Circulation Research. 2004;95:135-145
doi: 10.1161/01.RES.0000137170.41939.d9
(Circulation Research. 2004;95:135.)
© 2004 American Heart Association, Inc.
Is the Failing Heart Energy Starved?
On Using Chemical Energy to Support Cardiac Function
Joanne S. Ingwall,
Robert G. Weiss
From Brigham and Women’s Hospital (J.S.I.), Harvard Medical School, Boston, Mass; and Johns Hopkins Hospital and University School of Medicine (R.G.W.), Cardiology Division, Baltimore, Md.
Correspondence to Robert G. Weiss, MD, Johns Hopkins Hospital and University School of Medicine, Cardiology Division, 600 North Wolfe St, Carnegie 584, Baltimore, MD 21287-6568. E-mail rweiss{at}jhmi.edu
This Review is part of a thematic series on Unanswered Questions in Heart Failure, which includes the following articles:
Is Depressed Contractility Centrally Involved in Heart Failure?
What is the Role of ß-Adrenergic Signaling in Heart Failure?
What Mechanisms Underlie Diastolic Dysfunction in Heart Failure?
Is the Failing Heart Energy Starved?
What Causes Sudden Death in Heart Failure?
Is Abnormal Cell Growth and Hypertrophy the Cause of Heart Failure?
Steven Houser Guest Editor
 |
Abstract
|
|---|
The requirement of chemical energy in the form of ATP to support
systolic and diastolic work of the heart is absolute. Because
of its central role in cardiac metabolism and performance, the
subject of this review on energetics in the failing heart is
ATP. We briefly review the basics of myocardial ATP metabolism
and describe how this changes in the failing heart. We present
an analysis of what is now known about the causes and consequences
of these energetic changes and conclude by commenting on unsolved
problems and opportunities for future basic and clinical research.
Key Words: adenosine triphosphate • phosphocreatine • creatine kinase • familial hypertrophic cardiomyopathy • heart failure
|
Introduction
|
|---|
The energy starvation hypothesis suggesting that the failing
heart is energy-starved is decades old.
1,2 Because ATP is required
for normal systolic and diastolic contractile performance, the
idea that the failing heart is unable to meet the hemodynamic
requirements of the body because there is not enough chemical
energy available is logical. The hypothesis was initially set
aside for several reasons. First, it was unclear whether the
concentration of ATP ([ATP]) decreased. Second, it was reasoned
that even if there were decreases in [ATP] in the failing heart,
the remaining ATP should be sufficient to supply the ATP-requiring
reactions in the myocyte. Third, our understanding of how ATP
synthesis and use are regulated was remarkably incomplete. A
good example of our ignorance about cardiac energetics was the
use of inotropic agents to increase performance of the failing
human heart. While increasing performance, these agents did
so at great energetic cost and often resulted in increased,
rather than decreased, heart failure mortality.
There is now renewed interest in the energy-starvation hypothesis.3,4 New biophysical tools such as nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), and transgenesis using the mouse have allowed old questions to be revisited and new ones to be formulated. Combining old and new strategies to address the "energy starvation" hypothesis, we have learned much. We now know when and by how much [ATP] decreases in the hypertrophied and failing heart. We now know that despite increases in some ATP synthesizing pathways such as glycolysis, other pathways such as the creatine kinase (CK)–phosphocreatine (PCr) system decrease. Finally, we now have a better understanding of how the myocyte accomplishes the tasks of maintaining (near) normal ATP supply and high chemical driving forces for the ATP-requiring reactions when the left ventricular (LV) chamber thickens or dilates, wall stress increases, or the ventricular pump fails to recruit its contractile reserve.
|
ATP as the Universal "Currency" of Energy
|
|---|
The American Heritage Dictionary defines
energy as "the capacity
for doing work" and as "a source of usable power."
