CLINICAL STUDY
Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with 31P-SLOOP magnetic resonance spectroscopy
Meinrad Beer, MD*,*,
Tobias Seyfarth, MD*,
J.örn Sandstede, MD*,
Wilfried Landschütz, PhD ,
Claudia Lipke, MD*,
Herbert Köstler, PhD*,
Markus von Kienlin, PhD,
Kerstin Harre, MD ,
Dietbert Hahn, MD* and
Stefan Neubauer, MD
* Institut für Röntgendiagnostik, Würzburg, Germany
Physikalisches Institut V Am Hubland, Würzburg, Germany
Medizinische Klinik, Würzburg University, Würzburg, Germany
Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom
Manuscript received December 12, 2001;
revised manuscript received May 23, 2002,
accepted June 27, 2002.
* Reprint requests and correspondence: Dr. Meinrad Beer, Institut für Röntgendiagnostik, Universität Würzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany.
meinrad.beer{at}mail.uni-wuerzburg.de
 |
Abstract
|
|---|
OBJECTIVES: The purpose of the present study was to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in normal, hypertrophied, and failing human heart.
BACKGROUND: Conflicting evidence exists on the extent of changes of high-energy phosphate metabolites in hypertrophied and failing human heart. Previous reports using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) have quantified metabolites in relative terms only. However, this analysis cannot detect simultaneous reductions.
METHODS: Four groups of subjects (n = 10 each), were studied: volunteers and patients with hypertensive heart disease (HHD), aortic stenosis, and dilated cardiomyopathy (DCM). Left ventricular (LV) function and mass were measured by cine magnetic resonance imaging. Absolute and relative concentrations of PCr and ATP were determined by 31P-MRS with spatial localization with optimum pointspread function.
RESULTS: Left ventricular ejection fraction remained normal in HHD and aortic stenosis, but was severely reduced to 18% in DCM; LV mass was increased by 55%, 79%, and 68% respectively. In volunteers, PCr and ATP concentrations were 8.82 ± 1.30 mmol/kg wet weight and 5.69 ± 1.02 mmol/kg wet weight, and the PCr/ATP ratio was 1.59 ± 0.33. High-energy phosphate levels were unaltered in HHD. In aortic stenosis, PCr was decreased by 28%, whereas ATP remained constant. In DCM, PCr was reduced by 51%, ATP by 35%, and reduction of the PCr/ATP ratio by 25% was of borderline significance (p = 0.06). Significant correlations were observed among energetic and functional variables, with the closest relations for PCr.
CONCLUSIONS: In human heart failure due to DCM, both PCr and ATP are significantly reduced. Ratios of PCr to ATP underestimate changes of high-energy phosphate levels.
|
Abbreviations and Acronyms
| | ATP | | adenosine triphosphate | | AVD | | aortic valve disease | | DCM | | dilated cardiomyopathy | | EDV | | end-diastolic volume | | EF | | ejection fraction | | ESV | | end-systolic volume | | HHD | | hypertensive heart disease | | LV | | left ventricle/ventricular | | MRI | | magnetic resonance imaging | | NYHA | | New York Heart Association | | PCr | | phosphocreatine | | 31P-MRS | | phosphorus-31 magnetic resonance spectroscopy | | SLOOP | | spatial localization with optimum pointspread function |
|
In normal myocardium, the concentrations of the high-energy phosphate compounds adenosine triphosphate (ATP) and phosphocreatine (PCr) are tightly controlled over a range of performance, because ATP production by mitochondrial oxidative phosphorylation is closely coupled to ATP utilization by cytosolic adenosine triphosphatases (1). Adenosine triphosphate is the direct energy source for energy-consuming reactions in the cell, while PCr acts as an energy storage compound, and, in addition, as an energy transport molecule in the "creatine kinase-PCr energy shuttle" (2). A number of experimental studies have demonstrated that high-energy phosphate metabolism is deranged in hypertrophied and failing myocardium (see [3,4] for a review). Previous clinical studies using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to measure PCr/ATP ratios in human myocardium (5–16) have shown that this ratio is reduced in hypertrophied (16) and, even more so, in failing human myocardium (7,9,11). However, the PCr/ATP ratio is only an indirect measure of myocardial energetics, because two mechanisms can independently lead to its reduction (see [4] for review): 1) imbalance of myocardial oxygen supply and demand (i.e., ischemia) (17), and 2) reduction of the total creatine pool, a phenomenon known to occur in heart failure (18,19). Furthermore, simultaneous decreases of both PCr and ATP remain undetected when PCr/ATP ratios are used to estimate the energetic state of the injured heart.
