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European Journal of Heart Failure 2006 8(5):451-459; doi:10.1016/j.ejheart.2005.10.011
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© 2005 European Society of Cardiology

Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE

Imre Kovacsa, Janos Tothb, Jeno Tarjana and Akos Kollerb,c,*

a Markusovszky Hospital, Endothelium study group H-9700, Szombathely, Hungary
b Department of Pathophysiology, Semmelweis University H-1445, Budapest, Hungary
c Department of Physiology, New York Medical College Valhalla NY 10595, USA

* Corresponding author. Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. Tel.: +1 914 594 4085; fax: +1 914 594 4018. Email address: koller{at}nymc.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Impaired cardiac function is frequently accompanied by peripheral vascular dysfunction and a pro-inflammatory condition, which may be associated with elevated levels of angiotensin II. We hypothesized that the magnitude of flow mediated dilatation (FMD) of the brachial artery of post myocardial infarction patients will correlate with serum levels of tumor necrosis factor alpha (TNF{alpha}) and C-reactive protein (CRP), and that treatment with angiotensin converting enzyme inhibitors (ACEI) will increase FMD by reducing TNF{alpha} and CRP. Patients were treated with low dose (10 mg/day) quinapril (Q) or enalapril (E) and their effects on FMD and inflammatory markers were evaluated after 8 and 12 weeks. Before treatment, in both groups FMD showed a low value (Q: 2.95+0.42% and E: 3.3±0.33%), whereas TNF-{alpha} (Q: 31.65±8.23 pg/ml and E: 29.5±5.9 pg/ml) and CRP (Q: 7.28±2.96 mg/ml and E: 7.08±3.02 mg/ml) were elevated. In the Q group, but not in the E group FMD increased significantly, (to 5.96+1.10%), whereas TNF-{alpha} (19.0±12.21 pg/ml) and CRP (to 3.91±1.82 mg/L) significantly decreased after 8 and 12 weeks of Q treatment. Moreover, the magnitude of FMD showed a strong inverse correlation with serum levels of TNF-{alpha} and CRP after Q treatment. Thus, in post myocardial infarction patients endothelial dysfunction assessed by FMD correlates with elevated levels of plasma inflammatory markers, and low dose quinapril improves endothelial function, likely by reducing vascular inflammation.

Key Words: Endothelial function • Tissue renin–angiotensin system • Flow mediated dilatation • Vascular inflammation • Angiotensin converting enzyme inhibitor

Received January 27, 2005; Revised July 30, 2005; Accepted October 17, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Systemic vasomotor dysfunction frequently occurs in patients with impaired cardiac function following myocardial infarction [1-4]. This could lead to a vicious cycle by increasing the demand on the failing left ventricle. Indeed, several clinical and animal studies have documented dysfunction of peripheral resistance arteries [1,2] most notable, an impaired flow mediated dilation (FMD) of arteries in patients with failing hearts [2,5]. The response of vessels to an increase in flow is an important mechanism regulating peripheral vascular tone, hence blood flow and this response is mediated by several factors released from the endothelium [6,7]. It has been documented that in various diseases of the cardiovascular system, inhibitors of angiotensin converting enzyme (ACEI) exert a beneficial effect on the function of peripheral vessels, hence on FMD, suggesting that the renin-angiotensin system is upregulated in these patients [8-12].

Several mechanisms have been proposed to explain the beneficial effects of ACEI on endothelial function [8,12]. It is known that ACEI, in addition to inhibiting ACE, inactivate endogenous bradykinin, the potent vasodilator action of which is mediated by nitric oxide, prostaglandins and other factors released from the vascular endothelium [13,14]. Thus, by blocking bradykinin breakdown, ACEI could increase levels of these vasodilator factors. It has been suggested that up regulation of the renin-angiotensin system (RAS) may result in the induction of vascular oxidative stress [15-18], leading to reduction in the bioavailability of nitric oxide (NO).

