AJP - Heart Add DOIs to your references at manuscript stage!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 292: H387-H391, 2007. First published September 8, 2006; doi:10.1152/ajpheart.00737.2006
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
292/1/H387    most recent
00737.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maslov, M. Y.
Right arrow Articles by Weiss, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maslov, M. Y.
Right arrow Articles by Weiss, R. G.

Altered high-energy phosphate metabolism predicts contractile dysfunction and subsequent ventricular remodeling in pressure-overload hypertrophy mice

M. Y. Maslov,1,2 V. P. Chacko,2 M. Stuber,2 A. L. Moens,1 D. A. Kass,1 H. C. Champion,1 and R. G. Weiss1,2

1Department of Medicine, Cardiology Division, and 2Department of Radiology, Division of Magnetic Resonance Research, The Johns Hopkins Hospital, Baltimore, Maryland

Submitted 10 July 2006 ; accepted in final form 3 September 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
To study the role of early energetic abnormalities in the subsequent development of heart failure, we performed serial in vivo combined magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) studies in mice that underwent pressure-overload following transverse aorta constriction (TAC). After 3 wk of TAC, a significant increase in left ventricular (LV) mass (74 ± 4 vs. 140 ± 26 mg, control vs. TAC, respectively; P < 0.000005), size [end-diastolic volume (EDV): 48 ± 3 vs. 61 ± 8 µl; P < 0.005], and contractile dysfunction [ejection fraction (EF): 62 ± 4 vs. 38 ± 10%; P < 0.000005] was observed, as well as depressed cardiac energetics (PCr/ATP: 2.0 ± 0.1 vs. 1.3 ± 0.4, P < 0.0005) measured by combined MRI/MRS. After an additional 3 wk, LV mass (140 ± 26 vs. 167 ± 36 mg; P < 0.01) and cavity size (EDV: 61 ± 8 vs. 76 ± 8 µl; P < 0.001) increased further, but there was no additional decline in PCr/ATP or EF. Cardiac PCr/ATP correlated inversely with end-systolic volume and directly with EF at 6 wk but not at 3 wk, suggesting a role of sustained energetic abnormalities in evolving chamber dysfunction and remodeling. Indeed, reduced cardiac PCr/ATP observed at 3 wk strongly correlated with changes in EDV that developed over the ensuing 3 wk. These data suggest that abnormal energetics due to pressure overload predict subsequent LV remodeling and dysfunction.

high-energy phosphates; magnetic resonance imaging; magnetic resonance spectroscopy

CHRONIC PRESSURE OVERLOAD initiates a process that often results in left ventricular hypertrophy (LVH). Although LVH in the setting of pressure overload is felt to be an initially adaptive process, it can be followed by progressive ventricular dilatation, contractile dysfunction, and, ultimately, heart failure and increased cardiovascular mortality (11, 18). The magnitude of the pressure overload as well as many genetic and phenotypic factors, including neuroendocrine, intracellular signaling cascades, extracellular changes, and mechanical remodeling, all have been shown to contribute to the progression to failure in hypertrophic hearts (10, 20). Increased energy demand underlies many of these contributing factors, and thus an imbalance in metabolic energy supply and demand has been postulated as a central and potentially important factor contributing to heart failure development in LVH (15).

Myocardial energetic demands are met primarily through mitochondrial ATP production via oxidative phosphorylation, following the omnivorous metabolism of carbon substrates including fatty acids, glucose, lactate, and ketone bodies (24). The creatine kinase (CK) reaction serves as the prime cardiac energy reservoir, quickly and reversibly converting adenosine diphosphate and phosphocreatine (PCr) to ATP and creatine (16, 33). The temporal ATP buffering of CK helps meet cyclic energetic demands during cardiac contraction and especially following abruptly increased workloads. The CK reaction also may act as a spatial ATP buffer assisting in the delivery of high-energy phosphate from the mitochondria to the ATP utilization sites, which include myosin ATPase, sarcoplasmic reticular Ca-ATPase, and the Na/K exchanger.