More recently, measurement of absolute concentrations of high-energy phosphate metabolites in human heart has become feasible (20,21). We have previously reported on a new method for absolute quantification of myocardial high-energy phosphate concentrations, 31P-MRS with spatial localization with optimum pointspread function (SLOOP) (22). This method is based on a three-dimensional model that takes into account anatomic compartments determined from segmentation of 1H magnetic resonance images, B1 field maps, flip angles, and concentration calibrations.
In the present report, we employed the new tool of 31P-SLOOP MRS to measure absolute concentrations of myocardial high-energy phosphate metabolites in normal, hypertrophied, and failing myocardium. Our hypothesis was that absolute concentrations of ATP and PCr are reduced in hypertrophied and failing human myocardium and that, therefore, PCr/ATP ratios underestimate the true extent of energetic imbalance. Preliminary accounts of this work have appeared (23,24).
|
Methods
|
|---|
Volunteers.
The control group consisted of 10 age-matched, healthy volunteers (6 male, 4 female, age range 31 to 83 years, mean 59.2 ± 14.9 years) with no history of heart disease and normal cardiac function as measured by magnetic resonance imaging (MRI). Another group of 4 healthy volunteers (3 female, mean age 27.8 ± 4.3 years) had a repeated examination by MRS to determine intrasubject variability of the MRS measurement method (SLOOP).
Patients
Three evenly sized groups of patients were studied. There were no significant differences for height and weight among the patient groups. Ten patients had hypertensive heart disease (HHD) (7 male, 3 female, age range 39 to 73 years, mean 60 ± 11 years). Inclusion criteria were a history of hypertension for more than two years and a significant (more than two standard deviations above the mean value of the volunteer group) increase of left ventricular (LV) mass, as determined by MRI. Left ventricular ejection fraction (EF) was normal, and none of the patients complained of shortness of breath (New York Heart Association [NYHA] functional class 0). Ten patients had aortic valve stenosis (6 male, 4 female, age range 43 to 82 years, mean 67.6 ± 10.9 years). Inclusion criteria were severe aortic stenosis (aortic valve area <0.70 cm2) and planned surgical valve replacement. Left ventricular EF in all patients was >40%. Of 10 patients, 3 had mild (grade I) aortic regurgitation. Seven patients were in NYHA functional class II and three patients in NYHA functional class III. Ten patients had dilated cardiomyopathy (DCM) (6 male, 4 female, age range 32 to 68 years, mean 55.3 ± 11.2 years). Inclusion criterion was reduction of LV EF <40%, as determined by cine MRI. One patient was in NYHA functional class II, and nine patients were in NYHA functional class III. Ischemic heart disease was ruled out in all groups by cardiac catheterization.
None of the patients had a pacemaker, a history of metal fragments, implants, or vascular clips, severe arrhythmias, unstable angina pectoris, or claustrophobia. Written, informed consent was obtained from all patients and volunteers after the nature of the examination was fully explained, and the study was approved by the local ethics committee.
MRI
Magnetic resonance imaging was performed on a 1.5-T scanner (Magnetom VISION, Siemens, Erlangen, Germany). Subjects were studied in supine position using a phased-array body coil. Short- and long-axis cine MRI was performed using an electrocardiogram-triggered cine gradient echo two-dimensional sequence. Slice thickness was 8 mm, interslice gap 2 mm, using a breathhold technique in end-expiratory position with a repetition time of 100 ms, an echo delay time of 4.8 ms, and a flip angle of 30°. For functional analysis, all short-axis slices from the base to the apex were analyzed using Argus software, version VB31B (Siemens, Erlangen, Germany) as previously described (25,26). The following parameters were determined: LV end-diastolic volume (EDV) (in ml), LV end-systolic volume (ESV) (in ml), LV EF (in %), and LV mass (in g).
