COURSE OF POST COVID-19 DISEASE IN HEART FAILURE PATIENTS WITH MODERATELY REDUCED LEFT VENTRICULAR EJECTION FRACTION.

In this study, we assessed the impact of COVID-19 on the course of HFmrEF by determining the biomarkers furin and NT-proBNP, questionnaires (EQ-5D-5L), and cardiac ultrasound. A comprehensive examination of 72 patients with HFmrEF (main group) and 18 apparently healthy individuals (control group). The main group was divided into two subgroups depending on the history of coronavirus disease. All patients gave their consent to participate in the study. In the group of patients with a history of coronavirus infection compared to the patients without a COVID-19 history were established: significantly higher concentrations of NT-proBNP (1002.79±215.94 pg/ml and 405.37±99.06 pg/ml, respectively, p-value 0.01), uric acid (429.08±27.01 mmol/l vs. 354.44±28.75 mmol/l, p-value 0.04) and a lower furin to NT-proBNP ratio (0.87± 0.26 and 1.38 ± 1.16, p-value 0.045) in blood serum; using the EQ-5D-5L questionnaire, a significant deterioration of quality of life indicators (64.21±3.04 points vs. 72.81±1.82 points by VAS, p-value 0.02); higher indicators of LVMMi (157.39±6.14 g/m2 and 138.68±6.02 g/m2, p-value 0.03), LA dimensions (43.74±0.95 mm and 41.12±0.85 mm, p-value 0.04) and RA dimensions (40.76±1.23 mm and 37.75±0.85 mm, p-value 0.04). Coronavirus infection in patients with HFmrEF leads to disorders of intracardiac hemodynamics and persistent negative structural changes of the heart. The ratio of furin to NT-proBNP serum levels can be used to determine the impact of the HF syndrome itself on the patients' subjective assessment of their quality of life.

USE OF Β-ADRENOBLOCKERS IN PATIENTS WITH HEART FAILURE AND CONCOMITANT THYROID PATHOLOGY (LITERATURE REVIEW AND OWN OBSERVATIONS).

The systematization of literature data on the use of ß-adrenoblockers in patients with heart failure and concomitant thyroid pathology was carried out, and the results of our own study were presented. It has been suggested that the final chapter in the history of the use of ß-adrenoblockers in patients with heart failure with reduced left ventricular ejection fraction and thyroid pathology has not yet been written. Further studies are needed, including pharmacogenetic ones. The use of a selective ß-adrenoblockers - bisoprolol in patients with chronic heart failure with reduced left ventricular ejection fraction and concomitant low triiodothyronine syndrome does not lead to a decrease in the frequency of rehospitalization due to decompensation. At the same time, the frequency of rehospitalization in the group of patients with heart failure without low triiodothyronine syndrome is higher at a dose of 1.25-5.0 mg of bisoprolol compared with a higher dose. The effect of bisoprolol is reversed in patients with low triiodothyronine syndrome: the risk of re-hospitalization increases when the dose of bisoprolol is exceeded, there is a decrease in the serum level of triiodothyronine, an increase in thyroxine levels, a decrease in the ratio of triiodothyronine / thyroxine; further increase in the cavities of the heart and decrease in size. Probably, in patients with heart failure, against the background of low triiodothyronine syndrome, it is not advisable to titrate the dose of bisoprolol above 5 mg, and the time to titrate the drug to the indicated dose should be more than 63 days. Today it can be argued that, in general, recommendations for the use ß-adrenoblockers in patients with chronic heart failure with reduced left ventricular ejection fraction apply to patients with concomitant thyroid dysfunction, subject to the above restrictions.

[POLYMORPHISM OF THE BETA1- AND BETA2-ADRENORECEPTOR GENES AND BISOPROLOL EFFICIENCY IN PATIENTS WITH HEART FAILURE].

