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Contents
Contents
EDITORIAL......................................................................................................................................................................................3
Energetics in heart disease
D. Feuvray
BASIC ARTICLE..........................................................................................................................................................................5
Myocardial energetics and efficiency
E. Aasum
MAIN CLINICAL ARTICLE................................................................................................................................................9
Modulation of cardiac energetics as a target in ischemic heart disease
H. Ashrafian
METABOLIC IMAGING..................................................................................................................................................... 14
Glucose metabolism as a marker of myocardial ischemia
P. G. Camici
NEW THERAPEUTIC APPROACHES.................................................................................................................. 19
An expanded role for AMP kinase: self-renewal of the cardiomyocyte
K. K. Baskin and H. Taegtmeyer
FOCUS ON TRIMETAZIDINE (Vastarel®MR)............................................................................................... 25
Beneficial effects of trimetazidine (Vastarel®MR) in patients with chronic
heart failure
G. Fragasso, L. Alberti and L. Lauretta
CASE REPORT......................................................................................................................................................................... 29
Myocardial power delivery is impaired in progressive left ventricular pump failure:
a case report
F. L. Dini
REFRESHER CORNER..................................................................................................................................................... 33
Impact of fatty acid oxidation on cardiac efficiency
N. Fillmore and G. D. Lopaschuk
HOT TOPICS............................................................................................................................................................................... 38
Statin therapy: reduction in cardiovascular events still pays in new-onset diabetes
A. Huqi­
GLOSSARY................................................................................................................................................................................... 40
G. D. Lopaschuk
Heart Metab. (2011) 53:1
EDITORIAL - DANIELLE FEUVRAY
Energetics in heart disease
Danielle Feuvray, CNRS UMR 8162, Marie Lannelongue Hospital,
Le Plessis Robinson, France
Editorial
Correspondence: Danielle Feuvray, UPS & CNRS UMR 8162,
Marie Lannelongue Hospital, 92350 Le Plessis Robinson, France.
e-mail: [email protected]
E
ven subtle variations in the efficiency of energy generation or utilization may have a profound impact on cellular energy levels. Different cardiac pathologies can alter cardiac efficiency, both as a result of a decrease efficiency of producing ATP or alterations in the efficiency
of using ATP to produce contractile work. Given that the requirement for ATP for all metabolic
processes and for cell viability is absolute, a renewed interest in metabolism has led to identification of the molecular links between physiological and metabolic stimuli and the regulation of
gene expression in the heart. Metabolism remodels in the failing heart leading to the inability to
increase ATP supply. Ultimately, this may lead to a fall in ATP. The likely time line is decreased
energy production via the phosphotransferase reactions (creatine kinase and adenylate kinase)
leading to increases in ADP and AMP. As heart failure evolves, ATP synthesis from oxidation of
metabolic substrates by mitochondria, the major source of ATP in the heart, falls. Remodeling
of the failing myocardium is controlled by energy sensors, such as AMP-activated protein
kinase (AMPK) that regulates energy substrate metabolism and regulates transcription of
metabolic genes. This issue of Heart and Metabolism addresses the important topic of energetics in heart disease.
In the Basic Article, Dr. Aasum offers a concise review of myocardial energetic mechanisms,
focusing on alterations in processes related to energy production and energy utilization in the
failing heart. The Main Clinical Article by Dr. Ashrafian gives a clear and elegant overview of
successful metabolic therapies presently available, especially for chronic ischemic heart
disease. While considering the likely future directions for metabolic therapy, Dr. Ashrafian also
points out the need for greater experience with the existing metabolic therapies, which could
benefit most to those patients with concomitant metabolic disease, such as metabolic
syndrome or diabetes mellitus.
In this context the Refresher Corner article by Drs. Fillmore and Lopaschuk provides a
didactic summary of the state of the art, showing notably how metabolic substrates compete
at myocardial cell level for energy production and how they may affect cardiac efficiency.
Alterations in the balance between fatty acid and glucose use are known to occur in certain
heart pathologies such as during ischemia and in the failing heart. This leads to decreased cardiac efficiency through a number of mechanisms that are reviewed and discussed herein,
among which are intracellular ionic (H+, Na+, Ca2+) disturbances and their deleterious consequences. Measuring metabolic substrate utilization in humans has been difficult. The Metabolic
Imaging article by Dr. Camici underlines that although the quantification of glucose utilization
rates in patients encounters many difficulties, positron emission tomography with the glucose
Heart Metab. (2011) 53:3–4
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EDITORIAL - DANIELLE FEUVRAY
analogue 18F-fluorodeoxyglucose (FDG) may help to
establish values of the metabolic rates of glucose utilization in normal and pathologic conditions.
Furthermore, Drs. Baskin and Taegtmeyer provide an authoritative New Therapeutic Approaches
article that broadens the role of energy substrate
metabolism from a provider of ATP to a regulator of
self-renewal of cardiac myocytes. They highlight the
exciting new concept of how heart muscle cells can
renew themselves from within by the identification of
certain metabolic signals as a root cause for altered
rates of intracellular protein turnover and, hence,
self-renewal of cardiac myocytes. Metabolic remodeling precedes, triggers and sustains structural and
functional remodeling of the heart. As mentioned
before, AMPK supports energy provision in the
cell by sensing changes in the ratio [ATP]/[AMP]. In
4
addition, decrease in [ATP]/[AMP] and the subsequent
activation of AMPK regulate protein degradation.
Since individual proteins are degraded through the
ubiquitin proteasome system Drs. Baskin and Taegtmeyer investigated the role of AMPK in proteasomemediated protein degradation. They found that
proteasome-mediated protein degradation in the
heart is indeed increased with AMPK activation.
They therefore speculate that the activation of
AMPK results in enhanced availability of intracellular
amino acids for either ATP production or the synthesis of new proteins as the heart adapts to a new
physiological state. These most recent data advance
a new understanding of cardiac metabolism. They
should also set us on the path to develop novel strategies aimed at optimizing metabolic therapy in heart
disease. ●
Heart Metab. (2011) 53:3–4
BASIC
ARTICLE
- ELLEN AASUM
Myocardial energetics and efficiency
Ellen Aasum, Cardiovascular Research Group Faculty of Health Sciences, University of Tromsø, Norway
Correspondence: Ellen Aasum, Cardiovascular Research Group,
Institute of Medical Biology, Faculty of Health Sciences,
University of Tromsø, N-9037 Tromsø, Norway.
Tel: +47 77646486 fax: +47 77645440, e-mail: [email protected]
Abstract
In addition to structural and functional abnormalities, it is well established that energy homeostasis is
impaired in the failing heart. As the heart requires large amounts of energy to sustain its continuous
pumping activity, it is highly dependent on an optimal substrate metabolism with efficient ATP generation and utilization. Alterations in processes related to energy production as well as energy utilization in
the failing heart may lead to energetic imbalance, an inefficient hearts with impaired contractile reserve.
Keywords: cardiac energy metabolism; oxygen consumption; mechano energetics; heart failure
Basic Article
■ Heart Metab. (2011) 53:5–8
Introduction
The heart maintains its pumping action by converting chemical energy in metabolic substrates
into mechanical energy, and because of its high energy requirement and relatively low content
of high energy compounds (ATP and creatine phosphate [PCr]) ATP must be continuously
generated at a high rate. Thus, the heart must adjust energy production to energy utilization,
and at the same time secure an efficient energy transfer. These processes involve substrate
uptake, breakdown and entry into the Krebs cycle, as well as mitochondrial oxidative phosphorylation, ATP transfer (e.g., the creatine kinase energy shuttle), and hydrolysis at the energy
consuming sites. The metabolically healthy heart has the capacity to switch between lipids and
carbohydrates as energy substrates, and the fuel selection is to a large extent governed by the
availability of plasma substrates, as well as the levels of hormones (insulin and catecholamines)
in the circulation. Since the majority (>90%) of ATP production is derived from mitochondrial
oxidative phosphorylation, myocardial oxygen consumption (mVO2) in the normoxic heart can
be used as a measure of the total myocardial energy utilization. Mechanical efficiency, which
connote the ability of the heart to perform its functions, is the ratio between external (stroke)
work and mVO2 [1]. Decreased mechanical efficiency has been suggested to play a leading
role in the pathogenesis of a number of cardiovascular conditions leading to heart failure. The
imbalance between energy demand and availability will ultimately lead to an energetically compromised heart with reduced working capacity. As decreased efficiency will be particularly disadvantageous under conditions of reduced oxygen availability, it will also contribute to the
increased susceptibility of the failing myocardium to acute ischemia or hypoxia.
The failing heart is energetically compromised
In accordance with this notion, clinical and experimental studies on heart failure, using 31P
magnetic resonance spectroscopy (MRS), have revealed a decreased cardiac PCr:ATP ratio.
Heart Metab. (2011) 53:5–8
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Decreased PCr:ATP ratio has been shown to correlate with the severity of heart failure in patients with idiopathic dilated cardiomyopathy [2] and to be a predictor of mortality in these patients [3]. Decreased
PCr:ATP ratio is also found in hearts from type 2 diabetic patients [4], which show increased prevalence
and worsened prognosis of heart failure [5].
capacity and/or loss of functional coupling with
sites of energy utilization, can limit the heart’s ability
to generate work and thus contribute to cardiac
dysfunction.
Impaired ATP homeostasis in the failing heart is
obviously multifactorial and complex, including
reduced ATP production, loss of the total adenine
nucleotide pool and changes in the creatine kinase
system, which in turn affect the energy transport to
the energy consuming sites, such as myofibrils
and sarcoplasmatic reticulum (SR) [2,6–8]. The failing
heart is also characterized by altered energy substrate utilization. The mechanisms behind these
metabolic changes are complex due to the heterogeneous etiology of heart failure, as well as to differences in the progression of the disease. Experimental
models of heart failure generally report decreased
fatty acid oxidation and increased reliance on glucose
oxidation and glycolysis, with a depressed overall
oxidative metabolism in end-state failure [9]. Changes
in human hearts show less consistency with respect
to fuel selection, likely due to the complexity and
diversity of the metabolic status of these patients.
Patients with heart failure often have increased plasma
noradrenalin and free fatty acid concentrations reflecting stress hormone-induced lipolysis [10]. In addition,
co-morbidities such as obesity, insulin-resistance
and type 2 diabetes will influence myocardial substrate
utilization. In the uncompensated state, the fatty
acid oxidation pathway is generally down-regulated
(metabolic remodeling due to a decline in the activation
of the transcription factors PPARα), and glucose
uptake and oxidation is insufficient to secure an adequate energy production. Altered mitochondrial mass,
structure, and functional capacity have also been
demonstrated in failing myocardium. Whether inadequate oxygen availability or metabolic substrate supply
are limiting factors for oxidative capacity is not clear.
Several studies have, however, shown decreased
activity of the complexes of the respiratory chain,
Krebs’ cycle enzymes and the ATP synthase (F0F1)
[8], and functional studies also suggest that mitochondria from failing hearts are less coupled [11]. As there is
a clear correlation between oxidative ATP production
and heart work, decreased mitochondrial oxidative
Decreased myocardial mechanical efficiency in the failing heart is a consistent and early finding both clinically
and in experimental models. Assessment of myocardial mechanical efficiency is an important clinical
tool for evaluation of the outcome of therapies. As illustrated in the Fig. 1, energy is used for both mechanical
and non-mechanical processes in the heart. The latter
deals with energy used in excitation-contraction coupling (ECC), i.e., cardiac sarcoplasmic reticulum function, notably calcium pumping, and basal metabolism
(BM), and is consequently referred to as the workindependent mVO2. Energy for the mechanical
processes (total mechanical energy, TME), includes
generation of myocardial force and pressure in the ventricular wall (potential energy) and for ejection of blood
against an afterload pressure (external work, EW).
Oxygen cost for mechanical work is therefore workdependent and correlates closely with TME of the
heart (panel B). This principle implies that each step
co-determines the overall mechanical efficiency, and
that mechanical efficiency not only depends on intrinsic properties of the heart, but also strongly on hemodynamic conditions (loading conditions) [12]. Assessment of the relationship between mVO2 and TME in
experimental models of heart failure can reveal the
underlying mechanisms leading to mechanical inefficiency by identifying mechano-energetic changes in
the heart. Failing hearts in different experimental models (pressure/volume overload, coronary microembolisation, rapid ventricular pacing, diabetes, infarcted
hearts) have generally reveal unchanged or decreased
slope of this relationship, which suggest unchanged
or improved efficiency of the chemo-mechanical energy
transduction (contractile efficiency) [12]. These changes
may reflect an adaptive response to the impaired
energy balance, and has been associated with a shift
from the myosin heavy chain (MHC) α isoform to the
slower, but more economical, β isoform in rodent
models. The functional role of such a shift in MHC isoform in larger mammals (including human) is, however,
less clear.
6
Myocardial efficiency and mechano-energetics
Heart Metab. (2011) 53:5–8
BASIC
ARTICLE
- ELLEN AASUM
A
B
heat
y
nc
cie
Effi )
e
l
l
pe
cti
tra slo
on (1/
MVO2
C
mVO2
ATP
work-dependent mVO2
heat
ECC BM
heat
TME
ECC
PE
heat
EW
work-independent mVO2
BM
TME
Fig. 1 Panel A. Energy flow diagram from oxygen consumption to external work (EW) via ATP. ATP in the heart is used for nonmechanical activity (excitation-contraction coupling, ECC) and basal metabolism (BM), and for generating total mechanical energy (TME)
which includes generation of myocardial tension in the ventricular wall (potential energy, PE) within the ventricular wall and pressure in the left
ventricle for ejection of blood against an afterload pressure (external work, EW). Panel B. A linear relationship exists between total mechanical energy (TME) and mVO2, where the y-intercept defines the work-independent mVO2, and the inverse of the slope of the relationship will
indicate the efficiency of oxygen to TME (contractile efficiency). Adapted from Suga (1990) [12].
The failing heart shows increased oxygen cost
for non-mechanical processes
The y-intercept of the work-mVO2 relationship reflects
the oxygen cost for non-mechanical processes
(unloaded mVO2) [12], which is reported to be increased
in several models of heart failure. Altered unloaded
mVO2 may be related to altered myocardial Ca2+
handling, altered substrate utilization and/or induction
of oxygen wasting processes. Decreased sarcoplasmic reticulum (SR) Ca2+ATPase (called SERCA2 in the
heart) expression and activity are generally accepted
as important mediators of cardiac dysfunction in the
failing heart. As a compensatory mechanism, sarcolemmal Na+-Ca2+ exchange activity is increased,
which energetically will lead to a less efficient Ca2+
transport during excitation-contraction coupling. In
addition, increased sarcoplasmic reticulum Ca2+ leak,
as well as desynchronised Ca2+ release via SR calcium
channels may also contribute to increased oxygen
cost for Ca2+ handling in these hearts. The pivotal
role of SERCA2 in ventricular dysfunction is supported by studies demonstrating enhanced contractile
function via either transgenic approaches or adenoviral
gene transfer. Hence, supportive SERCA2 gene therapy is a potential treatment strategy for heart failure.
There are, however, controversies with regard to the
energetic consequence of such interventions [13].
