Heart and Metabolism

Is heart failure a metabolic disease?

René Lerch
Cardiology Center, Geneva University Hospital, Geneva, Switzerland

Correspondence: Professor René Lerch, Cardiology Center, Geneva University Hospital, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland.
Tel: +41 22 372 7193, fax: +41 22 372 7229, e-mail: rene.lerch@hcuge.ch

Although overall mortality from cardiovascular disease is declining, heart failure is increasing in prevalence and is becoming a major challenge in cardiovascular medicine. Heart failure is the endstage condition of most cardiovascular disorders including coronary artery disease, hypertension, valvular disease, congenital heart disease, and cardiomyopathy. Improved survival in these predisposing conditions, paradoxically, contributes to the overall increase in the number of patients experiencing late complications, including heart failure.
But why does the heart eventually fail? Understanding the critical event(s) leading to heart failure is essential for the improvement of strategies to maintain circulatory function in a compensated state for as long as possible. In the 1960s, research mainly focused on the hypothesis of depleted energy for contraction and relaxation. In part because no clear relationship could be found between a reduction in myocardial ATP content and contractile dysfunction, the “energy depletion hypothesis” lost popularity in the late 1970s. Instead, observations on activation of neurohormonal systems, accumulation of cytokines, downregulation of b-receptors, as well as altered expression of cytoskeletal, contractile, and calcium-handling proteins were seminal for the development of today’s therapeutic strategies.[1] Nevertheless, recent observations[2] in both animal models and patients have rekindled interest in myocardial energy metabolism of the failing heart and have motivated this issue of Heart and Metabolism.
In their introductory article, Paul Mohacsi and colleagues emphasize that despite progress in drug therapy, mortality in heart failure remains high. Some further improvement can be expected by more consequent implementation of optimal treatment with ACE inhibitors, b-blockers, and aldosterone antagonists to all eligible patients. Even if available treatment options do not cure the disease, they can considerably delay further deterioration of the clinical condition. Progression of heart failure to NYHA classes III and IV is associated with both increased mortality and an increase in the frequency of hospital admissions, which is of concern not only in terms of quality of life but also in terms of economic cost. The authors mention that many readmissions after discharge may be prevented by improved postdischarge care of patients.
The articles by William Stanley and Frans Visser critically review recent reports on changes in myocardial glucose and fatty acid metabolism during left ventricular dysfunction. Professor Visser emphasizes the role of radionuclide imaging in extracting metabolic information from patients noninvasively. Both authors agree that the overall picture of the pathogenetic role of substrate metabolism in heart failure is incomplete. A number of studies in animal models of left ventricular overload in response to hypertension, aortic banding, aorto-caval fistula, or infarction indicate that left ventricular remodeling is associated with a decrease in fatty acid oxidation and an acceleration of glycolysis, and, in some studies, an increase in glucose oxidation.[3–6] This suggests a return to a more fetal-like pattern of substrate metabolism during left ventricular remodeling, as pointed out by Professor Visser. Unfortunately, very few studies have specifically investigated the metabolic changes occurring during progression from compensated remodeling to overt heart failure. In this context, of interest are observations on the expression of regulatory genes of substrate metabolism which suggest downregulation of protein expression of enzymes of fatty acid oxidation at the moment of cardiac decompensation.[7] It may therefore be speculated that myocardial function might be compromised by a sudden restriction of fatty acid oxidation, leading to lack of energy and/or accumulation of potentially toxic fatty acid esters in the myocardium. However, as pointed out by Professor Visser, it remains to be determined whether these changes in gene expression are causally involved in progression to heart failure or are epiphenomena.
Dr Stanley challenges the hypothesis of restriction of fatty acid oxidation, referring to clinical observations in patients with NYHA class II–III heart failure that suggest a shift in the opposite direction in substrate use, from glucose to fatty acid oxidation.[8] He presents arguments indicating that high, rather than low, fatty acid oxidation may trigger rapid deterioration of function in the failing heart. From studies in hearts with transient ischemia it is known that inhibition of glucose oxidation under conditions of high fatty acid oxidation lowers metabolic efficiency in terms of contractile function, most likely by accumulation of protons. In his article Dr Stanley provides initial evidence from clinical and experimental studies indicating that pharmacological inhibition of fatty acid oxidation with etomoxir or trimetazidine may improve contractile function of failing hearts, similar to observations made during postischemic reperfusion.[9]
Is heart failure a metabolic disease? The question cannot be answered at present, nor probably in the foreseeable future. Heart failure is a multifactorial process and compromised energy metabolism may be just one part. However, there is increasing evidence that metabolic regulation is altered in failing hearts, potentially opening up new avenues for therapeutic interventions.

