Metabolic remodeling in chronic heart failure

Metabolic remodeling in chronic heart failure first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:guotao20@hotmail.com †E-mail:guotao20@hotmail.com guotao20@hotmail.com Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China Although the management of chronic heart failure (CHF) has made enormous progress over the past decades, CHF is still a tremendous medical and societal burden. Metabolic remodeling might play a crucial role in the pathophysiology of CHF. The characteristics and mechanisms of metabolic remodeling remained unclear, and the main hypothesis might include the changes in the availability of metabolic substrate and the decline of metabolic capability. In the early phases of the disease, metabolism shifts toward carbohydrate utilization from fatty acids (FAs) oxidation. Along with the progress of the disease, the increasing level of the hyperadrenergic state and insulin resistance cause the changes that shift back to a greater FA uptake and oxidation. In addition, a growing body of experimental and clinical evidence suggests that the improvement in the metabolic capability is likely to be more significant than the selection of the substrate. Chronic heart failure (CHF) Metabolic remodeling Metabolic substrate Metabolic capability Introduction 1 Chronic heart failure (CHF) is a complex clinical syndrome resulted from any structural or functional cardiac disorder that impairs the systolic and/or diastolic ability of the ventricle. Approximately 1%–2% of the adult population in developed countries suffer from CHF, with the prevalence rising to ≥10% among persons 70 years of age or older (McMurray et al., 2012 2012 ). CHF is a tremendous medical and societal burden. For the USA alone, the total annual cost of treatment for CHF is approximately USD28 billion. The number will continue to increase considering an aging population and the improved treatment of CHF (Neubauer, 2007 2007 ). The past decades have witnessed considerable progress in the treatment of CHF. The angiotensin-converting-enzyme inhibitors (ACEIs) (Hunt et al., 2009 2009 ; McMurray et al., 2012 2012 ), β receptor blockers (Hunt et al., 2009 2009 ; McMurray et al., 2012 2012 ), aldosterone antagonists (Pitt et al., 2003 2003 ; Zannad et al., 2011 2011 ), and resynchronization therapy (RCT) (Cleland et al., 2005 2005 ) have been wildly used in clinical applications and achieve remarkable outcomes. Nonetheless, CHF is still associated with an annual mortality rate of 10% (Neubauer, 2007 2007 ). Further exploration of the mechanisms of CHF and its corresponding interference is still one of the primary tasks in cardiology. A growing body of evidence suggests that metabolic remodeling might play a crucial role in the pathophysiology of CHF. Mechanism of chronic heart failure (CHF) 1 Neurohormone and ventricular remodeling 2 The classical mechanism of CHF includes neurohormone and ventricular remodeling. The portfolio of neurohormonal mechanisms that have been described thus far includes activation of the adrenergic nervous system and the renin-angiotensin system (RAS), which are responsible for maintaining cardiac output through increased retention of salt and water, peripheral arterial vasoconstriction, and increased contractility, and activation of the inflammatory mediators. The overexpression of the portfolios of biologically active molecules contributes to the disease’s progression by virtue of the deleterious effects exerted on the heart and circulation. Ventricular remodeling is a significant pathophysiology in CHF, which consists of three levels: (1) organic remodeling (Kemp and Conte, 2012 2012 ) that means the changes in the left ventricular (LV) mass, volume, shape, and composition of the heart; (2) cellular remodeling (Opie et al., 2006 2006 ; Kehat and Molkentin, 2010 2010 ) that means myocyte hypertrophy, alteration in the contractile properties of the myocyte, progressive necrosis, apoptosis, and autophagic cell death; (3) subcellular remodeling (Shah and Mann, 2011 2011 ) that means the varying degrees of changes in biochemical compositions and molecular structures of various subcellular organelles, such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, energetic metabolism, and nucleus (Dhalla et al., 2009 2009 ). Metabolic remodeling 2 Decherd and Visscher ( 1934 1934 ) proposed the concept of energy-starvation, which stated that varying degrees of decrease in the creatinine (Cr), adenosine triphosphate (ATP), and phosphocreatine (PCr) exist in failing myocardium. The hypothesis was put forward in late years by some recent studies (Ventura-Clapier et al., 2004 2004 ; Neubauer, 2007 2007 ; Doenst and Abel, 2011 2011 ; Azevedo et al., 2013 2013 ). Recently, some novel pharmaceuticals, e.g., ghrelin (Ledderose et al., 2011 2011 ) and allopurinol (Hirsch et al., 2012 2012 ; Opie, 2012 2012 ) have been used to treat CHF by improving the metabolism of myocardia. The most significant changes among metabolic remodeling are the availability of metabolic substrate and the decline of metabolic capability. Availability of metabolic substrate 