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(Radiology. 2001;219:637-643.)
© RSNA, 2001

Cardiac Imaging

Aortic Valve Replacement in Patients with Aortic Valve Stenosis Improves Myocardial Metabolism and Diastolic Function1

Hugo P. Beyerbacht, MD, Hildo J. Lamb, PhD, Arnoud van der Laarse, PhD, Hubert W. Vliegen, MD, Ferre Leujes, MSc, Marc G. Hazekamp, MD, Albert de Roos, MD and Ernst E. van der Wall, MD

1 From the Departments of Cardiology (H.P.B., A.v.d.L., H.W.V., F.L., E.E.v.d.W.), Radiology (H.J.L., A.d.R.), and Thoracic Surgery (M.G.H.), Leiden University Medical Center, Albinusdreef 2, 2333 2A Leiden, the Netherlands. Received March 13, 2000; revision requested May 14; revision received November 21; accepted December 11. Supported in part by the Stimuleringsfonds of the Dutch Heart Foundation the Netherlands Organization of Scientific Research grant #902-16-144. Address correspondence to H.J.L. (e-mail: h.j.lamb@lumc.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate whether functional and metabolic changes recover after aortic valve replacement (AVR).

MATERIALS AND METHODS: Eighteen men with aortic valve stenosis (mean pressure gradient ± SD, 79.9 mm Hg ± 15.1) underwent magnetic resonance (MR) imaging and phosphorus 31 MR spectroscopy. In nine patients who underwent AVR, MR imaging and spectroscopy were repeated 40 weeks ± 12 after AVR. Ten age-matched healthy men were control subjects.

RESULTS: Before AVR, the myocardial phosphocreatine (PCr)-to–adenosine triphosphate (ATP) ratio in the 18 patients was 1.24 ± 0.17 and 1.43 ± 0.14 in the control group (P < .01). In nine patients who underwent follow-up MR spectroscopy, the ratio increased from 1.28 ± 0.17 to 1.47 ± 0.14 (P < .05) following AVR. Before AVR, early acceleration peak corrected for cardiac output was (0.043 ± 0.008) x 10-3 sec-1 in patients and (0.081 ± 0.033) x 10-3 sec-1 in the control group (P < .05). After 40 weeks ± 12, the mean early acceleration peak corrected for cardiac output in the nine patients increased significantly to (0.055 ± 0.006) x 10-3 sec-1 (P < .05), although it was still significantly lower than that of the control group (P < .05). Before AVR, a significant correlation was found between the myocardial PCr-ATP ratio and left ventricular diastolic function (n = 18; P < .05).

CONCLUSION: Severe aortic valve stenosis leads to a decreased myocardial PCr-ATP ratio and impairment of left ventricular diastolic function; following AVR, the ratio normalizes completely, whereas function improves significantly. There is an association between altered myocardial high-energy phosphate metabolism and impaired left ventricular diastolic function.

Index terms: Aortic valve, 535.4534, 535.833 • Heart, hypertrophy, 524.833 • Heart, MR, 511.121416, 511.12145 • Heart, valves, 535.4534, 535.83 • Heart, ventricles, 524.12145


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Aortic valve disease is associated with increased pressure and/or volume load of the left ventricle (LV) and causes LV hypertrophy (1). LV hypertrophy can lead to systolic and diastolic function disturbances and is a recognized risk factor for cardiac morbidity and mortality (2). Previous animal studies (3,4) have shown that LV hypertrophy can also be accompanied by alterations in myocardial high-energy phosphate (HEP) metabolism.

Magnetic resonance (MR) imaging is a highly accurate technique for the evaluation of ventricular systolic and diastolic function, as well as LV dimensions (5). MR spectroscopy is a noninvasive and reproducible method that can be used to study myocardial HEP metabolism in vivo (6). Changes in myocardial HEP metabolism are usually expressed as a change in the myocardial phosphocreatine (PCr)-to–adenosine triphosphate (ATP) ratio. A recent study (7) showed that in patients with dilated cardiomyopathy, the myocardial PCr-ATP ratio may serve as a strong predictor for cardiovascular and total mortality. So far, a few MR spectroscopic studies (1,8,9) in patients with aortic valve disease have shown that this disease may lead to changes in myocardial HEP metabolism. However, it is not known whether these metabolic changes may reverse following aortic valve replacement (AVR).

