The Metabolic Impairment in Heart Failure – The Myocardial and Systemic Perspective
Appendix: Supplemental online material
Authors:
Wolfram Doehner, MD, PhD [1, 2]
Michael Frenneaux, MD [3]
Stefan D. Anker, MD, PhD [4]
Affiliation:
[1]
Centre for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Germany
[2]
Department of Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin
Berlin, Germany.
[3]
University of Aberdeen School of Medicine and Dentistry
[4]
Göttingen
Address for correspondence:
Wolfram Doehner, MD, PhD; Center for Stroke Research Berlin, Charité, Campus VirchowKlinikum, Augustenburger Platz 1, 13353 Berlin, Germany Tel.: +49 30 450 553 507; Fax
+49 450 553951; E-mail: wolfram.doehner@charite.de
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The concept of bioenergetic starvation in heart failure
The concept of a failing bioenergetic metabolism as the underlying principle of the failing myocardium
was proposed decades ago [1] and has been pursued ever since [2 - 8]. The contractile performance of
the myocardium throughout a lifetime demands a highly efficient and adaptable system of energy
generation, energy transfer and energy sensing. Accordingly, the ATP production of the heart exceeds
any other tissue, amounting to up to 6 kg per day, multiple times its own organ weight [9]. As the ATP
pool of the myocardium would last mere seconds of contractile activity, a constant turnover of energy
substrates into ATP needs to be maintained. Moreover, varying activity levels require rapid a response
of the energy supply. Specific characteristics of the myocardial metabolic apparatus to ensure this
adaptability include the wide range of suitable energy substrates applicable to the myocardium and
their well tuned dynamic mixture in substrate utilization according to supply, requirements and
surrounding conditions. Disturbance of this metabolic apparatus will inevitably result in impairment of
cardiac function. Indeed cardiac energetic impairment is a characteristic feature of several diseases of
heart muscle, including systolic heart failure of both ischemic and non ischemic etiologies,
hypertensive heart disease, heart failure with preserved ejection fraction (HFpEF), hypertrophic
cardiomyopathy (HCM), Fabry disease and Friedreich’s ataxia.
Physiology of myocardial energy metabolism
The heart is a metabolic omnivore, able to generate energy from several sources – carbohydrates,
fatty acids, ketones and amino acids. The adaptive regulation of the proportions and the shift between
these substrate is discussed below.
Carbohydrate metabolism comprises glycolysis, which occurs in the cytosol, and carbohydrate
oxidation which occurs in the mitochondrion. Glucose uptake occurs through both insulin dependent
(GLUT 4) and independent (GLUT 1) transporters. Pyruvate, the product of glycolysis is transported
into the mitochondrion by the mitochondrial membrane protein Pyruvate translocase (an active,
energy requiring process) and under aerobic conditions is converted to acetyl-CoA by a complex of
three enzymes called the Pyruvate dehydrogenase complex (PDH) located in the mitochondrial matrix.
PDH is subject to both negative regulation (by pyruvate dehydrogenase kinase) and positive regulation
(by pyruvate dehydrogenase phosphatase). PDH kinase is allosterically activated (i.e. PDH is inhibited)
by increases in the Acetyl CoA/CoA, ATP/ADP, and NADH/NAD+ ratios, and PDH phosphatase is
activated by a reduction in these ratios [10]. The kinase is also inhibited by the drug dichloroacetate
[11]. Glycolytic enzymes and PDH kinase are induced by hypoxia via HIF1, promoting anaerobic
glycolysis [12]. PDH thus represents a key rate limiting step in carbohydrate metabolism. Under
aerobic conditions acetyl-CoA is generated from Pyruvate by PDH and from fatty acid beta oxidation
(see below). Acetyl -CoA enters the TCA cycle (in the mitochondrial matrix) to generate NADH from
NAD+ which act as an electron donor to complex I of the electron transport chain (Figure 2).
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Fatty acids have the highest energy yield of all substrates per molecule metabolized and provide an
efficient means of generating energy providing oxygen supply is not limited and the metabolic
‘machinery’ is intact. The heart is able to metabolize fatty acids circulating in the plasma,
predominantly bound to plasma proteins or covalently bound to the triacylglycerol core of plasma
lipoproteins, or from breakdown of stored triglycerides within the myocyte. Plasma free fatty acid
(FFA) concentrations are predominantly determined by the hydrolytic activity of the enzyme
lipoprotein lipase (LPL), an enzyme that in turn is controlled by insulin. In insulin resistant states
plasma FFA are increased. The muscle isoform of LPL is activated by catecholamines and by glucagon.
