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(Circulation. 1999;100:2113-2118.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Progressive Loss of Myocardial ATP Due to a Loss of Total Purines During the Development of Heart Failure in Dogs
A Compensatory Role for the Parallel Loss of Creatine
From the NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (W.S., J.S.I.); the Cardiovascular and Pulmonary Research Institute, Allegheny University of Health Sciences, Pittsburgh, Pa (W.S., M.A.M., R.P.S.); and Weis Center for Research, Penn State University, College of Medicine, Hershey, Pa (K.A., M.U., S.F.V.).
Correspondence to Weiqun Shen, MD, PhD, 221 Longwood Ave, Room 247, Boston, MA 02115.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Whether myocardial ATP content falls in heart failure is a long-standing and controversial issue. The mechanism(s) to explain any decrease in ATP content during heart failure have not been identified.
Methods and Results—Cardiac dysfunction, heart failure, and a
prolonged steady state of heart failure were induced by chronic right
ventricular pacing for 1 to 2 weeks, 3 to 4 weeks, and 7 to
9 weeks in dogs. Cardiac function and myocardial O2
consumption (M
O2) were measured with the
dogs in the conscious state. ATP, total purine, and creatine were
measured in biopsy specimens obtained at each stage. ATP and the total
purine pool progressively fell at rates of 0.12 and 0.15 nmol ·
mg protein-1 · d-1, despite an
increase in MO2. The rate of loss of
creatine was 1.06 nmol · mg protein-1 ·
d-1, 7 times faster than the depletion of total
purine.
Conclusions—(1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.
Key Words: adenosine triphosphate • purine • creatine • oxygen • heart failure
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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ATP provides energy for contraction. ATP concentration in the normal heart is maintained constant, despite variations in cardiac performance, through balanced changes in the rate of ATP synthesis and utilization. Whether changes in ATP content occur and if so, whether they contribute to heart failure remains controversial. Some studies of failing human hearts have found decreased ATP content correlating with the extent of the impairment in cardiac function,1 while others have reported normal ATP content.2 Conflicting results have also been found from studies in animal models.3 4 5
One explanation for these apparently conflicting results is that the ATP content changes at various stages during the development of heart failure. Because of the difficulties inherent in conducting longitudinal studies of heart failure in both patients and animal models, this has not been tested. The mechanisms explaining the loss of ATP have not been identified.
The goals of the present study were, first, to determine whether
and, if so, when ATP content is reduced in the failing heart. If the
ATP content is decreased in the failing heart, our second goal was to
identify the mechanism(s) explaining the loss of ATP. Because the
purine pool must be preserved if a normal ATP content is to be
maintained, we tested whether and, if so, when the purine pool is
reduced in the failing heart. The loss of purine could result either
from an inhibition of de novo purine synthesis or failure of ATP
synthesis pathways (primarily oxidative
phosphorylation) to rephosphorylate ADP. To
assess whether ADP and AMP increase in the failing heart (and thereby
increase purine efflux), we also calculated the ADP and AMP contents.
Finally, we examined the role of creatine (Cr) in maintaining the
purine pool in the failing heart, because a decreased Cr could affect
the concentrations of ADP (and secondarily AMP) through the creatine
kinase (CK) reaction: PCr+ADP+H+
ATP+Cr, where
PCr is phosphocreatine.
To address these goals, the canine pacing model was used. The dogs were
paced for 1 to 2 weeks to induce subclinical cardiac dysfunction and
for 3 to 4 weeks to develop overt heart failure. To create a state of
chronic heart failure, the duration of pacing was extended another 4 to
5 weeks at a reduced pacing rate. In this way, we were able to study
cardiac function and myocardial high-energy contents at 3 different
stages during the development of heart failure as well as in the
control state. At each time, we obtained biopsy specimens for
measurement of tissue contents of ATP, its primary metabolites, and Cr.
