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14MEDICAL SCIENCES
BIOMARKERS OF INFLAMMATION AND ENDOGENIC DESTRUCTION IN PATIENTS WITH
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND WITH JOINING OF CORONARY
HEART DISEASE
Sierkova V.
MD, Dr., Professor, Department of internal medicine №1 National Pirogov Memorial Medical University, Vinnytsya, Ukraine
Lilevska A.
Assistant, Department of internal medicine №1 National Pirogov Memorial Medical University, Vinnytsya, Ukraine
Savytska O.
MD, Dr., Associate professor, Department of internal medicine №1 National Pirogov Memorial Medical University, Vinnytsya, Ukraine
ABSTRACT
The article is devoted to the to determine the significance of markers of systemic inflammation in the diagnosis of coronary heart disease (CHD) in patients with chronic obstructive pulmonary disease (COPD), and whether there is a link between these pathological conditions. The study included 153 people with COPD and 44 patients with stable CHD. The study was performed on the pulmonology and cardiology departments of Vinnytsya Regional Clinical Hospital named after M.I. Pirogov. It was revealed high levels of markers of systemic inflammation in COPD patients are associated with disease progression and the risk of developing CHD. Control of inflammatory markers is a necessary criterion in a personalized approach to the diagnosis, prognosis and therapeutic tactics used for COPD patients. Determining the level of highly sensitive C-reactive protein (hsCRP) and Pregnancy Associated Plasma Protein-A (PAPP-A) helps in the identification of individuals at high risk for cardiovascular pathology. An increase in the hsCRP level of more than 4,5 mg/l can be considered a predictor of CHD in patients with stable COPD. The prognostic significance of the increased hsCRP level grows if combined with changes in the general blood test and increased fibrinogen levels. Increased PAPP-A levels in the blood are an independent risk factor for the occurrence and progression of CHD in COPD patients.
Keywords: coronary heart disease, with chronic obstructive pulmonary disease, general blood test, fibrino-gen, highly sensitive C-reactive protein, Pregnancy Associated Plasma Protein-A.
Introduction. Coronary heart disease (CHD) and chronic obstructive pulmonary disease (COPD) remain an actual problem of the 21st century due to the high mortality and disability of the population of different countries of the world, as well as the multifactorial pathological processes underlying them. The fact that the COPD pathogenesis is multi-component is indisputable today, where the main mechanism is the inflammatory process, which locally affects the respiratory tract and has systemic manifestations [1]. The main causes of systemic reactions in patients with COPD are the inflammatory activity of lung tissue cells due to chronic inflammatory process, perfusion-ventilatory hypoxemia, tissue hypoxia, activation of neutro-phils/lymphocytes, increase in cytokine levels and "acute-phase" proteins [14]. According to current notions, the leading role in the pathogenesis of the progression of inflammation in COPD belongs to neutro-phils, but about a third of patients with COPD (according to various data - from 10 to 40%) show an eosinophilic endotype of inflammation, which today is considered an indicator of high comorbidity, high risk of heart disease, and the marker of the response to the therapy [8]. According to epidemiological studies, COPD patients have a two to three times higher risk of developing cardiovascular events, which are the reason for about 50% of the total COPD deaths [2]. Currently, the role of inflammatory factors in forming of local and systemic clinical manifestations of atherogenesis and
development of CHD is widely emphasized [3]. It has been shown that T-lymphocytes and monocytes/macro-phages are found in the intima of vessels at an early stage of atherosclerotic lesion formation, and in unstable plaques they make up more than 40% of the cellular composition of inflammatory infiltrates [4]. Analysis of experimental and multicenter clinical studies has shown that C-reactive protein levels and leukocytosis are the same independent risk factors for CHD as total cholesterol, hypertension, smoking, diabetes [5, 10]. Smoking, proinflammatory cytokines, affecting the vascular endothelium, increase its susceptibility to cholesterol, promoting the accumulation of cholesterol in the vascular walls.
Aim of the study: to determine the significance of markers of systemic inflammation in the diagnosis of coronary heart disease (CHD) in patients with chronic obstructive pulmonary disease (COPD), and whether there is a link between these pathological conditions.