Thus plasma FFA increased during sustained (but not short term) exercise [13] and crucially in heart
failure [14], which is typically associated with increased plasma catecholamines and often with insulin
resistance. Although some uptake of fatty acids occurs by passive diffusion, several uptake pathways
are also involved in this process, including fatty acid translocase (FAT/CD36), plasmalemmal fatty acidbinding protein (FABP pm ), and fatty acid transport protein (FATP) [15]. Within the cardiac myocyte,
long chain fatty acids are converted to long chain fatty acid acyl-CoA by the enzyme fatty acid acyl-CoA
synthase.
Unlike short chain fatty acids, long chain fatty acid acyl-CoA molecules are unable to cross the
mitochondrial membrane without further modification. The transfer across the mitochondrial
membrane is operated by the ‘carnitine Shuttle’, an enzymatic system consisting of enzymes Carnitine
palmitoyl transferase type 1 (CPT-1) and CPT-2 on the outer and inner mitochondrial membrane,
respectively. These enzymes catalyze the addition (CPT-1) and cleavage (CPT-2) of a Carnitine group to
a long chain acyl-CoA – carnitine complex which enables the trans-membrane transport. The Carnitine
Shuttle represents the rate limiting step in fatty acid metabolism. The activity of CPT 1 is potently
inhibited by malonyl-CoA which in turn is dependent on the activity of the enzymes acetyl-CoA
carboxylase (ACC) and malonyl-CoA decarboxylase (MCD). Pharmacological inhibitors of the carnitine
shuttle directly at CPT enzymes and at the level of malonyl-CoA exist (see below).
Finally, beta oxidation in the mitochondrial matrix comprises a recurring series of 4 reactions in which
the long chain acyl-CoA fatty acid molecule is shortened by two carbon atoms (yielding acetyl-CoA)
during each cycle. FADH2 and NADH are generated during each of these cycles and acetyl-CoA enters
the TCA cycle to generate NADH all providing reducing equivalents for the electron transport chain.
Ketone metabolism
In health ketone metabolism by the heart is very modest except under conditions of starvation when
plasma ketones are markedly increased. Plasma ketones are often increased in heart failure [16]. A
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moderate ketosis has been discussed as a compensatory mechanism in impaired insulin dependent
mitochondrial energy transduction [17, 18]
Amino acids
The heart can also metabolize branched chain amino acids (leucine, isoleucine and valine). The
important role of these amino acids in the heart has recently been reviewed [19]. These essential
amino acids are metabolized first to branched chain keto acids (BCKA’s) by the enzyme branched chain
aminotransferase (BCAT) and then to proprionyl-CoA by the BCKA dehydrogenase complex (BCKD).
Proprionyl-CoA may in turn be metabolized to acetyl-CoA or to succinyl-CoA and then enter the TCA
cycle. A phosphatase (PP2Cm) has been shown to be expressed in mitochondria in zebrafish embryo
and in adult mice and dephosphorylates (activates) the BCKD complex. PP2Cm is down-regulated by
stress and its expression is reduced in hypertrophic and failing hearts. This results in reduced
catabolism of branched chain amino acids. Since these amino acids are also important signaling
molecules this may have important effects in heart failure. They activate mTOR signaling, which
promotes cardiac hypertrophy and suppresses cardio-protective autophagy [20]. In mice fed a high fat
diet, addition of branched chain amino acids increased UCP expression in liver and skeletal muscle and
was associated with less weight gain than in control mice in which branched chain amino acids were
not supplemented [21].
Electron Transport Chain
At the inner mitochondrial membrane a series of redox reactions occurs with stepwise electron
transfer between five complexes in total and two carriers. A small amount of electron leakage may
occur during these processes, particularly at complex I and complex III, resulting in the generation of
superoxide. The energy released by each of these electron transfer steps is used to pump protons from
the mitochondrial matrix into the inter-membrane space, generating an electrochemical gradient
across the inner mitochondrial membrane. The flow back of protons into the mitochondrial matrix
through complex V releases the energy that drives the phosphorylation of ADP to ATP. Theoretically 38
molecules of ATP can be generated by the complete oxidation of one molecule of glucose through the
above processes (two each from glycolysis and the TCA cycle and 34 from the electron transport
chain), however in practice the net yield is somewhat less, in part because of some degree of
‘uncoupling’ of the electron transport chain. In heart muscle uncoupling protein (UCP)3 and to a lesser
extent UCP2 are expressed [22]. These UCP’s cause a modest degree of physiological proton leak
across the mitochondrial membrane and in doing so, can reduce superoxide production at complex 1
of the respiratory chain [23]. Cardiac UCP expression is increased by PPAR alpha activation [24], and in
patients undergoing coronary artery bypass grafting, cardiac UCP expression was related to plasma
free fatty acid levels [22]. Furthermore, the activity of UCP’s appears to be increased by superoxide
and by lipid peroxides within the mitochondrial matrix [25]. Teleologically the role of UCP’s in cardiac
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muscle may be to protect mitochondrial DNA from oxidative damage. Overexpression of UCP1 in
cultured cardiac myocytes protected against apoptosis induced by the addition of hydrogen peroxide
[26]. In patients undergoing implantation of a LV assist device for severe heart failure, cardiac UCP3
mRNA expression was reduced compared to donor heart muscle and substantially increased following
improvement of the heart failure by the LVAD [27].
