Myocardial Substrate Use Research Articles

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction

BackgroundMyocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size. ObjectivesGiven the central importance of mitochondria in reperfusion injury, we hypothesized that compared with immediate reperfusion (IR), LV unloading before reperfusion improves myocardial energy substrate use and preserves mitochondrial structure and function. MethodsTo explore the effect of LV unloading duration on infarct size, we analyzed data from the STEMI-Door to Unload (STEMI-DTU) trial and then tested the effect of LV unloading on ischemia and reperfusion injury, cardiac metabolism, and mitochondrial function in swine models of acute myocardial infarction. ResultsThe duration of LV unloading before reperfusion was inversely associated with infarct size in patients with large anterior STEMI. In preclinical models, LV unloading reduced the expression of hypoxia-sensitive proteins and myocardial damage due to ischemia alone. LV unloading with a transvalvular pump (TV-P) but not with venoarterial extracorporeal membrane oxygenation (ECMO) reduced infarct size. Using unbiased and blinded metabolic profiling, TV-P improved myocardial energy substrate use and preserved mitochondrial structure including cardiolipin content after reperfusion compared with IR or ECMO. Functional testing in mitochondria isolated from the infarct zone showed an intact mitochondrial structure including cardiolipin content, preserved activity of the electron transport chain including mitochondrial complex I, and reduced oxidative stress with TV-P–supported reperfusion but not with IR or ECMO. ConclusionsThese novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion.

TrimetaziDine as aPerformance-enhancING drug in heart failure with preserved ejection fraction (DoPING-HFpEF): rationale and design of aplacebo-controlled cross-over intervention study.

BackgroundCurrently, no specific treatment exists for heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) relaxation during diastole is a highly energy-demanding process, while energy homeostasis is known to be compromised in HFpEF. We hypothesise that trimetazidine – a fatty acid β‑oxidation inhibitor – improves LV diastolic function in HFpEF, by altering myocardial substrate use and improving the myocardial energy status.ObjectivesTo assess whether trimetazidine improves LV diastolic function by improving myocardial energy metabolism in HFpEF.MethodsThe DoPING-HFpEF trial is a randomised, double-blind, placebo-controlled cross-over intervention trial comparing the efficacy of trimetazidine and placebo in 25 patients with stable HFpEF. The main inclusion criteria are: New York Heart Association functional class II to IV, LV ejection fraction ≥50%, and evidence of LV diastolic dysfunction. Patients are treated with one 20-mg trimetazidine tablet or placebo thrice daily (twice daily in the case of moderate renal dysfunction) for two periods of 3 months separated by a 2-week washout period. The primary endpoint is the change in pulmonary capillary wedge pressure during different intensities of exercise measured by right heart catheterisation. Our key secondary endpoint is the myocardial phosphocreatine (PCr)/ATP ratio measured by phosphorus-31 magnetic resonance spectroscopy and its relation to the primary endpoint. Exploratory endpoints are 6‑min walk distance, N-terminal pro-brain natriuretic peptide levels, and quality of life.ConclusionThe DoPING-HFpEF is a phase-II trial that evaluates the effect of trimetazidine, a metabolic modulator, on diastolic function and myocardial energy status in HFpEF. [EU Clinical Trial Register: 2018-002170-52; NTR registration: NL7830]

Different physiological mechanisms underlie an adverse cardiovascular disease risk profile in men and women.

CVD affect about one-third of the population and are the leading cause of mortality. The prevalence of CVD is closely linked to the prevalence of obesity because obesity is commonly associated with metabolic abnormalities that are important risk factors for CVD, including insulin resistance, pre-diabetes, and type-2 diabetes, atherosclerotic dyslipidaemia, endothelial dysfunction and hypertension. Women have a more beneficial traditional CVD risk profile (lower fasting plasma glucose, less atherogenic lipid profile) and a lower absolute risk for CVD than men. However, the relative risk for CVD associated with hyperglycaemia and dyslipidaemia is several-fold higher in women than in men. The reasons for the sex differences in CVD risk associated with metabolic abnormalities are unclear but could be related to differences in the mechanisms that cause hyperglycaemia and dyslipidaemia in men and women, which could influence the pathogenic processes involved in CVD. In the present paper, we review the influence of a person's sex on key aspects of metabolism involved in the cardiometabolic disease process, including insulin action on endogenous glucose production, tissue glucose disposal, and adipose tissue lipolysis, insulin secretion and insulin plasma clearance, postprandial glucose, fatty acid, and triglyceride kinetics, hepatic lipid metabolism and myocardial substrate use. We conclude that there are marked differences in many aspects of metabolism in men and women that are not all attributable to differences in the sex hormone milieu. The mechanisms responsible for these differences and the clinical implications of these observations are unclear and require further investigation.

