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Effects of glutamine and valsartan on the brain natriuretic peptide and N-terminal pro-B-type natriuretic peptide of patients with chronic heart failure.

Byline: Mingliang Shao Congxin Huang Zhen Li Hui Yang and Qifan Feng

ABSTRACT

Objective: To analyze the effects of glutamine and valsartan on the brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of patients with chronic heart failure (CHF). Methods: A total of 140 CHF patients were divided into a treatment group and a control group by random drawing and were subjected to standard anti-heart failure treatment and administered with valsartan. Besides the treatment group was also intravenously transfused glutamine. The treatment lasted eight weeks.

Results: The overall efficacy of treatment group and control group were 98.6% and 90.0% respectively with a statistically significant difference (Pless than 0.05). The two groups had significantly increased left ventricular ejection fractions as well as significantly decreased left ventricular end-diastolic volumes and left ventricular end-diastolic dimensions after treatments (Pless than 0.05) compared with those before. There were also inter-group differences between these values (Pless than 0.05). After treatment the levels of BNP NT-proBNP and CD8+ in both groups significantly decreased (Pless than 0.05) whereas those of CD4+ significantly increased (Pless than 0.05). The two groups also had significantly different values (Pless than 0.05).

Conclusion: Glutamine in combination with valsartan enhanced the therapeutic effects by improving cardiac function which may be associated with decreased expressions of BNP and NT-proBNP and beneficial effects of glutamine on immune function.

KEY WORDS: Glutamine Valsartan Chronic heart failure Brain natriuretic peptide N-terminal pro-B-type natriuretic peptide.

INTRODUCTION

Chronic heart failure (CHF) which is a clinically common and complex syndrome has poor prognosis for being the ending of a variety of organic heart diseases.12 Currently CHF has become one of the severe diseases endangering human health with population aging and has thus attracted global attention. As a natriuretic endogenous peptide neurohormone brain natriuretic peptide (BNP) is mainly secreted by ventricular myocytes the synthesis of which is closely related with ventricular afterload and wall tension.34 Besides N-terminal pro-B-type natriuretic peptide (NT- proBNP) contains 108 amino acids after truncating 26 of them at the N-terminal.

In human body BNP is active and decomposes rapidly but the inactive NT-proBNP remains stable and thus allows easy detection.7 It is now well-established that over-activations of the renin- angiotensin-aldosterone system (RAAS) and the sympathetic nervous system dominantly control the vicious circle of cardiac remodeling and the deterioration of heart function.8 Accordingly it is of great significance to inhibit the over-activation and vicious circle of neurohumor and to reverse ventricular remodeling.9 Up to now angiotensin II receptor blockers (ARBs) are drugs that specifically block Ang II receptors effectively inhibit Ang II or aldosterone escape and provide clinical benefits for heart failure patients. Of all ARBs valsartan has been widely used to treat heart failure.

On the other hand glutamine a main immune nutrient provides nitrogen source for the synthesis of amino acids proteins and nucleic acids. Upon severe wasting diseases such as trauma heart failure major surgery and cancer human body begins to require a large amount of glutamine that if not supplemented in time will give rise to various diseases when exhausted.1112 Therefore we herein analyzed the influences of glutamine and valsartan on the BNP and NT-proBNP of CHF patients.

METHODS

Subjects: A total of 140 CHF patients enrolled in our hospital from September 2010 to January 2014 were selected in this study.

Inclusion criteria: The patients conforming to the diagnostic standards for CHF; the patients suffering from history or clinical manifestations of congestive heart failure for three months; the patients who had New York Heart Association (NYHA) Class III-IV; the patients with written consent.

Exclusion criteria: The patients with hepatic and renal insufficiency or myocardial infarction within three months; the patients who had received or were planning to receive heart transplantation; the patients who had stroke within three months; the patients having thyroid disease blood disorders endocrine disorders or connective tissue disease. There were 77 males and 63 females who were aged 41-79 years old (average: 66.44 13.73). NYHA classification: 80 cases of Class II 30 cases of Class III and 30 cases of Class IV; Disease type: 76 cases of coronary artery disease 34 cases of dilated cardiomyopathy 18 cases of hypertensive heart disease and 12 cases of rheumatic heart disease. They were then divided into a treatment group and a control group by random drawing (n=70) and their basic data such as gender age NYHA classification and disease type were similar (Pgreater than 0.05). Treatment methods:

Control group: This group was subjected to standard anti-heart failure treatment with ARBs Digitalis and diuretics (capoten hydrochlorothiazide and digoxin: 25 mg each qd) and was administered valsartan (Jiangsu Kanion Pharmaceutical Co. Ltd.

