Резюме
Лісовий В.М., Андон'єва Н.М., Гуц О.А. Системна запальна реакція як фактор прогресування ішемічної хвороби серця у пацієнтів з хронічною хворобою нирок на перитонеальному діалізі.
У статті представлені результати дослідження імунологічних (інтерлейкіни та білки гострої фази запалення) та метаболічних параметрів у пацієнтів з хронічною хворобою нирок (ХХН) на перитонеальному діалізі (ПД), (термін перебування на діалізі від 12 до 108 місяців), в різних клінічних групах: пацієнтів, що страждають стабільною стенокардією; безбольовою ішемією міокарда; ішемічною ділятаційною кардіоміопатією; перенесли гострий інфаркт міокарда в період дослідження і тих, що не мають ознак ішемічної хвороби серця (ІХС). У пацієнтів, що перенесли гострий інфаркт міокарда в період дослідження, відзначалося підвищення фактора некрозу пухлини альфа (ФНП-α), інтерлейкіну 1β (ІЛ-1β) і С-реактивного білка (СРБ) за кілька місяців до  гострої  коронарної  події. Комбінація високих показників інтерлейкіну (ІЛ-8); сироваткового амілоїду А-1 (САА-1), тригліцеридів (ТГ), фосфорно-кальцієвого множиння (Р × Са), інтактного паратиреоїдного гормону (і-ПТГ) була найбільш характерна для пацієнтів з безбольовою ішемією міокарда; меншою мірою - для хворих з ішемічною ділятаційною кардіоміопатією. Значне підвищення показників ліпопротеїнів низької щільності (ЛПНЩ) і тригліцеридів спостерігалося у групі пацієнтів, які страждають стабільною стенокардією. У хворих, які не мають ознак ІХС, спостерігалося зниження ліпопротеїнів високої щільності (ЛПВЩ), характерне практично для всіх пацієнтів на ПД. В цілому, системна запальна реакція може розглядатися як фактор прогресування ІХС у пацієнтів з ХХН на ПД тільки в комбінації з дисліпідемією та порушеннями кістково-мінерального обміну.
Ключові слова: хронічна хвороба нирок, перитонеальний діаліз, прогресування ішемічної хвороби серця, системна запальна реакція, інтерлейкіни, білки гострої фази запалення.
Резюме
Лесовой В.Н., Андоньева Н.М., Гуц Е.А. Системная воспалительная реакция как фактор прогрессирования ишемической болезни сердца у пациентов с хронической болезнью почек на перитонеальном диализе.
В статье представлены результаты исследования иммунологических (интерлейкины и белки острой фазы воспаления) и метаболических параметров у пациентов с хронической болезнью почек (ХБП) на перитонеальном диализе (ПД), (срок пребывания на диализе от 12 до 108 месяцев), в различных клинических группах: пациентов, страдающих стабильной стенокардией; безболевой ишемией миокарда; ишемической дилятационной кардиомиопатией; перенесших острый инфаркт миокарда в период исследования и не имеющих признаков ишемической болезни сердца (ИБС). У пациентов, перенесших острый инфаркт миокарда в период исследования, отмечалось повышение фактора некроза опухоли альфа (ФНО-α), интерлейкина 1β (ИЛ-1β) и С-реактивного белка (СРБ) за несколько месяцев до произошедшего острого коронарного события. Комбинация высоких показателей интерлейкина (ИЛ-8); сывороточного амилоида А-1 (САА-1), триглицеридов (ТГ), фосфорно-кальциевого произведения (Р×Са), интактного паратиреоидного гормона (и-ПТГ) была наиболее характерна для пациентов с безболевой ишемией миокарда; в меньшей степени - для больных с ишемической дилятационной кардиомиопатией. Значительное повышение показателей липопротеинов низкой плотности (ЛПНП) и ТГ наблюдалось в группе пациентов, страдающих стабильной стенокардией. У больных, не имеющих признаков ИБС, наблюдалось снижение липопротеинов высокой плотности (ЛПВП), характерное практически для всех пациентов на ПД. В целом, системная воспалительная реакция может рас-сматриваться как фактор прогрессирования ИБС у пациентов с ХБП на ПД только в комбинации с дислипидемией и нарушениями костно-минерального обмена.
Ключевые слова: хроническая болезнь почек, перитонеальный диализ, прогрессирование ишемической болезни сердца, системная воспалительная реакция, интерлейкины, белки острой фазы воспаления.
Summary
Lesovoy V.N., Andonieva N.M., Guts E.A. Systemic inflammatory response syndrome as a factor of progression of ischemic heart disease in patients with chronic kidney disease who receive PD therapy.
The article presents the results of the research into the immunological (interleukins and acute-inflammatory-phase proteins) and metabolic parameters in patients with chronic kidney disease (CKD) who receive peritoneal dialysis (PD therapy) (from 12 to 108 months) in different clinical patient groups: the patients who suffer stable angina pectoris; painless myocardial ischemia; ischemic dilated cardiomyopathy; and the patients who suffered acute myocardial infarction during the research and without ischemic heart disease (IHD). The high parameters of tumor necrosis factor-alpha (TNF-α); interleukin 1β (IL-1β) and С-reactive protein (СRP) had been detected several months before acute coronary syndrome in the patients who suffered acute myocardial infarction during the research. The combination of the high parameters of interleukin 8 (IL-8); serum amyloid A-1 (SAA-1); triglycerides (TG); Р×Са; i-PTH was most typical of the patients with painless myocardial ischemia and, to a degree, of the patients with ischemic dilated cardiomyopathy. The considerably heightened parameters of low density lipoproteins (LDL) and TG were observed in the group of patients who suffer stable angina. There was a decrease in the level of high density lipoproteins (HDL) in the patients who didn’t suffer IHD which is characteristic of practically all patients receiving PD therapy. In general systemic inflammatory response syndrome can be regarded as a factor of progression of ischemic heart disease in patients with CKD receiving PD therapy just in combination with lipid metabolism malfunction and mineral and bone disorder.
Key words: chronic kidney disease, peritoneal dialysis, progression of ischemic heart disease, systemic inflammatory response syndrome, interleukins, acute-inflammatory-phase proteins.

