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Am J Physiol Heart Circ Physiol 294: H1888-H1895, 2008. First published February 22, 2008; doi:10.1152/ajpheart.01286.2007
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Benefits of long-term β-blockade in experimental chronic aortic regurgitation

Eric Plante, Dominic Lachance, Serge Champetier, Marie-Claude Drolet, Élise Roussel, Marie Arsenault, and Jacques Couet

Groupe de Recherche sur les Valvulopathies, Centre de Recherche Hôpital Laval, Institut de Cardiologie de Québec, Université Laval, Sainte-Foy, Quebec, Canada

Submitted 2 November 2007 ; accepted in final form 18 February 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The objective of this study was to assess the long-term effects of β-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a β-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg·kg–1·day–1) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). β-Adrenergic receptor ratio (β1/β2) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the β-adrenergic receptor ratio.

aortic valve regurgitation; volume overload; β-blockers; adrenergic system

SEVERE AORTIC REGURGITATION (AR) is associated with a long asymptomatic period, during which the left ventricle (LV) progressively dilates and hypertrophies in response to a chronic volume overload. In parallel with LV dilatation, LV function will eventually decrease, symptoms will appear, and valve replacement surgery will become inevitable. In the past decades, several investigators have reported data suggesting that medical therapy with vasodilators, such as nifedipine and hydralazine, and angiotensin-converting enzyme inhibitors may reduce the aortic regurgitant volume and help maintain LV function (3). Nifedipine, a calcium channel blocker, seemed especially promising (20). However, the results of a recently published trial by Evangelista et al. (7) failed to confirm these positive effects of nifedipine or angiotensin-converting enzyme inhibitors compared with a placebo. This ongoing controversy regarding the medical management of chronic severe AR has transpired in the latest American Heart Association/American College of Cardiology Valvular Heart Disease Treatment Guidelines, which no longer recommends vasodilators for the medical management of chronic AR in patients with normal ventricular function (4). No drug has been clearly shown to slow LV dilatation, LV hypertrophy, and loss of systolic function or to have an impact on morbidity and mortality in chronic AR.

Focusing on a different target, our group previously reported in an animal model of chronic AR that the adrenergic system is abnormally activated and that blocking this system seems to play an important role in preventing LV dilatation, LV hypertrophy, and loss of systolic function (19). The present study was primarily designed to evaluate whether these beneficial effects of β-blockade on LV function and remodeling would persist and translate into a survival benefit in rats with severe AR in the long term.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animal model of AR. In 40 male Wistar rats (300–350 g body wt; Charles River, Montreal, Qc, Canada), severe AR was induced by retrograde puncture of the aortic valve leaflets as previously described (2, 17–19), and the animals were randomly divided in two groups (n = 20/group) as follows: 1) untreated AR and 2) AR treated with metoprolol (Met, 25 mg·kg–1·day–1; Sigma, Oakville, ON, Canada) in the drinking water. Ten sham-operated (carotid artery cannulation under anesthesia without AR induction) animals were used for comparison. The dose of Met was similar to that used previously. Significant physiological β-blockade had been previously confirmed by the blunted response of heart rate (HR) to adrenergic stimulation by dobutamine infusion (19). AR was considered severe by echocardiography by the presence of all the following criteria at the time of surgery: color-Doppler ratio of regurgitant jet width to LV outflow tract diameter >50%, retrograde holo-diastolic flow in proximal descending aorta with end-diastolic velocity >18 cm/s, ratio of time-velocity integral of reversed diastolic flow to forward systolic flow in descending thoracic aorta >60%, and acute increase in LV diastolic dimension during the surgical procedure. To qualify for inclusion in the study, the animals were required to demonstrate echocardiographic criteria of AR severity along with an acute drop of aortic diastolic pressure of ≥30%. Animals not meeting the echocardiographic and hemodynamic criteria were excluded from the study. Met treatment was started 2 wk after the surgical procedure to allow for recovery and continued for 12 mo thereafter. Animals were clinically evaluated daily by experienced animal laboratory technicians for the presence of signs of heart failure (increased respiratory rate/distress and/or peripheral edema) and were weighed weekly. At the end of the protocol, surviving animals were killed, hearts were quickly dissected, and all cardiac chambers were weighed. LVs were snap frozen in liquid nitrogen and kept at –80°C for further analysis. The protocol was approved by the Université Laval Animal Protection Committee according to the recommendations of the Canadian Council on Laboratory Animal Care.

