Changes In Myocardial Metabolism Research Articles

Capillary pruning couples tissue perfusion and oxygenation with cardiomyocyte maturation in the postnatal mouse heart.

Introduction: Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. Methods: In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Results: Although both drugs reduced capillary pruning, a combination of experiments based on ex vivo imaging, proteomics, electron microscopy and in vivo functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Discussion: Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage.

Characterization of a robust mouse model of heart failure with preserved ejection fraction.

Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as a result of high left ventricular (LV) diastolic pressure in the context of normal or near normal LV ejection fraction (LVEF; ≥50%). Challenges to create and reproduce a robust rodent phenotype that recapitulates the multiple comorbidities that exist in this syndrome explain the presence of various animal models that fail to satisfy all the criteria of HFpEF. Using a continuous infusion of angiotensin II and phenylephrine (ANG II/PE), we demonstrate a strong HFpEF phenotype satisfying major clinically relevant manifestations and criteria of this pathology, including exercise intolerance, pulmonary edema, concentric myocardial hypertrophy, diastolic dysfunction, histological signs of microvascular impairment, and fibrosis. Conventional echocardiographic analysis of diastolic dysfunction identified early stages of HFpEF development and speckle tracking echocardiography analysis including the left atrium (LA) identified strain abnormalities indicative of contraction-relaxation cycle impairment. Diastolic dysfunction was validated by retrograde cardiac catheterization and analysis of LV end-diastolic pressure (LVEDP). Among mice that developed HFpEF, two major subgroups were identified with predominantly perivascular fibrosis and interstitial myocardial fibrosis. In addition to major phenotypic criteria of HFpEF that were evident at early stages of this model (3 and 10 days), accompanying RNAseq data demonstrate activation of pathways associated with myocardial metabolic changes, inflammation, activation of extracellular matrix (ECM) deposition, microvascular rarefaction, and pressure- and volume-related myocardial stress.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an emerging epidemic affecting up to half of patients with heart failure. Here we used a chronic angiotensin II/phenylephrine (ANG II/PE) infusion model and instituted an updated algorithm for HFpEF assessment. Given the simplicity in generating this model, it may become a useful tool for investigating pathogenic mechanisms, identification of diagnostic markers, and for drug discovery aimed at both prevention and treatment of HFpEF.

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.

Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.

Diabetic cardiomyopathy was originally described as the presence of ventricular dysfunction in the absence of coronary artery disease and/or hypertension. It is characterized by diastolic dysfunction and is more prevalent in people with diabetes than originally realized, leading to the suggestion in the field that it simply be referred to as diabetic heart disease. While there are currently no approved therapies for diabetic heart disease, a multitude of studies clearly demonstrate that it is characterized by several disturbances in myocardial energy metabolism. One of the most prominent changes in myocardial energy metabolism in diabetes is a robust impairment in glucose oxidation. Herein we will describe the mechanisms responsible for the diabetes-induced decline in myocardial glucose oxidation, and the pharmacological approaches that have been pursued to correct this metabolic disorder. With surmounting evidence that stimulating myocardial glucose oxidation can alleviate diastolic dysfunction and other pathologies associated with diabetic heart disease, this may also represent a novel strategy for decreasing the prevalence of heart failure with preserved ejection fraction in the diabetic population.

Metabolic modulation as a common adaptive mechanism in patients with different subtypes of aortic valve stenosis

