Skuteczność redukcji hiperurykemii przy pomocy nisko dawkowej laseroterapii a leczenie nadciśnienia tętniczego

Yevhen L. Kovalenko1, Lesya A. Rudenko2, Oksana K. Melekhovets1, Antonina D. Chepeliuk1, Iurii V. Melekhovets1

1 Sumy State University, Sumy, Ukraine

2 Publishing scientific medical journals Aluna, Konstancin-Jeziorna, Poland

 

ABSTRACT

Introduction: Uric acid (UA) is the risk factors for the development of arterial hypertension (AH). Development of alternative methods of UA level reduction becomes relevant.

The aim – to determine the correlation between UA and endothelial dysfunction and blood pressure level (BP), and to evaluate the effectiveness of low level laser therapy (LLLT).

Material and methods: Patients were divided according to the BP level: the first group included 30 patients with the hyperuricemia and normal BP; the second group – 34 patients with hyperuricemia and AH. Endothelium function was evaluated by test with reactive hyperemia. LLLT was provided by using of the apparatus “Mustang-2000” with wavelength 635 nm.

Results: There is a mean value negative correlation on the Chaddock’s scale r = – 0,6209 between UA and ED; a mean value positive correlation r = 0,48 between UA and daySBP; a weak positive correlation r = 0,33 between UA and DayDBP. LLLT reduces UA level by 4,7% more effective in patients with hyperuricemia without AH than in patients with AH combined with hyperuricemia. LLLT can increase EDVD by 9,87%, reduce UA level by 15,4%, DaySBP and DayDBP – about 7% in patients with AH combined with hyperuricemia than in patients with hyperuricemia along.

Conclusion: Decreasing of DayDBP in hyperuricemia group and both DaySBP and DayDBP in the group of patients with AH combined with hyperuricemia demonstrated the influence of UA on EDVD and AH and the possibility to correct these cardiovascular risk factors with the using of LLLT.

 

Wiad Lek 2018, 71, 7, -1315

 

Introduction

According to ACC/AHA and JNC7 guidelines (2017), arterial hypertension (AH) is recognized as the leading cause of death throughout the world. People at the age of 45 with normal blood pressure (BP) are at risk of AH development in the next 10 years and the percentage in the different countries is about 92%. Dependence of the risk of cardiovascular disease (CVD) from AH level is logarithmic in nature: systolic blood pressure (SBP) in the range from 115 to 180 mm Hg and day diastolic blood pressure (DayDBP) from 75 to 105 mm Hg. Every increase of SBP level to 20 mm Hg or DayDBP to 10 mm Hg is associated with the doubling of risk of death from stroke and other vascular diseases [1]. In 2017 the American Heart Association made a controversial recommendation to lower the threshold for what constitutes high blood pressure from 140/80 mmHg to 130/80 mm Hg. It also recommended lowering the threshold for drug treatment in adults who are at high risk for CVD.  

So, arisen amount of hypertension patients with low-body BP-level will need an additional nonpharmacological correction of risk factors. Among the possible methods low level laser therapy may occupy advanced place.

Numerous papers prove the influence of uric acid (UA) on most risk factors for the development of AH [2]. Formation of different forms of chemically active oxygen with the help of xanthinoxidases is the link between UA level, endothelial dysfunction (ED) and AH. Clinical application of xanthinoxidase inhibitor allopurinol has uncomprehensive properties in correction of BP [3]. Considering this, development of alternative methods of UA level reduction (including drug-free ones) becomes relevant.

The aim

The objective of the study is to determine the correlation between UA level and endothelial dysfunction and blood pressure level, and to evaluate the effectiveness of low level laser therapy.

Material and methods

Total of 64 patients with hyperuricemia (UA>360 µmol/L) were included in the research; they were divided into two groups according to the level of BP: the first group (HU) included 30 patients with the normal level of average daily BP; the second group (HU+AH) included 34 patients with stage I AH. Secondary character of AH, bone pathology and decompensation of the comorbid conditions were the exclusion criteria. The groups were comparable in age and sex (table I).