Echocardiography. A complete M-mode, two-dimensional, and Doppler echocardiogram was performed on the animals under 1.5% inhaled isoflurane anesthesia with use of a 12-MHz probe with a Sonos 5500 echocardiograph (Philips Medical Imaging, Andover, MA) immediately before and during surgery, at 2 wk, and after 6 and 12 mo. The echocardiogram at 2 wk was performed to quantify AR before initiation of drug treatment to ensure that all animals still met the entry criteria. LV dimensions, wall thickness, ejection fraction, diastolic function, and cardiac output (ejection volume in the LV outflow tract x HR) were evaluated as previously reported. AR was semiquantified at each time point as described above. Only animals that met all the criteria of severe AR by semiquantification at each time point remained in the protocol.

Hemodynamic measurements. LV pressures and dP/dt (positive and negative) were measured invasively with a dedicated catheter under 1.5% isoflurane anesthesia after 12 mo in survivors. At other times during the protocol, systolic and diastolic blood pressures were measured noninvasively using the tail-cuff method. Met was continuously available in drinking water and was not stopped before the measurements were obtained. All experiments were performed during the same period of the day (morning).

Tissue analysis: cardiomyocyte cross-sectional area and evaluation of LV fibrosis. Sections from paraffin-embedded mid-LV portions were stained using Masson's trichrome. Three subendocardial sections/slides from all surviving animals were analyzed for the evaluation of cross-sectional area (CSA) of the cardiomyocytes as previously described (2, 17–19). These sections were also used to evaluate the proportion of LV subendocardial fibrosis as the blue (fibrosis)-to-red (myocytes) ratio by a computerized image analysis system (Image-Pro Plus, version 4.5, Media Cybernetics, Silver Spring, MD). The subendocardial sections were defined as the inner third of the LV wall facing the LV cavity.

Semiquantitative analysis of mRNA accumulation by RT-PCR. Total RNA extraction from the LV, reverse transcription, and DNA amplification by PCR of collagen types I and III, fibronectin, and pro-matrix metalloproteinase-2 (pro-MMP-2) were performed as described previously (17–19).

Analysis of mRNA accumulation by quantitative RT-PCR. Tissues stored frozen in RNAlater (Ambion, Austin, TX) were homogenized in TRIzol (Invitrogen) using a Polytron according to the standard TRIzol procedure. RNA (50 ng) was converted to cDNA using the QuantiTect reverse transcription kit (Qiagen, Valencia, CA) by a procedure that includes a genomic DNA elimination step. The cDNA was further diluted 10-fold with water before amplification (with the final concentration corresponding to 0.25 ng/µl of initial RNA). Diluted cDNA (1.25 ng) was amplified in duplicate (technical duplicates) by quantitative PCR in a thermal cycler (Rotor-Gene 6200, Corbett Life Science, Sidney, Australia) using the QuantiTect SYBR Green PCR kit and QuantiTect primer assays (preoptimized specific primer pairs from Qiagen; Table 1). Each run included one tube with water only (no template control), one tube with a representative RNA sample (no RT control), and a series of 10-fold dilutions of a representative cDNA sample to confirm the efficiency of the amplification reaction.