5 For the
heart, "work" includes excitation, contraction, relaxation,
and the molecular synthesis and degradation. The requirement
of chemical energy in the form of ATP to support systolic and
diastolic work of the heart is absolute. Hence, the focus of
this invited review is on the "source of usable power," namely
ATP. The concept that the potential energy stored in phosphoryl
bonds of ATP could be released for use and then regenerated
through substrate metabolism within the cell was described more
than 60 years ago.
6 Krebs et al
7 described phosphoryl bonds
as the "energy currency" of the cell nearly 50 years ago. The
basic concept of the phosphoryl bonds serving as "currency"
of energy is still valid. Here, we briefly review the basics
of ATP metabolism and then describe how this changes in the
failing heart. We present an analysis of what is now known about
the causes and consequences of these energetic changes and conclude
by commenting on unsolved problems and opportunities for future
basic and clinical research. Other important aspects of energetics
are discussed in other reviews in this series. Tools assessing
total energy demands of the heart have been elegantly described,
8–9a and their relation to heart failure is described by David Kass.
The role of calcium in heart failure is the focus of another
review by Houser and Margulies.
10 Detailed reviews of substrate
metabolism are available elsewhere.
3,11–14 Similarly,
the energetics of skeletal muscle of patients and animals with
heart failure is described elsewhere.
13,15
|
ATP and the Heart
|
|---|
Central to understanding cardiac energetics is the integration
of ATP-producing and ATP-utilizing pathways (
Figure 1).
16 The
primary ATP-utilizing reactions (shown on the right in
Figure 1)
are actomyosin ATPase in the myofibril, the Ca
2+-ATPase in
the sarcoplasmic reticulum, and the Na
+, K
+-ATPase in the sarcolemma.
Also shown is a growing polypeptide chain representing the requirement
of ATP for (macro)molecular synthesis (in the form of GTP for
protein synthesis); ATP is also used to degrade molecules. [ATP]
is maintained constant,
10 mmol/L, by the highly regulated integration
of the pathways for ATP use and its synthesis. ATP synthesis
by oxidative phosphorylation in the mitochondria is usually
sufficient to maintain normal [ATP], even when the work output
of the heart changes 3- to 5-fold. Quantitatively small contributions
to ATP synthesis also occur from substrate level phosphorylation
in the glycoltytic pathway and, to a lesser extent, in the tricarboxylic
acid cycle.
View larger version (45K):
[in this window]
[in a new window]
|
Figure 1. A cartoon16 summarizing the integration of the ATP synthesizing and utilizing reactions. The primary ATP utilizing reactions (shown on the right) are actomyosin ATPase in the myofibril, the Ca2+-ATPase in the sarcoplasmic reticulum, and the Na+, K+-ATPase in the sarcolemma. Also shown is a polypeptide chain representing the requirement of ATP for macromolecular synthesis. The primary ATP synthesizing pathways (left) are oxidative phosphorylation in the mitochondria and the glycolytic pathway. The creatine kinase and adenylate kinase phosphotransfer reactions are also shown. Adapted from Ingwall,16 with permission.
|
|
It is important to emphasize that the energetic state of the heart is not defined simply by the concentration of ATP. The amount of ATP made and used per minute (turnover) is many times greater than the size of the ATP pool. Thus, maintaining a high ATP supply is critically important for maintaining cardiac performance. The ability of the complex metabolic machinery in the heart to oxidize a variety of carbon-based fuels for ATP synthesis ensures that [ATP] remains constant despite varying ATP turnover rates.
