PROFIL LIPIDOWY, MARKERY REAKCJI OSTREJ FAZY ORAZ KWAS MOCZOWY U PACJENTÓW Z NADCIŚNIENIEM TĘTNICZYM I WSPÓŁWYSTĘPUJĄCĄ DYSPLAZJĄ TKANKI ŁACZNEJ

Yevheniya H. Zaremba, Nataliya O. Rak, Olha V. Zaremba, Olena V. Zaremba-Fedchyshyn, Marianna M. Virna,
Liliya O. Odnorih

Department of FPE Family Medicine, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

ABSTRACT

Introduction: Changes in the cardiovascular system can be divided into 2 groups due to the connective tissue dysplasia (CTD) and changes in the circulatory system, caused by pathological processes that arose on the basis of the connective structures failure. One of the risk factors of arterial hypertension (AH) remaining insufficiently studied is collagen pathology nondifferentiated connective tissue dysplasia (NCTD).

The presence of connective tissue in all organs and systems, the common origin of smooth muscles, blood and lymph from mesenchyma leads to dysplastic changes in any organ and system. NCTD is morphologically characterized by changes in collagen, elastic fibrils, glycoproteins, proteoglycans and fibroblasts, which are based on hereditary mutations of genes encoding the synthesis and spatial organization of collagen, structural proteins and protein-hydrocarbon complexes, enzymes and cofactors to them.

The aim was to study external and internal phenotypic signs of CTD, indicators of blood lipid spectrum, acute phase reactions and uric acid in patients with hypertension associated with CTD.

Materials and methods: The study implied examination of 52 patients (19 women and 33 men) with AH of the 2nd stage from 1st to 3rd degrees and CTD manifestations, which were on inpatient treatment in the cardiology department of the Lviv City Communal Clinical Emergency Hospital. The average age of patients was 61.14 ± 2.58 years. Patients were divided into 3 groups depending on the degree of hypertension. The first group (n = 5) included patients with AH of the 1st degree, the second (n = 28) – with AH of the 2nd degree, the third (n = 19) – with AH of the 3rd degree. The control group consisted of 25 practically healthy persons.

Patients underwent checkup, palpation, percussion, auscultation, laboratory examinations (blood lipid spectrum, CRP, serumukoid content and uric acid), instrumental studies (ECG, echocardiography, DBPM, ultrasound examination of the internal organs and lower limbs vessels, ultrasound examination of the sleep and vertebral arteries, X-ray examination of the bone and articular system), consultation of an ophthalmologist, a neuropathologist, a traumatologist and a dentist.

Results: In a comparative analysis between the control group and patients with stage ІІ hypertension of 1-3 grades, in 84.6% cases external and internal CTD signs were observed, and in 15.4% cases there were no manifestations. In applying the diagnostic criteria for assessing signs of CTD and stigmata of dysebryogenesis, different numbers of points were defined depending on the severity of the AH. The highest quantity of points was found in patients of the 3rd group (30,8 ± 0,81), which indicates a significant presence of external signs of CTD in comparison with the 1st and 2nd groups of patients (25.2 ± 1.38 and 26.7 ± 0.72), respectively.

Conclusions: The external and internal phenotypic signs of CTD of medium and severe expressiveness degree were revealed, however, most commonly they were observed in patients with hypertension of grade 3. The presence of positive correlations between the levels of TC, HDL-C, LDL-C, AC, UA and TG indicates its direct role in the pathogenesis of hypertension, and the combination with CTD complicates the underlined pathology. Screening of the studied indicators can improve the prognosis of the course and development of cardiovascular complications.