1 Energy metabolism in the normal heart 2 In the normal heart, this requirement of energy metabolism is met by the daily synthesis of approximately 30 kg of ATP (Ashrafian and Frenneaux, 2007 2007 ; Murray et al., 2007 2007 ). Exogenous substrates, such as fatty acids (FAs), glucose, pyruvate, lactate, and ketone bodies, generate energy through oxidative phosphorylation. The utilization of various substrates was influenced by the concentration of substrates (Ardehali et al., 2012 2012 ), the supply of oxygen (Sabbah et al., 2000 2000 ; Giordano, 2005 2005 ), the workload of the heart, and the systemic level of hormone (Tuunanen et al., 2006a 2006a ), etc. Approximately 60%–70% of the ATP requirement is met by the catabolism of FAs via β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation in the mitochondria (Rosca and Hoppel, 2010 2010 ). During the postprandial period and during exercise, the relative contribution of glucose catabolism increases and produces approximately 10%–40% of ATP (Abozguia et al., 2006 2006 ). About 60%–70% of ATP hydrolysis fuels contractile shortening, and the remaining 30%–40% is primarily used for ion pumps (Nagoshi et al., 2011 2011 ). The metabolisms of FAs and glucose are highly coupled in myocytes, with an increase in FAs metabolism causing a decrease in glucose metabolism, and vice versa. This high coupling was termed as “Randle cycle” in Randle et al. ( 1963 1963 ). Fetal metabolic phenotype 2 In CHF, the recognition concerning substrate utilization has not reached a consensus. One prevalent view supported by experimental (Recchia et al., 1998 1998 ) and most clinical (Dávila-Román et al., 2002 2002 ; de las Fuentes et al., 2003 2003 ) studies is the “reversion to the fetal metabolic phenotype” (Rajabi et al., 2007 2007 ; Turer et al., 2010 2010 ). The essence of reversion is a shift from a FAs metabolism to a glucose metabolism in failing myocardia, which is analogous to the metabolic behavior of the fetal heart. In utero, where oxygen tension is low and insulin levels are relatively high, glucose metabolism is the predominate source of myocardial fuel (Turer et al., 2010 2010 ). In addition, the reversion might involve the expression of some fetal genes (Finck and Kelly, 2006 2006 ; Dillon et al., 2012 2012 ). Features and mechanisms of the decline of FAs metabolism 3 The decline of FAs metabolism could be explained by some hypothesis. FAs provide the highest energy (ATP) yield per molecule of FAs through β-oxidation (Nagoshi et al., 2011 2011 ). However, glucose metabolism has a greater efficiency in producing high energy phosphates (Rosano et al., 2008 2008 ; Nagoshi et al., 2011 2011 ). In other words, for an equivalent amount of ATP synthesized, the FA oxidation requires approximately 10%–15% more oxygen compared to that of the glucose oxidation (Abozguia et al., 2009 2009 ). Consequently, the improvement of metabolic efficiency by the shift is considered to be adaptive (Nagoshi et al., 2011 2011 ). Its mechanism may include: Carnitine palmitoyltransferase type 1 (CPT-1) and medium chain acyl-CoA dehydrogenase (MCAD) were noteworthy enzymes. The former is a key rate-limiting enzyme responsible for transferring acyl-CoA into mitochondria (Martin et al., 2000 2000 ). The latter is one of the enzymes of FA β-oxidation. Some studies reported in heart failure models the decline of the protein levels of PPARα/RXRα/PGC-1α (Karbowska et al., 2003 2003 ; Sarma et al., 2012 2012 ), as well as the suppressed expression of CPT-1 (Sihag et al., 2009 2009 ; Karamanlidis et al., 2010 2010 ) and/or MCAD (Riehle and Abel, 2012 2012 ). These changes in the cellular and molecular levels were considered as potential mechanisms for the decline of FAs metabolism (Fig. 1 1 ). The decline of FAs metabolism and the incline of glucose metabolism Mechanisms of incline of glucose metabolism 3 The incline of glucose metabolism is supposed to be a reaction to the decrease of FA oxidation. Its mechanism involved adenosine monophosphate-activated protein kinase (AMPK) (Beauloye et al., 2011 2011 ) that is considered as the ‘fuel gauge’ of the cell, sensing states of low energy and activating practically all energy-producing processes (Doenst and Abel, 2011 2011 ). Impaired myocardial energetics resulted from the decrease of FA oxidation triggers AMPK, which promotes the translocation of the glucose transporters (GLUTs) onto the plasma membrane and enhances glucose uptake (Kolwicz and Tian, 2011 2011 ). In addition, AMPK stimulates phosphofructokinase 2 (PFK2), which generates fructose-2,6-diphosphate acting as a potent allosteric stimulant of the rate-limiting enzyme, PFK1 (Marsin et al., 2000 2000 ). This partially explains that inclined glucose metabolism mainly manifests in other catabolic pathways (e.g., glycolysis) instead of glucose oxidation (Kolwicz and Tian, 2011 2011 ) (Fig. 1 1 ). Non-fetal metabolic phenotype 2 Characteristics of substrate utilization 3 It is crucial to recognize that the concept of fetal-metabolic phenotype has not been observed in all studies of CHF. Some other studies reported opposite results: up-regulation of FAs metabolism