Alterations In Myocardial Metabolism Research Articles

Metabolic remodelling in human heart failure

In addition to the typical abnormalities in myocardial structure and function, it is well established that the cardiac metabolism is abnormal in patients with heart failure (HF). Insulin resistance is a common co-morbidity in HF patients and also modulates cardiac metabolism in HF. The notion that an altered myocardial metabolism may contribute to the disease pathogenesis and optimizing it may serve therapeutic purposes underscores the importance of identifying the metabolic characteristics of HF patients. In this paper, the literature on the metabolic changes in human HF is reviewed, and the effects of metabolic modulators on patients with HF are discussed.

Fatty Acid Imaging of the Heart

Imaging metabolic processes in the human heart yields valuable insights into the mechanisms contributing to myocardial pathology and allows assessment of the efficacy of therapies designed to treat cardiac disease. Recent advances in fatty acid (FA) imaging using positron emission tomography (PET) include the development of a method to assess endogenous triglyceride metabolism and the design of new fluorine-18 labeled tracers. Studies of patients with diabetes have shown that the heart is resistant to insulin-mediated glucose uptake and that metabolism of nonesterified FA is upregulated. Cardiac PET imaging has also recently shown the increase in myocardial FA uptake seen in obese patients can be reversed with weight loss. And a pilot study of patients with chronic kidney disease demonstrated that PET imaging can reveal myocardial metabolic alterations that parallel the decline in estimated glomerular filtration rate. Recent advances in FA imaging using single photon emission computed tomography (SPECT) have been accomplished with the tracer β-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid (BMIPP). Two meta-analyses showed this imaging technique has a diagnostic accuracy for the detection of obstructive coronary artery disease that compares favorably with SPECT myocardial perfusion imaging and that BMIPP imaging yields excellent prognostic data in patients across the spectrum of coronary artery disease. A recent multicenter study of patients presenting with acute coronary syndromes found BMIPP SPECT imaging has greater diagnostic sensitivity than, and enhances the negative predictive value of, clinical assessment alone. Because of their exquisite sensitivity, nuclear imaging techniques facilitate the study of physiologic processes that are the key to our understanding of cardiac metabolism in health and disease.

Multimodality Imaging in Diabetic Heart Disease

Diabetic heart disease is currently defined as left ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Its underlying etiology is likely to be multifactorial, acting synergistically together to cause myocardial dysfunction. Multimodality cardiac imaging, such as echocardiography, nuclear, computed tomography, and magnetic resonance imaging, can provide invaluable insight into different aspects of the disease process, from imaging at the cellular level for altered myocardial metabolism to microvascular and endothelial dysfunction, autonomic neuropathy, coronary atherosclerosis, and finally, interstitial fibrosis with scar formation. Furthermore, cardiac imaging is pivotal in diagnosing diabetic heart disease. Thus, the aim of the present review is to illustrate the role of multimodality cardiac imaging in elucidating the underlying pathophysiologic mechanisms of diabetic heart disease.

Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy

Diabetic cardiomyopathy is a type of cardiac dysfunction resulting from diabetes, independent of vascular or valvular pathology. It clinically manifests initially as asymptomatic diastolic dysfunction and then progresses to symptomatic heart failure. Two major contributors to the development of diabetic cardiomyopathy, which are unique to diabetes, are hyperglycemia and diabetes-related alterations in myocardial metabolism. Diabetes mellitus is characterized by reduced glucose and lactate metabolism and enhanced fatty acid metabolism, which are the early consequences of the disease. Studies on the effect of intensive glucose control on heart failure events in patients with diabetes have been conducted with neutral results. However, no study on the effect of metabolic modulators on the prevention of heart failure has been reported. Trimetazidine, a 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, shifts cardiac energy metabolism from free fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-KAT, and is used clinically as an effective antianginal agent. Studies have shown that trimetazidine improves heart function in patients with idiopathic cardiomyopathy and in diabetic patients with cardiac ischemia or heart failure. In addition to being effective, trimetazidine has only mild side effects. Therefore, instead of routine administration of trimetazidine for the treatment of diabetic cardiomyopathy, we hypothesize that the early application of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. In addition to life style modifications, ACEI, ARB, and beta-blockers, which have been recommended in the past, trimetazidine should be administered to those patients with impaired glucose tolerance or patients in the early course of diabetes. In this way, we may reduce the prevalence of heart failure and improve the long-term survival of patients with diabetes through early normalization of the myocardial substrate metabolism.