 

Wiad Lek 2018, 71, 2 cz. I, -360

 

Introduction

Major medical and social problems in Ukraine are associated with an increase in the incidence and prevalence of atherosclerosis. Arterial hypertension (AH) and coronary heart disease (CHD) lead to primary disability, high mortality among working-age people and a decrease in the life expectancy of the population. Currently it has been established that the prevalence of circulatory system diseases (CSD) is largely due to the high level of risk factors such as smoking, hypertension, obesity, hypercholesterolemia, uric acid level, etc. In 2016, the number of patients with CSD was 22 303 564 people, 10 421 402 of which were diagnosed with AH with 4 573 718 of them working (43.9% of adults) [1, 2].

One of the risk factors for cardiovascular disease (CVD) is dyslipidemia. According to the Framingham Study, hypercholesterolemia is observed in more than 40% of people with elevated blood pressure (BP), one in four has low high density lipoprotein cholesterol (HDL-C), and almost one in five – hypertriglycerolemia [3]. The next factor for CVD is an elevated level of C-reactive protein (CRP) and seromucoid, which can be used to improve the stratification of cardiovascular risk. CRP is a marker of negative changes in the lipid spectrum of the blood, its increase is accompanied by the elevation of total cholesterol (TC) and triglycerides (TG) levels, while the reduction of the systemic inflammatory process is associated with improved systolic function of the left ventricle and increased ejection fraction [4]. According to Lin C.L., Chen M.C. et al. (2015) uric acid (UA) itself is not a predictor of CVD, however with the development of chronic inflammation, causes endothelial dysfunction, fibrotic changes and remodeling of the blood vessels and the heart [5]. In recent years, their relationship has been widely considered, due to new data on the pathogenesis of hypertension: elevation of the UA stimulates the renin-angiotensin system, increases the tone of the renal vessels, disrupts the function of the endothelium, enhances adhesion and aggregation of platelets, affects lipid metabolism.

Changes in the cardiovascular system can be conventionally divided into 2 groups, due to CTD and changes in the organs of circulation, caused by pathological processes that arose on the basis of failure of the binding structures. One of the risk factors of arterial hypertension (AH) remaining insufficiently studied is collagen pathology – nondifferentiated connective tissue dysplasia (NCTD).

The presence of connective tissue in all organs and systems, the common origin of smooth muscles, blood and lymph from mesenchyma leads to dysplastic changes in any organ and system. NCTD is morphologically characterized by changes in collagen, elastic fibrils, glycoproteins, proteoglycans and fibroblasts, which are based on hereditary mutations of genes encoding the synthesis and spatial organization of collagen, structural proteins and protein-hydrocarbon complexes, enzymes and cofactors to them. [8, 9].

The basis of NCTD diagnosis are external and internal phenotypic manifestations, the detecting difficulties of which are associated with the lack of knowledge of signs and clinical manifestations of CTD [10]. NCTD research was carried out in relation to diagnostic methods, detection of biochemical markers, morphological substantiation of cardiovascular manifestations, and the use of metabolic therapy, nevertheless, the relationship of hypertension with NCTD and changes in blood lipid profile, levels of acute phase indices, uric acid and their effects on the course and prognosis the studied pathology remains obscure [11].

The aim

To investigate external and internal phenotypic signs of CTD, blood lipid spectrum indicators, acute phase reactions and uric acid in patients with hypertension associated with CTD.

Materials and methods

The study implied examination of 52 patients (19 women and 33 men) with AH of the 2-nd stage from 1-st to 3-rd degrees and CTD manifestations, which were on inpatient treatment in the cardiology department of the Lviv City Communal Clinical Emergency Hospital. The average age of patients was 61.14 ± 2.58 years. Patients were divided into 3 groups depending on the degree of hypertension. The first group (n = 5) included patients with AH of the 1-st degree, the second (n = 28) – with AH of the 2-nd degree, to the third (n = 19) – with AH of the 3-rd degree.

The control group consisted of 25 practically healthy persons.

Randomization of patients with hypertension was conducted in the order of admission to the hospital. The survey did not include patients with symptomatic hypertension, severe heart failure (III-IV FC according to NYHA), liver and kidney failure, cancer, autoimmune and infectious diseases.