The work was aimed at studying the relationship between the efficiency of bisoprolol and the polymorphism of ß1- and ß2-adrenergic receptors (ß-AR) genes in patients with heart failure. The two-year study included 251 patients with heart failure (with myocardial infarction on the background of coronary heart disease). During hospitalization, a standardized examination and prescription of therapy was carried out, including ß-adrenergic blocking agent (ß1-AB) - bisoprolol. Afterward, 61 (24.4%) patients stopped taking ß1-AB (bisoprolol) as a result of intolerance or violation of compliance; 190 patients took bisoprolol for 2 years. The frequency of rehospitalization (RH) due to decompensation of heart failure (HF) (or intravenous injection of loop diuretics), mortality, and the development of a composite endpoint (CE) for 2 years was taken into account. The control group consisted of 55 healthy individuals. Genotyping was performed using 3 polymorphisms (Gly389Arg of the ß1-АR gene, Ser49Gly of the ß1-АR gene, Gln27Glu of the ß2-АR gene) using the polymerase chain reaction. Genetic and epidemiological analysis was carried out using the SNPStats program. The use of bisoprolol with HF reduces the risk of re-hospitalization (odds ratio (OR)=0.519 (0.278-0.967); p=0.037) and CE (OR=0.494 (0.271-0.900); p=0.030) for 2 years of treatment. Treatment of patients with bisoprolol in a dose of >5 mg leads to a decrease in the risk of CE with G/A polymorphism Ser49Gly (c.145A> G) of the ß1-AR gene (OR=0.18 (0.04-0.84), with p=0.014). The use of this drug at this dose also leads to a decrease in the frequency of RH and CE with the homozygous genotype C (C/C) of the Gln27Glu polymorphism (c.79C>G) of the ß2-AR gene (OR=0.09 (0.02-0.46), at p=0.018 and OR=0.14 (0.04-0.58), at p=0.006, respectively).

[THE SYNDROME «LOW TRIIODOTHYRONINE¼ AND A COURSE A HEART FAILURE].

The study was aimed at investigation of the effect of the "low triiodothyronin syndrome" (LT3S) on the course of heart failure (HF) developed on the background of post-infarction cardiosclerosis. The biennial study included 157 patients with HF (with a myocardial infarction on the background of coronary heart disease). During hospitalization, a standardized assessment was carried out, hemodynamic parameters, clinical and biochemical blood tests, levels of thyroid hormones (thyroid stimulating hormone (TSH), free T3f and T4f, reverse T3r) were determined. Statistical analysis has shown that for the diagnosis of LT3S in patients with HF on the background of post-infarction cardiosclerosis, it is advisable to use serum T3f level, ≤2.07 pmol/l. The frequency of LT3S in patients with HF during hospitalization is 17.8%. Patients with LT3S are younger, have larger left ventricular size, lower ejection fraction, a high relative risk of re-hospitalization within 2 years due to decompensation of HF (2.224 [1.363-3.630]). A regression model of the re-hospitalization of patients with HF has been described, which included: weight, thyroxine and triiodothyronine concentrations, non-toxic goiter, growth, total cholesterol levels and LDL cholesterol, blood granulocyte content. It is shown that the risk of re-hospitalization of patients with HF due to decompensation of the disease increases when the equation of this model exceeds ≥1,321 (sensitivity - 93.78% and specificity - 40.45%, p=0.0001).

[Cardioprotective effects of flokalin: relative role of activation of sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels].