REFERENCES
1. Task Force of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J. 2001;22:1527–1560.

Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

Neubauer S, Horn M, Naumann A, Tian R, Hu K, Laser M, Friedrich J, Gaudron P, Schnackerz K, Ingwall JS, et al.

Medizinische Universitatsklinik, Wurzburg, Germany.

The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress.

PMID: 7883957 [PubMed - indexed for MEDLINE]

Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat.

Christe ME, Rodgers RL.

Department of Pharmacology and Toxicology, University of Rhode Island, Kingston 02881.

Metabolic fuel oxidation may be altered in left ventricular hypertrophy (LVH), but detailed characterizations are lacking. Although the spontaneously hypertensive rat (SHR) is a widely used experimental model of LVH, its myocardial fuel oxidation rates are unknown. The purpose of this study was to directly measure glucose and fatty acid (FA) oxidation in the SHR heart ex vivo under controlled loading conditions. Hearts from 15-week-old SHR and Sprague Dawley (SD) rats were perfused in a recirculating system and indices of cardiac performance were continuously monitored. The oxidation of glucose and palmitate were determined simultaneously at low and high workloads by the addition of U-14C-glucose and 9,10-3H-palmitate to the recirculating perfusate. The results demonstrate that FA oxidation of SHR hearts is profoundly suppressed (60-80%) relative to that of the normotensive SD strain, particularly at high workloads. Glucose oxidation is also moderately elevated, yielding a marked (four-to-five-fold) increase in the ratio of glucose/FA oxidation rates in the SHR hearts. Since more ATP is generated per mole of oxygen consumed when glucose is the fuel scource, these results are consistent with the hypothesis that a shift away from FA use toward glucose contributes to the preservation of energetic economy in stable, concentric LVH.

PMID: 7869397 [PubMed - indexed for MEDLINE]

Comment in:

Cardiovasc Res. 1999 Apr;42(1):12-4.

Insulin resistance in patients with cardiac hypertrophy.

Paternostro G, Pagano D, Gnecchi-Ruscone T, Bonser RS, Camici PG.

MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK.

OBJECTIVE: Animal studies suggest that left ventricular hypertrophy might be associated with insulin resistance and alterations in glucose transporters. We have previously demonstrated myocardial insulin resistance in patients with post-ischemic heart failure. The aim was to investigate whether myocardial insulin resistance could be demonstrated in human cardiac hypertrophy in the absence of hypertension, diabetes and coronary artery disease. METHODS: Eleven normotensive nondiabetic patients with cardiac hypertrophy due to aortic stenosis and angiographically normal coronary arteries were compared to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting (low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic hyperinsulinemia). Myocardial biopsies were obtained in order to investigate changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose transporters. RESULTS: During fasting, plasma insulin (7 +/- 1 vs. 6 +/- 1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable in patients and controls. By contrast, during clamp, MGU was markedly reduced in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1 ratio was shown by Western blot analysis in patients. CONCLUSIONS: Insulin resistance seems to be a feature of the hypertrophied heart even in the absence of hypertension, coronary artery disease and diabetes and may be explained, at least in part, by abnormalities in glucose transporters.