The control group consisted of 25 practically healthy persons.

Patients underwent checkup, palpation, percussion, auscultation, laboratory examinations (blood lipid spectrum, CRP, serumukoid content and uric acid), instrumental studies (ECG, echocardiography, DBPM, ultrasound examination of the internal organs and lower limbs vessels, ultrasound examination of the sleep and vertebral arteries, X-ray examination of the bone and articular system), consultation of an ophthalmologist, a neuropathologist, a traumatologist and a dentist.

Detection of external signs of CTD in patients with hypertension was carried out using anthropometric methods of investigation (assessment of body structure, skin condition, muscle, Kettle index, dolichostenomelia detection, flatfoot, deformities of the spine and chest, hypermobility of the joints). The results were evaluated using a table of diagnostic coefficients of CTD signs and small developmental anomalies (according to Yakovlev V.M. et al., 2008). When reaching the diagnostic threshold of 21 points, the conclusion about the presence of CTD was formulated. To determine the degree of severity of CTD, the tables of the importance of clinical markers (Kadurina T.M., Abbakumova L.N., 2008) were used. The degree of severity of CTD in each patient was established according to the sum of points: a slight degree of CTD – the sum of scores <20, the middle – 21-40, the heavy – 41 and more.

TC and HDL-C were determined by the A.N. Klimov and N.G. Nikulchev (1984) method,. The level of LDL-C was calculated using the Friedwald formula: LDL-C = TC – HDL-C – TG/ 2,2; AC was calculated by the formula A.N. Klimov (1984): AC = TC – HDL-C / HDL-C. Determination of blood lipid profile indexes was carried out by enzymatic method on a spectrophotometer FP-900 (Finland) using «Human» reagents. For the determination of CRP and serumukoid content latex turbidimetric method of investigation was used. Definition of UA was carried out by colorimetric enzymatic method on the Gobas 6000 analyzer using the Roche Diagnostics test system (Switzerland).

In order to obtain results of blood pressure measurements during the day, daily monitoring of blood pressure measurement using oscillometric method ABPM 50 (NEACO, London) was used. Registration of indicators of blood pressure was carried out every 15 minutes. in the active period of a day (daytime) and every 30 min. in the passive period (night). Target average of daily blood pressure levels was less than 130/85 mm Hg. (daytime – less than 140/80 mm Hg, at night – less than 120/80 mm Hg) and / or reduction of SBP / DBP by 10/5 mm Hg. and more [12].

Statistical processing of the results was performed using Microsoft Office Excel 2007 and «Statistica 10.0». Normal data is presented in the form of mean and standard deviation of M ± m, M is the mean value, m is the standard deviation. The probability of the difference between the groups in quantitative terms was estimated using the Student’s t-criterion. The difference in the figures was considered significant at p<0.05. To find out the correlations between the studied parameters, the methods of correlation analysis for parametric and nonparametric distribution types – the Pearson and Spirman criteria respectively. Reliable correlations were considered at p<0.05.

Results and discussion

As a result of the study, in patients with stage ІІ hypertension of 1-3 degrees, NCTDs of varying grades of severity were diagnosed. In the 1-st group (AH of the 1-st degree) in all patients (n = 5) a CTD of medium severity was found. In the 2-nd group of patients (AH of the 2-nd degree), the CTD of moderate severity was detected in 20 (72%), severe – in 8 patients (28%). In the 3-rd group of patients (AH of 3-rd degree) CTD of moderate severity was found in 8 (42.1%), severe – in 11 (57.9%) persons.

In a comparative analysis between the control group and patients with stage ІІ hypertension of 1-3 degrees, in 84.6% cases external and internal CTD signs were observed, and in 15.4% cases there were no manifestations. In applying the diagnostic criteria for assessing signs of CTD and stigmata of dysebryogenesis, different numbers of points were defined depending on the severity of the AH. The highest quantity of points was found in patients of the 3-rd group (30.8 ± 0.81), which indicates a significant presence of external signs of CTD in comparison with the 1-st and 2-nd groups of patients (25.2 ± 1.38 and 26.7 ± 0.72), respectively.