Two caveats should be considered, first that mRNA expression and protein expression may differ, and
secondly the activity as well as the expression of UCP’s is important in determining their function, and
as noted above this is determined by mitochondrial ROS generation [25]. In the study described above
in patients undergoing coronary artery bypass grafting in which UCP expression was related to plasma
free fatty acids, 40% had clinical heart failure, associated with higher plasma FFA [22]. There is thus a
lack of consistency regarding the role of uncoupling proteins in heart failure. Mitochondrial uncoupling
may also occur via the mitochondrial permeability transition pore (MPTP) and the mitochondrial ATP –
dependent Potassium channel (mito KATP ) the opening of both of which is increased by increased
mitochondrial ROS and the relevance of this to heart failure is discussed below.
Energy Transfer and the concept of phosphorylation potential
Whilst generation of ATP occurs in the mitochondria it is consumed mainly by the sarcomeric proteins,
and by ion channels. The predominant transfer mechanism is the creatine kinase (CK) system, with
isoforms in the mitochondria and cytosol. Mitochondrial CK generates Phosphocreatine (PCr) by
phosphorylating Creatine which is rapidly exported from the mitochondria as a transportable source of
energy. At the sites of energy utilization cytosolic CK catalyzes the release of ATP from PCr, and the
former is then coupled to ATPase processes. In addition to being the predominant means of transport
of ATP, PCr represents a ‘reservoir’ of ATP since cleavage of ATP from PCr can occur much more rapidly
than the de novo synthesis of ATP occurring in the mitochondria. Accordingly during prolonged
exercise, PCr is depleted in skeletal muscle because ATP is consumed faster than it can be produced in
the mitochondria and PCr levels then rapidly return to normal following exercise [28].
Techniques for the assessment of energetic status measure ‘average’ energetic status but local energy
availability at the sites of utilization are what really matter. The local free energy available to drive
reactions within the cell is determined by the ratio (ATP)/ (ADP) (Pi). From this it will be seen that it is
not just the availability of ATP that drives reactions, but that elevated concentrations of ADP can
substantially reduce the free energy even if ATP concentrations are only slightly reduced. This is the
case when CK flux is reduced as in heart failure. There is an active transport mechanism for the cellular
uptake of Creatine. Mice that overexpress this transporter have supra-normal creatine and PCr levels.
However, this leads to elevated free ADP levels because the heart is unable to phosphorylate this
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increased pool and consequently the free energy is reduced and these mice develop left ventricular
hypertrophy and then LV systolic dysfunction [29].
It will be clear that an exquisite system of energy sensing must exist in order to fine tune the complex
systems of energy generation, transfer and utilization. Description and discussion of these is beyond
the scope of this review except to say that some components of this sensing system are disrupted in
heart failure, e.g. the KATP channel [30] and the cytoskeleton which connects the mitochondria and
energy consuming organelles [31].
Substrate utilization and the importance of metabolic flexibility
As noted above the heart is able to use different substrates in different circumstances. This flexibility
plays a key role in normal physiological cardiac function. Fatty acid utilization provides the most
efficient way of generating energy when assessed in terms of ATP produced per gram of substrate
metabolized. However when assessed in terms of energy efficiency, i.e. production of ATP per unit of
oxygen consumed, it is less efficient than carbohydrate utilization. Under hypoxic conditions anaerobic
glycolysis provides the only means of energy generation. In fetal life, when oxygen availability is
reduced, energy production is dominantly via glucose and lactate utilization. As oxygen delivery
improves immediately with birth, the use of fatty acids as an energy source dramatically increases. In
the healthy adult under fasting conditions fatty acid utilization typically accounts for between 60 and
70% of energy generation. Under conditions of increased energy demand (e.g. exercise) an even
greater proportion of energy is derived from fatty acid utilization [32]. Under stress conditions such as
increased pressure load, injury, or ischemia, substrate utilization is shifted to the more oxygenefficient use of glucose.