Recent studies however, suggest that development of pro-inflammatory vascular phenotype may interfere with the function of vascular endothelium, as indicated by the elevated plasma level of markers of inflammation [19-21] that are associated with cardiac dysfunction [15]. Some of these markers are the increased activity of inflammatory cytokines, such as interleukins (IL), IL1 and IL6, and elevated levels of tumor necrosis factor-alpha (TNF-P) [22-24]. These mediators released from various cells and tissues induce synthesis of C-reactive protein (CRP) [23,24]. Elevated plasma levels of TNF-P and CRP may result in further endothelial damage [25,26].

On the basis of the aforementioned findings, we hypothesized that endothelial function correlates with inflammatory conditions. Specifically, we hypothesized that the magnitude of FMD of the brachial artery will correlate with serum levels of the inflammatory markers TNF-P and CRP, and that ACE inhibitors by reducing vascular inflammation will improve FMD.

Since blood pressure has been shown to affect the endothelial function of vessels [27-29], low doses of quinapril and enalapril (10 mg/day), which should not have a significant effect on blood pressure levels, were used.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
2.1. Experimental procedure
Fifty patients with impaired left ventricular function (ejection fraction (EF): 30-40%) following Q wave myocardial infarction and classified as NYHA class II/III were recruited. Patients with haemodynamic instability, decreased renal and liver function or with metabolic disease were excluded. Three patients did not comply with the protocol (they admitted to smoking), and one patient had a cough that may have been related to ACE inhibitor therapy. These four patients were not included in the study. Thus data from 46 patients were analyzed, 32 patients (24 men, 8 women) were randomised to quinapril and 14 patients (8 men, 6 women) to enalapril. The randomisation was performed such that the first two patients received quinapril (10 mg/day) and every third patient received enalapril (10 mg/day). Concomitant therapy, which included diuretics, β-blockers, digoxin, statins, and platelet aggregation inhibitors, was not different between the two groups. Treatment was started 5.44±0.9 months following myocardial infarction. The study protocol was approved by the ethics committee of the Institutions involved and informed consent was obtained from each participant. All procedures were performed in accordance with institutional guidelines.

Endothelial function of the brachial artery was investigated by means of a non-invasive flow mediated dilatation (FMD) technique, as described earlier [30]. Using high-resolution ultrasound, changes in brachial artery diameter were measured as described previously [31,32]. Ultrasound measurements were performed in the morning, after the patients had rested in a supine position for 30 min in standardized conditions in a quiet room. The high quality scans were recorded using a 7.5-MHz linear array ultrasound probe (HP Sonos 2000 ECG unit, Hewlett Packard) by trained physicians, who were unaware of the patient's condition or treatment assignment. Timing of each image frame with respect to the cardiac cycle was determined by simultaneous ECG recording. Ultrasound system video monitor scans of the brachial artery, approximately 5 cm above the elbow, were obtained in longitudinal sections, and the transducer was maintained in a fixed position relative to the patient's arm. Arterial blood flow velocity was measured by means of a pulsed Doppler signal, with the sample volume placed in the center of the artery. An increase in blood flow was induced by using a blood pressure cuff placed around the arm, the cuff was inflated to 300 mmHg, and then after 5 min of arterial occlusion the cuff was deflated. Subsequent to cuff deflation a brief reactive hyperaemia, high-flow state occurred in the brachial artery. It is thought that high-flow state results in an increase in wall shear stress, which elicits dilation of vessels, both in humans and [30,33] experimental animals [6]. The longitudinal image of the artery was recorded continuously from 30 s before and to 2 min after cuff deflation. A mid-artery pulsed Doppler signal was obtained immediately after cuff release and blood flow velocity during hyperaemia [34] after cuff deflation was assessed. Vessel diameter was measured at end diastole from super-VHS recordings by two investigators who were blinded to the patient's clinical characteristics and treatment. Measurements were taken from the anterior to the posterior interface between the media and adventitia. For the reactive hyperaemia scans, diameter measurements were taken from 30 to 90 s after cuff deflation, and the greatest diameter was used. The magnitude of FMD was indicated by the percentage change in brachial artery diameter, relative to baseline diameter before occlusion. Brachial blood flow was calculated from Doppler flow-velocity measurements. Repeated scans were recorded randomly and measured on two different occasions in all patients.