PMID: 10435017 [PubMed - indexed for MEDLINE]

Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts.

el Alaoui-Talibi Z, Landormy S, Loireau A, Moravec J.

Laboratorie d'Energetique et de Cardiologie Cellulaire, Institut National de la Sante et de la Recherche Medicale, Faculte de Pharmacie, Dijon, France.

Chronic volume overload was induced in 2-mo-old rats by surgical opening of the aortocaval fistula. Rats were killed 3 mo later and their hearts were atrially perfused. During the perfusions with 1.2 mM palmitate, mechanical performance of volume-overloaded hearts was significantly decreased both under conditions of a moderate work load and, mainly, after the clamp of the aortic outflow line. Respective O2 consumption rates as well as the rates of 14CO2 production from [U-14C]palmitate were decreased to the same extent. When 2.4 mM octanoate was used as the exogenous substrate, both the O2 consumption rates and the rates of CO2 production of volume-overloaded hearts became comparable to those of control hearts perfused with same substrate. Mechanical activity of volume-overloaded hearts returned to control values and remained stable during the entire perfusion period tested. Total tissue L-carnitine was decreased by approximately 30% in volume-overloaded hearts, which may suggest that palmitate oxidation has been limited at the level of carnitine-acylcarnitine translocase. However, our polarographic studies of the respiratory activity of isolated mitochondria indicated that the palmitoylcarnitine translocation proceeds normally. On the other hand, state 3 respiration of the mitochondria from volume-overloaded hearts supplemented with either palmitate or palmitate and L-carnitine was significantly lower than that of control ones. This may suggest that an alteration of the enzymes involved in long-chain fatty acid activation and/or long-chain fatty acyl transfer to L-carnitine has developed under conditions of chronic mechanical overloading of the heart.

PMID: 1533101 [PubMed - indexed for MEDLINE]

Altered expression of proteins of metabolic regulation during remodeling of the left ventricle after myocardial infarction.

Remondino A, Rosenblatt-Velin N, Montessuit C, Tardy I, Papageorgiou I, Dorsaz PA, Jorge-Costa M, Lerch R.

Cardiology Center, University Hospital, Geneva, Switzerland.

Non-infarcted myocardium after coronary occlusion undergoes progressive morphological and functional changes. The purpose of this study was to determine whether non-infarcted myocardium exhibits (1) alteration of the substrate pattern of myocardial metabolism and (2) concomitant changes in the expression of regulatory proteins of glucose and fatty acid metabolism. Myocardial infarction was induced in rats by ligation of the left coronary artery. One day and eight weeks after coronary occlusion, glucose and palmitate oxidation were measured. Expression of selected proteins of metabolism were determined one day to 12 weeks after infarction. One day after coronary occlusion no difference of glucose and palmitate oxidation was detectable, whereas after eight weeks, glucose oxidation was increased (+84%, P<0.05) and palmitate oxidation did not change significantly (-19%, P=0.07) in infarct-containing hearts, compared with hearts from sham-operated rats. One day after coronary occlusion, myocardial mRNA expression of the glucose transporter GLUT-1 was increased (+86%, P<0.05) and the expression of GLUT-4 was decreased (-28%, P<0.05) in surviving myocardium of infarct-containing hearts. Protein level of GLUT-1 was increased (+81%, P<0.05) and that of GLUT-4 slightly, but not significantly, decreased (-16%, P=NS). mRNA expressions of heart fatty acid binding protein (H-FABP), and of medium chain acyl-CoA dehydrogenase (MCAD), were decreased by 36% (P<0.05) and 35% (P=0. 07), respectively. Eight weeks after acute infarction, the left ventricle was hypertrophied and, at this time-point, there was no difference in the expression of GLUT-1 and GLUT-4 between infarcted and sham-operated hearts. However, myocardial mRNA and protein content of MCAD were decreased by 30% (P<0.01) and 27% (P<0.05), respectively. In summary, in surviving myocardium, glucose oxidation was increased eight weeks after coronary occlusion. Concomitantly, mRNA and protein expression of MCAD were decreased, compatible with a role of altered expression of regulatory proteins of metabolism in post-infarction modification of myocardial metabolism. Copyright 2000 Academic Press.