ATP-requiring reactions are inhibited by the accumulation of the products of ATP hydrolysis, namely ADP and inorganic phosphate (Pi): ATP 
ADP + Pi. To determine whether ATP-requiring reactions are limited because of insufficient chemical-driving forces, we need to know the concentrations of ADP and Pi as well as [ATP]. The ratio ([ATP]/[ADP][Pi], the phosphorylation potential (PP), determines the free energy available (
ATP) from the hydrolysis of ATP to drive ATP-requiring reactions. The chemical-driving force can be thought of as a battery used to fuel chemical reactions. Intracellular [ATP], [ADP], [Pi], and PP in normal ventricular tissue are 10 mmol/L, <50 µmol/L, <1 mmol/L, and >200 mmol/L–1, respectively. Note that classical biochemical tools used to analyze extracts of even carefully freeze-clamped tissue cannot provide accurate measures of free [ADP] or [Pi].17 For example, measures of total [ADP] in tissue extracts are in the 1 to 2 mmol/L range, whereas the size of the metabolically active pool or free ADP is 10 to 50 µmol/L, ie, 2 orders of magnitude lower. The physiologically relevant entity is the free [ADP]; it can be calculated from the CK equilibrium expression.18,19 [Pi] can also be overestimated, by as much as 10-fold. It is now possible to measure [ATP] and [Pi] and to obtain good estimates for [ADP] while simultaneously measuring indices of cardiac performance using 31P NMR spectroscopy, making it a useful tool for the study of energetics.
The heart uses energy reserve systems to maintain a high phosphorylation potential (and hence a favorable free energy of ATP hydrolysis, ATP) to drive ATPase reactions during variations in work output. The primary energy reserve compound in the heart is PCr, which is present in concentrations twice that of ATP. The enzyme CK transfers the phosphoryl group between ATP and PCr at a rate 10-times faster than the rate of ATP synthesis by oxidative phosphorylation:20 PCr + ADP + H+ 
creatine + ATP. Under conditions when ATP demand exceeds ATP supply, as in acute pump failure in ischemia and in chronic conditions of high wall stress, use of PCr via the CK reaction is one way that the heart maintains constant [ATP]. The CK reaction also maintains a low [ADP] and [Pi], thereby maximizing the phosphorylation potential.21 The enzyme adenylate kinase also functions to maintain high levels of ATP by transferring phosphoryl groups among the adenine nucleotides: 2ADP ATP + AMP. Glycogen is an indirect energy store in that its glucosyl units can be used to generate ATP through glycolytic and oxidative metabolism.22,23
|
ATP and the Failing Heart
|
|---|
Based on analysis of human biopsy specimens, we now know that
[ATP] is
25% to 30% lower in the failing human heart.
24,25 This
has been confirmed in heart failure patients by absolute quantification
of [ATP] using
31P NMR spectroscopy.
26 Longitudinal studies
of animal models of heart failure have provided us with insights
into when and why ATP is lost from the myocardium. Results using
a dog model of heart failure (pacing-induced)
27 show that the
loss of ATP in the failing myocardium is slow and progressive:
0.35% of the ATP pool per day. This low rate means that a decrease
in ATP content would not be easy to detect until the heart was
in severe failure, explaining the conflicting literature results
on this topic. This conclusion is well-supported by results
using other animal models of compensated and uncompensated LV
hypertrophy (LVH).
28–32
Studies in animal models of heart failure show that the loss of ATP in the failing heart is caused by loss in the total adenine nucleotide (TAN) pool.27,30,31 The failing heart is a unique example of a well-oxygenated heart33–35 in which a chronic mismatch between ATP synthesis and degradation results in loss of ATP and TAN; previously, ATP and TAN loss were observed only for conditions of hypoxia and ischemia. Whether ATP and TAN losses occur because de novo purine synthesis is slowed (or fails to increase to support a larger myocyte mass) or because reactions converting adenine nucleotides to diffusible purine nucleosides and bases are accelerated remain to be determined. Why [ATP] decreases by only 25% is not known, and the length of time the heart can tolerate this new steady-state also remains to be defined.
|
PCr and the Failing Heart
|
|---|
Creatine is not made in the heart but accumulates against a
large concentration gradient by means of a facilitated creatine
transporter.
36,37 In the normal heart, approximately two-thirds
of the total creatine pool is phosphorylated via the CK reaction
to form PCr and hence is chemically trapped.