31P magnetic resonance spectroscopy (MRS) is the only noninvasive technique capable of nondestructively measuring the CK metabolites PCr and ATP. The ratio PCr/ATP is one indicator of the energetic state of the myocardium that can be measured by 31P MRS, and this ratio is reduced in animal models of myocardial hypertrophy (21, 36) and in human LVH (9, 17, 26), as well as in chronic heart failure (CHF) (13, 25). Reduced PCr/ATP has been observed in pressure-overload LVH hearts from many species, including rats, dogs, and pigs (31, 36, 37). In mice, thoracic aortic constriction results in pressure-overload hypertrophy with subsequent dilatation and, ultimately, a high mortality (30). Work in our laboratory recently validated noninvasive MRS/MRI techniques that enable the noninvasive quantification of CK metabolites and myocardial anatomy and function in mice (8, 23).

We hypothesized that if reduced CK energy reserve contributes to the contractile dysfunction and ventricular dilatation that occurs as the compensated LVH heart progresses to heart failure, then the energetic abnormalities should occur before or at the same time as functional abnormalities and remodeling, and not after them. Although in vivo open-chest MRS studies have been performed in several LVH animal models, to our knowledge there have been no repeated studies in any species of serial CK energetics in the same animal and therefore none during the progression of pressure-overload LVH to LV dilatation and systolic dysfunction. We combined this new animal model with these noninvasive MRS/MRI techniques to test the hypotheses that a failing CK system contributes to the transition of pressure-overload LVH to CHF in mice and that a reduced PCr/ATP at an early stage predicts the subsequent remodeling process.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental animals. The studies were performed on adult male C57BL6/ mice (weight 20–28 g) as approved by the Institutional Animal Care and Use Committee.

Animal surgery. Pressure-overload nonischemic CHF was created in 12 mice by permanent thoracic aorta constriction (TAC) (29). Briefly, the aorta was approached via a minimal parasternal incision, and a partial ligature was placed around the transverse aorta. Nine animals that did not undergo surgery served as controls.

MRI/MRS study. In vivo MRI/MRS studies were carried out 3 and 6 wk after TAC surgery, as previously described (8, 23). Specifically, mice were positioned on a Plexiglas platform with temperature control (37 ± 1°C). ECG leads, respiratory pad, and thermo couple (SA Instruments) were used to monitor basic vital parameters. Anesthesia was induced by ~1% isoflurane in an air-oxygen mix and was adjusted during the experiment to keep the heart rate ~550–600 beats/min and the respiratory rate 100–120 breaths/min. Global LV function and energetics were studied during the same examination with 1H MRI and image-guided, spatially localized 31P MRS as previously reported (8, 23). The probe set included 22-mm 1H MRI and 11-mm 1P MRS coils. Experiments were carried out on a Bruker Biospec NMR/MRI spectrometer equipped with a 4.7-T/40-cm Oxford magnet and a 12-cm (inner diameter) actively shielded BGA-12 gradient set capable of developing gradient strength of up to 400 mT/m. LV function was quantified from multislice FLASH cine MRI (15 frames, TE = 1.8 ms, TR = 7 ms, flip angle = 30°) by using ECG and respiratory gating. Spatially localized 31P MRS was carried out using a one-dimensional chemical shift imaging sequence, with a 32-mm field of view and 32 phase encoding steps in the direction perpendicular to the plane of the coil, 64 averages per phase encoding step, a modified BIR4 adiabatic excitation pulse of 60° flip angle, and an interpulse delay of 1 s. All mice awoke within ~1 min after the study was over.

1H MR images were analyzed with ImageJ software and 31P MR spectra with in-house custom software (3). The largest and smallest LV volumes were visually identified as end-diastolic (EDV) and end-systolic volumes (ESV). LV mass was the sum of all end-diastolic cross-sectional slices of the LV epicardial and endocardial difference multiplied by 1.05 (cardiac tissue-specific gravity). The LV ejection fraction (EF) was calculated from the relative difference in EDV and ESV. The cardiac PCr/ATP ratio was quantified from the integrated peak areas of PCr and [beta-31P]ATP resonances from voxels intersecting the anterior LV wall and apart from chest skeletal muscle, as identified with 1H MR images as previously described (8, 23). Voxel shifting was performed when necessary to avoid chest muscle contamination (7).