Metabolismo energético del corazón y sus proyecciones en el tratamiento de la insuficiencia cardíaca

It is unknown why heart failure progresses even when patients are treated with the best therapy available. Evidences suggest that heart failure progression is due to loss of neurohumoral blockade in advanced stages of the disease and to alterations in myocardial metabolism induced, in part, by this neurohumoral activation. Alterations in cardiac energy metabolism, especially those related to substrate utilization and insulin resistance, reduce the efficiency of energy production, causing a heart energy reserve deficit. These events play a basic role in heart failure progression. Therefore, modulation of cardiac metabolism has arisen as a promissory therapy in the treatment of heart failure. This review describes myocardial energy metabolism, evaluates the role of impaired energy metabolism in heart failure progression and describes new therapies for heart failure involving metabolic intervention.

Heart energy metabolism and its role in the treatment of heart failure

It is unknown why heart failure progresses even when patients are treated with the best therapy available. Evidences suggest that heart failure progression is due to loss of neurohumoral blockade in advanced stages of the disease and to alterations in myocardial metabolism induced, in part, by this neurohumoral activation. Alterations in cardiac energy metabolism, especially those related to substrate utilization and insulin resistance, reduce the efficiency of energy production, causing a heart energy reserve deficit. These events play a basic role in heart failure progression. Therefore, modulation of cardiac metabolism has arisen as a promissory therapy in the treatment of heart failure. This review describes myocardial energy metabolism, evaluates the role of impaired energy metabolism in heart failure progression and describes new therapies for heart failure involving metabolic intervention.

Pre-Clinical Myocardial Metabolic Alterations in Chronic Kidney Disease

The risk for cardiovascular events conferred by decreased renal function is curvilinear with exponentially greater increases in risk as estimated glomerular filtration rate (eGFR) declines. In 13 non-diabetic pre-dialysis chronic kidney disease (CKD) patients, we employed quantitative F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) as a means to measure myocardial metabolic changes. Methods: Dynamic cardiac FDG PET images were acquired after 6 h fasting and glucose loading. Corrections for attenuation, scatter, randoms, dead time and decay were applied to the PET data and myocardial glucose utilization (MGU) was calculated using the Patlak method in conjunction with standardized myocardial regions of interest and an image-derived input function (left atrium). MGU was compared with eGFR based on a serum creatinine drawn within 2 weeks of the study date. Results: MGU was relatively uniform between the myocardial sectors (coefficient of variation = 16.2 ± 6.8%) within each patient. Between patients, whole myocardium MGU varied considerably with a range of 37.3–156.2 µmol/min/100 g and a mean of 68.9 ± 38.3 µmol/min/ 100 g. eGFR ranged from 11–89 ml/min/1.73 m² with a mean of 42.8 ± 26.9 ml/min/1.73 m². There was an inverse correlation between whole myocardium MGU and eGFR (Spearman’s rho correlation = –0.615, p = 0.025). In multivariate analysis, the relationship between MGU and eGFR was sustained with adjustment for age, race and gender (adjusted β = –1.56 ± 0.48, p = 0.01). There was no correlation between cardiac workload and eGFR (p = NS). Conclusions: A significant inverse correlation between MGU and eGFR is supportive of the hypothesis that CKD is associated with myocardial metabolic changes, which could not be attributed to demographic factors or cardiac workload. Dynamic FDG PET could provide a sensitive, non-invasive, quantitative tool for investigating pre-clinical myocardial abnormalities in patients with CKD.