We also measured myocardial O2 consumption
(MO2) in vivo to evaluate flux
through oxidative phosphorylation.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Preparation
Dogs (n=26) were chronically instrumented for assessment of hemodynamics and cardiac function.6 7 Briefly, dogs were instrumented with left ventricular (LV) pressure transducers (model P6, Konigsberg), aortic and coronary sinus catheters, ultrasonic dimension crystals across the LV cavity and the LV free wall, and transonic flow probes (Transonic Systems) on the left circumflex coronary artery. A screw-in–type pacing lead was attached to the right ventricular free wall, and left atrial pacing electrodes were also implanted. All wires and catheters were externalized. The dogs were allowed to recover completely for 2 to 3 weeks before experiments. Hemodynamics and cardiac function, including heart rate, mean arterial pressure, LV pressure and LV dP/dt, LV diameters and wall stress, and left circumflex coronary blood flow, were recorded with the dogs fully awake. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 93-23, revised 1985).
Chronic Pacing-Induced Heart Failure
Congestive heart failure was induced by chronic rapid right
ventricular (RV) pacing with a programmable pacemaker (Pace
Medical). The experimental dogs were divided into 4 groups: control
group (n=9), instrumented without pacing; 1- to 2-week pacing group
(n=5), pacing at 240 bpm for 9±2 days to produce cardiac dysfunction
without clinical signs of heart failure; 3- to 4-week pacing group
(n=7), pacing at 240 bpm for 25±2 days to induce heart failure; and 7-
to 9-week pacing group (n=6), pacing at 240 bpm for 3 to 4 weeks
followed by pacing at 210 bpm for another 4 to 5 weeks for a total of
56±5 days to create and maintain chronic heart failure. Before the
onset and at the end of the pacing protocol,
hemodynamics and cardiac function were assessed (for
all groups), and arterial and coronary sinus blood
samples were collected (only for the 1- to 2-week and 3- to 4-week
pacing groups). Myocardial O2 extraction was
calculated as the arterial and coronary
sinus blood O2 content difference, and
MO2 was calculated as the
product of O2 extraction and mean
coronary blood flow.
Biopsy and Analytical Assays
After the in vivo measurements were completed, the dogs were
anesthetized with pentobarbital sodium (25 mg/kg) and
ventilated with a respirator (Harvard), and the heart was exposed
through a left thoracotomy. With a high-speed air turbine biopsy drill
connected via a vacuum line to a bottle filled with liquid nitrogen,
transmural biopsies (1 mm in diameter) were obtained from both LV
and RV free walls and rapidly frozen (
1 second). Biopsy specimens
were stored at -80°C.
Tissue concentrations of the primary nucleotides, nucleosides, and bases were measured by high-performance liquid chromatography (HPLC, Waters). Purines were eluted from a YMC ODS-AQ column, 4.6x150 mm at room temperature isocratically with 0.05 mol/L phosphate buffer (pH 6.0) at a flow rate of 0.8 mL/min and were analyzed at 254 nm. Aliquots of the homogenate taken before centrifugation were made alkaline and incubated overnight at 38°C to solubilize total protein for Lowry protein assay.10 Another set of aliquots was used for measurement of total Cr.8
Data Analysis
LV fractional shortening (FS) was calculated as
100x(LVEDD-LVESD)/LVEDD, where LVEDD and LVESD denote the
end-diastolic and end-systolic LV internal
diameters. Wall stress (WS) was calculated by use of a cylindrical
model10 as 1.36(LVPxLVID)/2WT
(g/cm2), where LVP is LV pressure, LVID is LV
internal diameter, and WT is wall thickness. LVID and WT were measured
at end diastole and end systole.
Interstitial edema and fibrosis have been reported for this model.11 In the present study, the dry/wet weight ratio (0.22±0.01) and the protein/wet weight ratio (0.13±0.01) were not different among groups, showing that the failing hearts paced according to this protocol have neither edema nor fibrosis.7 Substrate amounts were normalized by the amount of Lowry protein (primarily myocyte protein) to minimize any contributions of edema and fibrosis.
