Sumaryczny wpływ choroby nadciśnieniowej oraz przewlekłego zapalenia trzustki na procesy warunkujące utrzymanie homeostazy

Liliya S. Babinets, Igor I. Medvid, Iryna I. Herasymets, Iryna O. Borovyk, Liudmyla M. Migenko, Bogdan O. Migenko, Svitlana S. Ryabokon, Neonila I. Korylchuk, Natalia E. Botcyk, Vadym M. Tvorko

SHII “I. Ya. Horbachevsky Ternopil state medical university of the Ministry of public health of Ukraine”, Ternopil, Ukraine,

ABSTRACT

Introduction: Abnormalities comorbidity – a frequent phenomenon in medical practice. This determines the relevance of research processes maintaining homeostasis with a combination of various diseases.

The aim of this study was to examine and compare the character of vegetative, antioxidant, kallikrein-kinin system and parameters of endogenous intoxication disorders in the patients with isolated essential hypertension and with combination of hypertonic disease and chronic pancreatitis.

Materials and Methods: Cardiointervalography was used in the research with definition of standard statistical and spectral heart rate variability. Determination of superoxide dismutase, glutathione, catalase, middle molecular peptides, total proteolytic activity of plasma by the hydrolysis of protamine sulfate, prekallikrein, kallikrein, α1-proteinase inhibitor, α2-macroglobulin and kininase II was conducted by laboratory methods.

Results: Sympathicotonia with the moderate tension of adaptation processes, violation of antioxidant protection, kallikrein-kinin system and displays of endogenous intoxication were found in the patients with isolated hypertension. Reduction of sympathicotonia, reducing total power spectrum, increasing the share of humoral-metabolic effects on heart rate, tendency to asympathicotonia autonomic reactivity, lower levels of superoxide dismutase, glutathione, prekallikrein, α2-macroglobulin, kininase II, higher levels of catalase, middle molecular peptides, total proteolytic activity of plasma kallikrein were observed upon accession the concomitant chronic pancreatitis.

Conclusions: The signs of compensatory mechanisms disruption and increased autonomic nervous system imbalance with a decrease in ductility autonomous processes in the load were determined upon accession the concomitant chronic pancreatitis. The combination of pathologies also accompanied by more severe manifestations of endogenous intoxication, significant violations of antioxidant and kallikrein-kinin systems.

Wiad Lek 2017, 70, 6 cz. I, 1037-1041

Introduction

Patients with hypertension have accompanying pathology in 58,4 % of cases. The average number of cardiovascular diseases per patient under the age of 60 years is 0.8, diseases of the digestive system 0.74, after 60 years 1.3 and 1.4, respectively [1]. This determines the relevance of studying the influence of the pathologies combination on processes maintaining homeostasis. Vegetative violations make a significant contribution to the progress widespread pathologies and affecting the effectiveness of various treatments [2, 3]. Practically there are no diseases in the development and course of which autonomic nervous system did not play the role [4, 5]. This creates the need to establish the existence and nature of the autonomic regulation disorders, their impact on the course and prognosis of comorbid pathologies. Hypertonic disease (HD) and concomitant chronic pancreatitis (CP) in non-remission phase were chosen for research.

HD ranks the first place in the prevalence among the non-communicable diseases. Globally, the overall prevalence of raised blood pressure in adults aged 25 and over was around 40% in 2008. Raised blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all annual deaths. Blood pressure levels have been shown to be positively and progressively related to the risk for stroke and coronary heart disease. Achieving of the stable compensation of the appointed disease is an extremely difficult task in which success is impossible without an adequate immunosuppressive therapy, aimed at the correction of violations at the all levels of pathogenesis [6].

The morbidity on CP in various European countries ranges from 4 to 25 cases per 100 000 population per year, and prevalence – 250-500 patients per 100 000 population. The frequency of CP among other pathologies of the digestive system is 6-9% and tends to increase [7].

The aim

The aim of this study was to examine and compare the character of vegetative, antioxidant, kallikrein-kinin system and parameters of endogenous intoxication disorders in the patients with isolated essential hypertension and with combination of hypertonic disease and chronic pancreatitis.