Toward Metabolomic Signatures of Cardiovascular Disease

Small biochemicals are the end result of all the regulatory complexity present in a cell, tissue, or organism, including transcriptional regulation, translational regulation, and posttranslational modifications. Metabolic changes are thus the most proximal reporters of the body’s response to a disease process or drug therapy. In 1971, Robinson and coworkers1 conceived the core idea that information-rich data reflecting the functional status of a complex biological system resides in the quantitative and qualitative pattern of metabolites in body fluids. In the same year, Horning and Horning2 first used the term metabolic profiling to describe the output of a gas chromatogram from a patient sample. This new approach to the quantitative metabolic profiling of large numbers of small molecules in biofluids was ultimately termed “metabonomics” by Nicholson et al3 and “metabolomics” by others. Article see p 207 Two core technologies are used to perform metabolic profiling: nuclear magnetic resonance and tandem mass spectrometry (MS/MS), as previously reviewed in Circulation: Cardiovascular Genetics. 4 Nuclear magnetic resonance requires relatively little sample preparation and is nondestructive, allowing for subsequent structural analyses. However, the method tends to have low sensitivity and can detect only highly abundant analytes. Tandem mass spectrometry (MS/MS), coupled with liquid chromatography, on the other hand, has much higher sensitivity for small molecules and is also applicable to a wide range of biological fluids (including serum, plasma, and urine). Recent advances in MS technology now enable researchers to determine analyte masses with such high precision and accuracy that metabolites can be identified unambiguously even in complex fluids. These technologies can be used to characterize biological samples either in a targeted manner or in a pattern discovery manner. In the former, the investigator targets a predefined …

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 …

Altered Myocardial Substrate Metabolism and Decreased Diastolic Function in Nonischemic Human Diabetic Cardiomyopathy: Studies With Cardiac Positron Emission Tomography and Magnetic Resonance Imaging

This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function. Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined. In 78 insulin-naive type 2 diabetes men (age 56.5 +/- 5.6 years, body mass index 28.7 +/- 3.5 kg/m(2), glycosylated hemoglobin A(1c) 7.1 +/- 1.0%; expressed as mean +/- SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 +/- 7.1 years, body mass index 27.0 +/- 2.5 kg/m(2), glycosylated hemoglobin A(1c) 5.3 +/- 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H(2)(15)O, carbon (11)C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy. In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 +/- 0.25 vs. 1.26 +/- 0.36, p = 0.003) and myocardial glucose uptake (260 +/- 128 nmol/ml/min vs. 348 +/- 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 +/- 31 nmol/ml/min vs. 68 +/- 18 nmol/ml/min, p = 0.021) and oxidation (85 +/- 30 nmol/ml/min vs. 63 +/- 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism. Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.

Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography

BackgroundIn vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.MethodsZucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.ResultsPET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase α1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).ConclusionUsing PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

Thallium-201 and I-123 Beta-Methyl Iodophenyl-Pentadecanoic Acid Dual Isotope Single Photon Emission Computed Tomography for Evaluating Reperfusion Injury After Successful Reperfusion Therapy

We report a reperfusion injury after rotational coronary atherectomy (RA) in a 66-year-old man with coronary artery disease. Submaximal exercise with thallium-201 single photon emission computed tomography (SPECT) imaging before reperfusion showed partially reversible perfusion defects in the apex and reversible perfusion defects in the anteroseptal area. Thallium-201 and I-123 beta-methyl iodophenyl-pentadecanoic acid (BMIPP) dual isotope SPECT was performed 5 days before and 1 hour after RA, and 1 month after RA. SPECT images at 1 hour after recovery of no reflow phenomenon after RA revealed enlargement of the defect sizes on thallium-201 and BMIPP uptakes in the anteroseptal area including the apex compared with those before RA. The defect size of thallium-201 uptake was progressively improved on 5 hour delayed redistribution imaging and 1 month after reperfusion compared with that of BMIPP uptake. In conclusion, the changes for the worse of thallium-201 uptake and fatty acid metabolism immediately after the no reflow phenomenon may indicate an injured membrane integrity with altered myocardial metabolism rather than myocardial ischemia. Thallium-201 and I-123 BMIPP dual isotope SPECT is useful for evaluating reperfusion injury after successful reperfusion therapy in a patient with acute coronary syndrome.

Abstract 5383: The Circadian Clock within the Cardiomyocyte is a Novel Mechanism Regulating Myocardial Triglyceride Metabolism

