Wpływ kwercetyny na parametry echokardiograficzne funkcji rozkurczowej lewej komory u osób z dną i pierwotnym nadciśnieniem tętniczym

Vitalii E. Kondratiuk, Yuliia P. Synytsia

Propedeutic Internal Medicine Department 2, Bogomolets National Medical University, Kyiv, Ukraine

ABSTRACT

Introduction: Gout is associated closely with an increased risk of cardiovascular (CV) events including heart failure.

The aim: Improvement of treating patients with gout and essential hypertension (EH) by applying course therapy of quercetin of the echocardiographic parameters of the left ventricular diastolic function.

Materials and methods: 84 male patients with gout and EH. The main group consists of 43 patients who have performed treatment with quercetin and a comparative group of 41 patients who were performed treatment without quercetin.

Results: In patients with gout in combination with EH, the addition of quercetin to antihypertensive and urate-lowering treatment have a protective effect on cardiac diastolic function (the baseline-adjusted changes during 12 months were significantly lower in the quercetin group than in the comparative group for E/e’ (-0,41± 0,01 vs. -0,08 ± 0,01, p = 0,001) and LV mass index, g/m2 (-3,28 ± 0,02 vs. -2,04 ± 0,03, p = 0,02). Also this combination contributed to faster and more pronounced achievement of the target level of uric acid (reduction by 33,7%), normalize renal function (the rate of glomerular filtration, ml/min/1,73 m2 level increase by 13,3%) and also had a cumulative antihypertensive effect (reduction of systolic blood pressure by 5,5% and diastolic blood pressure by 3,6%) without increasing the dose or adding new antihypertensive drugs.

Conclusion: adding quercetin to antihypertensive and urate-lowering regimens for 12 months in patients with gout and EH improve echocardiographic parameter of diastolic function left ventricular, purine metabolism, renal function and additional normalize blood pressure.

Wiad Lek 2018, 71, 8, -1559

INTRODUCTION

Gout is a common metabolic disorder characterized by hyperuricemia and chronic inflammation. There are controversial data on how the uric acid (UA) affects the cardiovascular system: on the one hand, it is a powerful antioxidant that neutralizes up to 70,0% free radicals in plasma [1] and increases production of nitric oxide and thus causes vasodilatation [2], and on the other hand, in the presence of hydrophobic conditions, it can act as a prooxidant, inducing intracellular and mitochondrial oxidant stress through stimulation of NADPH oxidase [3], as well as the synthesis of proinflammatory cytokines – interleukin-1, -6, -10, -18, endothelin-1, and tumor necrosis factor-alpha [4].

Gout is associated closely with an increased risk of cardiovascular (CV) events including heart failure [15-16]. Among patients with gout in the 2007–2008 National Health and Nutrition Examination Survey study, 71% had chronic kidney disease, 14% had a history of myocardial infarction, 11% had a history of heart failure, and 10% had a history of stroke [13]. Gout, not hyperuricemia alone, is associated with LV diastolic dysfunction and LA volume enlargement [14].

Given the above facts of the influence of the UA on the development of hypertension, endothelium disorder, inflammation, deterioration of the prognosis for patients with cardiovascular disease, the issue of optimizing the treatment of patients with gout in conjunction with hypertension and the search for new ways to correct metabolic disorders, the development of new effective prevention of possible further fatal cardiovascular events. Several observational studies and meta-analyses have suggested that treating hyperuricemia in patients with gout and may improve renal and CV outcomes [12]. Actual is the search for new safe, effective, economically sound drugs that could be recommended to patients with gout and essential hypertension (EH), one of them is quercetin.

Quercetin is an important flavonoid, which is present in red onions, apples, berries and red wine [8]. Many studies have shown that quercetin has antioxidant, anti-inflammatory, anticancer, immunomodulatory and vasodilating effects [5, 8, 9] and has been confirmed with safety and effectiveness of cancer [6]. Quercetin stimulates Na+ -K+ -2Cl cotransporter 1 (NKCC1), which is one of the most important ion transporters regulating the cytosolic Cl concentration (through elevation of Cl and reduction Na+ reabsorption in renal epithelial cells) [10]. Also, was studied X-ray crystal structure of a xanthine oxidase complex with the flavonoid inhibitor quercetin by a ping-pong mechanism [7, 11].