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  		Table 1. QuantiTect primer assays used in quantitative PCR analysis of gene expression

 
The quantification of gene expression was based on the –2{Delta}{Delta}Ct method (12). Briefly, mean cycle threshold (Ct) values of technical duplicates for each gene of interest were subtracted from the mean Ct value (hence, {Delta}Ct) of the control "housekeeping" gene β2-microgrobulin. The differences in the mean {Delta}Ct values between groups of rats ({Delta}{Delta}Ct) allow the calculation of relative levels of induction/repression of genes of interest.

Statistical analysis. Survival was analyzed by standard Kaplan-Meier analysis with log-rank test. Other results are presented as means ± SE unless specified otherwise. Intergroup comparisons were done using unpaired t-tests and intragroup comparisons with paired t-tests. Statistical significance was set at P < 0.05. Data and statistical analysis were performed using Graph Pad Prism version 4.02 for Windows (Graph Pad Software, San Diego, CA).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Survival. Met treatment was well tolerated. The survival curves of Met-treated and untreated animals are shown in Fig. 1. All Met-treated animals were alive after 6 mo compared with only 70% of the untreated animals. After 1 yr, the survival of the Met-treated animals was significantly better: 60% compared with 35% for the untreated group (P = 0.045). With the exception of one Met-treated animal, which developed clinical signs of heart failure, all deaths were sudden and occurred during the night (rats' active period).


Figure 1
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  		Fig. 1. Survival Kaplan-Meier curves of metoprolol (Met)-treated rats and untreated rats with severe chronic aortic valve regurgitation (AR).

 
Hemodynamic data. Hemodynamic data are summarized in Table 2. There were no significant differences in body weight (not shown), resting HR, cardiac output, systolic pressure, or pulse pressure after 6 or 12 mo between the Met-treated and untreated groups. β-Blockade was confirmed by the lower maximal HR response to a dobutamine infusion (20 µg·kg–1·min–1 iv) in Met-treated rats compared with untreated animals (AR), despite similar resting HR (maximal HR = 452 ± 12 and 415 ± 14 beats/min for AR and Met, respectively, P = 0.05). Invasive measurements showed no difference in positive and negative dP/dt between groups at the end of the protocol. However, LV end-diastolic pressures (LVEDP) were significantly lower in the Met-treated than untreated AR group (Table 2). LVEDP values in the Met-treated group were similar to those of normal sham-operated animals (8 ± 1.2 and 9 ± 1.0 mmHg, respectively, P = 0.71).


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  		Table 2. Hemodynamic data at 6 and 12 mo

 
Echocardiographic data. Echocardiographic data are summarized in Table 3. AR severity was reassessed at each echocardiographic examination and remained similar between both groups (data not shown). There were no significant differences in LV diastolic or systolic diameters between groups at 6 and 12 mo. LV ejection fraction remained above 50% in all groups. After 12 mo, LV ejection fraction tended to be slightly better in the Met-treated than untreated animals (57.3 ± 2.23% vs. 52.7 ± 1.80%, P = 0.16). Ejection fraction remained above 60% after 1 yr in 4 of 12 Met-treated rats compared with 0 of 7 untreated rats.


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  		Table 3. Echocardiographic data at 6 and 12 mo

 
A subgroup analysis of echocardiographic data after 6 mo showed that the animals that would survive the 1-yr protocol had similar end-diastolic diameters but smaller end-systolic diameters than the animal that would die before the end of the protocol (end-diastolic diameter = 11.5 ± 0.24 vs. 12.3 ± 0.21 mm, P = 0.22; end-systolic diameter = 7.1 ± 0.31 vs. 8.3 ± 0.30 mm, P = 0.012).

Measurement of LV hypertrophy. Echocardiographically measured LV weights were similar between groups after 6 mo. We found a strong trend toward smaller LV weights (weighed explanted hearts) in the Met-treated than untreated animals after 12 mo (1,695 ± 92.3 vs. 1,915 ± 59.9 g, P = 0.07). Cardiomyocyte CSA also tended to be smaller in the Met-treated group (50 ± 2.2 vs. 55 ± 3.1 arbitrary units), but this difference did not reach statistical significance (P = 0.14). There were no differences in lung or liver weight between groups (results not shown).

