[Role of Bradikynin in the Mechanism of Ischemic Preconditioning of the Heart. Prospects of Bradykinin Application in Cardiosurgical Praxis].

Bradykinin level is increased in myocardium in response to short-term ischemia/reperfusion that is one of the evidences of its trigger role in ischemic preconditioning (IP). Pharmacological induced increase of endogenous bradykinin and kallidin-like peptide levels in myocardium enhances cardiac tolerance to impact of ischemia/reperfusion. Experiments with genetically modified mice indicate that kinins are involved in preconditioning but they are not the only trigger of IP. The B2-receptor blocking abolishes antiarrhythmic, infarct reducing effects ofpreconditioning, eliminates IP-induced cardiac tolerance to oxidative stress. Exogenous bradykinin mimics inotropic and cardioprotective effects of IP but does not mimic antiarrhythmic effect of preconditioning. The intracoronary or intravenous bradykinin infusion enhances human heart resistance to ischemia/reperfusion. Implementation of the cardioprotective effect of IP is provided by the activation of multiple signaling pathways that involve: B2-receptor, calcitonin gene-related peptide, NO-synthase, guanylyl cyclase, cGMP, protein kinase G, mitochondrial KATP channels, reactive oxygen species, kinases C, ERK andAkt. To increase of the human heart tolerance to ischemia/reperfusion is necessary to develop B2-receptor agonists devoid hypotensive and pro-inflammatory properties.

[Reactive oxygen species are triggers and mediators of an increase in cardiac tolerance to impact of ischemia-reperfusion].

Reactive oxygen species (ROS) are triggers of ischemic preconditioning (IP). On the role of intracellular messengers of such cardioprotective effect of preconditioning claim: O2*, H2O2, OH*. However, we cannot exclude the possibility that other reactive oxygen metabolites also involved in the IP. Presented data suggest that IP enhances the production of ROS. The source of ROS may be mitochondrial respiratory chain and NADPH oxidase. Exogenous reactive oxygen species (O2*, H2O2) mimic the cardioprotective effect of preconditioning. Preconditioning prevents free radical damage of the heart during ischemia-reperfusion. The protective effect of IP is the consequence of reducing the production of ROS or the result of increased formation of endogenous antioxidants. Antioxidant enzymes are not involved in the protective effect of IP. Cardioprotective effect of many compounds (bradykinin, opioids, acetylcholine, phenylephrine, tumor necrosis factor-α, volatile anesthetics, protonophores, diazoxide, angiotensin II) depends on the increased production of ROS.

[Gastrointestinal hemorrhage in cardiosurgery in patients with endothelial dysfunction].

AIM: To estimate the prognostic value of the hypoxic test, intragastric pH-metry, and endothelial dysfunction in cardiosurgical patients at risk of gastrointestinal hemorrhage. MATERIALS AND METHODS: This prospective study approved by the ethical committee was performed based at the Department of Anesthesiology and Resuscitation, Research Institute of Cardiology, Tomsk, in 2012-2013. It included 30 patients who had previously undergone myocardial revascularization with artificial circulation. Gastroduodenal complications were predicted based on the results of the general hypoxic test, monitoring intragastric pH, and determination of endothelial function markers (endothelin-1, nitric oxide metabolites) intra- and postoperatively. RESULTS: 17 (56.7%) patients with negative results of hypoxic test were referred to the group at low-risk of gastrointestinal complications and given no antisecretory therapy. Plasma ET-1 level in the patients with gastric hemorrhage was almost 10 times that in the absence of complications. Multiple organ insufficiency was associated with a rise in RT-1 levels by the end of the first postoperative day. High ET-1 levels suggested the predominance of vasoconstrictive effect that eventually resulted in a break of the vascular wall and hypoperfusion of gastric mucosa. CONCLUSION: High ET-1 levels and disbalance of nitric oxide metabolites in blood are the main predictors of postoperative complications that characterize the functional state of vascular endothelium and may cause vascular rupture in case of the atherosclerotic process. The use of hypoxic test and gastric pH-metry in the preoperative period make it possible to distinguish patients that do not need preventive antisecretory therapy.