The observation that the total creatine pool is as much as 60% lower in LVH and heart failure was originally made in animal models.28,29 This was confirmed in human myocardial biopsy specimens in the mid 1980s in patients with severe aortic stenosis38 and in the 1990s in patients with severe heart failure.4 A recent study using 1H NMR spectroscopy demonstrated creatine depletion in human heart failure and, moreover, that the magnitude of the decrease was related to heart failure severity.39
Because CK is relatively abundant even in the failing heart,25,28–32,38,40 a lower total creatine pool means that [PCr] must also be lower. 31P NMR studies in the early 1990s by several groups41–44 showed that [PCr]/[ATP] is lower in dilated cardiomyopathy and heart failure. In Figure 2, typical 31P NMR spectra obtained noninvasively from normal and failing human hearts illustrate the changes in [ATP] and [PCr] that characterize the failing heart. Because we now know that [ATP] is also lower in severely failing human myocardium,24,26 the decrease in [PCr] reported by the ratio of [PCr] to [ATP] is underestimated in severe heart failure.27 Importantly, the [PCr]-to-[ATP] ratio is a good predictor of mortality in patients with dilated cardiomyopathy.45 In fact, over the course of several years, a low cardiac [PCr]/[ATP] is a better predictor of overall and cardiovascular mortality than New York Heart Association Class and LV ejection fraction (Figure 3).
View larger version (108K):
[in this window]
[in a new window]
|
Figure 2. Changes in cardiac 31P NMR spectra in heart failure. 1H NMR images (upper panel) and spatially localized 31P NMR spectra (bottom panel) are shown from a normal individual (left, A) and in a patient with idiopathic dilated cardiomyopathy (right, B). 31P NMR spectra were obtained from the regions of the anterior left ventricular wall denoted on the 1H NMR images between the white lines. In NMR spectra, the peak position is determined by the chemical moiety and the peak area is related to the amount of the chemical compound. The peaks, from left to right, are inorganic phosphate, creatine phosphate, and the [ -P], [ -P], and [ß-P] of ATP. In the normal human heart, the relative amount of creatine phosphate (PCr) is nearly twice that of ATP (lower left panel). In heart failure (lower right panel), the relative amount of PCr to ATP is reduced dramatically at rest. In measurements from several regions of this patient’s failing heart, mean [ATP] is reduced by 15% and [PCr] by >40% from that in normal subjects (R.G. Weiss and P.A. Bottomley, 2003, unpublished data).
|
|
View larger version (35K):
[in this window]
[in a new window]
|
Figure 3. Relationship between overall mortality (left panel) and cardiovascular mortality (right panel) in subjects with dilated cardiomyopathy and heart failure based on cardiac PCr/ATP (top row), NYHA Class (middle row), and left ventricular ejection fraction (bottom row). Note that cardiac energetics as measured by the myocardial PCr/ATP is a better predictor of overall and cardiovascular mortality than the usual clinical indices of ejection fraction and NYHA symptomatology. Reproduced from Figure 3 of Neubauer et al,45 with permission.
|
|
The observations that [PCr]/[ATP] and [PCr] are lower in both compensated LVH as well as failing hearts suggest that loss of creatine cannot be a specific marker of the failing heart. Instead, loss of PCr is a more general marker of a mismatch in the integration of the pathways maintaining sufficient ATP supply to meet the demand for ATP utilization. Mechanisms accounting for decreased [PCr] include decreased number of creatine transporters37 and changes in CK isozyme expression leading to a lower ratio of [PCr]-to-[total creatine].21
|
The Failing Heart Is Energy-Poor
|
|---|
The evidence amassed to date suggests that the following sequence
of events occurs in the progression to myocardial pump failure.