The function of endothelium was evaluated by means of non-invasive test with reactive hyperemia. Ultrasound machine SonoScape S6Pro with linear probe L741 and working frequency 6,6-11,0 MHz was used for measuring of brachial artery diameter. Imaging and anatomy characteristics were identified in two-dimensional scanning mode, dynamic parameters – in color flow mapping mode. Brachial compression and blood pressure measurement were performed by using of sphygmomanometer Little Doctor LD-SO13. Test with reactive hyperemia for defining of endothelium-dependent vasodilation (EDVD) was performed on fasting state a room temperature of 23°С. A day before performing the test, vasoactive drug, energy drinks, coffee, tea, smoking and alcohol consumption were discontinued. Blood pressure cuff, in which pressure was 50 mm Hg higher than systolic BP, was applied to the upper third of the arm – it temporarily blocked the blood flow in brachial artery. Compression was performed for 5 minutes, and then rapid decompression was performed. Artery size and blood flow criteria were defined 60 seconds after decompression. Absence of more than 10% increasing of brachial artery diameter in the test with reactive hyperemia or vasoconstriction were considered to be criteria of vasomotor endothelial dysfunction [4].

A 24 hour ABPM was performed by using of a 24 hour blood pressure monitor ABMP-50 HEACO. Reference indices of day systolic blood pressure (DaySBP) were ≤ 140 mm Hg, and day diastolic blood pressure (DayDBP) ≤ 90 mm Hg [5].

Biochemical blood tests were done according to standard technique. Patients were examined at baseline and after 2 weeks.

Low level laser therapy (LLLT) course was provided by using of sterile optical fiber with 500 μm which was inserted into the cubital vein of the patient and joined with radiant head of the apparatus “Mustang-2000” with wavelength 635 nm. Power at the end of the light guide was 1,5 mWt, irradiation power density in continuous operation was 0,2 W/cm2, fluence 0,2 J/cm2. Total irradiation dose of 900 sec exposures and the 10-procedure course was equal to 180 J/cm2.

Statistical processing of the obtained research results was carried out using statistical software package StatSoft Statistica. The minimum required sample size, sufficient to confirm the clinical relevance of the treatment, was defined at the planning stage of the studies. Obtained results have nonparametric distribution. Indexes were described with median and two quartiles (Q1 and Q3). The strength and direction of association between two ranked variables was determined by Spearman’s rank correlation coefficient.

Results and Discussion

To revealed correlation between UA level and changes in ED and BP in 64 patients who were enrolled in the research, correlational-regression analysis was performed. Thus, it was proved that there is a negative relationship with a mean value of correlation strength on the Chaddock’s scale r = – 0,6209 (p < 0,001) between UA and ED; a positive relationship with a mean value of correlation strength r 0,48 (p < 0,001) between UA and day SBP; a weak positive relationship r = 0,33 (p < 0,001) between UA and day DBP (table II).

Statistically significant difference between mean levels of UA in patients of both groups was found: patients of the group 2 with AH have 20% higher mean level of UA compared to the patients of the group 1 with normal pressure (table I). At the enrollment into research EDVD level was 28,4% higher in the group 1 compared to the group 2.

Dynamics of risk factor values in the both groups was evaluated before treatment and on 2 weeks’ follow-up (Table III).

Statistically significant elevations of EDVD by 35,5% compare with baseline level in the group 1 (HU) (p<0,05) and by 49,7% in the group 2 (HU+AH) (p<0,001) were obtained after performing of LLLT (figure 1-4).