Left ventricular ejection fraction (EF %), endothelial function (FMD %), tumour necrosis factor-alpha (TNF-P, monoclonal antibody, sandwich EIA) and C-reactive protein (CRP, high-sensitivity assay, Dade-Behring) were assessed in all patients. Ejection fraction was measured using Quinones method and by radionuclide ventriculography according to Schiller et al. [35,36] Blood samples were taken in the morning, following an overnight fast. All parameters were evaluated before treatment, and then after 8 and 12 weeks of quinapril or enalapril treatment.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
All data are expressed as mean±SEM. Differences between means were compared using paired or unpaired Student's t test, with Bonferroni correction for multiple comparisons. Changes in FMD were analyzed by 1-way ANOVA. The relationships between continuous variables were evaluated by linear regression. A value of P<0.05 was considered statistically significant.


   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
There were no significant differences in age (43.2±7.1 years), body mass index (26.7±2.1 kg/m2), systolic and diastolic blood pressure or ejection fraction between the treatment groups and these parameters did not change significantly during the course of study (Table 1). Ejection fraction was significantly lower in patients (33.6+35%) compared to a healthy control group from a similar cohort (61.5±7.1%) [36]. It is of note that EF is only an indicator of LV function and LV filling pressure, thus conclusions should be drawn with caution. All patients were classified as NYHA II/III.


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  		Table 1 Effects of quinapril and enalapril treatment on haemodynamic parameters

 
Fig. 1A shows that the mean FMD of the brachial artery at baseline was below 3%, which is substantially lower than values obtained in healthy control groups [37,38]. In contrast, levels of TNF-P and CRP at baseline were substantially higher (Fig. 1B and C) than those reported for healthy control groups [39,40]. Fig. 1A also shows that a significant increase in FMD occurred after 8 weeks of quinapril treatment, which was further enhanced at 12 weeks (FMD before treatment: 2.95±0.42%; at 8th week: 5.96±1.1%; and at 12th week: 6.42±1.21%). Also, the serum concentration of TNF-P and CRP decreased significantly after 8 and 12 weeks of quinapril treatment (Fig. 1B and C). In contrast, there was no change in FMD in the enalapril group (before treatment: 3.3±0.33%; at 8th week: 3.5±0.38%; at 12th week: 3.48±0.47%). In addition, serum concentrations of TNF-P and CRP remained elevated after 8 and 12 weeks of enalapril treatment (Fig. 1A, B, and C).


Figure 1
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  		Fig. 1 Flow-mediated dilatation (FMD %) of the brachial artery (A), serum levels of tumor necrosis factor-alpha (TNF-alpha pg/mL) (B) and C-reactive protein (CRP mg/L) (C) before (0 week) and after 8 and 12 weeks of quinapril or enalapril treatment. Data are expressed as mean±S.E.M. Asterisk indicates significant changes compared to before (0 week) treatment (p<0.05).

 
Fig. 2A depicts the relative changes in FMD and the corresponding changes in CRP and TNF-P in response to quinapril and enalapril treatment. These data clearly show that quinapril 10 mg/day caused a marked improvement in FMD of the brachial artery of patients with impaired ventricular function, whereas enalapril was ineffective. Moreover, changes in FMD were inversely mirrored by the changes in TNFP and CRP (Fig. 2 B and C). That is, there was a substantial reduction in these inflammatory markers as a result of quinapril, but not enalapril treatment.


Figure 2
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  		Fig. 2 Changes in flow-mediated dilatation (FMD %) of brachial artery (A), serum levels of tumor necrosis factor-alpha (TNF-alpha pg/mL) (B) and C-reactive protein (CRP mg/L) (C) as result of 8 or 12 weeks of quinapril or enalapril treatment. Data are expressed as mean±S.E.M. Asterisk indicates significant changes compared to 0-8 weeks treatment (p<0.05).

