Deranged Cardiac Metabolism and the Pathogenesis of Heart Failure

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Abstract

Activation of the neuro-hormonal system is a pathophysiological consequence of heart failure. Neuro-hormonal activation promotes metabolic changes, such as insulin resistance, and determines an increased use of non-carbohydrate substrates for energy production. Fasting blood ketone bodies as well as fat oxidation are increased in patients with heart failure, yielding a state of metabolic inefficiency. The net result is additional depletion of myocardial adenosine triphosphate, phosphocreatine and creatine kinase levels with further decreased efficiency of mechanical work. In this context, manipulation of cardiac energy metabolism by modification of substrate use by the failing heart has produced positive clinical results. The results of current research support the concept that shifting the energy substrate preference away from fatty acid metabolism and towards glucose metabolism could be an effective adjunctive treatment in patients with heart failure. The additional use of drugs able to partially inhibit fatty acids oxidation in patients with heart failure may therefore yield a significant protective effect for clinical symptoms and cardiac function improvement, and simultaneously ameliorate left ventricular remodelling. Certainly, to clarify the exact therapeutic role of metabolic therapy in heart failure, a large multicentre, randomised controlled trial should be performed.

Disclosure
GF has received travel grants from and performed remunerated lectures for Servier.
Correspondence
Gabriele Fragasso, Heart Failure Unit, Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E: gabriele.fragasso@hsr.it
Received date
18 December 2015
Accepted date
24 March 2016
Citation
Cardiac Failure Review, 2016;2(1):8–13
DOI
http://dx.doi.org/10.15420/cfr.2016:5:2

The development of heart failure is rarely dependent on primary alterations of cardiac metabolism. The majority of heart failure cases result from diseases of the cardiac muscle, most frequently ischaemic heart disease. However, whatever the cause of heart failure, the net result will be depletion of myocardial adenosine triphosphate (ATP), phosphocreatine and creatine kinase levels with decreased efficiency of mechanical work. Once heart failure has developed, the neurohormonal axis is activated with the aim to sustain haemodynamic failure. Activation of adrenergic and renin-angiotensin-aldosterone systems indirectly determine specific metabolic alterations in the cardiac and skeletal muscles. Over the last two decades, despite the adoption of drugs able to block neuro-hormonal activation in heart failure dramatically improving the overall prognosis of this deadly disease, mortality and morbidity remain a critical problem. In fact, apart from the well-known effects on chronotropism, inotropism, vascular tone and blood volume, the residual physiological effects of neuro-hormones indirectly determine a state of low metabolic efficiency in both the skeletal and cardiac muscles. The aim of this review is to analyse the metabolic derangement in the failing heart and, on this basis, speculate on possible new therapeutic targets.

Deranged Cellular Metabolism in Heart Failure

Under normal conditions, the healthy heart derives most of its energy from the free fatty acid (FFA) pathway that accounts for approximately two-thirds of energy production; the other source of energy being derived from glucose oxidation and lactate.1,2 FFA and glucose metabolism inter-regulate each other, a process referred to as the Randle cycle.3 Increasing FFA oxidation in the heart decreases glucose oxidation, while increasing glucose oxidation inhibits FFA oxidation. However, energy being derived from FFA oxidation is a less efficient source of energy than glucose oxidation (in terms of ATP produced per O2 molecules consumed) and determines a reduction of cardiac efficiency. In fact, the amount of ATP produced per O2 consumed is greater when glucose is oxidised compared with FFA and, therefore, FFA is a less efficient energy substrate than glucose. Elevated FFA oxidation can result in up to a 30 % decrease in cardiac efficiency.2

Progressive heart failure induces an imbalance between the requirement of cardiac tissue for oxygen and metabolic supplies and their availability, resulting in functional, metabolic and morphological alteration of the myocardium. At a cellular level, glucose uptake is decreased and conversion to lactate is increased; lactate uptake by the heart is switched to lactate production, and pyruvate is mostly transformed into lactate, thereby increasing cell acidosis. The FFA pathway is also slowed down, yet most of the produced energy comes from FFA oxidation, resulting in less ATP production. These metabolic changes lead to disruption of cell homeostasis, alterations in membrane structure and, ultimately, cell death. The following sections will attempt to clarify the mechanism at the base of these metabolic changes.

Effects of the Neuro-hormonal Activation on Metabolism of the Failing Heart

Neuro-hormonal activation significantly contributes to cardiac mechanical and metabolic inefficiency of the cardiac muscle and whole body of patients with heart failure. This vicious circle is likely mediated by increased use of non-carbohydrate substrates for energy production,2 resulting from different mechanisms. Adrenergically mediated increased peripheral lipolysis (wasting of subcutaneous fat and skeletal muscle) results in grossly augmented FFA availability. In fact, fasting blood ketone bodies4 as well as fat oxidation during exercise5 have been shown to be increased in patients with heart failure. Adrenergic activation may also induce insulin resistance, which is also associated with heart failure6 and may further contribute to increased circulating FFA levels by the development of ketosis and consequent impaired suppression of lipolysis. Indirect effects of augmented adrenergic tone in heart failure include increased heart rate, vasoconstriction and inotropism, which, in turn, may also indirectly contribute to a state of functional and metabolic inefficiency.