To calculate the cytosolic contents of ADP and AMP, we used the
equilibrium expressions for creatine kinase and adenylate
kinase.12 The equilibrium expression for the reaction
PCr+ADP+H+ ATP+Cr is
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ATP+AMP is
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Statistical Analysis
Data are expressed as mean±SEM. For
hemodynamic, cardiac function, and
MO2 data, Student’s
t test was used for paired comparisons. For the biochemistry
data, 1-way factorial ANOVA and Tukey’s highly significant difference
post hoc test for multiple comparison were used. For the longitudinal
changes in ATP and Cr and the sum of adenine nucleotides
with pacing time, curve fitting and regression analysis were
used. All statistical analyses used Statview (Brainpower,
Calabasas). Significant changes were considered for
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamics and Cardiac Function Measured in the Conscious State
Before the onset of pacing, hemodynamic and cardiac function parameters for each of the 3 pacing groups were not different from the control group (Table 1
). Exertional dyspnea and ascites did
not develop until after 2 to 3 weeks of pacing. Thus, there was cardiac
dysfunction without overt clinical signs of heart failure in dogs with
1- to 2-week pacing. Dogs with 3- to 4-week pacing were in severe heart
failure, and severe heart failure was successfully maintained for an
additional 4 weeks for the 7- to 9-week pacing group.
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Compared with baseline, there were similar increases in heart rate and
comparable decreases in mean arterial pressure, LV
systolic pressure, and LV dP/dt after pacing in all 3 pacing
groups. LVFS decreased in the 1- to 2-week pacing group and decreased
further in the 3- to 4-week and 7- to 9-week pacing groups. LV
end-systolic wall stress was elevated only in the 7- to 9-week
pacing group. LV end-diastolic pressure, diameter, and wall
stress were all increased in the 1- to 2-week pacing group, increased
further in the 3- to 4-week pacing group, and remained elevated in the
7- to 9-week pacing group (Table 1
).
Progressive Decrease in ATP
Figure 1 (left) shows data for LV
ATP content for each dog plotted against the duration of pacing. LV ATP
content decreased monotonically with pacing time at a rate of 0.12
nmol · mg protein-1 ·
d-1. Table 2 shows
these data arranged by group. Compared with the control group, the
change in LV ATP in the 1- to 2-week pacing group was not significant,
even though isovolumic and ejection phase indices in these dogs were
lower. LV ATP content was 11% lower (P<0.05 versus
control) in the 3- to 4-week pacing group and decreased by 20%
(P<0.05 versus control and 3- to 4-week pacing) in the 7-
to 9-week pacing group. ATP content in the RV was not different from
that in the LV for any of the 4 groups, showing that the magnitude of
the loss of ATP was similar for both ventricular
chambers.
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Progressive Depletion of Purines
To test whether the loss of ATP in the failing heart results from
the loss of purines or whether the products of ATP degradation
increased, thereby preserving the purine pool, we measured the primary
adenine nucleotides, nucleosides, and nucleobases in biopsy
samples from the 4 groups of dogs studied. The tissue contents of
adenosine, inosine, and hypoxanthine were barely detectable in
all 4 groups (data not shown). Because these metabolites were
present in only trace amounts, the sum of the 3
nucleotides, ATP+ADP+AMP, closely approximates the size of
the total adenine pool (TAN).
Analysis by groups revealed the same pattern for TAN as for ATP
(Table 2). LV TAN was similar for the control group and the 1-
to 2-week pacing group but was depleted by 15% (P<0.05) in
the 3- to 4-week pacing group and by 21% (P<0.05) in the
7- to 9-week pacing group. Figure 1 (middle) shows the data for
LV TAN for each dog plotted against days of pacing. TAN decreased
monotonically with pacing time. Regression analysis shows a
linear relationship between TAN and ATP contents (Figure 1, right). The changes in RV TAN were similar to those in LV TAN, but the
reduction occurred earlier (Table 2).
Tissue ADP and AMP contents were not significantly different among the
control and the 3 pacing groups (Table 2). However, as observed
for ATP and TAN, calculated cytosolic ADP and AMP contents
progressively decreased (Table 3).
