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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
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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
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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.
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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).
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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.
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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
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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.
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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
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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).
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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).
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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
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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).
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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. Energy metabolism and structural metabolism
Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
are as well affected on a systemic level. The HF
E-mail: [email protected].
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KEY WORDS cachexia, insulin resistance,
metabolism, muscle, sarcopenia, stroke
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