[PCr] decreases in hypertrophy and failure because of a mismatch
in ATP supply and demand. This is followed by a loss in [creatine]
by as much as 60% and by a decrease in [ATP]. The loss of creatine
is cardiac-specific and is nearly an order of magnitude faster
than loss of ATP.
27 ATP slowly and progressively decreases in
the dysfunctional and failing myocardium to a lower limit of
70% to 75% of normal values. The loss of ATP is caused by loss
of purines. Early in the evolution of heart failure, [ADP] (and
Pi) increases, leading to a decrease in
ATP, but with time,
as the absolute concentrations of ATP, ADP, and creatine decrease
in the failing heart, and the ratio of [ATP]-to-[ADP] and
ATP are reset to near normal values. How long any of these states
remain stable is not known.
The observation that [ATP] decreases in the failing heart means that the normal well-designed well-integrated metabolic machinery has failed. Moreover, because the [ATP]-poor state persists in the failing heart, the normal mechanisms that slowly replete the ATP pool after myocardial ischemia and infarction must also "fail." The decrease in [ATP] is important, not because [ATP] decreases to values below the Km for ATP of the ATPase reactions; it does not. It is important because it signals a massive change in normal metabolic regulation, one that is unable to support normal levels of either ATP or PCr. Here we list the primary changes in the ATP synthesis pathways now thought to occur in the failing heart.
|
On the Failure of ATP Synthesis Pathways to Prevent the Decrease in [ATP]
|
|---|
Mitochondrial protein activities measured in heart failure models
as diverse as the pacing dog
46 and the aortic banded rat
47 have
been shown to be decreased, but whether the changes are large
enough to limit the capacity for MVO
2 is not entirely clear.
27,46,48 Based on elegant measures of myoglobin saturation using NMR
spectroscopy, what is clear is that the hypertrophied/ failing
heart is not hypoxic.
34,35
At least some of the mechanisms responsible for the decreases in fatty acid oxidation in hypertrophied and failing heart have been identified.49 The coordinated downregulation of gene expression of enzymes controlling fatty acid oxidation is caused, at least in part, by decreases in expression of the nuclear receptors proliferator-activated receptor- and retinoid X receptor-46,48 and the master transcriptional regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor co-activator (PGC1-).47
The first observation of molecular remodeling or reprogramming in a model of LVH was a change in isozyme distribution of the glycolytic enzyme lactate dehydrogenase.50 It is now widely accepted that glucose uptake and utilization increase in hypertrophied and mildly failing heart.51–54 It is not yet clear how long this is sustained.
The large decrease in CK reaction velocity caused by decreases in both CK muscle-type isozyme activities and in creatine is only partially compensated for by increases in adenylate kinase reaction velocity and glycolytic rate.55
The sum of all these changes in ATP synthesis pathways fails to meet the chronic demand for ATP utilization in the failing heart. [ATP] decreases.
The decrease in fatty acid oxidation and increased reliance on glucose utilization in hypertrophied and failing hearts has often been described as a shift to the "fetal phenotype." It is important to point out that the "shift" is only partial, and even when the proportion of ATP synthesized from glucose increases many fold, aerobic metabolism is still dominant.
|
On Causes and Consequences
|
|---|
What are the causes and consequences of these metabolic changes?
Are they a cause or a consequence of the hemodynamic changes
that occur in the hypertrophied and failing heart? Is any one
of these changes sufficient to cause heart failure? Do they
contribute to the progressive decline in pump function?
In any discussion of causes and consequences, we need to distinguish among the cause of a specific molecular change, its consequence if any on systolic and diastolic function of the heart, and when the change occurs during the evolution to failure. To distinguish cause versus consequence, we can create gain and loss of function models for each molecular change identified in the failing heart and determine the consequences in the context of the normal heart and in the far more complex setting of the failing heart. This is a formidable challenge for at least 2 reasons. One is that it is unlikely that any single change leads to heart failure. Even the familial hypertrophic cardiomyopathy (FHC)–associated mutations are lethal in only a subset of carriers of the defective gene.56 The second is that the cell is designed to compensate for the loss of any important enzyme or pathway. Energetics is the prime example of this basic biologic principle. Myocytes are designed to make large amounts of ATP needed to meet varying needs of contraction from a variety of carbon-based substrates. When one pathway fails, there are others to compensate.