 
To further analyze the relationship between inflammatory markers and FMD we plotted each FMD data point against each value of TNFP and CRP in all conditions. Figs. 3A and 4A show that before treatment the values of TNFP and CRP were high, whereas FMD was low and the slope of correlation was low, as well. In response to quinapril treatment (8 and 12 weeks) there was a strong negative correlation between the level of TNFP and the magnitude of FMD (Fig. 3B and C). Similarly, quinapril treatment resulted in a strong negative correlation between the level of CRP and the magnitude of FMD (Fig. 4B and C). In other words, in patients treated with quinapril the inflammatory markers shifted to the left resulting in an upward shift in FMD. In the enalapril group the values of TNFP and CRP remained high and the magnitude of FMD remained low (Figs. 3B, C and 4B, C).


Figure 3
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  		Fig. 3 Correlation between tumor necrosis factor-alpha (TNF-alpha pg/mL) and flow-mediated dilatation (FMD %), before (A), after 8 weeks (B) and after 12 weeks (C) of quinapril (bullet) or enalapril ({circ}) treatment. Regression lines in panel B and C for quinapril: r=0.95 and r=0.89, p<0.05; and for enalapril: r=0.11 and r=0.04, N.S., respectively.

 


Figure 4
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  		Fig. 4 Correlation between C-reactive protein (CRP mg/L) and flow-mediated dilatation (FMD %) before (A), after 8 weeks (B) and after 12 weeks (C) of quinapril (bullet) or enalapril ({circ}) treatment. Regression lines in panel B and C for quinapril: r=0.97 and r=0.95, p<0.05; and for enalapril: r=0.14 and r=0.04, N.S., respectively.

 
We also found a significant positive linear correlation between TNF-P and CRP before, after 8 and 12 weeks of quinapril and enalapril treatment. (Fig. 5A, B, and C).


Figure 5
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  		Fig. 5 Correlation between tumor necrosis factor-alpha (TNF-P pg/mL) and C-reactive protein (CRP mg/L) before (A), after 8 weeks (B) and after 12 weeks (C) of quinapril (bullet) and enalapril ({circ}) treatment. Regression lines in panel A, B and C: r=0.88, r=0.89 and r=0.85, p<0.05, respectively.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
The salient findings of the present study are that in patients with impaired cardiac function following myocardial infarction FMD is low, whereas serum levels of TNFP and CRP are high. Moreover, after quinapril treatment, which increased FMD and reduced TNFP and CRP, there was a strong inverse correlation between FMD and the serum levels of TNFP and CRP. Enalapril was ineffective. We also found a strong positive correlation between the plasma levels of TNF-P and CRP.

The purpose of the present study was to test the hypothesis that FMD of the brachial artery in patients with impaired cardiac function correlates with the serum levels of TNF-P and CRP, indicators of an inflammatory condition and that ACE inhibitors, by reducing vascular inflammation, will improve FMD. First, we confirmed the findings of previous studies by showing that impaired cardiac function in post infarction patients is associated with peripheral vascular dysfunction [1-3,8-11]. Indeed, we found that in patients with impaired cardiac function following myocardial infarction FMD is greatly reduced (Fig. 1A) compared to a healthy age-matched group of individuals [37,38].

Several mechanisms could explain the reduction of FMD in the present study. It seems to be well established that increases in blood flow, likely via increases in wall shear stress [6,7,41] elicit the release of endothelial factors, most notably nitric oxide (NO). [6,7] Reduced NO-dependent dilations have been documented in arterial vessels after myocardial infarction and in cardiomyopathy [1-5]. Previous studies have also shown that ACE inhibitors improve FMD in these patients [8-10]. Several mechanisms have been proposed to explain the beneficial effects of ACEI on FMD. Since ACE is identical to kininase II, in addition to generating angiotensin II, it inactivates endogenous bradykinin, the potent vasodilator action of which is mediated by NO, prostaglandins and other factors released from the vascular endothelium [5,10,13,14]. Conversely, ACE inhibitors by blocking bradykinin breakdown could elicit increased levels of these vasodilator factors, hence augmenting FMD. In addition, ACEI by interfering with the sequestration of the B2 kinin receptors could reduce the desensitization of these receptors and enhance the vascular effects of bradykinin [42]. Also, binding of an ACE inhibitor to ACE may activate non-receptor signaling pathways, which may alter the expression of ACE itself [43].