Materials and methods. There were examined 197 men, 40-70 years old, with an average age of 56,4 ± 3,8 years. The patients were divided into 3 groups: group 1 - 44 patients with stable CHD of II and III functional class, group 2-76 patients diagnosed with COPD, group 3 - 77 patients with a combination of COPD and stable CHD of II and III functional class. The age, duration of COPD and CHD group were comparable. The control group consisted of 40 healthy individuals without signs of cardiovascular pathology.
The study was performed on the base of pulmonology and cardiology departments of Vinnytsya Regional Clinical Hospital named after Pirogov. Verification of COPD diagnosis and comprehensive assessment of the disease was performed according to the recommendations of GOLD [14]. The diagnosis of stable CHD was established in accordance with European guidelines [6, 7].
Exclusion criteria for the study were other respiratory diseases, decompensated diseases of the kidneys, liver, blood, endocrine system; systemic connective tissue diseases; oncological diseases; organic brain diseases, alcoholism, drug addiction, substance abuse, obesity more than II degree, hypertension 2-3 degrees. After obtaining written consent to participate in the study, all the patients underwent a comprehensive clinical, instrumental and laboratory examination. The body mass index, the smoker index were calculated, the COPD questionnaires were filled in: mMRC (Medical Research Council Dyspnea Scale), CAT (COPD Assessment Test). The complex of laboratory and instrumental studies included general blood test and urine analysis, biochemical profile, computer spirometry, pulse oximetry, chest radiography, electrocardiography. PAPP-A was determined by IBL-INTERNATIONAL PAPP-A US (ultra sensitive) Enzyme Immunoassay Kit (Germany). Statistical processing of the results was carried out by conventional methods of variational statistics using the software
package "Microsoft Excel" for "Windows 2010". The reliability of the results was evaluated using the Student's t test; differences at p <0,05 were considered significant. The relationship of traits was determined using Pearson and Spearman correlation coefficients (Rsp).
Results and Discussion. A large number of cells is involved in the production of inflammatory mediators, the leading role is played by leukocytes. Analysis of routine detailed general blood test in patients with CHD showed no significant increase in the total number of leukocytes compared with the control group (table 1). In patients with stable COPD and in patients with comorbid pathology, the leukocyte count was moderately increased compared to the control group, although it remained within the reference values.
COPD is thought to have predominantly neutro-philic inflammation of the respiratory tract, which is associated with chronic bronchitis and verified by increased levels of neutrophils in the peripheral blood. The highest blood neutrophilosis was detected in patients with isolated COPD - 80,14 ± 4,02%. The number of neutrophils in the group of patients with isolated stable CHD (71,34 ± 3,85%) was not different from the control group (p> 0,05), and with the combined pathology (76,31 ± 2,77%) was credibly higher than in the control group. The erythrocyte sedimentation rate (ESR) was significantly higher in COPD patients and with comorbid pathology than in the control group (p <0,05).
Table 1.
Criteria for inflammation in the subjects
Control (n=40) CHD 1 group (n=44) COPD 2 group (n=76) P1 COPD + CHD 3 group (n=77) P1 P2
Number of leuko- 5,41 ±0,83 6,84 ±1,31 8,31 ±1,07* >0,05 7,64 ±1,42* >0,05 >0,05
cytes,x109/L
Neutrophils,% 61,92 ±3,1 71,34 ±3,85 80,14 ±4,02* <0,05 76,31 ±2,77* >0,05 >0,05
Eosinophils,% 1,07 ±0,29 0,89 ±0,41 1,36 ±0,64 >0,05 1,61 ±0,48 <0,05 >0,05
Lymphocytes,% 24,39 ±0,92 26,56 ±0,88 18,57 ±0,74* <0,05 22,17 ±0,63 >0,05 <0,001
ESR, mm/hour 5,14 ±1,18 9,26 ±2,57 15,63 ±2,92* >0,05 13,50 ±3,12* >0,05 >0,05
hsCRP, mg/L 0,65 ±0,08 3,43 ±0,29* 4,79 ±0,31* >0,05 5,71 ±0,12* <0,001 <0,01
Fibrinogen, g/L 2,8 ±0,15 3,2±0,21 4,3±0,17* <0,05 4,2 ±0,19* <0,05 >0,05
Note: * - the differences of indicators in comparison with the control group is significant p <0,05; P1 - reliability of differences of indicators in comparison with group of patients with CHD; P2 - reliability of differences of indicators in comparison with group of patients with COPD.