Testosterone deficiency reduces cardiac hypertrophy in a rat model of severe volume overload.

The aim of the study was to characterize if the development of cardiac hypertrophy (CH) caused by severe left ventricle (LV) volume overload (VO) from chronic aortic valve regurgitation (AR) in male rats was influenced by androgens. We studied Wistar rats with/without orchiectomy (Ocx) either sham‐operated (S) or with severe AR for 26 weeks. Loss of testosterone induced by Ocx decreased general body growth. Cardiac hypertrophy resulting from AR was relatively more important in intact (non‐Ocx) animals than in Ocx ones compared to their respective S group (60% vs. 40%; P = 0.019). The intact AR group had more LV dilation, end‐diastolic LV diameter being increased by 37% over S group and by 17% in AROcx rats (P < 0.0001). Fractional shortening (an index of systolic function) decreased only by 15% in AROcx compared to 26% for intact AR animals (P = 0.029). Changes in LV gene expression resulting from CH were more marked in intact rats than in AROcx animals, especially for genes linked to extracellular matrix remodeling and energy metabolism. The ratio of hydroxyacyl‐Coenzyme A dehydrogenase activity over hexokinase activity, an index of the shift of myocardial substrate use toward glucose from the preferred fatty acids, was significantly decreased in the AR group but not in AROcx. Finally, pJnk2 LV protein content was more abundant in AR than in AROcx rats, indicating decreased activation of this stress pathway in the absence of androgens. In summary, testosterone deficiency in rats with severe LV VO resulted in less CH and a normalization of the LV gene expression profile.

April 2017 at a glance: cardiomyopathies and clinical trials

April 2017 at a glance: cardiomyopathies and clinical trials

Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis.

Iron replacement improves clinical status in iron-deficient patients with heart failure (HF), but the pathophysiology is poorly understood. Iron is essential not only for erythropoiesis, but also for cellular bioenergetics. The impact of myocardial iron deficiency (MID) on mitochondrial function, measured directly in the failing human heart, is unknown. Left ventricular samples were obtained from 91 consecutive HF patients undergoing transplantation and 38 HF-free organ donors (controls). Total myocardial iron content, mitochondrial respiration, citric acid cycle and respiratory chain enzyme activities, respiratory chain components (complex I-V), and protein content of reactive oxygen species (ROS)-protective enzymes were measured in tissue homogenates to quantify mitochondrial function. Myocardial iron content was lower in HF compared with controls (156 ± 41 vs. 200 ± 38 µg·g-1 dry weight, P < 0.001), independently of anaemia. MID (the lowest iron tercile in HF) was associated with more extensive coronary disease and less beta-blocker usage compared with non-MID HF patients. Compared with controls, HF patients displayed reduced myocardial oxygen2 respiration and reduced activity of all examined mitochondrial enzymes (all P < 0.001). MID in HF was associated with preserved activity of respiratory chain enzymes but reduced activity of aconitase and citrate synthase (by -26% and -15%, P < 0.05) and reduced expression of catalase, glutathione peroxidase, and superoxide dismutase 2. Myocardial iron content is decreased and mitochondrial functions are impaired in advanced HF. MID in HF is associated with diminished citric acid cycle enzyme activities and decreased ROS-protecting enzymes. MID may contribute to altered myocardial substrate use and to worsening of mitochondrial dysfunction that exists in HF.