THE AIM

Improvement of treating patients with gout and EH by applying course therapy of quercetin of the echocardiographic parameters of a left ventricular diastolic function.

MATERIALS AND METHODS

In order to achieve our goals we registered 118 male patients with gout and EH, were treated at the Kyiv City Clinical Hospital № 3 in the Department of Rheumatology and Cardiology in 2015-2017. All subjects signed their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Clinical Center of Ukraine. The diagnosis of gout was established in accordance with the recommendations of the American College of Rheumatologists and the European Anti-rheumatic League (ACR/EULAR, 2015), and EH according to the recommendations of the European Society for Hypertension (ESH) and the European Society of Cardiology (ESC) 2013. The criteria for exclusion from the study were the presence of an EH of the 1st or 3rd degree and stage I or III, a permanent form of arrhythmias (fibrillation and atrial flutter), chronic kidney disease stage 4-5, severe liver failure, diabetes mellitus, obesity of the 3rd degree, mental, cancer and infectious diseases.

For the correction of hyperuricemia, all patients with gout were recommended allopurinol at a starting dose of 100 mg/day with a gradual increase in this dose of 100 mg every 2 weeks. For correction of hypertension patients took losartan 100 mg/day, and if necessary in 2 weeks, amlodipine was added in a dose 5-10 mg/day. Patients with a blood pressure lower than 140/90 mm Hg. and with a concentration of UA greater than 360 μmol/l after 6 weeks of treatment were included in the treatment group (n = 84) for further purine exchange adjustment according to the proposed treatment method with quercetin. The patients were divided into 2 groups: main group – 43 (51,8 %) patients, who take quercetin and 41 (49,4 %) patients in the comparison group without quercetin (Fig. 1).

Patients in both treatment groups continued to receive appropriate antihypertensive therapy and gradually increased the dose of allopurinol 100 mg every 4 weeks until reaching the target UA (<360 μmol/L). The average daily dose of allopurinol after 6 months of treatment was 600 mg. The maximum daily dose of allopurinol was 800 mg. Patients in the main group, in addition to antihypertensive and urate-lowering therapy, received additionally flavonoid quercetin in doses 1000 mg 2 times per day for 30 minutes before meals for 6 months, then maintenance dose was 500 mg 2 times per day for another 6 months. The comparative group was based on baseline antihypertensive and urate-lowering therapy but without the addition of quercetin. Repeated examination of such patients was carried out before treatment and after 6 and 12 months of therapy.

Table 1 shows a comparison of the clinical characteristics at baseline and at 12 months and baseline-adjusted changes after 12 months between the two patient groups. There was no difference in the level of UA, blood pressure and body mass index between the groups were similar. Also, other parameters, such as lipid and renal profiles, were similar in the two groups throughout the study. The incidence of a previous history of CV diseases, including heart failure, was not different in the two groups.

All patients were given a comprehensive physical and laboratory-instrumental examination. Laboratory methods included: general clinical blood tests, urine and biochemical blood tests with purine, lipid and carbohydrate metabolism, renal filtration function, followed by calculating the rate of glomerular filtration (GFR) using the formula of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Blood samples were collected at baseline and after 6 and 12 months.

Echocardiography was performed in a standard manner using commercially available ultrasound diagnostic machines «iE 33 Philips» (USA). The recordings and measurements were performed in accordance with the guidelines issued by the American Society of Echocardiography [17]. Transmitral flow velocity was recorded from the apical long-axis or four-chamber view. The ratio of the peak early diastolic (E) and the peak atrial systolic (A) transmitral flow velocities were calculated (E/A). The deceleration time (DT) of early transmitral flow velocity was also measured. The mean peak early diastolic mitral annular velocity (e’) in the septal and lateral side was measured, and the ratio of E to e’ (E/e’) then calculated as a marker of left ventricular (LV) filling pressure. Also were measured LV end-diastolic dimensions (LVDd) and LV end-systolic dimensions (LVDs), the size of the left atrium (LA, cm). LV mass was calculated using the ASE convention [18]. Relative wall thickness was calculated as two times posterior wall thickness divided by LVDd.