[Opioids--triggers of adaptive phenomenon of ischemic preconditioning of heart].

It was established that short-term ischemia/reperfusion evokes an increase in myocardial tissue of enkephalin levels. A blockade of delta-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning both in vivo and in vitro. An inhibition of kappa-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning only in vitro. Agonists of mu-, delta1- delta- and kappa1-opioid receptors mimic the cardioprotective effect of preconditioning. Consequently, it can be argued that endogenous opioid peptides are triggers of ischemic preconditioning.

[Receptor and signalling mechanisms of antiarrhythmic effects of ischemic pre-conditioning].

It has been established that ischemic preconditioning (IP) exerts significant antiarrhythmic effects, as revealed in experiments both in vivo and in vitro. Consequently, processes arising within the myocardium play a key role in adaptive tolerance to ischemia/reperfusion. Preconditioning enhances cardiac electrical stability both in animals and humans. The antiarrhythmic effect of preconditioning is transient, with enhanced tolerance to ischemia-reperfusion triggered arrhythmogenesis dissipating 2-3 after the IP stimulus. The basis of the antiarrhythmic and cardioprotective effects of IP may differ. Preconditioning improves conduction of the cardiac electrical impulse, thereby preventing occurrence of re-entrant arrhythmias. NO-synthase and peroxynitrite play an important role in evolution of the antiarrhythmic effects of IP. Furthermore, intracellular Ca2+ may be a trigger of improved cardiac electrical stability after IP. It has been established that G(i/o)-protein coupled receptors are not involved in antiarrhythmic effects of IP, whereas bradykinin B2 and alpha1 adrenergic receptor activities are involved in IP-dependent improvements in cardiac electrical stability. Adenosine receptors contribute only partially to these effects. In terms of signalling mechanisms, protein kinase C appears essential to the antiarrhythmic effects of IP, whereas PI3-kinase and cyclooxygenase do not appear to be significantly involved. It has also been established that cardiac mast cells are involved in IP effects. Some data indicate that increased cardiac electrical stability with preconditioning depends upon mitoK(ATP) channel opening. Other data provide evidence that antiarrhythmic effects of preconditioning depends upon sarcK(ATP) channel opening. Some data indicate that an increase in electrical stability of heart after preconditioning depends upon mitoK(ATP) channel opening. Other data are evidence that antiarrhythmic effect of preconditioning depends upon sarCK(ATP) channel opening. Further work is needed to fully delineate the mechanistic basis of antiarrhythmic effects of IP.

[Hypoxic preconditioning of stem cells as a new approach to increase the efficacy of cell therapy for myocardial infarction].

During the last decade, stem cell research has developed at an accelerated pace. Various types of stem cells have been tested for myocardial infarction therapy. Despite the preclinical benefits of cell therapy success in clinical trials remains modest. The main obstacles to regeneration of the infarcted heart using stem cells are: 1) not every stem cell type can differentiate into cardiomyocytes; and 2) low survival rates of transplanted cells, due to the harsh environment of the infarcted myocardium. Hypoxic preconditioning (HP) has been shown to improve transplantation efficacy of mesenchymal stem cells and cardiac progenitor cells in animal models of myocardial infarction. It has also been shown that transplantation of preconditioned cells decreases infarct size, prevents postinfarction remodeling of the heart, and positively modulates development of ischemic cardiomyopathy. Hypoxic preconditioning also prevents extensive death of transplanted cells due to necrosis and apoptosis during long-term hypoxia or oxidative stress. The protective effect of HP is based on three main processes: (1) modification of cell phenotypes to help survival during hypoxia (enhancement of HIF-1alpha expression, ERK1/2 and Akt activation, enhancement of erythropoietin receptor expression and erythropoietin production, and an elevation in levels of antiapoptotic proteins Bcl-2 and Bcl-xL); (2) upregulation of various secretable factors including the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and expression of VEGF-2 and HGF-receptors; (3) enhancement in the formation of CXCR4 and CXCR7 receptors, which play an important role in mobilization and homing of stem cells in the ischemic region.

