Wzrost skuteczności leczenia chorych z niestabilną dławicą piersiową przy pomocy donorów tlenku AZOTU

Yevheniya Kh. Zaremba1, Olha V. Zaremba1, Nazar R. Fedchyshyn1, Victoria I. Tkachenko2, Oleh O. Kapustynskyy1

1 Lviv National Medical University named after Danylo Halytsky, Lviv, Ukraine

2 Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine

ABSTRACT

Introction: One of the leading pathogenetic factors of CVD is a violation of the function of the endothelium of the vessels, which leads to endothelial dysfunction.

The aіm: Increasing the efficiency of treatment of patients with NSAP based on the study of the dynamics of clinical picture, blood parametres, CRP, indices of endothelium dependent vasodilatation of the brachial artery with the use of arginine hydrochloride.

Materials and methods: The 45 patients with non-stable angina pectoris (NSAP), who were in inpatient treatment in the cardiological department of the Clinical city hospital of emergency care in Lviv, were examined. The average age of patients was 56.8 ± 4.9 years. The patients were divided into 2 groups depending on the treatment. The first group (22 patients) took the common basic therapy, based on the standards of treatment of patients with NSAP. Another group (23 patients) received common standard (basic) treatment plus arginine hydrochloride, as a endothelial protector. The control group included 15 practically healthy individuals. The statistical analysis of the materials was carried out using the Statistica 8.0 program with the definition of the Student’s t-criterion.

Results: When complex treatment of patients with NSAP using arginine hydrochloride improves the clinical picture faster than with basic therapy. After treatment, statistically significant changes in the lipid profile of the blood were observed only in the group of patients who underwent complex therapy with arginine hydrochloride, the level of total cholesterol, LDL cholesterol and atherogenic index decreased, HDL cholesterol increased compared with those before treatment. After the complex treatment, the rate CRP decreased on 40,8% (p <0,05) and on 29,7% (p> 0,05) in the basic therapy. After 30 days of treatment in the group of patients with intermittent use of arginine aspartate, a positive trend was observed in 74% of patients, considering that endothelial dysfunction was detected in 95.1% of patients before treatment.

Conclusions: Comprehensive treatment of patients with NSAP using arginine hydrochloride is more effective than basic therapy, as evidenced by faster normalization of the clinical picture of the disease, laboratory blood parameters, and improvement of the function of the endothelium.

Wiad Lek 2018, 71, 2 cz. II, -302

 

INTRODUCTION

For many years, the cardiovascular diseases (CVD) take the leading position among causes of mortality in patients of middle age and elderly patients in many countries around the world. According to WHO, 17.5 million people die every year due to CVD. The prevalence of ischemic heart disease remains at the first place among the CVD, its comorbidity with predominantly arterial hypertension increases the risk of developing almost all atherosclerotic cardiovascular complications and causes an important cardiological problem [1].

Today, the modern methods of prophylaxis and treatment of CVD consist of the early detection and correction of risk factors, which can improve the cardiovascular prognosis due to the pathophysiological mechanisms of their influence. There are uncorrected, so-called unmodified risk factors (gender, heredity), and corrected or modified (smoking, hypodynamia, malnutrition, overweight, arterial blood pressure above 140/90 mm Hg, hypercholesterolemia above 5 mmol / L, glucose metabolism disorder, excessive stress).

One of the leading pathogenetic factors of CVD is the endothelial dysfunction of the large and middle caliber vessels, which underlies in the development of atherosclerosis. The main cause of the progression of endothelial dysfunction is a sharp decline in nitrogen oxide (NO) production [2]. About 20 years ago, a new regulatory system was created in the human body, called the Nitrogen Oxide System. The founders of this discovery were the scientists R. Furchgott and J. Zawadzki, who proved the presence of the regulatory mechanism in the endothelium of the vessels, which is responsible for vasodilator responses during the action of endogenous and exogenous biologically active substances. During vasodilation, the endothelium secretes a factor called an endothelial relaxation factor. The connection between endothelial relaxation factor and nitrogen oxide (NO) is proved. R. Furchgott, L. Ignarro and F. Murad were awarded by the Nobel Prize in medicine and physiology in 1998 for the discovery of NO as a signaling molecule in the cardiovascular system [3].