and downregulation of glucose use in failing myocardium—the non-fetal metabolic phenotype (Paolisso et al., 1994 1994 ; Taylor et al., 2001 2001 ). Potential causation 3 The phenomenon of a shift towards FAs metabolism might be associated with two general metabolic backgrounds in CHF: the hyperadrenergic state and insulin resistance. The compensatory hyperadrenergic state that develops in CHF promotes the degradation of adipose tissue elevating the blood FA. These excess circulating FAs block the uptake of glucose by muscle (Opie and Knuuti, 2009 2009 ). Excess FAs can also cause abnormalities of mitochondrial function, including excessive formation of reactive oxygen species (ROS) (Tsutsui et al., 2011 2011 ) and oxygen wastage (Opie and Knuuti, 2009 2009 ). The high levels of plasma FAs activate uncoupling protein-2 and -3 (UCP-2 and -3) (Hesselink and Schrauwen, 2005 2005 ) which descend the gradient of proton in the mitochondria and cause oxygen wastage (Fig. 2 2 ). The decline of glucose metabolism and the incline of FAs metabolism Insulin resistance is prevalent in CHF and its potential mechanisms (Petersen and Shulman, 2006 2006 ; Tuunanen and Knuuti, 2011 2011 ) contain: chronically increased sympathetic nervous system (SNS) activity which leads to decreased insulin secretion, insulin responsiveness, and skeletal muscle blood flow. In addition, loss of skeletal muscle mass and sedentary lifestyle of the CHF patient might reduce insulin sensitivity. No matter what the hyperadrenegic state or insulin resistance might cause descent of the glucose metabolism (Fig. 2 2 ). Metabolic capability 1 Metabolic capability means changes in the energy-producing processes of the myocardium under conditions that directly or indirectly lead to CHF (Doenst and Abel, 2011 2011 ). As mentioned above, in different conditions, such as various CHF etiologies, different clinical staging, and metabolic backgrounds, the characteristics and mechanisms of the availability of metabolic substrate are diverse. Nonetheless, the following ideas, which reflect the myocardial metabolic capability, have been proposed beyond the one-sided emphasis on the shift of substrate utilization in CHF. Metabolic extremes 2 Metabolism intervened by humans, either as fuel overabundance or absence, can cause lipotoxicity or glucotoxicity, both of which are adverse for the failing heart and lead to contractile dysfunction (Taegtmeyer and Ballal, 2006 2006 ; Turer et al., 2010 2010 ). In other words, both glucose and FA oxidation are required for optimal function of the failing heart, which is supported by clinical studies of acipimox (a nicotinic acid derivatives with profound anti-lipolytic effects and can progressively decrease in the plasma level of FAs). Acipimox was hypothesized to enhance myocardium glucose metabolism and cardiac function by decreasing FAs metabolism (Tuunanen et al., 2006b 2006b ). However, this drug was found to be associated with a significant fall in cardiac work and efficiency. One possible explanation is the fact that although FA oxidation is reduced in the failing heart, it still represents a critical source of energy and its further inhibition by an aggressive pharmacological treatment would necessarily cause a functional derangement (Lionetti et al., 2011 2011 ). Metabolic flexibility 2 The healthy heart considered as a substrate omnivore has an ability to respond to a changing workload, substrate availability, circulating hormones, coronary flow, and fuel metabolism by choosing the right substrate at the right moment (Murray et al., 2007 2007 ; Turer et al., 2010 2010 ; Ventura-Clapier et al., 2011 2011 ). Metabolic inflexibility 2 Metabolic inflexibility means that the altered energy system of myocyte attenuates flexibility of the metabolism. Namely, failing myocyte lacks the metabolism ability to deal with hemodynamic stress (Yan et al., 2009 2009 ; Vadvalkar et al., 2013 2013 ). Evidences from pharmacological treatment 2 Trimetazidine and L -carnitine 3 Trimetazidine, inhibitors of FAs β-oxidation, is a partial inhibitor of the terminal enzyme in β-oxidation long-chain 3-ketoacyl thiolase. Several studies have shown that trimetazidine is well tolerated in CHF patients. Results generally support either a trend or significant improvement in the LV ejection fraction concomitant with a reduction in constraction (Sisakian et al., 2007 2007 ; Zhang et al., 2012 2012 ). In contrast, L -carnitine is a naturally occurring essential cofactor of FA metabolism and is synthesized endogenously or obtained from dietary sources. A systematic review and meta-analysis of 13 controlled trials ( n =3629) was conducted to determine the effects of L -carnitine vs. placebo or control on mortality, CHF, etc. Compared with the placebo or control, L -carnitine can significantly reduce these outcome events (Dinicolantonio et al., 2013 2013 ). Obviously, substrate utilizations of the two drugs are just the opposite; however, they can also improve the prognosis of CHF, which in itself indicates that the choice of substrate may not be important. The critical issue could be the metabolic capability. The