A number of studies have demonstrated that the eosinophilic type of inflammation in the bronchial tree in COPD patients is associated with a high rate of comorbid pathology [8]. We did not find a significant difference between the study groups of patients when assessing the number of eosinophils in leukocyte formulas, although there was a tendency to increase the number of eosinophils in patients with combined pathology compared with the group with isolated CHD. Thus, a total blood test showed that in COPD patients and when combined with COPD with stable CHD, there was a significant increase in total leukocyte count in the control group, mainly due to neutrophils, a moderate acceleration of ESR, which, to a certain extent,
indicates the presence of nonspecific inflammatory process.
Along with the average values of the general blood test in the examined groups of patients, we studied the frequency of deviations from normal values. The cutoff points from the norm were previously selected, which amounted to 7,61* 109/L for the number of leukocytes in the blood, for the absolute number of neutrophils - 4,85* 109/L, for eosinophils - 0,2* 109/L, and for ESR - 10,5 mm/ hour. An increase in leukocyte counts compared to the cut-off point occurred in 10 (22,7%) patients with coronary heart disease, 28 (36,8%) patients with COPD, and in 32 (41,6%) patients with associated cardiorespiratory pathology. An increase in neutrophil counts was observed more frequently and
was observed, respectively, in 15 (34,1%) patients with coronary heart disease, 39 (51,3%) patients with COPD and in 44 (57,1%) with the combination of COPD and CHD. Considering the possibility of eosinophilic inflammation endotype in COPD, we determined the frequency of increase in the absolute number of eosino-phils in the comparison groups, which was for the group of patients with CHD 3 (6,9%) patient, for patients with COPD - 14 (18,4%) and for the group of pa-
tients with combined pathology - 18 (23,4%). An increase in ESR was detected in groups of 10 (22,7%), 18 (23,7%) and 23 (29,9%) patients, respectively.
When comparing groups of patients with isolated COPD and COPD in combination with CHD using the method of binary logistic regression, we were unable to identify a reliable effect of CHD on the frequency of changes in the general blood test in the group of combined pathology (table 2).
Table 2.
The odds ratio when comparing the frequency of changes in blood counts in COPD patients without CHD and
with the combination of COPD and CHD
Frequency of changes of indicators COPD + CHD patients (n=77) COPD patients (n = 76) x2 P odds ratio (OR) confidence interval (CI)
Leukocytes 32 28 0,357 0,551 1,219 0,634-2,338
Neutrophils 44 39 0,523 0,470 1,265 0,669-2,398
Eosinophils 18 14 0,452 0,470 1,351 0,617-2,960
ESR 23 18 0,835 0,361 1,136 0,548-2,335
Fibrinogen 42 37 0,526 0,469 1,265 0,670-2,387
hsCRP 52 39 4,173 0,042 2,973 1,024-3,801
At the same time, when comparing the frequency changes in patients with combined pathology of such of changes in the parameters of the general blood test, indicators of inflammation as the number of leukocytes, the group with isolated CHD and the main group re- neutrophils and eosinophils (Table 3). vealed a significant effect of COPD on the frequency of
Table 3.
The odds ratio in the comparison of the frequency of changes in the total blood count in groups of patients with isolated CHD and with the combination of COPD and CHD
Frequency of indicators changes COPD patients +CHD (n = 77) Patients with CHD (n = 44) x2 P odds ratio (OR) confidence interval (CI)
Leukocytes 32 10 4,381 0,037 2,418 1,045-5,390
Neutrophils 44 15 5,955 0,015 2,578 1,194-5,565
Eosinophils 18 3 5,352 0,021 4,169 1,153-15,090
ESR 23 10 0,720 0,397 1,448 0,614-3.414
Fibrinogen 42 21 0,522 0,471 1,314 0,626-2,761
hsCRP 52 28 2,270 0,130 1,076 0,491-2,359
An increase of fibrinogen concentration in plasma, even within the reference values in patients with bronchial obstructive pulmonary disease, correlates with the risk of recurrent hospitalizations and an increased risk of complications of cardiovascular disease [11]. The level of fibrinogen in patients with angina pectoris increases before the development of myocardial infarction [12]. According to the results of our study, the level of fibrinogen in isolated and combined bronchopulmonary pathology was 1,5 times higher than in the control group (p <0,05). There were no significant effects of CHD on fibrinogen levels in patients with COPD: x2 = 0,52, OR - 1,265 with CI 0,670-2,387 (see Table 2).