LV fibrosis and extracellular matrix remodeling. Results for the semiquantification of subendocardial LV fibrosis are shown in Fig. 2. Although there were no significant differences between groups after 6 mo (19), a significant decrease in the amount of subendocardial fibrosis was clearly evident in the Met-treated group after 1 yr (P = 0,009). mRNA for fibronectin, collagen types I and III, and MMP-2 revealed no differences between groups after 1 yr (results not shown). Typical examples of Masson's trichrome staining of the LV in Fig. 2 demonstrate increased subendocardial fibrosis in the untreated group compared with the Met-treated group.


Figure 2
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  		Fig. 2. Left ventricular (LV) fibrosis and extracellular matrix remodeling after 12 mo. Top: quantification of blue-to-red ratio from Masson's trichrome-stained LV sections. Bottom: typical examples of Masson's trichrome-stained subendocardial LV sections from Met-treated and AR rats. Blue, collagen fibers; red, cardiomyocytes. Magnification x200.

 
Myosin heavy chain mRNA analyses. Real-time quantitative RT-PCRs evaluating the modulation of {alpha}- and β-myosin heavy chains (MHC) are illustrated in Fig. 3. AR animals had significantly lower levels of mRNA encoding the {alpha}-MHC and higher levels of β-MHC than normal rats. Met had no significant effect on this parameter.


Figure 3
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  		Fig. 3. Real-time quantitative RT-PCR of LV mRNA levels of myosin heavy chains (MHCs) after 12 mo. Values (means ± SE, n = 7–9/group) are reported in arbitrary units (AU). Sham-operated (sham) group mRNA levels were normalized to 1. *P < 0.05; **P < 0.01 vs. sham.

 
β-Adrenergic receptors. The gene expression of β1- and β2-adrenergic receptors in the LV of surviving animals by quantitative RT-PCR was evaluated (Fig. 4). mRNA levels of β1-adrenergic receptors were downregulated in untreated AR rats, whereas Met tended to normalize these levels. Opposite results were found for β2-receptors. Therefore, Met improved the ratio of β1 to β2 mRNA.


Figure 4
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  		Fig. 4. Real-time quantitative RT-PCR of LV mRNA levels of β-adrenergic receptors after 12 mo. Values are means ± SE (n = 7–9/group). Sham group mRNA levels were normalized to 1. *P < 0.05; **P < 0.01 vs. sham. #P < 0.05 vs. AR.

 
Two other components of the β1-adrenergic receptor pathway, the Gs protein {alpha}-subunit and the catalytic {alpha}-subunit of PKA, were analyzed. As depicted in Fig. 5, mRNA levels encoding Gs{alpha} protein were higher in AR animals but remained unchanged in Met-treated rats. mRNA levels for PKA decreased in AR animals compared with the sham-operated group, whereas those of Met-treated rats were not significantly different from controls.


Figure 5
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  		Fig. 5. Real-time quantitative RT-PCR of LV mRNA levels of Gs{alpha} and PKA catalytic {alpha}-subunit. Values are means ± SE (n = 7–9/group). Sham group mRNA levels were normalized to 1. *P < 0.05; **P < 0.01 vs. sham.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The management of chronic volume overload, such as chronic AR, remains controversial and widely debated. Vasodilators, mainly nifedipine, have been the cornerstone of pharmacological therapy of such patients for the past decades (3). However, the use of nifedipine and other vasodilators in AR was based on data that, unfortunately, could not be reproduced in a recently published placebo-controlled trial comparing nifedipine with enalapril in AR patients (7, 20). Consequently, these drugs have lost a lot of credibility, and many physicians are now skeptical that any pharmacological treatment can be effective in chronic AR.

