The relation between induced increases in cardiac work and phosphate metabolites was investigated in the canine heart in vivo to evaluate the role of ATP hydrolysis products, ADP and inorganic phosphate (Pi), in the control of myocardial oxygen consumption (MVO2). In these studies, myocardial blood flow and oxygen consumption were simultaneously measured with the 31P-nuclear magnetic resonance (NMR)-detected phosphate metabolites. Three protocols were used to increase myocardial work: pacing, epinephrine, and phenylephrine infusions. When these protocols were used, no or only slight changes in myocardial ATP, Pi, and creatine phosphate were observed with a greater than threefold increase in MVO2. The calculated intracellular free Mg concentration, ADP, and pH were also only slightly affected by these increases in work. These data indicate that a simple model involving the feedback of cytosolic ADP and Pi to the mitochondria regulating respiration is inadequate to explain respiratory control in vivo. These data suggest that some other parameters or cooperativity effects involving the phosphate metabolites must play a role in the feedback between respiration and work in the heart in vivo.

The goal of this study was to test the hypothesis that the relative amounts of the cardiac myosin heavy chain (MHC) isoforms MHC-alpha and MHC-beta change during development and transition to heart failure in the human myocardium. The relative amounts of MHC-alpha and MHC-beta in ventricular and atrial samples from fetal (gestational days 47--110) and nonfailing and failing adult hearts were determined. The majority of the fetal right and left ventricular samples contained small relative amounts of MHC-alpha (mean < 5% of total MHC). There was a small significant decrease in the level of MHC-alpha in the ventricles between 7 and 12 wk of gestation. Fetal atria expressed predominantly MHC-alpha (mean > 95%), with MHC-beta being detected in most samples. The majority of adult nonfailing right and left ventricular samples had detectable levels of MHC-alpha ranging from 1 to 10%. Failing right and left ventricles expressed a significantly lower level of MHC-alpha. MHC-alpha comprised approximately 90% of the total MHC in adult nonfailing left atria, whereas the relative amount of MHC-alpha in the left atria of individuals with dilated or ischemic cardiomyopathy was approximately 50%. The differences in MHC isoform composition between fetal and nonfailing adult atria and between fetal and nonfailing adult ventricles were not statistically significant. We concluded that the MHC isoform compositions of fetal human atria are the same as those of nonfailing adult atria and that the ventricular MHC isoform composition is different between adult nonfailing and failing hearts. Furthermore, the marked alteration in atrial MHC isoform composition, associated with cardiomyopathy, does not represent a regression to a pattern that is uniquely characteristic of the fetal stage.

Background: Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccination has important public health implications in the decision to vaccinate youth. Methods: We retrospectively collected data on patients <21 years-old presenting before 7/4/2021 with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac magnetic resonance imaging (cMRI) findings. Myocarditis cases were classified as confirmed or probable based on the Centers for Disease Control and Prevention definitions. Results: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (N=126, 90.6%) and White (N=92, 66.2%); 29 (20.9%) were Hispanic; and median age was 15.8 years (range 12.1-20.3, IQR 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the 2nd dose. Symptoms started a median of 2 days (range 0-22, IQR 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the ICU, two were treated with inotropic/vasoactive support, and none required ECMO or died. Median hospital stay was 2 days (range 0-10, IQR 2-3). All patients had elevated troponin I (N=111, 8.12 ng/mL, IQR 3.50-15.90) or T (N=28, 0.61 ng/mL, IQR 0.25-1.30); 69.8% had abnormal electrocardiograms and/or arrythmias (7 with non-sustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction (LVEF) <55% on echocardiogram. Of 97 patients who underwent cMRI at median 5 days (range 0-88, IQR 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with LVEF <55% on echocardiogram, all with follow-up had normalized function (N=25). Conclusions:Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cMRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Objectives-The goals of this study were to determine the role of OCT3 in the pharmacologic action of metformin and to identify and functionally characterize genetic variants of OCT3 with respect to the uptake of metformin and monoamines.Methods-For the pharmacologic studies, we evaluated metformin-induced activation of AMPK, a molecular target of metformin. We used quantitative PCR and immunostaining to localize the transporter and isotopic uptake studies in cells transfected with OCT3 and its nonsynonymous genetic variants for functional analyses.Results-Quantitative PCR and immunostaining showed that OCT3 was expressed high on the plasma membrane of skeletal muscle and liver, target tissues for metformin action. Both the OCT inhibitor, cimetidine, and OCT3-specific shRNA significantly reduced the activating effect of metformin on AMPK. To identify genetic variants in OCT3, we used recent data from the 1000 Genomes Project and the Pharmacogenomics of Membrane Transporters project. Six novel missense variants were identified. In functional assays, using various monoamines and metformin, 3 variants, T44M (c.131C>T), T400I (c.1199C>T) and V423F (c.1267G>T), showed altered substrate specificity. Notably, in cells expressing T400I and V423F, the uptakes of metformin and catecholamines were significantly reduced but the uptakes of metformin, MPP+ and histamine by T44M were significantly increased more than 50%. Structural modeling suggested that these two variants may be located in the pore-lining (T400) or proximal (V423) membrane-spanning helixes.Conclusion-Our study suggests that OCT3 plays a role in the therapeutic action of metformin and that genetic variants of OCT3 may modulate metformin and catecholamine action.