C-reactive protein activates the complement system, blocks the production of inflammatory mediators through binding of phospholipids of membranes, participates in the implementation of functions of immu-nocompetent cells - stimulates the uptake of lipoproteins by macrophages, enhances the adhesion of leukocytes to the endothelium, so enforces inflammation cascade of systemic manifestations. It is not only a marker of systemic inflammation, but also a factor in the development of atherosclerosis, partially activates
the endothelium and smooth muscle cells, can negatively affect at NO synthesis, enhancing endothelial dysfunction [9, 10].
According to our data, the hsCRP level was significantly higher in all patient groups compared to the control group (see Table 1). It is noteworthy that there is a significant increase in the level of hsCRP in patients with combined pathology of COPD and CHD. Increasing this rate by 1,7 times in patients with comorbid pathology compared with patients with isolated CHD and 1,2 times compared with patients on isolated COPD, respectively, increases the risk of pathological instability and cardiovascular catastrophes. According to ACC/AHA guidelines, hsCRP>2 mg/l is an independent cardiovascular risk factor in healthy subjects. The cut-off point we set for hsCRP did not differ from the conventional and was equal to 2,1 mg/l. Regression analysis confirmed the importance of increasing the level of hsCRP in the occurrence of CHD in patients with COPD- odds ratio was equal to 2,973, CI - 1,0243,801 (see table 2).
The influence of COPD on the frequency of the increase ESR, hsCRP, fibrinogen was less significant (see Table 3).
The data obtained gives the reason to think that the frequency of increasing hsCRP level in the blood is significantly affected by the presence of CHD in patients with combined pathology. When using multiple regression analysis, it was found that an increase in COPD patients with a hsCRP level of more than 4,5 mg4 gives the reason to suspect the presence of CHD in them, even in the absence of other reasons for its increase.
When comparing inflammatory activity in patients with isolated COPD with varying degrees of airflow limitation, it was determined that hsCRP tended to increase with decreasing of pulmonary function. In terms of total peripheral blood leukocyte count in the examined patients, it was highest in patients with very severe bronchial obstruction, and ESR in patients with COPD GOLD 3. According to several authors [13, 14, 15] the level of fibrinogen correlates with FEV1, risk of re-hos-pitalizations, the frequency of exacerbations of COPD. In our work, the level of fibrinogen was significantly higher in all groups of patients compared to the control group, but did not differ significantly in the subgroups.
When activated, inflammation increases the prote-olytic activity of macrophages with the participation of metalloproteinases, which leads to a decrease in the thickness and strength of the fibrotic atheroma. The presence of latent nonspecific vascular inflammation is a factor in endogenous destruction in atherosclerotic plaques [3]. Several studies have noted that elevation of PAPP-A (pregnancy-associated plasma protein A -zinc-containing matrix metalloproteinase) is associated with atheroma instability and is a predictor of adverse cardiac events [2]. The PAPP-A level in our study in the control group was 3,12 ± 0,42 mIU/L. In patients with stable CHD, the PAPP-A level moderately but significantly exceeded the control group (5,61 ± 0,23 mIU/l, p <0,05). In COPD patients, the degree of change in the PAPP-A level was unreliable (4,03 ± 0,32 mIU/l, p>0,05). When combined with CHD and COPD, a slightly higher degree of increase in PAPP-A was observed compared to the group of patients with isolated CHD (6,34 ± 0,26 mIU/l, p<0,05). An increase in PAPP-A compared to the cut-off point (3,5 mIU/l) occurred in 14 of 76 COPD patients, 37 of 44 patients with coronary heart disease, and 59 of 77 patients with comorbid pathology. Highly significant influence of CHD on the level of PAPP-A in patients with combined pathology was found: OR = 14,516, CI- 6,627-31,798, while the effect of COPD on the frequency of PAPP-A level increase was insignificant. The obtained data give grounds to consider the level of PAPP-A as a reliable criterion and predictor of CHD in patients with COPD.