Here we present 7 examples in which the relationship between cardiac pathophysiology and some aspect of energetics have been defined. Several examples focus on phosphotransferase reactions, a subject for which much is known.
|
On the Causes of Altered Energetic Phenotype Characteristic of the Failing Heart: The Relationship Between LV Pressure and Molecular Phenotype
|
|---|
Myocyte size, location, and ability to adapt to stress, as well
as hemodynamic factors, all play important roles leading to
altered gene expression in the failing heart. This is well-illustrated
by an early study in which cell size and enzyme activities of
several proteins known to change in cardiac hypertrophy and
failure were measured in myocytes isolated from different regions
of hypertensive and nonhypertensive hypertrophied rat hearts
(2 kidney, 1 clip model).
57 Some proteins increased in proportion
to myocyte size while others were relatively diluted, and still
others increased out of proportion to myocyte size. Regulation
of gene expression differed among neighboring cells within the
same organ. This myocyte study showed that gene expression changed
in response to sustained hemodynamic load.
The idea that sustained increased hemodynamic load causes changes in gene expression in some but not all proteins involved in energy utilization and synthesis is well-supported by a recent study showing that the decreases in MM-CK and mitochondrial (sMt)-CK isozymes, but not the increase in MB-CK, were reversed in heart failure patients given a ventricular assist device.58 These observations suggest that unloading the failing heart leads to a reversal toward the normal adult phenotype. The molecular details of how this occurs remain unknown, and additional reversal strategies need to be pursued.
|
Consequences of Reduced Phosphotransferase Activity: CK Activity and the Ability to Recruit Contractile Reserve
|
|---|
The relationship between energy reserve supplied from the transfer
of the phosphoryl group between ATP and PCr via the CK system
and contractile reserve (by which we mean the ability of the
heart to increase cardiac performance in response to demand)
has been defined for the normal heart by inhibiting the velocity
of the CK reaction acutely and chronically using several different
approaches. In one set of studies, energy reserve was acutely
decreased by
99% by chemically inhibiting CK activity.
59,60 Because the velocity of the CK reaction is directly proportional
to maximal enzyme activity (Vmax), this maneuver effectively
eliminated the primary energy reserve system in the heart. Care
was taken to test whether MVO
2, the MVO
2-work relation, adenylate
kinase capacity, and glycolytic rates were normal in these hearts;
none of these differed from control hearts; so, of all the ATP
supply reactions, only the CK reaction was eliminated. The primary
consequences of eliminating CK activity were (
Figure 4): (1)
at any workload, hearts with low levels of CK activity operate
at a lower
ATP ; this means that they have less free energy
available from ATP hydrolysis to support an increase in work;
(2) for the equivalent inotropic challenge, the increase in
contractile reserve in CK-inhibited hearts was much less than
for normal hearts; and (3) for the same energy expenditure,
there is less work output in CK-inhibited hearts. Thus, reducing
energy reserve via the CK system limits the contractile reserve
of the heart.