Longitudinal Evaluation of Left Ventricular Substrate Metabolism, Perfusion, and Dysfunction in the Spontaneously Hypertensive Rat Model of Hypertrophy Using Small-Animal PET/CT Imaging

Myocardial metabolic and perfusion imaging is a vital tool for understanding the physiologic consequences of heart failure. We used PET imaging to examine the longitudinal kinetics of (18)F-FDG and 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) as analogs of glucose and fatty acid (FA) to quantify metabolic substrate shifts with the spontaneously hypertensive rat (SHR) as a model of left ventricular hypertrophy (LVH) and failure. Myocardial perfusion and left ventricular function were also investigated using a newly developed radiotracer (18)F-fluorodihydrorotenol ((18)F-FDHROL). Longitudinal dynamic electrocardiogram-gated small-animal PET/CT studies were performed with 8 SHR and 8 normotensive Wistar-Kyoto (WKY) rats over their life cycle. We determined the myocardial influx rate constant for (18)F-FDG and (18)F-FTHA (Ki(FDG) and Ki(FTHA), respectively) and the wash-in rate constant for (18)F-FDHROL (K1(FDHROL)). (18)F-FDHROL data were also used to quantify left ventricular ejection fraction (LVEF) and end-diastolic volume (EDV). Blood samples were drawn to independently measure plasma concentrations of glucose, insulin, and free fatty acids (FFAs). Ki(FDG) and Ki(FTHA) were higher in SHRs than WKY rats (P < 3 × 10(-8) and 0.005, respectively) independent of age. A decrease in Ki(FDG) with age was evident when models were combined (P = 0.034). The SHR exhibited higher K1(FDHROL) (P < 5 × 10(-6)) than the control, with no age-dependent trends in either model (P = 0.058). Glucose plasma concentrations were lower in SHRs than controls (P < 6 × 10(-12)), with an age-dependent rise for WKY rats (P < 2 × 10(-5)). Insulin plasma concentrations were higher in SHRs than controls (P < 3 × 10(-3)), with an age-dependent decrease when models were combined (P = 0.046). FFA levels were similar between models (P = 0.374), but an increase with age was evident only in SHR (P < 7 × 10(-6)). The SHR exhibited alterations in myocardial substrate use at 8 mo characterized by increased glucose and FA utilizations. At 20 mo, the SHR had LVH characterized by decreased LVEF and increased EDV, while simultaneously sustaining higher glucose and similar FA utilizations (compared with WKY rats), which indicates maladaptation of energy substrates in the failing heart. Elevated K1(FDHROL) in the SHR may reflect elevated oxygen consumption and decreased capillary density in the hypertrophied heart. From our findings, metabolic changes appear to precede mechanical changes of LVH progression in the SHR model.

Radionuclide Imaging of Myocardial Metabolism

Cardiac health is dependent on the heart’s ability to utilize different substrates to support overall oxidative metabolism to generate ATP. Indeed, a loss in plasticity in substrate preference is characteristic of a variety cardiac diseases such as diabetic heart disease, in which fatty acid metabolism predominates, and dilated cardiomyopathy, in which glucose metabolism predominates. Because of the pleiotropic actions of myocardial substrate metabolism, a loss in plasticity in substrate preference can have detrimental effects well beyond impairment of energy production, including perturbations in various cell signaling pathways, alterations in cell growth, and decreased cell survival. Despite the rapid growth in our understanding of the relationship between altered myocardial metabolism and cardiac disease, many important questions remain. For example, what are the key determinants of changes in myocardial substrate use? When these changes do occur, to what extent are they adaptive or have the propensity to become maladaptive? And are these metabolic patterns of prognostic significance? Although transgenic models targeting vital aspects of myocardial substrate use are providing mechanistic insights into myocardial metabolic-functional relationships in various cardiac diseases, the relevance of the observed phenotypes to the corresponding human condition is frequently unclear. Likewise, applied genomics have identified numerous gene variants intimately involved in the regulation of myocardial substrate use, yet identifying all clinically relevant genetic variants remains elusive. As a consequence, there is an ever-growing demand for accurate noninvasive imaging approaches of myocardial substrate metabolism that provide links between the bench and the bedside. In this regard, radionuclide approaches have led the way. The most notable example of clinical applicability is the detection of ischemic but viable myocardium with positron emission tomography (PET) and 18F-fluorodexoglucose (FDG) for the treatment of patients with ischemic cardiomyopathy. In the subsequent discussion, advances in metabolic imaging using radionuclide approaches and their potential future applications …