All data are expressed as a mean ± standard deviation. All reported probability values were two-sided with a p-value <0.05 considered statistically significant. The percentage changes in the variables during the study period were calculated as (values obtained at 6 or 12 months after treatment randomization—the baseline value)/baseline value. The differences between the two groups were assessed, where appropriate, by either the Student’s t-test, Mann–Whitney test, or Fisher’s exact test. Data were analyzed using one-way ANOVA followed by (Repeated Measures Analysis of Variance with Effect Sizesand Powers). Statistical analysis was carried out using the STATISTICA 8.0.

RESULTS AND DISCUSSION

The total number of persons among the surveyed patients with diastolic dysfunction of the LV (DD LV) was 58 (69,0%) and frequency was similar in the two groups. Among the patients in the main group DD LV was found in 30 (69,8%) surveyed and 28 (68,3%) among the patients in the comparative group. During of the period of treatment with quercetin inclusion, the frequency of DD LV in the main group decrease from 69,8% at the baseline of treatment to 44,2% (p < 0,001) in 6 months of therapy and to 41,1% (p < 0,001) in 12 months and in the comparative group also decrease from 68,3% at the baseline of treatment to 60,3% (p = 0,07) in 6 months of therapy and to 50,0% (p = 0,02) in 12 months.

A complete list of changes in the echocardiographic parameters on the background of the treatment in both groups is shown in Table 2. Baseline parameter of DD LV – E/e’ was significantly higher in the main group than in the comparative group, the baseline-adjusted change in E/e’ during 12 months of treatment was significantly lower in the quercetin group than in the comparative group. LV mass index was also significantly lower in the main group than in the comparative group. Other echocardiographic indicators of a LV diastolic function have not significantly changed, although the trend for their improvement was observed in the main and in the comparative groups.

During of the period treatment with additional application of quercetin in 12 months, 7% of patients completely recovered DD VL from type I and 11,6% of patients had a transformation from type II DD LV to type І. In the comparative group, there was no complete recovery in the DD LV structure; only 10,0% of patients had a transformation from type II in I. However, the type III DD LV remained torpid in both study groups.

Also, positive dynamics was observed in the main group among the indicators characterizing the renal function: the level of creatinine significantly decreased by 10,8% (p = 0,03) in 6 months and continued to decrease to 22,0% (p < 0,01) in12 months of therapy. A similar picture was observed with an increase in GFR in 6 and 12 months by 6,9% (p = 0,04) and by 13,3% (p < 0,01) respectively. There were no statistically significant changes in the comparative group.

In patients with gout in combination with hypertension, after 6 months of complex therapy with the addition of quercetin of the target level of UA reached 34,9% patients, and in the comparison group only 30,0% patients. However, after 12 months, in the background of allopurinol application in the average dose of 600 mg per day, the target UA level in the main group reached 77,8% versus 55,0% patients in the comparative group (p < 0,05). In the main group the level of UA on average decreased by 24,6% (p < 0,001) for 6 months of treatment and by 33,7% (p < 0,001) – for 12 months. In the comparative group, after 6 months of therapy, the level of UA decreased by 14,5% (p = 0,01), and after 12 months – 20,3% (p < 0,01).

In patients with gout in combination with EH, the addition of quercetin to combined urate-lowering and antihypertensive therapy for 12 months contributed to faster and more pronounced achievement of the target level of UA (reduction by 33,7%), and also had a cumulative antihypertensive effect (reduction of systolic blood pressure (SBP ) by 5,5% and diastolic blood pressure (DBP by 3,6%)) without increasing the dose or adding new antihypertensive drugs.

The scientific novelty of the study is that on the basis of a complex analysis of structural and functional changes from the side of the cardiovascular system and the evaluation of metabolic disorders in gout patients in combination with EH, it is possible to identify the main pathogenetic links, the correction of which will prevent the possible cardiovascular catastrophes and improve the course the main illness is gout.