In experiments on isolated Langendorff perfused hearts of guinea pig with modeling of ischemia (20 min) and reperfusion (40 min) the cardioprotective effects of flokalin were shown. Preliminary preischemic perfusion of isolated heart with flokalin (5 mM) for 5 minutes has significantly improved the recovery of contractive function ofischemic myocardium at repcrfusion. Particularly, recovery of systolic and developed pressure was improved and the increasing of end-diastolic pressure in left ventricle was prevented. The vasoconstriction of coronary vessels was prevented and number of extrasystols at reperfusion of ischemic heart was decreased. Morphological studies have shown that flokalin prevents the significant damage of myocardial structure and the development of hypercontraction of myofibrils at ischemia-reperfusion of myocardium. It also preserves the intact sarcolemma and intracellular organelles. The intact structure of mitochondria also was saved by flokalin that maintains the energy potential of myocardium. Using the selective blocker of mitochondrial K(ATP) channels 5-hydroxydecanoate (200 mM) allows to determine the relative role of sarcolemmal and mitochondrial K(ATP) channels activation in these effects. It was shown that mitochondrial as well as sarcolemmal K(ATP) channels play role in the recovery of ischemic myocardium functions: first are responsible for recovery of contractive function and second are responsible for coronary blood flow recovery.

[The influence of the fluorine-containing activators of mitochondrial adenosine triphosphate sensitive potassium channels on the oxidative phosphorilation].

The cardioprotective mechanism of KATP channel openers and especially their influence on mitochondrial respiration has not been clarified yet. In this article we investigated the effect of DiazoFm and DiazoFp, the new fluor-containing analogues of diazoxide and the potential mitochondrial KATP channel openers, on the oxidative phosphorylation in the isolated mitochondria. It was shown that the influence of KATP channel openers on ADP-stimulated oxygen consumption (State 3) depended on the substrates we used (succinate or 2-oxoglutarate sodium). We have shown that the depression of State 3 was less when we used DiazoFm (30 MM) and DiazoFp (30 MM) in comparison with Diazoxide in experiments where succinate was used. The fluor-containing KATP, channels openers did not significantly change the activity of succinate dehydrogenase in comparison with diazoxide (it decreased succinate dehydrogenase activity by 27%). Thus, the fluor-containing analogues of diazoxide did not significant influence on the complex II of the respiratory chain. In the other experiments when we used 2-oxoglutarate sodium as an oxidative substrate, DiazoFp increased ADP-stimulated oxygen consumption by 33%. All the studied KATP openers have an uncoupling effect, regardless the substrates we used. This effect was more significant when we used succinate as a substrate. We have shown that the uncoupling effect of oxidative phosphorylation is a consequence of K channels activation. This statement was proved by 5-hydroxydecanoate (200 MM) with depressed influence of Diazoxide and its fluoring-containing analogues. Conclusion. The fluor-containig KATP channels openers had not direct influence on the respiratory chain in mitochondria, but activation mitochondrial KATP channels by them lead to uncoupling phosporylation and respiration.

[Effect of adenosine triphosphate-sensitve potassium channel activator flokalin on the isolated heart functions].

In the experiments, using isolated, perfused according to Langendorff heart of guinea pig, was investigated the effect of flokalin, a new fluor-containing opener of ATP sensitive channels (K(ATP)), upon the functioning of the heart. It was shown, that flokalin in a dose dependent manner dilates coronary vessels, decreases final diastolic pressure in the left ventricle and the rate of extrasystoles. Flokalin does not significantly affect the developing pressure in the left ventricle, max and min dP/dt, the frequency of cardiac contractions. 5-hydroxydecanoic acid (5-HD), an inhibitor of KATP in the mitochondrial membranes, increases the developing pressure in the left ventricle, max and min dP/dt, perfusion pressure in the coronary vessels. Simultaneously the final diastolic pressure in the left ventricle is decreased. Inhibition of K(ATP) channels in the mitochondrial membrane does not affect the vasodilatory effects of flokalin in the coronary vessels. This data, under the condition of specific action of 5-HD, permits us to suppose the participation of sarcolemmal KATP channels in the mentioned processes. It was shown that inhibition of mitochondrial K(ATP) channels results in decrease of the final diastolic pressure in the left ventricle and can enhance the effect of flokalin upon the final diastolic pressure, thus urging the idea of the leading role of sarcolemmal K(ATP) channels in the mentioned above processes.

[Fluorine-containing analog of diazoxide prevented apoptosis in neonatal cardiomyocytes during anoxia-reoxygenation]. / Ftorovanyi analoh diazoksydu poperedzhuie apoptoz neonatal'nykh kardiomiotsytiv pid chas anoksiï--reoksyhenatsiï.

