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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 13, 2014 ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00 PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.04.083 THE PRESENT AND FUTURE REVIEW TOPIC OF THE WEEK Metabolic Impairment in Heart Failure The Myocardial and Systemic Perspective Wolfram Doehner, MD, PHD,* Michael Frenneaux, MD,y Stefan D. Anker, MD, PHDz JACC JOURNAL CME This article has been selected as the month’s JACC Journal CME activity. pathophysiology. Metabolic failure in heart failure is emerging as an important facet in HF pathophysiology that may complement the Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. neuroendocrine activation as therapeutic target. CME Editor Disclosure: JACC CME Editor Ragavendra Baliga, MD, FACC, has reported that he has no financial relationships or interests to disclose. The ACCF designates this Journal-based CME activity for a maximum Author Disclosures: Drs. Doehner and Anker have received support from of 1 AMA PRA Category 1 Credit(s). Physicians should only claim the European Union Seventh Framework program (FP7 grant #241558, credit commensurate with the extent of their participation in the SICA-HF) and from the Verein der Freunde und Förderer der Berliner activity. Charité. Dr. Doehner has received support from the German Federal Ministry of Education and Research (BMBF) (Grant #01 EO 0801); and has Method of Participation and Receipt of CME Certificate received research support and speaker honoraria from Nutricia, Vifor To obtain credit for JACC CME, you must: Frenneaux is the inventor of method of use patents for Perhexiline in 1. Be an ACC member or JACC subscriber. heart muscle diseases. Dr. Anker has received consultancy honoraria 2. Carefully read the CME-designated article available online and in this from Bayer AG, BRAHMS GmbH, BG Medicine, Novartis, Abbott Vascular, Pharma, BRAHMS, Bristol Myers-Squibb, and Sanofi-Aventis. Prof. issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit. 4. Complete a brief evaluation. 5. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the GlaxoSmithKline, Reata, Vifor Pharma, Thermo Fisher, Cardiorentis, Relypsa, and Servier; and has received research support from Vifor Pharma, Novartis, Bayer AG, Abbott Nutrition, Thermo Fisher, and Amgen. Medium of Participation: Print (article only); online (article and quiz) activity. CME Term of Approval CME Objective for This Article: Metabolic aspects, comorbidities, and Issue date: September 30, 2014 maladaptation in HF patients will be explained as intrinsic features of HF Expiration date: September 29, 2015 From the *Centre for Stroke Research Berlin and Department of Cardiology, Campus Virchow-Klinikum Charité– Universitätsmedizin Berlin, Berlin, Germany; yUniversity of Aberdeen School of Medicine and Dentistry, Aberdeen, United Kingdom; and the zDepartment of Innovative Clinical Trials, University Medical Centre, Göttingen, Germany. Drs. Doehner and Anker have received support from the European Union Seventh Framework program (FP7 grant #241558, SICA-HF) and from the Verein der Freunde und Förderer der Berliner Charité. Dr. Doehner has received support from the German Federal Ministry of Education and Research (BMBF) (Grant #01 EO 0801); and has received research support and speaker honoraria from Nutricia, Vifor Pharma, BRAHMS, Bristol Myers-Squibb, and Sanofi-Aventis. Prof. Frenneaux is the inventor of method of use patents for Perhexiline in heart muscle diseases. Dr. Anker has received consultancy honoraria from Bayer AG, BRAHMS GmbH, BG Medicine, Novartis, Abbott Vascular, GlaxoSmithKline, Reata, Vifor Pharma, Thermo Fisher, Cardiorentis, Relypsa, and Servier; and has received research support from Vifor Pharma, Novartis, Bayer AG, Abbott Nutrition, Thermo Fisher, and Amgen. Manuscript received December 19, 2013; revised manuscript received April 3, 2014, accepted April 21, 2014. Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure Metabolic Impairment in Heart Failure The Myocardial and Systemic Perspective ABSTRACT Although bioenergetic starvation is not a new concept in heart failure (HF), recent research has led to a growing appreciation of the complexity of metabolic aspects of HF pathophysiology. All steps of energy extraction, transfer, and utilization are affected, and structural metabolism is impaired, leading to compromised functional integrity of tissues. Not only the myocardium, but also peripheral tissues and organs are affected by metabolic failure, resulting in a global imbalance between catabolic and anabolic signals, leading to tissue wasting and, ultimately, to cachexia. Metabolic feedback signals from muscle and fat actively contribute to further myocardial strain, promoting disease progression. The prolonged survival of patients with stable, compensated HF will increasingly bring chronic metabolic complications of HF to the fore and gradually shift its clinical presentation. This paper reviews recent evidence on myocardial and systemic metabolic impairment in HF and summarizes current and emerging therapeutic concepts with specific metabolic targets. (J Am Coll Cardiol 2014;64:1388–400) © 2014 by the American College of Cardiology Foundation. D espite therapeutic advances in heart failure need for treatment strategies tailored to specific (HF) therapy, the disease remains a major characteristics of patient subgroups. challenge. Between 1979 and 2004, the This review focuses on current bioenergetic