Factors that are associated with clinical forms of ischemic heart disease in patients with chronic kidney disease on peritoneal dialysis

UDC 616-092/61-004/005.4

Introduction

It is typical of modern treatment and diagnostics of chronic pathology, including chronic kidney disease (CKD), that patients have a combination of several pathological states. Meanwhile, high mortality of patients with CKD is caused, first of all, by cardiovascular pathology. It is possible to track a certain pattern: risk factors of CKD are, at the same time, risk factors of cardiovascular diseases [1]. Damage of cardiovascular system in CKD patients on peritoneal dialysis (PD) may have a significant effect on quality of their life and their survival. Most often such patients have ischemic heart disease (IHD) [2, 3]. Sclerotic involvement of coronary arte­ries begins with deposition of modified lipoproteins in intima with development of endothelial dysfunction and mediators of systemic inflammation, proinflammatory interleukins and acute-phase proteins, which play an important role in development of vascular wall damage, emergence and destabilization of atherosclerotic plaques with development of trombophilic complications and myocardial ischemia [4, 5]. Atherosclerotic calcareous infiltration of coronary arteries, which is localized in the intimal layer, is one of the leading factors of coronary risks [6, 7], whereas amorphous mineral deposits, on a circle of one or several elastic layers of vessel media, which is one of the major factors of left ventricular hypertrophy (LVH) development by CKD, along with disturbance of autoregulation of coronary flow, caused by hypertrophy of subepicardial arteries with ingibition of neoangiogenesis of myocardium capillaries, lead to left ventricular remodeling with the outcome in ischemic dilated cardiomyo­pathy (IDCM) and congestive heart failure (CHF) [8]. As LVH advances, the discrepancy between the myocardial mass and the volume of coronary flow increases that is in turn followed by decrease in coronary perfusion reserve and increase in risk of acute coronary events [9]. Systemic inflammatory reaction developing with CKD also leads to endothelial dysfunction. Tumor necrosis factor (TNF)-α is capable to start the cascade of synthesis of proinflammatory cytokines, including interleukin (IL)-1β causing proliferation of macrophages and IL-8 stimulating directed migration of neutrophils to the center of the vascular wall damage and activating proliferation of endotheliocytes and smooth muscle cells in the damaged vascular wall [10, 11]. The initiator of inflammation in this case are lipoproteins modified during oxidative stress that are also transport systems for some acute-phase proteins, namely, C-reactive protein (CRP), serum amyloid A (SAA) and apo A-I possessing high affinity to lipids and circulating in blood in association with different classes of lipoproteins.

The aim of this research was to identify the most probable metabolic and immunologic factors that are associated with various IHD clinical forms in CKD patients on PD.

Materials and methods

This was a clinical observational non-combined case-control study with a 12 months follow-up from June 2021 to June 2022 of 114 patients on PD on the basis of the Department of Nephrology and Peritoneal Dialysis of the Regional Clinical Center of Urology and Nephrology, who received PD treatment from 12 to 106 months with average duration 53,00; 22,56 months (inclusion criterion).

Written informed consent was obtained from all subjects, and the ethics committee of Kharkiv National Medical University approved the study protocol number 0111U001395. The study was performed in accordance with the precepts of the Declaration of Helsinki.

Most patients were 46–55 years old (middle age was 47.90; 12.81 years old). Concerning diseases leading to end stage renal failure were: in 67% patients — chronic glomerulonephritis, 11% — diabetic glomerulosclerosis, 9% — polycystic kidney disease, 7% — chronic pyelonephritis, 6% — hypertensive nephroangiosclerosis. The research didn’t include patients who had dialysis-associated peritonitis or acute myocardial infarction less than 3 months ago, as well as patients with acute inflammatory diseases at the moment of the research (exclusion criterion). All patients had sufficient indicators of adequacy of the PD procedure.

At the beginning of our research, we analyzed the results of Doppler echocardiographic studies in patients over time for the previous 1–3 years of the PD treatment which allowed to detect signs of IDCM and identify contraindications for bicycle exercise testing. We performed bicycle exercise testing using protocols of steadily increased load in order to diagnose painless myocardial ischemia. Various IHD clinical forms were stated when patients had attacks of stable angina, by detecting painless myocardial ischemia (by results of bicycle exercise testing), increasing IDCM phenomena (dilatation of heart cavities, diastolic dysfunction, calcareous infiltration and atheromatosis of aorta and heart valves by analyzing echocardiography tests over time), as well as in patients who had acute myocardial infarction during the research.

According to identified IHD clinical forms, all patients were divided into 5 clinical groups: patients who suffered myocardial infarction within 1–2 months after the beginning of our study (n=7), patients with stable angina of various functional classes (n=13), patients with painless myocardial ischemia (n=29), patients with ischemic dilated cardiomyo­pathy (n=51) and patients with no signs of IHD (n=14). Within this research, immunologic studies of all patients, in­cluding defining of IL-1β, IL-8 and TNF-α, as well as acute-phase proteins (CRP and SAA) by immunoenzyme methods, were conducted, and indicators of lipid and phosphorus-calcium exchange were defined (content of phosphorus, corrected calcium, intact parathyroid hormone (iPTH), phosphorus and calcium product). All studies were performed at the beginning of the research (before the stress test) and after 12 months over time; bicycle exercise testing (the stress test) was performed once.

Statistical data processing was carried out using SPSS 21.0 for Windows, a statistical software package for a personal computer. In order to check the normality of the distribution of traits, Shapiro — Wilk test was used. For indicators which values were subject to the normal distribution law, the mean and standard error of the mean were determined, and for indicators which distribution was different from the normal, medians and interquartile range were calculated. When comparing the two dependent groups, the Wilcoxon test was used. Differences were considered significant when p<0.05. To predict the clinical variant of IHD, a logistic regression method was used. For each clinical group of patients, a logistic regression equation was compiled, which determines the probability of emergence of IHD clinical form taking into account the indicators discussed above:

P=[1+exp(z)]^–1,

where P is a probability that an event will occur that is of interest; and z is a value of a logistic function which is determined by the formula:

z=b₁•x₁+b₂•x₂+…+b_n•x_n+b₀,

where x is a factor or a predictor, and b₁, b₂, b_n, b₀ are coefficients, calculation of which is a binary logistic regression task.

The verification of the significance of the selected coefficients was carried out using Wald statistics. All variables, in accordance with Wald statistics, are significant (p<0.05) and selected correctly.

Results

At the 1^st stage of our research, we identified the process of left ventricular remodeling over time in patients with various IHD clinical forms. Before beginning PD treatment, we didn’t identify any signs of LVH in 7 (6.1%) patients, 99 (86.8%) patients had concentric LVH, 39 of them (34.2% of total number of patients) had diastolic dysfunction (DD) of 1 type, 8 (7%) patients had eccentric LVH, 4 of them (3.5% of total number of patients) had symptoms of systolic dysfunction (for these patients the stress test was not performed). In 27 (23.7%) patients, DD of 1 type was combined with calcareous infiltration of heart valves and mitral regurgitation of II degree. Over time, in 12 months of PD treatment, 9 (7.9%) patients had no signs of LVH, 97 (85.1%) had concentric LVH, 51 of them (44.7% of total number of patients) had it in combination with DD of 1 type, still 8 (7%) patients had eccentric LVH, but only two of them (1.8% of total number of patients) had symptoms of systolic dysfunction. In 49 (43%) patients, DD of 1 type was combined with calcareous infiltration of heart valves and mitral regurgitation of II degree. Thus, Doppler echocardiographic studies over time in PD patients with CKD allowed to diagnose mainly concentric LVH, DD of 1 type and calcareous infiltration of heart valves, which are signs of IDCM.

We also performed bicycle exercise testing (with steadily increased load, up to standard criteria of termination of testing). The received results allowed us to diagnose IHD in the form of painless myocardial ischemia in 29 (25%) patients, but negative results of other patients’ testing was regarded conditionally as IHD absence (conditionally, since testing was stopped on submaximum powers due to «painless» criteria of termination) (Fig. 1).

Figure 1. Criteria for termination of bicycle exercise testing

From the prognostic point of view, painless myocardial ische­mia is adverse, as in a third of IHD patients with painless myocardial ischemia, myocardial infarction develops 5–6 times more often, and risk of CHF development is 1,5 times higher. During dynamic follow-up, none of the patients had clinical and ECG symptoms of de novo stable angina or increase of a func­tional class of already existing angina. Seven patients suffered acute myocardial infarction (5 patients from the group with painless myocardial ischemia and 2 patients from the group of the patients with no signs of IHD as acute coronary event emerged for the first time) 1–3 months after the beginning of the research. Echocardiographic research conducted in 1–3 months prior to myocardial infarction showed that all patients had concentric LVH and dense calcium on the cusps of the mitral valve.

In formation of various IHD clinical forms in CKD patients on PD, the important role also belongs to systemic inflammatory reaction as one of the main mechanisms of atherogenesis, for all stages of which, from the moment of initial changes until the development of complications, inflammatory markers, such as proinflammatory interleukins (IL-1β, IL-8, TNF-α) and acute-phase proteins (CRP and SAA), which were investigated at the 2^nd stage of our research, are characteristic [12].

Tabl. 1–2 present the medians and interquartile ranges of the metabolic and immunological parameters of patients in the 1^st month of study in patients from different clinical groups.

Table 1. Indicators of acute-phase proteins, bone mineral and lipid exchanges

Table 2. Indicators of IL for all patient groups

Tabl. 3–4 present statistically significant changes in metabolic and immunologic indicators over time (12 months of PD therapy) in different clinical groups of patients. The difference was considered significant when p-value was less than 0.05.

Table 3. Indicators of acute-phase proteins, bone mineral and lipid exchanges after 12 months

Table 4. Indicators of IL for all patient groups after 12 months

The most marked reliable immunologic and metabolic changes were found in patients with painless myocardial ische­mia: high levels of IL-8; SAA; TG; Са×Р. In patients suffering from stable angina, we identified the most marked changes in lipid metabolism: increased LDL and TG. In the group of patients with no signs of IHD, the indicators of immunologic and phosphorus-calcium metabolism were within the normal range, with the exception of HDL with a steady downward trend.

At the 3^rd stage of our research, we predicted the probability of particular IHD clinical forms in PD patients with the help of SPSS 21.0 for Windows, a statistical software package for a personal computer, and binary logistic regression. We used metabolic and immunologic indicators, which differed significantly in various clinical groups, as potential predictors of this process.

The comparison of group 3 (patients with painless myocardial ischemia) and group 1 (patients who suffered myocardial infarction) detected statistically reliable influence of CRP and TNF-α on probability of development of myocardial infarction in PD patients. At the same time, the probability of development of myocardial infarction increased in patients with dense calcium of the mitral valve (Fig. 2).

Figure 2. Probability of development of painless myocardial ischemia or acute myocardial infarction in CKD patients on PD

By comparing group 3 (patients with painless myocardial ischemia) and group 4 (patients with IDCM), the probability of development of IDCM was determined by such indicators as CRP, SAA and IL-8 (quality of the models’ predictive capabi­lity: р=1,000 — very high) (Fig. 3).

Figure 3. Probability of development of painless myocardial ischemia or ischemic dilated cardiomyopathy in CKD patients on PD

The obtained mathematical models showed that in the process of IHD progression in patients with CKD on PD, dyslipidemia and indicators of the systemic inflammatory response are of primary importance.

Discussion

The data obtained in our research coincide with the results of prospective ECAT studies, as well as of B.D. Johnson and al. (2004) who confirmed an important role of SAA in atherosclerosis pathogenesis, advance of chronic IHD, but not as predictor of acute cardiovascular risks [13]. Probably, substantial increase of SAA and IL-8 in the group of the patients with painless myocardial ischemia and IDCM proves that there is a distinct general inflammatory reaction in these clinical groups aimed at decreasing endothelial damage and restricting a necrosis zone of tiny ischemic foci in myocardium with development of diffuse cardiosclerosis and CHF (Fig. 4).

Figure 4. Metabolic and immunological indicators of chronic systemic inflammation

If immunologic participants of general inflammation reaction didn’t manage to limit the area of necrosis of such a small ischemic focus of myocardial damage, acute coronary event is most likely to develop (Fig. 5).

Figure 5. Metabolic and immunological indicators affecting the occurrence of an acute coronary event in CKD patients on PD

The practical significance of the obtained mathematical models is the possibility of non-invasive prediction of likelihood of various IHD clinical forms and timely determination of indications for coronary angiography in patients on renal replacement therapy. The presence of terminal CKD should not be a contraindication for coronary angiography and further intervention on coronary vessels during the development of coronary syndromes in this category of patients, which will improve the quality and increase the duration of their life.

Conclusions

1. Different IHD clinical forms in CKD patients on PD are associated with various factors, but, first of all, are initiated by disturbance of lipid exchange with subsequent immunologic shifts combined with left ventricular remodeling, calcareous infiltration and aortic fibrosis, cordial structures and heart valves.

2. Proinflammatory interleukins, such as TNF-α and IL-1β, as well as CRP are most probably predictors of acute coronary risks (acute myocardial infarction), whereas IL-8 and SAA are associated with IDCM and CHF in patients on PD.

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Надійшла до редакції/Received: 21.04.2023
Прийнято до друку/Accepted: 08.05.2023