In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1α levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart’s needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on “Assessing Cardiac Metabolism” seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity.

This study demonstrates that although anomalous origins of coronary arteries are rare in asymptomatic children, the prevalence is greater than that found in other prospective studies. Ischemia can occur with both ALMCA and ARCA even though patients remain asymptomatic. Because of the high risk of sudden cardiac death, aggressive surgical management and close follow-up are necessary.

preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H786-H793, 1998.-Hypothermia is known to protect myocardium during ischemia, but its role in induction of a protective stress response before ischemia has not been evaluated. As cold incites stress responses in other tissues, including heat shock protein induction and signaling mitochondrial biogenesis, we postulated that hypothermia in perfused hearts would produce similar phenomena while reducing injury during subsequent ischemia. Studies were performed in isolated perfused rabbit hearts (n ϭ 77): a control group (C) and a hypothermic group (H) subjected to decreasing infusate temperature from 37 to 31°C over 20 min. Subsequent ischemia during cardioplegic arrest at 34°C for 120 min was followed by reperfusion. At 15 min of reperfusion, recovery of left ventricular developed pressure (LVDP), maximum first derivative of left ventricular pressure (LV dP/dt max ), LV ϪdP/dt max , and the product of heart rate and LVDP was significantly increased in H (P Ͻ 0.01) compared with C hearts. Ischemic contracture started later in H (97.5 Ϯ 3.6 min) than in C (67.3 Ϯ 3.3 min) hearts. Myocardial ATP preservation and repletion during ischemia and reperfusion were higher in H than in C hearts. mRNA levels of the nuclear-encoded mitochondrial proteins adenine nucleotide translocase isoform 1 (ANT 1 ) and ␤-F 1 -adenosinetriphosphatase (␤-F 1 -ATPase) normalized to 28S RNA decreased in C hearts but were preserved in H hearts after reperfusion. Inducible heat shock protein (HSP70-1) mRNA was elevated nearly 4-fold after ischemia in C hearts and 12-fold in H hearts. These data indicate that hypothermia preserves myocardial function and ATP stores during subsequent ischemia and reperfusion. Signaling for mitochondrial biogenesis indexed by ANT 1 and ␤-F 1 -ATPase mRNA levels is also preserved during a marked increase in HSP70-1 mRNA.adenine nucleotide translocase isoform 1; ␤-F 1 -adenosinetriphosphatase; cold adaptation; inducible heat shock protein; myocardial reperfusion COLD-INDUCED STRESS is a phenomenon associated with an increase in inducible heat shock protein expression in various tissues (31,32). Particularly in brown adipose tissue, cold-induced stress or hypothermia also induces mitochondrial biogenesis (20,29,30). At the transcriptional level this is characterized by coordinated increases in expression of nuclear-and mitochondrial-encoded genes regulating mitochondrial membrane proteins (28). Although this signaling has been well characterized in brown adipose fat, it remains relatively unexplored in other mammalian tissues. This is surprising because stress responses in the heart secondary to heat shock or ischemia have been a major focus of investigation with respect to enhancement of tissue resistance to subsequent ischemia (14,21,33,35,40). Furthermore, hypothermia either singly or accompanied by cardioplegia is regularly employed in myocardial protection during heart surgery. T...