Since fatty acids is an energetically less efficient
energy substrate compared to glucose (i.e. require a
Heart Metab. (2011) 53:5–8
higher oxygen consuming due to a lower ATP:oxygen
ratio), the switch towards glucose in the failing heart is
generally regarded an adaptive mechanism. On the
other hand, the predominant myocardial fatty acid oxidation in diabetes has been associated with increased
mVO2 and decreased mechanical efficiency [9]. Based
on this, reduction of fatty acid oxidation by inhibiting
fatty acid transport into the mitochondria, or fatty acid
β-oxidation, has proven beneficial in animal models of
heart failure and in clinical trials [9,10,14,15]. Mjøs and
coworkers demonstrated more that 40 year ago, that
elevation of circulating fatty acids induced oxygen
wastage and decreased mechanical efficiency in an
open chest dog model [16]. This fatty acid-induced
increase in mVO2 is due to increased oxygen cost for
non-mechanical purposes [17], and cannot solely be
ascribed to increased fatty acid oxidation rate, as a
shift from glucose to fatty acid oxidation can only
account for approximately 1/3 of the increased
mVO2. Fatty acids are ligands for PPARα that regulate
the expression of uncoupling proteins (UCPs), and
although the role of mitochondrial uncoupling in heart
failure is not definitively established, UCP expression
has been shown to correlate to circulating fatty acid
concentrations in human and animal samples [11,18].
In experimental studies the presence of fatty acids has
also been shown to decrease cardiac mechanical efficiency, not only in the normal heart [17] but also in the
chronically infarcted rat heart [11]. Finally there are
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- ELLEN AASUM
evidence linking fatty acids and oxidative stress to
mitochondrial uncoupling in several models of heart
failure [10,19].
Despite favorable effects of current therapies, the
high mortality rate in heart failure indicates the need
for developing new and more targeted therapeutic
strategies [20]. While the current treatments of heart
failure (ACE inhibitors, cardiac β-blockers and resynchronization therapy) aim to decrease energy demand,
future strategies could focus on re-establishing the
energetic balance by also improving energy production and/or reducing processes leading to the
mechano-energetic uncoupling in the failing heart. ●
References
1. Bing RJ, Hammind MM, Handelsman JC, Powers SR, Spencer FC, Eckenhoff JE, Goodal MD, Hafkenschiel JH, Kety SS
(1949) The measurement of coronary blood flow, oxygen consumption, and efficiency of the left ventricle in man. Am Heart
J 38(1):1–24
2. Neubauer S (2007) The failing heart--an engine out of fuel.
N Engl J Med 356(11):1140–1151
3. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters
W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K (1997)
Myocardial phosphocreatine-to-ATP ratio is a predictor of
mortality in patients with dilated cardiomyopathy. Circulation
96(7):2190–2196
4. Scheuermann Freestone M, Madsen PL, Manners D, Blamire
AM, Buckingham RE, Styles P, Radda GK, Neubauer S,
Clarke K (2003) Abnormal cardiac and skeletal muscle energy
metabolism in patients with type 2 diabetes. Circulation 107(24):
3040–3046
5. Kannel WB, McGee DL (1979) Diabetes and cardiovascular
disease. The Framingham study. JAMA 241(19):2035–2038
6. Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011)
Bioenergetics of the failing heart. Biochim Biophys Acta
1813(7):1360–1372
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7. Ingwall JS, Weiss RG (2004) Is the failing heart energy
starved? On using chemical energy to support cardiac function. Circ Res 95(2):135–145
8. Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81(3):412–419
9. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley
WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258
10. Opie LH, Knuuti J (2009) The adrenergic-fatty acid load in
heart failure. J Am Coll Cardiol 54(18):1637–1646
11. Murray AJ, Cole MA, Lygate CA, Carr CA, Stuckey DJ, Little
SE, Neubauer S, Clarke K (2008) Increased mitochondrial
uncoupling proteins, respiratory uncoupling and decreased
efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol 44(4):694–700
12. Suga H (1990) Ventricular energetics. Physiol Rev 70(2):
247–277
13. Pinz I, Tian R, Belke D, Swanson E, Dillmann W, Ingwall JS
(2011) Compromised myocardial energetics in hypertrophied
mouse hearts diminish the beneficial effect of overexpressing
SERCA2a. J Biol Chem 286(12):10163–10168
14. Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G,
Ahmed I, Maher AR, Kaur K, Taylor J, Henning A, Ashrafian H,
Watkins H, Frenneaux M (2010) Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity
in symptomatic hypertrophic cardiomyopathy. Circulation
122(16):1562–1569
15. Fragasso G, Perseghin G, De CF, Esposito A, Palloshi A,
Lattuada G, Scifo P, Calori G, Del MA, Margonato A (2006)
Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate
ratio in patients with heart failure. Eur Heart J 27(8):942–948
16. Mjøs OD (1971) Effect of fatty acids on myocardial function
and oxygen consumtion in intact dogs. J Clin Invest
50:1386–1389
17. Korvald C, Elvenes OP, Myrmel T (2000) Myocardial substrate
metabolism influences left ventricular energetics in vivo. Am J
Physiol Heart Circ Physiol 278(4):H1345–H1351
18. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K
(2004) Uncoupling proteins in human heart. Lancet
364(9447):1786–1788
19. Echtay KS, Pakay JL, Esteves TC, Brand MD (2005) Hydroxynonenal and uncoupling proteins: a model for protection
against oxidative damage. Biofactors 24(1–4):119–130
20. Mudd JO, Kass DA (2008) Tackling heart failure in the twentyfirst century. Nature 451(7181):919–928
Heart Metab. (2011) 53:5–8
MAIN
CLINICAL ARTICLE
- HOUMAN ASHRAFIAN
Modulation of cardiac energetics
as a target in ischemic heart disease
Houman Ashrafian, Department of Cardiovascular Medicine, Oxford University, Oxford, United Kingdom
Correspondence: Houman Ashrafian, Department of Cardiovascular Medicine, University of Oxford,
John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
e-mail: [email protected]
Abstract
Substantial advances in mechanical and adjunctive pharmacological therapies have reduced the
consequences of ischemic heart disease. Despite these advances, cardiovascular disease and its
major contributor coronary artery disease continue to accrue substantial morbidity and mortality.
Metabolic therapies (ranging from insulin to fatty acid oxidation inhibitors and late sodium channel
current inhibitors) represent a novel and immediately clinical relevant class of therapies that can
contribute to improving patient outcomes. In the current article, I will discuss the basic biology of
cardiac metabolism and the clinical efficacy of agents, some of which have direct clinical applicability.
As well as outlining the considerations that may culminate in the effective deployment of these agents
in the care of patients, I also consider the likely future directions for metabolic therapy in cardiovascular disease.
Keywords: cardiac energetics; ischemic heart disease; metabolic therapies; cardiac metabolism
Main Clinical Article
■ Heart Metab. (2011) 53:9–13
Introduction
Cardiovascular disease remains the leading cause of mortality in the developed world and has
emerged as a major cause of morbidity and mortality in the developing world [1]. Ischemic
heart disease resulting from coronary artery disease, along with hypertensive heart disease,
represents the engine of cardiovascular mortality and is consequent upon the lifestyle changes
occurring with increasing “development” (e.g., smoking, obesity, psychosocial factors and
sedentary lifestyle) [2]. Advances in mechanical interventions (e.g., percutaneous coronary
intervention and coronary artery bypass surgery) that augment the oxygen supply to the myocardium coupled with therapies that reduce cardiac oxygen demand (e.g., β-blockers and
ivabradine, which reduces heart rate exclusively by acting on the sinus node-If current) are the
mainstay of current therapy. However, despite the use of these therapies, many patients
remain symptomatic, expanding the reservoir of aging patients who, having undergone the
demographic transition, ail with angina and chronic heart failure. To combat the morbidity and
mortality associated with these conditions, novel therapies are urgently required—therapies
that modify cardiac metabolism represent a hitherto practically unexplored group of treatments
that are increasingly recognized to have promise in addressing the chronic consequences of
cardiac disease [3].
Heart Metab. (2011) 53:9–13
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- HOUMAN ASHRAFIAN
Metabolic changes in the ischemic myocardium
It is frequently stated that the heart is capable of
metabolizing a range of substrates, including free
fatty acids (FFA), glucose and other carbohydrates
(e.g. pyruvate and lactate) and even amino acids. The
consequence of changing this substrate is less frequently considered.
A striking exemplification of the influence of metabolism on myocardial structure, albeit in the reptile hearts,
can be adduced from the influence of metabolism on
Burmese python hearts. These reptile hearts hypertrophy by >40% after the snakes’ monthly meal [4]. This
entirely physiological—and likely reversible—structural
change derives from the metabolism of a combination
of three fatty acids: myristic, palmitic, and palmitoleic
acids. Importantly, mice hearts also undergo cardiac
hypertrophy (~10%) when exposed to the same cocktail of FFA. Thus while the mammalian heart is therefore
a metabolic omnivore [5], the choice of substrate has
profound consequences on cardiac structure, energetics and function. For example, theoretically a complete
switch from FFA metabolism as an energy source to
glucose can save 11–13% of myocardial oxygen use
based on stoichiometric considerations (and by ~50%
as measured experimentally in pig and canine hearts).
The healthy adult myocardium, especially during
fasting, preferentially metabolizes FFA and their derivatives (60–100%) [3]. In hypertrophy and heart failure, it
is believed (though not unanimously accepted) that a
downregulation of fatty acid metabolism is compensated for by increased carbohydrate metabolism in
an attempt to spare oxygen. Although far from experimentally confirmed, during myocardial ischemia a
rapid activation of AMP-activated protein kinase
(AMPK) occurs, resulting in an activation of both glucose uptake and an increase in fatty acid oxidation [6].
It is therefore presumed that the ischemic myocardium
continues to rely on FFA metabolism with the attendant inefficiency of this substrate. Not only do FFA
confer an oxygen utilization penalty on the heart at a
time of blood/oxygen deficiency, but inappropriately
high FFA metabolism may, as Randle proposed,
compromise coupled glucose metabolism and have
especially adverse sequelae on ischemic hearts (e.g.,
due to the influence of excess FFA on calcium transients in ischemia).
Accordingly, substantial emphasis has been placed
on physiological or therapeutic strategies designed to
10
suppress FFA uptake and/or oxidation in order to stimulate coupled myocardial glucose utilization. Although
this substrate switch continues to be the primary focus
for metabolic therapies, it is increasingly recognized
that redox and aldehyde-induced stress responses
can effect a shift in glucose metabolism from glycolysis
to the pentose phosphate pathway [7]. Such studies
provide a rationale for investigating other such signaling
pathways with a broader view to elaborating resistance
against acute oxidative stress induced by ischemia/
reperfusion through metabolism.
Metabolic therapies
Glucose-insulin
In an attempt to recapitulate and exaggerate “physiological” glucose uptake into myocardium, Sodi-Pallares
et al., in 1962, successfully applied “polarizing solution”,
i.e., glucose-insulin-potassium infusion (GIK), for treatment of acute myocardial infarction. GIK infusion was
initially thought to confer benefit primarily by increasing
glycolysis and by reducing in FFA uptake and metabolism. More recently, we have demonstrated that
GIK treatment also engenders a number of signaling
changes (e.g., increased signaling protein phosphorylation and O-GlcNAcylation) likely to contribute to myocardial protection [8].
A number of early studies supported this early
promise, for example the ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group were able to
show a dramatic reduction of death rate of acute myocardial infarction from 11.5% in the control group to
6.7% in patients treated with GIK. However the negative results of large trials such as the CREATE-ECLA
trial, which studied 20,201 patients with ST-elevation
acute myocardial infarction, mostly in India and China,
have questioned the role of GIK in the context of modern reperfusion therapy [9]. The conclusions of the latter study are moderated by the observation that GIK
may have been given too late to be effective [10], its
efficacy may have depend on the dose, its efficacy
may have been limited by pharmacokinetics and pharmacodynamics and may depend on the exact population studied (including the nature of the adjunct pharmacology/coronary revascularisation).
Nevertheless, the current evidence suggests that
GIK provision as performed in existing trials does not
reduce mortality in patients with AMI but that tight
Heart Metab. (2011) 53:9–13
MAIN
CLINICAL ARTICLE
- HOUMAN ASHRAFIAN
glycemic control is beneficial [11]. One way in which
these limitations of insulin have been overcome is by
the use of the incretin glucagon-like peptide-1 (GLP-1),
which has demonstrable cardioprotective properties in
experimental models and patients with cardiac ischemia [12]. Indeed, there is accumulating evidence suggests that albiglutide, a novel longer lasting GLP-1,
rather akin to the early GIK studies, may protect the
heart against from ischemic injury by altering substrate
use and ameliorating cardiac energetics [13].
Partial fatty oxidation (pFOX) inhibitors
In order to achieve a more enduring and practicable
switch between FFA and carbohydrate metabolism,
a number of inhibitors of fatty acid oxidation have
been sought and executed. CPT-1 is the rate-limiting
enzyme that transports FFA into the mitochondria.
Pharmacological inhibition of CPT-1 by etomoxir,
oxfenecine and perhexeline and experimental malonyl
CoA decarboxylase inhibitors (which augments the
native CPT-1 inhibitor - malonyl CoA) have been
investigated in pre-clinical models and human studies of cardiac ischemia. Similarly, the β-oxidation
enzymes downstream of CPT-1, such as mitochondrial 3-ketoacyl-CoA thiolase inhibited by trimetazidine, are recognized to be therapeutic targets in the
treatment of ischemic heart disease. Notably, despite
the challenges of dose monitoring and intellectual property issues, both perhexiline and trimetazidine continue
to be used successfully in the clinical setting [14].
It is important to recognize that the more potent
pFOX inhibitors (inhibitors) tend to be limited by their
side effect of cardiac lipotoxicity arising from excess
cardiac lipid accumulation (etomoxir, oxfenecine). In
contrast, competitive inhibitors of these enzymes
such as perhexiline and trimetazidine, which allow
excess endogenous FFA to break through the inhibition, do not show such effects. It is likely, therefore,
that any successful cardiac metabolic therapy should
be carefully moderated in order to prevent extreme
inhibition of any single metabolic pathway, highly likely
to be harmful to an organ.
Late sodium channel current
In the ischemic myocardium, inhibition of the energyrequiring Na+/K+ ATPase and other ATP dependent
currents results in excess of myocellular sodium loading through failure of sodium efflux. The late sodium
current, as a result of its persistent flow throughout
Heart Metab. (2011) 53:9–13
the action potential, may make a substantial contribution to this ischemic sodium loading [15]. Excess
sodium loading increases oxidative stress, increases
myocellular calcium loading perhaps through the influence of sodium on calcium countertransport through
NCX and depletes mitochondria of their calcium (which
reduces the mitochondrial Kreb’s cycle activity and
exacerbates energy deficiency) [16]. The mechanism
through which blocking late inward sodium currents,
leads to a reduction in angina remains the subject
of active investigation but ranolazine, a late inward
sodium current blocker with pFOX activity [17] does
exhibit some anti-anginal properties [18].
The Future
A number of successful metabolic therapies are therefore presently available for clinical therapy, especially
for chronic ischemic heart disease. Two directions
remain to be pursued.