Therefore, the purpose of the present study was twofold: first, to confirm that aortic valve stenosis is associated with a decreased myocardial PCr-ATP ratio and to evaluate whether this change in myocardial HEP metabolism recovers after AVR and, second, to study whether LV diastolic dysfunction and LV geometry are related to disturbances in myocardial HEP metabolism and whether diastolic function improves following AVR.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Study Population
Eighteen male patients (mean age ± SD, 61.8 years ± 9.5) with aortic valve stenosis were examined with both MR spectroscopy and MR imaging. All patients underwent coronary angiography and showed no clinically relevant coronary artery disease (no lesions with >50% luminal stenosis). Patients had a peak-to-peak pressure gradient across the aortic valve of at least 60 mm Hg (mean, 79.9 mm Hg ± 15.1). In two patients, the aortic valve could not be passed in retrograde fashion with the catheter. In these two patients, the formula introduced by Lund et al (10) was used to calculate an estimate of peak-to-peak aortic valve pressure gradient from the peak instantaneous Doppler gradient. Aortic root angiography at most showed hemodynamically insignificant aortic regurgitation (grade 1 or 2; mean, 1.30 ± 0.67).

All patients underwent aortic valve surgery, and a subgroup of nine patients was reexamined with MR imaging and phosphorus 31 (31P) MR spectroscopy at 40 weeks ± 12 (range, 26–54 weeks) after valve replacement. A group of 10 healthy age-matched men (mean age, 60.2 years ± 3.9) served as control subjects. All members of the control group were healthy at physical examination, had a normal electrocardiogram at rest and during exercise stress testing, and had no history of cardiac disease or any other major illness. The baseline characteristics of all patients and control subjects are shown in Table 1; there were no significant differences between the groups. The protocol was approved by the human research committee of the hospital. All subjects provided informed consent prior to examination.


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  		TABLE 1. Characteristics of Control Subjects and Patients before Valve Replacement

 
MR Imaging
MR imaging was performed with a 1.5-T imager (ACS-NT15, Philips Medical Systems, Best, the Netherlands) by using prospective electrocardiographic triggering. A stack of short-axis images consisting of 10–12 sections with a thickness of 8 mm and an intersection gap of 1–2 mm (depending on heart size) was acquired by using breath-hold multishot echo-planar imaging. Images encompassed the entire LV. The imaging protocol was similar to that reported previously (11).

Phase-contrast flow-velocity measurements across the mitral valve orifice were obtained by using a gradient-echo sequence with retrospective electrocardiographic gating. Velocity maps were acquired across the mitral orifice by using a flip angle of 30° and an echo time of 10–12 msec. The image section had a thickness of 8 mm and a field of view of 350 mm and consisted of two measurements of a 128 x 128 acquisition matrix that was interpolated to a display matrix of 256 x 256 pixels. Depending on the actual heart rate, between 30 and 45 time frames were evenly distributed during the cardiac cycle, resulting in a temporal resolution of 25–30 msec. Total acquisition time was about 3 minutes. The maximum phase shift of 180° was set to occur at a velocity of 100 cm/sec.

MR Image Analysis
The MR images and velocity maps were analyzed with a remote workstation (Sparc; Sun Microsystems, Mountain View, Calif). The LV short-axis acquisitions were used to assess LV dimensions, wall mass, and systolic function. The endocardial and epicardial borders of the end-diastolic and end-systolic images from each short-axis section were manually traced by using the MR analytical software system MASS developed at our institution (12). Measurements were performed on separate occasions by two independent experienced observers (H.B.P, F.L.). Reported data represent the combined mean value from both observers. LV mass index (LVMI), cardiac output, and LV ejection fraction were calculated as described before (5).

Volumetric flow across the mitral valve was calculated by manually tracing the borders of the mitral valve in all time frames of the velocity map series by using an analytical software package (FLOW; Medis, Leiden, the Netherlands) (13). Contour tracings were drawn on two occasions by different observers. Flow curves were analyzed following a manual indication of the start of early and atrial filling, peak early and atrial filling, and the end of early and atrial filling, as reported previously (14) (Fig 1). To correct for differences in stroke volume and/or heart rate, the early wave acceleration and deceleration slopes were also normalized for cardiac output (see Discussion).