Statistical analysis. Data are expressed as means ± SD. Two-tailed, two-sample unequal variance t-tests were used for comparison of control and TAC animals, and paired t-tests were used for comparison of 3-wk TAC and 6-wk TAC animals. Differences were considered statistically significant at P < 0.05. The correlations between PCr/ATP3 wk and the changes in EDV ({Delta}EDV = EDV6 wk – EDV3 wk), PCr/ATP and EF, and PCr/ATP and ESV at 3 and 6 wk were analyzed with linear regression.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
A representative typical short-axis 1H MR image of a mouse heart and the corresponding cardiac 31P MR spectrum are shown in Fig. 1. Summary LV functional and high-energy phosphate data from normal hearts are shown in Table 1 and agree with published values (8, 23).


Figure 1
View larger version (35K):
[in this window]
[in a new window]

  		Fig. 1. Left: typical transverse short-axis 1H magnetic resonance (MR) image of a mouse thorax through the mid-left ventricular (LV) slice of the heart at end diastole. Right: 31P spectrum from the anterior cardiac slice is shown with the prominent peaks of creatine phosphate (PCr) and beta-phosphate of ATP ([beta-P]ATP).

 

View this table:
[in this window]
[in a new window]

  		Table 1. Morphology, function, and energetics in control and TAC mice

 
Three weeks following TAC, LV hypertrophy and dilatation developed as shown by an increase in mean LV mass (74 ± 4 vs. 140 ± 26 mg, control vs. 3-wk TAC, respectively; P < 0.000005; Table 1) and EDV (48 ± 3 vs. 61 ± 8 µl; P < 0.005). Reduced EF (62 ± 4 vs. 38 ± 10%, control vs. 3-wk TAC, respectively; P < 0.000005) and stroke volume (SV: 30 ± 1 vs. 23 ± 6 µl) with increased ESV (18 ± 1 vs. 37 ± 10 µl; P < 0.00003) exemplified the LV contractile dysfunction (Table 1). LVH and systolic abnormalities at 3 wk were accompanied by a 35% fall in the cardiac PCr/ATP ratio compared with that of normal animals (P < 0.0005; Table 1).

After an additional 3 wk (i.e., total 6 wk after TAC), LV mass increased further (140 ± 26 vs. 167 ± 36 mg, 3 wk vs. 6 wk, respectively; P < 0.01). Despite additional increases in EDV and ESV (61 ± 8 vs. 76 ± 8 µl and 37 ± 10 vs. 45 ± 9 µl, respectively; P < 0.001), EF remained at the 3-wk level as SV increased (Table 1). There was no further fall in the cardiac PCr/ATP ratio. Figures 2 and 3 display the relationship between PCr/ATP ratio and EF and ESV, respectively, at the 3- and 6-wk time points. The relations were minimal after 3 wk of TAC but became stronger at 6 wk (EF: r = 0.37 vs. 0.75, 3 wk vs. 6 wk, respectively, Fig. 2; ESV: r = –0.03 vs. –0.77, Fig. 3). Although cardiac PCr/ATP at 3 wk did not correlate with subsequent changes in EF, depressed LV energetics measured at 3 wk after TAC predicted the level of subsequent LV dilatation that evolved between the third and sixth week after TAC (r = –0.79) (Fig. 4).


Figure 2
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 2. Relationship between cardiac PCr/ATP as determined by 31P magnetic resonance spectroscopy (MRS) and ejection fraction (EF) at 3 wk [A; EF = –0.9.14(PCr/ATP) + 26.73, r2 = 0.142, r = 0.37] and 6 wk [B; EF = 29.75(PCr/ATP) +0.43, r2 = 0.56, r = 0.75] after transverse aorta constriction (TAC). The relationship evolves and becomes significant at 6 wk.

 

Figure 3
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 3. Relationship between cardiac PCr/ATP as determined by 31P MRS and end-systolic volume (ESV) at 3 wk [A; ESV = –0.76(PCr/ATP) + 38.78, r2 = 0.0009, r = –0.03] and 6 wk [B; ESV = –34.43(PCr/ATP) +92.08, r2 = 0.59, r = –0.77] after TAC. The correlation is significant at 6 wk.