Abstract Background Aortic valve stenosis (AS) is a rapidly growing global health problem due to aging and population growth. If treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function and marked increase of mortality. In conditions of AS or heart failure a cardiac remodelling occurs including a change in cardiac substrate utilization. However, it is difficult to determine the stage of AS-induced cardiac remodelling and therefore the reversibility of this changes after AVR. As cardiac metabolism might be therapeutic target for patients not recovering after valve replacement a better understanding of the metabolic remodelling in different AS subtypes is necessary. Metabolomics constitute a potent screening tool for defining changes in global and cardiac-specific metabolism in cardiovascular disease. Methods/Results Serum metabolomic profiling for 1293 metabolites was performed in serum samples of 40 AS-patients and 10 healthy controls using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. AS-patients were divided in four groups (10 patients/group) with respect to ejection fraction (EF, normal/reduced) and aortic valve gradient (&amp;gt; or &amp;lt;40 mmHg). Principal component analysis revealed a clear difference of metabolic profiles in AS-patients vs controls. However, less separation between AS-subtypes could be detected. A Random Forest Analysis comparing all AS-patients to healthy controls resulted in a predictive accuracy of 94%. In AS-patients we observed an increase of acyl carnitines compared to control indicating an alteration of myocardial free fatty acid oxidation. Moreover, we detected a higher ketone body concentrations in AS-patients that could serve as an alternative fuel source for the heart. Interestingly, no differences between the AS subgroups could be detected indicating that changes occur independently from EF and AS-gradient. Additionally, several compounds involved in nitrogen balance were increased in AS-patients while numerous amino acids were decreased, possibly also due to alternative energy production. Increased circulating heme catabolites have been associated with heart failure. Here, we found increased heme catabolites only in patients with low EF and high-gradient with unclear significance. Conclusion In summary, our study indicates a shift of cardiac substrate utilization in patients with AS from free fatty acid oxidation to alternative substrates like ketone bodies and amino acids. As no differences between AS subtypes were observed, this metabolic remodelling may occur as an adaptive mechanism independent from EF and AS-gradient in patients with severe AS. Since our study was conducted by an unspecific approach with a small sample size, further investigation is necessary for a better understanding of the specific myocardial metabolic changes in AS patients. Funding Acknowledgement Type of funding sources: None.

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats.

Aim: Evaluate the influence of doxycycline, an anti-inflammatory and matrix metalloproteinase (MMP) inhibitor, on the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Methods: We allocated male Wistar rats into four groups: control (C), doxorubicin (D), doxycycline (inhibitor of MMP, IM), and Dox + doxycycline (DIM). Groups IM and DIM received doxycycline (5 mg/kg, IP) once a week for 4 weeks. In addition, 48 h after every doxycycline injection, groups D and DIM received Dox (5 mg/kg, IP). We performed echocardiogram and evaluated TIMP-4 and collagen I protein expression, MMP-2 activity, and oxidative stress and myocardial metabolism. Results: Doxorubicin promotes left atrium (LA) and left ventricle (LV) dilatation and decreases in LV fractional shortening, which was improved by doxycycline. Moreover, doxycycline attenuated the LV cardiomyocyte hypertrophy and collagen type I expression. Doxorubicin increased phosphofructokinase and decreased beta-hydroxyacyl Co-A dehydrogenase, pyruvate dehydrogenase, citrate synthase, and ATP synthase activity, which was partially attenuated by doxycycline. Lastly, doxycycline improved antioxidant enzyme activity in the DIM group. Conclusion: Doxorubicin increases oxidative stress and promotes changes in myocardial energy metabolism, accompanied by structural and functional changes. Doxycycline attenuated the doxorubicin-induced cardiotoxicity, at least in part, through changes in myocardial energy metabolism.

Metabolic Regulation of Cardiac Regeneration.

The mortality due to heart diseases remains highest in the world every year, with ischemic cardiomyopathy being the prime cause. The irreversible loss of cardiomyocytes following myocardial injury leads to compromised contractility of the remaining myocardium, adverse cardiac remodeling, and ultimately heart failure. The hearts of adult mammals can hardly regenerate after cardiac injury since adult cardiomyocytes exit the cell cycle. Nonetheless, the hearts of early neonatal mammals possess a stronger capacity for regeneration. To improve the prognosis of patients with heart failure and to find the effective therapeutic strategies for it, it is essential to promote endogenous regeneration of adult mammalian cardiomyocytes. Mitochondrial metabolism maintains normal physiological functions of the heart and compensates for heart failure. In recent decades, the focus is on the changes in myocardial energy metabolism, including glucose, fatty acid, and amino acid metabolism, in cardiac physiological and pathological states. In addition to being a source of energy, metabolites are becoming key regulators of gene expression and epigenetic patterns, which may affect heart regeneration. However, the myocardial energy metabolism during heart regeneration is majorly unknown. This review focuses on the role of energy metabolism in cardiac regeneration, intending to shed light on the strategies for manipulating heart regeneration and promoting heart repair after cardiac injury.