Virtually every mammalian cell, including the cardiomyocyte, has an intrinsic molecular circadian clock. The cardiomyocyte circadian clock has recently been shown to directly mediate diurnal variations in myocardial gene expression, metabolism, and contractile function. This includes modulation of the heart’s acute transcriptional response to increased circulating fatty acids, in a time-of-day-dependent manner. We therefore hypothesized that disruption of the cardiomyocyte circadian clock would impair metabolic adaptation of the heart to high fat feeding. Wild type (WT) and cardiomyocyte-specific circadian clock mutant (CCM) mice were fed either a control or high fat diet (10% and 45% calories from fat, respectively) for 16 weeks, after which myocardial adaptation was assessed at transcriptional, metabolic, and functional levels. Ex vivo mouse heart perfusions in the working mode revealed that high fat feeding induced alterations in myocardial metabolism ( e.g. reduced carbohydrate oxidation; p&lt;0.01) and contractile function ( e.g. depressed cardiac power; p&lt;0.01) in WT, but not CCM, hearts. Furthermore, the ability to decrease reliance on endogenous substrate utilization during an acute increase in fatty acid availability ex vivo was abolished in hearts from CCM mice fed the high fat diet (p&lt;0.05), suggesting potential alterations in triglyceride metabolism. Consistent with the latter, microarray analysis revealed that the cardiomyocyte circadian clock regulates expression of several genes involved in triglyceride turnover. For example, diurnal variations in expression of diacylglycerol acyltransferase 2, which promotes lipogenesis, and rates of myocardial triglyceride synthesis both peak in the middle of the active phase (2- and 3- fold, trough-to-peak, respectively; p&lt;0.05), which are abolished in CCM hearts. These data provide direct evidence that the cardiomyocyte circadian clock regulates myocardial triglyceride metabolism at multiple levels. We postulate that disruption of this intramyocellular mechanism may contribute to altered myocardial metabolism and contractile dysfunction observed during cardiac hypertrophy, diabetes mellitus, and/or shift work.

Abstract 3138: The Effect of Interactions among Variants of CD36 on Hypertensive Heart Disease Phenotypes

Alterations in myocardial metabolism are implicated in mediating hypertensive heart disease (HHD). We hypothesize that variants in CD36 modulate HHD phenotypes both individually and collectively via interactions among CD36 variants and with those in other metabolic regulatory genes. Cardiovascular (CV) phenotypes were characterized by echocardiography and carotid artery ultrasonography. The association between race-specific CD36 tagSNPs (r 2 &gt;0.8) and HHD traits were tested in Caucasian (C, n=608) and African-American (AA, n=228) adults. Association between dependent variables and individual SNPs were tested by regression analysis adjusting for known confounding covariates. Tests for interaction were carried out by first examining within-gene cis -interactions by regression against haplotypes in CD36, followed by exploratory analysis of cross-gene interactions between CD36 and PPARα, PPARγ, and PGC1α using Bayesian network (BNT) analyses. A total of 14 and 52 CD36 SNPs in C and AA, respectively, were evaluated. In C, no significant main effects for individual CD36 SNPs were detected while 3 CD36 haplotypes were associated with LV diastolic function, LV mass, and LV ejection fraction suggesting a role for interaction of cis -acting elements. In AA, 15 individual SNPs and 17 CD36 haplotypes were associated with HHD-related traits. Exploratory BNT analyses including significant haplotypes from the 4 genes identified meaningful gene-gene interactions in both races, highlighting the complex nature of interactions among CD36 and metabolic regulatory genes in the etiology that deserves further investigation. Figure. BNT of all significant (p=0.05) haplotypes from CD36, PGC1α, PPARα, PPARγ in the African-American cohort. Dependent variable (LVM/HI 27 ) and body mass index (potential covariate) shown in orange.

Exercise training impacts the myocardial metabolism of older individuals in a gender-specific manner

Aging is associated with decreases in aerobic capacity, cardiac function, and insulin sensitivity as well as alterations in myocardial substrate metabolism. Endurance exercise training (EET) improves cardiac function in a gender-specific manner, and EET has been shown to improve whole body glucose tolerance, but its effects on myocardial metabolism are unclear. Accordingly, we studied the effect of EET on myocardial substrate metabolism in older men and women. Twelve healthy older individuals (age: 60-75 yr; 6 men and 6 women) underwent PET with [(15)O]water, [(11)C]acetate, [(11)C]glucose, and [(11)C]palmitate for the assessment of myocardial blood flow (MBF), myocardial O(2) consumption (MVo(2)), myocardial glucose utilization (MGU), and myocardial fatty acid utilization (MFAU), respectively, at rest and during dobutamine infusion (10 microg.kg(-1).min(-1)). Measurements were repeated after 11 mo of EET. Maximal O(2) uptake (Vo(2max)) increased (P = 0.005) after EET. MBF was unaffected by training, as was resting MVo(2); however, posttraining dobutamine MVo(2) was significantly higher (P = 0.05), as was MGU (P < 0.04). Although overall dobutamine MFAU was unchanged, posttraining dobutamine MFAU increased in women (P = 0.01) but decreased in men (P = 0.03). Thus, EET in older individuals improves the catecholamine response of myocardial glucose metabolism. Moreover, gender differences exist in the myocardial fatty acid metabolic response to training. These findings suggest a role for altered myocardial substrate metabolism in modulating the cardiovascular benefits of EET in older individuals.