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Progressive Decrease in Cr
Figure 2 shows a progressive
decrease in LV Cr content with pacing time. Cr was reduced by 15% in
the 1- to 2-week pacing group, then by 28% in the 3- to 4-week pacing
group, and by 41% in the 7- to 9-week pacing group (all
P<0.05). The similar decreases in Cr content were also
observed in the RV, but the reduction of Cr was more severe in the 1-
to 2-week pacing group (29%, P<0.05) (Table 2).
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ATP Synthesis Rate
To examine whether the reduced ATP content in the pacing-induced
failing heart is due to lower capacity for oxidative
phosphorylation,
MO2 was measured directly.
Values for MO2,
coronary blood flow, arterial and coronary
sinus blood O2 content, and
O2 extraction in dogs with 1- to 2-week pacing
and 3- to 4-week pacing are shown in Table 4.
MO2 was the same as for
baseline in the 1- to 2-week pacing group and was 38±11%
(P<0.05) higher in dogs in the 3- to 4-week pacing group.
The increase in MO2 was
accompanied by an increase in coronary blood flow.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Pacing-Induced Heart Failure in Dogs
In the pacing-induced heart failure model used here, animals develop progressive ventricular dilation with decreased myocardial contractility.6 7 This model has been used to study some biochemical alterations in the failing heart,3 14 but none of those studies achieved a chronic steady state of heart failure, performed a longitudinal analysis of pump function and biochemistry of ATP, or identified the mechanisms for ATP depletion during the development of heart failure. In the present study, animals were paced for different lengths of time and different rates to establish 4 distinct conditions, namely, control, cardiac dysfunction, heart failure, and chronic heart failure, allowing a longitudinal analysis of the biochemistry of ATP.
ATP Content
The results presented here for ATP content measured
during the development of cardiac dysfunction and failure provide a
likely explanation for the conflicting literature results on this
subject. ATP content decreased monotonically with time of pacing at a
rate of 0.35% of the total ATP pool per day. Thus, the reduction of
ATP content is not large enough to be easily detected until heart
failure is severe. Of note, the magnitude of the decrease in ATP in the
severely failing dog heart observed here (20%) is similar to the
decrease in ATP found for severely failing small-animal15
and human16 hearts.
The observation that ATP content is lower than normal in the severely failing heart requires reinterpretation of the PCr/ATP values measured by 31P NMR spectroscopy for the failing human heart.17 The significance of changes in this ratio has focused on decreases in PCr. Because ATP content also decreases, these changes in PCr have been underestimated by as much as 20%.
Possible Mechanisms for the Mismatch Between ATP Synthesis and
Degradation
A major result of our study is that the decrease in the TAN
size closely parallels the loss in ATP content. The progressive
depletion of TAN in the failing heart indicates that the rate of ATP
synthesis fails to match the rate of ATP degradation. There are several
ways this mismatch could occur. One way is failure to synthesize the
purine ring via de novo pathways while a balance is maintained
(although at different absolute rates) among the other pathways for ATP
synthesis and utilization. Zimmer et al18 measured the
rate of de novo adenine synthesis in the normal beating mammalian (rat)
heart in situ. If their value of 0.86 nmol · mg
protein-1 · d-1
applies to the dog heart, then a reduction of only 17% in the rate
of de novo purine synthesis would account for the loss of TAN observed
here (0.15 nmol · mg protein-1 ·
d-1). These observations merit further
study.
Another mechanism that could explain the loss of purine independently
of the rate of de novo purine synthesis is a failure of the
primary pathways for ATP synthesis to meet increased demand caused by
pacing tachycardia. Compared with control,
MO2 was unchanged in the 1- to
2-week pacing group when the ATP content was close to normal but was
38% higher in the hearts with severe failure (3- to 4-week pacing
group) when the ATP content was lower than for control. These data are
consistent with those of others.19 20 21
Importantly, these results indicate that the increase in
MO2 was not sufficient to
prevent purine loss.
Does Loss of Creatine Preserve the Purine Pool?
