Metabolic Heart Failure Research Articles

Cardiac mitochondrial energy metabolism in heart failure: Role of cardiolipin and sirtuins

Mitochondrial oxidation of fatty acids accounts for the majority of cardiac ATP production in the heart. Fatty acid utilization by cardiac mitochondria is controlled at the level of fatty acid uptake, lipid synthesis, mobilization and mitochondrial import and oxidation. Consequently defective mitochondrial function appears to be central to the development of heart failure. Cardiolipin is a key mitochondrial phospholipid required for the activity of the electron transport chain. In heart failure, loss of cardiolipin and tetralinoleoylcardiolipin helps to fuel the generation of excessive reactive oxygen species that are a by-product of inefficient mitochondrial electron transport chain complexes I and III. In this vicious cycle, reactive oxygen species generate lipid peroxides and may, in turn, cause oxidation of cardiolipin catalyzed by cytochrome c leading to cardiomyocyte apoptosis. Hence, preservation of cardiolipin and mitochondrial function may be keys to the prevention of heart failure development. In this review, we summarize cardiac energy metabolism and the important role that fatty acid uptake and metabolism play in this process and how defects in these result in heart failure. We highlight the key role that cardiolipin and sirtuins play in cardiac mitochondrial β-oxidation. In addition, we review the potential of pharmacological modulation of cardiolipin through the polyphenolic molecule resveratrol as a sirtuin-activator in attenuating mitochondrial dysfunction. Finally, we provide novel experimental evidence that resveratrol treatment increases cardiolipin in isolated H9c2 cardiac myocytes and tetralinoleoylcardiolipin in the heart of the spontaneously hypertensive rat and hypothesize that this leads to improvement in mitochondrial function. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

RATIONALE FOR APPLICATION, AND BENEFITS OF TRIMETAZIDINE IN HEART FAILURE BY ITS INFLUENCE OF MYOCARDIUM METABOLISM

Heart failure (HF) is systemic and multiple organ syndrome, with metabolic insufficiency as one of its main causes. Heart metabolism disorders in HF activate other processes that futher worsens progression of the disease. Recent data shows that correction of energy metabolism in the heart by suppression of fatty acids (FA) oxydation and/or increase of glucose oxydation is one of promising approaches in HF patient’s treatment. Clinical studies showed that addition of trimetazidine to standard medication therapy improves sympthoms, cardiac function and prognosis in HF patients, not influencing negatively hemodynamics. The review is focused on rationale for and clinical benefits of trimetazidine application according to its influence on myocardial metabolism in HF. Also a very high level of preparedness of the drug to inclusion into main guidelines on HF is pointed on.

Sex-specific cardiac cardiolipin remodelling after doxorubicin treatment.

BackgroundImbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity. Growing evidence links phospholipid alterations especially cardiolipins (CLs) to defects in mitochondrial function and energy metabolism in heart failure. We have shown recently that doxorubicin cardiotoxicity is more severe in male than female Wistar rats. We aimed to study whether this sex specificity is linked to differences in cardiac phospholipid profiles.ResultsAdult male and female rats were injected 2 mg/kg doxorubicin weekly for 7 weeks. Cardiac phospholipid molecular species were determined by liquid chromatography coupled with mass spectrometry fragmentation (LC)/MSn. Sex difference in phosphatidylethanolamine and phosphatidylcholine species containing docosahexaenoic and docosapentaenoic acyl chains was observed, females having more than males. In both sexes, doxorubicin induced an important loss of the main CL(18:2)4, while the level of monolysocardiolipin MLCL(18:2)3 remained stable. However, a severe remodelling appeared in treated rats with the longest CL acyl chains in doxorubicin-treated females, which might compensate for the loss of tetra-linoleoyl CL. The level of oxidized cardiolipin was not particularly increased after doxorubicin treatment. Finally, expression of genes involved in the biosynthesis of fatty acid appeared to be decreased in doxorubicin-treated males.ConclusionsThese results emphasize for the first time the cardiac remodelling in the phospholipid classes after doxorubicin treatment. These observations suggest that doxorubicin has a sex-specific impact on the heart phospholipidome especially on cardiolipin, an essential mitochondrial lipid. Further studies are needed to better understand the roles of lipids in the anthracycline cardiotoxicity and sex differences, but phospholipid cardioprotection seems a valuable new additive therapeutic strategy for anthracycline cardiotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0039-5) contains supplementary material, which is available to authorized users.

Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets.