Reciprocal regulation of fatty acid and carbohydrate metabolism
Randle described nearly 50 years ago the competition of fatty acids and glucose for substrates
resulting in reciprocal regulation of the metabolism of one by the other[33]. Thus fatty acid
metabolism inhibits carbohydrate oxidation. This is because fatty acid metabolism increases the ratios
of Acetyl Co A/CoA and NADH/NAD+, inhibiting PDH activity, and increases cytoplasmic citrate, which
in turn inhibits glycolysis. Conversely, when carbohydrate oxidation is increased, citrate from the TCA
cycle can be exported to the cytoplasm where it is converted to Acetyl Co A by the enzyme citrate
lyase (an energy dependent process) and thence by ACC to malonyl-CoA, which inhibits CPT-1. Citrate
allosterically regulates both of these enzymes (For review see [34].
Regulation of expression of genes encoding fatty acid metabolism and of mitochondrial biogenesis
The transcription of genes encoding fatty acid metabolism is powerfully regulated by the peroxisome
proliferator-activated receptors , (PPAR’s) of which the alpha gamma and delta forms are expressed in
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the heart. These form heterodimers with Retinoid X receptors that bind to promoter regions of a large
number of genes involved in metabolism. The activity of this complex is positively regulated by
cytosolic fatty acids (increasing fatty acid gene expression when fat ‘load’ is increased). Activation of
the PPAR alpha/RXR receptor complex increases expression of mitochondrial uncoupling proteins. The
activity of the PPAR gamma/ RXR complex is also increased by the transcriptional coactivator
Peroxisome proliferator – activated receptor gamma coactivator one alpha (PGC – 1 alpha). PGC - one
alpha is widely expressed in tissues in which mitochondria are abundant and in which there is a high
level of oxidative metabolism. It plays a central role in the control of energy metabolism, not only
increasing the expression of genes involved in fatty acid metabolism, but also increasing expression of
the gene encoding GLUT 4 [35] and inducing mitochondrial biogenesis [36]. In skeletal muscle its
expression is increased by chronic exercise training [37] resulting in a switch from glycolytic to more
oxidative fibers, and in small mammals it is activated by cold, playing a key role in thermogenesis via
upregulation of UCP 1 in brown fat. It also interacts with other transcription factors including nuclear
respiratory factors (NRF’s) the latter playing a role in the enhanced mitochondrial biogenesis induced
by PGC - one alpha [38]. In addition it induces expression of sirtuin 3 (SIRT 3) in muscle cells and
hepatocytes , which also plays a role in mitochondrial biogenesis as well as in induction of ROS –
detoxifying enzymes [39]. It also promotes calcineurin activation [40]. A number of factors upregulate
PGC – one alpha expression, including reactive oxygen species [41], cAMP response element-binding
proteins (CREB) , and the metabolic sensory AMP kinase (AMPK) [42] and sirtuin 1 (SIRT 1) [43].
Assessment of cardiac energetic status using 31P MRS and PET scan.
Whilst early studies of cardiac energy metabolism involved direct measurement of cardiac high energy
phosphates in heart muscle tissue, the field was revolutionized by the development of phosphorous31 magnetic resonance spectroscopy (31P MRS). More recently techniques have been developed to
measure the rate of CK flux which has been shown to be dramatically reduced in heart failure [44].
Another molecular imaging technique of relevance is Positron Emission Tomography (PET) which is
mainly concerned with organ specific oxygen consumption and substrate (i.e. glucose and fatty acid)
turnover and tissue perfusion [45].
The inhomogeneous distribution of energetic processes and -flux adds further to the complexity of
assessing myocardial energy metabolism. In fact, intracellular compartmentalization of energetic
processes prohibit the determination of metabolism simply by measuring the average cellular levels
[46]. Both, energy production and utilization are spatially and temporally coordinated in energetic
microdomains that are embedded with the cellular structures according to functional and structural
requirements [47]. The interaction with cell organelles contributes to the control of metabolic activity
and energy flux [48]. Thus sensitivity to ADP depends on the intact cytoskeleton and disruption of
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cellular integrity results in increased ADP sensitivity and impaired mitochondrial energy generation
[49].