Analysis of baseline levels of daily average BP shows significant differences between groups: for group HU – DaySBP 129 mmHg, DayDBP 81 mmHg, for group HU+АH – DaySBP 149 mmHg (р<0,001), DayDBP 90 mmHg (р<0,05) respectively. After the treatment, there has been a reduction of BP in both groups: group HU – DaySBP 125 mmHg, reduction 3,1% (р >0,05); DayDBP 74 mmHg, reduction 8,6% (р<0,05); group HU+АH – DaySBP 141 mmHg, reduction 5,7% (р<0,05); DayDBP 87 mmHg, reduction 3,3% (р<0,05). DaySBP in the group HU was reducing in the range of reference values and was statistically unreliable. In the group HU+АH statistically reliable decreasing in both DaySBP and DayDBP was determined.

At baseline the level of UA in the groups was significantly different: mean UA level in the HU+AH group by 7,7% higher than in the HU group (р<0,05). Before LLLT the level of UA in the group HU was 457 µmol/L, after – 390 µmol/L; so, reduction degree was of 14,7% (р<0,05). Result of LLLT treatment in the group HU+AH – reduction of UA level by 15,9% (р<0,05): from 496 µmol/L to 417 µmol/L.

LLLT reduces UA level by 4,7% more effective in patients with hyperuricemia without AH than in patients with AH combined with hyperuricemia. LLLT can increase EDVD by 9,87%, reduce UA level by 15,4%, DaySBP – by 7,16%, DayDBP – by 7% in patients with AH combined with hyperuricemia than in patients with hyperuricemia along.

The research found that there is mean negative correlation between the level of uric acid and EDVD and mean positive correlation with DaySBP. Patients of the group 1 had normal EDVD indices before enrolment despite hyperuricemia, whereas the group 2 had AH development and a reduced EDVD level. From the obtained results, critical for the development of endothelial dysfunction and arterial hypertension threshold of UA is higher than a defined reference value. LLLT as an alternative method of correction of UA and BP level is based on the theory that provides the existence of target-acceptor for the action of laser irradiation. Extracellular superoxide dismutase Cu-Zn (SOD) is regarded as being such an acceptor [6]. In the course of review of SOD absorption spectrum, it was proved that this enzyme is a chromophore-acceptor of laser irradiation with wavelength of 422-650 nm and the enzyme activates upon interaction with laser irradiation [7]. Among all superoxide dismutase 1, 2 and 3 representatives, extracellular form SOD3 attracts the most attention. It is a secretory enzyme localized in plasma and endothelium [8]. Decreasing of SOD3 activity leads to accumulation of, decreasing of nitric oxide synthase activity and decreasing of NO production [9]. In our view, this may explain increasing of EDVD of brachial artery after the LLLT course – that was demonstrated in our research. It should be noted that reactive oxygen species can independently stimulate xantinoxidase activity. It causes the increasing of uric acid synthesis [10]. Due to extracellular localization, SOD3 has an important role to block production that decreases the activity of xantinoxidase and UA level [11]. Thus, we can explain an effective decrease of UA level obtained after LLLT.

In addition, xantinoxidase in UA synthesis is a source of reactive oxygen species [12]. Data about photorelaxation in coronary arteries [13] confirm vasodilatory properties of LLLT and demonstrate coincide with the results of our research that identified a significant decreasing of day SBP in patients with hyperuricemia combined with arterial hypertension. So, using of LLLT as a method of drug-free correction of UA requires further research.

Conclusion

Moderate strength of positive correlation between uric acid level and DaySBP and negative between uric acid level and EDVD in both groups confirms the role of UA as an early marker of AH development.

Decreasing of DayDBP in hyperuricemia group and both DaySBP and DayDBP in the group of patients with AH combined with hyperuricemia demonstrated the influence of UA on EDVD and AH and the possibility to correct these cardiovascular risk factors with the using of LLLT.

References

1. Whelton PK, et al. 2017 High Blood Pressure Clinical Practice Guideline: Executive Summary Page 1 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, рр 18-35.

2. RashikaEl Ridi, Hatem Tallima Physiological functions and pathogenic potential of uric acid: A review Journal of Advanced Research Volume 8, Issue 5, September 2017, Pages 487-493 doi:  10.1016/j.jare.2017.03.003

3. Braunwald’s heart disease: a textbook of cardiovascular medicine, Peter Libby, et al., 8th ed. 2013 Volume 3, pp. 1070.