 

Figure 4
View larger version (5K):
[in this window]
[in a new window]

  		Fig. 4. Relationship between PCr/ATP at 3 wk (PCr/ATP3 wk) and the change in LV end-diastolic volume ({Delta}EDV) from 3 to 6 wk [{Delta}EDV = –20.35(PCr/ATP3 wk) + 41.82, r2 = 0.61, r = –0.79]. Reduced cardiac PCr/ATP at 3 wk predicts subsequent remodeling as indexed by the change in EDV.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
There are five major findings in this report. These are the first cardiac MRS studies performed in serial fashion with repeated measures in the same animal as a pathological process evolves. Second, this mouse model of pressure-overload hypertrophy mimics the contractile and energetic abnormalities (reduced PCr/ATP) of human pressure-overload hypertrophy. Third, abnormalities in cardiac energy metabolism occur early in pressure-overload LVH. Fourth, the contemporaneous relationship between altered energetics and contractile function and ventricular geometry is not constant but, in fact, changes over time in pressure-overload LVH and is strongest late in the remodeling process. Fifth, early energetic changes predict the extent of subsequent LV remodeling, consistent with the hypothesis that altered energy metabolism contributes to heart failure progression.

The pathology of LVH has been extensively studied for decades, and abnormalities in CK energy metabolism, as indicated by the cardiac PCr/ATP, were previously reported in larger animal models of chronic pressure-overload and human LVH (1, 4, 17, 31, 37). Although abnormal energetics was consistently found across species, it was not clear whether altered energetics occurred before or as a consequence of LV contractile dysfunction and dilatation.

This serial use of in vivo MRS in the same animals allowed the exploration of changes in energetics, contractile dysfunction, and LV anatomy over time as LVH evolves. These observations not only show that this murine model of pressure-overload LVH mimics the anatomic and energetic changes observed in human LVH (14, 17), but they also provide important insights into the causes and consequences of LVH pathophysiology. Abnormalities in energetics were observed early in the remodeling process. There was no further fall in PCr/ATP from 3 to 6 wk, but the correlation with EF and ESV strengthened over time. This demonstrates that the relationship between cardiac PCr/ATP and contractile function is not constant within a given animal and suggests that impaired energetics may play a role in the transition of LVH to heart failure. This observation also may be important for interpreting apparent inconsistencies in published human cardiac energetic data. Although low PCr/ATP is a consistent finding in human heart failure, some studies have reported a correlation between PCr/ATP and contractile measures (4, 12), whereas other studies have not (13, 25). Although differences among patient groups may explain the differences, these data indicate that the relationship between energetics and function is dynamic during disease evolution and suggest the possibility that differences in disease duration among patient groups may explain, in part, the variability in the relationship between energetics and function.

How could impaired energy metabolism contribute to the progression to heart failure in hypertrophic hearts? LVH is thought to be an adaptive change following chronic pressure-overload that supports pump function according to the circulation demands of the body. Particularly, increased mechanical work causes structural and metabolic remodeling with synthesis of ATP-requiring structural proteins such as actin and myosin. Myocardial contraction and wall stress are the major ATP expenditures, and these too are increased in pressure-overload LVH. Many ion pumps are also energy dependent, such as the Na-K-ATPase and the sarcoplasmic reticulum Ca-ATPase, which may be altered in LVH.

There are several limitations to this work. It is not known whether the energetic response to stress in the mouse is identical to that of larger mammalian species, including humans. Although differences in cardiac energetics have been identified across species (19), the PCr/ATP is commonly studied as an important energetic parameter. It is encouraging that the in vivo PCr/ATP is similar in normal murine and human hearts (8, 22, 34), that the acute response to adrenergic or exercise stress is comparable in murine and larger hearts (2, 23, 27, 34), and that cardiac PCr/ATP is chronically 25–35% lower in pressure-overload LVH hearts from mice through humans (1, 4, 17, 28, 31, 37). Nevertheless, serial studies of energetics in larger animals and especially humans with LVH would be of considerable interest. Although the PCr/ATP is an important energetic parameter, it does not directly reflect ATP flux through CK. The use of in vivo 31P MRS to measure CK flux is now possible (5, 6, 28, 35) but is not yet available in mice. If developed, this capability would allow greater insight into the role of altered energetics in LVH progression in the mouse model. Measures of myocardial creatine content would also be of interest, since creatine loss may be partially responsible for lower PCr/ATP in LVH.