Myocardial metabolism and cardiac performance in obesity and insulin resistance

Obesity, insulin resistance, and their frequent complication of type 2 diabetes are risk factors for left ventricular diastolic dysfunction, systolic dysfunction, and clinical heart failure. Although obesity, insulin resistance, and diabetes are risk factors for coronary artery disease, and hence ischemic cardiomyopathy-related heart failure, there is increasing evidence that these three risk factors are implicated in the development of cardiac dysfunction not related to epicardial coronary disease. There are several mechanisms by which this triad may cause cardiac dysfunction, including alterations in myocardial metabolism, which may initially be adaptations but evolve into maladaptive responses over time. Recent advances in our understanding of these mechanisms will aid in the development of novel therapies, including metabolic manipulations that could prevent and treat cardiac dysfunction in patients with obesity, insulin resistance, and diabetes.

Alterations in Myocardial Metabolism in the Diabetic Myocardium

Free fatty acids are the preferred substrate for the myocardium. However, under conditions of ischemia, glucose becomes the primary myocardial energy source. Its metabolism avoids the toxic end-products of free fatty acids, which include oxygen free radicals. Patients with diabetes mellitus have impaired uptake of glucose. As a consequence the diabetic myocardium relies heavily on free fatty acid metabolism as its energy source. The results of these alterations in myocardial metabolism ultimately contribute to changes in endothelial function, inflammation, and oxidative stress. This review describes the defects in diabetic myocardial metabolism and how they contribute to cardiovascular dysfunction. The mechanisms by which intravenous insulin infusions can be used to modulate these changes in myocardial metabolism to improve clinical outcomes are discussed.

Arginase: a modulator of myocardial function

when nitric oxide (NO) donors were first administered to isolated, normal cardiomyocytes, a negative, cGMP-dependent inotropic effect was observed, whereas inhibitors of NO synthases (NOS) had no effect. Further studies then demonstrated a biphasic contractile response to exogenous NO and cGMP,

Metabolic therapy for the diabetic patients with ischaemic heart disease

Diabetic patients with ischaemic heart disease have a greater amount of myocardial ischaemia, often silent, and an increased incidence of heart failure compared to nondiabetic patients. This is the result of altered myocardial metabolism and accelerated atherogenesis with involvement of peripheral coronary segments causing chronic hypoperfusion and diffuse hybernation. In patients with diabetes mellitus and myocardial ischaemia, the metabolic changes occurring as a consequence of the mismatch between blood supply and cardiac metabolic requirements are heightened by the diabetic metabolic changes. An important metabolic alteration of diabetes is the increase in free fatty acid concentrations and increased muscular and myocardial free fatty acid uptake and oxidation. This increased uptake and utilization of free fatty acid during stress and ischaemia is responsible for the increased susceptibility of the diabetic heart to myocardial ischaemia and to a greater decrease of myocardial performance for a given amount of ischaemia compared to nondiabetic hearts. Given the metabolic alterations of the diabetic heart at rest and during episodes of myocardial ischaemia, a therapeutic approach aimed at an improvement of cardiac metabolism through manipulations of the utilization of metabolic substrates should result in an improvement of myocardial ischaemia and of left ventricular function. Modulation of myocardial free fatty acid metabolism should be the key target for metabolic interventions in patients with coronary artery disease with and without diabetes. In diabetic patients, the effects of modulation of free fatty acid metabolism should be even greater than those observed in patients without diabetes. The inhibition of FFA oxidation with trimetazidine improves cardiac metabolism at rest, decreases cardiac ischaemia and therefore prevents the decline of left ventricular function due to chronic hypoperfusion and repetitive episodes of myocardial ischaemia. Because of its effect on cardiac metabolism at rest, its effects on myocardial ischaemia and left ventricular function trimetazidine should always be considered for the treatment of diabetic patients with ischaemic heart disease with or without left ventricular dysfunction.

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.