Importantly, the consequences of acutely decreasing energy reserve on contractile reserve demonstrated by this experiment also apply to chronic conditions of decreased energy reserve. The velocity of the CK reaction was chronically decreased by replacing creatine in the diet of rats with one of two creatine analogs, ß-guanidinoproprionic acid or ß-guanidinopbutyric acid.61 These creatine analogs are poor substrates for the CK reaction and, at the doses delivered, reduced [PCr] and CK reaction velocity by 70%. As observed for hearts with lower CK reaction velocity caused by acutely inhibiting the enzyme, isolated hearts that were creatine-depleted were unable to perform as much work as normal hearts. At any LV volume, contractile performance was lower than in controls. At peak work states, contractile performance assessed as the product of heart rate and developed pressure (RPP) in creatine-depleted hearts was only 60% of control. Reduced [PCr] compromises the rate of phosphoryl transfer between mitochondria and sites of utilization not only in the sarcomere but also in the sarcoplasmic reticulum. Particularly noteworthy are observations using other models showing that changes in CK compartmentation alter adenine nucleotide channeling among organelles and calcium homeostasis.62–64
Using transgenesis to chronically reduce either CK or adenylate kinase (the other major phophotransferase) activity in the mouse heart, similar conclusions can be drawn. For mouse hearts with ablated muscle isoform of CK (MM-CK) and sMtCK activities (only BBCK activity remained), the same increase in RPP lead to a greater change in ATP .65 Studies using otherwise normal mouse hearts deficient in adenylate kinase 1 have shown that even though flux through the CK reaction and glycolysis increased to compensate for the loss in adenylate kinase, more ATP per contraction was used in adenylate kinase 1-deficient muscle.66 Thus, in both acute and chronic phosphoryl-transfer–deficient states, there is a greater energy cost for work produced, and the efficiency of energy transduction is compromised.
How does this apply to the failing heart? The failing heart is "energy-starved" with respect to its capacity to rapidly resynthesize ATP via the CK system. Based on experiments in normal animal hearts and in models of heart failure showing similar relationships for energy reserve via the CK system and contractile reserve of the heart (for example, Figure 5),40 we conclude that the decreased energy reserve of the failing heart contributes to its decreased contractile reserve. The energy-poor heart cannot recruit its contractile reserve without expending a disproportionate amount of energy and this property of the failing heart is associated with worse clinical outcomes (see below).
|
Consequences of Increased [ADP]: On the Energetic Causes of Diastolic Dysfunction
|
|---|
Diastolic dysfunction in the absence of systolic failure occurs
in approximately half of all heart failure patients. One of
the consequences of the decrease in [PCr] without a concomitant
decrease in [creatine] observed during early stages of heart
failure is increased cytosolic [ADP]. The possibility that higher
cytosolic [ADP] is sufficient to slow dissociation of the cross-bridges
enough to slow relaxation in the intact heart as it does in
skeletal muscle has been tested.
67,68 Free [ADP] was manipulated
in a whole heart (rat) preparation without substantially altering
any of the other known regulators of contraction, namely ATP,
Pi, H
+, or Ca
2+; the rate of ATP synthesis from glycolysis was
also unchanged. In the normal heart, this was accomplished by
chemically inhibiting CK to varying degrees.
68 In the heart
hypertrophied because of aortic banding, the changes were the
result of the perturbations in the CK-PCr that occur during
hypertrophy and failure.
67 In both settings, a monotonic relationship
between increased LV end diastolic pressure and increased [ADP]
was found (
Figure 6). Taken together, these studies demonstrate
that increases in the average cytosolic [ADP] in the absence
of changes in any of the other known regulators of myofilament
function are sufficient to slow cross-bridge cycling and thereby
contribute to the observed diastolic dysfunction.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 6. Relationship between the increase in [ADP] and the increase in LV end-diastolic pressure (EDP) in isolated perfused rat hearts in which [ADP] was altered by inhibiting creatine kinase to varying extents. Because all other known regulators of EDP were help-constant, these results show that increased [ADP] is sufficient to slow cross-bridge cycling in the heart. Reproduced from Tian et al,68 with permission.
|
|
|
Consequences of Increased [AMP]: AMP-Dependent Protein Kinase and Cytosolic AMP-Specific 5'-Nucleotidase
|
|---|
When [ADP] increases, cytosolic [AMP] also must increase as
a result of the adenylate kinase reaction: 2ADP
ATP + AMP.