The rationale for vasodilator use in AR was to help decrease preload and afterload regurgitant volume. Our group has been evaluating a completely different target in chronic AR by studying the role of the adrenergic system in an animal model in rats (19). In the present study, we report that 1 yr of treatment with a β-adrenergic blocker (Met) improves survival in rats with severe AR. Despite its relatively low dose for rats (25 mg·kg–1·min–1), Met resulted in a significant level of physiological β-blockade as shown by the blunted HR response to adrenergic stimulation by dobutamine and significant effects on the β1-to-β2-adrenergic receptor ratio. To our knowledge, this is the first report of such an observation.

The role of β-blockade in the management of AR has been explored by other investigators in animal models (1, 19, 21, 23–27) (Table 4). These studies have suggested that adrenergic blockade may be beneficial in animal models of acute AR, although none of them evaluated the long-term effects in a chronic AR model. Table 5 summarizes the few studies performed in humans related to the hypothesis of the role of the adrenergic system or β-blockade in AR (6, 9, 10, 14, 16). Clearly, no hard conclusions can be derived from these data, but the conclusions of these small trials, as well as previous animal studies, seem to support our hypothesis that the adrenergic system is involved in the myocardial remodeling associated with AR. None of these studies were designed to evaluate the effects of β-blockers on survival.


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  		Table 4. Animal studies suggesting a role of the adrenergic system or β-adrenergic blockade in AR

 

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  		Table 5. Published studies (humans) suggesting a role of adrenergic system or β-blockade in AR

 
In the present study, death occurred suddenly without any warning signs of impending heart failure. There was a clear decrease in subendocardial fibrosis and a strong trend toward less LV hypertrophy (P = 0.07) in Met-treated animals. Myocardial fibrosis and hypertrophy are factors known to increase the risk of sudden death in other cardiac diseases. All Met-treated and untreated animals had an ejection fraction very close to or above 50% at the end of the protocol and were not in heart failure. Their LVs were, however, significantly dilated. These results raise the hypothesis that severe LV dilatation and hypertrophy combined with increased myocardial fibrosis are proarrhythmogenic in this AR animal model and that the deaths of the animals in our protocol were probably arrhythmic in nature. Clearly, heart failure was not the cause of death of our animals. A subgroup analysis showed smaller LV at midterm of the protocol in the survivors. However, ejection fractions were similar and close to normal after 6 and 12 mo in the survivors, thereby lending further support to the antiarrhythmic hypothesis, rather than an anti-heart failure effect. However, the protocol was not primarily designed to assess arrhythmias. Therefore, direct proof of excess arrhythmias in the untreated group compared with the group treated with the β-blocker was not found in this protocol, and this hypothesis deserves further investigation.

β-Blockers have been proven to decrease the risk of sudden death in other cardiac diseases such as congestive heart failure by counteracting the negative effects of an overactivated adrenergic system and restoring the sympathetic-parasympathetic balance. β-Blockers may have acted in the same way in our animals with severe chronic AR but preserved LV ejection fraction. Indeed, we observed that Met improved the ratio of gene expression of the β1- and β2-adrenergic receptors, which was shifted toward less β1 and more β2 in untreated AR animals.

Myocardial contractility is affected by multiple factors interacting with each other. MHCs are a key component of myocardial contractility (8). Rodent hearts mostly express {alpha}-MHC, with a high {alpha}-MHC-to-β-MHC ratio, and most cardiomyopathy models induce a shift in this ratio (decreased {alpha}-MHC and increased β-MHC). This shift was never documented in a model of chronic AR; therefore, we do so for the first time. Moreover, the adrenergic system is a key determinant in the expression of myosin subtypes and, therefore, is directly linked with our main hypothesis. Adrenergic stimulation favors {alpha}-MHC expression, whereas β-blockade will induce β-MHC. On the basis of previous studies by other investigators in other animal models (mostly transgenic mice), it was thought that hearts expressing more β-MHC would cope less well and develop more hypertrophy in response to chronic stress (8). In the present study, we show that β-blockade does not restore a normal {alpha}-MHC-to-β-MHC ratio and even tends to increase the level of β-MHC. Despite the tendency to increased β-MHC, the animals survived longer and tended to have less hypertrophy. These findings do not support the hypothesis that increased β-MHC is deleterious in our model. It is known that β-MHC has the ability to generate contractile force with less energy consumption than {alpha}-MHC. We suggest that this may be a protective mechanism against chronic stress in AR. This hypothesis should be investigated in upcoming studies focusing on myocardial metabolism in chronic AR.