[Neuroprotective and cardioprotective effects of hypothermic preconditioning].

The literature data testify the there is an early and delayed hypothermic preconditioning of brain. Neuroprotective effect of early hypothermic preconditioning is a result of activation of adenosine A1 receptors, KATP-channels. Ras protein and predetermined by a decrease in the synthesis of NO*. The infarct-sparing effect of delayed hypothermic preconditioning of brain is depended upon protein synthesis de novo. The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning is depended upon activation of protein kinase C, AMP-activated protein kinase (AMPK) and inhibition of MPT pore. The reactive oxygen species are triggers and mediators of hypothermic preconditioning of heart.

[Intraoperative hypoxic preconditioning as a method of neuroprotection in operations on internal carotid arteries].

The present work was aimed at assessing safety and efficacy of hypoxic preconditioning of the brain as a method of protecting the central nervous system during operations on the internal carotid artery in patients presenting with atherosclerotic lesions of the carotid arteries. The study included a total of 72 patients who underwent carotid endarterectomy for haemodynamically significant atherosclerosis of carotid arteries. Based on the obtained findings, a conclusion was made on a possibility of using intraoperative hypoxic preconditioning for prevention of ischaemic complications from the development in the perioperative period.

[Hypoxic preconditioning as novel approach to prophylaxis of ischemic and reperfusion damage of brain and heart].

Analysis of published data indicates that delayed hypoxic preconditioning essentially increases a cardiac and brain tolerance to ischemia-reperfusion. There are no experimental data in the literature on the neuroprotective effect of early hypoxic preconditioning in vivo. Clinical observations indicated that early hypoxic preconditioning exerts cardioprotective and neuroprotective effects. The single works testify that cardioprotective effect of delayed hypoxic preconditioning depend on the activation of inducible NO-synthase, KATP-channels and KCa-channels. Neuroprotective effect of hypoxic preconditioning is a consequence: (1) erythropoietin receptor stimulation and (2) an elevation of activity of PI3-Akt and ERK1/2 kinases. The supposed end effector of brain hypoxic preconditioning is MPT-pore.

[Signalling mechanisms of cardioprotective effect of hypothermic preconditioning].

The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, and exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning depends upon 3-adrenergic receptor stimulation, an increase in cAMP levels, activation of protein kinase A and protein kinase C, AMP-activated protein kinase (AMPK) and mitochondrial permeability transition pore blocking. The hypothermic preconditioning had no effect on the phosphorylation of GSK-3J3 (glycogen synthase kinase-3beta) and Akt-kinase. The reactive oxygen species end endogenous catecholamines are triggers or mediators of hypothermic preconditioning of heart.

[Hypoxic preconditioning is a phenomenon increasing tolerance of cardiomyocytes to hypoxia-reoxygenation].

The work covers the problem of hypoxic preconditioning (HP) carried out in isolated cardiomyocytes. Papers on delayed HP in vivo are comparatively few, and only some single works are devoted to early preconditioning in vivo. It has been established that the HP limits necrosis and apoptosis of cardiomyocytes and improves contractility of the isolated heart after ischemia (hypoxia) and reperfusion (reoxygenation). It was found that adenosine was a trigger of iP in vitro. It was proved that NO* was a trigger of HP both in vitro and in vivo. It was shown that reactive oxygen species also were triggers of hypoxic preconditioning. It was shown that ERK1/2 and p38 kinase played important role in delayed HP in vitro.

[Delta-opioid receptor activation prevents appearance of irreversible damages of cardiomyocytes and exacerbates myocardial contractility dysfunction during ischemia and reperfusion].