Cardiac energetic impairment in heart failure
Reduced cardiac energetic status has been reported in patients with heart failure irrespective of
etiology. In one study of patients with dilated cardiomyopathy, a substantially reduced baseline
cardiac PCr/ATP ratio ( <1.6) was a powerful predictor of subsequent mortality [50]. CK flux is reduced
by approximately 50% in patients with heart failure [44]. CK flux has also been shown to be reduced in
patients with hypertensive left ventricular hypertrophy, especially in those undergoing transition to
heart failure [51]. Myocardial ATP levels are maintained at normal levels in early HF and decrease only
in advanced stages. Total creatine and phosphocreatine, in turn, decrease early in the disease course
resulting in decline of CrP/ATP ratios in parallel to disease severity [52].
Cardiac PCr/ATP ratio was also markedly reduced in patients with heart failure with preserved left
ventricular ejection fraction (HFpEF) and appears to play a role in the dynamic impairment of LV active
relaxation occurring during exercise in these patients [53]. Cardiac energetic impairment is also seen in
other heart muscle diseases, including hypertrophic cardiomyopathy [54, 55] Fabry disease [56] and
Friedreich’s ataxia [57].
Cardiac energetic impairment occurs at multiple points in the cascade of energy generation, transfer
and utilization in heart failure. These will be reviewed below.
Reduced energy generation
Altered substrate utilization:
There has been a considerable focus on changes in substrate utilization in heart failure and in left
ventricular hypertrophy and on the impact of these changes on energy generation. Whilst there has
been much debate about the inconsistent changes in distribution of fatty acid vs carbohydrate
utilization in both experimental models of heart failure and in patients, it seems that overall the
capacity to utilize both major fuel sources is reduced.
In general, there is a reduction in fatty acid oxidation and an increase in glycolysis in these models.
While this shift in substrate utilization characterizes the reversion to a fetal pattern of energy
metabolism, several studies have addressed the question of whether this downregulation of fatty acid
oxidation is adaptive or maladaptive. The data have been conflicting. In the spontaneously
hypertensive rat there is frequently an inherited deficiency of expression of CD 36 that limits uptake of
long chain fatty acids into the cardiac myocyte, with an attendant increase in glucose uptake. Dietary
supplementation with short and medium chain fatty acids (which are not dependent on CD 36 to enter
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the cardiac myocyte) reduces glucose uptake, suppresses hyperinsulinemia, restores cardiac
responsiveness to adrenergic stress and reduces the development of left ventricular hypertrophy
despite the fact that blood pressure is not altered [58, 59]. Similarly, the PPAR alpha activator
Fenofibrate slows progression of left ventricular systolic dysfunction in a porcine model of rapid pacing
induced heart failure [60]. As noted above the PGC one-alpha knockout mouse develops an age related
cardiomyopathy [61]. Furthermore, inherited disorders associated with impaired fatty acid oxidation
are often associated with the development of left ventricular hypertrophy and/or heart failure [62].
Conversely the PPAR alpha knockout mouse has a relatively mild phenotype, with age related cardiac
fibrosis but essentially normal basal cardiac function despite markedly downregulated fatty acid
oxidation, increased glucose uptake and reliance on carbohydrate oxidation [63]. However the cardiac
response of these mice to inotropic stimulation is blunted and can be rescued by upregulation of the
GLUT 1 transporter [64]. GLUT 1 overexpression also prevents progression of hypertrophy to heart
failure in the aortic constriction model [65]. Furthermore cardiac specific overexpression of the PPAR
alpha gene is also associated with the development of heart failure [66]. Plasma free fatty acids are
typically increased in heart failure (due to catecholamine induced activation of lipoprotein lipase).
Since fatty acid oxidation is reduced there is usually an elevated fat content in cardiac myocytes which
might be anticipated to increase expression of UCP’s – however as noted above some studies have
suggested the converse. This and other mechanisms discussed below may increase proton leak across
the mitochondrial membrane and reduce the efficiency of energy generation.
In most experimental models of left ventricular hypertrophy and heart failure, glucose uptake and
glycolysis are either maintained or enhanced. Insulin resistance is common in human and experimental
heart failure, and accordingly GLUT 4 expression is often decreased in experimental models of LVH and
of heart failure [67, 68], However GLUT 1 expression is increased providing the basis for the
maintained or increased glucose uptake. GAPDH and phosphoglycerate kinase (PGK) enzyme activities
were increased in the murine thoracic aortic constriction and coronary artery ligation models of heart
failure [69]. Despite the maintained or augmented glucose uptake and glycolysis, carbohydrate
oxidation is reduced in several models of LVH and of heart failure due to reduced activity of the
pyruvate dehydrogenase enzyme complex and anaplerotic reactions are insufficient to compensate for
the PDH block [70].