Potential Therapeutic Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in the Context of Ischemic Heart Failure: A State-of-the-Art Review.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-diabetic agents that block the reabsorption of glucose in the proximal convoluted tubule of the nephron, thereby contributing to glycosuria and lowering blood glucose levels. SGLT2 inhibitors have been associated with improved cardiovascular outcomes in patients with diabetes, including a reduced risk of cardiovascular death and hospitalizations for heart failure. Recently, DAPA-HF and EMPEROR REDUCED trials showed the beneficial cardiovascular effect of SGLT2 inhibitors in patients with heart failure with consistently reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Moreover, some exploratory studies suggested that these drugs improve Left Ventricular (LV) systolic function and oppose LV adverse remodeling in patients with HFrEF. However, the exact mechanisms that mediated for this benefit are not fully understood. Beyond glycemic control, enhanced natriuresis, increased erythropoiesis, improved endothelial function and changes in myocardial metabolism may all play an active role in SGLT2 inhibitors' cardiovascular benefits. A deep understanding of the pathophysiological interplay is key to define which HF phenotype could benefit more from SGLT2 inhibitors. Current evidence on the comparison of different HF etiologies is limited to posthoc subgroup analysis of DAPA-HF and EMPEROR-REDUCED, which showed similar outcomes in patients with or without ischemic HF. On the other hand, in earlier studies of patients suffering from diabetes, rates of classic ischemic endpoints, such as myocardial infarction, stroke or coronary revascularization, did not differ between patients treated with SGLT2 inhibitors or placebo. The aim of this review is to discuss whether SGLT2 inhibitors may improve prognosis in patients with ischemic HF, not only in terms of reducing re-hospitalizations and improving LV function but also by limiting coronary artery disease progression and ischemic burden.

Abstract 3659: Early in vivo detection of radiation-induced cardiotoxicity

Abstract Background: Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation, which is a common treatment for malignancies like lung cancer. There is currently no standardized program for follow-up of RIHD in cancer survivors. Therefore, there is an acute need for developing detection of RIHD at a stage that offers potential for early intervention and reversibility. The gold standard for detection of global cardiac dysfunction is echocardiography. However, this current paradigm detects cardiac changes in metrics such as Left Ventricular Ejection Fraction (LVEF), which are relatively late manifestations in the pathology of cardiotoxicity, decreasing the possibility of reversing such damage. We sought to assess radiation-induced changes significantly earlier than the current standard of care by measuring the efficiency of the tricarboxylic acid cycle in cardiac mitochondria; we hypothesized that radiation leads to impaired mitochondrial function, causing increased conversion of pyruvate to lactate in the cytosol and decreased conversion in the mitochondria. In order to non-invasively measure this impairment, we utilized Magnetic Resonance Spectroscopy (MRS) to track the fate of hyperpolarized (HP) C-13 pyruvate. Methods: Sprague-Dawley rats underwent baseline and post treatment echocardiography and HP C-13 pyruvate MRS at multiple timepoints. Half of the animals underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions, a paradigm similar to a common dose given to lung cancer patients. Results: In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac function (determined by bicarbonate-to-lactate ratio in myocardial mitochondria) compared to pre-radiation baseline (p=0.02, one-tailed paired t-test) as early as 1 week post treatment. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (p=0.95). Comparatively, no significant changes in LVEF or global longitudinal strain were observed in either the cardiac irradiation or control group of rats until 2 months post treatment. Conclusion: Radiation-induced myocardial mitochondrial dysfunction is an early event that can be characterized and detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation prior to onset of echocardiographic changes. For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. This technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually. Citation Format: Jayesh Sharma, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, Jaemo Park, Craig Malloy, Vlad Zaha, Prasanna Alluri. Early in vivo detection of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3659.

Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart

Cardiac contractile strength is recognised as being highly pH-sensitive, but less is known about the influence of pH on cardiac gene expression, which may become relevant in response to changes in myocardial metabolism or vascularization during development or disease. We sought evidence for pH-responsive cardiac genes, and a physiological context for this form of transcriptional regulation. pHLIP, a peptide-based reporter of acidity, revealed a non-uniform pH landscape in early-postnatal myocardium, dissipating in later life. pH-responsive differentially expressed genes (pH-DEGs) were identified by transcriptomics of neonatal cardiomyocytes cultured over a range of pH. Enrichment analysis indicated “striated muscle contraction” as a pH-responsive biological process. Label-free proteomics verified fifty-four pH-responsive gene-products, including contractile elements and the adaptor protein CRIP2. Using transcriptional assays, acidity was found to reduce p300/CBP acetylase activity and, its a functional readout, inhibit myocardin, a co-activator of cardiac gene expression. In cultured myocytes, acid-inhibition of p300/CBP reduced H3K27 acetylation, as demonstrated by chromatin immunoprecipitation. H3K27ac levels were more strongly reduced at promoters of acid-downregulated DEGs, implicating an epigenetic mechanism of pH-sensitive gene expression. By tandem cytoplasmic/nuclear pH imaging, the cardiac nucleus was found to exercise a degree of control over its pH through Na+/H+ exchangers at the nuclear envelope. Thus, we describe how extracellular pH signals gain access to the nucleus and regulate the expression of a subset of cardiac genes, notably those coding for contractile proteins and CRIP2. Acting as a proxy of a well-perfused myocardium, alkaline conditions are permissive for expressing genes related to the contractile apparatus.

Strategies for Imaging Metabolic Remodeling of the Heart in Obesity and Heart Failure.

Define early myocardial metabolic changes among patients with obesity and heart failure, and to describe noninvasive methods and their applications for imaging cardiac metabolic remodeling. Metabolic remodeling precedes, triggers, and sustains functional and structural remodeling in the stressed heart. Alterations in cardiac metabolism can be assessed by using a variety of molecular probes. The glucose tracer analog, 18F-FDG, and the labeled tracer 11C-palmitate are still the most commonly used tracers to assess glucose and fatty acid metabolism, respectively. The development of new tracer analogs and imaging agents, including those targeting the peroxisome proliferator-activated receptor (PPAR), provides new opportunities for imaging metabolic activities at a molecular level. While the use of cardiac magnetic resonance spectroscopy in the clinical setting is limited to the assessment of intramyocardial and epicardial fat, new technical improvements are likely to increase its usage in the setting of heart failure. Noninvasive imaging methods are an effective tool for the serial assessment of alterations in cardiac metabolism, either during disease progression, or in response to treatment.

Combined Cardiac Fluorodeoxyglucose–Positron Emission Tomography/Magnetic Resonance Imaging Assessment of Myocardial Injury in Patients Who Recently Recovered From COVID-19

