MORPHOLOGICAL AND STRUCTURAL CHANGES IN MYOCARDIUM, LIPID AND CARBOHYDRATE METABOLISM DURING DIFFERENT OUTCOMES OF CHRONIC HEART FAILURE IN PATIENTS WITH ISCHEMIC HEART DISEASE AND DIABETES MELLITUS TYPE II

Diabetes mellitus (DM) type II is an independent risk factor for cardiovascular system injury. To avoid progression of ischemic heart failure (IHF) it is important to find early signs of myocardial injury also as carbohydrate and lipid metabolism alterations. The objective of the study: to establish features of structural and functional changes in myocardium, carbohydrate and lipid metabolism, in patients with different outcomes of chronic heart failure (CHF), caused by IHD and DM type II. Material and methods. Examination of 100 patients who have CHF with IHF and DM type II was performed. Patients were divided in two groups, according to outcome: group I (n=66) – patients with favorable outcome, mean age 60.0 [55.8; 63.3] years, group II (n=34) – unfavorable outcome of CHF, mean age 58.0 [55.0; 60.3] years. We analysed complaints, cardiologycal anamnesis, cardiovascular risk factors, and physical examination data. Transthoracic echocardiography (TTE), carbohydrate and lipid panel were assessed to find out early specific signs of myocardial injury. Results. We find out statistically significant associations between TTE results, lipid panel and CHF progression in study population. Conclusions. Comparative analysis showed that degree of CHF in patients with IHD and DM type II that have preserved LV EF is associated with: duration of DM and CHF, arterial hypertension (AH) level and degree of carbohydrate and lipid metabolism disturbances. Early TTE signs of unfavorable outcome are: increase of transmitral deceleration time (Dt), increase of mean PA pressure (PA MP) even in range lower the 20 mmHg.


Introduction
There are 415 millions of patients around the world with diabetes mellitus (DM), 90 % of them have DM type II [1]. Despite available scientific data about risk factors and DM-screening Original Research Article: full paper (2020), «EUREKA: Health Sciences» Number 1 programs running, incidence of disease still increases. According to experts of International Diabetic Federation (IDF), in 2035 amount of people with DM type II will reach 592 million, this is approximately every tenth. This shows significance of ongoing study on genotype and phenotype of DM to individualise treatment for this kind of patients [2]. DM type II leads to micro-and macrovascular complications, and after that ischemic heart disease (IHD). Epidemiological data shows that cardiovascular complications are the main reason of morbidity and mortality among patients with DM (80 % of patients with DM type II mortality is connected to cardiovascular complications) [2]. Almost in 50 % patients that have IHD, diagnosis of the DM type II, impaired glucose tolerance or impaired fasting glucose is found first time. According to this, American Heart Association (AHA) established presence of DM type II as equivalent of high risk of vascular complications, which is comparable with present cardiovascular diseases [3].
Nowadays there is a big interest in pathophysiological mechanisms, responsible for changes in cardiomyocites during DM type II [1]. Hyperglycemia leads to decrease in ability to resist oxidative stress by increase of glucose utilisation in citric acid pathway, increase in inflammatory response, that have influence on lipid metabolism and immune response, and leads to chronic inflammation in arterial vessel wall, endomyocardial fibrosis, necrosis and apoptosis of endothelial cells and cardyomiocytes [4,5]. This mechanisms combined with disorders of mineral metabolism, impairment of Са 2+ regulation of myofilament function, increase of active oxygen forms level, increased lipotoxycity, autonomic nervous system dysfunction, which one, according to progressive autonomic neuropathy, decrease vasodilative effect of sympathetic stimulation to coronary vessels resistance -thus accelerates coronary vessels calcification and appearance of CHF with DM type II [6,7].
Despite present scientific data of DM type II influence on cardiovascular pathology, pathophysiology of myocardial ischemia during DM type II needs further investigation. One group of patients with DM type II have coronary artery disease that prevents normal blood flow to myocardium, another have microvascular changes without plaques, and absence or presence of endothelial dysfunction [8]. There is lack of data about main aspects of diabetic coronary microvascular dysfunction in structure of cardiovascular diseases, role of genetic types of ATP-dependent potassium channels that determine course of IHD by balancing coronary blood flow and cardiac performance [9,10].
In modern era, it is important to study mechanisms of development and specific clinical signs of CHF on the early stage. Investigations should lead to development of new methods and materials of prophylactic and treatment.
The objective of the study: to highlight patterns of cardiac morphology and function, lipid and carbohydrate metabolism during different courses of heart failure in patients with IHF and DM type II.