Nitrogen oxide is present in all endothelial cells, regardless of their size and function. Normally, NO is constantly released in the endothelium in low doses to support blood vessels in the state of dilation and to prevent adhesion of blood cells. The ability of the endothelial cells to release the endothelial relaxation factor decreases when the interaction of various factors (mechanical, infectious, metabolic, immune, etc.) occurs, whereas the formation of vasoconstrictor factors persists or increases, thus a condition called endothelial dysfunction is formed [4].

The key point in the development and progression of vascular disease is the regulation of Nitrogen Oxide System and the bioavailability of substrates or cofactors [5]. Therefore, the patients with CVD need additional medical products in complex therapy that would correct the altered endothelial function. The one of these medicines is a nitrogen oxide donator – arginine hydrochloride.

THE AIM

The aim of the study was to increase the efficiency of treatment in patients with non-stable angina pectoris on the basis of studying the dynamics of clinical symptoms, lipid spectrum of blood, C-reactive protein, indexes of endothelium-dependent vasodilatation of the brachial artery with the use of a nitrogen oxide donator (Tivortin®, Yuria-Pharm pharmaceutical corporation, Ukraine).

MATERIALS AND METHODS

The 45 patients with non-stable angina pectoris (NSAP), who were in inpatient treatment in the cardiological department of the Clinical city hospital of emergency care in Lviv, were examined. The average age of patients was 56.8 ± 4.9 years. The patients were divided into 2 groups depending on the treatment. The first group (22 patients) took the common basic therapy, based on the standards of treatment of patients with NSAP (nitrates, antiplatelet agents, anticoagulants, ACE inhibitors, statins, β-blockers, calcium channels antagonists) [6]. Another group (23 patients) received common standard (basic) treatment plus arginine hydrochloride, as a endothelial protector (intravenous 100 ml containing 4.2 g arginine hydrochloride 1 time per day for 10 days, followed by oral administration of 10 ml syrup of arginine aspartate twice daily for 1 month). The control group included 15 practically healthy individuals.

The patients were examined by the general clinical examination (complaints, anamnesis of disease and life, clinical status), the analysis of the lipid profile of the blood, determination of C-reactive protein before and after 10 days of treatment, as well as the index of endothelium-dependent vasodilatation of the shoulder arteries before and after one month of treatment. The lipid blood spectrum was determined by the enzyme method on the analyzer PP-900 (Finland), total cholesterol and HDL cholesterol were determined by method of AN Klimova, NG Nykulcheva (1984); LDL-cholesterol – according to the Friedwald formula (LDL=Total cholesterol – HDL – TG / 2.2 mmol / L). The determination of the C-reactive protein was carried out in a European-quality certified lab “Synevo” using a latex turbidimetric method on a Cobas 6000 analyzer (with module 501) using test systems (Roche Diagnostics, Switzerland).
The study of endothelial function was carried out by non-invasive method of studying the state of peripheral vessels using mechanical stimulation of synthesis and production of NO by an increased flow of blood. The changes in diameter of the artery in response to increased blood flow pressure were investigated as endothelium-dependent vasodilatation [7]. The vessel’s motor function of the brachial artery was studied using duplex ultrasound scanning using a linear transducer 7.5 MHz on the Ultima PA Expert apparatus (Ukraine). The compression of the shoulder artery was carried out by pumping air of the pneumatic cuff superimposed on the shoulder at 50 mm Hg more than initial level of blood pressure with subsequent blasting in 5 minutes. The following parameters were measured: 1) the initial internal diameter of the brachial artery (D1) in millimeters; 2) internal diameter of the brachial artery (D2) in mm after decompression for 60 seconds; 3) the magnitude of the increase in the diameter of the brachial artery after 60 seconds after the removal of the cuff (decompression) in % by the formula: increment = [(D2-D1) / D1] x100%. The character of the reaction of the brachial artery to decompression was evaluated. The reaction was considered as normal (sufficient) if an increase in the diameter of the brachial artery was more than 10% of the initial level after decompression. The reaction was considered as lowered (insufficient) with ≤ 10% of the baseline level, paradoxical – in case of the development of vasoconstriction [8].