The novel observation that the early reduction in PCr/ATP predicts the degree of subsequent LV dilatation is consistent with the hypothesis that energetic abnormalities contribute to ventricular remodeling and the development of heart failure. This is in line with prior clinical reports that agents with beneficial effects on ventricular remodeling, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, all reduce energetic demand in failing and hypertrophic hearts (20, 32). This observation also suggests that metabolic interventions designed to improve energetics early in the disease may limit subsequent remodeling. However, the current studies do not show cause and effect. Another plausible explanation is that the early fall in PCr/ATP reflects cellular injury due to pressure overload and that subsequent remodeling results from the injury with altered energetics another consequence, and not the cause, of the remodeling. Put another way, it is possible that the sicker or more stressed animals had lower PCr/ATP and were also destined to have more remodeling. To resolve this question, future studies are needed with metabolic interventions to determine whether augmenting myocardial PCr/ATP in this setting improves myocardial function and limits the subsequent remodeling process.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-63030 and HL-61912 as well as the David E. Gibbons Grant-in-Aid Award from the Mid-Atlantic Affiliate of the American Heart Association.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. G. Weiss, Carnegie 584, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-6568 (e-mail: rweiss{at}jhmi.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bache RJ, Zhang J, Murakami Y, Zhang Y, Cho YK, Merkle H, Gong G, From AH, Ugurbil K. Myocardial oxygenation at high workstates in hearts with left ventricular hypertrophy. Cardiovasc Res 42: 616–626, 1999.[Abstract/Free Full Text]
  2. Balaban RS, Kantor HL, Katz LA, Briggs RW. Relation between work and phosphate metabolites in the in vivo paced mammalian heart. Science 232: 1121–1123, 1986.[Abstract/Free Full Text]
  3. Barker PB, Sibisi S. Non-linear least squares analysis of in vivo 31P NMR data (Abstract). Soc Magn Res Med 9: 1089, 1990.
  4. Beer M, Seyfarth T, Sandstede J, Landschutz W, Lipke C, Kostler H, von Kienlin M, Harre K, Hahn D, Neubauer S. 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 40: 1267–1274, 2002.[Abstract/Free Full Text]
  5. Bittl JA, Balschi JA, Ingwall JS. Contractile failure and high-energy phosphate turnover during hypoxia: 31P-NMR surface coil studies in living rat. Circ Res 60: 871–878, 1987.[Abstract/Free Full Text]
  6. Bittl JA, Ingwall JS. Intracellular high-energy phosphate transfer in normal and hypertrophied myocardium. Circulation 74: I-96–I-101, 1987.
  7. Bottomley PA, Hardy CJ, Roemer PB, Weiss RG. Problems and expediencies in human 31P spectroscopy: the definition of localized volumes, dealing with saturation and the technique-dependence of quantification. NMR Biomed 20: 284–289, 1989.
  8. Chacko VP, Aresta F, Chacko SM, Weiss RG. MRI/MRS assessment of in vivo murine cardiac metabolism, morphology, and function at physiological heart rates. Am J Physiol Heart Circ Physiol 279: H2218–H2224, 2000.[Abstract/Free Full Text]
  9. Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet 338: 973–976, 1991.[CrossRef][ISI][Medline]
  10. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65: 45–79, 2003.[CrossRef][ISI][Medline]
  11. Grossman W. Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med 69: 576–584, 1980.[CrossRef][ISI][Medline]
  12. Hansch A, Rzanny R, Heyne JP, Leder U, Reichenbach JR, Kaiser WA. Noninvasive measurements of cardiac high-energy phosphate metabolites in dilated cardiomyopathy by using 31P spectroscopic chemical shift imaging. Eur Radiol 15: 319–323, 2005.[CrossRef][ISI][Medline]
  13. Hardy CJ, Weiss RG, Bottomley PA, Gerstenblith G. Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 122: 795–801, 1991.[CrossRef][ISI][Medline]
  14. Heineman FW, Balaban RS. Phosphorus-31 nuclear magnetic resonance analysis of transient changes of canine myocardial metabolism in vivo. J Clin Invest 85: 843–852, 1990.[ISI][Medline]
  15. Ingwall JS. Is cardiac failure a consequence of decreased energy reserve? Circulation 87: VII-58–VII-62, 1993.