Interestingly, recent studies suggest that other mechanisms may also contribute to the ACEI-induced improvement of FMD in patients with impaired cardiac function. It has been shown that upregulation of the renin-angiotensin system (RAS) results in the induction of vascular oxidative stress [15-18,44], leading to reduction in the bioavailability of NO. ACE inhibitor therapy with quinapril selectively improved endothelium-dependent vasodilator responsiveness by increasing NO bioavailability in patients with coronary artery disease, likely by protecting NO from oxidative inactivation by reducing NADPH oxidase-derived superoxide and increasing superoxide dismutase activity [17]. It is known that nitric oxide is not only a dilator, but also an antioxidant [16] and that several cardiovascular diseases, such as myocardial ischaemia, heart failure [9], experimental and clinical hypertension, [18,29,45] aging, [46] hyperhomocysteinaemia [47] and conditions, in which the plasma level of angiotensin II is increased, are associated with vascular oxidative stress [17,18,48]. This is supported by the findings that in many instances, inhibition of ACE improves endothelial function [8-12].

Recent studies suggest that inflammatory processes may underlie the vascular endothelial dysfunction in cardiovascular diseases, such as heart failure and suggest a potential role for angiotensin II and various inflammatory cytokines in these processes [20-24,49]. Furthermore, chronic inflammation is the hallmark of the development of atherosclerosis, both in coronary vessels leading to ischaemic heart disease and alterations in peripheral vessel function resulting in circulatory disturbances in various organs and tissues [50]. Although, it is known that ACE is a key factor in the development of vascular diseases, several aspects of its mechanism of action remain uncertain. It is thought that elevated angiotensin II promotes inflammatory processes [51] via induction of oxidative stress and various cytokines [49]. Thus it was logical to hypothesize that, if indeed, angiotensin II is related to vascular wall inflammation, then endothelial function should be correlated with markers of these processes and ACE inhibitors should modulate this correlation.

We found that TNFP and CRP levels of patients were significantly elevated before treatment. Quinapril treatment significantly reduced both TNFP and CRP and improved FMD (Figs. 1 and 2). Moreover, further analysis of our data revealed that FMD had a strong inverse linear correlation with TNFP and CRP after treatment with quinapril (Figs. 3 and 4). These findings suggest that FMD is determined by pathomechanisms mirrored in the serum levels of TNFP and CRP. Recent investigations have proposed that increased production of cytokines, such as TNFP by various cells in the inflammatory state, leads to the de novo hepatic synthesis of acute phase reactants, such as CRP [23]. It is thought that CRP has a predictive value in the early development of atherosclerosis as shown by Hashimoto et al. in carotid arteries [52]. The level of CRP increases in acute coronary syndromes, even in the absence of major myocardial necrosis [40]. In the present study a strong positive linear relationship between TNFP and CRP was shown in our patients (Fig. 5). Quinapril treatment reduced TNFP and CRP levels, supporting the idea that inhibition of ACE results in reduction of inflammatory processes. We speculate that reduction in the inflammatory condition of vessels may increase the bioavailability of NO hence increasing FMD in patients treated with quinapril. This idea is supported by studies of Venugopal et al. [26] in human aortic endothelial cells in culture (HAEC) showing that exogenous CRP by reducing eNOS activity and thus cGMP level elicits endothelial dysfunction. Collectively, these findings support the idea that the pro-inflammatory state of the vascular wall is related to endothelial dysfunction and up-regulated RAS, as indicated by the inverse correlation between FMD and plasma inflammatory markers.