31P-MRS
The 31P-MRS measurements were performed on the same 1.5-T scanner using the SLOOP technique as recently described (22). Briefly, patients were positioned in prone position on a commercially available, double resonant 31P/1H-surface coil to reduce breathing artifacts. For absolute quantification, an external reference containing 20 ml 3.4 M phenyl phosphonic acid was placed below the coil. Anatomic information was obtained acquiring short-axis 1H-images with a two-dimensional gradient echo sequence technique (field of view 400 x 400 mm2, 30 contiguous slices, slice thickness 8 mm). After an automatic phase-sensitive map-shim, a phosphorus-31 three-dimensional chemical shift imaging sequence was started (double-oblique orientation, field of view 400 x 400 x 320 mm3, 16 x 16 x 8 phase encoding steps). To increase the signal-to-noise ratio, nuclear Overhauser enhancement was employed (27). Total examination time ranged from 45 to 60 min, depending on the heart rate. A Sun Sparc Station 20 (Sun Microsystems, Grasbrunn, Germany) was used for postprocessing as previously described (22). The short-axis images were manually segmented. Briefly, the SLOOP program was run to reconstruct local spectra, taking into account the B1-field strength, the flip angle, and standard T1 values (28). The resonance amplitudes in the local spectra were fitted using the advanced method for accurate, robust, and efficient spectral fitting (29). The amplitude of the resonance of gamma ATP was taken as the value for ATP. In addition, nuclear Overhauser enhancement effects were considered as previously described (23). Owing to the optimal adaptation of voxel shape to anatomic regions, no blood correction was necessary. The localization criterion of the compartment "LV myocardium" was calculated for contamination from blood or chest wall for every examination as described (22).
Statistics
All data are presented as mean ± SD. For statistical analysis, analysis of variance was used to test for differences among all groups of subjects. Where analysis of variance indicated significant group differences, Scheffé F test was then used to test for differences between individual groups, and a p value of <0.05 was considered statistically significant.
|
Results
|
|---|
Myocardial function and mass.
Left ventricular volumes and mass of volunteers and patients are summarized in Table 1. In volunteers, measurements were in agreement with previously published values (25,26,30). Left ventricular EDV and ESV were unchanged in patients with HHD and aortic valve disease (AVD) but were significantly elevated in DCM (3.3-fold for EDV and 8.8-fold for ESV compared with volunteers). This clearly demonstrates that substantial LV dilation occurred in DCM but not in the other groups of patients. For all groups, stroke volume and cardiac output, studied under resting conditions, were normal, attesting to the fact that all patients were compensated at rest. Left ventricular EF (69 ± 6% in volunteers) was normal in patients with HHD and tended to be reduced in AVD. In DCM, a substantial reduction of EF was found (18 ± 6%), attesting to severe LV dysfunction. Left ventricular mass was significantly increased in all patient groups (by 55%, 79%, and 68% for HHD, AVD, and DCM, respectively), demonstrating the presence of LV concentric (HHD, AVD, unchanged LV volumes) and eccentric (DCM, increased LV volumes) hypertrophy.
Cardiac high-energy phosphate metabolism
Representative 31P-SLOOP MRS spectra are shown in Figure 1. The line width of PCr peaks was comparable in all four groups (data not shown). Figure 2 demonstrates individual and mean values for absolute concentrations of PCr and ATP as well as for PCr/ATP ratios. In volunteers, the PCr concentration was 8.8 ± 1.3 mmol/kg heart weight, ATP was 5.7 ± 1.0 mmol/kg, and PCr/ATP ratios were 1.59 ± 0.33. Intrasubject variability was 4.8% and 7.0% for PCr and ATP, respectively. In patients with HHD, PCr and ATP concentrations as well as PCr/ATP ratios remained at normal levels. In patients with aortic stenosis, PCr concentrations (by 28%; 6.3 ± 1.5 mmol/kg; p < 0.05 vs. volunteers) were significantly reduced, whereas PCr/ATP ratios (1.30 ± 0.20) and ATP concentrations (4.9 ± 0.9 mmol/kg) showed a trend for a reduction (by 19% and 14%, respectively). In patients with DCM, a highly significant reduction of PCr concentrations (by 51%; 4.3 ± 1.2; p < 0.005 vs. volunteers) was recorded. Furthermore, myocardial ATP concentrations were also found to be significantly reduced, on average by 35% (3.7 ± 0.5 mmol/kg; p < 0.017 vs. volunteers). On the other hand, the observed decrease of the PCr/ATP ratio (by 25%) was of borderline statistical significance (p = 0.06 vs. volunteers).
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1 31P-spatial localization with optimum pointspread function spectra obtained from left ventricular myocardium. (a) Healthy volunteer; (b) hypertensive heart disease; (c) aortic valve disease; (d) dilated cardiomyopathy. Concentrations for phosphocreatine (PCr) and adenosintriphosphate (ATP) and PCr/ATP ratios were as follows: (a) 9.4, 5.7, 1.65; (b) 9.5, 6.0, 1.58; (c) 5.9, 4.5, 1.31; (d) 2.8, 2.6, 1.08.