Materials and methods

The study involved 25 patients with HD, 40 – with HD and concomitant CP in nonremission phase, 15 healthy people. The middle-aged was (47,7±١,٢) years. Patients had treatment in day care policlinic and gastroenterology department of Ternopil city municipal hospital №2. There were 36 men (45,0 %) and 44 women (55,0 %). Diagnosis HD, its stage and the extent determined in accordance with the recommendations of European Society of Cardiology [8]. The average duration of HD was (10,2±0,93) years. The severity of CP assessed based on the International Classification M-ANNHEIM [9]. The average duration of concomitant CP was (5,5±0,7) years.

Research of autonomic regulation conducted by assessing heart rate variability (HRV) with help of software and hardware system Cardio US ECG 01. Recording was performed at rest and during performance of orthostatic test. There were identify the standard statistical and spectral parameters of HRV [10].

Laboratory research of antioxidant, kallikrein-kinin systems and the severity of endogenous intoxication were conducted. Evaluation of antioxidant defense system was based on the indicators of superoxide dismutase (SOD), reduced glutathione (SH-4) and catalase. Endogenous intoxication represented by the medium molecular size peptides with a maximum absorption at 254 nm (MMSP 254) and 280 nm (MMSP 280). The total proteolytic activity (PRA) were determined by plasma hydrolysis of protamine sulfate, kallikrein (CC), prekallikrein (PKK), α1-protease inhibitor (α1-PI), α2-macroglobulin (α2-MG) and kininase II [11].

Results

In analyzing of HRV parameters in the patients with HD sympathicotonia was found: stress index (SI) – 190,58±16,11; the ratio of low frequency to high frequency vibrations (LF/HF) – 2,99±0,21 (table 1). Also marked the reduction of nerve regulation component, mainly due to HF ((17,63±1,64) %) and the growing the influence of humoral and metabolic factors (very low frequency VLF) on the heart rate ((35,68±4,30) %). Index of regulatory systems activity (IRSA) was correspond to a moderate tension – (5,45±٠,٣٩) points.

Joining concomitant HP accompanied decline of the sympathetic nervous system influence: SI104,68±4,34; LF/HF – 1,30,11. Here vegetative background of 65,0 % of patients was appropriate to eutonia, 25,0 % sympathicotonia, 10,0 % vagotonia. Also at comorbidity a significant reduction in total power of spectre (ТР – (678,6±90,3) ms2), component nervous of heart rate regulation (HF – (16,55±1,57) %, LF – (19,83±1,61) %) and a more pronounced increase in humoral and metabolic effects (VLF – (63,63±3,00) %) were observed. The absolute value of VLF in this group was no different from the control group – (352,3±28,7) ms2. In our opinion, this is caused by the development of hypertrophy and fibrosis in the wall of the left ventricle at the progression of HD, leading to the decrease in the density ofneuroreceptors and violation of segmental autonomic regulation (development neurocardiopatia). In 17 of 40 patients TP background value wasn’t exceed 400 ms2. This is considered an independent predictor of cardiovascular complications and equivalent target organ damage at the HD.

Activity of regulatory systems corresponded the expressed tension – (5,45±0,39) points. IRSA at combined HD and CP showed great strain in 25,0 % of cases and in 12,5 % – showed asthenia. This indicates the presence of a pronounced violation of adaptation mechanisms in the case of comorbidity.

Inadequate autonomous reactivity (AR) was observed in the given group during orthostatic test. This may indicate that the autonomic nervous system as a result of the accession of concomitant CP is making greater efforts to support the background state, thus decreasing its ability to adequately respond to stress.

TR correlation with cardiovascular risk (r=-0,509, p=0,0000) was found in patients with HD. Additional correlations of TP with duration of combined course of HD and CP (r=-0,449, p=0,0037), index of left ventricular mass (r=-0,545, p=0,0003), severity index of CP by M-ANNHEIM (r=-0,398, p=0,0110) were determined at the combined HD and CP. On this basis, it is concluded that the decline of TR accompanied by an increased risk of cardiovascular complications, severe course of CP. This points to the informative of this indicator dynamics in assessing prognosis as at isolated HD, and when it combined with the concomitant CP.

The laboratory data at the isolated HD shows a reduction of antioxidant protection of the body: SOD – (49,91±1,21) U/ml erythrocytes; SH-4 – (48,22±1,29) mmol/l (table 2). Higher level of catalase ((34,74±١,٤٢) ٪) is explained by the increased its revenues to the blood due to the cytolysis. Increase indicators of endogenous intoxication was revealed: MMSP 254 – (416,06±8,85); MMSP 280 – (207,20±7,03). This is regarded as a violation of homeostasis by increasing catabolism processes. Kallikrein-kinin system was in a state of reduced activity. This was reflected in the low level of KK ((37,88±5,94) mсmol/(min*l)), increasing of inhibitor α2MG ((0,81±0,02) g/l) and kininase ІІ ((٣٠٤,٩٧±٥,١٧) mсmol/(min*l)). Low activity of kallikrein-kinin system at isolated HD accompanied by a decrease of bradykinin, which is formed under the influence of the KK and has hypotensive effect.