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  		Figure 1. Line graphs of mitral valve flow are shown for a healthy control subject (solid line) and a patient before (dotted line) and after (dashed line) AVR. Typical early and atrial filling waves can be determined. Note the differences in peak heights and slopes between the graphs for the control subject and the patient.

 
MR Spectroscopy
31P MR spectroscopy was performed with a 1.5-T system (S15 Gyroscan; Philips Medical Systems). A 100-mm-diameter single-tuned circular surface coil was used for transmission and detection of the radio-frequency signals. Myocardial 31P MR spectra were obtained from the anterior wall of the LV, with subjects in supine position, as described previously (6) (Fig 2). Acquisition of 31P MR spectra was triggered 200 msec after the R wave of the electrocardiographic signal, with a minimum recycle time of 3 seconds. Volumes of interest were selected with two-dimensional image-selected in vivo spectroscopy combined with one-dimensional spectroscopic imaging. Acquisition time for a single spectrum was 30 minutes. All other technical details were similar to those reported previously (6).



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  		Figure 2. Sensitive volumes positioned in an optimal orientation relative to the LV on the basis of A, transverse and B, sagittal spin-echo scout MR images. By using two-dimensional image-selected in vivo spectroscopy and one-dimensional chemical shift imaging (spectroscopic imaging), the one-dimensional phase-encoding bar, with 32 rows of 1-cm thickness each, is angulated around the caudocranial body axis perpendicular to the chest wall. In this way, chest wall muscle is excluded from the first row containing myocardial tissue, row 25. B, By adjusting the level of the volume selection in the caudocranial direction, contamination of the sensitive volumes by diaphragm muscle and liver tissue is prevented. A and B, The white square on the chest wall originates from a sample in the center of the 10-cm-diameter surface coil. C, Resulting 31P MR spectra are shown separately for each row. On the basis of strict criteria previously published (6), cardiac spectra were identified and summed to provide one 31P MR spectrum. The PCr-ATP ratio and an estimate of the noise percentage are shown on the right for each spectrum.

 
Spectral Quantification
The 31P MR spectra were transferred to a remote workstation (Sparc; Sun Microsystems) for analysis. Spectra from rows in the cardiac region were first analyzed separately (Fig 2), followed by multiplication with a weighting factor reflecting the sensitivity profile of the surface coil. Rows containing cardiac signals were then added, resulting in a single 31P MR spectrum of the anterior LV wall. Strict criteria were used to identify those spectra that were not contaminated by signal arising from extracardiac tissue, by using the same method as reported previously (6). The ATP level in the cardiac 31P MR spectra was corrected for the ATP contribution from blood present in the volume of interest (15). Spectra were also corrected for partial saturation effects (16). Mean repetition time was 3.6 seconds, resulting in a correction factor of 1.35, which was applied to all blood-corrected cardiac PCr-ATP ratios. Other technical details were similar to those reported previously (6).

Statistical Analysis
Reported data are expressed as mean values plus or minus 1 SD. When applicable, paired two-tailed Student t tests were used; otherwise, unpaired two-tailed Student t tests were used. A P value of less than .05 was considered to indicate a statistically significant difference. Pairwise correlations were determined by using linear regression analysis to determine associations between LV geometry, LV function, and myocardial PCr-ATP ratio.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Myocardial Function
Overall, aortic valve stenosis led to increased LV mass and to an impairment in diastolic heart function, whereas systolic function was not affected in patients compared with matched healthy control subjects (Table 2). The results for all 18 patients who underwent MR imaging before valve replacement were not significantly different from the results in the subgroup of nine patients who were reexamined with MR imaging 40 weeks ± 12 after AVR (Table 2).