Material and methods
We performed complex examination of 100 male patients with ischemic CHF with IHD and DM type II after in-hospital treatment. All patients signed an informed consent to participate in the study.
Examination was performed in therapy department of community-owned non-profit organization "City clinic of urgent and emergency medicine named after prof. A. I. Meschaninov" Kharkiv`s City Council, Ukraine, between February 2015 and January 2017.
The authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study. No funding for this study.
Complaints, cardiological anamnesis, cardiovascular risk factors, physical examination data, laboratory and instrumental examination, including 12-leads ECG, were analysed. AP was measured three times on both brachial arteries in sitting position, not earlier than 30 minutes after physical exertion, with mean AP (MAP) calculated. Pulse AP (PAP) was measured as difference between systolic AP (sAP) and diastolic AP (dAP). Mean AP (MAP) calculations are: MAP=0.42*(sAP-dAP)+dAP.
Insulin We measured endothelium dependent dilation in the brachial arteries (EDD). Degree of EDD was measured by reactive hyperemia, observed by wide-broad linear probe 5-12 MHz in colour doppler mode three times in left and right brachial arteries with 15 minutes interval, method by Celermajer D. S. [14] modified after Ivanova A. V. [15].
Statistical analysis was performed with SPSS 19 software for Windows. Quantitative variables are described as median (М), 25 and 75 quartiles (M [Q1; Q3]) qualitative data -as frequency of the events (% from normal observations). In order to identify differences between independent samples was used Mann-Whitney U-criteria. Frequency of sign occurrence in groups was compared by χ 2 criteria.
Duration of IHD varies from 5 to 10 years. Duration of DM type II -from 5 to 9 years. Family history of DM type II had 36.4 % of patients in group I and 58.8 % in group II (р=0.03). Every patient with DM type was in subcompensated state (fasting glucose <7.6 mmol/l, glycated haemoglobin <8.0 %).

Discussion
HFpEF is a complex clinical condition, both in terms of diagnosis and treatment of this syndrome. In the actual practice of the physician, it is found that patients with HFpEF are receiving the same treatment as patients with HFrEF [16,17]. However, if prognosis for RAAS blockers, beta-blockers, or mineralocorticoid receptor antagonists has been shown to improve prognosis for patients with HFpEF, there is no evidence for the efficacy of these drugs in patients with HFpEF [18].
In our study, unfavourable outcome of CHF in patients with СHD and DM type II was associated with higher incidence of СHD and DM duration; also, there was tendency of higher age.
In group II rates of DM type II family history, AP level was significantly high, also there was a tendency to higher incidence of СHD family history and lower physical exertion tolerance.
Unfavourable outcome of CHF was associated with more severe lipid and carbohydrate disturbances. Lipid metabolism disturbance leads to severe forms of DM type II that is also demonstrated in another study. A study of the state of lipid metabolism in patients with coronary heart disease and CHF showed in 45.9 % of cases of hypercholesterolemia, in 62 % -increase in low-density lipoprotein, in 15.3 % -decrease in high-density lipoprotein [19].
To date, the possibility of identifying patients who are prone to the progression of LV diastolic dysfunction in CHF is widely discussed in the literature. Early detection of these patients and more careful monitoring can help improve treatment outcomes and develop new treatment options [20,21].
Even if patients with CHD and DM type II have LV EF preserved (HFpEF), in case of unfavourable outcome EF was significantly lower and was a strong predictor of one. All patients had left ventricle diastolic dysfunction 1 degree, despite normal LALD, but median was higher in group II. DT was higher in group II, that shows more severe diastolic dysfunction degree.
Group II is characterized by higher rate of endothelial dysfunction, which shows severe remodelling processes in vessels.
The coexistence of HFpEF and type 2 diabetes predicts an increased risk of morbidity and mortality. Therefore, there is an increasing need to find new diagnostic tools and treatments to improve clinical outcomes in patients with CHF and type 2 diabetes. Accordingly, it is important for both states to optimize drug therapy and lifestyle while balancing the potential for side effects of medication. Although there are no specific guidelines for the management of patients with HFpEF suffering from diabetes [22].
Limitations of the study. Our study is limited by the number of patients with strict inclusion criteria. This failed to analyse the association of CHD and DM type II in patients with borderline LV EF.
Prospects for further research. Detection of simple predictors of adverse CH course in patients with CHD and DM type II is an urgent task of modern medicine. Achieving this goal makes it possible to stratify a group of patients with high-risk CH complications for closer observation. The increase in the number and groups of patients with CH, the duration of follow-up, will help to identify more sensitive predictors of adverse course of pathology.

Conclusions
Severity of CHF with preserved LV EF in patients with IHD and DM type II is associated with disease duration, AH level and severity of lipid and carbohydrate metabolism disturbances. Higher blood level of total low-density lipoproteins, HbAc1, glycemia, index HOMA and atherogenic index was in patients with unfavourable outcome.
In patients with unfavourable outcome was more low LV EF but in range not lower than 50 % and EDD.
Early markers of unfavourable outcome are increase of dT and increases of PA MP even in range not higher than 20 mmHg.