The significance of the results of the study in clinical practice is to substantiate the feasibility of using in routine practice an ultrasound examination of the major vessels of the head and neck, the renal arteries and the echocardiography to detect early changes from the side of the cardiovascular system with the further prevention of their progression. To prove the medical, social and economic feasibility of using quercetin for the treatment of patients with gout in combination with EH, which will improve purine metabolism, the state of the cardiovascular system, normalize blood pressure, improve the clinical course of the underlying disease, as well as the quality of life.

CONCLUSIONS

The study demonstrated that adding quercetin to antihypertensive and urate-lowering regimens for 12 months in patients with gout and EH improve echocardiographic parameter of diastolic function left ventricular, purine metabolism, renal function and additional normalize blood pressure. These results suggest that quercetin is potentially a beneficial agent for treating patients with gout and EH.

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Yuliia P. Synytsia

29 Myru St., 08132 Vyshneve, Ukraine

tel: +380675274622

e-mail: ysinitsa@ukr.net

Received: 07.08.2018

Accepted: 05.11.2018

Fig.1. Study participant flow diagram.

Table I. Characteristics between the two groups

Variables

Baseline

24 months

Least square means of baseline-adjusted changes

Main group

(n = 43)

Comparative group

(n = 41)

p value

Main group

(n = 43)

Comparative group

(n = 41)

p value

Main group

(n = 43)

Comparative group

(n = 41)

p value

Age, year

57,2 ± 7,8

56,2 ± 6,9

0,59

Body mass index, kg/m2

30,9 ± 3,9

31,1 ± 3,9

0,88

29,8 ± 3,8

30,8 ± 3,7

0,82

-0,12 ± 0,14

-0,28 ± 0,11

0,21

Systolic blood pressure, mmHg

137,1 ± 7,9

138,8 ± 6,4

0,65

129,5 ± 8,1

149,0 ± 12,4

0,65

-0,03 ± 0,01

-0,08 ± 0,04

0,03

Diastolic blood pressure, mmHg

84,4 ± 5,5

84,4 ± 9,7

0,21

80,8 ± 7,5

94,4 ± 9,7

0,21

-0,04 ± 0,02

-0,12 ± 0,08

0,04

Heart rate, beats/min

72 ± 12

70 ± 11

0,62

73± 12

69 ± 11

0,62

-0,31 ± 0,22

0,25 ± 0,18

0,12

Uric acid, μmol/L

532 ± 96,9

496,3 ± 63,1

0,21

301 ± 26,7

341,3 ± 24,2

0,12

-0,01 ± 0,02

-0,04 ± 0,02

0,01

Total cholesterol, mmol/L

5,6 ± 2,2

5,5 ± 1,8

0,82

5,3

5,3

0,24

-0,31 ± 0,06

-0,18 ± 0,14

0,27

HDL cholesterol, mmol/L

3,3 ± 0,8

3,3 ± 0,9

0,67

3,2 ± 0,8

3,3 ± 0,9

0,43

-0,91 ± 0,75

-0,98 ± 0,86

0,52

Triglycerides, mmol/L

2,1 ± 0,8

2,2 ± 0,8

0,34

2,1 ± 0,8

2,1 ± 0,8

0,31

-0,8 ± 0,10

-0,8 ± 0,12

0,43

Creatinine, μmol/L

108,3 ± 17,9

103,23 ± 15,9

0,30

84,8 ± 10,2

92,1 ± 9,8

0,01

-0,02 ± 0,04

-0,03 ± 0,05

0,03

eGFR, ml/min/1,73 m2

81,4 ± 18,4

82,7 ± 15,3

0,85

92,2 ± 16,4

89,7 ± 13,5

0,07

3,14 ± 0,9

2,91 ± 0,74

0,06

Fasting plasma glucose, mmol/L

5,5 ± 1,1

5,6 ± 1,2

0,54

5,7 ± 1,1

5,6 ± 1,1

0,47

1,7 ± 0,5

1,9 ± 0,6

0,57

High-sensitive CRP, ng/mL

6,2 ± 1,3

6,4 ± 1,2

0,24

5,9 ± 1,3

6,2 ± 1,3

0,08

-0,42 ± 0,11

-0,31 ± 0,20

Dyslipidemia,n (%)