The critical step in evaluating whether the loss of purine
is due primarily to failure of the ATP-synthesizing pathways to meet
demand or to inhibition of de novo purine synthesis (or both) is
assessment of whether cytosolic ADP and AMP levels are higher. It is
important to point out that tissue ADP content obtained from HPLC
measures the sum of the small cytosolic pool of ADP (20 to 100
µmol/L) and the large pool of ADP released from proteins such as
actin (0.5 to 1 mmol/L). Thus, increases in cytosolic ADP content
cannot be (and were not) detected against this large background of
protein-bound ADP. Changes in cytosolic ADP content are best estimated
from the CK equilibrium expression.
It is clear from the CK equilibrium expression that cytosolic [ADP]
would increase if the [PCr]/[ATP] fell and the total creatine pool
remained unchanged. Free [ADP] would nearly double in the two heart
failure groups if the total Cr content remained at the normal level
(Table 3). Under these conditions, the pathway for ATP
degradation would be stimulated, and purine would be lost from the
cells. This is the typical scenario that accounts for loss of purines
in ischemia and hypoxia.22 But, as
reported here, a different metabolic pattern occurs in this
model of heart failure. The Cr pool is not preserved but rather is
progressively depleted in the failing heart at a rate 7 times faster
than for purines. As a result, the ratio of PCr to Cr is nearly
normal.
Maintaining a normal PCr/Cr ratio has two important correlates. The
first is that [ADP] is maintained close to normal levels (Table 3). As a consequence, the loss of the purine pool would be
minimized. It is important to emphasize that the loss of purine
observed in the present study would be even greater if the Cr pool
were not decreased.
The second correlate is that ATP/ADP is maintained at near normal
levels, despite decreased [ATP] (Table 3). Because ATP/ADP is
the critical ratio driving all of the ATPase reactions in the cell, the
preservation of ATP/ADP suggests that the loss of Cr may be adaptive.
Although the loss of Cr reduces the capacity of the CK reaction for ATP
resynthesis,15 the analysis presented here
shows that the loss of Cr also minimizes the reduction of the purine
pool, maintaining a nearly normal ATP/ADP. Although supporting high
workload is important, maintaining nearly normal PCr/Cr and ATP/ADP
ratios is more important, indeed essential, for cell survival.
The results of this analysis are consistent with the
following model of energetics in the failing heart: (1) loss of Cr
plays a quantitatively important role minimizing the loss of purine
pool and maintaining a normal ATP/ADP ratio; (2) the increase in
MO2 partially compensates for
the increased energy demand, but the increase is not sufficient to
salvage ADP levels; and (3) de novo purine synthesis is likely to be
inhibited in the failing heart and could account for the loss of purine
in the failing heart.
Conclusions
There is a progressive decrease in ATP and the total purine pool
in the failing heart. Thus, despite increased
MO2, the pathways for ATP
synthesis fail to meet the metabolic demands of the failing
heart, raising the possibility that de novo purine synthesis is
inhibited. Loss of creatine is also progressive and occurred at a rate
7 times faster than loss of ATP. Thus, even at the time when ATP
content has not yet fallen substantially from control levels, there is
a decrease in the Cr pool. These results suggest that loss of Cr could
be a sensitive and early marker of cardiac dysfunction associated with
heart failure. We suggest that the primary consequence of the loss of
Cr may be a compensatory mechanism minimizing the reduction of the
adenine nucleotide pool in the failing heart.
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Acknowledgments |
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This study was supported by US Public Health Service grants HL-59139, HL-37404, HL-33107 (to Dr Vatner), HL-49574 (subcontract), HL-52350 (to Dr Ingwall), and NRSA HL-09669 (to Dr Shen). We acknowledge Rong Tian and Kurt W. Saupe for helpful discussions and Ilana Reis, Thomas Patrick, Song-Jung Kim, and Raymond K. Kudej for technical support.
Received February 23, 1999; revision received June 21, 1999; accepted June 24, 1999.