application of thiamin in CHF may provide some clues in this regard. Thiamin 3 Thiamin plays an important role in the reaction of the central pathway for energy production. It is a catalyst in the reactions of pyruvate to acetyl CoA and α-ketoglutarate to succinyl CoA in the Krebs cycle and functions as a coenzyme with transketolase. A 2-carbon unit from α-ketose is transferred to an aldose by transketolase in the pentose phosphate pathway (Wooley, 2008 2008 ). A cross-sectional study reported that 33% of hospitalized patients with CHF have erythrocyte thiamin pyrophosphate levels suggestive of thiamin deficiency (Hanninen et al., 2006 2006 ). It is possible that thiamin deficiency, by limiting the metabolic capability, might contribute to myocardial dysfunction. Previous thiamin supplementation trials in patients with CHF have reported significant improvements in the cardiac function (Azizi-Namini et al., 2012 2012 ). In addition to thiamin, there are many targets that can affect the metabolic capability. By interfering with them, we need to see whether we can improve these outcomes for the patients with CHF, which remains to be researched in the future. In addition to thiamin, there are some indicators that have been proposed for evaluating or affecting the metabolic ability. In human heart failure caused by dilated cardiomyopathy (DCM), both PCr and ATP are significantly reduced (Beer et al., 2002 2002 ). Meanwhile, the myocardial PCr-to-ATP ratio, measured noninvasively with 31P-MR spectroscopy, offers significant independent prognostic information on cardiovascular mortality in patients with DCM (Neubauer et al., 1997 1997 ). Conclusions 1 In the early phases of CHF, there is a shift towards carbohydrate utilization from FA oxidation. Along with the progress of the disease, increasing levels of hyperadrenergic state and insulin resistance cause the opposite changes that shift back to greater FA uptake and oxidation, and lower glucose metabolism. In the advanced cases of severe CHF, there are obvious reductions in both FA oxidation and carbohydrate utilization (Neubauer, 2007 2007 ; Rajabi et al., 2007 2007 ; van Bilsen et al., 2009 2009 ; Turer et al., 2010 2010 ; Tuunanen and Knuuti, 2011 2011 ). However, improvements in the metabolic capability and efficiency are likely to be more significant than the selection of the substrate (Kolwicz and Tian, 2011 2011 ; Lionetti et al., 2011 2011 ). Nevertheless, there are still fundamental gaps in knowledge including whether observed shifts in cardiac substrate utilization are adaptive or maladaptive, causal or an epiphenomenon of CHF, whether we can improve these outcomes for the patients with CHF by interfering with metabolic capability (Turer et al., 2010 2010 ). More studies, especially long-term large sample experiments, are warranted to clarify these observations. References K Abozguia , K Clarke , L Lee , M Frenneaux . Modification of myocardial substrate use as a therapy for heart failure . Nat Clin Pract Cardiovasc Med , 2006 . 3 ( 9 ): 490 - 498 . 16932766 DOI: 10.1038/ncpcardio0583 http://doi.org/10.1038/ncpcardio0583 . Modification of myocardial substrate use as a therapy for heart failure K Abozguia , GN Shivu , I Ahmed , TT Phan , MP Frenneaux . The heart metabolism: pathophysiological aspects in ischaemia and heart failure . Curr Pharm Des , 2009 . 15 ( 8 ): 827 - 835 . 19275646 DOI: 10.2174/138161209787582101 http://doi.org/10.2174/138161209787582101 . The heart metabolism: pathophysiological aspects in ischaemia and heart failure Z Arany , H He , J Lin , K Hoyer , C Handschin , O Toka , F Ahmad , T Matsui , S Chin , PH Wu , 等 . Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle . Cell Metab , 2005 . 1 ( 4 ): 259 - 271 . 16054070 DOI: 10.1016/j.cmet.2005.03.002 http://doi.org/10.1016/j.cmet.2005.03.002 . Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle H Ardehali , HN Sabbah , MA Burke , S Sarma , PP Liu , JG Cleland , A Maggioni , GC Fonarow , ED Abel , U Campia , 等 . Targeting myocardial substrate metabolism in heart failure: potential for new therapies . Eur J Heart Fail , 2012 . 14 ( 2 ): 120 - 129 . 22253453 DOI: 10.1093/eurjhf/hfr173 http://doi.org/10.1093/eurjhf/hfr173 . Targeting myocardial substrate metabolism in heart failure: potential for new therapies H Ashrafian , MP Frenneaux . Metabolic modulation in heart failure: the coming of age . Cardiovasc Drugs Ther , 2007 . 21 ( 1 ): 5 - 7 . 17285357 DOI: 10.1007/s10557-007-6000-z http://doi.org/10.1007/s10557-007-6000-z . Metabolic modulation in heart failure: the coming of age PS Azevedo , MF Minicucci , PP Santos , SA Paiva , LA Zornoff . Energy metabolism in cardiac remodeling and heart failure . Cardiol Rev , 2013 . 21 ( 3 ): 135 - 140 . 22990373 DOI: 10.1097/CRD.0b013e318274956d http://doi.org/10.1097/CRD.0b013e318274956d . Energy metabolism in cardiac remodeling and heart failure P Azizi-Namini , M Ahmed , AT Yan , M Keith . The role of B vitamins in the management of heart failure . Nutr Clin Pract , 2012 . 27 ( 3 ): 363 - 374 . 