Despite recent advances in therapy, heart failure remains a major cause of mortality and morbidity and is a growing healthcare burden worldwide. Alterations in myocardial energy substrate metabolism are a hallmark of heart failure, and are associated with an energy deficit in the failing heart. Previous studies have shown that a metabolic shift from mitochondrial oxidative metabolism to glycolysis, as well as an uncoupling between glycolysis and glucose oxidation, plays a crucial role in the development of cardiac inefficiency and functional impairment in heart failure. Therefore, optimizing energy substrate utilization, particularly by increasing mitochondrial glucose oxidation, can be a potentially promising approach to decrease the severity of heart failure by improving mechanical cardiac efficiency. One approach to stimulating myocardial glucose oxidation is to inhibit fatty acid oxidation. This review will overview the physiological regulation of both myocardial fatty acid and glucose oxidation in the heart, and will discuss what alterations in myocardial energy substrate metabolism occur in the failing heart. Furthermore, lysine acetylation has been recently identified as a novel post-translational pathway by which mitochondrial enzymes involved in all aspects of cardiac energy metabolism can be regulated. Thus, we will also discuss the effect of acetylation of metabolic enzymes on myocardial energy substrate preference in the settings of heart failure. Finally, we will focus on pharmacological interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, transcriptional regulation of fatty acid oxidation, and glucose oxidation to treat heart failure.

Heart Failure With Preserved Ejection Fraction: What Is in a Name?

Evidence-based management of heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF) remains a major gap in the care of patients with HF. Clinical trials directed toward the population with HFpEF have been disappointing, although renin-angiotensin-aldosterone system blockade appears to prevent HF in populations predisposed to HFpEF. This paradox may partly be because of inhomogeneity within the HF populations studied. Although the term HFpEF is often used to imply a specific diagnosis, in fact this constellation may be due to a large variety of disease states with different underlying pathophysiologic mechanisms. Furthermore, in patients with HF, regardless of LVEF, myocardial dysfunction is common during both systole and diastole, and LVEF is influenced at least as much by the pattern of left ventricular remodeling as it is by myocardial contractility. The most common clinical-pathologic syndrome responsible for HFpEF is strongly associated with hypertension, with the metabolic syndrome, and with older age. Recent findings support that this condition is mediated via endothelial dysfunction, inflammation, oxidative stress, myocyte hypertrophy, and altered collagen turnover. We, therefore, propose the terms "metabolic HF" and "senile HF" to describe this specific disease state. The search for therapies designed to prevent, halt, or reverse HF should more strongly focus on populations carefully selected to represent specific underlying cardiovascular disease states.

The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination

The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARα, but not PPARβ/δ or PPARγ in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARα activity and acyl-carnitine intermediates, while MuRF1−/− hearts exhibited increased PPARα activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARα, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARα, along with three specific lysines (292, 310, 388) required for MuRF1's targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARα, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure.

Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models.

The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure. However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart. This review discusses new insights into metabolic adaptations in heart failure. A particular focus lies on data obtained from mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolic pathway and how these differently affect cardiac function. Based on studies in which these mouse models were exposed to ischaemic and non-ischaemic heart failure, we discuss whether and when modulations in FA metabolism are protective against heart failure.

Does myocardial iron load determine the severity of heart insufficiency?