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  		TABLE 2. LV Geometry and Function before and after AVR

 
Before valve replacement, the mean LVMI in nine patients who underwent follow-up MR imaging was 139.8 g/m2 ± 32.8 compared with 68.6 g/m2 ± 7.9 in control subjects (P < .001). After 40 weeks ± 12, the mean LVMI of the nine patients had decreased significantly to 107.0 g/m2 ± 30.7 (P < .005), which was still significantly higher than the mean LVMI in control subjects (P < .005). Before valve replacement, the early acceleration peak corrected for cardiac output was (0.043 ± 0.008) x 10-3 sec-1, compared with (0.081 ± 0.033) x 10-3 sec-1 in control subjects (P < .05). After 40 weeks ± 12, the mean early acceleration peak corrected for cardiac output of the nine patients had increased significantly to (0.055 ± 0.006) x 10-3 sec-1 (P < .05), which was still significantly lower than that in control subjects (P < .05) (Table 2).

Myocardial Metabolism
Typical 31P MR spectra obtained from a patient with aortic valve stenosis before and after valve replacement are shown in Figure 3. An overview of MR spectroscopic results of patients and control subjects is presented in Figure 4. The mean myocardial PCr-ATP ratio in the 18 patients with aortic valve stenosis who underwent MR spectroscopy before valve replacement was 1.24 ± 0.17, which was significantly lower than that in the 10 control subjects, who had a mean PCr-ATP ratio of 1.43 ± 0.14 (P = .006). In the subgroup of nine patients who underwent follow-up MR spectroscopy, the myocardial PCr-ATP ratio increased significantly from 1.28 ± 0.17 before valve replacement to 1.47 ± 0.14, measured 40 weeks ± 12 after valve replacement (P = .017); the latter was similar to the PCr-ATP in the 10 control subjects (1.43 ± 0.14, P > .05).



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  		Figure 3. 31P MR spectra acquired from the LV anterior wall in a patient with severe aortic valve stenosis before (left) and after (right) AVR. Note the increase in the myocardial PCr-ATP ratio following AVR. Three separate peaks of ATP are indicated by {alpha}, ß, and {gamma}.

 


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  		Figure 4. Graph shows the myocardial PCr-ATP ratios of all 18 patients examined with MR spectroscopy before AVR and of the nine patients who underwent follow-up MR spectroscopy 40 weeks ± 12 after AVR. Ratios of the 10 control subjects are displayed as reference. Mean values (± SD) are indicated by symbols with error bars. Note the increases in the myocardial PCr-ATP ratio after AVR in seven of nine patients.

 
Relation between LV Geometry, LV Function, and Myocardial HEP Metabolism
Correlations between LV geometric and LV functional parameters were determined for all 18 patients before valve replacement and for the 10 control subjects. To that purpose, three baseline LV geometric parameters—LVMI, LV end-diastolic volume index, and LVMI-LV end-diastolic volume index ratio—were analyzed for correlation to a number of selected baseline LV systolic and diastolic function parameters. Impaired diastolic filling was associated with increasing LV wall mass, reflected by a significant correlation between LVMI and early wave acceleration peak (r = -0.52, P = .005, y = -860.51x + 165.8) and early deceleration peak (r = 0.56, P = .002, y = 1557.8x + 160.5). Both were corrected for cardiac output. In addition, concentric LV hypertrophy was associated with impaired diastolic filling, illustrated by significant correlations found between the LVMI-LV end-diastolic volume index ratio and early wave acceleration peak (r = -0.63, P < .001, y = -4.1752x + 11.306) and early deceleration peak (r = 0.61, P < .001, y = 2.174x - 5.6605).

For all 18 patients before valve replacement and the 10 control patients, myocardial HEP metabolism data were analyzed for correlation to a number of selected parameters describing LV geometry and function. The myocardial PCr-ATP ratio was modestly correlated (r = 0.37, P = .05, y = 0.033x - 0.0105) to the early wave mean acceleration corrected for cardiac output, and the myocardial PCr-ATP ratio was negatively correlated to the early deceleration peak corrected for cardiac output (r = -0.39, P = .04, y = -0.034x + 0.0147). There was no significant correlation between the PCr-ATP ratio and LVMI (r = -0.33, P = .09, y = -79.875x + 219).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The present study was designed to assess myocardial HEP metabolism, LV geometry, and LV function in patients with severe aortic valve stenosis, both before and 40 weeks ± 12 (range, 26–54 weeks) following AVR. Our main finding was that impaired myocardial HEP metabolism in patients with aortic valve stenosis recovers completely following valve replacement. We also found a statistically significant correlation between myocardial HEP metabolism and LV diastolic function.