In case of comorbidity the violations of antioxidant system and manifestations of endogenous intoxication were more pronounced: SOD – (39,83±0,50) U/ml erythrocytes; SH-4 – (38,86±0,64) mmol/l; catalase (45,24±1,37) %; MMSP 254 – (564,80±8,19); MMSP 280 – (264,38±6,19). The degree of proteolytic system activation was (48,26±1,52) mmol of arginine /(h*l). The overall breakdown of proteins was also stimulated by more active kininogenase that is displayed by the increase of the KK ((182,48±1,37) mсmol/(min*l)), decrease of its inactive precursor content (PКК – (٥٠,٣٩±١,٧٣) mсmol of arginine /(min*l)) and inhibitor α2MG ((1,77±0,04) g/l). Decrease of kininase ІІ ((١٧٣,44±٢,٨١) mсmol/(min*l)) show the weakening of incentive mechanisms in the body against kinins overproduction. Increased activity of the kallikrein-kinin system at comorbidity of HD and CP causes the enhances inflammation and swelling of the pancreas.

Thus, HD itself or, especially, in conjunction with the concomitant CP accompanied by autonomic disorders, violations of antioxidant, kallikrein-kinin systems and manifestations of endogenous intoxication.

Discussion

Received data changes of HRV in patients with HD were compared with results of other studies. It is established that as the disease progresses happens development of left ventricular hypertrophy and fibrosis in the myocardium with decrease of b1-receptors density. That causes decrease in statistical power and spectral performance. Available decrease the total power range by reducing the HF and LF, with relative preservation of power in the range of VLF. That explaining by compensatory domination of neurohumoral effects on heart rate at the failure of nerve influences as a result of neurocardiopatia [12].

There may be a possible explanation, which is in the reducing of the sino carotid areas sensitivity, reducing impulsation in the centers of medulla oblongata through a feedback mechanism, which results in activation of central regulatory bodies in order to maintain an adequate level of geodynamics. The inverse relationship between the total power spectrum and the level of blood pressure, structural and functional parameters of myocardium (namely the mass index of left ventricular) was observed [13, 14]. Regarding the HD in some studies the tendency to sympathicotonia in this pathology with excessive reactions to stress and violation of adaptive processes was confirmed [15, 16]. Diagnostic value of neurocardiomyopathy consists in the fact that together with left ventricular hypertrophy, heart failure and other changes, it should be seen as a marker of target organ damage (heart). Accordingly, the opportunity is given to use the data for HRV risk stratification of cardiovascular complications at HD [10, 17].

In the available literature is insufficient data concerning the state of emergency in patients with isolated CP among the adult population. In some studies in these patients was found sympathicotonia that explained the inclusion of compensatory mechanisms at the chronic pathological process of the pancreas. Also the exhaustion of the autonomic reactivity revealed already during the first year of CP formation [18, 19]. The great changes observed in the VNS at the CP comorbidity with other common pathology. Thus, in the patients with CP, combined with chronic bronchitis, according to the frequency analysis of HRV, there is strengthening of parasympathetic effects that adversely affected the condition of the bronchial tree [7]. Combination of CP with chronic cholecystitis and chronic gastroduodenitis and also with chronic cholecystitis and duodenal ulcer based on the HRV data revealed the prevalence of sympathicotonia [20]. Based on the above, it is relevant the investigation of VNS indicators in various categories of patients with CP. Published data about the state of the VNS with comorbid course of GC and CP was not found.

Confirmed that oxidative stress plays an important role in the pathogenesis of HD and CP [21, 22], but data about the features of antioxidant protection with a combination of these diseases was not enough. Another study confirmed that the accession of concomitant gastroenterological diseases (chronic non-calculous cholecystitis) while HP led the growth of endogenous intoxication [23]. Reduced production of kinins at HD also has been confirmed by a number of studies [24, 25]. At comorbidity proteolysis strengthening was detected that reminded the state of kallikrein-kinin system during the exacerbation of isolated CP [26, 27].