Reduced exercise capacity, fatigue and breathlessness are the most common symptoms in heart failure (HF) patients [ [1] McMurray J.J. Adamopoulos S. Anker S.D. et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2012; 14: 803-869 Crossref PubMed Scopus (68) Google Scholar ]. The mechanism responsible for the development of these symptoms is not fully understood, however the most important factors involved are: decreased peripheral circulatory perfusion with reduced oxygen delivery and impaired peripheral muscle strength and oxygen utilization due to iron deficiency [ 2 Jankowska E.A. von Haehling S. Anker S.D. Macdougall I.C. Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur. Heart J. 2013; 34: 816-829 Crossref PubMed Scopus (252) Google Scholar , 3 von Haehling S. Steinbeck L. Doehner W. Springer J. Anker S.D. Muscle wasting in heart failure: An overview. Int. J. Biochem. Cell Biol. 2013; 45: 2257-2265 Crossref PubMed Scopus (35) Google Scholar , 4 Ventura-Clapier R. Exercise training, energy metabolism, and heart failure. Appl. Physiol. Nutr. Metab. 2009; 34: 336-339 Crossref PubMed Scopus (32) Google Scholar ]. Iron as a component of many enzymes (including oxidative and respiratory chains) participating in crucial biological events, in muscles, plays a key role in oxygen uptake, transport, and storage, as well as oxidative metabolism, catalysis and energy production [ 5 Palus S. von Haehling S. Springer J. Muscle wasting: an overview of recent developments in basic research. Int. J. Cardiol. 2014; 176: 640-644 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar , 6 Ingwall J.S. Energy metabolism in heart failure and remodelling. Cardiovasc. Res. 2009; 81: 412-419 Crossref PubMed Scopus (339) Google Scholar ]. Targeting these abnormalities by the correction of iron deficiency (with or without anemia) with intravenous iron brings a functional benefit to such patients [ 7 Anker S.D. Colet J.C. Filippatos G. et al. Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. Eur. J. Heart Fail. 2009; 11: 1084-1091 Crossref PubMed Scopus (86) Google Scholar , 8 Ponikowski P. van Veldhuisen D.J. Comin-Colet J. et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur. Heart J. 2014; 36: 657-668 Crossref PubMed Scopus (656) Google Scholar ]. Role of quantitative myocardial-iron in hemodialysis-dependent end-stage renal disease subjectsInternational Journal of CardiologyVol. 256PreviewFirst of all, I'd like to thank Leszek et al. for putting light on such a promising topic on myocardial-iron load and severity of heart insufficiency [1]. Full-Text PDF

Ketone Body Metabolism Attenuates Oxidative Stress and Cardiac Remodeling in Pressure Overload Heart Failure

The shift of energy substrate from fatty acid to glucose accompanied by myocardial energy compromise is the hallmark of metabolic remodeling in pathological cardiac hypertrophy. However, it has not been investigated the pathogenic contribution of ketone body metabolism in heart failure. Pressure overload heart failure was introduced with the transverse aortic constriction (TAC). Microarray and mitochondrial iTRAQ proteomics revealed that the expression of Bdh1, an enzyme that catalyzes the NAD+/NADH coupled interconversion of acetoacetate and beta-hydroxybutyrate (betaOHB), was increased 2.5-fold in TAC-operated heart. Ketone body oxidation determined by measuring 14CO2 released from [1-14C] betaOHB in the isolated perfused hearts was upregulated 1.8-fold in TAC-operated heart. To investigate the functional significance of increased ketone body oxidation we generated heart-specific Bdh1 Tg mice which had 1.7-fold increase of ketone body oxidation in the heart. When subjected to TAC operation Bdh1 Tg mice were resistant to cardiac hypertrophy, contractile dysfunction, and fibrosis. Immunochemical detection of carbonylated proteins demonstrated that protein oxidative damage was ameliorated in Bdh1 Tg mice. In vitro study with rat neonatal cardiomyocytes revealed that the adenovirus-mediated Bdh1 overexpression decreased ROS production and apoptosis. The present study demonstrates that ketone body oxidation is promoted in hypertrophied hearts. Increased ketone body utilization reduces oxidative stress and protects against heart failure progression after chronic pressure overload.

Mechanical unloading promotes myocardial energy recovery in human heart failure.

Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. We compared metabolomic, gene transcript, and protein data from 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure tissue: 2.6-fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1A, 1.3-fold) and estrogen-related receptor α (ERRA, 1.2-fold) and γ (ERRG, 2.2-fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with left ventricular assist device improved all of these metabolic and transcriptional defects. These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart.

Imaging of Myocardial Oxidative Metabolism in Heart Failure

Metabolic imaging has a potential for better understanding of pathophysiology of heart failure. C-11 acetate is taken up by the heart, rapidly converted to acetylCoA and readily metabolized to C-11 CO2 through TCA cycle with oxidative phosphorylation. Thus, the myocardial turnover rate of this tracer is tightly correlated with its clearance of C-11 CO2, reflecting overall oxidative metabolism. The heart relies on aerobic oxidative substrate for the generation of ATP, which is required to maintain its contractile function. The progression to heart failure is associated with a gradual decline in the activity of mitochondrial respiratory pathways, leading to diminished capacity for ATP production. The work metabolic index can also be estimated by the combination of C-11 acetate PET and hemodynamics by echocardiography, the metabolic index is a significant marker to understand the pathophysiology of heart failure as well as myocardial oxidative metabolism.