Invasive intracardiac pressure measurements revealed a significant improvement of LVEDP in Met-treated compared with untreated AR animals. Filling pressures were similar in the Met-treated and normal sham-operated animals. This finding combined with less subendocardial fibrosis demonstrates a beneficial effect of β-blockade on diastolic properties of the LV. Fibroblast proliferation and collagen secretion are regulated by the adrenergic system (5). Fibroblasts express β-adrenergic receptors on their cell membranes, and β-blockers have been shown to reduce myocardial fibrosis. Therefore, our finding that β-blockers reduce myocardial fibrosis were expected. Interestingly, mRNA expression of collagens, as well as fibronectin and MMP-2, was abnormally high after 6 mo in the same model (19), whereas we found no remaining significant alterations after 12 mo. It has been shown by others that a decreased degradation is the most important factor for the accumulation of fibrosis in AR. Our results suggest that, between 6 and 12 mo, the fibrotic process has either ended or reached equilibrium as stated earlier.

There are no large-scale studies of the natural history of patients with AR with normal ejection fraction in a homogeneous comparable cohort. Current data are clearly imperfect and derived from the summary of many small series, very heterogeneous in nature, of 30 to ~100 patients each, with a follow-up ranging from 3 to 14 yr (4). In those studies, mortality rates were low. However, the latest 2006 American College of Cardiology/American Heart Association guidelines point out that one-quarter of patients who die or develop systolic dysfunction do so before the onset of any warning symptoms. Sudden death, although relatively rare, has been reported in asymptomatic patients with normal LV ejection fraction. Ventricular arrhythmias have been reported in patients with AR and were correlated with the degree of ventricular enlargement (11, 13, 15, 22). However, those studies were not designed to address the issue of mortality in patients displaying more ventricular arrhythmias. Our study suggests that animals with severe AR experienced sudden arrhythmic deaths and that treatment with a β-blocker decreases mortality.

Clearly, the results of a study performed on animals cannot be directly transposed to humans. The dose of Met administered to the animals was relatively small for a rat and did not induce any significant resting bradycardia. Whether the same results would have been obtained in the presence of bradycardia with use of larger doses of Met is unknown. HR and all other hemodynamic parameters were evaluated in anesthetized rats; the effects on hemodynamics while the animals were awake are unknown. Many unanswered questions remain before this treatment can be tested in humans.

In summary, we report for the first time in a rat model of severe chronic AR that long-term treatment with Met 1) improves survival by decreasing sudden death, 2) normalizes LV filling pressures, 3) decreases subendocardial myocardial fibrosis, and 4) improves myocardial β-adrenergic receptor ratio. Further studies are needed to better understand the interactions between these beneficial effects of blocking the adrenergic system in chronic AR.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by operating grants to J. Couet and M. Arsenault from the Canadian Institutes of Health Research (MOP-61818), the Heart and Stroke Foundation of Canada, and the Quebec Heart Institute. E. Plante and D. Lachance are recipients of studentships from the Canadian Institutes for Health Research.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Arsenault or J. Couet, Institut de Cardiologie de Québec, 2725 chemin Sainte-Foy, Sainte-Foy, (Quebec), Canada G1V 4G5 (e-mail: marie.arsenault{at}crhl.ulaval.ca or jacques.couet{at}med.ulaval.ca)

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
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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