The statistical analysis of the materials was carried out using the Statistica 8.0 program with the definition of the Student’s t-criterion.

RESULTS AND DISCUSSION

As a result of the analysis, it was found that the use of a nitric oxide donator (arginine hydrochloride) in the complex treatment of patients with NSAP decreases the number of anginous attacks in 96.1% of patients, increases the tolerance to physical activity in 93.3% of patients, in contrast to the group of patients receiving only baseline therapy – in 85.1% and 81.5% respectively. The patients, who received arginine hydrochloride, were well tolerated to intravenous administration, which contributed to the normalization of blood pressure, did not affect the frequency of cardiac contractions (table I).

The analysis of the lipid profile of the blood in both groups of patients with NSAP showed the significantly abnormal levels total cholesterol, LDL and HDL: the level of total cholesterol was higher on 36%, LDL exceeded the level of healthy persons on 27.9%, HDL- decreased on 32.2%, the atherogenic index was tripled (p<0.001) (table II).

At the 10th day of treatment, statistically significant changes in the lipid profile of the blood were noted only in the group of patients who underwent complex therapy using arginine hydrochloride: the level of total cholesterol decreased on 30,8% (p<0,01), LDL levels – on 30,2% (p<0,01), atherogenic index – on 44,5% (р<0,001), HDL increased on 22,1% (р<0,05) in comparison with the levels before treatment.

Thus, in both groups of patients with non-stable angina pectoris prior to treatment the significant increase in the levels of total cholesterol, LDL and atherogenic index were revealed with the statistically substantiated decrease of the antiatherogenic factor – HDL. After the treatment, a tendency to improvement of the lipid profile of the blood was showed in both groups, but statistically significant changes were observed only after complex treatment with arginine hydrochloride, in the other group of patients the results were less pronounced and statistically unreliable.

The C-reactive protein as a risk factor and deterioration of the prognosis in patients with coronary heart disease was increased in 3 times prior to treatment, but after complex treatment with arginine hydrochloride its level decreased on 40,8% (p <0,05), when in group with basic therapy – only on 29,7% (p> 0,05).

An important functional consequence of endothelial damage and its function is the reduction of vasodilation in response to various pharmacological and physiological stimuli, including reactive hyperemia. The one of the methods for evaluating the function of the endothelium and the individual risk of development in patients with CVD was established during the study of the degree of dilatation of the brachial artery during reactive hyperemia using ultrasound. The 31 patients (68.9% of all patients) had an inadequate extension of the shoulder artery before the treatment that indicates endothelial dysfunction due to metabolic abnormalities of NO by the endothelial relaxation factor. The paradoxical reaction to the compression of the vessel was found in 11 patients (24.4%), which is characteristic of more severe endothelial dysfunction, while in the remaining 3 patients (6.7%) had the increase in the diameter of the brachial artery after decompression more than 10%, which is considered as normal. After 30 days of treatment, the positive dynamics was detected in 74% of patients of the group of patients with per oral arginine aspartate – the endothelium-dependent vasodilatation of the brachial artery was normalized, it became more than 10%, indicating an improvement in the state of the endothelium (endothelial dysfunction was noted at 95.1 % of patients before the treatment). In patients in the group with basic treatment the endothelial dysfunction was noted in 95.5%, among them an increase in the diameter of the brachial artery after decompression was less than 10% in 72.7% of patients, a paradoxical reaction to compression (vasoconstriction) was noted in 22.8% of patients. After 30 days of standard basic treatment, the normalization of the indexes was observed only in 45.5% of patients (Fig. 1).

CONCLUSIONS

1. Complex treatment of patients with non-stable angina pectoris with the use of arginine hydrochloride is more effective than conventional therapy, as evidenced by the faster normalization of the clinical symptoms of the disease, laboratory blood parameters, and improvement of the function of the endothelium.

2. Tivortin® can be successfully used in home and day care settings.

3. In patients with CVD it is necessary to detect and correct the risk factors of the development of CVD, dyslipidemia, increased C-reactive protein and violations of the vasodilatation of brachial artery as a manifestation of endothelial dysfunction.