Metabolic toxicity of the heart: Insights from molecular imaging

There is convincing evidence that alterations in myocardial substrate use play an important role in the normal and diseased heart. In this review, insights gained by using quantitative molecular imaging by positron emission tomography and magnetic resonance spectroscopy in the study of human myocardial metabolism will be discussed, and attention will be paid to the effects of nutrition, gender, aging, obesity, diabetes, cardiac hypertrophy, ischemia, and heart failure. The heart is an omnivore organ, relying on metabolic flexibility, which is compromised by the occurrence of defects in coronary flow reserve, insulin-mediated glucose disposal, and metabolic-mechanical coupling. Obesity, diabetes, and ischemic cardiomyopathy appear as states of high uptake and oxidation of fatty acids, that compromise the ability to utilize glucose under stimulated conditions, and lead to misuse of energy and oxygen, disturbing mechanical efficiency. Idiopathic heart failure is a complex disease frequently coexisting with diabetes, insulin resistance and hypertension, in which the end stage of metabolic toxicity manifests as severe mitochondrial disturbance, inability to utilize fatty acids, and ATP depletion. The current literature provides evidence that the primary events in the metabolic cascade outlined may originate in extra-cardiac organs, since fatty acid, glucose levels, and insulin action are mostly controlled by adipose tissue, skeletal muscle and liver, and that a broader vision of organ cross-talk may further our understanding of the primary and the adaptive events involved in metabolic heart toxicity.

Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion

Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not been established. We applied a mass spectrometry-based platform to profile 63 intermediary metabolites in serial paired peripheral arterial and coronary sinus blood effluents obtained from 37 patients undergoing cardiac surgery, stratified by presence of coronary artery disease and left ventricular dysfunction. The myocardium was a net user of a number of fuel substrates before ischemia, with significant differences between patients with and without coronary artery disease. After reperfusion, significantly lower extraction ratios of most substrates were found, as well as significant release of 2 specific acylcarnitine species, acetylcarnitine and 3-hydroxybutyryl-carnitine. These changes were especially evident in patients with impaired ventricular function, who exhibited profound limitations in extraction of all forms of metabolic fuels. Principal component analysis highlighted several metabolic groupings as potentially important in the postoperative clinical course. The preexisting ventricular state is associated with significant differences in myocardial fuel uptake at baseline and after ischemia/reperfusion. The dysfunctional ventricle is characterized by global suppression of metabolic fuel uptake and limited myocardial metabolic reserve and flexibility after global ischemia/reperfusion stress in the setting of cardiac surgery. Altered metabolic profiles after ischemia/reperfusion are associated with postoperative hemodynamic course and suggest a role for perioperative metabolic monitoring and targeted optimization in cardiac surgical patients.

The absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover

Intramyocardial lipid handling in pressure-overload-induced heart failure remains poorly understood, and the balance between endogenous and exogenous lipid utilization for mitochondrial ATP production is essentially unknown. In this study, we determined the contribution of endogenous triacylglycerols (TAG) to mitochondrial oxidation relative to that of exogenous palmitate, glucose, and endogenous glycogen in the failing, pressure-overloaded rat heart. TAG content and turnover were also assessed to determine if lipid availability and mobility were altered. Dynamic-mode 13C NMR was performed in intact hearts from aortic banded and sham operated Spraque-Dawley rats perfused with 13C-labeled palmitate or glucose to assess TAG turnover rate and palmitate oxidation rate. The fractional contributions from palmitate, glucose, glycogen, and TAG to mitochondrial ATP production were determined from NMR analysis of heart extracts. TAG oxidation was not evident in HF, whereas the contribution of TAG to oxidative ATP production was significant in shams. TAG content was 39% lower in HF compared to sham, and TAG turnover rate was 60% lower in HF. During adrenergic challenge, TAG sources were again not oxidized in the HF group. In early cardiac failure, endogenous TAG oxidation was reduced in parallel to increased carbohydrate oxidation, with no change in exogenous palmitate oxidation. This finding was consistent with reduced TAG storage and mobilization. These data further elucidate the role of intermediary and lipid metabolism in the progression of LVH to failure, and contribute to emerging evidence linking the disruption of myocardial substrate use to cardiomyopathies.