Conclusion

1. In the group of patients with HD statistical and spectral parameters indicated sympathicotonia (SI – 53,80±5,42, LF/HF – 2,99±0,21). The moderate stress adaptation process was discovered (IRSA – (3,76±٠,٤٠) points).

2. Joining the concomitant CP accompanied by decrease of sympathicotonia and the emergence of the most significant autonomic disorders, low value of the total power spectrum (ТР – (678,6±90,3), мs2), the prevalence of humoral-metabolic effects on heart rate (VLF – (63,63±3,00), %), expressed tensions of the adaptive processes (IRSA – (5,45±0,39)). Inadequate response to orthostatic test (AR – (0,58±0,04)) suggests the tension of vegetative background provision with decreasing of autonomous processes plasticity at the load. This indicates the presence of disruption of compensatory mechanisms and strengthening of VNS imbalance in the given group is patients.

3. In patients with essential hypertension disorders of antioxidant protection, signs of endogenous intoxication, decreased activity of the kallikrein-kinin system were observed. The appearance of the concomitant CP negatively influenced on the processes maintaining homeostasis. Violation of antioxidant indicators there were significant on 23.3%, the severity of endogenous intoxication prevailed on 31.7%. There was a strengthening of catabolism through activation of the kallikrein-kinin system.

4. A statistically determined significant correlation relationship pointed to the importance of total power spectrum dynamics in assessing of cardiovascular risk of HD (r=-0,509, p=0,0000) and course the concomitant CP (r=-0,398, p=0,0110).

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ADDERSS FOR CORRESPONDENCE

Igor I. Medvid

Tatarska Str., 15/11, 46011 Ternopil, Ukraine.

tel: +380-97-845-97-77

email: medvid_ii@meta.ua

Received: 20.06.2017

Accepted: 12.10.2017

Table I. Indicators of HRV

Indicators of

HRV

Research groups

Control

(n=15)

HD

(n=25)

HD+CP

(n=40)

TP, ms2

2801,6±143,8

1854,2±١٣3,9*

678,6±90,3*

(р<0,001)

HF, %

35,31±1,91

17,63±١,64*

16,51,57*

LF, %

48,03±2,18

46,70±2,93

19,81,61*

(р<0,001)

VLF, %

16,67±1,10

35,68±4,30*

63,63±3,00*

(р<0,001)

LF/HF

1,46±0,14

2,99±0,21*

1,30,11

(р<0,001)

IRSA, points

2,20,33

3,76±0,40*

5,45±0,39*

(р<0,01)

SI

53,80±5,42

190,58±16,11*

104,68±4,34*

(р<0,001)

AR

1,30,12

1,65±0,18

0,50,04*

(р<0,001)

Notes:

* – probability of the indicators difference regarding to the control group (р<0,05);

р – probability of the indicators difference in the group of HD and in the group of HD with CP.

Table II. Laboratory indicators

Indicators

Research groups

Control

(n=15)

HD

(n=25)

HD+CP

(n=40)

SOD, U/ml erythrocytes

61,65±0,97

49,91±1,21*

39,83±0,50*

(р<0,001)

SH-4, mmol/l

60,41±1,15

48,22±1,29*

38,80,64*

(р<0,001)

Catalase, %

17,96±0,50

34,74±1,42*

45,24±1,37*

(р<0,001)

MMSP 254

332,45±3,79

416,06±8,85*

564,80±8,19*

(р<0,001)

MMSP 280

148,07±1,39

207,20±7,03*

264,36,19*

(р<0,001)

PRA, mmol of arginine /(h*l)

30,11±0,74

27,01±1,20*

48,26±1,52*

(р<0,001)

KK, mсmol/(min*l)

53,96±1,68

37,88±5,94*

182,41,37*

(р<0,001)

PKK, mсmol of arginine /(min*l)

75,32±2,05

78,78±1,81*

50,39±1,73*

(р<0,001)

α1-PI, g/l

1,49±0,03

1,43±0,02*

1,79±0,02*

(р<0,001)

α2MG, g/l

1,47±0,02

1,77±0,04*

0,81±0,02*

(р<0,001)

Kininase ІІ, mсmol/(min*l)

269,72±0,63

304,97±5,17*

173,42,81*

(р<0,001)

Notes:

* – probability of the indicators difference in relation to the control group (р<0,05);

р – probability of the indicators difference in the group of HD and in the group of HD with CP.