Angiotensin II is also an important regulator of cardiac energy metabolism and function.7 There are several mechanisms through which angiotensin II contributes to heart failure occurrence and persistence. Angiotensin II damages mitochondria in the cardiomyocyte by increasing reactive oxygen species production8 and affects mitochondrial oxidative phosphorylation, including FFA oxidation.9,10 These data suggest that angiotensin II affects FFA oxidation. There is also evidence that angiotensin II regulates glucose oxidation7,11 and its inhibition may exert beneficial effects. In addition, by decreasing oxidative metabolism, angiotensin II can compromise ATP production, thus reducing its availability.12 In this context, angiotensin II antagonism represents an attractive therapeutic approach. Studies using the euglycaemic insulin clamp technique have indicated that the beneficial effect of angiotensin II is exerted on insulin sensitivity. In fact, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists have been shown to improve both left ventricular function and glucose homeostasis.13,14 Increased blood flow in skeletal muscle, accumulation of bradykinin or more efficient insulin release may be suggested as potential modes of action.

Endothelial dysfunction, a critical component in the progression of heart failure, may result from increased oxidative stress, secondary to activation of the adrenergic and the renin-angiotensin systems and to the production of inflammatory cytokines.15 In heart failure, the role of reduced bioavailability of nitric oxide (NO) is still under debate,16,17 while increased endothelin-1 (ET-1) levels are a mainstay.18 Growth factors, vasoactive substances and mechanical stress contribute to the increased ET-1 levels in patients with heart failure. Despite the known adaptative aspect of supporting contractility of the failing heart, persistent increases in cardiac ET-1 expression in the failing heart have a pathophysiological maladaptive aspect and are associated with the severity of myocardial dysfunction.19 It has been observed that trimetazidine could reduce endothelin release in patients with cardiac disease.20,21 Trimetazidine-induced reduction of intracellular acidosis in ischaemic myocardium might not only influence myocardial but also endothelial membranes.22 By decreasing endothelial damage, trimetazidine could inhibit ET-1 release that, in turn, may decrease myocardial damage. A second hypothesis is that, by just decreasing the effects of chronic myocardial ischaemia, trimetazidine could inhibit ET-1 release. Therefore, the observed decrease in ET-1 release with trimetazidine, could likely be linked to trimetazidine-induced reduction of myocardial ischaemia. Finally, keeping in mind the close relation between endothelium and insulin sensitivity, the observed effects of trimetazidine on endothelial function could also explain the beneficial action of trimetazidine on glucose metabolism.

In the same context, the potential beneficial effect of 6 weeks of oral L-arginine supplementation on endurance exercise, an important determinant of daily-life activity in patients with chronic stable heart failure, has been assessed.23 L-Arginine is the precursor of endogenous NO, which is a potent vasodilator acting via the intracellular second-messenger cyclic guanosine monophosphate. In healthy individuals, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production. The results of this study show that arginine enhanced endurance exercise tolerance, reducing both heart rate and circulating lactate levels, suggesting that chronic arginine administration might be useful as a therapeutic adjuvant to improve the patient’s physical fitness.

In summary, in the failing heart neuro-hormonal activation determines a combination of direct and indirect haemodynamic and metabolic actions, which, despite a potential teleological purpose, will eventually lead to further deterioration of cardiac function, mainly mediated by the resulting decreased metabolic efficiency of the cardiomyocytes. Specific therapies may attenuate these effects.

Abnormal Glucose Metabolism in Heart Failure

As glucose and lactate are more efficient fuels for aerobic respiration, increasing the use of these substrates can improve the oxygen consumption efficiency of the myocardium by 16–26 %.24 In addition, skeletal muscle glucose uptake in the heart and arm is inversely related to serum FFA levels25 and increased FFA flux from adipose tissue to non-adipose tissue amplifies metabolic derangements that are characteristic of the insulin resistance syndrome.26 Further findings suggest that raised FFA levels not only impair glucose uptake in heart and skeletal muscle but also cause alterations in the metabolism of vascular endothelium, leading to premature cardiovascular disease.27