IMPACT OF TREATMENT OF OBESE AND DIBABETIC MICE WITH A NOVEL AMINOSTEROL ON SYSTEMIC METABOLIC HOMEOSTASIS AND MYOCARDIAL MITOCHONDRIAL FUNCTION.

Background Cardiovascular disease is the main cause of mortality in diabetes and cardiac dysfunction is due in part to altered myocardial substrate use, occurring in part because of mitochondrial dysfunction and mitochondrial uncoupling. A novel aminosterol, MSI-1436, was recently administered to mouse models of obesity. Short-term treatment resulted in a dramatic reversal of many metabolic disturbances that characterize diabetes. We hypothesized that MSI-1436 would also reverse mitochondrial dysfunction in diabetes. Results Treatment with MSI-1436 resulted in a significant reduction in BW in ob/ob mice compared with ob/ob mice treated with the metabolically inactive control sterol squalamine (SQ). Treatment with MSI-1436 also normalized glucose tolerance in ob/ob mice. State 3 respirations from SQ treated ob/ob hearts were increased and ATP synthesis and ATP/O ratios were decreased compared with WT mice. MSI-1436 treated hearts from ob/ob mice had decreased state 3 respirations compared with SQ treated ob/ob mice, and ATP production decreased further. The mitochondria remained uncoupled as evidenced by reduced ATP/O ratios. Discussion/Conclusions Treatment with MSI-1436 resulted in a significant reduction in BW and normalization of glucose tolerance. However, it was ineffective in reversing mitochondrial dysfunction and uncoupling in cardiac muscle. It may be possible that MSI-1436 could be toxic to these mitochondria or ob/ob hearts may have chronically adapted to use FAs as their primary substrate and are unable to efficiently respond to such an acute treatment. Longer-duration studies will need to be undertaken to test this hypothesis.

Modification of myocardial substrate use as a therapy for heart failure

Despite advances in treatment, chronic heart failure is still associated with significant morbidity and a poor prognosis. The scope for further advances based on additional neurohumoral blockade is small. Effective adjunctive therapies acting via a different cellular mechanism would, therefore, be attractive. Energetic impairment seems to contribute to the pathogenesis of heart failure. The findings from several studies have shown that the so-called metabolic agents could have potential as adjunctive therapies in heart failure. These agents cause a shift in the substrate used by the heart away from free fatty acids, the oxidation of which normally provides around 70% of the energy needed, towards glucose. The oxygen cost of energy generation is lessened when glucose is used as the substrate. In this review we aim to draw attention to the metabolic alteration in heart failure and we present evidence supporting the use of metabolic therapy in heart failure.

Hyperhomocysteinemia Alters The Cardiac Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress

Hyperhomocysteinemia (HHcy) has been considered a vascular disease which is associated with increased levels of reactive oxygen species resulting in scavenging of nitric oxide (NO). However, little is known of the impact on cardiac function and myocardial metabolism. L-Homocysteine was intravenously infused into conscious adult male dogs (titrated to give plasma homocysteine up to 10μM over 120 minutes). There was no change in any hemodynamic parameters between baseline and HHcy. Veratrine induced NO dependent coronary vasodilation (Bezold-Jarisch reflex) was reduced by 29% which was restored by simultaneous infusion of ascorbic acid. Myocardial substrate use was calculated as coronary sinus-arterial difference times coronary blood flow. Acute HHcy significantly increased glucose uptake (1.7±1.2 to 6.8±1.2 μmol/min) and decreased FFA uptake (6.0±1.6 to 3.1±1.0 μmol/min). Lactate uptake was also increased (3.9±3.0 to 11.2±6.1 μmol/min). Myocardial oxygen consumption (MVO2) of LV tissue from chronic HHcy dogs (fed with methionine for 2 weeks) was also measured in vitro in response to bradykinin (BK). BK-induced reduction in MVO2 was significantly decreased by HHcy and this effect was completely inhibited with coincubation with ascorbic acid, tempol, or apocynin. In conclusion, HHcy modulates the substrate use of heart by inhibiting NO bioavailability through the generation of superoxide. The progression of the disease associated with HHcy should also be evaluated based on alterations in the regulation of cardiac metabolism and substrate use. Supported by HL-PO1-43023 grant.