|
|
View larger version (13K):
[in this window]
[in a new window]
|
Figure 2 Absolute and relative concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in volunteers (VOL) and in patients with hypertensive heart disease (HHD), aortic valve disease (AVD), and dilated cardiomyopathy (DCM). Individual as well as mean ± SD values are shown for each group. Analysis of variance results were as follows: PCr: VOL vs. HHD p = 0.85, VOL vs. AVD p = 0.01*, VOL vs. DCM p < 0.000001*; HHD vs. AVD p = 0.04*, HHD vs. DCM p < 0.00001*, AVD vs. DCM p < 0.03*. ATP: VOL vs. HHD p = 0.96, VOL vs. AVD p = 0.29, VOL vs. DCM p < 0.0003*; HHD vs. AVD p = 0.58, HHD vs. DCM p < 0.002*, AVD vs. DCM p = 0.052. PCr/ATP ratio: VOL vs. HHD p = 0.99, VOL vs. AVD p = 0.26, VOL vs. DCM p = 0.06, HHD vs. AVD p = 0.39, HHD vs. DCM p = 0.11, AVD vs. DCM p = 0.89.
|
|
Correlations among cardiac function, clinical status, and energetics
Figure 3 shows correlations among functional and energetic variables. Left ventricular EF correlated significantly with PCr, ATP, and PCr/ATP ratios, but the closest relationship was found for PCr and the weakest for PCr/ATP ratios. The same pattern was observed for the correlation of EDV and ESV (PCr: r = –0.69, p < 0.0001; ATP: r = –0.56, p < 0.001; PCr/ATP: r = –0.43, p < 0.01) with the three energetic parameters. The correlations of LV mass and energetic parameters were generally weaker than those of energetics and volumes/EF, with PCr concentrations showing the highest (r = –0.46, p < 0.01), PCr/ATP intermediate (r = –0.37, p < 0.017), and ATP the lowest, in fact nonsignificant, correlation (r = 0.31, p = 0.053). Thus, absolute concentrations showed closer correlations with indices of cardiac dysfunction and dilation than PCr/ATP ratios. Furthermore, LV mass was not a strong predictor of changes in absolute or relative levels of cardiac high-energy phosphates.
View larger version (24K):
[in this window]
[in a new window]
|
Figure 3 Correlations among functional and metabolic variables in volunteers (VOL) and in patients with hypertensive heart disease (HHD), aortic valve disease (AVD), and dilated cardiomyopathy (DCM). Correlations are shown for phosphocreatine (PCr) concentration and adenosintriphosphate (ATP) concentration, and PCr/ATP ratios with ejection fraction (EF) (left column) and end-diastolic volume (EDV) (right column). Diamonds = VOL; squares = HHD; triangles = AVD; circles = DCM.
|
|
For subjects in NYHA functional classes 0 (volunteers and hypertension), II, and III, PCr levels were 8.38 ± 1.54, 6.78 ± 1.11 (p < 0.05 NYHA II vs. III), and 4.23 ± 1.01 (p < 0.05 NYHA II or III vs. NYHA 0), respectively; ATP levels were 5.63 ± 1.04, 5.03 ± 0.81 (p < 0.05 NYHA II vs. III), and 3.58 ± 0.64 (p < 0.05 NYHA III vs. NYHA 0), respectively; and PCr/ATP ratios were 1.57± 0.34, 1.36 ± 0.22, and 1.21 ± 0.30 (p < 0.05 NYHA III vs. NYHA 0), respectively. Thus, energetic variables also correlated with the clinical status.
|
Discussion
|
|---|
In the present report, we demonstrate that absolute myocardial concentrations of PCr are reduced in patients with aortic stenosis and that absolute concentrations of both PCr and ATP are decreased in DCM. Furthermore, both PCr and ATP concentrations correlated significantly with LV volumes, EF, and clinical status.
Volunteers.
In volunteers, cardiac volumes and masses were all within the range reported previously for larger groups of normal subjects (25,26). Using SLOOP, we determined the PCr concentration as 8.8 ± 1.3 mmol/kg heart weight and ATP as 5.7 ± 1.0 mmol/kg. Previous MRS studies of volunteers reported PCr values ranging between 7.9 and 13.5 mmol/kg heart weight and ATP values ranging from 4.8 to 8.2 mmol/kg (20–22,31,32). The measurements reported for intrastudy variability using SLOOP here are based on a small volunteer group. Nevertheless, the values reported compare favorably with the only previous report on intrasubject variability using quantitative MRS methods (31) (4% to 7% vs. 18% to 25% for PCr and ATP). The lower variability of PCr values compared with ATP is most likely due to the increased signal-to-noise ratio of PCr amplitudes.