The evidence in clinical heart failure is somewhat conflicting. The consensus of the studies is that
down-regulation of fatty acid oxidation may be a relatively late feature [71]. Cross heart sampling
studies with stable isotope infusion have reported divergent results, one reporting reduced and
another preserved fatty acid utilization [72, 73]. There have been several PET based studies
investigating cardiac substrate utilization in heart failure also reporting conflicting results. DavillaRoman and colleagues reported reduced fatty acid utilization and increased glucose uptake [74]
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whereas Taylor and colleagues reported increased fatty acid utilization and reduced glucose uptake
[75]. Notably, PET does not assess carbohydrate oxidation per se but only measures glucose uptake.
In summary in most experimental models hypertrophied and failing hearts have a reduced capacity to
metabolize both major fuel sources (carbohydrate and fatty acids) which is in line with the concept of
bioenergetics starvation. The data in clinical heart failure is less consistent but at least in severe heart
failure the same changes are evident.
Mitochondrial density and mitochondrial subpopulations in heart failure
There are two distinct subpopulations of mitochondria within cardiac and skeletal myocytes, a
subsarcolemmal (SSM) group with a large lamellar morphology situated just below the sarcolemma,
and a intermyofibrillar (IFM) group which are much smaller, with less internal complexity which are
situated between the myofilaments (Hoppel C Int J Biochem Cell Biol 2009). The IFM group provide
energy for the contractile apparatus and the SSM group for other cellular functions including ion
channels. These subpopulations differ in their response to disuse and exercise training, with much
more marked increases in size and greater enhancement of fatty acid oxidation capacity in SSM
mitochondria in skeletal muscle in response to training (Koves T et al Am J Physiol Cell Physiol 2005).
In experimental heart failure due to pressure overload there appears to be a differential effect on
the function of the two groups of mitochondria in cardiac muscle, with a significantly greater
impairment of state 3 respiration in IFM vs SSM [76]. In contrast, cardiac SSM are more susceptible
to ischemic damage caused by calcium overload mediated cytochrome C release compared with IFM
[77].
In compensated pressure overload cardiac hypertrophy there is an increase in mitochondrial number
in proportion to the increase in myocardial mass to match the increased energy demand [78].
Mitochondrial division is under the control of PGC1 alpha. This increases the transcriptional activity
of nuclear respiratory factors (NRF’s) that in turn bind to mitochondrial transcription factor A
(mtTFA) thereby increasing transcription of mitochondrial genes. NRF’s also increase the expression
of nuclear genes encoding fatty acid oxidation enzymes and respiratory chain proteins [79]. Whereas
in compensated hypertrophy cardiac PGC one alpha expression is increased, in experimental models
of heart failure it is reduced [79]. For example in heart failure due to aortic banding in rats there
was reduced expression of PGC one alpha, NRF 2 and mtTFA with a parallel reduction in oxidative
capacity and oxidative enzyme activities in both cardiac and skeletal muscle [80].
In human heart failure reduced mitochondrial transcription factor expression, mitochondrial density
and expression of MRNA for mitochondrially encoded components of the respiratory chain appear
to be a late feature in both cardiac and skeletal muscle, with evidence that beta blockers may have a
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protective effect [81]. Redox stress appears to play a key role in mediating the hypertrophic
response both via activation of nuclear transcription factors such as NFAT 2 and MEF 2 and by
increasing the expression and activity of PGC one alpha [82]. However PGC one alpha in turn
increases expression of the potent mitochondrial antioxidants SOD 2 and Thioredoxin [83],
representing an important feedback mechanism.
Defects in electron transport chain function in heart failure
Abnormalities of function of the individual components of the electron transport chain have been
described in heart failure but there are substantial inconsistencies between studies that almost
certainly relate at least in part to differences in experimental methodology and in particular sample
preparation. Most studies have used freeze- thawed homogenates of cardiac or skeletal muscle. In a
variety of models of heart failure, and in explanted hearts from patients undergoing transplantation,
decreases in the activities of complex1, 111 and/or 1V and a marked reduction in complex V (ATP
synthase) activity has been reported [84, 85, 86]. Additionally, reduced adenine nucleotide
translocase (ANT) activity is reported due to a shift in isoform expression, with an increase in ANT1
and a reduction in ANT1 in tissue from explanted hearts of patients with dilated cardiomyopathy
[87] and from endomyocardial biopsies from patients with mild heart failure due to DCM but not in
heart failure of other etiologies [88]. However, Rosca and colleagues have argued that the use of
freeze-thawed preparations to assess the function of individual ETC complexes may lead to
erroneous conclusions [79]. The optimum integrated functioning of the electron transport chain is
dependent on the organization of the individual components into clusters (respirasomes) embedded
in the inner membrane phospholipid bilayer.