4. Andreas J. Flammer, Todd Anderson, David S. Celermajer The Assessment of Endothelial Function – From Research into Clinical Practice. Circulation. 2012 Aug 7; 126(6): 753–767. doi:  10.1161/CIRCULATIONAHA.112.093245

5. Ehud Grossman Ambulatory Blood Pressure Monitoring in the Diagnosis and Management of Hypertension Diabetes Care 2013 Aug; 36(Supplement 2): S307-S311.https://doi.org/10.2337/dcS13-2039.

6. Lim W1, Kim JLim CKim SJeon SKarna SCho MChoi HKim O. Effect of 635 nm light-emitting diode irradiation on intracellular superoxide anion scavenging independent of the cellular enzymatic antioxidant system. Photomed Laser Surg. 2012 Aug;30(8):451-9. doi: 10.1089/pho.2011.3199. Epub 2012 Jul 9.

7. Y. A. Vladimirov, T. V. Zhydkova, Y. V. Proskurnina, D. Y. Izmaylov Bout activation mechanism of SOD activity in action of laser and light-emiting diode irradiation of cells and tissues of human and animals. Photobiology and experimental photomedicine 1, 2 ‘2012: 112-117.

8. Ehab H. SarsourAmanda L. Kalen, and Prabhat C. Goswami. Manganese Superoxide Dismutase Regulates a Redox Cycle Within the Cell Cycle. Antioxid Redox Signal. 2014 Apr 1; 20(10): 1618–1627. doi:  10.1089/ars.2013.5303

9. Sergio Di Meo,  ,  Tanea T. Reed,  Paola Venditti,  and Victor Manuel Victor. Role of ROS and RNS Sources in Physiological and Pathological Conditions.Oxidative Medicine and Cellular Logevity. 2016; 2016: 1245049. Published online 2016 Jul 12. doi:  10.1155/2016/1245049

10. Daria Pasalic,1,* Natalija Marinkovic,2 and Lana Feher-Turkovic3 Uric acid as one of the important factors in multifactorial disorders – facts and controversies. Biochem Medica (Zagreb). 2012 Feb; 22(1): 63–75.

11. Erin L. Foresman and Francis J. Miller, Jr. Extracellular but not cytosolic superoxide dismutase protects against oxidant-mediated endothelial dysfunction. Redox Biol. 2013; 1(1): 292–296. Published online 2013 May 24. doi: 10.1016/j.redox.2013.04.003

12. Eric E. Kelley. A New Paradigm for XOR-Catalyzed Reactive Species Generation in the Endothelium. Pharmacol Rep. 2015 Aug; 67(4): 669–674. doi:10.1016/j.pharep.2015.05.004

13. Plass CA1, Wieselthaler GMPodesser BKPrusa AM. Low-level-laser irradiation induces photorelaxation in coronary arteries and overcomes vasospasm of internal thoracic arteries. Lasers Surg Med. 2012 Nov;44(9):705-11. doi: 10.1002/lsm.22075. Epub 2012 Sep 24.

 

Authors’ contributions:

According to the order of the Authorship

Conflict of interest:

The Authors declare no conflict of interest

CORRESPONDING AUTHOR

Oksana K. Melekhovets

Sumy State University

1 Sanatorna Str., 40018, Sumy, Ukraine

tel: +380667122929

e-mail: melekhovets.oksana@gmail.com

Received: 05.07.2018

Accepted: 20.09.2018

Table I. Main characteristic of the HU (hyperuricimic) and HU+AH (hyperuricimic+arterial hypertension) group. Data are expressed as mean +SD. e GFR is expressed as median [25- 75 percentile]

Index, unit of measurement

Investigated groups

P1-2-value

HU

n = 30

HU + AH

n = 34

Age

48 [29-51]