HHD
In the patients with long-standing hypertension, substantial LV hypertrophy was present, as attested to by a 55% increase in myocardial mass, but LV EF and volumes were normal. Previously, Okada et al. (31) reported on eight patients with HHD and, in agreement with our findings, found that PCr/ATP ratios as well as absolute levels of PCr and ATP remained unchanged. On the other hand, Lamb et al. (16) found PCr/ATP ratios in hypertensive patients to be reduced by 14% and 18% both at rest and during exercise, respectively. Whether in human HHD, PCr concentrations remain at normal levels or are slightly reduced, our data indicate that, in human myocardium, significant LV hypertrophy is not always associated with reduced PCr content.
Aortic stenosis
In patients with aortic stenosis, substantial LV hypertrophy was present with a 79% increase in myocardial mass, whereas LV volumes and EF were still unchanged. Phosphocreatine levels were reduced by 28%; ATP levels (–14%) only showed a trend for a reduction. Absolute levels of high-energy phosphates in aortic stenosis have previously been examined using only invasive myocardial biopsy measurements. Here, significant changes of high-energy phosphates as well as of total creatine content have been reported (33–35). In the present study, PCr/ATP ratios (–19%) showed a trend for reduction, which did not reach statistical significance. Previous studies demonstrated reductions of PCr/ATP ratios in patients with AVD. However, patients with more severe, decompensated stages were included in these studies (11,14,36). Using quantitative MRS techniques, analysis of absolute PCr levels allows one to detect significant changes of energy metabolism even when LV function is still preserved. It is intriguing, and the reasons remain unclear, why, for a similar extent of myocardial hypertrophy, energetic changes do (aortic stenosis) or do not (HHD) occur in human myocardium, resulting in a poor correlation of LV mass and cardiac energetics. The mechanisms behind these differential responses of human cardiac energetics to different types of myocardial hypertrophy clearly necessitate further study.
Heart failure/DCM
In patients with DCM, severe systolic dysfunction was attested to by a decrease of LV EF to 18 ± 6%, and several-fold increases of LV ESV and EDV, while a 68% increase of LV mass indicated eccentric LV hypertrophy. Previous MRS studies of absolute concentrations in human heart failure are unavailable, but a number of reports have examined high-energy phosphates in biopsies taken from patients with DCM. Nascimben et al. (18) found total creatine levels to be reduced by 51% in agreement with the reduction of PCr levels by 51% in our own observations. Reductions of ATP levels by 39% (35% in our study) have been observed (37). Only one previous study (38) found no change of ATP levels in failing human myocardium, but in that study absolute ATP levels were low for both volunteers and patients. Moreover, Bashore et al. (39) found significant linear correlations between ATP levels and indices of systolic and diastolic function. Experimental studies (40), analyzing changes of high-energy phosphate metabolism during development of heart failure, observed progressive reductions of both ATP (by up to 20%) and total creatine content (by up to 41%). Thus, our data allow us to make two important observations: 1) in severe heart failure due to DCM, absolute ATP concentrations are significantly reduced; and 2) because simultaneous reductions of both ATP and PCr occur, the PCr/ATP ratio, measured by "conventional" MRS, significantly underestimates true changes of PCr concentrations in heart failure, in our study by 26%.
Study limitations
Spatial localization with optimum pointspread function determines high-energy phosphate concentrations in relation to myocardial mass. The biochemically relevant denominator would be total cardiomyocyte volume. Intuitively, it is unlikely, that the observed magnitude of changes of PCr and ATP concentrations in heart failure is due to decreases in cardiomyocyte volume, but unfortunately, current literature data are unavailable on quantification of total cardiomyocyte volume fraction in human cardiac hypertrophy and failure. Previous experimental studies using other MRS methodologies have shown agreement of in vivo MRS and in vitro biopsy measurements. For the SLOOP method, such experimental validation is still outstanding. Importantly, however, the determined values for volunteers are in close agreement with published biopsy measurements (4,22).
Also, one should be aware that thinner myocardial walls may lead to systematically different partial volume effects, in particular in patients with DCM compared with normal volunteers. As SLOOP determines the localization criterion, the maximum contamination by other compartments can be analyzed. When we performed this analysis, no significant differences for contamination by chest wall muscle or chamber blood were found between volunteers and the three patients groups (data not shown). Otherwise the particular phase cancellation properties of the SLOOP reconstruction may slightly alleviate but certainly not circumvent this difficulty. This question cannot be fully assessed until a substantially higher spatial resolution is achievable, for instance at higher magnetic fields.