22516940 DOI: 10.1177/0884533612444539 http://doi.org/10.1177/0884533612444539 . The role of B vitamins in the management of heart failure C Beauloye , L Bertrand , S Horman , L Hue . AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure . Cardiovasc Res , 2011 . 90 ( 2 ): 224 - 233 . 21285292 DOI: 10.1093/cvr/cvr034 http://doi.org/10.1093/cvr/cvr034 . AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure M Beer , T Seyfarth , J Sandstede , W Landschutz , C Lipke , H Köstler , M von Kienlin , K Harre , D Hahn , S Neubauer . Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy . J Am Coll Cardiol , 2002 . 40 ( 7 ): 1267 - 1274 . 12383574 DOI: 10.1016/S0735-1097(02)02160-5 http://doi.org/10.1016/S0735-1097(02)02160-5 . Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy JGF Cleland , JC Daubert , E Erdmann , N Freemantle , D Gras , L Kappenberger , L Tavazzi . The effect of cardiac resynchronization on morbidity and mortality in heart failure . N Engl J Med , 2005 . 352 ( 15 ): 1539 - 1549 . 15753115 DOI: 10.1056/NEJMoa050496 http://doi.org/10.1056/NEJMoa050496 . The effect of cardiac resynchronization on morbidity and mortality in heart failure VG Dávila-Román , G Vedala , P Herrero , L de las Fuentes , JG Rogers , DP Kelly , RJ Gropler . Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy . J Am Coll Cardiol , 2002 . 40 ( 2 ): 271 - 277 . 12106931 DOI: 10.1016/S0735-1097(02)01967-8 http://doi.org/10.1016/S0735-1097(02)01967-8 . Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy G Decherd , MB Visscher . Energy metabolism of the failing heart . J Exp Med , 1934 . 59 ( 2 ): 195 - 199 . 19870240 . Energy metabolism of the failing heart L de las Fuentes , P Herrero , LR Peterson , DP Kelly , RJ Gropler , VG Dávila-Román . Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease . Hypertension , 2003 . 41 ( 1 ): 83 - 87 . 12511534 DOI: 10.1161/01.HYP.0000047668.48494.39 http://doi.org/10.1161/01.HYP.0000047668.48494.39 . Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease NS Dhalla , HK Saini-Chohan , D Rodriguez-Leyva , V Elimban , MR Dent , PS Tappia . Subcellular remodelling may induce cardiac dysfunction in congestive heart failure . Cardiovasc Res , 2009 . 81 ( 3 ): 429 - 438 . 18852252 DOI: 10.1093/cvr/cvn281 http://doi.org/10.1093/cvr/cvn281 . Subcellular remodelling may induce cardiac dysfunction in congestive heart failure LM Dillon , AP Rebelo , CT Moraes . The role of PGC-1 coactivators in aging skeletal muscle and heart . IUBMB Life , 2012 . 64 ( 3 ): 231 - 241 . 22279035 DOI: 10.1002/iub.608 http://doi.org/10.1002/iub.608 . The role of PGC-1 coactivators in aging skeletal muscle and heart JJ Dinicolantonio , CJ Lavie , H Fares , AR Menezes , JH O′Keefe . L -carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis . Mayo Clin Proc , 2013 . 88 ( 6 ): 544 - 551 . DOI: 10.1016/j.mayocp.2013.02.007 http://doi.org/10.1016/j.mayocp.2013.02.007 . L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis T Doenst , ED Abel . Spotlight on metabolic remodelling in heart failure . Cardiovasc Res , 2011 . 90 ( 2 ): 191 - 193 . 21429943 DOI: 10.1093/cvr/cvr077 http://doi.org/10.1093/cvr/cvr077 . Spotlight on metabolic remodelling in heart failure BN Finck , DP Kelly . PGC-1 coactivators: inducible regulators of energy metabolism in health and disease . J Clin Invest , 2006 . 116 ( 3 ): 615 - 622 . 16511594 DOI: 10.1172/JCI27794 http://doi.org/10.1172/JCI27794 . PGC-1 coactivators: inducible regulators of energy metabolism in health and disease FJ Giordano . Oxygen, oxidative stress, hypoxia, and heart failure . J Clin Invest , 2005 . 115 ( 3 ): 500 - 508 . 15765131 DOI: 10.1172/JCI24408 http://doi.org/10.1172/JCI24408 . Oxygen, oxidative stress, hypoxia, and heart failure SA Hanninen , PB Darling , MJ Sole , A Barr , ME Keith . The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure . J Am Coll Cardiol , 2006 . 47 ( 2 ): 354 - 361 . 16412860 DOI: 10.1016/j.jacc.2005.08.060 http://doi.org/10.1016/j.jacc.2005.08.060 . The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure MK Hesselink , P Schrauwen . Uncoupling proteins in the failing human heart: friend or foe? . Lancet , 2005 . 365 ( 9457 ): 385 - 386 . 15680450 DOI: 10.1016/S0140-6736(05)17823-4 http://doi.org/10.1016/S0140-6736(05)17823-4 . Uncoupling proteins in the failing human heart: friend or foe? GA Hirsch , PA Bottomley , G Gerstenblith , RG Weiss . Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts . J Am Coll Cardiol , 2012 . 59 ( 9 ): 802 - 808 . 22361399 DOI: 10.1016/j.jacc.2011.10.895 http://doi.org/10.1016/j.jacc.2011.10.895 . Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts SA Hunt , WT Abraham , MH Chin , AM Feldman , GS Francis , TG Ganiats , M Jessup , MA Konstam , DM Mancini , K Michl , 等 . 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation . J Am Coll Cardiol , 2009 . 53 ( 15 ): e1 - e90 . 19358937 DOI: 10.1016/j.jacc.2008.11.013 http://doi.org/10.1016/j.jacc.2008.11.013 . 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation JM Huss , DP Kelly . Mitochondrial energy metabolism in heart failure: a question of balance . J Clin Invest , 2005 . 115 ( 3 ): 547 - 555 . 