Modulation of Myocardial Energetics

The traditional paradigm for heart failure management centered on mitigating the hemodynamic changes that occur in response to the failing heart. Subsequently, pharmacological modulation of neurohormonal activation and more recently cardiac resynchronization have been shown to reverse ventricular remodeling and to slow disease progression. Despite these advances in therapy, successful treatment of heart failure remains challenging, with rates of hospitalization in the United States exceeding 1 million per year and the annual number of heart failure–related deaths increasing steadily.1 Unfortunately, the history of drug development for heart failure has been marked by many disappointments, most notably the excess mortality associated with oral positive inotropes that were targeted at improving hemodynamics. In addition, more recent interventions aimed at interrupting endothelin and cytokine signaling or reducing oxidative stress have yet to fulfill hopes for novel biological therapies. Thus, new therapeutic strategies are needed to alter the natural history of the disease and to slow or reverse current epidemiological trends. The report by Lee and colleagues2 in this issue of Circulation points toward the promise of an alternative approach based on favorably influencing the efficiency of myocardial energetics, thereby increasing cardiac performance without depending on changes in oxygen consumption or improvement in hemodynamics. Article p 3280 The study of agents aimed at enhancing myocardial energy efficiency has focused principally on shifting myocardial substrate use toward more oxygen-efficient pathways.3 Although the complete oxidation of fatty acids to CO2 yields more adenosine triphosphate (ATP) per molecule of CO2 produced than does complete oxidation of glucose, a greater amount of oxygen is required to completely oxidize a fatty acid of equivalent carbon-chain length. Therefore, for a given amount of oxygen consumed, metabolism of glucose is more “oxygen efficient,” producing ≈15% more ATP (Figure).3,4 Production of ATP and consumption of …

Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28-37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased beta-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-alpha regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-alpha regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

Imaging of myocardial metabolism.

There is compelling evidence that alterations in myocardial substrate use play a key role in a variety of normal and abnormal cardiac conditions such as aging, left ventricular hypertrophy, and diabetic heart disease. However, it is unclear whether the metabolic changes are adaptive or maladaptive. Development of transgenic models targeting key aspects of myocardial substrate use, such as uptake, oxidation, and storage, is accelerating our understanding of the metabolic perturbations of cardiac disease. However, whether the metabolic phenotype in these models is relevant to the human condition is frequently unknown. The importance of altered myocardial metabolism in the pathogenesis of cardiac disease is underscored by the current robust development of novel therapeutics that target myocardial substrate use. Currently, magnetic resonance spectroscopy, single photon emission computed tomography, and positron emission tomography are the 3 methods available to image myocardial substrate metabolism. In this review the role of metabolic imaging in the study of specific cardiac disease processes will be discussed. Both the current and future capabilities of metabolic imaging to furthering our understanding of cardiac disease are highlighted.

In vivo models of myocardial metabolism during ischemia: Application to drug discovery and evaluation

This review examines the in vivo techniques that are available for evaluation of the metabolic effects and efficacy of agents intended for the treatment of myocardial ischemia. Energy substrate metabolism is complex, and requires simultaneous measurement of a variety of processes in order to obtain a thorough understanding of the biochemical mechanisms underlying any functional response. Small animals (from the mouse to the rabbit) are generally not very useful in the study of cardiac metabolism in vivo because it is not possible to sample the coronary venous drainage and measure the rate of substrate uptake or metabolite efflux. Anesthetized open-chest swine or dog models allows simultaneous serial measurement of myocardial substrate use, and repeated tissue sampling for the activities and contents of key enzymes and metabolites. The swine model is particularly good because pigs, like humans, lack innate collateral vessels, thus one can induce regional myocardial ischemia in the left anterior descending coronary artery and sample the venous effluent from the anteior interventricular vein. In this review the biochemical and physiological methods that can be used in conjunction with this preparation are described.