Greater experience with existing therapies
Substantial advances have been made in developing
and demonstrating the safety and efficacy of a number
of metabolic agents for the treatment of ischemic heart
disease. Indeed a number of these agents, e.g., ranolazine and trimetazidine, have been tested in clinical
trials. The paucity of use of these agents partially
reflects the requirement for further education of clinical
colleagues. However, perhaps a more trenchant reason for the lack of extensive use of these agents
derives from a lack of clarity about the ideal context
for their use. Existing agents such as β-blockers,
nitrates, calcium channel antagonists and specific
rate-limiting agents, such as ivabradine, all successfully mitigate the consequences of ischemia in many
patients. One of the challenges for many practitioners
is, to identify the population in which these products
will offer them the most adapted benefits, e.g., those
with concomitant metabolic disease such as the
metabolic syndrome/diabetes mellitus or those with
ventricular dysfunction, whose cardiac metabolic
dysfunction may respond especially well to metabolic
modulation.
Novel metabolic therapies
While inhibition of FFA oxidation continues to represent
a credible strategy for the treatment of chronic ischemia, there is substantial potential for identifying novel
metabolic nodes for treatment. Existing interesting
11
MAIN
CLINICAL ARTICLE
- HOUMAN ASHRAFIAN
metabolic therapies such as dichloroacetate which,
through liberating pyruvate dehydrogenase from its
kinase inhibitors, augments carbon flux into the
Kreb’s cycle have been disappointing by virtue of
their pharmacokinetics and their potential side effects.
However, there are a number of novel avenues to pursue. Firstly, it is increasingly recognized that as well as
their roles in energy generation, metabolites can
marshal a wider group of biological responses that
are amenable to therapeutic modulation. For example,
the Kreb’s cycle intermediate, succinate, acting through
G protein-coupled receptor-91, can determine angiogenesis as a response to chronic ischemic stress.
This observation supports the contention that a broader
vision of metabolic manipulation is likely to elevate metabolic therapy beyond energy modulation [19]. Pursuing this theme further, established metabolic therapies
such as GIK and more specifically agents such as glucosamine post-translationally modify serine and threonine residues of proteins by the O-linked attachment
of the monosaccharide β-N-acetyl-glucosamine (i.e.,
O-GlcNAcation) [20]. As well as subserving metabolic
benefits, metabolic therapies also have profound influences on other aspects of cardiac biology as diverse as
contractility and clock function [21].
3.
4.
5.
6.
7.
8.
9.
10.
11.
Conclusion
Accordingly, the future of metabolic therapies likely
lies in a redoubling of clinical efforts to apply existing
therapies to patients likely to benefit most from them,
and to recognize the potentially beneficial consequences of metabolic therapies on exciting novel biological pathways, a better understanding and application of which holds promise for conferring additional
benefits to patients with acute or chronic cardiac
ischemia. ●
12.
13.
14.
Acknowledgements This research is supported by the
Oxford British Heart Foundation Centre of Research Excellence Award.
15.
16.
References
1. Kim AS, Johnston SC (2011) Global variation in the relative
burden of stroke and ischemic heart disease. Circulation
124:314–323
2. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F,
McQueen M, Budaj A, Pais P, Varigos J, Lisheng L (2004)
Effect of potentially modifiable risk factors associated with
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myocardial infarction in 52 countries (the INTERHEART study):
case-control study. Lancet 364:937–952
Ashrafian H, Frenneaux MP, Opie LH (2007) Metabolic
mechanisms in heart failure. Circulation 116:434–448
Riquelme CA, Magida JA, Harrison BC, Wall CE, Marr TG,
Secor SM, Leinwand LA (2011) Fatty acids identified in the
Burmese python promote beneficial cardiac growth. Science
334:528–531
Taegtmeyer H (2002) Switching metabolic genes to build a
better heart. Circulation 106:2043–2045
Dyck JR, Lopaschuk GD (2006) AMPK alterations in cardiac
physiology and pathology: enemy or ally? J Physiol 574:95–
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Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane
S, Matsuhashi T, Katsumata Y, Zhang Y, Ito H, Nagahata Y,
Marchitti S, Nishimaki K, Wolf AM, Nakanishi H, Hattori F,
Vasiliou V, Adachi T, Ohsawa I, Taguchi R, Hirabayashi Y,
Ohta S, Suematsu M, Ogawa S, Fukuda K (2009) Metabolic
remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circulation
Research 105:1118–1127
Howell NJ, Ashrafian H, Drury NE, Ranasinghe AM, Contractor
H, Isackson H, Calvert M, Williams LK, Freemantle N, Quinn
DW, Green D, Frenneaux M, Bonser RS, Mascaro JG, Graham TR, Rooney SJ, Wilson IC, Pagano D (2011) Glucoseinsulin-potassium reduces the incidence of low cardiac output
episodes after aortic valve replacement for aortic stenosis in
patients with left ventricular hypertrophy / clinical perspective.
Circulation 123:170–177
The CREATE-ECLA Trial Group (2005) Effect of glucoseinsulin-potassium infusion on mortality in patients with acute
ST-segment elevation myocardial infarction. JAMA 293:437–
446
Apstein CS, Opie LH (2005) A challenge to the metabolic
approach to myocardial ischaemia. Eur Heart J 26:956–959
Zhao YT, Weng CL, Chen ML, Li KB, Ge YG, Lin XM, Zhao
WS, Chen J, Zhang L, Yin JX, Yang XC (2010) Comparison of
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therapy in acute myocardial infarction: a contemporary metaanalysis of randomised controlled trials. Heart 96:1622–1626
Read PA, Hoole SP, White PA, Khan FZ, O’Sullivan M, West
NE, Dutka DP (2011) A pilot study to assess whether
glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv 4:266–272
Bao W, Aravindhan K, Alsaid H, Chendrimada T, Szapacs M,
Citerone DR, Harpel MR, Willette RN, Lepore JJ, Jucker BM
(2011) Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury:
evidence for improving cardiac metabolic efficiency. PLoS One
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Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley
WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258
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Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Bohm M,
O’Rourke B, Maack C (2010) Elevated cytosolic Na+
increases mitochondrial formation of reactive oxygen species
in failing cardiac myocytes. Circulation 121:1606–1613
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Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 93:
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Nash DT, Nash SD (2008) Ranolazine for chronic stable
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19. Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH,
Honore JC, Kermorvant-Duchemin E, Varma DR, Tremblay S,
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a novel post-translational modification linking myocardial
metabolism and the cardiomyocyte circadian clock. J Biol
Chem doi: 10.1074/jbc.M111.278903
13
METABOLIC
IMAGING
- PAOLO G CAMICI
Glucose metabolism as a marker
of myocardial ischemia
Paolo G Camici, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy
Correspondence: Paolo G Camici, Via Olgettina 60, 20132 Milan, Italy.
e-mail: [email protected]
Abstract
Although the heart is omnivorous, glucose becomes the key substrate under conditions of stress.
The utilization of exogenous glucose by the myocardium can be assessed non-invasively using positron
emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG). Several studies
have demonstrated that glucose utilization is increased at peak stress and during conditions of reduced
oxygen supply. Moreover, glucose utilization remains elevated after an episode of transient ischemia,
which constitutes a sort of “metabolic memory”. PET with FDG also permits the identification of
“hibernating myocardium”. This allows a more accurate stratification of patients with post-ischemic
left ventricular dysfunction and identification of those that might benefit most from coronary
revascularization.
Keywords: coronary artery disease; myocardial metabolism; myocardial ischemia; positron emission
tomography.
Metabolic Imaging
■ Heart Metab. (2011) 53:14–18
14
Introduction
The human heart in the fasting state extracts free fatty acid (FFA), glucose, lactate, pyruvate, and
ketone bodies from the systemic circulation. A small but consistent net uptake of circulating glucose by the heart is normally demonstrable in the fasting state with a reported arterial-venous
(AV) difference ranging from 0.15 to 0.23 mmol/l, corresponding to a fractional uptake of only
3% and to an average oxygen extraction ratio of ~27%. Measurements of the rate of glucose
oxidation by radiolabelled techniques in healthy volunteers have shown that, at the most, only
about 30% of the glucose uptake is rapidly oxidized, and about 15% is converted to lactate [1].
Cardiac glucose metabolism during fasted and fed states
There is a general consensus that FFA is the major fuel for cardiac muscle in the fasting, postabsorptive state. In various studies using the coronary sinus (CS) catheterization technique, net
uptake of FFA from the arterial circulation has been found consistent. At arterial FFA levels in
the 0.5 to 0.9 mmol/l range, the reported AV differences is 0.14 to 0.20 μmol/ml, which correspond to oxygen extraction ratios of up to 40%. If a total coronary blood flow of ~250 ml/min
is assumed, then the heart of fasting subjects at rest consumes up to about 50 μmol/min of FFA,
or up to 10% of the whole body FFA turnover (8 μmol/min/kg), despite receiving only 5% of
cardiac output. In general, the fate of FFA is largely complete oxidation in the Krebs’ cycle
with a lesser component undergoing re-esterification to tissue triglycerides. The fact that the
Heart Metab. (2011) 53:14–18
METABOLIC
- PAOLO G CAMICI
IMAGING
respiratory quotient of the heart in the fasting state is
on average 0.74 indicates that the greater part of the
extracted FFA is oxidized [1] (Fig. 1).
The oxidative use of lipid (FFA) and carbohydrate
(glucose and lactate) fuel is reciprocally regulated
through the operation of Randle’s cycle [2]. Feeding,
by increasing both insulin and glucose concentrations
shifts myocardial metabolism towards preferential carbohydrate usage, both for oxidative energy generation
and for glycogen synthesis (Fig. 1).
Cardiac glucose metabolism during conditions
of reduced oxygen supply
During conditions of reduced oxygen supply, the oxidation of all substrates is decreased while anaerobic
metabolism is activated (Fig. 2). In patients with coronary artery disease (CAD) and stable angina pectoris,
GLYCOGEN
net lactate release in the CS can be demonstrated during pacing stress. However, this occurs in only 50% of
patients, and no relationship can be demonstrated
between lactate production and the severity of ischemia [3]. In patients with chronic angina, a significant
release of alanine in the CS and an increased myocardial uptake of glutamate could be demonstrated at rest
and following pacing [4–5). These two phenomena
result from increased transamination of excess pyruvate to alanine with glutamate serving as NH2 donor. In
addition, release of citrate (a known inhibitor of glycolysis) in the CS can be demonstrated following pacing
in patients with stable angina.
Positron emission tomography
The utilization of exogenous glucose by the myocardium
can be assessed using positron emission tomography
INS
GLYCOGEN
G
G–6–P
F–6–P
+
–
G
G–6–P F–6–P
PFK
F 1,6 bis P
–
F 1,6 bis P
TRIOSE
TRIOSE
GAPDH
LACTATE
INHIBITION
P
LACTATE
Acetyl CoA
NADH2
P
PDH
–
FFA
Acetyl CoA
CITRATE
excess
CITRATE
normal
ATP
O2
ATP
O2
ADP
Pi
Fasted
NO
INHIBITION
GAPDH
PDH
FFA
PFK
ADP
Pi
Fed
Fig. 1 Left panel: Inhibited glycolysis in fasted state. Overall control of pathways of glycolysis, which is taken as the conversion of G-6-P
to P. The inhibition of glycolysis at the level of phosphofructokinase is the result of accumulation of excess citrate during oxidation of FFA.
Pyruvate dehydrogenase is inhibited by accumulated NADH2 the result of β-oxidation of fatty acids. Right panel: Overall patterns of glycolysis in the fed state. Besides direct acceleration of glucose uptake as a result of high circulating levels of glucose and insulin, there is indirect acceleration of glycolysis as blood FFA levels decrease, and the inhibition of phosphofructokinase by citrate is removed. G-6-P glucose6-phosphate, P pyruvate, G glucose, F-6-P fructose 1,6 phosphate, PFK phosphofructokinase, F 1,6 bis P fructose1,6 diphosphate,
GAPDH glyceraldehyde phosphate dehydrogenase, NADH2 reduced form of nicotine edenine dinucleotide, PDH pyruvate dehydrogenase.
Heart Metab. (2011) 53:14–18
15
METABOLIC
- PAOLO G CAMICI
IMAGING
GLYCOGEN
+
HYPOXIA
ATP
CP
Pi +
G–6–P
G
INS
B
+
+
PFK
+
F 1,6 bis P
TRIOSE
INHIBITION
REMOVED
NAD
LACTATE
P
NADH2
–
O2
FDG uptake in patients with CAD and stable angina
NADH2 electron
transport
ATP
CITRATE
Acetyl CoA
FFA
PDH
Wash
out
ADP
Pi
Fig. 2 Mechanisms whereby mild ischemia increases glycolysis.
Note especially a direct effect of hypoxia on glucose transport,
and acceleration of phosphofructokinase (PFK) activity by decreasing adenosine triphosphate (ATP), creatin phosphate (CP)
and an increase of inorganic phosphate (Pi) as well as a decrease
of citrate. Note inhibition of pyruvate dehydrogenase (PDH)
by NADH2
(PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG). FDG is transported into the myocyte
by the same trans-sarcolemmal carrier as glucose
and is then phosphorylated to FDG-6-phosphate
by the enzyme hexokinase. This is essentially a unidirectional reaction and results in FDG-6-phosphate
accumulation within the myocardium, as no glucose6-phosphatase (the enzyme that hydrolyses FDG6-phosphate back to free FDG and free phosphate)
has yet been identified in cardiac muscle. Thus, measurement of the myocardial uptake of FDG is proportional to the overall rate of trans-sacolemmal transport
and hexokinase-phosphorylation of exogenous (circulating) glucose by heart muscle.
A number of kinetic modeling approaches have
been used for the quantification of glucose utilization
rates using FDG. The major limitation of these
approaches is that quantification of glucose metabolism requires the knowledge of the lumped constant, a factor that relates the kinetic behavior of FDG
16
to naturally occurring glucose in terms of the relative
affinity of each molecule for the trans-sarcolemmal
transporter and for hexokinase. Unfortunately, the
value of the lumped constant in humans under different physiological and pathophysiological conditions is
not known, thus making precise in vivo quantification
of myocardial metabolic rates of glucose practically
impossible. Still current measurements of the uptake
of FDG (particularly if obtained under standardized
conditions) allow comparison of absolute values from
different individuals and may help to establish the
absolute rates of glucose utilization (in FDG units) in
normal and pathologic myocardium.
Different patterns of myocardial glucose utilization
have been observed in patients with CAD studied
using FDG. In patients with stable angina studied at
rest, after overnight fast, regional myocardial glucose
utilization was homogeneously low and comparable
with that in normal subjects. In contrast, in patients
with unstable angina, myocardial glucose utilization at
rest was increased even in the absence of symptoms
and electrocardiographic signs of acute ischemia [6].
In patients with stable angina, a prolonged increase in
FDG uptake could be demonstrated in post-ischemic
myocardium in the absence of symptoms or perfusion
abnormalities, which suggests a sort of post-ischemic
“metabolic memory” [7]. Subsequent studies in animals have indicated that this increased post-ischemic
glucose utilization is mainly finalized to replenish myocardial glycogen stores which were depleted during
ischemia [1].