When external phenotypic signs were detected in patients with hypertension, the most common manifestations of CTD were skin striae, which accounted in the 1-st group for 60%, in the 2-nd – for 81.8%, and the 3-rd – for 50% of patients, the hypermobility of the joints of mild degree was observed in the 1-st group in 20%, 2-nd – in 25%, 3-rd – in 70% of patients. The pathology of the spine in the form of scoliosis of mild degree was observed in all patients of three clinical groups. The other most common external signs of CTD were: flatfoot, accounted in the 1-st group of patients for 60%, in the 2-nd – for 81.8%, in the 3-rd – for all patients (n = 19). The appearance of patients with hypertension was supplemented with stigmas of dysembriogenesis, among which the macroaccumulation of the first toe in the 1-st group was observed in 80%, in the 2-nd – in all patients (n = 28), and in the 3-rd – in 90% (Figure 1).

Among the internal signs of NCTD in patients with hypertension, the abnormal chords in the ventricles of the heart (HVAC) were most often observed, which in the 1-st group of patients accounted for 40%, in the 2-nd – for 45.5%, in the 3-rd – for 60%, what indicates the inferiority of the connective tissue of the heart. Eye pathology in the form of angiopathy of the retina was found in the 1-st group in 60%, in the 2-nd – 90%, 3-rd – in all patients (n = 19), abnormalities of the gall bladder (bendings, membranes) in the 1-st group were diagnosed in 60%, in the 2-nd – in 18.2 %, in the 3-rd – in 40% of patients. Congenital malformation of the cerebral vessels was observed in the 1-st and 2-nd groups, in 60% of cases, in the 3-rd – 90.9% of patients (Figure2).

When applying the diagnostic criteria for assessing the signs of CTD and stigmata of dysembriogenesis a different number of points is determined depending on the AH severity grade (Table I).

The highest number of points was found in patients of the 3-rd group (30.8 ± 0.81), which indicates a significant presence of external signs of CTD in comparison with the 1-st (p<0.005) and the 2-nd (p<0.001) groups of patients (25.2 ± 1.38 and 26.7 ± 0.72), respectively.

It was established that in groups of patients with hypertension associated with CTD, marked increase of TC in the 2-nd group of patients was noted by 20.3% (p <0.05) compared with the 1-st group and by 18.8% (p <0.05) in the 3-rd group compared with the 2-nd group of patients. There is an increase in LDL-C in the 3-rd group of patients by 25.5% (p <0.05) when compared with group 1 and by 20% (p <0.05) when compared with group 2. In patients with hypertension of 3-rd degree, the level of AC in 23.9% (p <0.05) higher than in the cases 2-nd degree hypertension and by 45.5% (p <0.01) is higher compared with the group of patients with hypertension of the 1-st degree of severity. A significant increase in CRP in the 3-rd group of patients (p <0.05) was detected by 61,8% when compared with the 1-st group of patients. The level of UA was elevated by 31.2% (p <0.05) when compared with the 1-st and 2-nd groups of patients and by 33.3% (p <0.01) when compared to the 1-st and 3-rd groups, which is considered a zone of increased risk of cardiovascular complications (Table II).

The level of HDL-C in the 1st group of patients was 1.4 ± 0.04, which is 13.7% higher than in the 2-nd group of patients, where the index was 1.2 ± 0.08 and 3.6% higher than in the 3-rd group of patients (1.3 ± 0.13).

In the correlation analysis it was established in the 1-st group of patients there was a strong feedback between TC and TG (r = -0.90, p<0.05), HDL-C (r = -0.67, p<0.05) and correlation of mild intensity in the 1-st and 2-nd groups of patients between TC and AC (r = 0.25, p<0.05).