Although measurement of absolute concentrations of high-energy phosphate metabolites is a significant step forward, for a complete causal analysis, we must be able to measure ATP turnover rates and calculate free ADP concentrations and the free energy change of ATP hydrolysis (delta G) (4,41,42). Therefore, simultaneous measurement of myocardial total creatine content is required. This may be achievable by a combination of 31P-MRS and 1H-MRS. Such measurements will be the focus of our (43) and other groups’ (e.g., 44) future work, and should finally answer the question of the true functional role of myocardial high-energy phosphate metabolism in human heart failure.
|
Footnotes
|
|---|
Supported by a grant from the Interdisziplinäres Zentrum für Klinische Forschung, Universität Würzburg, part F2 (01 KS 9603) and by the British Heart Foundation.
|
References
|
|---|
1. Balaban RS, Kantor HL, Katz LA, Briggs RW. Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science. 1986;232:1121–1123[Abstract/Free Full Text]
2. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the "PCr circuit" for cellular energy homeostasis. Biophys J. 1992;281:21–40
3. Ingwall JS. Is cardiac failure a consequence of decreased energy reserve? Circulation. 1993;87(Suppl 7):58–62
4. Neubauer S. High-energy phosphate metabolism in normal, hypertrophied and failing human myocardium. Heart Failure Rev. 1999;4:269–280[CrossRef]
5. Bottomley PA. Noninvasive study of high-energy phosphate metabolism in human heart by depth-resolved 31P NMR spectroscopy. Science. 1985;229:769–772[Abstract/Free Full Text]
6. Bottomley PA, Weiss RG, Hardy CJ, Baumgartner WA. Myocardial high-energy phosphate metabolism and allograft rejection in patients with heart transplants. Radiology. 1991;181:67–75[Abstract/Free Full Text]
7. Hardy C, Weiss RG, Bottomley PA, Gerstenblith G. Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J. 1991;122:795–801[CrossRef][Medline]
8. De Roos A, Doornbos J, Luyten PR, Oosterwaal LJMP, van der Wall EE, den Hollander JA. Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy. J MRI. 1992;2:711–719
9. Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Circulation. 1992;86:1810–1818[Abstract/Free Full Text]
10. Schaefer S, Schwartz GG, Steinman SK, Meyerhoff DJ, Massie BM, Weiner MW. Metabolic response of the human heart to inotropic stimulation: in vivo phosphorous-31 studies of normal and cardiomyopathic myocardium. Magn Reson Med. 1992;25:260–271[Medline]
11. Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low PCr to ATP ratio in failing hypertrophied myocardium by 31P magnetic resonance spectroscopy. Lancet. 1991;338:973–976[CrossRef][Medline]
12. Yabe T, Mitsunami K, Okada M, Morikawa S, Inubushi T, Kinoshita M. Detection of myocardial ischemia by 31P magnetic resonance spectroscopy during handgrip exercise. Circulation. 1994;89:1709–1716[Abstract/Free Full Text]
13. Neubauer S, Horn M, Pabst T, et al. Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur Heart J. 1985;16:115–118
14. Neubauer S, Horn M, Pabst T. Cardiac high-energy phosphate metabolism in patients with aortic valve disease assessed by 31P-Magnetic Resonance Spectroscopy. J Invest Med. 1997;45:453–462[Medline]
15. Conway MA, Bottomley PA, Ouwerkerk R, Radda GK, Rajagopalan B. Mitral regurgitation: impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans. Circulation. 1998;97:1716–1723[Abstract/Free Full Text]
16. Lamb HJ, Beyerbracht HP, van der Laarse A, et al. Diastolic function in hypertensive heart disease is associated with altered myocardial metabolism. Circulation. 1999;99:2261–2267[Abstract/Free Full Text]
17. Neubauer S, Horn M, Naumann A, et al. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest. 1995;95:1092–1100[Medline]
18. Nascimben L, Ingwall JS, Pauletto P, et al. The creatine kinase system in failing and nonfailing human myocardium. Circulation. 1996;94:1894–1901[Abstract/Free Full Text]
19. Neubauer S, Remkes H, Spindler M, et al. Downregulation of the Na+-Creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation. 1999;100:1847–1850[Abstract/Free Full Text]
20. Bottomley PA, Hardy CJ, Roemer PB. Phosphate metabolite imaging and concentration measurements in human heart by nuclear magnetic resonance. Magn Reson Med. 1990;14:425–434[Medline]
21. Bottomley PA, Atalar E, Weiss RG. Human cardiac high-energy phosphate metabolite concentrations by 1D-resolved NMR spectroscopy. Magn Reson Med. 1996;35:664–670[Medline]
22. Meininger M, Landschütz W, Beer M, et al. Concentrations of human cardiac phosphorus metabolites determined by SLOOP 31P NMR spectroscopy. Magn Reson Med. 1999;39:679–685
23. Beer M, Landschütz W, Meininger M, et al. Determination of absolute concentrations of cardiac high-energy phosphates using 31P-MR-spectroscopy and SLOOP in healthy and diseased myocardium. Rofo Fortschr Geb Roentgenstr Neuen Bildgeb Verfahr. 1999;171:65–68[Medline]
