were treated as per the standard line of management on the advice of the treating physician/ cardiologist. In the present study there is Summary: signicant association seen between serum magnesium level and arrhythmia, morbidity of the study subjects, need of ventilator support, mortality, history of alcoholics, serum potassium level and serum troponin. I level in the study subjects. On the basis of present study, it is concluded that Magnesium plays a cardinal role in management and prevention of complications related to cardio-vascular event and its estimation in acute myocardial infarction serves as a tool for assessment of severity of the disease and envisage possible adverse outcomes including prevention of morbidities and mortality associated with hypomagnesemia in acute myocardial infarction patients

Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection.

Sirtuin 5 (SIRT5) is a predominantly mitochondrial enzyme catalyzing the removal of glutaryl, succinyl, malonyl, and acetyl groups from lysine residues through a NAD+-dependent deacylase mechanism. SIRT5 is an important regulator of cellular homeostasis and modulates the activity of proteins involved in different metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, fatty acid oxidation, electron transport chain, generation of ketone bodies, nitrogenous waste management, and reactive oxygen species (ROS) detoxification. SIRT5 controls a wide range of aspects of myocardial energy metabolism and plays critical roles in heart physiology and stress responses. Moreover, SIRT5 has a protective function in the context of neurodegenerative diseases, while it acts as a context-dependent tumor promoter or suppressor. In addition, current research has demonstrated that SIRT5 is implicated in the SARS-CoV-2 infection, although opposing conclusions have been drawn in different studies. Here, we review the current knowledge on SIRT5 molecular actions under both healthy and diseased settings, as well as its functional effects on metabolic targets. Finally, we revise the potential of SIRT5 as a therapeutic target and provide an overview of the currently reported SIRT5 modulators, which include both activators and inhibitors.