51 [31-59]

>0,05

Sex, men, n (%)

14(46%)

16(47%)

>0,05

Daytime SBP, (mmHg)

129 [118; 142 ]

149 [132; 192]

<0,05

Daytime DBP, mmHg

81 [72;89]

90 [75; 107]

<0,05

Uric acid, µmol/L

457(425-487)

496(480-560)

<0,05

Glycosylated hemoglobin, %

5,7(4,6-5,9)

5,8(4,4-5,7)

>0,05

Glomerular filtration rate, mL/min

110(89-120,1)

112(90-123)

>0,05

Body mass index

23,8(23,0-24,1)

22,1(19,8-25,0)

P1-2>0,05

P1-2 – the significance of the difference between the 1 st and 2 nd group before treatment

p-values were calculated using Spiermen test or independent t-tests appropriate

Table II. Correlation between the level of uric acid and endothelial-dependent vasodilation, daytime systolic and diastolic arterial pressure (n=64)

Index

EDVD

Daytime SBP

Daytime DBP

r

-0,6209

0,485854

0,332786

p

< 0,001

< 0,001

< 0,001

p-values were calculated using Spiermen test or independent t-tests appropriate

Table III. Influence of the low level laser therapy on the dynamics of indicators of endothelium dependent vasodilation (EDVD), daytime systolic and diastolic blood pressure (DaySBP/ DayDBP), uric acid(UA) level in the studied groups (Me [min; max], n= 64).

Index, unit of measurement

Investigated groups

P-value

HU (n = 30)

HU + AH (n = 34)

Before LLLT

After LLLT

Before LLLT

After LLLT

1

2

3

4

EDVD (%)

12,02

[8,25; 21,23]

18,65

[8,82; 28,23]

8,6

[1,2; 13,95]

17,09

[5,47; 26,5]

P1-3<0,001

P1-2 <0,05

P3-4<0,001

P2-4<0,05

Δ1 % 35,5

Δ2 % 49,7

DaySBP (mmHg)

129

[118; 139 ]

125

[116; 131]

149

[132; 192]

141

[125; 178]

P1-3<0,001

P1-2 >0,05

P3-4<0,05

P2-4<0,001

Δ1 % -3,1

Δ2 % -5,7

DayDBP (mmHg)

81 [72;89]

74 [70; 86]

90 [75; 107]

87 [71; 103]

P1-3<0,05

P1-2 <0,05

P3-4<0,05

P2-4<0,05

Δ1 % -8,6

Δ2 % -3,3

Uric Acid (µmol/L)

457

[361; 622]

390

[168;542]

496

[355; 678]

417

[226; 657]

P1-3<0,05

P1-2 <0,05

P3-4<0,05

P2-4<0,05

Δ1 % -14,7

Δ2 % -15,9

Notes: P1-3 – the significance of the difference between the 1 st and 2 nd group before treatment; P1-2 – the significance of the difference between the indicators in the 1st group before and after treatment; P3-4 – the significance of the difference between the values in the 2nd group before and after treatment; P2-4 – the significance of the difference between the 1 st and 2 nd group after treatment.

Figure 1. The diameter of the brachial artery (4.7 mm) and the peak systolic blood flow (68 cm / sec) in a patient from the group HU + AH at the baseline.

Figure 2. The brachial artery diameter (5,02 mm) dynamic after performing the test with reactive hyperemia; EDVD 6.8% and peak systolic blood flow (72 cm / sec) in the patient from the group HU + AH at the baseline.

Figure 3. The diameter of the brachial artery (4.6 mm) and the peak systolic blood flow (66 cm / sec) in a patient from the group HU + AH after LLLT before performing the test with reactive hyperemia.

Figure 4. The brachial artery diameter (5.5 mm) dynamic; EDVD 19.6% and peak systolic blood flow (57 cm / sec) after performing the test with reactive hyperemia in the patient from the group HU + AH after LLLT.