15765136 DOI: 10.1172/JCI24405 http://doi.org/10.1172/JCI24405 . Mitochondrial energy metabolism in heart failure: a question of balance G Karamanlidis , L Nascimben , GS Couper , PS Shekar , F del Monte , R Tian . Defective DNA replication impairs mitochondrial biogenesis in human failing hearts . Circ Res , 2010 . 106 ( 9 ): 1541 - 1548 . 20339121 DOI: 10.1161/circresaha.109.212753 http://doi.org/10.1161/circresaha.109.212753 . Defective DNA replication impairs mitochondrial biogenesis in human failing hearts J Karbowska , Z Kochan , RT Smolenski . Peroxisome proliferator-activated receptor α is downregulated in the failing human heart . Cell Mol Biol Lett , 2003 . 8 ( 1 ): 49 - 53 . 12655356 . Peroxisome proliferator-activated receptor α is downregulated in the failing human heart I Kehat , JD Molkentin . Molecular pathways underlying cardiac remodeling during pathophysiological stimulation . Circulation , 2010 . 122 ( 25 ): 2727 - 2735 . 21173361 DOI: 10.1161/CIRCULATIONAHA.110.942268 http://doi.org/10.1161/CIRCULATIONAHA.110.942268 . Molecular pathways underlying cardiac remodeling during pathophysiological stimulation CD Kemp , JV Conte . The pathophysiology of heart failure . Cardiovasc Pathol , 2012 . 21 ( 5 ): 365 - 371 . 22227365 DOI: 10.1016/j.carpath.2011.11.007 http://doi.org/10.1016/j.carpath.2011.11.007 . The pathophysiology of heart failure Jr SC Kolwicz , R Tian . Glucose metabolism and cardiac hypertrophy . Cardiovasc Res , 2011 . 90 ( 2 ): 194 - 201 . 21502371 DOI: 10.1093/cvr/cvr071 http://doi.org/10.1093/cvr/cvr071 . Glucose metabolism and cardiac hypertrophy L Lai , TC Leone , C Zechner , PJ Schaeffer , SM Kelly , DP Flanagan , DM Medeiros , A Kovacs , DP Kelly . Transcriptional coactivators PGC-1α and PGC-1β control overlapping programs required for perinatal maturation of the heart . Genes Dev , 2008 . 22 ( 14 ): 1948 - 1961 . 18628400 DOI: 10.1101/gad.1661708 http://doi.org/10.1101/gad.1661708 . Transcriptional coactivators PGC-1α and PGC-1β control overlapping programs required for perinatal maturation of the heart C Ledderose , S Kreth , A Beiras-Fernandez . Ghrelin, a novel peptide hormone in the regulation of energy balance and cardiovascular function . Recent Pat Endocr Metab Immune Drug Discov , 2011 . 5 ( 1 ): 1 - 6 . 22074572 DOI: 10.2174/187221411794351897 http://doi.org/10.2174/187221411794351897 . Ghrelin, a novel peptide hormone in the regulation of energy balance and cardiovascular function V Lionetti , WC Stanley , FA Recchia . Modulating fatty acid oxidation in heart failure . Cardiovasc Res , 2011 . 90 ( 2 ): 202 - 209 . 21289012 DOI: 10.1093/cvr/cvr038 http://doi.org/10.1093/cvr/cvr038 . Modulating fatty acid oxidation in heart failure AS Marsin , L Bertrand , MH Rider , J Deprez , C Beauloye , MF Vincent , G van den Berghe , D Carling , L Hue . Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia . Curr Biol , 2000 . 10 ( 20 ): 1247 - 1255 . 11069105 DOI: 10.1016/S0960-9822(00)00742-9 http://doi.org/10.1016/S0960-9822(00)00742-9 . Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia MA Martin , MA Gomez , F Guillen , B Bornstein , Y Campos , JC Rubio , CS de la Calzada , J Arenas . Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure . Biochim Biophys Acta Mol Basis Dis , 2000 . 1502 ( 3 ): 330 - 336 . DOI: 10.1016/S0925-4439(00)00061-2 http://doi.org/10.1016/S0925-4439(00)00061-2 . Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure JJ McMurray , S Adamopoulos , SD Anker , A Auricchio , M Bohm , K Dickstein , V Falk , G Filippatos , C Fonseca , MA Gomez-Sanchez , 等 . ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 . Eur Heart J , 2012 . 33 ( 14 ): 1787 - 1847 . 22611136 DOI: 10.1093/eurheartj/ehs104 http://doi.org/10.1093/eurheartj/ehs104 . ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 AJ Murray , LM Edwards , K Clarke . Mitochondria and heart failure . Curr Opin Clin Nutr Metab Care , 2007 . 10 ( 6 ): 704 - 711 . 18089951 DOI: 10.1097/MCO.0b013e3282f0ecbe http://doi.org/10.1097/MCO.0b013e3282f0ecbe . Mitochondria and heart failure T Nagoshi , M Yoshimura , GM Rosano , GD Lopaschuk , S Mochizuki . Optimization of cardiac metabolism in heart failure . Curr Pharm Des , 2011 . 17 ( 35 ): 3846 - 3853 . 21933140 . Optimization of cardiac metabolism in heart failure S Neubauer . The failing heart—an engine out of fuel . N Engl J Med , 2007 . 356 ( 11 ): 1140 - 1151 . 17360992 DOI: 10.1056/NEJMra063052 http://doi.org/10.1056/NEJMra063052 . The failing heart—an engine out of fuel S Neubauer , M Horn , M Cramer , K Harre , JB Newell , W Peters , T Pabst , G Ertl , D Hahn , JS Ingwall , 等 . Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy . Circulation , 1997 . 96 ( 7 ): 2190 - 2196 . 9337189 DOI: 10.1161/01.CIR.96.7.2190 http://doi.org/10.1161/01.CIR.96.7.2190 . Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy LH Opie . Allopurinol for heart failure: novel mechanisms . J Am Coll Cardiol , 2012 . 59 ( 9 ): 809 - 812 . 22361400 DOI: 10.1016/j.jacc.2011.09.072 http://doi.org/10.1016/j.jacc.2011.09.072 . Allopurinol for heart failure: novel mechanisms LH Opie , J Knuuti . The adrenergic-fatty acid load in heart failure . J Am Coll Cardiol , 2009 . 54 ( 18 ): 1637 - 1646 . 