National Medicine Permit No. H20090262 80 mg qd) simultaneously for eight consecutive weeks. Treatment group: In addition to the drugs mentioned above this group was also intravenously administered glutamine (Sino-Swed Pharmaceutical Co. Ltd. National Medicine Permit No. H20053409 0.5 mg/kg) by a micro-infusion syringe pump at the speed of 4-5 ml/h for eight consecutive weeks once a week.

Observation indices: Detection of BNP and NT- proBNP: Blood (3 ml) was intravenously collected added into an EP tube containing EDTA-Na2 and centrifuged at 3000 rpm for 10 min to separate the plasma. The levels of BNP and NT-proBNP were detected by the enzyme linked immunoassay with a quick bedside testing instrument (Bosch USA). Detection of cardiac function: Left ventricular end- systolic dimension (LVESD) left ventricular end- diastolic dimension (LVEDD) and left ventricular ejection fraction (LVEF) were detected before and after treatment by an experienced sonographer with a Vivid 7 color Doppler ultrasonography (GE USA).

Evaluation on therapeutic effects: Markedly effective: Basically controlled clinical symptoms and recovery of over two NYHA classes; effective: gradually controlled clinical symptoms and recovery of one NYHA class; ineffective: uncontrolled clinical symptoms and recovery of less than one NYHA class or even deterioration. Detection of T-lymphocyte subsets: Plasma BNP was collected and measured with a kit purchased from Biosino Bio-Technology and Science Inc. (China) with the levels of CD4+ and CD8+ as the main indices.

Statistical analysis: The data were analyzed by SPSS 18.0. The numerical data were expressed as (mean standard deviation) and compared by independent samples t-test and paired t test and the categorical data were expressed as absolute number or percentage and compared with the Chi-square test. Pless than 0.05 was considered statistically significant.

RESULTS

Changes in levels of BNP and NT-proBNP: After treatment the levels of BNP and NT-proBNP decreased significantly compared with those before

Table-I: Changes in levels of BNP and NT-proBNP (x s).

Group###Case number (n)###BNP (ng/L)###NT-proBNP (fmol/ml)

###BeforeAfter###Before After

Treatment group 70###298.9820.83 45.9312.17###4.560.78 2.610.45

Control group###70###300.3221.62 98.3713.87###4.590.67 3.440.67

t###0.2877.984###0.387 9.331

P###less than 0.05less than 0.05###less than 0.05 less than 0.05

Table-II: Changes in cardiac function indices (x s)

Group###Case number (n)###LVEF (%)###LVEDV (mm)###LVEDD (mm)

###Before After###Before###After###BeforeAfter

Treatment group 70###35.568.2445.874.91###249.6445.95165.0932.9893.6515.9661.6716.33

Control group###70###35.568.4740.985.33###252.5265.87206.8740.8393.7816.0974.9616.00

t###0.000 4.983###0.329 7.948 0.0349.223

P###greater than 0.05 less than 0.05###greater than 0.05 less than 0.05 greater than 0.05less than 0.05

(Pless than 0.05) and the treatment group had significantly lower values than the control group did (Pless than 0.05) (Table-I).

Changes in cardiac function indices: The two groups had significantly increased LVEFs as well as significantly decreased LVEDVs and LVEDDs after treatments (Pless than 0.05) compared with those before. Moreover there were also inter-group differences between these values (Pless than 0.05) (Table-II).

Overall therapeutic effects: The overall effective rates of the treatment group and the control group were 98.6% and 90.0% respectively with a statistically significant difference (Pless than 0.05) (Table-III).

Changes in T-lymphocyte subsets: After treatment the levels of CD8+ in both groups significantly decreased (Pless than 0.05) whereas those of CD4+ significantly increased (Pless than 0.05). Meanwhile the two groups also had significantly different values (Pless than 0.05) (Table-IV). DISCUSSION

CHF as the end stage of heart diseases originating from various reasons other than a simple hemodynamic disorder involves many neurohormonal factors that keep worsening this disease.13 Traditionally; CHF is treated targeting hemodynamic disorders which mitigates symptoms by being heart-strengthening diuretic and blood vessel-dilating. However this protocol fails to stop the development of CHF or to raise the survival rate.14 The onset and development of heart failure stem from ventricular remodeling on which the activation of neuroendocrine exerts adverse regulating effects. Particularly long-term over- activation of RAAS predominantly participates in cardiac remodeling and progressive deterioration of CHF.15 As a specific Ang II receptor-blocking agent; valsartan can postpone the development of cardiovascular disease by effectively inhibiting

Table-III: Overall therapeutic effects (n).