PET with FDG for the identification of hibernating
myocardium
In the current era of coronary revascularization and
thrombolysis, it has become increasingly apparent
that restoration of blood flow to asynergic myocardial
segments may result in improved regional and global
LV function [8–10]. The greatest clinical benefit is seen
in those patients with the most severe forms of dysfunction. Initial studies indicated that myocardial ischemia and infarction could be distinguished by analysis of
PET images of the perfusion tracer 13NH3 and the glucose analogue FDG acquired after an oral glucose
load. Regions which showed a concordant reduction
in both myocardial blood flow and FDG uptake (“flow-
Heart Metab. (2011) 53:14–18
METABOLIC
A
IMAGING
- PAOLO G CAMICI
0,45 µmol/g/min
Anterior
Lateral
Septum
B
0,14 µmol/g/min
Anterior
Lateral
Inferoposterior
Short Axis - Basal LV
Septum
Inferoposterior
Short Axis - Mid LV
Fig. 3 Myocardial viability in two patients with coronary artery disease and severe chronic left ventricular dysfunction assessed by PET with
18
F-labelled fluorodeoxyglucose (FDG) during hyperinsulinemic euglycemic clamp. Both patients had previous myocardial infarctions. The
scan illustrated in panel A shows that FDG uptake in the previously infarcted antero-septal segment is 0.45 μmol/min/g, suggesting
the presence of viable myocardium. In the scan illustrated in panel B the uptake of FDG in the anterior wall and the interventricular septum
is significantly reduced (0.14 μmol/min/g), suggesting absence of viability in this large area. A cut-off point of 0.25 μmol/min/g is routinely
used in our laboratory to differentiate between viable and non-viable myocardium. This cut-off value was derived from our database
of patients with coronary artery disease and chronic left ventricular dysfunction who underwent FDG-PET and were subsequently revascularized. The proportion of dysfunctional segments that improved following revascularization increased linearly with FDG uptake. To determine the value of FDG uptake above which the best prediction of improvement in functional class of at least one grade could be obtained,
a receiver-operator characteristic curve (ROC) was constructed. According to this analysis the optimal operating point on the curve (point
of best compromise between sensitivity and specificity) was at the FDG uptake value of 0.25 μmol/min/g.
metabolism match”) were labeled as predominantly
infarcted, whereas regions in which FDG uptake was
relatively preserved or increased despite having a perfusion defect (“flow-metabolism mismatch”) were considered to represent jeopardized viable myocardium
[11]. The uptake of FDG by the myocardium, however,
depends on many factors such as dietary state, cardiac workload, and response of the tissue to insulin,
sympathetic drive and the presence and severity of
ischemia. These factors contribute to variability in
FDG imaging in the fasted or glucose-loaded state,
confusing data interpretation.
mic euglycemic clamp, essentially the simultaneous
infusion of insulin and glucose acting on the tissue as
a metabolic challenge and stimulating maximal FDG
uptake (see Fig. 3). This leads to optimization of
image quality and enables PET studies to be performed under standardized metabolic conditions,
which allows comparison of the absolute values of
the metabolic rate of glucose (μmol/g/min) amongst
different subjects and centers [12].
With the recent suggestion that semi-quantitative
and quantitative analyses of FDG uptake may enhance
detection of viable myocardium, there was an urgent
need to rigorously standardize the study conditions.
Furthermore, many patients with coronary artery disease are insulin resistant, i.e., the amount of endogenous insulin released after feeding will not induce maximal stimulation due to partial resistance to the action
of the hormone. This may result in poor FDG image
quality after an oral glucose load. To circumvent the
problem of insulin resistance, an alternative protocol
has been recently applied to PET viability studies.
The protocol is based on the use of the hyperinsuline-
Although the heart is omnivorous, glucose becomes
the key substrate under conditions of stress. Several
studies have demonstrated that glucose utilization is
increased at peak stress and during conditions of
reduced oxygen supply. Moreover, glucose utilization remains elevated after an episode of transient
ischemia, which constitutes a sort of “metabolic
memory”. PET with FDG also permits the identification of “hibernating myocardium”. This allows a
more accurate stratification of patients with postischemic left ventricular dysfunction and identification of those that might benefit most from coronary
revascularization. ●
Heart Metab. (2011) 53:14–18
Conclusion
17
METABOLIC
IMAGING
- PAOLO G CAMICI
References
1. Camici PG, Ferrannini E, Opie LH (1989) Myocardial metabolism in ischemic heart disease: basic principles and application to imaging by positron emission tomography. Prog Cardiovasc Dis 32:217–238
2. Randle PJ, Hales CN, Garland PB et al (1963) The glucose
fatty acid cycle. Its role in insulin sensitivity and the metabolic
disturbances of diabetes mellitus. Lancet 1:785–789
3. Markham RV, Winniford MD, Firth BG et al (1983) Symptomatic electrocardiographic, metabolic, and hemodynamic alterations during pacing-induced myocardial ischemia. Am J Cardiol 51:1589–1594
4. Mudge GH, Mills RW, Taegtmeyer H et al (1976) Alter ations of
myocardial amino acid metabolism in chronic ischemic heart
disease. J Clin Invest 58:1185–1192
5. Brodan V, Fabian J, Andel M et al (1978) Myocardial amino
acid metabolism in patients with chronic ischemic heart disease. Basic Res Cardiol 73:160–170
6. Araujo LI, Camici PG, Spinks T, Jones T, Maseri A (1988)
Abnormalities in myocardial metabolism in patients with unsta-
18
7.
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9.
10.
11.
12.
ble angina as assessed by positron emission tomography.
Cardiovasc Drugs Ther 2:41–46
Camici PG, Araujo L, Spinks T et al (1986) Increased uptake of
F18-flurodeoxyglucose in postischemic myocardium of patients
with exercise-induced angina. Circulation 74:81–88
Marinho NVS, Keogh BE, Costa DC, Lammertsma AA, Ell PJ,
Camici PG (1996) Pathophysiology of chronic left ventricular dysfunction: New insights from the measurement of absolute myocardial blood flow and glucose utilization. Circulation 93:737–744
Camici PG, Wijns W, Borgers M, De Silva R, Ferrari R, Knuuti
J, Lammertsma AA, Liedtke AJ, PaternostroG, Vatner SF
(1997) Pathophysiological mechanisms of chronic reversible
left ventricular dysfunction due to coronary artery disease
(hibernating myocardium). Circulation 96:3205–3214
Wijns W, Vatner SF, Camici PG (1998) Hibernating myocardium. N Engl J Med 339:173–181
Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern
M, Phelps M, Schelbert H (1986) Reversibility of cardiac wallmotion abnormalities predicted by positron tomography.
N Engl J Med 314:884–888
Camici PG, Prasad S, Rimoldi O (2008) Stunning, hibernation
and assessment of viability. Circulation 117:103–114
Heart Metab. (2011) 53:14–18
NEW THERAPEUTIC
APPROACHES
- KEDRYN K. BASKIN
An expanded role for AMP kinase:
self-renewal of the cardiomyocyte
Kedryn K. Baskin and Heinrich Taegtmeyer, Department of Internal Medicine, Division of Cardiology,
University of Texas Medical School at Houston, University of Texas Health Science Center at Houston,
Houston, Texas, USA
Correspondence: Heinrich Taegtmeyer, MD, DPhil, Professor of Medicine,
University of Texas Medical School at Houston, 6431 Fannin, MSB 1.246, Houston, TX 77030, USA.
Tel.: 713-500-6569, fax: 713-500-0637, e-mail: [email protected]
Abstract
Our work on atrophic remodeling of the heart has caused us to appreciate a simple principle in biology:
from the cell cycle to the Krebs cycle, there is no life without cycles. While the potential for cellular
regeneration receives much attention, the dynamics of intracellular protein turnover have received only
selective consideration. Although the concept of the “dynamic state of body constituents” has existed
since the 1940s, the idea that heart muscle cells renew themselves from within is relatively new. The
rationale is as follows. For the last 30 years, we (and many others) have elucidated the interaction of
metabolic pathways for energy provision and contraction of the heart. Work in the field has uncovered
novel metabolic regulators of enzyme action, yet much less attention has been given to the impact of
myocardial energy metabolism on myocardial protein turnover. We therefore began to consider metabolic signals as putative regulators of myocardial protein synthesis and degradation. In a broad sense,
we sought to establish mechanisms underlying the self-renewal of intact cardiomyocytes, because we
have observed that atrophic remodeling of the heart simultaneously activates pathways of intracellular
protein synthesis and degradation. We determined how metabolic signals regulate protein degradation,
and tested the hypothesis that there is a direct link between intermediary metabolism and protein degradation and that the specific molecular mechanisms involve 5′ AMP-activated protein kinase (AMPK)
regulation of ubiquitin ligases. We review our first results on metabolic signals as regulators of myocardial protein turnover that seek to broaden the role energy substrate metabolism from a provider of ATP
to a regulator of self-renewal of the cardiomyocyte.
Keywords: AMPK; protein degradation; cardiac metabolism
New Therapeutic Approaches
■ Heart Metab. (2011) 53:19–24
Introduction
Our work on atrophic remodeling of the heart has led us to appreciate a simple principle in biology: from the cell cycle to the Krebs cycle, there is no life without cycles. While cellular regeneration of the heart receives much attention [1], the dynamics of intracellular protein turnover
have received only selective consideration [2]. Undoubtedly stem (or precursor) cells contribute
to the replacement of cardiomyocytes after injury, but they contribute little to cardiomyocyte
renewal during normal aging [3]. Although Schoenheimer’s concept of the “dynamic state of
body constituents” has existed for some time [4], the idea that heart muscle cells renew themselves from within is relatively new. We will begin to address this concept with a review on the
Heart Metab. (2011) 53:19–24
19
transcriptional role for 5′ AMP-activated protein
kinase (AMPK) on protein degradation pathways.
For the last 50 years many laboratories have elucidated the interaction of metabolic pathways for energy
provision and contraction in the heart. Work in the field
has uncovered novel metabolic regulators of enzyme
action, yet the impact of myocardial energy metabolism on myocardial protein turnover has not been considered. After we discovered that cardiac atropohy is
not a simple mirror image of hypertrophy [5], we are
now proposing that metabolic signals are putative
regulators of myocardial protein synthesis and degradation. In a broad sense we seek to establish mechanisms underlying the self-renewal of the intact cardiomyocyte. The rationale arises from our observation
that atrophic remodeling of the heart simultaneously
activates pathways of intracellular protein synthesis
and degradation [5] and the following considerations.
First, a large number of models already exist that
identify molecular targets of myocardial hypertrophy
and atrophy [6,7]. Secondly, metabolism is the first
responder to any form of stress [8]. We have evidence
suggesting that the process of metabolic remodeling
precedes, triggers and sustains both structural and
functional remodeling of the heart [9]. We propose
that modulation of metabolic stresses provides a
means to remove damaged or redundant proteins
and replace them with new, functional proteins (Fig. 1).
Furthermore, the identification of metabolic signals
which govern cardiac remodeling will set us also on
the path to develop novel strategies aiming at specific
metabolic intermediaries as modulators of cardiomyocyte size.
- KEDRYN K. BASKIN
Metabolism
ATP/AMP, Metabolites
(Proteins)
PD
Protein
Degradation
Protein
Synthesis
PS
Ser A Tyr in *P
he Lys
sn G
Thr Le
u Phe Asp al Pro
V
G
His ly Ile Trp
a
l
Arg
A
Cys His
t
APPROACHES
Me
NEW THERAPEUTIC
(Amino Acids)
Fig. 1 The balance of protein synthesis (PS) and degradation (PD)
determines size and function of cardiomyocytes. Damaged,
misfolded, or useless proteins are degraded to amino acids that
are used for the synthesis of new, functional proteins.
metabolically and structurally. Excessive remodeling
results in the enlargement of cardiomyocytes, which
translates into an overall increase in heart size. The
transition from hypertrophy to heart failure, or the transition from adaptation to maladaptation of the heart,
remains elusive. Consequently it seems to us critical
to know more about the mechanisms that control the
rebuilding of the cardiomyocyte.
Intracellular protein turnover in perspective
Our most recent ideas advance a new understanding of cardiac metabolism as an integral part of the
self-renewing myocyte as highlighted below. These
ideas result from our investigations on switching of
metabolic genes and atrophic remodeling of the cardiomyocytes in response to mechanical unloading.
The depressing statistics on heart failure are widely
known [10]. Yet in spite of broad and formidable
efforts, there is no cure in sight because the cellular
and molecular mechanisms are still not completely
understood. Accepted features in the development
of heart failure are cardiac hypertrophy and impaired
ATP production, which develop in response to both
endogenous (genetic) and exogenous (environmental)
changes. We propose that metabolic remodeling
(which is potentially reversible) precedes, triggers and
sustains structural and functional remodeling [11]. In
order for the heart to adapt to various types of stress,
individual heart muscle cells change or “remodel” both
We are operating under the premise that during
steady state conditions rates of myocardial protein
synthesis (PS) and protein degradation (PD) are equal
[12,13]. The intrinsic mechanism of self-renewal of the
cardiomyocyte requires the regulated degradation of
damaged, misfolded, or useless proteins and their
replacement by new and functional proteins (Fig. 1).
Protein turnover therefore constitutes a major line of
defense for protein quality control of the cardiomyocytes [14]. The rate of myocardial protein turnover is
much faster than it is generally assumed, with the
half-life of individual myocardial proteins ranging from
several hours to several days [12]. The term “self-
20
Heart Metab. (2011) 53:19–24
NEW THERAPEUTIC
APPROACHES
renewal of the cardiomyocyte” gives exciting new
meaning to the concept of “cardiac plasticity” [6].
We do not know at present to what extent biochemical signals regulate protein degradation and protein
synthesis. We have preliminary evidence which suggests that metabolic signals, i.e., changes in intracellular metabolite levels in response to stress, may activate
pathways of protein degradation and protein synthesis
[5,15].
Lastly, and perhaps most importantly, for nearly a
century the study of cardiac metabolism has concerned itself with energy substrate metabolism and
contraction of the heart [16,17]. This focus has culminated in a recent review proclaiming that the failing
heart is an “engine out of fuel” [18]. We have questioned this concept because the non-ischemic, failing
heart is always well supplied with nutrients, and the
heart is actually drowning in fuel [19]. Not surprisingly,
attempts to restore normal contractile function in the
failing heart by metabolic interventions have not been
consistently successful [20,21]. It is much more likely
that intermediary metabolism, rather than impaired fuel
supply, is the culprit. We consider altered fuel metabolism (leading to either a decrease or an increase of
certain metabolic signals) as a root cause for altered
rates of intracellular protein turnover and, hence, selfrenewal of the cardiomyocyte.
Taken together, we propose that the “metabolic”
approach to myocardial protein synthesis and degradation provides a new framework that will expose new
regulators driving self-renewal of cardiomyocytes from
within. We focus on the ubiquitin proteasome system
(UPS).
The ubiquitin proteasome system and AMPK
Intracellular protein degradation is a complex and
highly controlled process that is integrated with the
environment of the cell. We have recently identified a
metabolic signal that regulates protein degradation in
the heart and the corresponding mechanisms by
which it does so, specifically pertaining to the ubiquitin
proteasome system (UPS). Our studies suggest that
the adenine nucleotides ATP and AMP are metabolic
signals that regulate protein degradation. AMPactivated protein kinase (AMPK) supports energy provision in the cell by sensing changes in the ratio [ATP]:
[AMP]. Therefore, our working hypothesis was that
metabolic signals (decrease in [ATP]:[AMP]) and the
Heart Metab. (2011) 53:19–24
- KEDRYN K. BASKIN
subsequent activation of AMPK, regulate protein degradation. We have tested the hypothesis by modulating AMPK in vitro and in vivo to define the mechanisms
by which AMPK is involved in protein degradation [22].