Cardiolipin (CL) is a phospholipid that appears to play a particularly important role in this
organization of ETC components into respirasomes. Cardiolipin content is subject to remodeling by
Tafazzin (catalyzes acylation) and mitochondrial phospholipase A (catalyzes deacylation) [89]. Barth
syndrome (associated with LV non compaction) is an X linked disorder due to mutations of the gene
encoding Tafazzin resulting in defective cardiolipin remodeling and respirasome destabilization [90].
The process of freeze- thawing and the use of detergents for solubilization alter the membrane
cadiolipin content and therefore result in disruption of the normal respirasome organization. This
may be overcome by using isolated mitochondria or tissue homogenates from fresh tissue and
cardiolipin can be restored using exogenous soybean asolectin. Using these techniques in a canine
microembolism model of heart failure Rosca and colleagues showed that the defect in cardiac
mitochondria lay in the organization into respirasomes rather than in the individual ETC complexes
[91]. They subsequently showed in the same model that this was not due to changes in cardiolipin in
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the mitochondrial membrane, rather to cAMP induced threonine phosphorylation of the ‘free’ ETC
components that prevented their incorporation into respirasomes [89]. Rosca and colleagues
propose that the loss of this organization not only reduces the activity of the ETC but also increases
electron slippage at complexes 1 and 111 thereby increasing ROS production resulting in further
oxidative damage to ETC components [79].
Increased mitochondrial ROS and its consequences for energy production:
There is evidence of increased mitochondrial ROS production in heart failure [92]. A functional block
has been reported in complex 1 of the electron transport chain probably due to post translational
modification, resulting in increased superoxide production [93]. Superoxide production may also
potentially occur from complex III. In turn, superoxide degradation by the enzymes manganese
superoxide dismutase, glutathione peroxidase and catalase is a NADPH dependent process. However
less NADPH is available in CHF. Therefore the combination of increased superoxide generation and
reduced activities of catalase and glutathione peroxidase are likely to result in hydrogen peroxide
accumulation within the mitochondria.
A mitochondrial isoform of NADPH (NOX4) also exists and its activity is Angiotensin II dependent
(increased in heart failure). ROS generated by NADPH oxidase further stimulates generation of ROS
by the ETC (ROS induced ROS production) causing amplification of oxidative stress and it is proposed
this leads to progressive mitochondrial dysfunction [94].
Increased mitochondrial ROS have a number of deleterious consequences on mitochondrial function:
a. they cause mitochondrial DNA damage, resulting in impairment of production/ function of
mitochondrially encoded enzymes and other proteins including respiratory chain complexes,
potentially leading to a vicious cycle of further increases in ROS production [95]
b. ROS and reactive nitrogen species may potentially cause post translational modification of
mitochondrial enzymes/proteins [96]
c. they activate MAP kinase systems, resulting in hypertrophy and fibrosis [97]
d. They increase mitochondrial uncoupling via increased activity of the mitochondrial
permeability transition pore (MPTP), inner membrane anion channel (IMAC) and the
mitochondrial ATP – dependent Potassium channel (mito K ATP ) [92]. Furthermore superoxide
and lipid peroxides increase the activity of mitochondrial UCP’s [25]. Whilst the data on UCP
expression in heart failure has therefore been conflicting as discussed earlier, there seems
little doubt that functionally mitochondrial uncoupling is increased in heart failure. Consistent
with this concept, inhibition of opening of the MPTP by Cyclosporine increased ATP generation
in failing cardiomyocytes [98]
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Disturbed energy transfer and energy sensing
As noted above, the CK system is the principal means of energy transfer within the cardiac myocyte.
There is a substantial impairment of this process in heart failure, manifest as a reduction in CK flux of
approximately 50% in patients with heart failure [44]. There is a reduction in expression of the
Creatine – sodium co-transporter in heart failure [99]. This is the mechanism by which Creatine enters
the cardiac myocyte. Total Creatine kinase expression is also reduced in heart failure. Finally there is a
reduction in the activity of CK. The reduction in activity of the myofibrillar isoform of CK appears to be
due to increased cytosolic oxidative stress, arising from multiple sources but particularly NADPH
oxidase and xanthine oxidase [100]. Following successful therapy with a left ventricular assist device in
patients with severe heart failure, an increase in both CK expression and activity was reported [101].