Group###Case number (n)###Markedly effective###Effective###Ineffective###Overall effective rate

Treatment group 70 60 9 1###98.6%

Control group###70 40237###90.0%

###5.442

P###less than 0.05

Table-IV: Changes in T-lymphocyte subsets (% x s).

###Group###Case number (n)###CD4+###CD8+

###BeforeAfter###Before After

###Treatment group 70###35.932.98 50.983.18###31.374.71###19.764.78

###Control group###70###36.003.67 45.393.76###31.784.26###25.964.10

###t###0.2875.898###0.438###7.001

###P###less than 0.05less than 0.05###less than 0.05###less than 0.05

Ang II or aldosterone escape with the maximum effective rate of only about 90% though.16 On the other hand glutamine is crucial for the metabolism and synthesis of nucleic acids and mainly energizes the metabolic activities of intestinal mucosal cells so supplementing exogenous glutamine has evident protective effects on the intestinal mucosal barrier.17 In the meantime it is able to stimulate human body to produce glucagon and to boost the intestinal immune function. In this study the overall effective rates of the treatment group and the control group were 98.6% and 90.0% respectively with a statistically significant difference (Pless than 0.05). It has been reported that glutamine can enhance anti-oxidative capacity promote intestinal tract movement improve state of nutrition and thus benefit the recovery of cardiac function.

Besides glutamine maintains the integrity of intestinal mucosa protects the structure and function of intestinal mucosa prevents endotoxin from entering the blood circulation and decreases the expressions of inflammatory cytokines and endotoxin thus reducing the risk of multi-system organ damage. The onset and development of CHF involve activation of the sympathetic nervous system and enhanced synthesis and release of BNP from the dilated atrium and ventricle. When over-activated BNP can dilate the blood vessels and facilitatethe natriuresis of CHF patients by regulating the specific receptors of the kidney and vascular smooth muscle.Upon severe heart failure however this beneficial effect is compensated by vasoactive substance-induced powerful vasoconstriction and sodium retention thereby leading to poor diagnosis. It is now well-known that CHF results in ventricular remodeling by elevating cardiac load.

As a result more NT-proBNP is released because of increased wall tension. Actually NT-proBNP is not released from necrotic cardiac muscle. Instead it mainly originates from the survival cardiac muscle under augmented local tension. Additionally increase in the degree of coronary artery stenosis which is associated with the increase in involvedblood vessels is able to alarm the degree of CHF.20In this case abundant glutamine supplies intestinal mucosal cells with necessary energy and raw materials reduces the formation of cell membrane lipid peroxides and thus minimizes the damage to cardiac function. In general it contributes to the release of some hormones elevates the activity of intestinal glutaminase stimulates the pancreas and choleresis resists the oxidative injury of oxygen free radicals to biomembrane and increases the survival rate of cells.

The two groups had significantly increased LVEFs as well as significantly decreased LVEDVs and LVEDDs after treatments (Pless than 0.05) compared with those before. In addition there were also inter-group differences between these values (Pless than 0.05).

CHF patients are prone to body function decline and immune afunction that may induce vicious circle by leading to intestinal hypoperfusion and translocation of normal flora into blood. Under this circumstance glutamine supplementation improves gastrointestinal functions by enhancing immune function and by boosting nutritional status. Furthermore supplementation of exogenous glutamine can alleviate vigorous decomposition and metabolism circumvent its deficiency under stress facilitate a variety of synthesis and metabolism and exert immune-enhancing effects.15 In this study the levels of CD8+ in both groups significantly decreased after treatment (Pless than 0.05) whereas those of CD4+ significantly increased (Pless than 0.05). The two groups also had significantly different values (Pless than 0.05).

In summary valsartan when combined with glutamine has satisfactory therapeutic effects on CHF patients by being conducive to cardiac function which is related with the decreased expressions of BNP and NT-proBNP as well as the beneficial effects of glutamine on immune function.

Conflicts of interest: All the authors declare no conflicts of interest.

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Publication:Pakistan Journal of Medical Sciences
Date:Feb 28, 2015
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