УДК 616.61-008.64 612.339.1

Харьковский национальный медицинский университет

проспект Ленина, 4, Харьков, 61022,Украина 

Kharkiv National Medical University,

4 Lenin Avenue, Kharkiv,61022,Ukraine

lena_guts@list.ru

Current recommendations for the prevention of cardiovascular disease are paying great attention to the identification and correction of risk factors, assessing the likelihood of complications and prognosis of cardiovascular disease [4,13,17]. Ischemic heart disease is one of the major causes of cardiac disease in patients with CKD on PD, which even with adequate renal replacement therapy tends to progress, manifested acute coronary syndrome or chronic heart failure [8.14]. In studying the characteristics of the method of PD the most important for this type of dialysis coronary risk factors which include dyslipidemia, and chronic systemic inflammation that play an important role in atherogenesis, including the initiation of atherogenic process, the development of damage to the vessel wall, the instability of the atheroma and the occurrence of thrombotic complications were identified [5,12]. Synergistic effects have disturbances of bone and mineral metabolism which are characteristic of CKD patients on PD [2].

The main mediators of the systemic inflammatory response are: TNF which is able to "run" the cascade synthesis of proinflammatory cytokines, including IL-1β, causing proliferation of macrophages, and IL-8 which stimulates the directed migration of neutrophils to the site of damage to the vessel wall and activates endothelial cell proliferation and smooth muscle cells in the damaged vessel wall [3,11]. The initiator of inflammation in this case are modified in the course of oxidative stress lipoproteins [1,9,10] which are also the transport systems for some acute-phase proteins, namely, CRP, SAA1 and apo (a1)-lipoproteins that have high tropism to lipids and circulate in the blood in association with different classes of lipoproteins [1,15]. More likely that in the acute phase of inflammation hepatocytes secrete not lipoproteins, but only functional complexes CRP and VLDL-apo (a1)-HDL-SAA1 in the blood [8,16].