19850204 DOI: 10.1016/j.jacc.2009.07.024 http://doi.org/10.1016/j.jacc.2009.07.024 . The adrenergic-fatty acid load in heart failure LH Opie , PJ Commerford , BJ Gersh , MA Pfeffer . Controversies in ventricular remodelling . Lancet , 2006 . 367 ( 9507 ): 356 - 367 . 16443044 DOI: 10.1016/s0140-6736(06)68074-4 http://doi.org/10.1016/s0140-6736(06)68074-4 . Controversies in ventricular remodelling G Paolisso , A Gambardella , D Galzerano , A D′Amore , P Rubino , M Verza , P Teasuro , M Varricchio , F D′Onofrio . Total-body and myocardial substrate oxidation in congestive heart failure . Metabolism , 1994 . 43 ( 2 ): 174 - 179 . 8121298 DOI: 10.1016/0026-0495(94)90241-0 http://doi.org/10.1016/0026-0495(94)90241-0 . Total-body and myocardial substrate oxidation in congestive heart failure KF Petersen , GI Shulman . Etiology of insulin resistance . Am J Med , 2006 . 119 ( 5S1 ): S10 - S16 . 16563942 DOI: 10.1016/j.amjmed.2006.01.009 http://doi.org/10.1016/j.amjmed.2006.01.009 . Etiology of insulin resistance B Pitt , W Remme , F Zannad , J Neaton , F Martinez , B Roniker , R Bittman , S Hurley , J Kleiman , M Gatlin , 等 . Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction . N Engl J Med , 2003 . 348 ( 14 ): 1309 - 1321 . 12668699 DOI: 10.1056/NEJMoa030207 http://doi.org/10.1056/NEJMoa030207 . Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction M Rajabi , C Kassiotis , P Razeghi , H Taegtmeyer . Return to the fetal gene program protects the stressed heart: a strong hypothesis . Heart Fail Rev , 2007 . 12 ( 3-4 ): 331 - 343 . 17516164 DOI: 10.1007/s10741-007-9034-1 http://doi.org/10.1007/s10741-007-9034-1 . Return to the fetal gene program protects the stressed heart: a strong hypothesis PJ Randle , PB Garland , CN Hales , EA Newsholme . The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus . Lancet , 1963 . 281 ( 7285 ): 785 - 789 . . The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus P Razeghi , ME Young , JL Alcorn , CS Moravec , OH Frazier , H Taegtmeyer . Metabolic gene expression in fetal and failing human heart . Circulation , 2001 . 104 ( 24 ): 2923 - 2931 . 11739307 DOI: 10.1161/hc4901.100526 http://doi.org/10.1161/hc4901.100526 . Metabolic gene expression in fetal and failing human heart FA Recchia , PI McConnell , RD Bernstein , TR Vogel , X Xu , TH Hintze . Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog . Circ Res , 1998 . 83 ( 10 ): 969 - 979 . 9815144 DOI: 10.1161/01.RES.83.10.969 http://doi.org/10.1161/01.RES.83.10.969 . Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog C Riehle , ED Abel . PGC-1 proteins and heart failure . Trends Cardiovasc Med , 2012 . 22 ( 4 ): 98 - 105 . 22939990 DOI: 10.1016/j.tcm.2012.07.003 http://doi.org/10.1016/j.tcm.2012.07.003 . PGC-1 proteins and heart failure GM Rosano , M Fini , G Caminiti , G Barbaro . Cardiac metabolism in myocardial ischemia . Curr Pharm Des , 2008 . 14 ( 25 ): 2551 - 2562 . 18991672 DOI: 10.2174/138161208786071317 http://doi.org/10.2174/138161208786071317 . Cardiac metabolism in myocardial ischemia MG Rosca , CL Hoppel . Mitochondria in heart failure . Cardiovasc Res , 2010 . 88 ( 1 ): 40 - 50 . 20668004 DOI: 10.1093/cvr/cvq240 http://doi.org/10.1093/cvr/cvq240 . Mitochondria in heart failure GC Rowe , A Jiang , Z Arany . PGC-1 coactivators in cardiac development and disease . Circ Res , 2010 . 107 ( 7 ): 825 - 838 . 20884884 DOI: 10.1161/CIRCRESAHA.110.223818 http://doi.org/10.1161/CIRCRESAHA.110.223818 . PGC-1 coactivators in cardiac development and disease HN Sabbah , VG Sharov , S Goldstein . Cell death, tissue hypoxia and the progression of heart failure . Heart Fail Rev , 2000 . 5 ( 2 ): 131 - 138 . 16228140 DOI: 10.1023/A:1009880720032 http://doi.org/10.1023/A:1009880720032 . Cell death, tissue hypoxia and the progression of heart failure S Sarma , H Ardehali , M Gheorghiade . Enhancing the metabolic substrate: PPAR-α agonists in heart failure . Heart Fail Rev , 2012 . 17 ( 1 ): 35 - 43 . 21104312 DOI: 10.1007/s10741-010-9208-0 http://doi.org/10.1007/s10741-010-9208-0 . Enhancing the metabolic substrate: PPAR-α agonists in heart failure AM Shah , DL Mann . In search of new therapeutic targets and strategies for heart failure: recent advances in basic science . Lancet , 2011 . 378 ( 9792 ): 704 - 712 . 21856484 DOI: 10.1016/s0140-6736(11)60894-5 http://doi.org/10.1016/s0140-6736(11)60894-5 . In search of new therapeutic targets and strategies for heart failure: recent advances in basic science S Sihag , S Cresci , AY Li , CC Sucharov , JJ Lehman . PGC-1α and ERRα target gene downregulation is a signature of the failing human heart . J Mol Cell Cardiol , 2009 . 46 ( 2 ): 201 - 212 . 19061896 DOI: 10.1016/j.yjmcc.2008.10.025 http://doi.org/10.1016/j.yjmcc.2008.10.025 . PGC-1α and ERRα target gene downregulation is a signature of the failing human heart H Sisakian , A Torgomyan , A Barkhudaryan . The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy . Acta Cardiol , 2007 . 62 ( 5 ): 493 - 499 . 17982971 . The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy WC Stanley , FA Recchia , GD Lopaschuk . Myocardial substrate metabolism in the normal and failing heart . Physiol Rev , 2005 . 85 ( 3 ): 1093 - 1129 . 