32 (74,4)

31 (75,5)

0,18

Cerebrovascular disease, n (%)

9 (20,9)

8 (19,5)

0,22

Duration of gout, years

6,6 ± 3,2

6,0 ± 3,1

0,31

Duration of hypertension, years

6,7 ± 3,0

6,3 ± 3,0

0,40

Medications:

losartan, 100 mg per day, n (%)

43 (100)

41 (100)

0,99

43 (100)

41 (100)

0,99

amlodipine, 5 mg per day, n (%)

25 (58,1)

21 (51,2)

0,75

28 (65,1)

23 (56,1)

0,75

amlodipine, 10 mg per day, n (%)

18 (41,9)

20 (48,8)

0,37

15 (34,9)

18 (43,9)

0,37

Notes: Data for categorical variables are given as number (%); data for continuous variables given as mean ± standard deviation. Skewed data were calculated after logarithmic translation. In the right column, values are shown as baseline-adjusted least square mean ± standard error

Table II. Comparisons of echocardiographic parameters at baseline, 24 months and baseline-adjusted changes after 24 months of treatment

Variables

Baseline

24 months

Least square means of baseline-adjusted changes

Main group

(n = 43)

Comparative group

(n = 41)

p value

Main group

(n = 43)

Comparative group

(n = 41)

p value

Main group

(n = 43)

Comparative group

(n = 41)

p value

E, cm/s

70,1 ± 5,3

68,1 ± 3,3

0,34

72,1 ± 4,3

68,2 ± 4,1

0,28

-0,81± 0,01

1,7 ± 0,02

0,41

e’, cm/s

7,95 ± 1,3

7,91± 2,2

0,18

8,9± 2,3

8,11 ± 3,3

0,04

0,35 ± 0,08

0,13 ± 0,02

0,002

E/e’

8,8 ± 1,7

8,6 ± 1,2

0,31

8,1 ± 0,14

8,4 ± 1,2

0,07

-0,41± 0,01

-0,08 ± 0,01

0,001

A, cm/s

74,1 ± 7,3

62,2 ± 8,4

0,06

73,1 ± 6,1

64,3 ± 4,4

0,11

-0,16 ± 0,02

2,4 ± 0,01

0,31

E/A

1,1 ± 0,06

1,13 ± 0,07

0,74

1,2 ± 0,05

1,16 ± 0,07

0,37

0,02 ± 0,02

0,04 ± 0,02

0,65

Deceleration time, msec

210,9 ± 27,2

197,5 ± 25,4

0,07

208,4 ± 27,2

198,9 ± 27,1

0,16

-0,24 ± 0,03

0,02 ± 0,03

0,32

LV mass, g

217,7 ± 26,3

220,1 ± 28,2

0,24

207,9 ± 26,4

218,9 ± 28,4

0,09

-0,44 ± 0,08

-0,04 ± 0,03

0,18

LV mass index, g/m2

112,8 ± 18,1

109,4 ± 19,5

0,41

100,7 ± 14,4

99,5 ± 15,7

0,21

-3,28 ± 0,02

-2,04 ± 0,03

0,02

Relative wall thickness

0,41 ± 0,02

0,40 ± 0,02

0,64

0,42 ± 0,08

0,41 ± 0,05

0,35

0,02 ± 0,01

0,02 ± 0,01

0,85

LA dimension, mm

40,3 ± 17,9

40,2 ± 15,9

0,30

39,8 ± 10,2

39,1 ± 9,8

0,82

-0,02 ± 0,01

-0,03 ± 0,05

0,83

Notes: Data for categorical variables are given as number (%); data for continuous variables given as mean ± standard deviation. In the right column, values are shown as baseline-adjusted least square mean ± standard error

E early diastolic velocity, e’ early diastolic mitral annular velocity, LV left ventricular, LA left atrial