Although myocardial injury can occur with acute COVID-19, there is limited understanding of changes with myocardial metabolism in recovered patients. To examine myocardial metabolic changes early after recovery from COVID-19 using fluorodeoxyglucose-positron emission tomography (PET) and associate these changes to abnormalities in cardiac magnetic resonance imaging (MRI)-based function and tissue characterization measures and inflammatory blood markers. This prospective cohort study took place at a single-center tertiary referral hospital system. A volunteer sample of adult patients within 3 months of a diagnosis of COVID-19 who responded to a mail invitation were recruited for cardiac PET/MRI and blood biomarker evaluation between November 2020 and June 2021. Myocardial inflammation as determined by focal fluorodeoxyglucose (FDG) uptake on PET. Demographic characteristics, cardiac and inflammatory blood markers, and fasting combined cardiac 18F-FDG PET/MRI imaging were obtained. All patients with focal FDG uptake at baseline returned for repeated PET/MRI and blood marker assessment 2 months later. Of 47 included patients, 24 (51%) were female, and the mean (SD) age was 43 (13) years. The mean (SD) interval between COVID-19 diagnosis and PET/MRI was 67 (16) days. Most patients recovered at home during the acute infection (40 [85%]). Eight patients (17%) had focal FDG uptake on PET consistent with myocardial inflammation. Compared with those without FDG uptake, patients with focal FDG uptake had higher regional T2, T1, and extracellular volume (colocalizing with focal FDG uptake), higher prevalence of late gadolinium enhancement (6 of 8 [75%] vs 9 of 39 [23%], P = .009), lower left ventricular ejection fraction (mean [SD], 55% [4%] vs 62% [5%], P < .001), worse global longitudinal and circumferential strain (mean [SD], -16% [2%] vs -17% [2%], P = .02 and -18% [2%] vs -20% [2%], P = .047, respectively), and higher systemic inflammatory blood markers including interleukin 6, interleukin 8, and high-sensitivity C-reactive protein. Among patients with focal FDG uptake, PET/MRI, and inflammatory blood markers resolved or improved at follow-up performed a mean (SD) of 52 (17) days after baseline PET/MRI. In this study of patients recently recovered from COVID-19, myocardial inflammation was identified on PET in a small proportion of patients, was associated with cardiac MRI abnormalities and elevated inflammatory blood markers at baseline, and improved at follow-up.

Serial change in perfusion\u2013metabolism mismatch after coronary artery bypass grafting

ObjectiveMyocardial ischemia is known to suppress fatty acid metabolism and favor glucose metabolism. However, changes in myocardial metabolism after coronary revascularization are not fully elucidated.MethodsThirty-eight patients with coronary artery disease were retrospectively enrolled. These patients had undergone stress perfusion single photon emission computed tomography (SPECT) and 123I-BMIPP SPECT in both the short-term (6.4 ± 4.7 months) and mid-term (29.9 ± 7.2 months) after isolated coronary artery bypass grafting. Tracer uptake was graded using a 17-segment, 5-point scoring model. Serial changes in SRS (summed rest score), SDS (summed difference score), the BMIPP score (total defect score of BMIPP), and the mismatch score (BMIPP score–SRS) were evaluated. In addition, persistent perfusion–metabolism mismatch (PM) was defined as mismatch score minus SDS of 3 or more during the mid-term postoperative period. The clinical parameters associated with PM were examined.ResultsFrom short- to mid-term postoperative period, the extent of infarcted myocardium (SRS) did not change significantly (7.8 ± 8.0 to 7.1 ± 7.0, P = 0.117). The extent of ischemic myocardium (SDS), the BMIPP score and the mismatch score, which reflects perfusion–metabolism mismatch, were significantly improved (2.0 ± 2.8 to 0.7 ± 1.0, P = 0.010; 12.2 ± 9.0 to 9.5 ± 7.9, P < 0.001; 4.4 ± 3.7 to 2.5 ± 2.6, P < 0.001; respectively). Remarkably, perfusion–metabolism mismatch persisted in 13 patients (34%) even in the mid-term postoperative period. eGFR and SYNTAX score were independent predictors of persistent perfusion–metabolic mismatch in multivariable analysis (OR = 0.951, 95% CI 0.898–0.985, P = 0.010 and OR = 1.126, 95% CI 1.011–1.254, P = 0.031, respectively). The mismatch score both in the short- and mid-term significantly correlated with SYNTAX score (r = 0.400 and r = 0.472, respectively).ConclusionsFatty acid metabolism disturbance improved from short- to mid-term postoperative period in patients with successful reperfusion by coronary artery bypass grafting. However, in patients with severe atherosclerosis, impaired fatty acid metabolism was sustained until the mid-term postoperative period, even though ischemia had resolved.

Metformin Prevents Low-dose Isoproterenol-induced Cardiac Dilatation and Systolic Dysfunction in Male Sprague Dawley Rats.