Intracellular protein degradation in cardiomyocytes
is controlled by independent but interrelated processes: UPS-mediated proteolysis and autophagy.
While autophagy can degrade whole organelles, individual proteins are degraded through the UPS [13].
Ubiquitin ligases confer specificity to the system by
the selective ubiquitination of target proteins which
are then degraded by the proteasome [2]. Two
muscle-specific ubiquitin ligases, muscle atrophy
F-box (MAFbx/atrogin-1) and muscle ring finger-1
(MuRF1), are critical regulators of cardiac protein degradation and myocardial mass. Studies in vivo have
demonstrated that overexpressing atrogin-1 in the
heart attenuates the development of hypertrophy
[23], while the deletion of MuRF1 results in increased
hypertrophy [24]. These experiments highlight the
importance of atrogin-1 and MuRF1 in regulating
heart size. However, the mechanisms by which the
ligases themselves are regulated are not completely
understood.
Early studies in the heart in vivo demonstrated that
nutrient deprivation decreases protein synthesis and
increases fractional rates of protein degradation [25].
Starvation decreases the intracellular concentration of
ATP and, consequently, AMPK is activated in order to
provide energy to maintain normal cellular function. It is
well established that AMPK regulates energy substrate
metabolism, inhibits protein synthesis [26], and regulates transcription of metabolic genes [27]. Although it
has recently been reported that starvation induces
autophagy in cardiomyocytes through AMPK [28], a
role of AMPK in the cardiac UPS had never been considered before.
In order to investigate the role of AMPK in the UPS,
we first verified that substrate deprivation in cardiomyocytes (CM) enhances protein degradation (PD),
as has been shown already in vivo [25]. Protein degradation was enhanced in CM during starvation, but
decreased with bortezomib, a proteasome inhibitor,
or with 3-methyladenine (3-MA), an inhibitor of autophagy. These results suggest that, like autophagy [28],
proteasome-mediated degradation is important during
nutrient starvation in CM. Given the importance of
atrogin-1 and MuRF1 in regulating protein degradation
21
NEW THERAPEUTIC
APPROACHES
and cardiac size [23,24], we quantified their expression in parallel experiments. Atrogin-1 and MuRF1
levels were significantly increased with starvation,
which also correlated with enhanced AMPK activity
(Fig. 2). We also found that direct AMPK activation,
independent of nutrient starvation, increased both
atrogin-1 and MuRF1 expression, which was significantly impaired with AMPK inhibition. Consequently,
protein degradation in the heart is increased with
Relative mRNA levels
(Fold change)
A
Atrogin-1
6
MuRF1
4
2
0
0
2
4
8
24
Nutrient Deprivation (hrs)
B
pAMPK
pAMPK/AMPK
Atrogin-1
MuRF1
Fold Change
(normalized to GAPDH)
AMPK
Atrogin-1
MuRF1
GAPDH
4
3
2
1
0
Control
Control
Nutrient
Deprivation
Nutrient
Deprivation
Protein Degradation
(% total protein)
C
10
Untreated
Bortezomib
3-MA
8
6
4
2
0
Control
Nutrient
Deprivation
Fig. 2 Nutrient deprivation increases expression of ubiquitin ligases
and enhances protein degradation. (A) Atrogin-1 and MuRF1 mRNA
expression in nutrient deprived NRVM. (B) Relative protein levels
and quantification in NRVM after 24 hours of nutrient deprivation.
(C) Protein degradation in NRVM after 24 hours of nutrient deprivation with 1μmol/L Bortezomib or 10μmol/L 3-methyladenine treatment. Data are mean ± SEM of 3 independent experiments performed in triplicate. *P<0.01 vs control or untreated, †P<0.01 vs
control or complete nutrients (reprinted with permission from [22]
©2011 Wolters Kluwer Health).
22
- KEDRYN K. BASKIN
AMPK activation, but proteasome-mediated protein
degradation downstream of AMPK requires MuRF1
[22]. The conclusions are shown in the schematic
(Fig. 3).
Perspective
We have shown that AMPK regulates ubiquitin ligases
in the rodent heart. The present work extends the long
established concept of the “dynamic state of body
constituents” [4] to a specific situation when the heart
adapts to changes in its metabolic environment. Protein turnover constitutes a major line of defense for
protein quality control of the cardiomyocytes [14] and
is a major mechanism of adaptation in the heart.
Therefore it is of interest to understand how protein
degradation is regulated under various circumstances
in the heart. Markers of the UPS are upregulated in the
heart in several settings of cardiac remodeling [13], but
it is not clear exactly how the markers themselves are
regulated. AMPK regulates cellular homeostasis in part
by inhibiting the mTOR pathway [26] and thus by
decreasing protein synthesis, while at the same time
AMPK activates autophagy [28].
It is well known that AMPK is a central regulator of
fuel homeostasis, but studies have until now predominantly focused on the effects of AMPK activation on
energy substrate metabolism [29]. The active subunit
of AMPK is highly expressed in the heart, and is preferentially localized to the nucleus [30]. It is therefore not
surprising that AMPK also transcriptionally regulates
metabolic gene expression. Earlier reports in liver
show that AMPK activation represses transcription,
but little is known about AMPK-regulated transcription
in the heart. AMPK activates transcription [27], and the
activation of PGC1α by AMPK leads to increased mitochondrial gene expression [31]. Still, the importance of
AMPK in transcription is only now coming into focus.
AMPK regulates entire transcriptional programs, and
not only transcription of individual genes, by regulating
histone 2B [32]. We have now expanded the role of
AMPK in both cellular homeostasis and transcriptional
regulation in the heart [22].
The AMPK activator and anti-diabetic drug metformin has proven to have beneficial outcomes in heart
failure patients with diabetes [21]. The role of protein
turnover in hearts of these patients could not be
investigated. However, based on our experimental
findings, AMPK-regulated protein degradation may be
Heart Metab. (2011) 53:19–24
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APPROACHES
- KEDRYN K. BASKIN
Metabolic Stress
(Nutrient Deprivation)
Protein Degradation
AMPK
Cardiomyocyte
Remodeling
ATP
AMP
MEF2
MuRF1
Fig. 3 AMPK regulates MuRF1 transcription in a MEF2-dependent manner. This leads to increased protein degradation in the cardiomyocyte and increased remodeling (reprinted with permission from [22] ©2011 Wolters Kluwer Health).
protective because of enhanced protein quality control
[14]. Activation of AMPK results in increased rates of
protein degradation, and consequently leads to remodeling of the heart. The immediate cardiometabolic
environment may determine whether the remodeling
is beneficial or detrimental. We speculate that the activation of AMPK results in enhanced availability of intracellular amino acids for either ATP production or the
synthesis of new proteins as the heart adapts to a
new physiologic state. This self-renewal of the cardiomyocytes would mean an expanded role for 5′ AMPactivated protein kinase in the heart. ●
Acknowledgements The authors’ lab is supported, in part,
by grants from the US Public Health Service (2R01 HL61483-10) and the American Heart Association (Predoctoral
Fellowship 11PRE5200006). We thank Mrs. Roxy A. Tate for
expert editorial assistance.
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3. Hsieh PC, Segers VF, Davis ME et al (2007) Evidence from a
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5. Razeghi P, Sharma S, Ying J, Li YP, Stepkowski S, Reid MB,
Taegtmeyer H (2003) Atrophic remodeling of the heart in vivo
simultaneously activates pathways of protein synthesis and
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6. Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med
358:1370–1380
7. Baskin K, Taegtmeyer H (2011) Taking pressure off the heart:
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8. Goodwin GW, Taylor CS, Taegtmeyer H (1998) Regulation of
energy metabolism of the heart during acute increase in heart
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9. Taegtmeyer H, Golfman L, Sharma S, Razeghi P, van Arsdall
M (2004) Linking gene expression to function: Metabolic flexibility in the normal and diseased heart. Ann N Y Acad Sci
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10. Roger VL, Go AS, Lloyd-Jones DM et al (2011) Heart disease
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13. Razeghi P, Baskin KK, Sharma S, Young ME, Stepkowski S,
Essop MF, Taegtmeyer H (2006) Atrophy, hypertrophy, and
hypoxemia induce transcriptional regulators of the ubiquitin
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14. Wang X, Robbins J (2006) Heart failure and protein quality
control. Circ Res 99:1315–1328
15. Depre C, Shipley GL, Chen W et al (1998) Unloaded heart in
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WC (2010) Myocardial fatty acid metabolism in health and
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Heart Metab. (2011) 53:19–24
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VASTAREL®MR - GABRIELE FRAGASSO
Beneficial effects of trimetazidine
®
(Vastarel MR) in patients
with chronic heart failure
Gabriele Fragasso, Luca Alberti and Ludovica Lauretta, Division of Metabolic and Cardiovascular Sciences,
Istituto Scientifico H San Raffaele, Milano, Italy
Correspondence: Gabriele Fragasso MD, Heart Failure Unit, Division of Metabolic and Cardiovascular Sciences,
Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milano, Italy.
Tel.: +39 02 26437366, fax: +39 02 26437395, e-mail: [email protected]
Abstract
The possibility of modifying cardiac metabolism by switching the fuel used by the myocardium could
become increasingly important, especially in clinical conditions characterized by reduced energy availability, such as heart failure. Trimetazidine (Vastarel®MR), an inhibitor of free fatty acid (FFA) oxidation,
holds the characteristics to play a fundamental role in the therapeutic strategy of patients with heart failure. More specifically, shifting the energy substrate preference away from FFA metabolism and toward
glucose metabolism has been shown to be an effective adjunctive treatment in terms of myocardial
metabolism and left ventricular function improvement. These effects seem operative in heart failure
syndromes regardless of their etiopathogenetic cause and are not confined to those of ischemic origin.
In this paper, the recent literature on the beneficial therapeutic effects of trimetazidine on left ventricular
dysfunction and heart failure is reviewed and discussed.
Keywords: systolic-dysfunction heart failure; left ventricular function; metabolic therapy; energy
expenditure
Focus on Vastarel®MR
■ Heart Metab. (2011) 53:25–28
Introduction
Trimetazidine (TMZ) (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride) (Vastarel®MR) has
been reported to exert anti-ischemic properties without affecting myocardial oxygen consumption and blood supply [1]. The beneficial effect of this agent has been attributed to preservation
of phosphocreatine and ATP intracellular levels [2] and reduction of cell acidosis [3–4], calcium
overload [4] and free-radical-induced injury caused by ischemia [5]. More importantly, TMZ MR
affects myocardial substrate utilization by inhibiting oxidative phosphorylation and by shifting
energy production from free fatty acids (FFA) to glucose oxidation [6–7]. This effect appears
to be predominantly caused by a selective block of long chain 3-ketoacyl CoA thiolase activity,
the last enzyme involved in β-oxidation [8].
Effects of TMZ in patients with chronic heart failure
In chronic heart failure therapeutic strategies have traditionally focused on the modification of
hemodynamic alterations that occur in the failing heart. However, in addition to hemodynamic
Heart Metab. (2011) 53:25–28
25
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VASTAREL®MR - GABRIELE FRAGASSO
alterations, heart failure causes deep changes both in
systemic and in cardiac metabolic milieu. In this context, recent studies performed in small groups of
patients with post ischemic left ventricular dysfunction, have shown that TMZ may be beneficial in terms
of left ventricular function preservation and control of
symptoms [9–15]. On this basis, it has been shown
that this pharmacological approach could also be
useful in the treatment of patients with heart failure of
various etiologies [16–19].
The beneficial effect of TMZ on left ventricular function has been attributed to preservation of intracellular
phosphocreatine (PCr) and adenosintriphosphate
(ATP) [2]. Previous clinical studies using phosphorus31 magnetic resonance spectroscopy to measure
PCr/ATP ratios in human myocardium have shown
that this ratio is reduced in failing human myocardium
[20]. The PCr/ATP ratio is a measure of myocardial
energetics, and its reduction may depend on imbalance of myocardial oxygen supply and demand [21]
and reduction of the total creatine pool, a phenomenon known to occur in heart failure [22]. In a recent
study performed in patients with heart failure of different etiologies who were receiving full standard medical
therapy, TMZ-induced improvement of functional
class and left ventricular function was associated with
a 33% improvement of the PCr/ATP ratio, supporting
the hypothesis that TMZ probably preserves myocardial high-energy phosphate intracellular levels [23].
These results appear particularly interesting in view of
previous evidence indicating that the PCr/ATP ratio is a
significant predictor of mortality [24].
Effects of TMZ on whole body energy metabolism
of patients with heart failure
A higher resting metabolic rate has been observed
in patients with heart failure [25–27], and this factor
probably contributes to progressive worsening of the
disease. Rate of energy expenditure is related to
increased serum FFA oxidation and both energy
expenditure and serum FFA oxidation are inversely
correlated with left ventricular ejection fraction and
positively correlated with growth hormone concentrations, epinephrine and norepinephrine [28]. Norepinephrine increases whole body oxygen consumption,
circulating FFA concentrations, and FFA oxidation [29].
These changes have been attributed to stimulation of
26
hormone-sensitive lipase in adipose tissue, and to
stimulation of oxygen consumption independent of
lipolysis by norepinephrine [30]. This data, together
with close correlations between plasma norepinephrine concentrations, energy expenditure at rest and
FFA oxidation, make increased sympathetic activity
the most likely explanation for alterations in fuel
homeostasis in patients with HF [30]. Therefore, intervention strategies aimed at optimizing global and cardiac metabolism, could be useful for interrupting the
vicious circle of reduced function at greater metabolic
expenses in different cardiac conditions [31]. In a very
recent study, it has been shown that 3 months of treatment with TMZ added to usual treatment consistently
reduces whole body resting energy expenditure along
with improved functional class, quality of life and left
ventricular function in patients with systolic heart failure, regardless of its etiology and diabetic status [32]
(Fig. 1). The observation that the beneficial effect of
TMZ on left ventricular function is also paralleled by a
reduction of whole body rate of energy expenditure
when compared to patients on conventional treatment
underlies the possibility that the effect of TMZ may be
mediated through a reduction of metabolic demand at
the level of the peripheral tissues and, in turn, in some
sort of central (cardiac) relief. Therefore, reduction of
whole body energy demand could be one of the principal mechanisms by which TMZ could improve symptoms and left ventricular function in patients with heart
failure.
Kcal / die
1700
1679
± 304
1690
± 337
1677
± 264
1650
Baseline
3 months
follow-up
1580
± 263
1600
1550
1500
1450
1400
1350
1300
p: 0.03
Conventional
Therapy
Conventional Therapy
+ TMZ
Fig. 1 Rate of energy expenditure (Kcal/die) measured by indirect
calorimetry at baseline and 3 months follow-up in patients with heart
failure receiving conventional therapy alone (left histograms) or conventional therapy plus trimetazidine (right histograms) (adapted with
permission from reference [32]).
Heart Metab. (2011) 53:25–28
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VASTAREL®MR - GABRIELE FRAGASSO
Additional potential beneficial pharmacological
effects of TMZ in heart failure
It has been observed that TMZ could reduce endothelin release in cardiac patients [12, 33–34]. Growth
factors, vasoactive substances and mechanical stress
are involved in the endothelin-1 (ET-1) increase in heart
failure patients. Despite the known adaptive aspect of
supporting contractility of the failing heart, persistent
increases in cardiac ET-1 expression in the failing
heart have a pathophysiological maladaptive aspect
and are associated with the severity of myocardial dysfunction [35].