Conflicting results of prospective studies in the general population of patients on direct correlation of CRP and SAA1 in combination with different classes of lipoproteins to the progression of coronary artery disease were published [8,11].

The purpose of this study was to determine the value of pro-inflammatory interleukins and acute-phase proteins as factors of the progression of coronary artery disease in patients with CKD on PD.

Materials and methods. We examined 80 patients treated with peritoneal dialysis during from 12 to 108 months (median - 36 months), the mean age was 47 ± 1,8 years. 39 of these patients were women and 41 were men. The patients were divided into nosologic units as follows: 51 (63.7%) – the patients with chronic glomerulonephritis, 13 (16.3%) – the patients with polycystic kidney disease, 11 (13.8%) – the patients with diabetic glomerulosclerosis, 3 (7%) – the patients with hypertension, nefroangiosklerozom, and 2 (2.5%) – the patients with chronic pyelonephritis.   

 In order to diagnose the progression of coronary artery disease and the identification of silent myocardial ischemia Doppler echocardiographic studies of patients over time were analyzed at the beginning of the study, for the previous 1-3 years of patients’ stay in PD with the calculation of systolic thickening of the left ventricle; bicycle exercise ECG stress test was produced. In accordance with the findings and the results of follow-up of patients in the dynamics in 3-6 months, all patients were divided into five clinical groups:

         Group 1 - Patients with a history of myocardial infarction within 1-2 months after the start of the study (acute coronary syndrome).

         Group 2 - patients with stable angina, different functional classes.

         Group 3 - patients with ischemic dilated cardiomyopathy.

         Group 4 - patients with silent myocardial ischemia.

         Group 5 - patients with no signs of coronary artery disease.

The study excluded patients with acute and chronic inflammatory disease exacerbation, and patients with a history of myocardial infarction or peritonitis dialysis for 3 months before the study.

In this work all patients underwent general clinical and immunological studies including determination of IL-1β, IL-8 and TNF-α, and the definition of acute-phase proteins (CRP and SAA1) by immunoassay methods, determined lipid profile by the colorimetric method of photometry, estimated rates of calcium-phosphorus metabolism (phosphorus, calcium, adjusted for albumin, and PTH-, calculated calcium-phosphorus product).

Statistical analyzes were conducted using the statistical software package for PC STATISTIKA6.

Results and discussion: For the diagnosis of coronary artery disease progression doppler echocardiographic studies were conducted in the dynamics each year with the calculation of systolic wall thickening of the left ventricular myocardium to detect silent myocardial ischemia. Disturbing signal mismatch in myocardial oxygen demand and its blood supply is anginal pain, but 50-75% of ischemic episodes are silent, which is associated with the violation of the sensitivity of the nerve endings due to neuropathy, developing, including the toxic effect of some cytokines in chronic renal failure. It is a poor prognosis, as in one third of patients with CHD and silent myocardial ischemia myocardial infarction develops in 5-6 times more, 1.5 times higher risk of developing congestive heart failure (CHF) [2,5]. During the period of follow-up of patients over time in our study, none of the patients did not appear clinical and ECG signs of stable angina de novo or increase existing functional class of stable angina, but suffered five-acute myocardial infarction (4 - from a group of silent myocardial ischemia and 1 - of a group of patients who had no signs of coronary artery disease, as first emerged acute coronary event). With echocardiography study for 1-3 months before myocardial infarction all patients had concentric left ventricular hypertrophy and the presence of calcifications in the mitral valve.