Myocardial metabolic abnormalities are well-recognized alterations in chronic heart failure, effects that may contribute to progressive cardiac dysfunction. However, whether metabolic alterations in-part mediate their deleterious effects by modifying the chronic impact of excess low-dose sympathetic stimulation on cardiac chamber dilatation is uncertain. We therefore aimed to determine the effect of metformin administration on cardiac function and mitochondrial architectural changes in a rat model of chronic sympathetic-induced left ventricular (LV) remodeling and systolic dysfunction [daily subcutaneous isoproterenol (ISO) injection at a low dose of 0.02 mg/kg for 7 months]. Echocardiography was used to assess in vivo LV dimensions and function, and mitochondrial and myofibril arrangement was assessed using transmission electron microscopy. Seven months of low-dose ISO administration increased LV diastolic diameter (in mm) [control (CONT): 7.29 ± 0.19 vs. ISO: 8.76 ± 0.21; P = 0.001], an effect that was attenuated by metformin (ISO + MET: 7.63 ± 0.29 vs. ISO: P = 0.001) administration. Similarly, ISO increased LV end-systolic diameter (CONT: 4.43 ± 0.16 vs. ISO: 5.49 ± 0.16: P < 0.0001), an effect prevented by metformin (ISO + MET: 4.04 ± 0.25 vs. ISO: P < 0.0001). Moreover, chronic ISO administration reduced LV endocardial fractional shortening (P = 0.0001), midwall fractional shortening (P = 0.0001), and ejection fraction (P = 0.0001), effects similarly prevented by metformin administration. Furthermore, changes in mitochondrial arrangement and relative mitochondrial area (CONT: 37.7 ± 2.2 vs. ISO: 28.1 ± 2.9; P = 0.05) were produced by ISO administration, effects prevented by metformin. In conclusion, metformin offers cardiac protection against chronic sympathetic-induced LV dilatation and systolic dysfunction. These data support a role for myocardial metabolic changes in mediating LV dilatation and LV dysfunction produced by chronic neurohumoral activation in cardiac disease.

Early In Vivo Detection of Radiation-Induced Cardiotoxicity With Hyperpolarized C-13 Pyruvate Magnetic Resonance Spectroscopy

Radiation therapy is commonly used for treatment of patients with intrathoracic malignancies, such as lung cancer, esophageal cancer, and lymphoma. Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation. Therefore, there is an acute need for development of non-invasive approaches for detection of RIHD at a stage that offers potential for early intervention and reversibility. Cardiac mitochondrial dysfunction is a hallmark of radiation-induced cardiac injury. During aerobic respiration, pyruvate enters the tricarboxylic acid cycle and is metabolized into bicarbonate in mitochondria. We hypothesized that radiation-induced mitochondrial dysfunction results in decreased conversion of pyruvate to bicarbonate in the mitochondria and increased conversion to lactate in cytosol. We sought to non-invasively assess radiation-induced changes in mitochondrial myocardial metabolism by tracking the fate of hyperpolarized (HP) C-13 pyruvate utilization using Magnetic Resonance Spectroscopy (MRS).Sprague-Dawley rats (n = 10) underwent baseline echocardiography and HP C-13 pyruvate MRS. Rats in the cardiac radiation group (n = 5) underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions. All rats underwent repeat echocardiography and hyperpolarized C-13 pyruvate MRS one week later.For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac bicarbonate-to-lactate ratio compared to pre-radiation baseline (P = 0.02, one-tailed paired t-test), suggesting increased metabolism of pyruvate into lactate in the cytoplasm (at the expense of metabolism into bicarbonate in the mitochondria) due to mitochondrial dysfunction. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (P = 0.90). No significant changes in left ventricular ejection fraction or global longitudinal strain were observed in either the cardiac irradiation or control group of rats at this time point.Radiation-induced myocardial mitochondrial dysfunction is an early event and can be detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation, and prior to onset of echocardiographic changes. Due to its non-invasive nature, this technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually.