TMZ-induced reduction of intracellular acidosis in
ischemic myocardium could not only influence
myocardial but also endothelial membranes [5]. By
decreasing endothelial damage, TMZ could inhibit
ET-1 release that, in turn, will finally decrease myocardial damage. A second hypothesis is that, by just
decreasing the effects of chronic myocardial ischemia,
TMZ could inhibit ET-1 release. Therefore, the
observed decrease in ET-1 release with TMZ, could
likely be linked to TMZ-induced reduction of myocardial ischemia. Finally, keeping in mind the close relation
between endothelium and insulin sensitivity, the
observed effects of TMZ on endothelial function
could also explain the beneficial action of TMZ on glucose metabolism. In fact, apart from improving left
ventricular function in cardiac patients, it has been
recently shown that TMZ could also improve overall
glucose metabolism in the same patients, indicating
an attractive ancillary pharmacological property of
this class of drugs [12, 33]. In fact, the known insulin
resistant state in most cardiac patients is certainly
aggravated in those patients with overt diabetes. This
is particularly relevant in patients with both diabetes
and left ventricular dysfunction. In this context, the
availability of glucose and the ability of cardiomyocytes
and skeletal muscles to metabolize glucose are grossly
reduced. Indeed, since a major factor in the development and progression of heart failure is already a
reduced availability of ATP, glucose metabolism alterations could further impair the efficiency of cardiomyocytes to produce energy. By inhibiting fatty acid
oxidation, TMZ stimulates total glucose utilization,
including both glycolysis and glucose oxidation. The
effects of TMZ on glucose metabolism could therefore
be dependent by a) improved cardiac efficiency;
b) improved peripheral glucose extraction and utiliza-
Heart Metab. (2011) 53:25–28
tion. Both mechanisms could definitely be beneficial in
heart failure patients.
Systematic literature search on the beneficial
effect of TMZ in heart failure
A systematic search of the literature was recently conducted by Gao et al. to identify randomized controlled
trials of TMZ for heart failure [36]. They considered
reports of trials comparing TMZ with placebo control
for chronic heart failure in adults, with outcomes
including all-cause mortality, hospitalization, cardiovascular events, changes in cardiac function parameters and exercise capacity. The results of the
search identified 17 trials with data for 955 patients.
TMZ therapy was associated with a significant
improvement in left ventricular ejection fraction in
patients with both ischemic (7.37%; 95% CI 6.05
to 8.70; p<0.01) and non-ischemic heart failure
(8.72%; 95% CI 5.51 to 11.92; p<0.01). With TMZ
therapy, New York Heart Association classification
was also improved (p<0.01), as was exercise duration
(p<0.01). More importantly, TMZ had a significant protective effect for all-cause mortality (RR 0.29; 95% CI
0.17 to 0.49; p<0.00001) and cardiovascular events
and hospitalization (RR 0.42; 95% CI 0.30 to 0.58;
p<0.00001). These data confirm that TMZ might be
an effective strategy for treating heart failure and that
a large multicenter randomized controlled trial should
be performed, in order to clarify its therapeutic role in
this setting.
Conclusion
TMZ could have an important role in the therapeutic
strategy of patients with heart failure. More specifically,
shifting the energy substrate preference away from
fatty acid metabolism and toward glucose metabolism
appears as an effective adjunctive treatment in
patients with heart failure, in terms of left ventricular
metabolism and function improvement. These effects
are operative in heart failure syndromes regardless of
their etiopathogenetic cause and are not confined to
those of ischemic origin.
However, despite a very recent meta-analysis has
evidenced that these benefits also translate into
improved survival, a randomized placebo controlled
multicenter trial is definitely warranted in order to
objectively investigate the role of TMZ in the therapeutic armamentarium of heart failure. ●
27
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Heart Metab. (2011) 53:25–28
CASE
REPORT
- FRANK LLOYD DINI
Myocardial power delivery is impaired
in progressive left ventricular pump failure:
a case report
Frank Lloyd Dini, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy.
Correspondence: Frank Lloyd Dini, Cardiovascular Diseases Unit 1, Cardiac, Thoracic and Vascular Department,
Azienda Universitaria Ospedaliera Pisana, Via Paradisa 2, 56100 Pisa, Italy
Tel.: +39 (050) 995307; fax: +39 (050) 995308, e-mail: [email protected]
Abstract
The driving force for the flow of blood is the total energy imparted to it that corresponds to the mechanical, external work performed by the ventricle. In the cardiovascular system, the pumping power of the
heart can be determined by cardiac power output, which is the product of cardiac output and mean
blood pressure. Similarly to power-to-weight ratio, that is a measurement of the actual performance
of any engine, maximal left ventricular power output-to-left ventricular mass is an index of cardiac
performance potentially useful in patients with heart failure. In this case report, an example of the
usefulness of this parameter is described in a patients with advanced heart failure secondary to dilated
cardiomyopathy.
Keywords: heart failure; dilated cardiomyopathy; echo stress
Case Report
■ Heart Metab. (2011) 53:29–32
Introduction
In attempting to characterize a system composed of an energy source and pipes conducting
this energy, the usual parameters used for this purpose are the power of the energy generator
and the resistance of the conducting pipes [1]. In the cardiovascular system, the pumping
power of the heart can be determined by cardiac power output, which is the product of cardiac output (CO) and mean blood pressure (BP). By incorporating both flow and pressure in a
single entity, cardiac power output represents the amount of energy imparted by the left ventricle to the volume of blood ejected per second [2]. Cardiac power output can be invasively and
noninvasively assessed during maximal exercise or pharmacological stress test [3–7].
Power-to-weight ratio is a measure that is widely applied to mechanical engines to compare
the performance of vehicles, aircrafts, and other mobile power sources. Similarly to powerto-weight ratio, peak power output-to-left ventricular (LV) mass (peak power-to-mass) is an
index of LV performance potentially useful in patients with cardiac diseases. This parameter
allows us to assess the relationship between cardiac power measurements and most of
the recruitable myocardial reserve available at maximum workload. As a result, peak
power-to-mass may be interpreted as a measure of myocardial efficiency, that is a ratio that
incorporates the degree of the external work per unit of time and the maximal work possible.
Heart Metab. (2011) 53:29–32
29
CASE
REPORT
- FRANK LLOYD DINI
Although the denominator of this equation cannot be
measured, it can be argued that in normal ventricles
the amount of LV mass is comparative to myocardial
power delivery, whereas a disproportion between LV
performance and mass is suggestive of the maladaptive features of LV remodeling [1]. To date, peak
power-to-mass can be easily assess during exercise
or dobutamine stress echocardiography and resulted
to be valuable to measure cardiac pumping capacity
especially in patients with cardiomyopathies. In the
following case report, the clinical significance of peak
power-to-mass is described.
Case report
The clinical, biochemical and echocardiographic data
of a 64-year-old man with idiopathic dilated cardiomyopathy hospitalized because of symptoms of
congestive heart failure (HF) are reported. After stabilization, cardiac right-sided catheterization was carried out
using a 7F MPA1 catheter (Cordis, Miami, FL). Mean
pulmonary capillary wedge pressure was determined
automatically by the monitoring system (Horizon 9000
WS, Mennen Medical Ltd, Israel). LV end-diastolic
pressure was recorded using a 6F 145° pigtail catheter
(Cordis, Miami, FL). Hemodynamic measurements
were acquired before any injection of the contrast
medium. LV end-systolic and end-diastolic meridional
wall stresses were estimated using invasive measurements of LV pressures. The patient was submitted to
a comprehensive transthoracic echocardiography
using commercially available Acuson Sequoia C256
ultrasound instrument (Mountain View, CA) with
2nd-harmonic imaging and a 3.5-MHz transducer.
Two-dimensional and color-flow Doppler images
were obtained in standard parasternal and apical
views. The LV mass was determined by using the
M-mode method according to the recommendations
of the European Society of Echocardiography [2]. A
symptom-limited graded bicycle semi-supine exercise
was performed at an initial workload of 20 watts lasting
for one minute; thereafter the workload was increased
stepwise by 10 watts every minute. A 12-lead electrocardiogram and blood pressure determination were
performed at baseline and every minute thereafter. At
baseline and at peak exercise, Doppler-derived CO at
LV outflow tract, heart rate (HR) and arterial systolic
blood pressure (BP) and diastolic BP (by cuff sphygmomanometer) were measured. Mean BP was estimated
30
as follows: diastolic BP + 1/3 (systolic BP – diastolic
BP). Stroke volume (SV) was calculated as stroke
distance × LV outflow tract area and CO as SV × HR
as previously described [3]. LV power output was
measured as the product of CO and mean BP.
In meter-kilogram-second units, the conversion is
106 ml/m3 for SV, and 133 pa (pascal)/mmHg for pressure. Power-to-mass was calculated as LV power output per 100 gram of LV mass: 100 x LV power output
divided by LV mass (watt/100 g).
The characteristics of the patient during the hospitalization are shown in Table 1 and Table 2. He was in
NYHA class III and his LV ejection fraction (EF) was
21%. The electrocardiogram showed a sinus rhythm
and a complete left branch bundle block. B-type natriuretic peptide (BNP) level was 498 pg/ml. The workload reached at the end of the stress test performed
the day before discharge was 70 watts. At maximum
exercise, mean BP was 107 mmHg, SV was 80 ml and
HR was 145 beats per minute; entering these values in
the above formulas, we get: BP = 133 × 103 = 13,699
pa, SV = 35 × 10-6 m3 and then we can calculate
power as (13,699 × 35 × 145 × 10-6)/60 = 1.15 watt.
LV mass was 349 g. A simplified formula to calculate
power output-to-mass is: 0.222 × CO (l/min) × mean
BP (mmHg)/LV mass (g) = (0.222 × 5 × 103)/349 =
0,33 watt/100 g. The patient underwent cardiac resynchronization therapy and was implanted with an automatic cardioveter defibrillator. Then, he was discharged with a therapy that included furosemide,
angiotensin converting inhibitors, aldosterone antagonists, beta-blockers and digoxin. Six months later, he
Variable
Age, years
Body surface area
Right atrial pressure (mmHg)
Pulmonary artery systolic pressure (mmHg)
Pulmonary artery diastolic pressure (mmHg)
Pulmonary artery mean pressure (mmHg)
Pulmonary capillary wedge pressure (mmHg)
Left ventricular end-diastolic pressure (mmHg)
Cardiac output (l/min)
Cardiac index (l/min/m2)
Left ventricular end-systolic stress (kdyne/cm2)
Left ventricular end-diastolic stress (kdyne/cm2)
64
26
10
58
30
30
33
25
3.4
1.7
53
183
Table 1 Clinical and hemodynamic characteristics of the patient
described in the case report.
Heart Metab. (2011) 53:29–32
CASE
REPORT
- FRANK LLOYD DINI
Before After
Resting variables
Heart rate (bpm)
Mean blood pressure (mmHg)
End-diastolic volume (ml)
End-systolic volume (ml)
Stroke volume (ml)
Stroke volume index (ml/m2)
Ejection fraction (%)
Cardiac output (l/min)
Cardiac index (l/min/m2)
Power output (watt)
Power output-to-mass (watt/100 g)
Exercise
Workload (watt)
Heart rate (bpm)
Mean blood pressure (mmHg)
End-diastolic volume (ml)
End-systolic volume (ml)
Stroke volume (ml)
Stroke volume index (ml/m2)
Ejection fraction (%)
Cardiac output (l/min)
Cardiac index (l/min/m2)
Power output (watt)
Power output-to-mass (watt/100 g)
81
89
205
162
43
23
21
3.5
1.8
1.15
0.20
65
60
206
161
45
24
22
2.9
1.5
0.39
0.11
70
145
103
165
130
35
18
21
5.0
2.6
0.69
0.33
60
85
73
181
141
40
21
22
3.4
1.8
0.55
0.16
Table 2 Clinical and echo-Doppler-derived hemodynamic
characteristics of the patient described in the case report.
was re-hospitalized for worsening HF. LV EF was not
different with respect to the previous hospitalization
and no relevant changes were apparent for most of
the other echocardiographic and Doppler parameters.
Pre-discharge BNP was 1072 pg/ml. The exercise
stress test was repeated before discharge. Peak
power output-to-mass at exercise stress test was
0.16 watt/100 g. Four months later the patient died
due to refractory progressive pump failure.
Discussion
This case report describes a case of dilated cardiomyopathy accompanied by a severe deterioration of
cardiac pumping capacity. The patient developed a
progressive refractory heart failure, which was clearly
evident at the time of the first exercise stress test,
where peak cardiac power output showed only a
blunted increase during the exercise. Neither optimized medical treatment nor cardiac resynchroniza-
Heart Metab. (2011) 53:29–32
tion therapy were able to retard the progression of
the disease.
This report shows the importance of measuring cardiac pumping capacity during exercise stress echocardiography for risk stratification of patients with
advanced HF. It is interesting to note that resting LV
EF did not change between the first and the second
hospitalization. LV EF is the most frequently used index
of LV performance, but it may not accurately reflect
myocardial contractility and provides little prognostic
information in patients with advanced HF. The interpretation of an EF less than 30% in a NYHA class I
patient with mild LV dilation may be quite different
from that an individual with class III symptoms associated with a severely dilated left ventricle. Both EF
declines reflect chamber remodeling despite relative
preserved stroke volume. However, in one instance,
LV remodeling dominates this decline, with a near normal residual myocardium capable of providing adequate cardiac reserve. In the other, the entire LV myocardium is depressed with little reserve pumping
capacity. These two situations may look similar when
assessed by conventional measures, such as EF or
wall motion score index, yet be very different by
alternative methods, such as cardiac power output
performed under stress.
Although cardiac power output is a well-established
parameter of ventricular function that can be noninvasively acquired during exercise testing, it does not consider alterations in cardiac size and structure that may
have an impact on the outcome of patients with HF.
The novelty of peak power-to-mass (and peak massto-power) is that it encompasses LV mass, that is a
major feature of the alterations in ventricular structure
that occurs as a part of normal growth or due to a
pathologic process, and similarly to EF, that is the
ratio between the stroke volume and LV end-diastolic
volume, provides integrate information on cardiac
function and ventricular remodeling. The amount of
LV mass may be equated to the energy stored in the
myocardium according to the principle of equivalence
of mass and energy as affirmed by Einstein’s theory of
relativity. An example of this is physiological hypertrophy that is induced by exercise training, whereas the
phenotypes that appear in chronically overloaded
ventricles are pathological because they are accompanied by maladaptive changes [4,5]. The discrepancy
between a severely depressed cardiac power output
31
CASE
REPORT
- FRANK LLOYD DINI
albeit an increased LV mass is likely to reveal the presence of maladaptive LV remodeling and this may
reflect the inefficiency of the system to comply with
the body’s metabolic needs. Adverse or maladaptive
LV remodeling is a major factor that affects the outcome of patients with advanced HF due to LV systolic
dysfunction [6].
The effects of intervening LV hypertrophy on recruitable cardiac power output are important to establish
the significance of LV remodeling. When the recruitable power output per unit of LV mass decreases due to
progressively decreasing ability of the myocardium to
generate force to overcome the load, LV function
rapidly deteriorates. Furthermore, the high LV enddiastolic volume and pressure promote subendocardial ischemia that aggravates LV dysfunction and
neurohormonal activation, decreases exercise capacity and increases the risk of ventricular arrhythmias.
Another factor that may contribute to maladaptive LV
remodeling is the inadequate growth of myocardial
microvasculature accompanying myocardial hypertrophy [7].
Peak power-to-mass provided incremental prognostic information over resting LV EF as well as other
LV parameters recorded under stress. In our experience, the cutoff value for peak cardiac powerto-mass that accurately predicts all-cause mortality
or HF hospitalization is 0.58 watt/100 g, but its impact
on prognosis is clearer if the patient achieves a peak
cardiac power-to-mass less than 1.0 watt/100 g after
optimal tailored therapy or myocardial revascularization with interventional cardiac procedures or resynchronization therapy [6].
By coupling peak exercise LV power output and LV
mass, peak power-to-mass is useful to identify
patients with adverse LV remodeling during stress
echocardiography and may provide additional prognostic information either in association with resting
echocardiographic studies or cardiopulmonary exercise testing. LV hypertrophy is almost always present
in patients with chronic systolic HF accompanied by
32
LV dilatation and low EF, is typically eccentric, and is
frequently associated with a normal or lower than normal LV wall thickness [8]. Despite that changes in LV
geometry and wall thickness may be temporarily useful
in maintaining myocardial pump function, they occurs
at significant high cost and are commonly followed by
the unfavorable consequences of dilation. LV enlargement increases the force that must be generated to
exceed end-diastolic wall stress and to achieve a
given level of cavity pressure. ●
References
1. Dini FL (2011) Assessment of cardiac dynamics during stress
echocardiography by the peak power output-to-left ventricular
mass ratio. Future Cardiol 7:347–356
2. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E,
Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J,
Solomon S, Spencer KT, St John Sutton M, Stewart W (2006)
Recommendations for chamber quantification: a report from the
American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing
Group, developed in conjunction with the European Association
of Echocardiography, a branch of the European Society of Cardiology. Eur J Echocardiography 7:79–108
3. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA
(2002) Doppler Quantification Task Force of the Nomenclature
and Standards Committee of the American Society of Echocardiography. Recommendations for quantification of Doppler
echocardiography: a report from the Doppler Quantification
Task Force of the Nomenclature and Standards Committee of
the American Society of Echocardiography. J Am Soc Echocardiogr 15:167–184
4. Ingwall JS, Weiss RG (2004) Is the failing heart energy starved?
On using chemical energy to support cardiac function. Circ Res
95:135–145
5. Neubauer S (2007) The failing heart-an engine out of fuel.
N Engl J Med 356:1140–1451
6. Dini FL, Mele D, Conti U, Ballo PC, Citro R, Menichetti F, Marzilli
M (2010) Peak power output-to left ventricular mass: An index
to predict ventricular pumping performance and morbidity in
advanced heart failure. J Am Soc Echocardiogr 23:1259–1265
7. Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri
S, Hawkins ET, Goldstein S (1991) A canine model of chronic
heart failure produced by multiple sequential coronary microembolizations. Am J Physiol 260:H1379–H1384
8. Dini FL, Capozza P, Donati F, Simioniuc A, Corciu AI, Fontanive
P, Pieroni A, Di Bello V, Marzilli M (2011) Patterns of left ventricular remodeling in chronic heart failure: Prevalence and prognostic implications. Am Heart J 161:1088–1095
Heart Metab. (2011) 53:29–32
REFRESHER
CORNER
- NATASHA FILLMORE
Impact of fatty acid oxidation
on cardiac efficiency
Natasha Fillmore and Gary D. Lopaschuk, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute,
University of Alberta, Edmonton, Canada
Correspondence: Dr. Gary Lopaschuk, 423 Heritage Medical Research Center, University of Alberta,
Edmonton, Canada T6G 2S2.
Tel.: (780) 492-2170; fax: (780) 492-9753, e-mail: [email protected]
Abstract
Alterations in energy substrate preference by the heart can lead to significant changes in cardiac
efficiency. Cardiac efficiency, which is the amount of work produced by the heart per energy (O2) consumed, is dependent not only on the efficiency of producing energy (ATP), but also on the efficiency of
using energy to produce contractile work. Using fatty acids as a source of fuel has the potential to alter
both of these pathways. The mitochondrial oxidation of fatty acids utilizes more O2 per molecule of ATP
produced than most other sources of fuel. High rates of fatty acid oxidation also inhibit glucose oxidation in the heart, which can result in alterations in ionic homeostasis, such that more of the ATP
produced in the heart is used for non-contractile purposes. Combined, the excessive use of fatty acids
by the heart can result in a significant decrease in cardiac efficiency. In certain heart pathologies, such
as during and following ischemia or in the failing heart, cardiac efficiency is also decreased. Alterations
in the balance between fatty acid and carbohydrate use contribute to these alterations in cardiac
efficiency. In this review we will focus on how alterations in cardiac energy metabolism alter cardiac efficiency, as well as on how alterations in energy metabolism that occur in heart failure and ischemia result
in decreased cardiac efficiency.
Keywords: fatty acid β-oxidation; uncoupling proteins; mitochondrial thioesterase; glucose oxidation;
glycolysis
Refresher Corner
■ Heart Metab. (2011) 53:33–37
Introduction
The heart has a very high energy demand, while essentially having no energy reserves. For
example, consumption of the main energy currency of the heart, adenosine triphosphate
(ATP), is so high that in the contracting heart the entire pool of ATP turns over approximately
6 to 8 times a minute [1]. In order to produce this large amount of ATP, the heart consumes a
number of different energy substrates, including fatty acids (FAs), glucose, lactate, ketones,
pyruvate, and amino acids. Most of the ATP produced requires the consumption of O2 for
mitochondrial oxidative metabolism (Fig. 1) [1]. However, the efficiency of producing ATP can
vary dramatically depending on the type of energy substrate used. An example of this is the
utilization of FAs, which while being a plentiful source of energy, is also a particularly inefficient
source of energy [1]. Different cardiac pathologies can also alter cardiac efficiency, both as a
result of a decreased efficiency of producing ATP or alterations in the efficiency of using ATP
to produce contractile work [1].
Heart Metab. (2011) 53:33–37
33
REFRESHER
A
CORNER
- NATASHA FILLMORE
Fatty acid
Glucose
CD36/FAT
GLUT4
B
H+
H
Fatty acid
Glucose
+
H+
H+
Na+ / H+
Transporter
Glycolysis
2ATP
2ADP + 2H+
FACS
H+
H+ +
H
Fatty acyl CoA
Pyruvate
Lactate
Ca2+
Fatty Acyl CoA
ATP
Pyruvate
H
ETC
H+
Na+ / Ca2+
Exchanger
Na+
+
H+
H+ H+
PDH
Acetyl CoA
NADH,
FADH2
Na+
Na+
TCA Cycle
Na+ / Ca2+
Exchanger
H+ H+
H+
Cytosol
H+
Mitochondrial
Matrix
Ca2+
H+
Extracellular
Sarcolemma
Cytosol
Fig. 1 Cardiac efficiency is decreased by elevated glycolysis and fatty acid oxidation. A. Elevated fatty acid oxidation can reduce cardiac
efficiency through a number of mechanisms including inhibition of glucose oxidation and increasing glycolysis. Fatty acyl CoA inhibits PDH,
thereby inhibiting glucose oxidation. Under certain conditions glycolysis can become elevated to make up for reduced oxidative metabolism. Protons accumulate because the co-transport of protons with pyruvate into the mitochondria is decreased and cause acidosis. Acidosis can decrease contractile force by decreasing the responsiveness of myofilaments to calcium. The use of ATP for ionic homeostasis can
reduce cardiac efficiency. B. Return of intracellular pH (low pH caused by uncoupled elevated glycolysis) to normal upon reperfusion
decreases cardiac efficiency by affecting ionic homeostasis. A large trans-sarcolemmal proton gradient forms that increases the exchange
of the Na+/H+ transporter resulting in further elevation of intracellular Na+. In response, the Na+/Ca2+ exchanger works in reverse mode,
moving calcium into the cell. This results in an overload of intracellular calcium. More energy is expended maintaining calcium homeostasis.
PDH pyruvate dehydrogenase
Cardiac efficiency is often expressed as a measure
of the amount of cardiac work produced per amount of
energy (O2) consumed by the heart (cardiac work/
MVO2 ratio) [2]. It is not surprising that alterations in
energy metabolism can alter cardiac efficiency, since
cardiac work requires ATP and production of ATP via
mitochondrial oxidative metabolism requires O2. The
type of substrate utilized in the production of ATP via
oxidative metabolism affects cardiac efficiency. In
addition, metabolic by-products produced during
ATP production also have the potential to alter cardiac
efficiency.
34
Energy metabolism and cardiac efficiency
Efficiency of ATP production
A major determinant of cardiac efficiency is the type of
fuel being utilized for ATP production. The efficiency with
which FAs and glucose are utilized to produce ATP differs [1]. The production of 31 ATP by one glucose molecule going through glycolysis and glucose oxidation
(GO) requires 6 O2. For the production of 105 ATP by
palmitate oxidation, 23 O2 are required. Therefore, more
oxygen is used per ATP produced during fatty acid oxidation (FAO) compared to coupled GO, making FAs a
Heart Metab. (2011) 53:33–37
REFRESHER
CORNER
- NATASHA FILLMORE
less efficient substrate than glucose for energy production. In addition, FAO inhibits GO [1]. When the FA supply to the heart rises, assuming O2 availability, the rate of
FAO increases and GO decreases. This explains why
under conditions in which circulating free FAs are elevated (such as heart failure [HF], ischemia, and type II
diabetes) cardiac efficiency is decreased.
Futile cycling
In addition to being less efficient at ATP production per
O2 consumed, FAs can also decrease cardiac efficiency through a number of other mechanisms. This
is evident from the fact that there is a large discrepancy
between the degree of inefficiency observed in ATP
production/O2 consumed, and actual measurements
of cardiac efficiency in the heart (cardiac work/MVO2)
[1]. At most, elevated FAO should decrease efficiency
by 10 to 12% [1]. In reality, cardiac efficiency has been
shown to be decreased by as much as 30% [3]. One
possible mechanism to explain this is long-chain FA
activation of Ca2+ channels in the sarcolemma [4]. A
rise in cytosolic Ca2+ results in more energy being
expended to keep cytosolic Ca2+ levels normal.
Another mechanism that has been proposed involves
FA inhibition of ATP removal from the mitochondria
by inhibition of adenine nucleotide transferase [1]. Yet
another potential mechanism involved in FA-induced
inefficiency is the presence of futile cycles.
One such futile cycle involves the uncoupling proteins. The uncoupling proteins UCP2 and UCP3 are
present in ventricular muscle [2]. These proteins are
classically believed to work by dissipating the intermembrane proton gradient (Fig. 2). FAs are believed to work
through UCP2 and UCP3 to mediate the uncoupling of
oxidative phosphorylation [2,5]. Further, UCP2 and
UCP3 expression correlate positively with circulating
FA levels in the failing human heart [6]. UCP3 may also
contribute to cardiac efficiency by transporting FA
anions out of the mitochondrial matrix [2,7].
FAs in the cytoplasm can also cycle between their
acyl-coenzyme A (CoA) moieties and intracellular triacylglycerol pools [1]. Two high energy phosphates are
required to esterify FA to CoA, which can then either
be directed to mitochondrial FA β-oxidation or complex lipid synthesis in the heart (such as triacylglycerols). FAs liberated from the triacylglycerol pool prior to
subsequent β-oxidation create a futile cycle, potentially
contributing to a decreased cardiac efficiency.
Fatty acid inhibition of glucose oxidation
Another pathway by which FAs may decrease cardiac
efficiency is secondary to GO inhibition [1]. FAO products can inhibit GO (i.e., the Randle Cycle) (Fig. 1).
This FA inhibition of GO is more dramatic than the
effects of FAs on glycolysis [1]. This can result in a scenario where glycolysis is uncoupled from GO, which
Fatty acyl CoA
H+
UCP
H+
H+
H+
IV
H+
Electron
H+ transport
chain
II
I
H+
Fatty acyl CoA
ATP
ADP
III
H+
H+
F0/F1
ATPase
H+
Mitochondrial
thioesterase
CoA
Fatty acid
anion
Mitochondrial
matrix
UCP
Fatty acid
anion
Inter
membrane
Fig. 2 Mechanisms of uncoupling protein reduction of cardiac inefficiency. Uncoupling proteins dissipate the high proton concentration
in the mitochondrial intermembrane space by transferring the hydrogen back into the mitochondrial matrix. UCP3 may also reduce cardiac
efficiency by transferring fatty acid anions out of the mitochondrial matrix. CoA coenzyme A, UCP uncoupling protein
Heart Metab. (2011) 53:33–37
35
REFRESHER
CORNER
- NATASHA FILLMORE
can result in elevated lactate and proton levels causing
intracellular acidosis [2,8]. The co-transport of protons
with pyruvate into the mitochondria is decreased
because pyruvate is not taken into the mitochondria
when glycolysis is uncoupled from GO. Although glycolysis produces ATP without consuming O2, an increase
in glycolysis in the presence of low GO rates can result
in the accumulation of metabolic byproducts in the
heart, that include both lactate and protons [1] (Fig. 1).
The clearance of these protons can result in Na+ and
Ca2+ accumulation in the heart (Fig. 1), requiring ATP to
remove these ions [1]. This can lead to a decrease in
cardiac efficiency, as ATP is redirected away from contractile function and towards ionic homeostasis [1].
of oxidative metabolism in the heart [2,11,12]. This is
likely explained by the exposure of ischemic hearts to
high plasma FAs and to direct changes in the intracellular control of FAO, which combine to inhibit GO
[1,11]. It is important to note that unlike the normal
heart, exposure of the ischemic heart to FAs does
not inhibit glycolysis, and that glycolytic rates are
increased in the ischemic heart [11].
Altered energy metabolism in ischemic heart disease
Increased glycolysis and impaired GO in the ischemic
heart result in lactate and proton accumulation in the
ischemic myocardium. Indeed, uncoupling of glycolysis
from GO can largely explain the acidosis observed in the
severely ischemic heart. As described above, accumulation of protons can lead to Na+ and Ca2+ overload in
the heart, resulting in decreased cardiac efficiency as
ATP is used to attempt to restore ionic homeostasis [1].
Prominent alterations in energy metabolism occur in
the setting of myocardial ischemia and reperfusion
that result in reduced cardiac efficiency (Fig. 3a) [1].
In the ischemic heart, energy metabolic rates are
dependent upon the degree of ischemia. Because of
the reduced oxygen availability both GO and FAO are
reduced in the ischemic heart [2,9,10]. Interestingly,
during mild ischemia FAO predominates as the source
Lack of recovery of cardiac function and efficiency
upon reperfusion is also explained by the alterations in
metabolism during ischemia and reperfusion [2,13,14].