Introduction to special issue on cardiac metabolism in hypertrophy and failure

Interest has been growing over the last dozen years in understanding the role of myocardial energy metabolism in the development and progression of heart failure. Clinical efforts have focused on using indices of cardiac metabolic dysfunction to diagnose heart failure and optimize treatment strategies, and to develop pharmacological interventions to treat this malignant disorder. This important topic was addressed in a 2002 Special Issue of Heart Failure Reviews entitled ‘‘Myocardial Energy Metabolism in Heart Failure’’ [1]. Over the last decade, there has been much progress in our understanding of the role of energy metabolism in the pathophysiology of heart failure, and thus now, it is time for an update. This special issue on ‘‘Cardiac Metabolism in Hypertrophy and Failure’’ presents recent advances in this area and aims to bring you up to date. These reviews emerged from the presentations given at the 10th Annual Meeting of the Society for Heart and Vascular Metabolism, which was held at Merton College at the University of Oxford. This outstanding conference was organized by Kieran Clarke, Stefan Neubauer, and colleagues, and provided attendees with an outstanding presentation of the latest advances in this important area of heart failure research. While there are many aspects of myocardial energy metabolism in hypertrophy and failure that remain poorly understood and are currently under intense investigation, there have also been meaningful advances in recent years. It has been long appreciated that cardiac metabolism is significantly perturbed in heart failure and that metabolic and bioenergetic modulation remains a potential therapeutic target. The papers presented in this special issue present the latest techniques for evaluating cardiac metabolism in humans, explore novel signaling mechanisms that regulate metabolism in the failing heart, and examine in depth the mitochondrial adaptations in response to hypertrophy and failure. In addition, the impact of heart failure on skeletal muscle metabolism is reviewed, as well as the latest finding on the effects of adipocyte-derived hormones on the heart. Medical treatments for heart failure have changed little over the last decade and are still primarily aimed at symptom relief and with suppressing the over activation of neural–hormonal systems. These therapies only slow the progression of the disease, and thus, there is clearly room for novel drugs targeted to optimizing energy metabolism and preserving mitochondrial function in the failing heart. It is hoped that the papers in this Special Issue of Heart Failure Review will shed light on the critical questions in the field, and I hope it will inspire others to pursue new directions in this emerging area of heart failure research.

Cardiac Metabolism in Heart Failure

The heart has a high rate of ATP production and turnover that is required to maintain its continuous mechanical work. Perturbations in ATP-generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure (HF) revealed several metabolic alterations called metabolic remodeling, ranging from changes in substrate use to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during HF. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to HF by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in HF not only results in impaired cardiac energetics but also induces other processes implicated in the development of HF such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in HF may have significant therapeutic relevance that goes beyond the energetic aspect.

Effect of chronic hypoxic hypoxia on oxidation and glucuronidation of carvedilol in rats

Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (±S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 ± 16 and 156 ± 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 ± 8 and 113 ± 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure.

Mechanical Unloading through Ventricular Assist Devices Increases Myocardial Content of Unsaturated Acyl-CoA Species in Patients with Advanced Heart Failure

Purpose Heart failure (HF) is associated with abnormal metabolism and lipotoxicity. Fatty acids (Fas) and fatty acyl-CoAs may act as important mediators of lipotoxicity but their composition in human HF is unclear. We analyzed acyl-CoA and FA species in patients with HF before and after implantation of a ventricular assist device (LVAD) and controls. Methods and Materials Serum and myocardium were collected from 20 pats before and 15 pats after LVAD placement and 10 controls (con). FA and fatty acyl-CoA content were measured by LC/MS. Results Myocardial total fatty acyl-CoA (2.0±0.4 vs. 4.8±0.4 nmol/g in con, p 0.05) compared to con indicating reduced cardiac lipid uptake. Myocardial fatty acyl-CoA species C14, C16, C18, C16:1, C18:2, C18:1 and C20:4 were lower in HF compared to con (all p Conclusions HF is associated with decreased cardiac Fas and fatty acyl-CoA content. Mechanical unloading improves myocardial and skeletal metabolism with increased fatty acyl-CoAs and increased unsaturated fatty acyl-CoAs, suggesting increased lipid uptake. Thus, impaired lipid metabolism in HF can be corrected by LVAD therapy and potentially with pharmacologic therapies.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN(mtFHH) and T2DN(mtWistar), where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN(mtFHH) and T2DN(mtWistar) showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN(mtFHH) showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN(mtFHH), which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN(mtFHH) were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.

Targeting myocardial substrate metabolism in heart failure: potential for new therapies

The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.

Optimization of Cardiac Metabolism in Heart Failure

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.

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.