In experiments on the primary culture of isolated neonatal rat cardiomyocytes it was established that anoxia-reoxygenation activated the process of programmed cell death, apoptosis. The amount of apoptotic cells (defined by fragmentation of a nucleus with Hoechst 33342 staining) during anoxia-reoxygenation was increased in 2.1 fold (P < 0.05). The amount of living and necrotic cells was not changed significantly. Apoptosis of neonatal cardiomyocytes during anoxia-reoxygenation was prevented by activation of ATP-dependent potassium (K(ATP)) channels with diazoxide. Synthesized by us the fluorine-containing analogue of diazoxide had the similar effect: the amount of apoptotic cells was decreased to 3.7% that was similar to control meaning. Application of glybenclamide, which completely abrogated the action of diazoxide and its fluorine-containing analogue, allows us to assert that antiapoptotic effect of the substances mentioned above depends on K(ATP) channels opening.

[Study of the mechanism of action of novel fluoro-containing analogs of diazoxide on the vascular tonus]. / Doslidzhennia mekhanizmu diï novykh ftorvmisnykh analohiv diazoksydu na sudynnyi tonus.

On the isolated preparations of rat aorta it was shown that the new fluoro-containing analogues of diazoxide (DiazoFp and DiazoFm) elicit vasodilatatory effects related to the activation of ATP-sensitive potassium channels. It was established that DiazoFp is a more powerful vasodilator than DiazoFm and diazoxide. It was proposed that DiazoFp action consists of two components: direct activation of sarcKATP channels and activation of sarcKATP channels, through activation of mitoKATP channels.

[Effect of modification in cell membrane fatty acid composition on adrenergic cardiac and vascular reactivity]. / Vplyv modyfikatsiï zhyrnokyslotnoho skladu klitynnykh membran na adrenerhichnu reaktyvnist' sertsia ta sudyn.

The work is dedicated to examination of the effect an omega-3 polyunsaturated fatty acids (PUFA) on vascular and cardiac reactivity in intact animals. In experiments on isolated perfused rat hearts and isolated rings of rat aorta it was shown that reactivity in rats with modified membranes was lesser than in control animals after adding norepinephrine in raising concentrations. Use of omega-3 PUFA resulted in the decrease of omega-6 PUFAs (arachidonic acid (AA)) content, while omega-3 PUFAs (EPA, DHA) content in cardiomyocytes membranes increased. Besides that it was shown that after omega-3 PUFA enriched diet NO3- content increased in cardiac tissues and blood.

[ATP-sensitive potassium channels and changes in their functional activity during streptozocin-induced diabetes mellitus]. / ATF-chutlyvi kaliievi kanaly ta zmin ïkh funktsional'noï aktyvnosti pry tsukrovomu diabeti, vyklykanomu vvedenniam streptozototsynu.

Attenuation in the vasodilatory effects of a new synthesized opener of ATP-sensitive K' channels on isolated aorta strips of rat has been shown under experimental (streptozocin-induced) diabetes mellitus. The level of that attenuation depended on the nature of initial vasoconstriction. The most pronounced decrease--43.34% as compared to the control responses in healthy rats, we observed after norepinephrine-induced vasoconstriction. Following preliminary angiothensin-induced vasoconstriction and potassium depolarization, attenuation in vasoconstriction was 20.37% and 22.4%, respectively. Norepinephrine inhibited vasodilator effects of phlocalin in the aorta of diabetic rats much more significantly, as compared to those after potassium depolarization. Inhibitory effects of angiothensin II in rats with diabetes mellitus did not differ from those in the control rats. At the same time, constrictory responses to biological active agents were preserved and they did not differ from those in control rats. We suggest that impairment in vascular reactivity under diabetes mellitus, at least in part, depends on the changes in the functioning of ATP-sensitive potassium channels.