In patients with hypertension of the 2-nd degree, direct correlation links between TC and LDL-C (r = 0.94, p<0.05), AC (r = 0.25, p<0.05) were established. The feedback of the mild intensity between the TC and UA (r = -0.13, p<0.05), TG (r = -0.19, p<0.05) was revealed.

In the analysis of correlation links in patients with hypertension of the 3-rd degree, direct links were established between TC and LDL-C (r = 0.60, p<0.05), AC (r = 0.52, p<0.05), UA (r = 0.40, p<0.05), TG (r = 0.41, p<0.05). The presence of direct correlations can be considered as one of the risk factors for the development of cardiovascular complications.

Conclusions

1. In the comparative analysis between the control group and patients with stage II hypertension of 1-3 grades in 84.6% of cases a number of external and internal CTDs were observed, and 15.4% had no manifestations.

2. It was noted that the external and internal phenotypic signs of the CTD of moderate and severe expressiveness was most commonly observed in patients with hypertension of grade 3.

3. The presence of positive correlations between the levels of TC, HDL-C, LDL-C, AC, UA and TG indicates its direct role in the pathogenesis of hypertension, and the combination with CTD complicates the underlined pathology. Screening of the studied indicators can improve the prognosis of the course and development of cardiovascular complications.

References

1. Derzhavna sluzhba statystyky Ukrainy: Demohrafichna ta sotsialna statystyka / Okhorona zdorov’ia. Zakhvoriuvanist naselennia (za danymy Ministerstva okhorony zdorov’ia): http: // www.ukrstat.gov.ua /. 2017.

2. Kovalenko V.M., Kornatskyi V.M. Problema zdorov’ia i tryvalosti zhyttia v suchasnykh umovakh. Kyiv; 2017, p. 299.

3. Syvolap V.V. Vizir-Tronova O.V. Dyslipidemiia i arterialna hipertenziia: kardiovaskuliarni aspekty. Materialy XVI Natsionalnoho konhressu kardiolohiv Ukrainy. Ukrainskyi kardiolohichnyi zhurnal. 2017; 1:66.

4. Amelina T.M., Hinhuliak O.M. Dynamika rivnia S-reaktyvnoho bilka krovi ta stan koronarnoho i funktsionalnoho rezerviv u khvorykh na stabilnu stenokardiiu. Materialy XVI Natsionalnoho konhressu kardiolohiv Ukrainy. Ukrainskyi kardiolohichnyi zhurnal. 2017; 1:74.

5. Kondratiuk V.Y., Y.P. Synytsia, Deryzemlia I.O. Rol sechovoi kysloty v porushenni diastolichnoi funktsii sertsia. Materialy XVI Natsionalnoho konhresu kardiolohiv Ukrainy. Ukrainskyi kardiolohichnyi zhurnal. 2017; 1:158.

6. Koval S.M., Bozhko V.V., Penkova M.Y. Hiperurikemiia ta sumarnyi ryzyk uskladnen u patsiientiv z hipertonichnoiu khvoroboiu (za danymy klinichnoho doslidzhennia). Ukrainskyi revmatolohichnyi zhurnal. 2014;42-48.

7. Zaremba Y.K., Rak N.O., Hryb N.V. Zv’iazok mizh nedyferentsiiovanoiu dysplaziieiu spoluchnoi tkanyny ta arterialnoiu hipertenziieiu. Zdorov’ia i suspilstvo. 2017; 1(2):139-140.

8. Nechaeva H.Y., Yakovlev V.M., Konev V.P. Dysplazyia soedynytelnoi tkany: osnovnye klynycheskye syndromy, formulyrovka dyahnoza, lechenye. Lechashchyi vrach. 2008; 2:22-25.

9. Kaduryn T.Y. Nasledstvennye kollahenopatyy: klynyka, dyahnostyka, lechenye, dyspanseryzatsyia. SPb: Nevskyi dyalekt; 2000, p. 271.