Global Energy Expenditure in Heart Failure

Energy consumption at rest appears higher in patients with heart failure than in healthy subjects.28–30 It has been shown that increased rate of energy expenditure is related to increased serum FFA oxidation and that both energy expenditure and serum FFA oxidation are inversely correlated with left ventricular ejection fraction and positively correlated with growth hormone, epinephrine and norepinephrine concentrations.31 Norepinephrine increases whole-body oxygen consumption, circulating FFA concentrations, and FFA oxidation.32 These changes have been attributed to stimulation of hormone-sensitive lipase in adipose tissue, and to stimulation of oxygen consumption independent of lipolysis by norepinephrine.33 These data, together with close correlations between plasma norepinephrine concentrations, energy expenditure at rest and FFA oxidation, make increased sympathetic activity the most likely explanation for alterations in fuel homeostasis in patients with heart failure.33 Therefore, intervention strategies aimed at optimising global and cardiac metabolism could be useful for interrupting the vicious circle of reduced function at greater metabolic expenses in different cardiac conditions.

Pharmacological Implications of Impaired Myocardial Metabolism in Heart Failure

Given the above-described pathophysiological background and the difficulty of standard treatment to control the total symptomatic and prognostic burden in many patients with heart failure, it seems logical to consider pharmacological manipulation of cardiac energy metabolism as an adjunctive therapeutic option. Optimisation of cardiac energy metabolism is based on promoting cardiac glucose oxidation.

Metabolic Vicious Circle in Heart Failure

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Stimulation of myocardial glucose oxidation can be achieved either directly with stimulation of glucose metabolism, or indirectly through inhibition of fatty acid beta-oxidation, in order to shift energy substrate utilisation away from fatty acid metabolism and towards glucose metabolism which, as explained above, is more efficient in terms of ATP production per mole of oxygen used. Therefore, metabolic therapy could play a beneficial role in terms of glucose metabolism homeostasis.

The concept that drugs able to promote the use of glucose and non-fatty substrates by the mitochondria may increase metabolic efficiency and function of the failing heart has prompted several clinical studies. Experimental studies have first shown that stimulation of pyruvate dehydrogenase activity leads to enhanced glycolysis and use of lactate by the myocardium for aerobic respiration.34 Myocardial consumption of FFA is simultaneously inhibited, with the overall effect of a change of substrate use from predominantly non-esterified FFA to glucose and lactate,35 finally resulting in improved left ventricular mechanical efficiency.36

Trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine dihydrochloride) has been shown to directly inhibit FFA oxidation by blocking 3-ketoacyl-coenzyme A thiolase (3-KAT), the last enzyme involved in beta-oxidation,37 although this issue remains controversial.38,39 Trimetazidine affects myocardial substrate use by inhibiting oxidative phosphorylation and by shifting energy production from FFA to glucose oxidation (see Figure 1).40 Several studies have outlined the potential benefits of this agent on regional and global myocardial dysfunction.41–49 3-KAT inhibitors could also play a beneficial role in terms of glucose metabolism homeostasis at both cardiac and skeletal muscle level. The beneficial effect of trimetazidine on left ventricular function, has been attributed to preservation of phosphocreatine (PCr) and ATP intracellular levels.50 Clinical studies using phosphorus-31 magnetic resonance spectroscopy to measure PCr:ATP ratios in human myocardium have shown that this ratio is reduced in failing human myocardium.51 The PCr:ATP ratio is a measure of myocardial energetics and its reduction may depend on imbalance of myocardial oxygen supply and demand,52 and reduction of the total creatine pool, a phenomenon known to occur in heart failure.53 In a study performed in patients with heart failure of different aetiologies receiving full standard medical therapy, it was observed that the trimetazidineinduced improvement of functional class and left ventricular function was associated with an improvement of PCr:ATP ratio, supporting the hypothesis that trimetazidine may preserve myocardial high-energy phosphate intracellular levels.54 These results appear particularly interesting, especially in view of previous evidence indicating the PCr:ATP ratio as a significant predictor of mortality.55 In fact, imetazidine has been shown to improve prognosis in patients with heart failure in a multicentre retrospective cohort study56 and in two meta-analyses.57,58 On this basis, its use in patients with heart failure has been advocated in a recently published position paper.59

Similarly to trimetazidine, ranolazine has also been shown to significantly improve left ventricular performance in experimental models of heart failure.60–63 Sabbah et al. measured haemodynamics before and 40 minutes after intravenous ranolazine administration in a canine model of heart failure.60 Results in 13 experimental dogs were compared with those obtained in eight normal healthy dogs. Ranolazine significantly decreased left ventricular end-diastolic pressure and increased left ventricular ejection fraction in the absence of any effects on heart rate or blood pressure. In subsequent experiments from the same laboratory, Chandler et al. reproduced these findings and determined that the improvement in left ventricular performance was not associated with an increase in myocardial oxygen consumption (MO2) compared with an intravenous infusion of dobutamine that improved left ventricular performance to a similar extent, but was associated with a significant increase in MO2 requirements.61

Overall, these data confirm that selective inhibition of 3-KAT represents a new therapeutic window in the treatment of patients with heart failure of different aetiologies.