Return of intracellular pH to normal upon reperfusion
can be deleterious. This is because, by modulating the
Na+/H+ transporter and the Na+/Ca2+ exchanger,
changes in intracellular ion concentrations occur that
contribute to impaired cardiac function and efficiency
A
B
Ischemia
Fatty acids
Glucose oxidation
Mitochondrial oxidation
Fatty acid oxidation
Glycolysis
Protons
Glycolysis
Intracellular calcium and sodium
Protons
Intracellular calcium and sodium
ATP utilization for noncontractile
purposes
Heart Failure
ATP utilization for noncontractile purposes
Oxygen consumption/ATP
produced
Cardiac efficiency
Cardiac
efficiency
Fig. 3 Cardiac inefficiency in the ischemic heart and the failing heart. A. During ischemia and reperfusion fatty acid levels rise resulting
in elevated fatty acid oxidation. This results in decreased glucose oxidation and elevated glycolysis. As a result of glycolysis and glucose
oxidation being uncoupled, proton levels rise causing an overload of sodium and calcium. More energy is expended to maintain ionic
homeostasis resulting in a decrease in cardiac efficiency. Through other mechanisms, fatty acids also reduce cardiac efficiency. B. In heart
failure, a reduction in overall oxidative metabolism results in elevated uncoupled glycolysis resulting in decreased cardiac efficiency through
similar mechanisms as described for ischemia
36
Heart Metab. (2011) 53:33–37
REFRESHER
CORNER
- NATASHA FILLMORE
[2]. The large trans-sarcolemmal proton gradient that
forms increases the exchange of the Na+/H+ transporter resulting in further elevation of intracellular Na+.
In response, the Na+/Ca2+ exchanger reverse mode is
activated. The movement of calcium into the cell via
the Na+/Ca2+ exchanger results in an overload of intracellular calcium and thus more energy being expended
to maintain calcium homeostasis.
As would be expected, cardiac efficiency and function is reduced in mildly ischemic hearts exposed to
high levels of FAs [11]. If a heart is subjected to global
ischemia, FA β oxidation decreases secondary to a
lack of O2 availability for mitochondrial oxidative phosphorylation [15]. During reperfusion FAO recovers,
resulting in GO remaining low [2,8,13,14]. Therefore,
while glycolysis can remain high during reperfusion, it
can still be uncoupled from GO resulting in elevated
lactate and proton production [2,13]. Changes in
FA supply, the type of oxidative metabolism, and
increased glycolysis are responsible for the cardiac
inefficiency observed during ischemia and reperfusion.
Energy metabolism and cardiac efficiency
in heart failure
Alterations in energy substrate metabolism accompanying HF are extremely complex, in part due to the heterogeneous nature of HF [1]. In general, however, as HF
progresses, what is observed is a decrease in overall
mitochondrial oxidative capacity and an increase in glucose uptake and glycolysis [1]. FAO rates have been
shown to be elevated, unchanged or decreased in HF
(see [1] for review). The increase in glycolysis in HF is an
adaptive response to compensate for decreased mitochondrial oxidative capacity. This increase in glycolysis
with a low mitochondrial capacity to oxidize glucose can
exacerbate lactate and proton production, in a manner
similar to that seen in the ischemic heart (Fig. 3b). Since
FAO competes with GO, FAs can further exacerbate this
uncoupling. Support for this concept comes from a
number of clinical studies in which FAO inhibition in HF
improved both cardiac efficiency and function.
Conclusions
Alterations in cardiac energy metabolism can profoundly
affect cardiac efficiency. Excessive use of FAs has been
shown to be especially important, either by decreasing
the efficiency of producing ATP, or by decreasing ATP
availability for contractile function. Strategies aimed at
Heart Metab. (2011) 53:33–37
optimizing cardiac energy metabolism have the ability
to improve cardiac efficiency and function. For example,
the Randle cycle is being targeted in order to increase
GO and decrease FAO [1]. Therefore, understanding
how energy metabolism affects cardiac efficiency is
important for improving the treatment of heart disease. ●
Acknowledgements Gary D. Lopaschuk is a Scientist of the
Alberta Heritage Foundation for Medical Research.
References
1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley
WC (2010) Myocardial fatty acid metabolism in health and
disease. Physiol Rev 90:207–258
2. Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD
(2011) Targeting fatty acid and carbohydrate oxidation - A
novel therapeutic intervention in the ischemic and failing
heart. Biochim Biophys Acta 1813:1333–1350
3. How OJ, Aasum E, et al (2005) Influence of substrate supply
on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts. Am J Physiol Heart Circ Physiol
288:H2979–2985
4. Huang JM, Xian H, Bacaner M (1992) Long-chain fatty acids
activate calcium channels in ventricular myocytes. Proc Natl
Acad Sci U S A 89:6452–6456
5. Boehm EA, et al (2001) Increased uncoupling proteins and
decreased efficiency in palmitate-perfused hyperthyroid rat
heart. Am J Physiol Heart Circ Physiol 280: H977–983
6. Murray AJ, Anderson RE, et al (2004) Uncoupling proteins in
human heart. Lancet 364:1786–1788
7. Seifert EL, Bezaire V, Estey C, Harper ME (2008) Essential role
for uncoupling protein-3 in mitochondrial adaptation to fasting
but not in fatty acid oxidation or fatty acid anion export. J Biol
Chem 283:25124–25131
8. Dennis SC, Gevers W, Opie LH (1991) Protons in ischemia:
where do they come from; where do they go to? J Mol Cell
Cardiol 23:1077–1086
9. Lloyd SG, et al (2004) Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat
heart. Am J Physiol Heart Circ Physiol 287:H351–62
10. Whitmer JT, Idell-Wenger JA, Rovetto MJ, Neely JR (1978)
Control of fatty acid metabolism in ischemic and hypoxic
hearts. J Biol Chem 253:4305–4309
11. Folmes CD, et al (2009) High rates of residual fatty acid oxidation during mild ischemia decrease cardiac work and efficiency. J Mol Cell Cardiol 47:142–148
12. Neely JR, Liedtke AJ, Whitmer JT, Rovetto MJ (1975) Relationship between coronary flow and adenosine triphosphate
production from glycolysis and oxidative metabolism. Recent
Adv Stud Cardiac Struct Metab 8:301–321
13. Liu Q, Docherty JC, et al (2002) High levels of fatty acids delay
the recovery of intracellular pH and cardiac efficiency in
post-ischemic hearts by inhibiting glucose oxidation. J Am Coll
Cardiol 39:718–725
14. McVeigh JJ, Lopaschuk GD (1990) Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat
hearts. Am J Physiol 259: H1079–1085
15. Neely JR, Morgan HE (1974) Relationship between carbohydrate and lipid metabolism and the energy balance of heart
muscle. Annu Rev Physiol 36:413–459
37
HOT
TOPICS
- ALDA HUQI
Statin therapy: reduction in cardiovascular
events still pays in new-onset diabetes
Alda Huqi, Cardiovascular Medicine Division, Cardio Thoracic Department, University of Pisa, Pisa, Italy,
and University of Alberta, Edmonton, Alberta, Canada
Hot Topics
Correspondence: Dr. Alda Huqi, Cardiovascular Medicine Division, Cardio Thoracic Department, University of Pisa,
Via Paradisa, 2, 56100 Pisa, Italy. And: 423 Heritage Medical Research Center, University of Alberta,
Edmonton, Alberta T6G 2S2, Canada.
Tel: +39 32972 56426 e-mail: [email protected]
38
W
ith a few exceptions [1], in the past two decades the benefit of statin therapy has been
reproducible irrespective of the individual drug, population subset or prevention strategy
(i.e., primary or secondary) used [2]. In addition to the established benefits, the decision to use
statin therapy has recently been reinforced by the introduction of generic formulation drugs
(i.e., simvastatin, lovastatin and pravastatin) in the market. Accordingly, the need for expanding
the indications was met in the 2011 European Society of Cardiology (ESC) guidelines for the
management of dyslipidemia [3]. These guidelines confirm that patients with a risk score of
≥10%, those with established cardiovascular disease (CVD), type II or I diabetes or chronic kidney disease have a class I indication, level of evidence (LoE) A to receive aggressive statin
treatment in order to achieve low density lipoprotein cholesterol (LDL-C) levels of less than
70 mg/dl. In these guidelines, it is also recommended that a drug therapy with statins be considered in patients with a risk score of <1% who have LDL-C levels of ≥190 mg/dl (Class IIa,
LoE A), and in those patients with a risk score from 1 to 5% who have LDL-C levels of
100–190 mg/dl (Class IIa recommendation, LoE A), or ≥190 mg/dl (Class I recommendation
and LoE A).
However, recent data suggest that statin therapy is associated with an increased incidence
of new-onset diabetes. The incident finding in large clinical trials [4–6] of increased new-onset
diabetes was in fact confirmed recently in two well-conducted metanalysis [7,8]. The first one
[7], including 91,140 patients, showed that, as compared to patients receiving placebo,
patients receiving statin therapy had a 9% increase in relative risk for developing diabetes
(odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02–1.17). More specifically, 1 out of
255 patients would develop diabetes during a 4-year period of statin therapy. The second
metanalysis [8] assessed whether, among those patients receiving statins, an intensive-dose
treatment regimen would further increase the incidence of new-onset diabetes. Data from five
clinical trials including 32,752 patients showed that, as compared to moderate-dose therapy,
an intensive treatment strategy was associated with a further 12% increase in relative risk for
developing new-onset diabetes (OR 1.12, 95% CI 1.04-1.22). Therefore, during a year of statin
treatment, one out of 498 patients would develop new-onset diabetes if in the intensive treatment arm. However, on the other hand, 1 out of 155 of the same patient population would
experience less cardiovascular events because of the intensive treatment. Although no plausible biological effects can yet be identified, the dose-dependence relationship observed in the
Heart Metab. (2011) 53:38–39
HOT
TOPICS
- ALDA HUQI
latter study further confirmed that statin therapy is
associated with an increased risk for new-onset
diabetes.
The status quo of statin therapy can therefore be
summarized as follows: on one hand, as supported
also by the availability of generic formulations and
establishment of new guidelines, there is a strong
willingness to extend treatment indications; however,
on the other hand, there is also an increasing concern
regarding the incidence of new-onset diabetes, particularly for the low risk patient population.
Given such statements, how is the clinician supposed to weight the benefits and risks of statin treatment in the individual patient?
Following the recent meta-analysis, another, very
elegant study, that might actually help answer this
question was published [9]. This study used an established computer simulation model to project costeffectiveness of statin therapy in an era where a more
aggressive statin treatment is being sought, low cost
generic formulations are available and side effects
such as new-onset diabetes are better defined. The
authors found that lowering LDL-C thresholds to
<130 mg/dl for patients with no risk factors and to
<100 mg/dl for patients with one risk factor and treating all moderate and moderately high risk patients
regardless of LDL-C levels would provide additional
health benefits. Most importantly, these benefits were
not negatively affected by the inclusion in the analysis
of statin-associated diabetes or other severe hypothetical side effects.
In conclusion, as outlined by the recently published
ESC guidelines [3], broadening of the indications to
statin therapy appears reasonable. With regards to
the individual patient, one should keep in mind that
Heart Metab. (2011) 53:38–39
the odds of developing diabetes from statin therapy
are lower than those of reducing cardiovascular
events. Therefore, if the former occurs, statin therapy
is theoretically supposed to provide a payback by
reducing the risk for cardiovascular events, one of
the major complications of diabetes. ●
References
1. Ray KK, Seshasai SR, Erqou S et al (2010) Statins and allcause mortality in high-risk primary prevention: a meta-analysis
of 11 randomized controlled trials involving 65,229 participants.
Arch Intern Med 170(12):1024–1031
2. Mills EJ, Wu P, Chong G et al (2010) Efficacy and safety of
statin treatment for cardiovascular disease: a network metaanalysis of 170,255 patients from 76 randomized trials. QJM
104(2):109–124
3. Reiner Z, Catapano AL, De Backer G et al (2010) ESC/EAS
Guidelines for the management of dyslipidaemias: The Task
Force for the management of dyslipidaemias of the European
Society of Cardiology (ESC) and the European Atherosclerosis
Society (EAS). Eur Heart J 32(14):1769–1818
4. Freeman DJ, Norrie J, Sattar N et al (2001) Pravastatin and the
development of diabetes mellitus: evidence for a protective
treatment effect in the West of Scotland Coronary Prevention
Study. Circulation 103(3):357–362
5. Sever PS, Dahlof B, Poulter NR et al (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients
who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised
controlled trial. Lancet 361(9364):1149–1158
6. Ridker PM, Danielson E, Fonseca FA et al (2008) Rosuvastatin
to prevent vascular events in men and women with elevated
C-reactive protein. N Engl J Med 359(21):2195–2207.
7. Sattar N, Preiss D, Murray HM et al (2010) Statins and risk of
incident diabetes: a collaborative meta-analysis of randomised
statin trials. Lancet 375(9716):735–742
8. Preiss D, Seshasai SR, Welsh P et al (2011) Risk of incident
diabetes with intensive-dose compared with moderate-dose
statin therapy: a meta-analysis. JAMA. Jun 305(24):2556–2564
9. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L (2011) Cost-effectiveness of statin therapy for primary
prevention in a low-cost statin era. Circulation 124(2):146–153
39
GLOSSARY - GARY D. LOPASCHUK
AMP-activated protein kinase (AMPK)
AMPK is a key kinase that controls many cellular processes, particularly pathways involved in cellular
energy status. AMPK is activated during metabolic
stress, where it then can either activate energyproducing pathways or inhibit energy-consuming
pathways. For these reasons, it has been termed a
“fuel gauge” of the cell.
of key proteins involved in the control of fatty acid
oxidation.
mTOR pathway
Mammalian target of rapamycin (mTOR) is a kinase
that is a member of the phosphatidylinositol kinase
family. The mTOR pathway functions as a key signaling pathway involved in the control of cell growth and
proliferation. mTOR is activated in response to a number of upstream signaling molecules, including insulin
and growth factors such as IGF-1 and IGF-2. The term
mTOR arose since rapamycin was originally shown to
inhibit the mTOR pathway.
SERCA2
Sarcoplasmic/endoplasmic reticulum calcium ATPase
2 (SERCA2) is the enzyme primarily responsible for the
transport of calcium into intracellular sarcoplasmic
reticulum (SR) and endoplasmic reticulum (ER). SR is
an intracellular organelle in heart and skeletal muscle
that stores calcium. During excitation-contraction coupling, release of calcium for the SR is the major source
of calcium that initiates contraction. SERCA2 initiates
relaxation of muscle by re-sequestering the calcium
back up into the SR.
PGC-1α
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcription co-activator that
plays a key role in the regulation of cellular energy
metabolism. Activation of PGC-1α increases mitochondrial biogenesis. In muscle PGC-1α activation
results in a muscle that is more oxidative and less
glycolytic.
PPARα
Peroxisome proliferator-activated receptor α (PPARα)
is a nuclear receptor involved in the transcriptional
regulation of proteins. This includes the transcription
40
Proteosomes
Proteosomes are large protein complexes inside cells
that function to degrade damaged proteins. Proteases
in the proteasome degrade these proteins into short
amino acid peptides.
Ubiquitination
Ubiquitination is a process in cells in which proteins are
“tagged” with a small protein called ubiquitin. This can
lead to further ubiquitination of the protein, which then
targets the protein for degradation by proteasomes.
Ubiquitin ligases
Ubiquitin ligases are enzymes in cells that catalyze the
ubiquitination reaction. These ubiquitinated proteins
are then targeted for degradation by proteasomes.
As a result, ubiquitine ligases are key enzymes involved
in cellular protein degradation. ●
Heart Metab. (2011) 53:40