10. Dotsenko N.Y. Kardyolohycheskye aspekty dysplazyy soedynytelnoi tkany u vzroslykh. Zaporizhzhia; 2012, p. 96.

11. Dotsenko N.Y., Herasymenko L.V., Boev S.S. et al. Proiavlenyia neklassyfytsyrovannoi dysplazyy soedynytelnoi tkany v zavysymosty ot vozrasta. Prohnoz. Ukrainskyi revmatolohichnyi zhurnal. 2012; 1: 19-23.

12. Viunitska L.V., Lunova H.H. C-reaktyvnyi bilok u laboratornii diahnostytsi ta otsintsi ryzyku aterosklerozu. Zb. nauk prats spivrob. NMAPO im. P.L. Shupyka. 2014; 23:522-528.

13. Zaremba Y.K., Rak N.O., Shevchun-Pudlyk O.M. Nedyferentsiiovana dysplaziia spoluchnoi tkanyny, yak odna z proiaviv rozvytku arterialnoi hipertenzii. Zbirnyk prats naukovo-praktychnoi konferentsii z mizhnarodnoiu uchastiu «Pervynna medychna dopomoha: krashchi praktyky simeinoi medytsyny». 2017; 27-29.

14. Zaremba Y.K., Rak N.O., Zaremba-Fedchyshyn O.V. et al. Osoblyvosti perebihu arterialnoi hipertenzii poiednanoi z dysplaziieiu spoluchnoi tkanyny v praktytsi simeinoho likaria. Zdorov’ia suspilstva. 2017; 3(6):20-27.

 

ADDRESS FOR CORRESPONDENCE

Nataliya O. Rak

Danylo Halytsky Lviv National Medical University

Department of FPE Family Medicine

69 Pekarska str., Lviv, 79010, Ukraine

tel.: +38 (068) 010-90-29

e-mail.: rnolegivna@gmail.com

Received: 20.02.2018

Accepted: 10.04.2018

Fig. 1. External phenotypic signs of connective tissue dysplasia in patients with arterial hypertension

Fig. 2. Internal signs of connective tissue dysplasia in patients with arterial hypertension

Table I. The mean of points according to the diagnostic coefficients tables of connective tissue dysplasia signs and small developmental abnormalities in patients with arterial hypertension

Indicator

Group 1

Group 2

Group 3

р 1-2

р 13

р 23

The mean of points

25,2±1,38

26,7±0,72

30,8±0,81

>0,05

<0,005

<0,001

Table II. Indicators of blood lipid spectrum, acute phase reactions and uric acid in patients with arterial hypertension combined with connective tissue dysplasia

Indicators

Group 1

(n=5)

Group 2

(n=28)

Group 3

(n=19)

р 12

р 13

р 23

TC, mmol / l

4,24±0,25

5,32±0,34

6,55±0,43

<0,05

<0,01

<0,05

HDL-C, mmol / l

1,39±0,04

1,2±0,08

1,34±0,13

>0,05

>0,05

>0,05

LDL-C, mmol / l

3,13±0,44

3,36±0,39

4,20±0,20

>0,05

<0,05

<0,05

VLDL-C,

mmol / l

0,47±0,04

0,83±0,13

0,89±0,19

>0,05

>0,05

>0,05

TG, mmol / l

1,23±0,12

1,65±0,26

2,28±0,57

>0,05

>0,05

>0,05

AC

2,65±0,28

3,70±0,27

4,86±0,48

<0,05

<0,01

<0,05

CRP, mg / l

7,80±1,71

15,40±4,98

20,43±4,20

>0,05

<0,05

>0,05

Seromucoid, cond. units

0,15±0,01

0,21±0,03

1,95±1,4

>0,05

>0,05

>0,05

Uric acid, μmol / l

240,00±20,73

348,87±28,68

359,76±24,11

<0,05

<0,01

>0,05