27 A beneficial consequence of increased [AMP] is activation of
AMP-dependent protein kinase (AMPK). AMPK acts as a "low-on-fuel"
warning system.
69 By means of phosphorylation of specific proteins,
increased AMPK activity remodels metabolic pathways for ATP
synthesis toward greater metabolic efficiency. Activation of
AMPK during
acute low-energy states switches off ATP-consuming
pathways such as fatty acid synthesis and activates ATP-producing
pathways such as fatty acid oxidation and increased glucose
uptake. AMPK has also been shown to function in this way in
chronic low-energy states, including cardiac hypertrophy and
failure
70 and skeletal muscle depleted of ATP.
71 In hypertrophied
(rat) hearts transitioning to failure, elevations in [AMP] and
AMPK activity, isoform-specific alterations in AMPK expression
and increased basal glucose uptake rates have all been observed.
70 Activation of AMPK led to a coordinate control of glucose supply
and utilization, leading to higher rates of glycolytic ATP production.
Increased AMPK activity also increases peroxisome proliferator-activated
receptor
co-activator (PGC-1
) expression,
72 a transcriptional
co-activator that promotes mitochondrial biogenesis and oxidative
phosphorylation.
73–75
But elevated [AMP] also has detrimental consequences. Increased [AMP] also activates cytosolic 5'-AMP–specific 5'-nucleotidase, the primary enzyme responsible for the conversion of AMP to adenosine in muscle cells.76–79 Increased adenosine concentrations leads to increased rate of purine and hence TAN loss. These 2 apparently conflicting consequences of increased [AMP] merit further study.
|
Increased Susceptibility of the Hypertrophied and Failing Heart to Acute and Chronic Stress
|
|---|
A characteristic of the failing myocardium is the failure to
increase flux through the ATP synthesis pathways so that normal
[ATP] and [PCr] are maintained. Once the state of diminished
energy reserve is reached, regardless of cause, the heart has
little contractile reserve and is at high risk for acute mechanical
failure during an abrupt increase in work state, a hypoxic or
ischemic insult, or an arrhythmia. Imposing a severe supply/demand
mismatch on the already energetically compromised failing heart
could lead to acute failure. One demonstration of the greater
susceptibility of the energy-depleted heart is the faster rate
of loss of systolic performance during zero-flow ischemia in
isolated mouse hearts deficient in the MM-CK and sMtCK genes.
80 Another is the example shown studying myocardial infarction
in the rat.
81 Myocardial [PCr] and CK reaction velocity were
decreased by
90% and [ATP] by 18% (a profile similar to the
heart failure phenotype) in rats fed with the creatine analog
ß-guanidinoproprionic acid, a competitive inhibitor
of creatine transport and the CK reaction. Unlike control rat
hearts that survived acute myocardial infarction, the 24-hour
mortality of rats with severely compromised CK-PCr system was
100%.
|
The Effect of Ischemia on Energetics in the Failing Heart
|
|---|
Many patients with heart failure have underlying ischemic disease
that contributes to both the onset and progression of heart
failure. Because ischemia, defined as an imbalance of oxygen
supply and demand, alters myocardial metabolism even before
the onset of heart failure, this review focused primarily on
animal and human studies without underlying coronary disease.
In this way, we focus on heart failure per se and not the well-known
metabolic consequences of ischemia or their complex interaction.
It is unclear whether ischemia at the cellular level in the
absence of coronary stenoses contributes to the onset or progression
of heart failure as the determinants of oxygen demand, heart
rate, and wall stress, increase. Recent studies, including those
of myoglobin oxygenation, in several animal models indicate
that inadequate oxygen supply or demand ischemia does not contribute
significantly to heart failure progression.
33–35
|
Increased Energy Use With Normal ATP Supply: The Energetic Phenotype of Familial Hypertrophic Cardiomyopathy
|
|---|
Top
Abstract
Introduction
), cardiomyopathic heart (
). Reproduced from Tian et al,