24. Neubauer S, Beer M, Landschütz W, et al. Absolute quantification of high energy phosphate metabolites in normal, hypertrophied and failing human myocardium. MAGMA. 2000;11:73–74[Medline]
25. Sandstede JJW, Lipke C, Kenn W, Beer M, Pabst T, Hahn D. Cine MR imaging after myocardial infarction: assessment and follow-up of regional and global left ventricular function. Int J Cardiac Imaging. 1999;15:435–440[CrossRef][Medline]
26. Sandstede JJW, Lipke C, Beer M, et al. Analysis of first-pass and delayed contrast-enhancement patterns of dysfunctional myocardium on MR imaging: use in the prediction of myocardial viability. Am J Roentgenol. 2000;174:1737–1740[Abstract/Free Full Text]
27. Bottomley PA, Hardy CJ. Proton Overhauser enhancements in human cardiac phosphorus NMR spectroscopy at 1.5 T. Magn Reson Med. 1992;24:384–390[Medline]
28. Bottomley PA, Ouwerkerk R. Optimum flip angles for exciting NMR with uncertain T1 values. Magn Reson Med. 1994;32:137–141[Medline]
29. Vanhamme L, van den Boogaart A, van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson. 1997;129:35–43[CrossRef][Medline]
30. Lorenz CH, Walker ES, Morgan VL, Klein SS, Graham TP Jr. Normal human right and left ventricular mass systolic function and gender differences by cine magnetic resonance imaging. J Card Magn Reson. 1999;1:7–21
31. Okada M, Mitsunami K, Inubushi T, Kinoshita M. Influence of aging or left ventricular hypertrophy on the human heart: contents of phosphorous metabolites measured by 31P-MRS. Magn Reson Med. 1998;39:772–782[Medline]
32. Yabe T, Mitsunami K, Inubushi T, Kinoshita M. Quantitative measurements of cardiac phosphorus metabolites in coronary artery disease by 31P magnetic resonance spectroscopy. Circulation. 1995;92:15–23[Abstract/Free Full Text]
33. Swain JL, Sabina RL, Peyton RB, Jones RN, Wechsler AS, Holmes EW. Derangements in myocardial purine and pyrimidine nucleotide metabolism in patients with coronary artery disease and left ventricular hypertrophy. Proc Natl Acad Sci U S A. 1982;79:655–659[Abstract/Free Full Text]
34. Peyton RB, Jones RN, Attarian D, et al. Depressed high-energy phosphate content in hypertrophied ventricles of animal and man. Ann Surg. 1982;196:278–284[Medline]
35. Ingwall JS, Kramer MF, Fifer MA, et al. The creatine kinase system in normal and diseased myocardium. N Engl J Med. 1985;313:1050–1054[Abstract]
36. Beer M, Viehrig M, Sandstede J, et al. Analysis of cardiac energy metabolism in valve disease using 31P-MR-spectroscopy. Radiologe. 2000;40:162–167[CrossRef][Medline]
37. Starling RC, Hammer DF, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem. 1998;180:171–177[CrossRef][Medline]
38. Regitz V, Fleck E. Myocardial adenine nucleotide concentrations and myocardial norepinephrine content in patients with heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol. 1992;69:1574–1580[CrossRef][Medline]
39. Bashore TM, Magorien DJ, Letterio J, Shaffer P, Unverferth DV. Histologic and biochemical correlates of left ventricular chamber dynamics in man. J Am Coll Cardiol. 1987;9:734–742[Abstract]
40. Shen W, Asai K, Uechi M, et al. 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. Circulation. 1999;100:2113–2118[Abstract/Free Full Text]
41. Blamire AM, Rajagopalan B, Radda GK. Measurement of myocardial pH by saturation transfer in man. Magn Reson Med. 1999;41:198–203[CrossRef][Medline]
42. Bottomley PA, Hardy CJ. Mapping creatine kinase reaction rates in human brain and heart with 4 tesla saturation transfer 31P NMR. J Magn Reson. 1992;99:443–448
43. Schneider J, Fekete E, Weisser A, Neubauer S, Haase A, von Kienlin M. Reduced 1H-NMR visibility of creatine in isolated rat hearts. Magn Reson Med. 2000;43:497–502[CrossRef][Medline]
44. Bottomley PA, Weiss RG. Non-invasive magnetic-resonance detection of creatine depletion in non-viable infarcted myocardium. Lancet. 1998;351:714–718[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
A. Gupta, V. P. Chacko, and R. G. Weiss
Abnormal energetics and ATP depletion in pressure-overload mouse hearts: in vivo high-energy phosphate concentration measures by noninvasive magnetic resonance
Am J Physiol Heart Circ Physiol,
July 1, 2009;
297(1):
H59 - H64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Bottomley, K. C. Wu, G. Gerstenblith, S. P. Schulman, A. Steinberg, and R. G. Weiss
Reduced Myocardial Creatine Kinase Flux in Human Myocardial Infarction: An In Vivo Phosphorus Magnetic Resonance Spectroscopy Study
Circulation,
April 14, 2009;
119(14):
1918 - 1924.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F Franceschi, J-C Deharo, R Giorgi, Y By, C Monserrat, J Condo, Z Ibrahim, A Saadjian, and R Guieu
Peripheral plasma adenosine release in patients with chronic heart failure
Heart,
April 1, 2009;
95(8):
651 - 655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. E. Hudsmith and S. Neubauer
Magnetic resonance spectroscopy in myocardial disease.