  16. Ingwall JS, Kramer MF, Fifer MA, Lorell BH, Shemin R, Grossman W, Allen PD. The creatine kinase system in normal and diseased human myocardium. N Engl J Med 313: 1050–1054, 1985.[Abstract]
  17. Lamb HJ, Beyerbacht HP, van der Laarse A, Stoel BC, Doornbos J, van der Wall EE, de Roos A. Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 99: 2261–2267, 1999.
  18. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: 1561–1566, 1990.[Abstract]
  19. Loiselle DS, Gibbs CL. Species differences in cardiac energetics. Am J Physiol Heart Circ Physiol 237: H90–H98, 1979.[Abstract/Free Full Text]
  20. Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111: 2837–2849, 2005.
  21. Massie B, Schaefer S, Garrcia J, McKirnan MD, Schwartz GG, Wisneski JA, Weiner MW, White FC. Myocardial high-energy phosphate and substrate metabolism in swine with moderate left ventricular hypertrophy. Circulation 91: 1814–1823, 1995.
  22. Menon RS, Hendrich K, Hu X, Ugurbil K. 31P NMR spectroscopy of the human heart at 4T: detection of substantially uncontaminated cardiac spectra and differentiation of subepicardium and subendocardium. Magn Reson Med 26: 368–376, 1992.[ISI][Medline]
  23. Naumova AV, Weiss RG, Chacko VP. Regulation of murine myocardial energy metabolism during adrenergic stress studied by in vivo 31P NMR spectroscopy. Am J Physiol Heart Circ Physiol 285: H1976–H1979, 2003.[Abstract/Free Full Text]
  24. Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 36: 413–459, 1974.[CrossRef][ISI]
  25. Neubauer S, Krahe T, Schindler R, Horn M, Hillenbrand H, Entzeroth C, Mader H, Kromer EP, Riegger GAJ, Lackner K, Ertl G. 31P Magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease: altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86: 1810–1818, 1992.
  26. Okada M, Mitsunami K, Yabe T, Morikawa S, Inubushi T. Influence of aging and hypertrophy on the human heart: concentrations of phosphorus metabolites measured by 31P NMR spectroscopy. Circulation 86: I-694, 1992.
  27. Schaefer S, Schwartz GG, Steinman SK, Meyerhoff DJ, Massie BM, Weiner MW. Metabolic response of the human heart to inotropic stimulation: in vivo phosphorus-31 studies of normal and cardiomyopathic myocardium. Magn Reson Med 25: 260–272, 1992.[ISI][Medline]
  28. Smith CS, Bottomley PA, Gerstenblith G, Schulman SP, Weiss RG. Altered creatine kinase ATP kinetics in failing hypertrophied human myocardium. Circulation 114: 1151–1158, 2006.
  29. Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccola M, Dostmann WR, Smith CJ, Kass DA. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 96: 100–109, 2005.[Abstract/Free Full Text]
  30. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Gabrielson K, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11: 214–222, 2005.[CrossRef][ISI][Medline]
  31. Tian R, Nascimben L, Ingwall JS, Lorell BH. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 96: 1313–1319, 1997.
  32. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 342: 1441–1446, 1993.[CrossRef][ISI][Medline]
  33. Wallimann T. Bioenergetics. Dissecting the role of creatine kinase. Curr Biol 4: 42–46, 1994.[CrossRef][ISI][Medline]
  34. Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med 323: 1593–1600, 1990.[Abstract]
  35. Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci USA 102: 808–813, 2005.[Abstract/Free Full Text]
  36. Ye Y, Gong G, Ochiai K, Liu J, Zhang J. High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation 103: 1570–1576, 2001.
  37. Zhang J, Merkle H, Hendrich K, Garwood M, From AHL, Ugurbil K, Bache RJ. Bioenergetic abnormalities associated with severe left ventricular hypertrophy. J Clin Invest 92: 993–1003, 1993.[ISI][Medline]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
M. van Bilsen, F. A. van Nieuwenhoven, and G. J. van der Vusse
Metabolic remodelling of the failing heart: beneficial or detrimental?
Cardiovasc Res, November 6, 2008; (2008) cvn282v2.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
H Watkins, H Ashrafian, and W J McKenna
The genetics of hypertrophic cardiomyopathy: Teare redux
Heart, October 1, 2008; 94(10): 1264 - 1268.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
292/1/H387    most recent
00737.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maslov, M. Y.
Right arrow Articles by Weiss, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maslov, M. Y.
Right arrow Articles by Weiss, R. G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.