Diastolic Function
Impaired diastolic function in aortic valve stenosis is an important independent risk factor for early and late mortality after AVR (17). In the present study, all patients with aortic valve stenosis demonstrated impaired diastolic filling due to increased LV diastolic pressure, increased chamber stiffness, and/or LV chamber dilatation (18–24). In addition, increased LV wall stress also impairs diastolic function (25). Following AVR, the LV geometry and diastolic properties improved significantly, illustrated by a decrease in LVMI, and an increase of the early wave acceleration slope corrected for cardiac output. From previous studies (26,27), it is known that diastolic function deteriorates early after surgery for aortic valve stenosis, due to a relative increase of interstitial fibrosis but may recover completely late after AVR due to regression of both muscular and nonmuscular tissue. Complete normalization of diastolic function may take up to 10 years, since the regression of interstitial fibrosis is a slow process (26,27).

An interesting result with regard to the assessment of diastolic function was the inability of the early-to-atrial peak ratio to discriminate between patients with aortic valve stenosis and control subjects, whereas other diastolic function parameters were significantly different between patients and control subjects (Table 2). Probably, the early-to-atrial peak ratio is affected by many factors, such as heart rate, stroke volume, and age (22,23) that limit its usefulness as discriminative parameter of diastolic function.

Myocardial Metabolism
The present spectroscopic results obtained before AVR are in close agreement with previous findings in other studies (1,8,9) that also showed a reduced myocardial PCr-ATP ratio in patients with aortic valve disease. However, to our knowledge, the effect of AVR on myocardial HEP metabolism has not yet been described. Noninvasive insight into myocardial HEP metabolism may become a valuable tool for the assessment of aortic valve disease. In patients with dilated cardiomyopathy, the myocardial PCr-ATP ratio has been useful in the prediction of cardiovascular mortality (7).

A reduced myocardial PCr-ATP ratio may be an indicator of myocardial ischemia, as was shown by Weiss et al (28) in patients with severe stenosis (>70%) of either the left anterior descending coronary artery or left main coronary artery. In that study, myocardial ischemia was induced by means of hand-grip exercise, resulting in a decrease in the myocardial PCr-ATP ratio, which reflected a transient imbalance between oxygen supply and demand during stress in the myocardium with compromised blood flow.

Although all patients in the present study were without relevant coronary artery disease, low myocardial PCr-ATP values determined at rest before AVR can still result from myocardial ischemia. The underlying mechanism may be that, even at rest, decreased coronary flow reserve and abnormal coronary blood flow velocity profiles also lead to an unbalanced myocardial oxygen supply and demand in the hypertrophied heart. The latter was previously observed (25,29) in patients with aortic valve stenosis who had angina pectoris or syncope and normal coronary arteries. In addition, in a study by Wood (30), patients with aortic valve stenosis and normal coronary arteries showed histologic changes suggestive of ischemia. The observed decrease in coronary flow reserve and abnormal coronary blood flow velocity profiles have been found to correlate with increased LV peak systolic pressure and with an increase in LV wall mass that is not sufficient to compensate for increased LV wall stress (25,29). Relief of LV wall stress by means of AVR immediately leads to normalization of the diastolic coronary flow velocity profile (25,29).

The recovery of the myocardial PCr-ATP ratio after AVR may indicate that the metabolic demand of the myocardium is reduced and that the coronary blood flow improved after relief of the pressure overload (25). Therefore, a low myocardial PCr-ATP ratio may be indicative of severe LV wall stress experienced by the LV myocardium caused by chronic pressure overload, which is comparable to results from a previous study (31) in patients with hypertensive heart disease. Consequently, the myocardial PCr-ATP ratio may be interpreted as a new indicator of myocardial stress and ischemia. Detection of (silent) myocardial ischemia at rest in patients with aortic valve stenosis at 31P MR spectroscopy is clinically important, since the prognosis and survival of patients with aortic valve stenosis with angina pectoris and syncope is severely impaired, compared with those of patients with aortic valve stenosis without myocardial ischemia (32).