15987803 DOI: 10.1152/physrev.00006.2004 http://doi.org/10.1152/physrev.00006.2004 . Myocardial substrate metabolism in the normal and failing heart H Taegtmeyer , K Ballal . No low-fat diet for the failing heart? . Circulation , 2006 . 114 ( 20 ): 2092 - 2093 . 17101867 DOI: 10.1161/CIRCULATIONAHA.106.659235 http://doi.org/10.1161/CIRCULATIONAHA.106.659235 . No low-fat diet for the failing heart? M Taylor , TR Wallhaus , TR Degrado , DC Russell , P Stanko , RJ Nickles , CK Stone . An evaluation of myocardial fatty acid and glucose uptake using pet with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure . J Nucl Med , 2001 . 42 ( 1 ): 55 - 62 . 11197981 . An evaluation of myocardial fatty acid and glucose uptake using pet with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure H Tsutsui , S Kinugawa , S Matsushima . Oxidative stress and heart failure . Am J Physiol Heart Circ Physiol , 2011 . 301 ( 6 ): H2181 - H2190 . 21949114 DOI: 10.1152/ajpheart.00554.2011 http://doi.org/10.1152/ajpheart.00554.2011 . Oxidative stress and heart failure AT Turer , CR Malloy , CB Newgard , MV Podgoreanu . Energetics and metabolism in the failing heart: important but poorly understood . Curr Opin Clin Nutr Metab Care , 2010 . 13 ( 4 ): 458 - 465 . 20453645 DOI: 10.1097/MCO.0b013e32833a55a5 http://doi.org/10.1097/MCO.0b013e32833a55a5 . Energetics and metabolism in the failing heart: important but poorly understood H Tuunanen , J Knuuti . Metabolic remodelling in human heart failure . Cardiovasc Res , 2011 . 90 ( 2 ): 251 - 257 . 21372005 DOI: 10.1093/cvr/cvr052 http://doi.org/10.1093/cvr/cvr052 . Metabolic remodelling in human heart failure H Tuunanen , E Engblom , A Naum , M Scheinin , K Nagren , J Airaksinen , P Nuutila , P Iozzo , H Ukkonen , J Knuuti . Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction . J Card Fail , 2006 . 12 ( 8 ): 644 - 652 . 17045185 DOI: 10.1016/j.cardfail.2006.06.005 http://doi.org/10.1016/j.cardfail.2006.06.005 . Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction H Tuunanen , E Engblom , A Naum , K Nagren , B Hesse , KE Airaksinen , P Nuutila , P Iozzo , H Ukkonen , LH Opie , 等 . Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure . Circulation , 2006 . 114 ( 20 ): 2130 - 2137 . 17088453 DOI: 10.1161/CIRCULATIONAHA.106.645184 http://doi.org/10.1161/CIRCULATIONAHA.106.645184 . Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure SS Vadvalkar , CN Baily , S Matsuzaki , M West , YA Tesiram , KM Humphries . Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of type 1 diabetes . Biochem J , 2013 . 449 ( 1 ): 253 - 261 . 23030792 DOI: 10.1042/BJ20121038 http://doi.org/10.1042/BJ20121038 . Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of type 1 diabetes M van Bilsen , FA van Nieuwenhoven , GJ van der Vusse . Metabolic remodelling of the failing heart: beneficial or detrimental? . Cardiovasc Res , 2009 . 81 ( 3 ): 420 - 428 . 18854380 DOI: 10.1093/cvr/cvn282 http://doi.org/10.1093/cvr/cvn282 . Metabolic remodelling of the failing heart: beneficial or detrimental? R Ventura-Clapier , A Garnier , V Veksler . Energy metabolism in heart failure . J Physiol , 2004 . 555 ( Pt1 ): 1 - 13 . 14660709 DOI: 10.1113/jphysiol.2003.055095 http://doi.org/10.1113/jphysiol.2003.055095 . Energy metabolism in heart failure R Ventura-Clapier , A Garnier , V Veksler , F Joubert . Bioenergetics of the failing heart . Biochim Biophys Acta , 2011 . 1813 ( 7 ): 1360 - 1372 . 20869993 DOI: 10.1016/j.bbamcr.2010.09.006 http://doi.org/10.1016/j.bbamcr.2010.09.006 . Bioenergetics of the failing heart JA Wooley . Characteristics of thiamin and its relevance to the management of heart failure . Nutr Clin Pract , 2008 . 23 ( 5 ): 487 - 493 . 18849553 DOI: 10.1177/0884533608323430 http://doi.org/10.1177/0884533608323430 . Characteristics of thiamin and its relevance to the management of heart failure J Yan , ME Young , L Cui , GD Lopaschuk , R Liao , R Tian . Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity . Circulation , 2009 . 119 ( 21 ): 2818 - 2828 . 19451348 DOI: 10.1161/CIRCULATIONAHA.108.832915 http://doi.org/10.1161/CIRCULATIONAHA.108.832915 . Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity F Zannad , JJ McMurray , H Krum , DJ van Veldhuisen , K Swedberg , H Shi , J Vincent , SJ Pocock , B Pitt , EHS Group . Eplerenone in patients with systolic heart failure and mild symptoms . N Engl J Med , 2011 . 364 ( 1 ): 11 - 21 . 21073363 DOI: 10.1056/NEJMoa1009492 http://doi.org/10.1056/NEJMoa1009492 . Eplerenone in patients with systolic heart failure and mild symptoms L Zhang , Y Lu , H Jiang , L Zhang , A Sun , Y Zou , J Ge . Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis . J Am Coll Cardiol , 2012 . 59 ( 10 ): 913 - 922 . 22381427 DOI: 10.1016/j.jacc.2011.11.027 http://doi.org/10.1016/j.jacc.2011.11.027 . Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis Compliance with ethics guidelines Jing WANG and Tao GUO declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1300137 2013-05-13 2013-07-19 2013-07-04 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2013 2013 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 08 14