References

1. Кovalenko V. N., Kornackiy V.M. Regionalni medico-socialni problemi hvorob sistemi krovoobigu. Dinamika ta analiz. Kyiv, 2016, 240 p.

2. Elskiy V.N. Vatutin N.T., Kalinkina N.V. et al. Rol disfunkcii endotelia v geneze serdechno-sosudistyh zabolevanij. Journal AMN Ukrainy. 2008;14 (1):51–62.

3. Bryan N.S., Bian K., Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Frontiers in Bioscience. 2009;14:1–18.

4. Babushkina A.V. L-аrginin s tochki zrenia dokazatelnoy medicini. Ukr.Med.Chasopys. 2009; 6 (74) XI – XII:43-48.

5. Moybenko А. А., Dosenko V. Е., Parhomenko А. N. et all. Endogennie mehanismi kardioprotekcii kak osnova patogeneticheskoy terapii zabolevaniy serdca. Kyiv: Naukova dumka, 2008, 520 p.

6. Unifikovaniy klinichniy protocol pervinnoi, vtorinnoi (specializovanoi) ta tretinnoi (visokospecializovanoi) medichnoi dopomogi «Gostriy koronarniy syndrome bez elevacii segmenta ST»: Order of Health Ministry of Ukraine №164 from 03.03.2016. Kyiv, 2016, 73 p.

7. Gkaliagkousi E., Ritter J., Ferro А. et al. Platelet-derived nitric oxide signaling and regulation. Circ. Res. 2007;101(7):654–662.

8. Correti M., Anderson T.J., Benjamin E.J. et al. Guidelines for the ultrasound assessment of endothelium-dependent flow-mediated vasodilatation of the brachial artery. J. Amer. Coll. Cardiology. 2002;39:257-265.

ADDRESS FOR CORRESPONDENCE

Olha V. Zaremba

tel: +380930235260

e-mail: zarembaolga82@gmail.com

Received: 08.10.2017

Accepted: 30.03.2018

Table I. Dynamics of the clinical symptoms in patients with non-stable angina pectoris during the treatment

Symptoms

Basic therapy (n=22)

Complex therapy with arginine hydrochloride (n=23)

Overload (breast) pains

85,1 %

96,1 %

Number of nitroglycerin tablets

0,7

0,2

Increase tolerance to physical activity

81,5%

93,3%

Palpitation

77,7 %

83,8 %

Abnormalities in heart rhythm

78,3 %

84,5 %

Total weakness

86,9 %

96,4 %

Тable II. Indexes of lipid blood spectrum and C-reactive protein in patients with non-stable angina pectoris during the treatment (M±m)

Indexes

Control
(п=١٥)

Basic therapy
(
n=22)

Complex therapy with arginine hydrochloride (n=23)

Before treatment
(р)

After treatment

1)

Before treatment (р)

After treatment

1)

Total cholesterol, mmol/l

4,67 ± 0,43

7,31 ± 0,64**

6,21 ± 0,58

7,34 ± 0,65**

5,08 ± 0,54*

LDL, mmol/l

2,48 ± 0,24

3,44 ± 0,36#

2,96 ± 0,26

3,48 ± 0,38#

2,43 ± 0,22*

HDL, mmol/l

1,24 ± 0,13

0,84 ± 0,08*

0,96 ± 0,11

0,88 ± 0,08#

1,13 ± 0,09#

Atherogenic index, U

2,02 ± 0,20

6,72 ± 0,62**

4,73 ± 0,47#

6,78 ± 0,64**

3,76 ± 0,34**

С– reactive protein, mg/l

2,1 ± 0,6

7,4 ± 1,5 **

5,2 ± 0,9

7,6 ± 1,2 **

4,5 ± 0,6 #

# – p<0,05; * – p<0,01

** – p<0,001 – the difference is significant in comparison with the indexes of healthy persons

р1- the difference is significant in comparison with the indexes before treatment

Figure 1. Dynamics of the endothelium-dependent vasodilatation of the brachial artery index in patients with non-stable angina pectoris during the course of treatment