Combined Metabolic Action of Beta-blockers and Trimetazidine

ACE inhibitors and beta-blockers remain the clinical mainstay of the treatment of heart failure. It is interesting to note that beta-blockers may yield an ancillary metabolic effect. Their principal mechanism of action is based on reduction of oxygen consumption by reduced heart rate and inotropism. However, a direct complementary metabolic effect could be exerted by beta-blockers themselves, by reducing peripheral lipolysis and determining reduction of FFA availability. There is indeed evidence that beta-blockade can reduce FFA use in favour of greater glucose use in patients with cardiac disease.64 This change in myocardial energetics could provide a potential mechanism for the decreased MO2 and improved energy efficiency seen with beta-adrenoreceptor blockade in the treatment of ischaemic heart disease and heart failure.65

The issue of whether non-selective, compared with selective betaadrenoreceptor blockers are more efficient in shifting total body substrate use from lipid to glucose oxidation66 remains controversial.67 Nevertheless, a better metabolic disposition of non-selective betablockers may contribute to improved survival rates observed with their use.68 In addition, central inhibition of sympathetic nervous activity with moxonidine has been associated with increased mortality rates in patients with chronic heart failure.69 In fact, despite a significant reduction of cathecolamine spillover and, consequently, heart rate, moxonidine has been shown to increase FFA use and increase MO2 consumption.70 This could be the reason for the failure of central sympathetic inhibition in preventing death in long-term studies in patients with chronic heart failure. It also indicates that the predominant mechanism of action of beta-blockers in cardiac syndromes is likely related to mechanisms of action other than simple heart rate reduction. In patients with heart failure the magnitude of heart rate reduction may therefore be a marker of improved functional response following beta-blockade administration, a consequent effect rather than a mechanism. Nonetheless, a clinical trial in which the cardiac ‘funny’ (If) channel inhibitor ivabradine (a pure heart rate-lowering agent) was added to beta-blockade (SHIFT [Systolic Heart Failure Treatment With the lf Inhibitor Ivabradine Trial]) clearly demonstrated that the greater the heart rate reduction the greater the reduction of hospitalisation events in patients with heart failure.71 Therefore, apart from the importance of heart rate lowering per se, a complementary synergistic metabolic action of beta-blockers and trimetazidine can be hypothesised: whereas the former reduce FFA availability, the latter decrease their cardiac use. Overall, this drug-induced metabolic shift could reduce FFA oxidation and increase the flux through pyruvate dehydrogenase with a consequent energy-sparing effect.54,72

Additional data also suggest that the metabolic effect of trimetazidine may also take place in other organs and tissues.72 In fact, apart from a reduction of whole-body energy demand, a trend for a reduction of whole-body lipid oxidation and of fasting plasma FFA concentration has also been observed.72 This general metabolic shift could reduce the overall metabolic requirements of the body, resulting in an attractive adaptation strategy in the context of coronary and myocardial insufficiencies. Interestingly, beta-blockers have also been shown to exert a direct effect on whole-body metabolism. In trained athletes, beta-adrenergic blockade abolishes the marked increase in plasma glucose levels during intense exercise as a result of enhanced peripheral glucose uptake, with no significant change in glucose production.73 These effects of adrenergic blockade on glucose kinetics could be mediated by direct effects or indirectly through changes in lipid substrates and/or counter-regulatory hormones.

Other Inhibitors of Fatty Acids Oxidation

Etomoxir, perhexiline and oxfenicine are carnitine palmitoyltransferase I (CPT-I) inhibitors. CPT-I is the key enzyme for mitochondrial FFA uptake; its inhibition, therefore, reduces FFA oxidation and their inhibitory effect on pyruvate dehydrogenase. As a consequence, glucose oxidation is increased.74,75 Etomoxir, initially developed as an antidiabetic agent, has been observed to improve left ventricular performance of pressure-overloaded rat heart.76 These effects have been considered due to a selective modification of gene expression of hypertrophic cardiomyocytes.77 Etomoxir has also been shown to increase phosphatase activation, have a direct effect on peroxisome proliferator-activated receptor-alpha and upregulate the expression of various enzymes involved in beta-oxidation.77 The first clinical trial employing etomoxir in patients with heart failure showed a significant clinical and cardiac function improvement.78 In experimental animal studies, etomoxir has also been shown to improve glucose metabolism.79 However, the use of etomoxir may be limited by the observations that it may cause cardiac hypertrophy80 and oxidative stress.81

Analogous to etomoxir, perhexiline and oxfenicine, originally classified as calcium antagonists, reduce cardiac use of long-chain fatty acids by inhibiting CPT-I.82–84 They were initially developed as antianginal agents.85,86 However, they have since been employed in patients with heart failure. In a previous study, metabolic modulation with perhexiline improved maximal oxygen consumption at the cardiopulmonary exercise test, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics.87 More recently, and similarly to trimetazidine, perhexiline has been shown to improve cardiac energetics and symptom status with no evidence of altered cardiac substrate use, further supporting the hypothesis of energy deficiency in heart failure and further consideration of metabolic therapies in its management.88 Therefore, similarly to 3-KAT inhibitors, CPT-I inhibitors may represent a novel treatment in patients with heart failure with a good safety profile, provided that the dosage is adjusted according to plasma levels.

FFA Inhibition in Older Patients

Age-related changes of mitochondria impair the human host cells homeostasis and contribute to the development of most common ageing diseases. Older subjects without overt cardiac diseases are prone to develop heart failure with preserved ejection fraction. Risk factors do not fully account for the aged heart functional loss that might be underlined by a common pathogenic denominator (i.e. cell energy alteration at mitochondrial level in organs requiring high energy). In older men without overt cardiovascular disease, the presence of prepathologic conditions (pre-hypertension, reduced insulin sensitivity, impaired myocardial contractile reserve, inadequate vasodilation due to endothelial dysfunction, reduced cardiomyocytes renewal, systemic inflammation and raised coagulation capacity) are possibly related to reduced mitochondrial function and density. Several studies have indeed shown reduced mitochondrial content and function with ageing, leading to the theory that decreased mitochondrial content and increased uncoupling with age compromises the energy state of the cell.89 Indeed, altered beta-oxidation increases the reliance on long-chain fatty acids relative to glucose with subsequent decrease of cellular metabolic efficiency at any given level of tissue activity. On this basis, in older patients with coronary artery disease, partial fatty acid oxidation inhibition by trimetazidine added to standard optimal medical therapy has been shown to improve reverse remodelling of chronically dysfunctional myocardium90 and improve cardiac symptoms and quality of life.91 The observed improvement could be related to increased cellular energy reserve,54 which could be pivotal in a context of ageing-induced reduction of mitochondrial efficiency.

The Importance of a Correct Metabolic Substrate Availability

It remains questionable whether metabolic substrate availability rather than pharmacological shift from fatty acids to glucose oxidation may be appropriate in patients with long-lasting heart failure.92 In fact, the anti-lipolytic drug acipimox, which reduces substrate availability and impairs fatty acid oxidation, has been shown to worsen left ventricular function in patients with idiopathic dilated cardiomyopathy.93 In addition, when substrate availability is acutely modulated during exercise testing in patients with stable coronary artery disease and preserved left ventricular function using a high-carbohydrate meal versus a high-fat meal, a lower ischaemic threshold and greater ischaemia magnitude is observed following the high-carbohydrate meal.94 Reduced lipid uptake and disposal in the setting of heart failure may represent therefore a maladaptive response. A recent study evaluated the metabolic and functional effects of high- and low-serum FFA availability in the presence of normal fasting serum glucose and insulin concentrations.95 In patients with chronic heart failure, short-term reduction in serum FFA concentration, while serum glucose and insulin concentrations remained closed to the fasting levels, induced an impairment of left ventricular energy metabolism and left ventricular function at rest. A two-fold serum FFA increment in the same experimental conditions did not induce any detectable change.95 Although in previous studies pharmacological manipulation of the heart substrates preferences has been shown to exert beneficial effects, these data demonstrate that direct deprivation of energy substrates is detrimental for cardiac metabolism and function. The clinical fallout is that metabolic manipulation at the systemic level may be considered in order to optimise the treatment of these patients; we also believe that special cautions should be considered when iatrogenic and acute changes of substrates and regulatory hormones of glucose and FFA metabolism are to be performed in these extremely vulnerable patients.

Conclusion

All cardiac syndromes may induce and be maintained by modifications of cardiac metabolism. Heart failure may be dependent on and promote metabolic changes in part through neurohormonal activation determining an increased use of non-carbohydrate substrates for energy production. This metabolic adaptation yields a state of metabolic inefficiency. The net result is depletion of myocardial ATP, phosphocreatine and creatine kinase levels with decreased efficiency of mechanical work. Different therapeutic approaches have been developed to manipulate cardiac energy metabolism. However, the most effective approach consists in modifying substrate use by the failing heart and includes several pharmacological agents. These agents have been originally adopted to increase the ischaemic threshold in patients with effort angina. However, the results of current research support the concept that shifting the energy substrate preference away from fatty acid metabolism and glucose metabolism could be an effective adjunctive treatment in patients with heart failure. Nevertheless, the exact role of metabolic therapy in heart failure is yet to be established, and a large multicentre randomised trial is necessary.

References
  1. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipids. Progr Cardiovasc Dis 1972;15:289–329.
    Crossref | PubMed
  2. Lopaschuk GD, Ussher JR, Folmes CD, et al. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207–58.
    Crossref | PubMed
  3. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;281:785–9.
    Crossref | PubMed
  4. Lommi J, Kupari M, Koskinen P, et al. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol 1996;28:665–72.
    Crossref | PubMed
  5. Riley M, Bell N, Elborn JS, et al. Metabolic response to graded exercise in chronic heart failure. Eur Heart J 1993;14:1484–8.
    Crossref | PubMed
  6. Paolisso G, De Riu S, Marrazzo G, et al. Insulin resistance and hyperinsulinemia in patients with chronic heart failure. Metabolism 1991;40:972–7.
    Crossref | PubMed
  7. Mori J, Basu R, McLean BA, et al. Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ Heart Fail 2012;5:493–503.
    Crossref | PubMed
  8. Dai DF, Johnson SC, Villarin JJ, et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 2011;108:837–46. 
    Crossref | PubMed
  9. Pellieux C, Aasum E, Larsen TS, et al. Overexpression of angiotensinogen in the myocardium induces downregulation of the fatty acid oxidation pathway. J Mol Cell Cardiol 2006;41:459–66.
    Crossref | PubMed
  10. Pellieux C, Montessuit C, Papageorgiou I, Lerch R. Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-alpha. Cardiovasc Res 2009;82:341–50.
    Crossref | PubMed
  11. Mori J, Alrob OA, Wagg CS, et al. Ang II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4. Am J Physiol Heart Circ Physiol 2013;304:H1103–13.
    Crossref | PubMed
  12. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 2014;171:2080– 90.
    Crossref | PubMed
  13. Vermes E, Ducharme A, Bourassa MG, et al. Tardif, for the studies of left ventricular dysfunction. enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;107:1291–6.
    Crossref | PubMed
  14. Yusuf S, Ostergren JB, Gerstein HC, et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005;112:48–53.
    Crossref | PubMed
  15. Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69:1596– 601.
    Crossref | PubMed
  16. Parodi O, De Maria R, Roubina E. Redox state, oxidative stress and endothelial dysfunction in heart failure: the puzzle of nitrate-thiol interaction. J Cardiovasc Med 2007;8:765–74.
    Crossref | PubMed
  17. Traverse JH, Chen Y, Hou M, Bache RJ. Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure. Am J Physiol Heart Circ Physiol. 2002;282:H2278–83. 
    Crossref | PubMed
  18. Kiowski W, Sutsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732–36.
    Crossref | PubMed
  19. Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al. Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin production in the heart and beneficial effect of endothelin A antagonist on survival and cardiac function. Circulation 1999;99:2171–6.
    Crossref | PubMed
  20. Fragasso G, Piatti P, Monti L, et al. Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: evaluation of the protective role of the metabolic modulator trimetazidine. J Am Coll Cardiol 2002;39:413–9.
    Crossref | PubMed
  21. Monti LD, Setola E, Fragasso G, et al. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab 2006;290:E54–9.
    Crossref | PubMed
  22. Maridonneau-Parini I, Harpey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol 1985;20:148–51.
    Crossref | PubMed
  23. Doutreleau S1, Mettauer B, Piquard F, et al. Chronic L-arginine supplementation enhances endurance exercise tolerance in heart failure patients. Int J Sports Med 2006;27:567–72.
    Crossref | PubMed
  24. Lopaschuck GD, Stanley WC. Glucose metabolism in the ischemic heart. Circulation 1997;95:313–5.
    Crossref | PubMed
  25. Nuutila P, Knuuti MJ, Raitakari M, et al. Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol 1994;267:E941–6.
    PubMed
  26. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002;23:201–29.
    Crossref | PubMed
  27. Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia 2002;45:623–34.
    Crossref | PubMed
  28. Peabody FW, Meyer AL, Du Bois EF. The basal metabolism of patients with cardiac and renal disease. Arch Int Med 1916;17:980–1009.
  29. Riley M, Elborn JS, McKane WR, et al. Resting energy expenditure in chronic cardiac failure. Clin Sci 1991;80:633–9.
    Crossref | PubMed
  30. Poehlman ET, Scheffers J, Gottlieb SS, et al. Increased resting metabolic rate in patients with congestive heart failure. Ann Intern Med 1994;121:860–2.
    Crossref | PubMed
  31. Lommi J, Kupari M, Yki-Järvinen H. Free fatty acid kinetics and oxidation in congestive heart failure. Am J Cardiol 1998;81:45– 50.
    Crossref | PubMed
  32. Steinberg D, Nestel PJ, Buskirk ER, Thompson RH. Calorigenic effect of norepinephrine correlated with plasma free fatty acid turnover and oxidation. J Clin Invest 1964;43:167–76.
    Crossref | PubMed
  33. Landsberg L, Saville ME, Young JB. Sympathoadrenal system and regulation of thermogenesis. Am J Physiol 1984;247:E181–9.
    PubMed
  34. Mc Veigh JJ, Lopaschuck GD. Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Physiol 1990;259:H1070–85.
    PubMed
  35. Nicholl TA, Lopaschuck GD, McNeill GH. Effects of free fatty acids and dichloroacetate on isolated working diabetic rat hearts. Am J Physiol 1991;261:H1053–9.
    PubMed
  36. Bersin RM, Wolfe C, Kwasman M, et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 1994;23:1617–24.
    Crossref | PubMed
  37. Kantor PF, Lucien A, Kozak R, Lopashuck GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580–8.
    Crossref | PubMed
  38. Lopaschuk GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2003;93:e33–7.
    Crossref | PubMed
  39. MacInness A, Fairman DA, Binding P, et al. The antianginal trimetazidine does not exert its functional benefit via inhibition of mithochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2003;93:e26–32.
    Crossref | PubMed
  40. Fantini E, Demaison L, Sentex E, et al. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol 1994;26:949–58.
    Crossref | PubMed
  41. Brottier L, Barat JL, Combe C, et al. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J 1990;11:207–12.
    PubMed
  42. Lu C, Dabrowski P, Fragasso G, Chierchia SL. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998;82:898–901. 
    Crossref | PubMed
  43. Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001;22:2164–70.
    Crossref | PubMed
  44. Fragasso G, Piatti PM, Monti L, et al. Short- and long-term beneficial effects of partial free fatty acid inhibition in diabetic patients with ischemic dilated cardiomyopathy. Am Heart J 2003;146:E18.
    PubMed
  45. Rosano GMC, Vitale C, Sposato B, et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16. 
    PubMed
  46. Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:161–5.
    Crossref | PubMed
  47. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol 2006;48:992–8.
    Crossref | PubMed
  48. Sisakian H, Torgomyan A, Barkhudaryan A. The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy. Acta Cardiol 2007;62:493–9.
    Crossref | PubMed
  49. Di Napoli P, Di Giovanni P, Gaeta MA, et al. Trimetazidine and reduction in mortality and hospitalization in patients with ischemic dilated cardiomyopathy: a post hoc analysis of the Villa Pini d’Abruzzo Trimetazidine Trial. J Cardiovasc Pharmacol 2007;50:585–9.
    Crossref | PubMed
  50. Lavanchy N, Martin J, Rossi A. Anti-ischemia effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart. Arch Int Pharmacodyn Ther 1987;286:97–110.
    PubMed
  51. Conway MA, Allis J, Ouwerkerk R, et al. Detection of low PCr to ATP ratio in failing hypertrophied myocardium by 31P magnetic resonance spectroscopy. Lancet 1991;338:973–6.
    Crossref | PubMed
  52. Yabe T, Mitsunami K, Inubushi T, Kinoshita M. Quantitative measurements of cardiac phosphorus metabolites in coronary artery disease by 31P magnetic resonance spectroscopy. Circulation 1995;92:15–23. 
    Crossref | PubMed
  53. Nascimben L, Ingwall JS, Pauletto P, et al. The creatine kinase system in failing and nonfailing human myocardium. Circulation 1996;94:1894–901.
    Crossref | PubMed
  54. Fragasso G, De Cobelli F, Perseghin G, et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 2006;27:942–8.
    Crossref | PubMed
  55. Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997;96:2190–6.
    Crossref | PubMed
  56. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: Results from an international multicentre retrospective cohort study. Int J Cardiol 2013;163:320–5.
    Crossref | PubMed
  57. Gao D, Ning N, Niu X, et al. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart 2011;97:278–86.
    Crossref | PubMed
  58. Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol 2012;59:913–22..
    Crossref | PubMed
  59. Lopatin YM, Rosano GM, Fragasso G, et al. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol 2015;203:909–15.
    Crossref | PubMed
  60. Sabbah HN, Chandler MP, Mishima T, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002;8:416–22. 
    Crossref | PubMed
  61. Chandler MP, Stanley WC, Morita H, et al. Short-term treatment with ranolazine improves mechanical efficacy in dogs with chronic heart failure. Circ Res 2002;91:278–80.
    Crossref | PubMed
  62. Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;5:741–7.
    Crossref | PubMed
  63. Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996;28:353–62.
    Crossref | PubMed
  64. Wallhaus TR, Taylor M, DeGrado TR, Russell DC. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001;103:2441–6.
    Crossref | PubMed
  65. Spoladore R, Fragasso G, Perseghin G, et al. Beneficial effects of beta-blockers on left ventricular function and cellular energy reserve in patients with heart failure. Fundam Clin Pharmacol 2013;27:455–64. 
    Crossref | PubMed
  66. Podbregar M, Voga G. Effect of selective and nonselective beta-blockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Cardiac Fail 2002:8:369–78.
    Crossref | PubMed
  67. Sharma V, Dhillon P, Wambolt R, et al. Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin (STZ) diabetic rat. Am J Physiol Heart Circ Physiol 2008;294:H1609–20.
    Crossref | PubMed
  68. Poole-Wilson P, Swedberg K, Cleland J, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13.
    Crossref | PubMed
  69. Cohn JN1, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central sympathetic inhibition with sustainedrelease moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003;5:659–66.
    Crossref | PubMed
  70. Mobini R, Jansson PA, Bergh CH, et al. Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the imidazoline I1-receptor agonist moxonidine. Clin Sci 2006;110:329–36.
    Crossref | PubMed
  71. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.
    Crossref | PubMed
  72. Fragasso G, Salerno A, Lattuada G, et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart 2011;97:1495–500.
    Crossref | PubMed
  73. Howlett KF, Watt MJ, Hargreaves M, Febbraio MA. Regulation of glucose kinetics during intense exercise in humans: effects of alpha- and beta-adrenergic blockade. Metabolism 2003;52:1615–20.
    Crossref | PubMed
  74. Lopashuck GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988;63:1036–43.
    Crossref | PubMed
  75. Ratheiser K, Schneeweiss B, Waldhäusl W, et al. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulindependent diabetes mellitus. Metabolism 1991;40:1185–90.
    Crossref | PubMed
  76. Turcani M, Rupp H. Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation 1997;96:3681–6.
    Crossref | PubMed
  77. Zarain-Herzberg A, Rupp H. Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Expert Opin Investig Drugs 2002;11:345–56.
    Crossref | PubMed
  78. Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci 2000;99:27–35.
    Crossref | PubMed
  79. Schmitz FJ, Rösen P, Reinauer H. Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor etomoxir. Horm Metab Res 1995;27:515–22.
    Crossref | PubMed
  80. Cabreros A, Merlos M, Laguna JC, Carrera MV. Down-regulation of acyl-CoA oxidase gene expression and increased NF-kappaB activity in etomoxir-induced cardiac hypertrophy. J Lipid Res 2003;44:388–98. 
    Crossref | PubMed
  81. Merrill CL, Ni H, Yoon LW, et al. Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. Toxicol Sci 2002;68:93–101.
    Crossref | PubMed
  82. Kennedy JA, Kiosoglus AJ, Murphy GA, et al. Effect of perhexilline and oxfenicine on myocardial function and metabolism during low flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol 2000;36:794–801.
    Crossref | PubMed
  83. Jeffrey FM, Alvarez L, Diczku V, et al. Direct evidence that perhexiline modifies myocardial substrate utilization from fatty acids to lactate. J Cardiovasc Pharmacol 1995;25:469–72.
    Crossref | PubMed
  84. Stephens TW, Higgins AJ, Cook GA, Harris RA. Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J 1985;227:651–60.
    Crossref | PubMed
  85. Bergman G, Atkinson L, Metcalfe J, et al. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris. Eur Heart J 1980;1:247–53.
    PubMed
  86. Cole PL, Beamer AD, McGowan N, et al. Efficacy and safety of perhexiline maleate in refractory angina: a double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 1990;81:1260–70.
    Crossref | PubMed
  87. Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure. A randomized, controlled trial of short-term use of a novel treatment. Circulation 2005;112:3280–8.
    Crossref | PubMed
  88. Beadle RM, Williams LK, Kuehl M, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail 2015;3:202–11.
    Crossref | PubMed
  89. Johannsen DL, Conley KE, Bajpeyi S, et al. Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity. J Clin Endocrinol Metab 2012;97:242–50.
    Crossref | PubMed
  90. Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J 2004;25:1814–21.
    Crossref | PubMed
  91. Marazzi G, Gebara O, Vitale C, et al. Effect of trimetazidine on quality of life in elderly patients with ischemic dilated cardiomyopathy. Adv Ther 2009;26:455–61.
    Crossref | PubMed
  92. Neubauer S. The failing heart. An engine out of fuel. N Engl J Med 2007;356:1140–51.
    Crossref | PubMed
  93. Tuunanen H, Engblom E, Naum A, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 2006;114:2130–7.
    Crossref | PubMed
  94. Fragasso G, Montano C, Lattuada G, et al. A high carbohydrate meal yields a lower ischemic threshold than a high fat meal in patients with stable coronary disease. Int J Cardiol 2011;147:209–13.
    Crossref | PubMed
  95. Salerno A, Fragasso G, Esposito A, et al. Effects of shortterm manipulation of serum FFA concentrations on left ventricular energy metabolism and function in patients with heart failure: no association with circulating bio-markers of inflammation. Acta Diabetol 2015;52:753–61.
    Crossref | PubMed