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 J. H. Traverse, Y. Chen, M. Hou, Y. Li, and R. J. Bache Effect of K+ATP Channel and Adenosine Receptor Blockade During Rest and Exercise in Congestive Heart Failure Circ. Res., June 8, 2007; 100(11): 1643 - 1649. [Abstract] [Full Text] [PDF]
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R. M. Gill, J. C. Braz, N. Jin, G. J. Etgen, and W. Shen Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2782 - H2790. [Abstract] [Full Text] [PDF]
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Q. Hu, X. Wang, J. Lee, A. Mansoor, J. Liu, L. Zeng, C. Swingen, G. Zhang, J. Feygin, K. Ochiai, et al. Profound bioenergetic abnormalities in peri-infarct myocardial regions Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H648 - H657. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, I. Poornima, P. Parikh, M. Magovern, Y.-T. Shen, and R. P. Shannon The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1871 - 1881. [Abstract] [Full Text] [PDF]
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 N. Paolocci, B. Tavazzi, R. Biondi, Y. A. Gluzband, A. M. Amorini, C. G. Tocchetti, M. Hejazi, P. M. Caturegli, J. Kajstura, G. Lazzarino, et al. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 506 - 513. [Abstract] [Full Text] [PDF]
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Y.-M. Cha, P. P. Dzeja, M. M. Redfield, W. K. Shen, and A. Terzic Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1686 - H1692. [Abstract] [Full Text] [PDF]
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A. V. Naumova, V. P. Chacko, R. Ouwerkerk, L. Stull, E. Marban, and R. G. Weiss Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H837 - H843. [Abstract] [Full Text] [PDF]
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 J. Wallis, C. A. Lygate, A. Fischer, M. ten Hove, J. E. Schneider, L. Sebag-Montefiore, D. Dawson, K. Hulbert, W. Zhang, M. H. Zhang, et al. Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure: Insights From Creatine Transporter-Overexpressing Transgenic Mice Circulation, November 15, 2005; 112(20): 3131 - 3139. [Abstract] [Full Text] [PDF]
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 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
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W. Shen, R. M. Gill, J.-P. Zhang, B. D. Jones, A. K. Corbly, and M. I. Steinberg Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1508 - H1514. [Abstract] [Full Text] [PDF]
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 R. G. Weiss, G. Gerstenblith, and P. A. Bottomley ATP flux through creatine kinase in the normal, stressed, and failing human heart PNAS, January 18, 2005; 102(3): 808 - 813. [Abstract] [Full Text] [PDF]
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Y. Chen, M. Hou, Y. Li, J. H. Traverse, P. Zhang, D. Salvemini, T. Fukai, and R. J. Bache Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H133 - H141. [Abstract] [Full Text] [PDF]
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 L. Nascimben, J. S. Ingwall, B. H. Lorell, I. Pinz, V. Schultz, K. Tornheim, and R. Tian Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart Hypertension, November 1, 2004; 44(5): 662 - 667. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, D. Elahi, T. Hentosz, A. Doverspike, R. Huerbin, L. Zourelias, C. Stolarski, Y.-t. Shen, and R. P. Shannon Recombinant Glucagon-Like Peptide-1 Increases Myocardial Glucose Uptake and Improves Left Ventricular Performance in Conscious Dogs With Pacing-Induced Dilated Cardiomyopathy Circulation, August 24, 2004; 110(8): 955 - 961. [Abstract] [Full Text] [PDF]
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J. S. Ingwall and R. G. Weiss Is the Failing Heart Energy Starved?: On Using Chemical Energy to Support Cardiac Function Circ. Res., July 23, 2004; 95(2): 135 - 145. [Abstract] [Full Text] [PDF]
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A. V. Gourine, Q. Hu, P. R. Sander, A. I. Kuzmin, N. Hanafy, S. A. Davydova, D. V. Zaretsky, and J. Zhang Interstitial purine metabolites in hearts with LV remodeling Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H677 - H684. [Abstract] [Full Text] [PDF]
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M. van Bilsen, P. J.H Smeets, A. J Gilde, and G. J van der Vusse Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res, February 1, 2004; 61(2): 218 - 226. [Abstract] [Full Text] [PDF]