Bovine polymerized hemoglobin increases cardiac oxygen consumption and alters myocardial substrate metabolism in conscious dogs: role of nitric oxide.

We investigated the effect of bovine polymerized hemoglobin-based oxygen carrying (HBOC) solution on myocardial oxygen consumption (MVO2) and substrate use. At 15 min after the end of HBOC infusion (20% blood volume, i.v.) in nine permanently instrumented conscious dogs, mean arterial pressure and coronary blood flow were both increased by 41+/-5% and 93+/-20% (p<0.01) without affecting late diastolic coronary resistance and left ventricular dP/dtmax. Administration of HBOC did not affect arterial PO2 or O2 content, but significantly decreased coronary sinus PO2 and O2 content by 21+/-3% and 36+/-3%, respectively. MVO2 was increased from 7.2+/-0.8 to 15+/-1.8 ml O2/min (p<0.01). Despite an increase in triple product from 44+/-2 to 56+/-3 (p<0.01) 15 min after HBOC, the ratio of MVO2 and triple product was markedly elevated by 62+/-19%. Myocardial free fatty acid consumption was decreased from 14+/-1 to 4.5+/-2.2 microEq/min, whereas consumption of lactate increased from 19+/-6 to 69+/-10 micromol/ min and that of glucose increased from 1.0+/-0.5 to 10+/-3 mg/min (all p values, <0.05). These metabolic changes were not observed in dogs that received angiotensin II at a dose used (20-40 ng/kg/min, i.v.) to match those hemodynamic effects of HBOC. These results suggest that administration of HBOC increases coronary blood flow and MVO2 and shifts cardiac metabolism from using free fatty acid to using lactate and glucose in conscious dogs at rest. These metabolic changes are independent of the HBOC-induced change in hemodynamics.

Myocardial substrate uptake and oxidation during and after routine cardiac surgery

Objective: This study was designed to clarify whether myocardial substrate uptake and oxidation change after a period of hypothermic cardioplegic arrest during coronary artery bypass grafting procedures. Methods: In 30 patients arterial and coronary sinus blood was sampled and coronary sinus flow measurements were performed before and after sternotomy and 10 minutes, 20 minutes, 50 minutes, and 6 hours after release of the aortic crossclamp. Measurement of free fatty acids, lactate, glucose, oxygen content, and carbon dioxide content in arterial and coronary sinus blood allowed calculations of myocardial substrate use, respiratory quotients, and myocardial oxidation rates of carbohydrates and fat. Results: Uptake of free fatty acids and lactate was significant throughout the study and did not change in association with release of the crossclamp. Free fatty acid and lactate uptake measured 6 ± 4 μmol/min and 23 ± 26 μmol/min, respectively, before crossclamping compared with 8 ± 7 μmol/min and 19 ± 21 μmol/min, respectively, after release of the clamp. Glucose uptake was significant only during the first hour after crossclamp release and increased from 7 ± 50 to 28 ± 34 μmol/L after crossclamp release. Myocardial oxygen consumption did not change significantly (0.5 ± 0.2 mmol/L compared with 0.35 ± 0.2 mmol/L) after release of the crossclamp. Myocardial oxygen extraction ratio decreased from 58% ± 8% to 41% ± 13% after crossclamp release. Respiratory quotient increased after crossclamp release (0.85 ± 0.2 compared with 1.00 ± 0.2), which implies that carbohydrate oxidation increased at the expense of free fatty acid oxidation. Conclusion: We conclude that hypothermic cardioplegic arrest during coronary artery bypass graft operations is associated with a transiently increased uptake and oxidation of carbohydrates during the immediate reperfusion phase. (J Thorac Cardiovasc Surg 1999;118:71-80)