It can be considered that increased local inflammation in the bronchi and pulmonary parenchyma exerts a systemic effect and contributes not only to the progression of COPD, but also to the activation of systemic vascular inflammation, the development and progression of atherosclerosis and cardiac pathology with the subsequent destabilization of atherosclerotic. This may be indicated by the correlation between PAPP-A content and blood hsCRP levels in patients with COPD
and coronary heart disease (r = 0,41, p<0,05). We found no convincing correlation of PAPP-A level with age (r = 0,18), body mass index (r = 0,17).
Conclusion. The development of inflammatory syndrome, which becomes systemic in COPD, indicates the transition of the pathological process to a new quality - from isolated damage of the bronchopulmo-nary system to damage the entire body.
The results of the study indicate that high levels of markers of systemic inflammation in COPD patients are a factor in the rapid progression of the disease, high risk of exacerbation of COPD, risk of developing coronary atherosclerosis, CHD. Control of inflammatory markers is a necessary criterion in a personalized approach to the diagnosis, prognosis and accepted therapeutic tactics for COPD patients. Plasma marker of chronic systemic latent inflammation hsCRP is required for the identification of individuals at high risk for cardiovascular pathology. Detection of increased (more than 4,5 mIU/l) level of PAPP-A in the blood plasma of patients with COPD makes it possible to distinguish risk groups for CHD, even in the absence of its explicit clinical manifestations.
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RAPID RESPONCE WITH USE IN RADIOSENSITIZER OF STEREOTACTIC RADIOSURGERY IN THE TREATMENT OF BRAIN METASTASES POSTERIOR FOSSA
Griazov A.
State Institution «Institute of neurosurgery named after academic A.P.Romodanov of NAMS of Ukraine», Kiev, Ukraine
Gryazov A.
P.L. Shupyk National Medical Academy of Postgraduate Education, Kiev, Ukraine
Medvedovskaya Yu.
State Institution «Institute of neurosurgery named after academic A.P.Romodanov of NAMS of Ukraine», Kiev, Ukraine
ABSTRACT
The role of hypoxic radiosensitizers (RS), metronidazole (M) and nimorazole (N), during stereotactic radiosurgery (SRS) in the treatment of metastases (MTS) of the posterior fossa (PF) was studied. The results obtained during the first three weeks (7, 14, and 21 days after SRS) demonstrated the high efficiency of radiosurgery using MTS, in the form of a rapid decrease in tumor volume, swelling zone, and signs of mass effect, comparable to surgical resection.
Stereotactic radiosurgery + hypoxic radiosensitization (SRS+RS) was performed in 20 patients with metastases of posterior fossa, who took 2 g orally before a 2-hour radiosurgery session. metronidazole (12 patients), or 2g. nimorazole (8 patients). In 7 patients, the primary tumor was non-small cell lung cancer (NSCLC), in 6 - breast cancer (BC), in 4 - melanoma (ML) and in 3 - renal cell carcinoma (RCC).
Each patient was observed for 3 weeks, every 7 days. The control was carried out according to MRI. MRI data were compared before and after radiosurgery. Both linear dimensions and metastasis volume were measured, as well as a decrease in tumor volume as a percentage of the original volume. To compare the effect of treatment of SRS without the use of RS, a control group of 8 patients with metastases of PF who received SRS without prior administration of radiosensitization preparations was presented.
In all 20 patients, the size of metastases decreased already at the first MRI control, 7 days after SRS + M. On average, a decrease in the volume of metastases occurred by 40% of the initial volume (in the range from 20 to 60%) during the first 7 days after SRS + RS, by 46% (in the range from 24 to 68%) during 14 days and by 50 % (in the range from 30 to 70%) within 21 days after SRS + RS. Edema was completely reduced in 62.5% of foci after 7 days, in the remaining 37.5% it decreased by more than 50% 14 and 21 days after SRS + RS. Neurological status improved in all 20 patients during the first week after SRS + RS. There were no signs of local or remote tumor recurrence over the indicated period of time. Of the side effects apparently associated with taking metronidazole in two patients, hiccups were noted (on the second and third day after SRS + M).
In the control group, changes in the volume of metastases (increase or decrease) after SRS during the first three weeks did not occur.