Pera orange (Citrus sinensis) and Moro orange (Citrus sinensis (L.) Osbeck) juices attenuate left ventricular dysfunction and oxidative stress and improve myocardial energy metabolism in acute doxorubicin-induced cardiotoxicity in rats

ObjectivesDoxorubicin is a highly effective chemotherapeutic agent for treating several types of cancer; however, it can induce cardiotoxicity. We evaluated the influence of Pera and Moro orange juices on cardiac remodeling induced by acute administration of doxorubicin in rats. MethodsWe allocated 120 male Wistar rats into six groups: control (C), Pera orange juice (PO), Moro orange juice (MO), doxorubicin (D), doxorubicin + Pera orange juice (DPO), and doxorubicin + Moro orange juice (DMO). Groups PO and DPO received Pera orange juice, MO and DMO received Moro orange juice, and C and D received water with maltodextrin (100 g/L) for 4 wk. Subsequently, groups D, DPO, and DMO received 20 mg/kg doxorubicin and C, PO, and MO received saline. Echocardiogram and euthanasia were performed 48 h after doxorubicin injection. Juice and animal-serum flavonoid identification and quantification were evaluated by liquid chromatography/electrospray ionization multistage mass spectrometry. Oxidative stress and myocardial metabolism were evaluated by spectrophotometry. ResultsSystolic and diastolic left ventricular dysfunction increased oxidative stress and pathologic changes in myocardial energy metabolism of rats treated with doxorubicin. Intake of both orange juices improved left ventricular function, decreased oxidative stress, and attenuated the myocardial energy metabolism changes. Moro orange juice had a more pronounced effect than Pera orange juice in glutathione peroxidase activity, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activity. ConclusionsPera and Moro orange juices attenuated cardiac remodeling induced by doxorubicin, improved myocardial energy metabolism, and attenuated oxidative stress. However, Moro orange juice was more effective than Pera orange juice in modifying energy metabolism.

Dynamic FDG PET Imaging to Probe for Cardiac Metabolic Remodeling in Adults Born Premature.

Individuals born very premature have an increased cardiometabolic and heart failure risk. While the structural differences of the preterm heart are now well-described, metabolic insights into the physiologic mechanisms underpinning this risk are needed. Here, we used dynamic fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET-MRI) in young adults born term and preterm during normoxic (N = 28 preterm; 18 term) and hypoxic exposure (12% O2; N = 26 preterm; 17 term) to measure the myocardial metabolic rate of glucose (MMRglc) in young adults born term (N = 18) and preterm (N = 32), hypothesizing that young adults born preterm would have higher rates of MMRglc under normoxic conditions and a reduced ability to augment glucose metabolism under hypoxic conditions. MMRglc was calculated from the myocardial and blood pool time-activity curves by fitting the measured activities to the 3-compartment model of FDG kinetics. MMRglc was similar at rest between term and preterm subjects, and decreased during hypoxia exposure in both groups (p = 0.02 for MMRglc hypoxia effect). There were no differences observed between groups in the metabolic response to hypoxia, either globally (serum glucose and lactate measures) or within the myocardium. Thus, we did not find evidence of altered myocardial metabolism in the otherwise healthy preterm-born adult. However, whether subtle changes in myocardial metabolism may preceed or predict heart failure in this population remains to be determined.

Variations in Energy Metabolism Precede Alterations in Cardiac Structure and Function in Hypertrophic Preconditioning.