Energy sensing mechanisms are also disturbed in heart failure e.g. the KATP channel and the
cytoskeleton which permits cross –talk between the mitochondria and the energy consuming
organelles [30, 31].
Insulin resistance in heart failure
The substrate shift and diversions in genetic regulation, enzymatic activity and mitochondrial efficacy
in HF is extremely complex. The metabolic phenotype represents the main characteristics of insulin
resistance. The link between diabetes and HF was recognized in the 19th century [102] and a strong
relationship between both diseases has been firmly established. Beyond a mere co-morbidity, mutual
augmentation of both diseases exists contributing to onset, disease progression and mortality of
patients. Hyperglycemia is commonly addressed as the major factor explain the cross talk between
DM and HF. It should be noted, however, that hyperglycemia is a secondary effect of impaired glucose
utilization while the true underlying mechanism may in fact be insulin resistance. Accordingly,
increased insulin excretion was observed in patients with HF compared to controls as much as 20 years
before the diagnosis of HF was made [103]. Insulin resistance is an etiologic factor in the development
of HF [104] and, in turn, progresses in HF secondary to HF severity [105]. This role of insulin resistance
in HF is not fully explained by the metabolic risk profile summarized in the metabolic syndrome which
is of course a pre-requisite of ischemic type heart failure. In fact, insulin resistance should be regarded
a principal metabolic feature within HF pathophysiology (Figure 3), with the classical metabolic
syndrome potentially exerting an additive effect on even more advance insulin resistance [106]. In
support of this concept, it was recently shown that cardiac unloading by LV assist device resulted in
restored myocardial substrate utilization with higher glucose and lower lipid oxidation and improved
insulin / PI3K / Akt signaling and restored systemic insulin sensitivity [107]. It is important to note for
both pathophysiologic considerations as for diagnostic and therapeutic implications, that this insulin
13
Doehner et al.
Metabolic failure in heart failure (online Appendix)
resistance is not limited to the myocardium itself but has systemic effects [108]. With 80% of total
glucose uptake in vivo the skeletal muscle is the main glucose utilizing organ [109] and has been shown
to be insulin resistant in HF patients [22]. As the immediate consequence of impaired insulin
dependent energy metabolism it is no surprise that insulin resistance in CHF correlates directly with
symptomatic status [106, 110]. Moreover, insulin resistance has been as independent prognostic
marker without presence of diabetes [105, 111].
The clinical and diagnostic perception of insulin resistance is commonly limited to the glucose
regulatory function of insulin being defined by impaired cellular glucose uptake, hyperinsulinemia and
(as a relatively late effect) hyperglycemia. By contrast, insulin is a hormone with truly pleiotropic
actions being involved in a vast number of, neuroendocrine, immunologic, vascular and anabolic
signaling pathways that cannot be reviewed here in detail. The net effect of insulin resistance on these
multiple other pathways is only incompletely understood and decreased signaling (resistance),
increased signaling (hyperinsulinemia) or balanced signaling may all be possible at individual pathways
to a varying extent. Neuroendocrine activation, impaired vasodilation [112], anabolic failure, and
lipotoxicity with ROS accumulation are all highly relevant in the setting of HF and may contribute to
further disease progression and symptomatic aggravation.
Mechanisms of IR in HF
The complex interplay of mechanisms that cause insulin resistance in patients with CHF are not
entirely understood. Multiple factors such as catecholamines, inflammatory cytokines, oxidative stress,
and tissue hypo-perfusion are well established to interfere with insulin signaling and are activated in
HF patients (Figure 3). The individual contribution of these factors in HF patients may be highly
variable depending on disease severity, degree of acute decompensation and etiological factors [113].
In stable, ambulatory patients with CHF, catecholamine levels and TNF-alpha did not show an
association with insulin resistance [114]. In this study, leptin levels were elevated in HF even when
corrected for total fat mass and tightly associated with insulin resistance in CHF patients. Further,
blunted expression of insulin dependent glucose transporter GLUT4 [115] and the reciprocal regulation
between FFA and glucose utilization in skeletal muscle and myocardium have been reported [22]. Low
tissue perfusion due to reduced vascularization and endothelium dysfunction may further decrease
glucose and insulin transport and uptake. Also, medications for heart failure such as statins [116] and
diuretics [117] and spironolactone [118] may unfavorable interfere with insulin sensitivity.
Finally, a sedentary life style may add to the impairment of insulin sensitivity as muscle deconditioning
is a fast although reversible negative stimulus for impaired insulin mediated glucose utilization [119].
14
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Metabolic failure in heart failure (online Appendix)
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