J. Am. Coll. Cardiol. Img.,
January 1, 2009;
2(1):
87 - 96.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Beer, D. Wagner, J. Myers, J. Sandstede, H. Kostler, D. Hahn, S. Neubauer, and P. Dubach
Effects of Exercise Training on Myocardial Energy Metabolism and Ventricular Function Assessed by Quantitative Phosphorus-31 Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging in Dilated Cardiomyopathy
J. Am. Coll. Cardiol.,
May 13, 2008;
51(19):
1883 - 1891.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Eisen
Exercise Training and Myocardial Energetics in Patients With Heart Failure: When More Is Less
J. Am. Coll. Cardiol.,
May 13, 2008;
51(19):
1892 - 1895.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Pinz, S. E. Ostroy, K. Hoyer, H. Osinska, J. Robbins, J. D. Molkentin, and J. S. Ingwall
Calcineurin-induced energy wasting in a transgenic mouse model of heart failure
Am J Physiol Heart Circ Physiol,
March 1, 2008;
294(3):
H1459 - H1466.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C. Sparagna, A. J. Chicco, R. C. Murphy, M. R. Bristow, C. A. Johnson, M. L. Rees, M. L. Maxey, S. A. McCune, and R. L. Moore
Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure
J. Lipid Res.,
July 1, 2007;
48(7):
1559 - 1570.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Neubauer
The Failing Heart -- An Engine Out of Fuel
N. Engl. J. Med.,
March 15, 2007;
356(11):
1140 - 1151.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Y. Maslov, V. P. Chacko, M. Stuber, A. L. Moens, D. A. Kass, H. C. Champion, and R. G. Weiss
Altered high-energy phosphate metabolism predicts contractile dysfunction and subsequent ventricular remodeling in pressure-overload hypertrophy mice
Am J Physiol Heart Circ Physiol,
January 1, 2007;
292(1):
H387 - H391.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Horowitz and J. A. Kennedy
Time to Address the Cardiac Metabolic "Triple Whammy": Ischemic Heart Failure in Diabetic Patients
J. Am. Coll. Cardiol.,
December 5, 2006;
48(11):
2232 - 2234.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Smith, P. A. Bottomley, S. P. Schulman, G. Gerstenblith, and R. G. Weiss
Altered Creatine Kinase Adenosine Triphosphate Kinetics in Failing Hypertrophied Human Myocardium
Circulation,
September 12, 2006;
114(11):
1151 - 1158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
G. Perseghin, P. Fiorina, F. De Cobelli, P. Scifo, A. Esposito, T. Canu, M. Danna, C. Gremizzi, A. Secchi, L. Luzi, et al.
Cross-Sectional Assessment of the Effect of Kidney and Kidney-Pancreas Transplantation on Resting Left Ventricular Energy Metabolism in Type 1 Diabetic-Uremic Patients: A Phosphorous-31 Magnetic Resonance Spectroscopy Study
J. Am. Coll. Cardiol.,
September 20, 2005;
46(6):
1085 - 1092.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
R. Ventura-Clapier, A. Garnier, and V. Veksler
Energy metabolism in heart failure
J. Physiol.,
February 15, 2004;
555(1):
1 - 13.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez
Cardiomyocyte apoptosis in hypertensive cardiomyopathy
Cardiovasc Res,
September 1, 2003;
59(3):
549 - 562.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods