Course and prognostic significance of inflammatory reactions in patients with myocardial infarction accompanied by diabetes mellitus and obesity

The dissertation is devoted to the study of the features of inflammatory reactions in patients with myocardial infarction accompanied by type II diabetes mellitus and obesity, as well as to the assessment of the prognostic value of inflammatory markers in this group of patients. The work is aimed at analyzing the dynamics of C-reactive protein and pro- and anti-inflammatory cytokines (IL 4, IL 6, IL 8, IL 10, IFNγ) in the acute period of the disease and at comparing the obtained data with the clinical course and long-term outcomes of myocardial infarction.

The study has shown that in patients with concomitant type II diabetes mellitus and/or obesity, myocardial infarction is characterized by a more severe and complicated course, and the levels of a number of cytokines and CRP in the early stages of the disease can serve as predictors of an unfavorable course and long-term prognosis, which is of importance for the individualization of management tactics for such patients.

Inflammation as a pathological process has been known to physicians for many centuries. Descriptions of its signs can be found in ancient books. Although since the time of Celsus and Galen a wealth of data has been accumulated on the causes and mechanisms of inflammation and on its influence on the human organism, to this day this process remains an important problem and an object of study in virtually all branches of medicine. Many recent studies have been devoted to the investigation of inflammatory markers in various diseases and to their significance for the diagnosis and prognosis of the course of these diseases and for the choice of therapeutic tactics [7, 15, 17, 38, 53, 85, 118, 177].

In the second half of the 20th – beginning of the 21st century, non-communicable diseases, primarily diseases of the cardiovascular system, have become the main danger to public health and the main problem for healthcare. In this connection, scientific and clinical interest within the problem of inflammation has shifted from the detection of relatively severe inflammation to the diagnosis of subclinical inflammation. Cardiovascular mortality in Russia over the past 15 years has increased 1.5-fold. Every year in Russia about 1 million people die from cardiovascular diseases. These rates are considerably higher than in the developed countries of Europe, the USA, and Japan. Among these diseases, ischemic heart disease (IHD) occupies a leading place – 51% [33, 130]. Expert assessments indicate that, in terms of mortality among the working-age population, cardiovascular diseases rank second, and for many patients myocardial infarction (MI) becomes the culmination of their development.

In recent years the role of inflammation in the course and prognosis of IHD and, in particular, of myocardial infarction has been discussed ever more widely. The understanding of the role of cellular reactions in MI has deepened substantially in recent years. A number of plasma biochemical factors participating in this complex reaction have been identified. It has been proved that among the inflammatory factors in MI the so-called acute-phase reactants are of the greatest significance. The most studied among them are C-reactive protein (CRP), interleukins (IL) 1 and 6, orosomucoid, α1-antitrypsin, fibrinogen, haptoglobin, and complement components. The dynamics of changes in these inflammatory indices in myocardial infarction have been described: their rise from day 1 of the disease, reaching a maximum by day 7, with subsequent gradual decrease and normalization by day 28 [35]. However, the clinical significance of each of these indices has not yet been fully determined.

Questions concerning the features of the course of MI in patients with various concomitant pathologies have concerned researchers for many years, because solving this question at an early stage of the disease makes it possible to choose an individual management strategy for the patient, providing the best chances in a given patient. At present, the results of studies of inflammatory marker levels in MI and their relationship with life prognosis and the risk of complications are being widely discussed.

As is known, male sex and such previous manifestations of IHD as severe and long-standing angina or prior MI are associated with an increased risk of coronary complications in MI. Signs of increased risk are left ventricular (LV) dysfunction, congestive heart failure, as well as arterial hypertension, overweight, and diabetes mellitus (DM). Most of the well-known risk factors for IHD are also signs of poor prognosis in acute coronary syndrome (ACS). To date, the prognosis for patients with diabetes mellitus complicated by myocardial infarction remains unfavorable, and mortality from MI in this category of patients is still considerably higher in the presence of diabetes mellitus [108, 169]. The higher MI mortality in diabetic patients is due to various mechanisms affecting myocardial function and blood supply, and to the propensity for thrombosis characteristic of these patients. Of no less importance is long-term mortality, caused by frequent recurrent infarctions and fatal ventricular arrhythmias.