We also found that enalapril did not increase FMD. One can argue that the doses of enalapril and quinapril used in the present study are not an equivalent for blocking the RAS. However previous studies suggest that quinapril and enalapril in the doses used in our study were likely to be adequate to inhibit RAS [53,54]. Similar comparable cardiovascular effectiveness has been reported by others in different age groups [55].

Nevertheless, differences in tissue selectivity may underlie the differential effects of quinapril and enalapril on endothelial function. Lyons et al. showed that quinapril is a more effective inhibitor of vascular tissue ACE then enalapril [56]. Differences in the vascular action of various ACE inhibitors could be due to their binding characteristics to tissue ACE [51]. It has been recognized that there is genetic variability in ACE [12] and differences in the site of action of ACE inhibitors regarding plasma and tissue effects [51,57,58]. Although, both quinapril and enalapril have similar beneficial cardiovascular effects, quinapril seems to cause greater improvement in endothelial function [1,2,8,9]. In a comparative study in patients with heart failure, Hornig et al. showed that parenteral administration of quinapril, but not enalapril increased FMD of the radial artery, due to increased bioavailability of NO [9], a finding that is in line with the present study. Indeed, it has been suggested that quinapril is a more effective inhibitor of vascular tissue ACE than enalapril, as shown by the greater inhibition of angiotensin I-induced vasoconstriction compared to that of enalapril [56,59]. These findings support our suggestion that quinapril, likely due to its greater affinity to tissue ACE, provides an effective inhibition of vascular inflammation associated with cardiac dysfunction and thus improved endothelial function.

Our findings are in line with previous clinical trials, such as AIRE with ramipril [60,61] and TRACE with trandolapril [62,63] showing that administration of ACE inhibitors results in similar beneficial effects in the early post infarction period with mild heart failure, by reducing cardiac failure, mortality and sudden death. The clinical effects of providing appropriate endothelial protection by ACEI, is that the reduced release of NO from systemic peripheral vessels could increase the stiffness of large arteries and the resistance of microvessels, both of which can impose further demand on the ischaemic heart, and thus lead to heart failure [64,65].

Previous studies in isolated arterioles [28] and in aortic banded rats [29] suggest that high intraluminal pressure initiates oxidative stress, pro-inflammatory processes and activates the vascular renin-angiotensin system. Thus in the present study we chose a low dose of ACE inhibitors (10 mg/day), which did not significantly affect the blood pressure of patients. Thus, the beneficial effect of low dose quinapril is unlikely to be due to its blood pressure lowering action. This study suggests that a low dose of quinapril can be used to improve endothelial function, especially for patients in whom reduction of blood pressure is not the primary aim of therapy and partial preservation of other RAS related mechanisms is also a consideration. We speculate that the relative tightness of the patient group regarding age and body mass index may be responsible for the observed significant changes in such a relatively small group of patients. Nevertheless, because the present study was conducted in a small group of patients, the interpretation of results needs to be made with caution. Also, although we used equivalent doses of ACE inhibitors with regard to their cardiovascular action [53] it cannot be excluded that a higher dose of enalapril (when tissue selectivity became less important) by more effectively inhibiting ACE could improve endothelial function in patients with cardiac dysfunction.

In conclusion, in patients with myocardial infarction-induced impaired left ventricular function endothelial dysfunction assessed by flow mediated dilation of the brachial artery inversely correlates with elevated plasma levels of the inflammatory markers TNFP and CRP. In addition low doses of quinapril, likely by reducing vascular inflammation, improve vascular endothelial function. This study provides an additional rationale for using ACE inhibitors with high tissue affinity to improve endothelial function and reduce vascular inflammation, both of which may delay the further development of peripheral vascular disease and heart failure in post myocardial infarction patients.


   Acknowledgement
 
This work was supported by NIH HL-46813, AHA NE Affiliate 0555897T, USA and Hungarian Natl. Sci. Res. Founds, OTKA T048376 and M45186.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 

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