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J. G. Crilley, E. A. Boehm, E. Blair, B. Rajagopalan, A. M. Blamire, P. Styles, W. J. McKenna, I. Ostman-Smith, K. Clarke, and H. Watkins Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1776 - 1782. [Abstract] [Full Text] [PDF]
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Y.-M. Cha, P. P. Dzeja, W. K. Shen, A. Jahangir, C. Y. T. Hart, A. Terzic, and M. M. Redfield Failing atrial myocardium: energetic deficits accompany structural remodeling and electrical instability Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1313 - H1320. [Abstract] [Full Text] [PDF]
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W. Shen, R. M. Gill, B. D. Jones, J.-P. Zhang, A. K. Corbly, and M. I. Steinberg Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 673 - 680. [Abstract] [Full Text] [PDF]
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 P.A. Poole-Wilson Who are the enemies? Lack of oxygen Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G15 - G19. [Abstract] [PDF]
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M. Beer, T. Seyfarth, J.o. Sandstede, W. Landschutz, C. Lipke, H. Kostler, M. von Kienlin, K. Harre, D. Hahn, and S. Neubauer Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with 31P-SLOOP magnetic resonance spectroscopy J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1267 - 1274. [Abstract] [Full Text] [PDF]
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 J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl Control of Coronary Blood Flow during Exercise Experimental Biology and Medicine, April 1, 2002; 227(4): 238 - 250. [Abstract] [Full Text] [PDF]
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L. Dai, P. S. Brookes, V. M. Darley-Usmar, and P. G. Anderson Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO{middle dot} Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2261 - H2269. [Abstract] [Full Text] [PDF]
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M. Horn, H. Remkes, H. Stromer, C. Dienesch, and S. Neubauer Chronic Phosphocreatine Depletion by the Creatine Analogue {beta}-Guanidinopropionate Is Associated With Increased Mortality and Loss of ATP in Rats After Myocardial Infarction Circulation, October 9, 2001; 104(15): 1844 - 1849. [Abstract] [Full Text] [PDF]
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J. Liu, C. Wang, Y. Murakami, G. Gong, Y. Ishibashi, C. Prody, K. Ochiai, R. J. Bache, C. Godinot, and J. Zhang Mitochondrial ATPase and high-energy phosphates in failing hearts Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1319 - H1326. [Abstract] [Full Text] [PDF]
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Y. Ye, C. Wang, J. Zhang, Y. K. Cho, G. Gong, Y. Murakami, and R. J. Bache Myocardial creatine kinase kinetics and isoform expression in hearts with severe LV hypertrophy Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H376 - H386. [Abstract] [Full Text] [PDF]
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 P. A. Bottomley and R. G. Weiss Noninvasive Localized MR Quantification of Creatine Kinase Metabolites in Normal and Infarcted Canine Myocardium Radiology, May 1, 2001; 219(2): 411 - 418. [Abstract] [Full Text]
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Y. Ye, G. Gong, K. Ochiai, J. Liu, and J. Zhang High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts : A New Porcine Model Circulation, March 20, 2001; 103(11): 1570 - 1576. [Abstract] [Full Text] [PDF]
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J. G. Crilley, E. A. Boehm, B. Rajagopalan, A. M. Blamire, P. Styles, F. Muntoni, D. Hilton-Jones, and K. Clarke Magnetic resonance spectroscopy evidence of abnormal cardiac energetics in Xp21 muscular dystrophy J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1953 - 1958. [Abstract] [Full Text] [PDF]
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 D. Pucar, E. Janssen, P. P. Dzeja, N. Juranic, S. Macura, B. Wieringa, and A. Terzic Compromised Energetics in the Adenylate Kinase AK1 Gene Knockout Heart under Metabolic Stress J. Biol. Chem., December 22, 2000; 275(52): 41424 - 41429. [Abstract] [Full Text] [PDF]
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D. Pucar, P. P. Dzeja, P. Bast, N. Juranic, S. Macura, and A. Terzic Cellular Energetics in the Preconditioned State. PROTECTIVE ROLE FOR PHOSPHOTRANSFER REACTIONS CAPTURED BY 18O-ASSISTED 31P NMR J. Biol. Chem., November 21, 2001; 276(48): 44812 - 44819. [Abstract] [Full Text] [PDF]
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