In addition, overweight and obesity (particularly abdominal obesity) are a risk factor for heart disease, and the presence of obesity in patients with IHD promotes its progression and increases mortality [5, 88, 148]. At the same time, the mean age at which the first myocardial infarction develops decreases by 4–8 years. The significance of obesity as a risk factor for cardiovascular diseases (CVD) has increased considerably in recent years, because the prevalence of obesity in the world population has risen. In Western Europe, more than half of adults aged 35–65 years are either overweight (body mass index (BMI) 25 to 29.9 kg/m2) or obese (BMI more than 30 kg/m2); in the USA, one third of the entire population is overweight (exceeding the ideal weight by 20% or more); in Russia, about 30% of working-age persons are obese, and 25% are overweight [25].

By now, sufficient data have been accumulated on the close association between the presence of DM and obesity and an elevated baseline level of inflammatory markers [86, 161]. However, the role of this "background" inflammation in the course and prognosis of MI in such patients remains incompletely resolved.

In view of all the above, the aim of our investigation was to analyze the features of the course of MI in patients with concomitant DM and obesity and to reveal the relationship between the dynamics of inflammatory indices and the course and outcomes of the disease.

To achieve this aim, the following tasks were set:

1. To evaluate the course of MI depending on concomitant DM and obesity.

2. To evaluate long-term outcomes of the disease depending on the presence of concomitant DM and obesity.

3. To determine the dynamics of CRP, pro-inflammatory (interferon γ (IFN γ), IL 6, IL 8) and anti-inflammatory cytokines (IL 4, IL 10) in patients with MI.

4. To determine the dynamics of CRP and cytokines (IFN γ, IL 4, IL 6, IL 8, IL 10) in patients with MI and concomitant type II DM.

5. To determine the dynamics of CRP and cytokines (IFN γ, IL 4, IL 6, IL 8, IL 10) in patients with MI and concomitant obesity.

6. To compare the dynamics of CRP and cytokines (IFN γ, IL 4, IL 6, IL 8, IL 10) with the course of MI.

7. To compare the dynamics of CRP and cytokines (IFN γ, IL 4, IL 6, IL 8, IL 10) with the long-term outcomes of MI.

Scientific novelty of the study.

In this work, for the first time, the levels of pro- and anti-inflammatory cytokines have been compared with the features of the course and with the short- and long-term prognosis of acute myocardial infarction in patients with and without concomitant type II diabetes mellitus and obesity, and an association has been revealed between a marked increase in the concentrations of CRP, IL 4, IL 8, IL 10 from the first day of MI (and IL 6 from day 7) and the complicated course of the disease and unfavorable long-term prognosis (recurrent MI, death).

The work has studied the influence of prior risk factors (type II diabetes mellitus and obesity) on the features of the inflammatory response in the acute period of myocardial infarction, on the course of the disease and on its long-term prognosis, and has revealed that myocardial infarction in patients with such concomitant diseases as type II diabetes mellitus and obesity is characterized by a more severe and complicated course; in this category of patients there is a more pronounced, compared with MI without concomitant diseases, increase in pro-inflammatory cytokines (except for IL 6 in concomitant DM) and a relative depression of the synthesis of anti-inflammatory IL 10.

Practical significance.

The presence of concomitant type II diabetes mellitus and/or obesity in patients with myocardial infarction has an adverse effect on the course of the disease and on its long-term prognosis.

Determination of inflammatory markers (CRP, IFNγ, IL 4, IL 6, IL 8, IL 10) in the blood of patients on the first day of myocardial infarction with subsequent monitoring of changes in these indices over time makes it possible to identify patients at increased risk of an unfavorable course and outcome of the disease. Thus, for example, a marked rise in the concentrations of CRP, IL 8, IL 10, IL 4, IFNγ, IL 6 on the first day of the disease and/or an excessively low value of the concentrations of IFNγ and IL 6 in patients with MI should be regarded as a powerful predictor of a complicated course of the disease and of an unfavorable long-term prognosis, up to a lethal outcome. Thus, comparison of the levels of inflammatory markers with the presence of prior risk factors (in particular type II diabetes mellitus and obesity) in patients with myocardial infarction helps to individualize the approach to the treatment and rehabilitation of a specific patient, taking into account the risk parameters identified.

Implementation of the results in practice.

The main propositions of the dissertation have been introduced and are used in the work of the cardiac intensive care unit and the cardiology unit for patients with myocardial infarction of City Clinical Hospital No. 13 of Moscow and of the 2nd cardiology unit with cardiac intensive care block of City Clinical Hospital No. 15 of Moscow. The results of the study are used in the educational process at the Department of Outpatient Therapy of the Moscow Faculty of the Russian State Medical University.