There are two types of vascular calcification, divided by the location and connection with the formation of atherosclerotic plaque. The first type - atherosclerotic calcification, which is localized in the intimal layer, flows with cell death, inflammation, lipid deposition and the subsequent formation of atherosclerotic plaques that is a leading factor in acute coronary risks. The second type - amorphous mineral deposits around the circumference of one or more layers of elastic media of the vessel - one of the key drivers of concentric left ventricular hypertrophy, remodeling of the left ventricle with the outcome in ischemic dilated cardiomyopathy [8,16]. In the progression of coronary artery disease in patients with CKD in PD both types of vascular calcification play a major role, along with the systemic inflammatory response, as one of the basic mechanisms of atherogenesis, which at all stages, from the inception of the initial changes to the development of complications, is characterized by the presence of markers of inflammation - inflammatory interleukins (IL-1β; IL-8, TNF-α) and acute-phase proteins (CRP and SAA1) [4.12].

Table 1 shows the performance of interleukins for all groups of patients without their value over time, as for all clinical groups, their trends remained almost identical to the baseline values, except for patients with acute myocardial infarction, in which 1-2 months before an acute coronary event initially high levels of TNF-α -13,2 ± 0,5 (p ˂ 0.01) and IL-1β - 12,9 ± 0,09 (p ˂ 0,01) came to the norm, as well as the value of CRP, as can be seen from Table 2. The most pronounced reliable immunological and metabolic changes found in patients with silent myocardial ischemia: high levels of IL-8 - 71,3 ± 1,6 (p ˂ 0,05); SAA1 - 2,5 ± 0,9 (p ˂ 0 05) TG - 2,7 ± 0,9 (p ˂ 0,05); Ca × P - 5,4 ± 0,7 (p ˂ 0,01). Identical, but slightly lower values, they are also in a clinical group of patients with ischemic dilated cardiomyopathy. In patients with stable angina, we found the most pronounced changes in lipid metabolism: increased LDL - 3,1 ± 0,8 (p ˂ 0,01) and TG - 2,2 ± 0,8 (p ˂ 0,01). In the group of patients with no signs of ischemic heart disease, the immunological and bone mineral metabolism were normal, except for HDL-1, 1 ± 0,7 (p ˂ 0,5), lower values ​​were observed in all clinical groups, but this group had the lowest.

Table 1. Indicators of interleukins for all patient groups

      *р<0,01 **р<0,05 - compared with patients with no signs of coronary artery disease

        Table 2. Indicators of acute-phase proteins, bone mineral and lipid exchanges

*р<0,01 **р<0,05 - compared with patients with no signs of coronary artery disease

Our data are consistent with the prospective studies ECAT, and Johnson BD and colleagues, who have confirmed the important role of the SAA1 in the pathogenesis of atherosclerosis, the progression of chronic ischemic heart disease, but not as a predictor of acute cardiovascular events [4,8]. Perhaps, a significant increase SAA1 (2-3 times) and IL-8 in patients with silent myocardial ischemia and ischemic dilated cardiomyopathy demonstrates steadfastly existing statement of the general reaction of inflammation in these clinical groups, aimed at reducing endothelial damage and restriction necrotic area of small ischemic lesions in the myocardium with the development of subsequent cardiosclerosis diffuse and chronic heart failure. If the limitation of the zone of necrosis of such a small myocardial ischemic lesion participants overall immunological inflammatory reaction is not possible, acute coronary event develops in most cases.

Conclusion: Systemic inflammatory response in patients with chronic kidney disease on PD as a factor of progression of CHD is closely related to dyslipidemia and vascular calcification against a background of mineral and bone metabolism.

Among the pro-inflammatory interleukins and acute-phase proteins, the combination of high levels of IL-8, SAA1 with hypertriglyceridemia and high calcium-phosphorus product may be a factor in the progression of chronic ischemic heart disease with the development of ischemic dilated cardiomyopathy and heart failure.

Predictors of acute coronary risks may be the increase of TNF-α, IL-1β and CRP for 1-2 months before the incident of acute coronary events.

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