Relation between Function and Metabolism
LV filling determined before AVR showed an association with myocardial HEP metabolism. These results agree well with the hypothesis previously postulated by Osbakken et al (3) that changes in myocardial creatine kinase kinetics may contribute to diastolic dysfunction and with previous observations in the hypertensive heart (31). The exact nature of the relation between myocardial HEP metabolism and diastolic heart function is not yet clear. One hypothesis is that the lower PCr content leads to lower levels of ATP at the sarcomeres in hypertrophied hearts, which is not compensated for by increased mitochondrial ATP production (33). Lower cytosolic ATP levels lead to impaired Ca2+ sequestration by the sarcoplasmic reticulum and impaired relaxation in cardiomyocytes and may be responsible for diastolic dysfunction in hypertensive myocardium at the cellular level (34–36). A second hypothesis, described in a report of an elegant animal study by Spindler et al (37), is that ADP could have accumulated at the sarcomeres, leading to slowed myosin cross-bridge cycling (38).

Another important observation in the present study was the absence of a significant correlation between myocardial PCr-ATP ratio and LVMI. An increase in LVMI should be considered a necessary adaptation of the heart to increased wall stress. As long as the heart is sufficiently able to reduce wall stress, LV hypertrophy by itself may have no negative consequences for cardiac HEP metabolism. As mentioned before, angina pectoris is particularly common in patients with aortic valve stenosis with an insufficient increment of LV wall mass relative to increased LV wall stress, which suggests that appropriate LV hypertrophy may even be beneficial (25).

In a recent study by Pluim et al (14), a normal myocardial PCr-ATP ratio was found in a group of male elite cyclists with increased LVMI, also indicating that increased LV mass is not a prerequisite for changes in myocardial HEP metabolism. Accordingly, in patients with hypertension and increased LV mass, myocardial PCr-ATP ratio and LVMI did not show a significant correlation (31). As a result, the myocardial PCr-ATP ratio may serve as a marker for the metabolic condition of the myocardium, whereas a reduced PCr-ATP ratio may be indicative of an unbalanced oxygen supply and demand (7–9,15,28,31, 39,40). However, prospective studies of patients with aortic valve stenosis are needed to answer the question of whether a subnormal myocardial PCr-ATP ratio is an independent risk factor for morbidity and/or mortality.

Limitations
In the present study, a limited number of subjects were examined, especially at follow-up, mainly because of the long examination time needed for the combined MR imaging and 31P MR spectroscopy. However, the sample size was sufficient to show statistically significant differences between the healthy control group and patients and to show significant correlations between myocardial function and metabolism. In addition, the present results show a statistically significant influence of aortic valve stenosis on LV geometry, LV function, and, especially, myocardial HEP metabolism.

Furthermore, PCr-ATP ratios reported in the present study for the normal human heart were in the lower range of previously reported (6) values, which ranged from 0.9 to 2.1. In that previous report, we extensively discussed this issue and concluded that the major difference is most likely caused by the lower saturation correction factor used in studies from our institution.

In conclusion, severe aortic valve stenosis leads to changes in myocardial HEP metabolism, as reflected by a decreased myocardial PCr-ATP ratio and to impairment of LV diastolic function. Following AVR, the myocardial PCr-ATP ratio normalizes completely, whereas LV diastolic function improves significantly. Moreover, there is an association between altered myocardial HEP metabolism and impaired LV diastolic function. Since the myocardial PCr-ATP ratio returns to normal values with relief of cardiac stress following AVR, a myocardial PCr-ATP ratio may serve as a novel indicator for myocardial stress.


   ACKNOWLEDGMENTS
 
We thank Christine Larrewyn from the Department of Thoracic Surgery, Leiden University Medical Center, for her kind assistance in the recruitment of patients.


   FOOTNOTES
 
Abbreviations: ATP = adenosine triphosphate, AVR = aortic valve replacement, HEP = high-energy phosphate, LV = left ventricle, LVMI = LV mass index, PCr = phosphocreatine

Author contributions: Guarantors of integrity of entire study, H.P.B., H.J.L., A.d.R., E.E.v.d.W.; study concepts and design, all authors; literature research, H.P.B., H.J.L.; clinical studies, H.P.B., H.J.L., E.E.v.d.W.; data acquisition, H.P.B., H.J.L.; data analysis/interpretation, all authors; statistical analysis, H.P.B., H.J.L.; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, all authors.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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