con- number of HF hospitalizations in the United States cepts in HF, with particular emphasis on involvement tripled, with more than 80% of cases among patients of peripheral tissues and organs in the complex age 65 years or older (1). The neuroendocrine activa- imbalance of energy metabolism and hormonal and tion paradigm is the cornerstone of current patho- inflammatory regulation and on current and emerging physiological most therapeutic concepts. Targeting the metabolic aspect current medical therapies that impact survival block of HF with novel, specific interventions may emerge as neuroendocrine activation (Central Illustration). How- a new frontier in HF therapy, complementary to the ever, evidence is mounting that this does not fully neuroendocrine paradigm. understanding of HF, and explain the complexity of HF pathophysiology. Additional mechanisms, such as inflammatory activation PERIPHERAL METABOLISM IN HF and metabolic impairment, are increasingly the focus of research for novel therapeutic concepts. Because of increased recognition of the metabolic Metabolic failure as an important underlying perspective, HF is currently appreciated as a sys- mechanism is neither a new nor an exclusive concept temic and multiorgan syndrome (Central Illustration). for HF, but is a typical adaptive biological response to Activated feedback signals from peripheral reflex injury. In HF, the metabolic perspective is usually circuits (2), systemic dysregulation of several hor- attributed to the myocardium. (See the Online monal pathways (3), and global metabolic imbalance Appendix for an overview of current concepts of (4) are intrinsic features of HF pathophysiology. myocardial metabolic and energetic failure.) Systemic metabolic concepts have pathophysiologic Beyond myocardial metabolic failure, systemic and therapeutic implications. Signals, such as (peripheral) metabolic regulation is increasingly inflammation, insulin resistance, anabolic blunting, recognized as contributing both to major symptoms and oxygen radical accumulation, not only affect the (muscle weakness, fatigue, exercise limitation, and myocardium, but exert detrimental effects on a dyspnea) and to disease progression. Along with systemic level. These peripheral metabolic derange- prolonged patient survival in a stable, recompensated ments contribute to the major symptoms and disease state, new clinical features and comorbidities of long- progression of HF. Moreover, specific metabolic term disease progression, such as the development of therapeutic concepts to improve substrate utilization insulin resistance, anemia, hyperuricemia, and car- and energetic efficiency will affect both myocardial diac cachexia, are coming to the fore. The growing and peripheral tissues, namely skeletal muscle complexity of HF pathophysiology will increase the (Figure 1). 1389 1390 Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure ABBREVIATIONS AND ACRONYMS CHF = congestive heart failure CPT = carnitine palmitoyltransferase FFA = free fatty acid GH = growth hormone HF = heart failure Although skeletal muscle is the obvious complementary to the general amino acid control target of metabolic failure and subsequent pathway (7). The normal anabolic response to insulin decline in functional capacity, other tissue and amino acid stimulation was reduced in HF pa- compartments, such as fat and bone, are tients by more than 50% because of both a blunted similarly involved. The interaction of meta- protein anabolic response (8) and increased proteoly- bolic signals between these tissues, global sis (9). Even in nondiabetic patients, insulin resistance effects on body composition changes, and in HF progresses in parallel to HF severity and predicts the development of sarcopenia and cachexia impaired functional capacity of cardiovascular and, will be discussed. particularly, of muscle function (10). Beyond mor- IGF = insulin-like growth factor ANABOLIC LV = left ventricular FAILURE. Metabolic derange- ments in congestive heart failure (CHF) can PDH = pyruvate dehydrogenase complex be described globally as an overall catabolic/ ROS = reactive oxygen species anabolic imbalance (5), with blunted anabolic TZD = thiazolidinediones capacity and catabolic dominance. Anabolic blunting includes a range of signals (6). bidity, insulin resistance is a prognostic factor predicting reduced survival independent of other established prognostic markers (11) and may be regarded as a principal metabolic feature of HF pathophysiology. Multiple signals in a complex interplay of mechanisms contribute to insulin resistance in HF, including neurohormonal activation (catechol- INSULIN RESISTANCE. Detailed information on in- amines), inflammatory cytokines (tumor necrosis fac- sulin resistance can be found in the Online Appendix. tor [TNF]-alpha), oxidative stress (reactive oxygen Beyond its glucoregulatory effect, insulin is 1 of species [ROS]), and hemodynamic impairment (tissue the strongest anabolic stimulatory signals, acting hypoperfusion) (Figure 2, right) (12,13). Impaired in- via repression of catabolic genes and activation of sulin signaling may, in turn, drive HF progression via transcription factor 4 (also called CREB2), and is multiple mechanisms, such as impaired metabolic C E N T R A L I L L U S T R A T I O N Evolving Paradigm of HF Pathophysiology Advancing complexity of heart failure (HF) pathophysiology from a mere hemodynamic disorder to an increasingly systemic involvement of neurohormonal, immune, and metabolic pathways. Current therapeutic concepts focus exclusively on hemodynamic failure and neuroendocrine activation (left column). Novel therapies are warranted to target crucial components of HF pathophysiology, such as metabolic failure and inflammatory activation. ACE ¼ angiotensin-converting enzyme; AT Rec ¼ angiotensin receptor; CRT ¼ cardiac resynchronization therapy; H-ISDN ¼ hydralazine and isosorbide dinitrate; ICD ¼ implantable cardioverter-defibrillator; LVAD ¼ left ventricular assist device; MR ¼ mineralocorticoid receptor; TNF ¼ tumor necrosis factor; Tx ¼ therapy; XO ¼ xanthine oxidase. Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure F I G U R E 1 Myocardial Energy Metabolism Cellular energy metabolism from substrate utilization to oxidative phosphorylation to energy transfer for energy-requiring processes. Current therapeutic concepts to improve energetic efficiency (purple arrows) predominantly target proportional substrate use by decreasing fatty acid metabolism and increasing glucose oxidation. ADP ¼ adenosine diphosphate; ATP ¼ adenosine triphosphate; CPT ¼ carnitine palmitoyltransferase; Cr ¼ free creatine; FA ¼ fatty acid; FFA ¼ free fatty acids; G6P ¼ glucose-6-phosphate; GLUT4 ¼ glucose transporter 4; HK ¼ hexokinase; LPL ¼ lipoproteinlipase; MCD ¼ malonyl-CoA decarboxylase; PCr ¼ phosphocreatine; PDH ¼ pyruvate dehydrogenase; ROS ¼ reactive oxygen species; TCA ¼ tricarboxylic acid cycle (Krebs cycle); TG ¼ triglycerides; UCP ¼ uncoupling protein; ß-ox ¼ beta oxidation. efficacy, tissue fibrosis, apoptosis, and lipotoxicity that tested the GH administration as a therapeutic (Figure 2, left). approach in patients with CHF (16). GROWTH HORMONE RESISTANCE. The growth hor- ANABOLIC mone (GH)–insulin-like growth factor-1 (IGF-1) axis is ficiencies, such as low dehydroepiandrosterone sul- STEROID METABOLISM. Anabolic a key regulatory pathway of anabolic signaling, with fate, testosterone, or IGF-1 levels are common findings de- Akt/mTOR as downstream mediators. An acquired in HF (6). In HF patients, this steroid metabolism GH-resistant state has been described in HF, with a impairment translates into impaired exercise capacity typical pattern of high GH levels and low IGF-1 levels and symptomatic status (17). Each anabolic hormone (14). GH levels were increased 3-fold in CHF patients deficit independently predicts poor prognosis, with with significant weight loss (i.e., cachexia) compared additive effects if more than 1 is decreased (6). with noncachectic patients and healthy subjects. In A range of hormones involved in metabolic control, contrast, IGF-1 levels are reduced, particularly in pa- such as ghrelin (18), leptin (13), resistin (19), adipo- tients with cachexia (15). Acquired GH resistance may nectin (20), and natriuretic peptides (21), are imbal- explain the disappointing results of several studies anced in CHF. Additional factors, beyond the scope of 1391 1392 Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure this review, also contribute to controlling the meta- as a clinical manifestation of catabolic dominance and bolic balance. The central regulation of appetite with an indicator of progressing disease. mutual interaction of the lateral (feeding area) and medial (satiety area) hippocampal nuclei is under the control of a multitude of mediators (e.g., neuropeptide Y, leptin, orexin, inflammatory cytokines, and others), and their abnormal regulation impacts feeding behavior. Indeed, reduced appetite is common in HF patients (4). Furthermore, gastrointestinal absorption is impaired in CHF, adding to the imbalance between nutritional supply and energy demands (22). SKELETAL MUSCLE. Skeletal muscle is the main effector organ for physical activity and the body’s largest amino acid storage pool. Accordingly, 2 major issues for skeletal muscle metabolism in HF need to be addressed: 1) impaired energy metabolism affecting contractile function; and 2) structural metabolism to balance the body’s protein pool. Indeed, a generalized metabolic myopathy, characterized by decreased oxidative capacity, impaired substrate use and energy transfer, and an overall catabolic/anabolic imbalance, TISSUE WASTING IN CHF has been suggested for HF (5,23). The overall net catabolic dominance (outlined in beta, and gamma are central players in the regulation the preceding text) accounts for systemic tissue of energy metabolism in heart and skeletal muscle wasting. Skeletal muscle wasting may be the most (24). Impaired regulation via the inducible coactivator, clinically relevant aspect, as it determines physical PCGC-1 alpha, has been linked to reduced muscle Peroxisome proliferator-activated receptors alpha, capacity and symptomatic severity of HF. However, oxidative capacity. Increased proinflammatory cyto- fat and bone tissue are also affected by global cata- kine levels (particularly TNF-alpha, interleukin [IL]-6, bolic dominance. As a consequence of global tissue and IL-1ß), both in the circulation and locally in skel- wasting, weight loss, the hallmark of cardiac cachexia etal muscle tissue, have been described in HF (25). (see later discussion), may occur in the course of HF These cytokines trigger multiple signaling cascades F I G U R E 2 Insulin Resistance: Intrinsic Feature in HF Pathophysiology The vicious cycle of insulin resistance as an intrinsic component of heart failure (HF) pathophysiology. Several features of HF trigger insulin resistance (right section in red). In turn, insulin resistance induces a range of signals responsible for HF progression. Accordingly, insulin resistance is a major underlying mechanism of the reciprocal interaction between congestive HF and diabetes mellitus, with hyperglycemia only exerting additive effects in overt DM. AGE ¼ advanced glycation end products; PARP ¼ poly(ADP-ribose) polymerase; PKC ¼ protein kinase C; SNS ¼ sympathetic nervous system; TNF ¼ tumor necrosis factor; other abbreviations as in Figure 1. Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 1393 Metabolic Failure in Heart Failure such as inducible nitric oxide synthase activity and ROS accumulation, impaired contractile capacity, decreased energetic efficiency via increased uncoupling protein activation, insulin resistance, growth suppression, and catabolic activation (26). Myostatin, a cytokine of the transforming growth factor (TGF)-beta family has garnered increasing attention as a potent muscle growth regulator. It is most abundantly expressed in skeletal muscle, with lower, but inducible, expression in the heart and in adipose tissue (27). A systemic effect of myostatin spillover from the myocardium in HF patients may contribute to fiber type-shifting (28), insulin resistance, and skeletal muscle wasting (29). The skeletal muscle protein pool undergoes constant synthesis and degradation with a highly regulated and balanced turnover rate. In HF, a global imbalance accounts for muscle wasting (i.e., sarcopenia) or, ultimately, development of cachexia (see later discussion). Up to 68% of CHF patients show signs of muscle atrophy (30). This process starts early in the course of the disease, even before weight loss can be detected, when replacement of muscle tissue F I G U R E 3 Independent Lipolysis Pathways in CHF Independent signaling pathways of increased lipolytic activity in heart failure. All 3 pathways are activated in congestive heart failure (CHF). ANP ¼ A-type natriuretic peptide; AR ¼ adrenergic receptor; BNP ¼B-type natriuretic peptide; cAMP ¼ cyclic adenosine by nonfunctional tissue may occur. These skeletal monophosphate; cGMP ¼ cyclic guanosine monophosphate; c-Jun = N-terminal kinases; muscle metabolic abnormalities may be more rele- CNP = C-type natriuretic peptide; FFA = free fatty acids; JNK ¼ c-Jun N-terminal kinase; vant to explaining major HF symptoms such as fatigue, exercise limitation, and dyspnea than central MAPK ¼ mitogen activated protein kinase; NP rec ¼ natriuretic peptide receptor; PKA ¼ protein kinase A; PKG ¼ protein kinase G; TG ¼ triglyceride; TNF ¼ tumor necrosis factor. hemodynamic parameters (31). FAT TISSUE. Identification of the lipocyte hormone lipolysis signaling pathway was recently described, leptin was the first to establish the endocrine activity in which natriuretic peptides (NPs) exert lipolytic of fat tissue. Adipose tissue is actively involved in activity, with A-type NPs having the strongest effect metabolic regulation in HF. Multiple signals and me- (35). Importantly, hormone-sensitive lipase activa- diators from adipose tissue participate in local and tion by NPs is independent of cAMP signaling. systemic metabolic crosstalk affecting feeding, en- Instead, NP receptor binding promotes a cyclic gua- ergy nosine monophosphate pathway to activate lipase in expenditure, insulin resistance, and body composition (32) (Online Appendix). Catabolic activation is particularly parallel to (but independent of) the catecholamineapparent in adipose tissue, as several independent path- induced cAMP-protein kinase A pathway (36). Catecholamines, TNF-alpha, and NPs are all ways exert lipolytic signals on hormone-sensitive increased in HF, suggesting that lipolysis is pro- lipase (Figure 3). First, catecholamines, via beta- foundly and multiply activated, as has indeed been adrenoceptors, are classical signals for lipolysis by observed (37). Moreover, lipogenetic enzymes, such activation of adenylate cyclase and increased cyclic as fatty acid synthase and acetyl CoA carboxylase, are adenosine monophosphate (cAMP) synthesis. In under insulin control and, as outlined earlier, the humans, the balance between lipolytic beta-receptor antilipolytic effect of insulin may be blunted in the expression and inhibitory alpha2-receptor expres- insulin-resistant conditions of HF (38). Adipose- sion determines the net effect of catecholamines on derived signals contribute to paracrine and systemic lipolysis (33). As a second complex lipolytic signal, metabolic regulation. Leptin levels, which are tightly the cytokine TNF-alpha induces lipolysis through regulated by the amount of fat tissue, are elevated in mitogen activated protein kinases p44/42 and JNK via HF, and an association with insulin resistance has cAMP increase and lipase activation (34). NF-kappaB been observed (13). However, in cachectic patients, activation promotes expression of lipogenesis genes. after adjustment for the severely reduced fat tissue TNF-alpha also attenuates insulin-mediated anti- mass, a hyperleptinemic state is apparent (14). Adi- lipolytic signals and interacts with other adipokines, ponectin, an adipokine with multiple metabolic ac- such as adiponectin and IL-1. A third independent tions, increases both locally and globally with HF 1394 Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure severity (39) and is highest in cachectic patients or more (excluding edema-related weight shift) (20,40). Reports on adiponectin as independent pre- was confirmed as a strong, independent predictor dictor of increased mortality support the significance of increased mortality (51). Similarities with other of fat tissue and its metabolic interactions for HF chronic illnesses suggest a common final pathway in pathophysiology and outcome (20,39). the metabolic response, regardless of the origin of the BONE TISSUE. Osteopenia and genuine osteoporosis beyond normal age-related associations have been observed in HF and advance with higher stages of the disease (41). Patients with severe HF and those with cachexia demonstrate pronounced loss of bone mass (42), although no direct associations with impaired left ventricular (LV) ejection fraction or peak VO 2 were observed (43). In advanced HF, significant bone loss occurs frequently (in 30% of patients [44]) and as a component of overall tissue wasting (see later discussion). A number of bone tissue metabolic markers are abnormally regulated in HF, such as osteocalcin, ß-cross Laps, osteoprotegerin, RANK, and RANKL (see Zittermann et al. [45] for review). Increased osteolytic activation seems to be the dominant factor, with impaired bone formation being of secondary relevance (46). Osteolytic stimulation in HF is likely the result of multiple factors, including vitamin D insufficiency, elevated parathyroid hormone levels (41), renal dysfunction, reduced anabolic stimulation (such as from IGF-1), proinflammatory activation, disuse atrophy, and HF-related drug administration such as vitamin K antagonists and loop diuretics (45). illness (52). To improve clinical awareness and early medical intervention, a common definition of cachexia in chronic illness was proposed, defining cachexia as weight loss of $5% in #12 months in the presence of an underlying illness, when accompanied by 3 of 5 symptomatic and biochemical criteria (53). The seemingly small amount of weight lost underscores that even mild tissue wasting in the presence of an illness such as HF is a significant sign of catabolic stimulation. IRON DEFICIENCY BEYOND ANEMIA Until recently, surprisingly little attention was paid to anemia in HF, presumably because mild anemia is very common in HF and is often regarded by clinicians as merely the result of hemodilution due to fluid retention. Recent studies have shown that iron deficiency is the most common cause of anemia in HF, accounting for up to 73% of cases in severe HF (54). Absolute iron deficit with depletion of endogenous iron stores may result from covert blood loss and/or nutritional deficit. More importantly, a functional iron deficiency may develop in HF as a consequence of latent inflammatory activation. In this CARDIAC CACHEXIA. As described in the previous regularly observed situation, despite only marginally text, systemic catabolic/anabolic imbalance leads to decreased endogenous iron stores, circulatory iron tissue wasting, weight loss, and ultimately to devel- for transfer to iron-dependent tissues is reduced. opment of cachexia. Although wasting has been Hepcidin, the central regulator of the iron homeo- observed in HF since ancient times as a signum mali stasis, controls both gateways for circulatory iron ominis (47), or a sign of ill omen, increasing interest balance: duodenal iron absorption from the intestine has recently focused on clinical implications, patho- and release from enterocytes and endogenous iron physiologic mechanisms, and, most importantly, stores in macrophages (55). Hepcidin inhibits the iron therapeutic options for cardiac cachexia. Cachexia export protein ferroportin, blocking iron export from is recognized today as a severe complication of CHF cells into the circulation (56). Hepcidin expression is that worsens clinical symptoms and carries a partic- regulated by signals of iron balance, erythropoietic ularly grave prognosis. Mortality in HF patients with activity, and hypoxia. Additionally, proinflammatory cachexia was as high as 50% at 18 months of follow- stimuli, such as lipopolysaccharide and cytokines up, compared with 17% in noncachectic patients (48). IL-1 and -6, are potent inducers of hepcidin via the Factors triggering progression from clinically and JAK/STAT pathway (57), over-riding erythropoietic weight-stable ambulatory CHF to a metabolically signals (58). Under bacterial stress, iron would be imbalanced and weight-losing state are not under- sequestered, thus depriving iron-dependent bacterial stood. Early stages of mild weight loss may go metabolism. However, in HF and other chronic ill- unrecognized by doctors and patients (49). A pre- nesses, low-grade chronic inflammatory activation cachexia phase has been defined to emphasize may block endogenous iron stores, preventing ade- an “at risk” state (50). Biochemical features of meta- quate iron utilization for erythropoietic and metabolic bolic failure (e.g., inflammation, impaired glucose demands. Anemia of chronic illness, the prevalent tolerance, anemia, hypoalbuminemia, or anorexia) type of anemia in HF (59), has been defined on this may already be apparent. A body weight loss of 6% basis (60). Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure Recent evidence suggests that beyond impairing trials with and without XO inhibition. Therapeutic XO oxygen transport capacity (i.e., low hemoglobin), inhibition favorably affects a range of surrogate tissue iron deficiency also has significant implications markers (72). In contrast, treatments using uricosuric for mitochondrial oxygen utilization in HF. Replen- treatment (73) or further enzymatic UA degradation ishment of depleted iron stores by intravenous iron (74) to lower UA levels without XO inhibition did not supplementation in HF patients improved their yield similar beneficial effects. symptomatic status and exercise capacity (61), regardless of the presence of anemia, and did not METABOLIC THERAPEUTIC INTERVENTIONS depend on increasing hemoglobin levels. In accordance with this study, iron deficiency has been shown Better understanding of the underlying mechanisms to exert an additive effect on impaired exercise ca- have made metabolic and bioenergetic regulation a pacity in HF patients with and without anemia (62). promising target for novel therapy concepts. (For At the cellular level, most of the iron is transferred to principles of bioenergetic metabolism and alterations mitochondria, where it is assigned to 3 major pro- in HF, see the Online Appendix.) A number of thera- cessing pathways: 1) synthesis of bioactive heme; 2) pies developed on the basis of pathophysiologic synthesis of iron-sulfur clusters; or 3) mitochondrial concepts have been investigated, as outlined in pre- iron storage (63). Whereas heme is the central pros- vious sections, and early trials have reported prom- thetic group of all hemoproteins, including hemo- ising results (Figure 1). Despite these advances, no globin, iron-sulfur clusters are required for electron approved medical therapy specifically targeting the transport ability in the mitochondrial respiratory metabolic facet of HF currently exists. chain and for many other enzymatic electron transfer THERAPIES THAT ALTER SUBSTRATE UTILIZATION. activities in the mitochondrion, cytosol, and nucleus. Although fatty acid oxidation theoretically requires Mitochondrial iron storage is controlled by mito- approximately only 10% to 12% more oxygen per chondrial ferritin, which sequesters iron in order to molecule of ATP generated than glucose oxidation, prevent uncontrolled oxidative reactions (64). in vivo studies have shown a substantial reduction in cardiac mechanical efficiency of approximately 40% HYPERURICEMIA to 50% (75). This is thought to be due to increased mitochondrial uncoupling (Online Appendix) and Hyperuricemia is commonly present in CHF and is to fatty acids undergoing futile metabolic cycles. strongly associated with disease severity (65) and Whereas glucose uptake is typically maintained or mortality (66). Accordingly, uric acid (UA) has been even increased in HF, carbohydrate oxidation is included as a metabolic marker and an independent reduced due to a block at the level of the pyruvate factor in the Seattle Heart Failure Survival Score (67). dehydrogenase (PDH) complex. This led to the The debate is ongoing as to whether UA has a func- concept that increased PDH activity (either directly or tional role in HF pathophysiology or is merely a dis- via reduced fatty acid oxidation) would substantially ease progression marker. Currently, up-regulated increase the efficiency of energy generation in HF. xanthine oxidase (XO) enzymatic activity is seen as Dichloroacetate, which increases PDH activity, is the key pathophysiologic feature of hyperuricemia. It clinically used in the treatment of lactic acidosis, and results from a number of factors, including increased increases LV contractile work in HF patients while tissue turnover, tissue hypoxia (68), catabolism (65), reducing insulin resistance (69), and cell death. Accelerated Several drugs have been evaluated that putatively purine degradation and direct XO stimulation by inflammatory cytokines and oxygen radicals (70) work via inhibition of fatty acid utilization. Reduction in plasma free fatty acid levels by account for XO’s up-regulated activity. With the inhibiting adipose lipoprotein lipase activity. degradation of xanthin and hypoxanthin to UA, XO Nicotinic acid derivatives, such as acipimox, sub- produces stoichiometric quantities of free oxygen stantially reduce plasma free fatty acids (FFAs) via radicals (ROS), and is a major source of ROS. XO- inhibition of adipose lipoproteinlipase. As assessed derived ROS accounts for a range of detrimental by positron emission tomography, acute administra- effects on endothelial function, contractility, inflam- tion of acipimox in patients with HF reduced fatty matory and acid uptake and increased glucose uptake, but did not decreased metabolic efficacy (see Doehner and Land- improve LV contractility and mechanical efficiency messer [71] for review). Increased XO-dependent ROS (77). The PDH block may not have been alleviated production as an underlying pathologic mechanism acutely, and therefore, low carbohydrate oxidation received further support from multiple interventional would remain. Moreover, acutely reduced plasma activation, mitochondrial damage, myocardial oxygen consumption (76). 1395 1396 Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure FFA may deprive the heart of this important fuel. isolated rat hearts, which is associated with devel- Longer-term (28-day) therapy in patients with sys- opment of LV hypertrophy (93). tolic HF was recently tested and showed no effects on Partial inhibition of fatty acid beta oxidation. LV systolic function (78). Trimetazidine and ranolazine both inhibit fatty acid Reduction of fatty acid utilization via CPT1/2 beta oxidation. Like perhexiline, trimetazidine is an i n h i b i t i o n . The carnitine shuttle is the rate-limiting effective anti-anginal agent, reducing fatty acid up- step in fatty acid metabolism, and therefore is an take and increasing glucose oxidation due to PDH attractive therapeutic target. Malonyl-CoA is a potent activation (94). In a positron emission tomography endogenous inhibitor of CPT1. Increased malonyl- study in patients with dilated cardiomyopathy, tri- CoA and subsequent CPT1 inhibition can be ach- metazidine had little effect on fatty acid uptake from ieved by inhibiting malonyl-CoA decarboxylase, the the bloodstream, but appeared to reduce fatty acid enzyme catalyzing malonyl-CoA degradation. This utilization from intracellular fat stores and increased results in reduced fatty acid utilization and increased insulin sensitivity (95,96). Trimetazidine improves carbohydrate oxidation (79). There are also direct cardiac energetic status (phosphocreatine/ATP ratio) pharmacological inhibitors of the carnitine shuttle. in patients with HF (97) and improves symptomatic Etomoxir and oxfenicine irreversibly inhibit CPT1, status, including New York Heart Association func- whereas perhexiline reversibly inhibits CPT1 and 2 in tional class and exercise time, LV ejection fraction, and isolated liver and cardiac mitochondria (80). Oxfeni- hospitalization due to HF. In addition to inhibiting cine slowed HF development in a canine rapid pacing lipid oxidation, recent evidence suggests that ranola- HF model (81). Etomoxir improved contractile LV zine’s predominant therapeutic benefit may relate to dysfunction and exercise hemodynamics in experi- inhibition of the slow inward sodium-channel (98). mental (82) and in clinical HF (83), but a randomized controlled trial was terminated very early because of substantial increases in liver transaminases (84). Perhexiline is an effective antianginal agent that was used in the 1970s and early 1980s, but was voluntarily withdrawn by the manufacturers because INSULIN SENSITIZERS AND GLUCOREGULATORY AGENTS. Global insulin resistance is characteristic of HF (see Online Appendix for principles of insulin resistance in HF); thus, improving insulin sensitivity is an intriguing option. of apparently idiosyncratic cases of liver toxicity T h i a z o l i d i n e d i o n e s . Thiazolidinediones (TZDs) are and peripheral neuropathy. Subsequent studies (80) insulin demonstrated that this toxicity resulted from phos- activated pholipid accumulation in liver and peripheral nerves theoretical advantages of insulin sensitization in HF, sensitizers and peroxisome receptor-gamma agonists. proliferatorDespite the due to variations in metabolic degradation via the TZDs cause fluid retention, probably explaining the Cyp2D6 enzyme. The toxic accumulation is prevent- increased HF symptoms and hospitalizations in a able by monitoring plasma levels with appropriate study of 4,447 type 2 diabetic patients in which dose titration (85). In randomized controlled trials, rosiglitazone was compared with metformin plus a perhexiline in addition to standard therapy improved sulfonylurea (99). peak oxygen consumption, LV ejection fraction, and The confirmed weight gain with TZD therapy is quality of life (Minnesota Living With Heart Failure conventionally seen as an unwanted side effect in questionnaire score) (86) and cardiac energetic status diabetic patients, resulting from improved anabolic (phosphocreatine/ATP ratio [87]). Additional effects capacity and restored insulin sensitivity. However, of perhexiline include reduced generation of super- this anticatabolic effect is intriguing in chronic ill- oxide by NOX 2 enzymes (88), reduced expression of nesses with catabolic dominance, such as HF. Indeed, thioredoxin-interacting protein (an inhibitor of thio- a retrospective analysis of the PROactive study has redoxin and of glycolysis [89]) and inhibition of shown that glitazone-induced weight gain in diabetic mTOR C1 (potentially leading to improved cell sur- patients with cardiovascular comorbidity was associ- vival via increased autophagy [90]). ated with improved survival (100). CPT1 inhibition was also reported with the beta- M e t f o r m i n . Biguanides (metformin) improve insulin blockers carvedilol and metoprolol (91,92) and with sensitivity and have beneficial effects on mortality amiodarone (80). Sulfo-N-succinimidyl esters of long (101) and cardiopulmonary function (102). Metformin chain fatty acids, including sulfo-N-succinimidyl carries an extremely small risk of inducing lactic palmitate and sulfo-N-succinimidyl oleate inhibit acidosis in HF patients (103), resulting in caution long chain fatty acid uptake into the cell via the in its use in diabetics with HF. It acts (at least in CD36 transporter. Accordingly, sulfo-N-succinimidyl part) via phosphorylation (activation) of adenosine palmitate was shown to reduce palmitate uptake in monophosphate kinase, a key energy sensor. Recent Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure data from a large primary care database in Scotland has substantial shown that metformin treatment in type 2 diabetic observed in cardiac muscle with HF development. patients with HF resulted in lower all-cause mortality than in those treated with other agents (104). amelioration of proteomic changes Coenzyme Q10 carries electrons from complex I to III in the electron transport chain, and acts as an antiox- As insulin resistance is a relevant feature of idant. Plasma and cardiac tissue levels are reduced in HF pathophysiology, antidiabetic treatments aiming HF (113). There have been several studies of coenzyme merely at higher endogenous or administered insulin Q10 supplementation in HF, with variable results. A levels may seem less suitable for metabolic in- meta-analysis showed an almost 4% improvement in terventions in HF. INCRETIN-BASED LV ejection fraction, but the benefit was markedly THERAPIES. Glucagon-like pep- tide (GLP)-1 has insulin-sensitizing actions, but pre- lower in patients taking standard therapies, including angiotensin-converting enzyme inhibitors (114). dominantly stimulates insulin release and also has THERAPIES THAT MAY IMPROVE ENERGY TRANSFER. direct receptor-mediated action in heart and other As a consequence of ROS, especially derived from XO tissues. Oral dipeptidyl peptidase-4 inhibitors reduce and nicotinamide adenine dinucleotide phosphate GLP-1 breakdown, thereby increasing endogenous (NADPH) oxidase, myofibrillar creatine kinase activity plasma GLP-1 levels. Only limited data exist on the is reduced. A recent nonrandomized study reported potential role of these drugs in CHF. A controlled that acute intravenous allopurinol increased creatine study investigated the impact of the dipeptidyl kinase flux in HF patients (115). Allopurinol reduces peptidase-4 inhibitor saxagliptin on cardiovascular oxidative stress by inhibiting XO. As discussed outcomes in 16,492 type 2 diabetic patients at 2-year earlier, a range of surrogate markers suggest a clinical follow-up. Saxagliptin did not reduce either the pri- benefit of XO inhibition as a tailored therapy option in mary endpoint (cardiovascular death, nonfatal MI, HF with hyperuricemia (116). In a large retrospective nonfatal ischemic stroke) or the secondary endpoint study of 4,785 patients with HF and hyperuricemia, a (hospitalization for HF, coronary revascularization, or 35% mortality reduction was observed with high-dose unstable angina), but more patients in the saxagliptin allopurinol group were hospitalized for HF (105). therapy (117). A randomized controlled trial of oxy- S u l f o n y l u r e a s . Sulfonylureas inhibit the compared with low-dose allopurinol ATP- purinol (the active metabolite of allopurinol) in HF sensitive potassium channel that is protective in patients, OPT-CHF (Oxypurinol Therapy for Conges- ischemia. However, a recent analysis of a large data- tive Heart Failure), could not, however, confirm a base of patients presenting with acute coronary syn- clinical benefit of this therapy (118). drome showed that diabetic patients had a greater Skeletal and cardiac muscle creatine content is risk of death or HF within 30 days compared with reduced in HF, largely due to reduced expression of the nondiabetic patients, although this risk was no higher creatine-sodium cotransporter (as discussed earlier). in diabetic patients treated with sulfonylureas prior In 1 study, intravenous creatine improved LV ejection to admission (106). fraction (119). Although there is some evidence of MITOCHONDRIAL-TARGETED THERAPY TO IMPROVE RESPIRATORY CHAIN FUNCTION. Mice overexpress- ing mitochondrial catalase have a significant life- improved skeletal muscle function and exercise duration with chronic oral carnitine administration, there is no evidence of improved cardiac function (120). aging OTHER THERAPIES WITH “METABOLIC” ACTION. HF (107,108). Mitochondrially-targeted peptides with patients have low cardiac tissue carnitine levels potent antioxidant effects were recently developed. (121). Several carnitine supplementation studies in The Szeto-Schiller (SS31) peptide is a positively HF reported variable results, warranting further span extension and attenuated cardiac charged free-radical scavenger that can accumulate investigation (122). The testosterone deficit has been more than 1,000-fold in mitochondria (109). SS31 proposed as a novel therapeutic target in HF patients. markedly ameliorated angiotensin II–induced car- Testosterone replacement therapy was reported to diomyopathy in a murine model; prevented cardiac improve exercise capacity and symptomatic status in hypertrophy, fibrosis, and diastolic dysfunction (110); men with CHF (123). Known cardiotoxic effects and and improved mitochondrial function and skeletal other side effects of anabolic steroids may hinder muscle performance in aged mice (111). In a murine wider acceptance of this therapeutic option. thoracic aortic constriction HF model, Dai et al. (112) Iron supplementation improved symptomatic sta- reported amelioration of LV systolic dysfunction tus patients with systolic HF and iron deficit (61); this by SS31 treatment, associated with a reduction in was the first successful implementation of a specific mitochondrial oxidative damage markers and a metabolic treatment in HF (124). 1397 1398 Doehner et al. JACC VOL. 64, NO. 13, 2014 SEPTEMBER 30, 2014:1388–400 Metabolic Failure in Heart Failure CONCLUSIONS metabolic phenotype is characterized by insulin resistance and global anabolic blunting and catabolic The complex interactions between metabolic, immu- overactivity. The increasing pathophysiologic under- nologic, and neuroendocrine signals in HF are still standing combined with novel ideas for targeted incompletely understood. Evidence is mounting that metabolic treatments suggest that the metabolic facet the abnormal and imbalanced metabolism represents of HF may emerge as the next frontier in HF therapy. an intrinsic aspect of HF pathophysiology, with fundamental symptomatic and prognostic implica- REPRINT REQUESTS AND CORRESPONDENCE: Dr. tions. The concept of metabolic failure in HF should Wolfram Doehner, Center for Stroke Research Berlin not be limited to impaired myocardial energy utili- and Department of Cardiology, Charité, Campus Virchow- zation. 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