Recent studies have unveiled that myocardial hypertrophic preconditioning (HP), which is produced by de-banding (De-TAC) of short-term transverse aortic constriction (TAC), protects the heart against hypertrophic responses caused by subsequent re-constriction (Re-TAC) in mice. Although cardiac substrate metabolism is impaired in heart failure, it remains unclear about the role of HP-driven energetics in the development of cardiac hypertrophy. Here, we investigated energy metabolism, cardiac hypertrophy, and function following variational loading conditions, as well as their relationships in HP. Male C57BL/6J mice (10–12 weeks old) were randomly subjected to Sham, HP [TAC for 3days (TAC 3d), de-banding the aorta for 4 days (De-TAC 4d), and then re-banding the aorta for 4 weeks (Re-TAC 4W)], and TAC (TAC for 4 weeks without de-banding). Cardiac echocardiography, hemodynamics, and histology were utilized to evaluate cardiac remodeling and function. The mRNA expression levels of fetal genes (ANP and BNP), glucose metabolism-related genes (glut4, pdk4), and fatty acid oxidation-related genes (mcad, pgc1α, mcd, pparα) were quantitated by real-time quantitative PCR. Activation of hypertrophy regulators ERK1/2, a metabolic stress kinase AMP-activated protein kinase (AMPK), and its downstream target acetyl-coA carboxylase (ACC) were explored by western blot. Compared with TAC 4W mice, Re-TAC 4W mice showed less impairment in glucose and fatty acid metabolism, as well as less cardiac hypertrophy and dysfunction. Moreover, no significant difference was found in myocardial hypertrophy, fibrosis, and cardiac function in TAC 3d and De-TAC 4d groups compared with Sham group. However, glut4, pdk4, mcad, pgc1α, mcd, and pparα were all decreased, while AMPK and ACC were activated in TAC 3d and returned to Sham level in De-TAC 4d, suggesting that the change in myocardial energy metabolism in HP mice was earlier than that in cardiac structure and function. Collectively, HP improves energy metabolism and delays cardiac remodeling, highlighting that early metabolic improvements drive a potential beneficial effect on structural and functional restoration in cardiac hypertrophy.

Abstract 16538: Circulating Ketone Levels are Associated With Myocardial Infarct Size and Left Ventricular Function in Patients Presenting With St-Elevation Myocardial Infarction

Background: Circulating ketone bodies (KB) are increased in patients with heart failure, corresponding with increased utilization of KB as a cardiac fuel. Whether circulating KB are increased in patients presenting with ST-elevation myocardial infarction (STEMI) and whether this is associated with infarct size is unknown. Methods: KB were measured in 379 non-diabetic participants of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (GIPS) III trial (Clinicaltrial.gov Identifier: NCT01217307). Non-fasting plasma concentrations of the KB beta-hydroxybutyrate, acetoacetate, acetone were measured at presentation, 24 hours and 4 months after STEMI presentation using nuclear magnetic resonance spectroscopy. Associations of circulating KB with myocardial infarct size and left ventricular ejection fraction (both detected with MRI at 4 months after STEMI) were determined using multivariable linear regression analyses. Results: Circulating KB were higher at baseline (total KB 520 [315-997](median [IQR], μmol/L), compared to 206 [174-246] at 24 hours and 166 [143-201] at 4 months ( P &lt;0.001 for all)). KB at 24 hours were positively associated with enzymatic infarct size, HbA1C and beta-blocker use. KB at 24 hours were independently associated with MRI outcomes at 4 months. Higher KB was associated with larger myocardial infarct size (total KB: standardized β=0.17, 95%-confidence interval (CI) (0.04-0.31), P =0.012) and lower ejection fraction (standardized β=-0.15, 95%-CI (-0.29- -0.009), P =0.037). Conclusion: Circulating KB are increased in patients with STEMI and are independently associated with myocardial infarct size and left ventricular function after 4 months of follow-up. The increase in circulating KB may reflect maladaptive changes of myocardial metabolism during the acute phase.

Energy Metabolism in Exercise-Induced Physiologic Cardiac Hypertrophy.

Physiologic hypertrophy of the heart preserves or enhances systolic function without interstitial fibrosis or cell death. As a unique form of physiological stress, regular exercise training can trigger the adaptation of cardiac muscle to cause physiological hypertrophy, partly due to its ability to improve cardiac metabolism. In heart failure (HF), cardiac dysfunction is closely associated with early initiation of maladaptive metabolic remodeling. A large amount of clinical and experimental evidence shows that metabolic homeostasis plays an important role in exercise training, which is conducive to the treatment and recovery of cardiovascular diseases. Potential mechanistic targets for modulation of cardiac metabolism have become a hot topic at present. Thus, exploring the energy metabolism mechanism in exercise-induced physiologic cardiac hypertrophy may produce new therapeutic targets, which will be helpful to design novel effective strategies. In this review, we summarize the changes of myocardial metabolism (fatty acid metabolism, carbohydrate metabolism, and mitochondrial adaptation), metabolically-related signaling molecules, and probable regulatory mechanism of energy metabolism during exercise-induced physiological cardiac hypertrophy.