PMID: 11040106 [PubMed - indexed for MEDLINE]

The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review).

Sack MN, Kelly DP.

Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

During cardiac hypertrophy and in the failing heart, the chief myocardial energy substrate switches from fatty acids to glucose. In this review, we describe recent progress in the elucidation of the molecular regulatory events involved in the dramatic downregulation of the expression of fatty acid utilization enzymes during development of cardiac hypertrophy and failure. Much of this work has focused on the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD), which catalyzes a pivotal step in the mitochondrial fatty acid -oxidation (FAO) cycle. In vivo ventricular pressure overload studies performed in mice transgenic for human MCAD promoter fragments linked to reporter genes have shown that transcription is markedly downregulated within seven days of pressure overload. The temporal pattern of this alteration in MCAD gene expression has also been characterized in a rat model of progressive pressure overload-induced left ventricular hypertrophy (LVH) and heart failure (HF) [SHHF/Mcc-facp (SHHF) rat]. MCAD mRNA levels are downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and immunodetectable levels of MCAD enzyme were not significantly reduced until the HF stage, indicating additional compensatory control at the translational or post-translational levels in the hypertrophied but non-failing ventricle. FAO enzyme expression was also shown to be downregulated in human subjects with dilated cardiomyopathy compared to age-matched controls. Taken together, these results have identified a gene regulatory program that is involved in the alterations in myocardial energy substrate utilization in the failing heart. The temporal correlation of diminished enzyme expression with onset of heart failure suggests that this alteration in lipid metabolism may play a role in the pathogenesis of pressure-overload induced heart failure. This gene regulatory pathway should be a useful target for experimental studies aimed at the molecular pathogenesis of the transition from stable cardiac hypertrophy to overt heart failure.

Publication Types:

Review
Review, Tutorial

PMID: 9852194 [PubMed - indexed for MEDLINE]

Total-body and myocardial substrate oxidation in congestive heart failure.

Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F.

Department of Geriatric Medicine and Metabolic Diseases, 1st Medical School, Naples, Italy.

Congestive heart failure is a condition associated with increased plasma norepinephrine levels, which have been demonstrated to impair glucose handling. In the present study, 10 patients suffering from congestive heart failure and 10 healthy age- and body mass index-matched subjects were submitted to a hyperinsulinemic (insulin infusion rate, 0.5 mU/kg.min-1) glucose clamp, while simultaneous D-3H-glucose infusion and indirect calorimetry allowed for determination of glucose turnover parameters and substrate oxidation, respectively. On a separate day, basal local (myocardial) indirect calorimetry was also performed. Our data demonstrate that in congestive heart failure, fasting myocardial glucose oxidation (Gox) was inhibited with a simultaneous increase in lipid oxidation (Lox). In our patients, a significant decrease in total-body insulin-stimulated glucose metabolism (31.0 +/- 0.5 v 20.3 +/- 0.4 mumol/kg.min-1, P < .01) and nonoxidative glucose metabolism (18.9 +/- 1.1 v 11.0 +/- 0.5 mumol/kg.min-1, P < .05) was also found. Such latter changes were also associated with a simultaneous overdrive of Lox (0.4 +/- 0.2 v 1.9 +/- 0.2 mumol/kg.min-1, P < .02) that was correlated with an enhanced availability of plasma free fatty acids (FFAs).

PMID: 8121298 [PubMed - indexed for MEDLINE]

Etomoxir: a new approach to treatment of chronic heart failure.

Bristow M.

Department of Cardiology, University of Colorado Health Sciences Center, Denver 80262, USA.

PMID: 11089814 [PubMed - indexed for MEDLINE]

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