It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min reperfusion. This effect was completely abolished by pretreatment with a delta-antagonist naltrindole or a non-selective agonist naloxone. It was found that preactivation of cardiac delta-OR exacerbates reperfusion contractility dysfunction of the heart. This effect was also eliminated by opioid receptor antagonists. It is suggested that stimulation of cardiac delta-OR prevents irreversible cardiac cell damage but exacerbates contractility dysfunction during ischemia and reperfusion in vitro.

[The effect of dalargin and des-Tyr-dalargin on the functional state of intact and ischemized-reperfused myocardium]. / Vliianie dalargina i dez-tir-dalargina na funktsional'noe sostoianie intaktnogo serdtsa i miokarda podvergnutogo vozdeistviiu ishemii-reperfuzii.

Experiments on isolated perfused rat heart showed that dalargin, an antagonist of mu- and delta-opioid receptors, favors a decrease in the parameters of contractility of intact myocardium, while not influencing the pumping function (systolic and diastolic contractility) of reperfused myocardium. At the same time, des-Tyr-dalargin (the non-opioid analog of dalargin) suppresses the contractility of both the intact heart and the isolated myocardium subjected to global ischemia and reperfusion. Both dalargin and des-Tyr-dalargin reduced the incidence of reperfusion-induced arrhythmia, but did not affect the coronary flow before ischemia and after restoration of the coronary flow. It is suggested that the effect of dalargin is related to activation of the cardiac delta-opioid receptors, while the inotropic action of des-Tyr-dalargin involves other receptor mechanisms.

[Antiarrhythmic and cardioprotective effect of stimulation of delta1-opiate receptors in myocardial ischemia and reperfusion]. / Antiaritmicheskii i kardioprotektornyi éffekt stimuliatsii delta1-opiatnykh retseptorov v usloviiakh ishemii i reperfuzii miokarda.

Pretreatment with intravenous peptide delta1-opioid receptor (OR) agonist DPDPE (0.5 mg/kg) decreases the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The agonist of delta2-OR DSLET has no effect on arrhythmias in coronary artery occlusion and reperfusion. Pretreatment with selective delta-antagonists ICI 174,864 (2.5 mg/kg) eliminates an antiarrhythmic effect of DPDPE. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l and/or 0.5 mg/l fifteen min before ischemia also decreases the incidence of reperfusion arrhythmias in a concentration-dependent manner. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l decreases creatine kinase levels in the coronary sinus effluent. However, DPDPE has no cardioprotective effect in a concentration of 0.5 mg/l or after intravenous administration. It is suggested that antiarrhythmic and cardioprotective effects of DPDPE during reperfusion may be due to stimulation of cardiac delta1-receptors.

[Pharmacological prevention of cerebrovascular complications in cardiac patients after coronary artery bypass surgery]. / Medikamentoznaia profilaktika tserebrovasculiarnykh oslozhnenii u bol'nykh ishemicheskoi bolezn'iu serdtsa posle aortokoronarnogo shuntirovaniia.

The aim of the study was to evaluate cognitive functions and cerebral perfusion in cardiac patients following coronary artery bypass graft surgery (CABG) and to investigate a potential of pharmacological prevention of neurocognitive deficit and cerebral perfusion disorders. Forty patients undergone CABG with cardiopulmonary bypass (CPB) were included in the study. For prevention of cerebral perfusion impairments and cognitive deficit, instenon ("Nycomed") was administered to 18 of the patients. The results revealed that the use of instenon allowed reducing a negative effect of CABG with CPB on neuropsychological state of the patients, thus preventing cerebral perfusion disturbances during surgery intervention.

[Stimulation of peripheral delta1-opioid receptors as a method of preventing ischemic and reperfusion arrhythmia: role of K(ATP)-channels]. / Stimuliatsiia perifericheskikh delta(1)-opioidnykh retseptorov kak sposob profilaktiki ishemicheskikh i reperfuzionnykh aritmii: rol' K(ATP)-kanalov.

Preliminary administration of the delta 1-opioid receptor (delta 1-OR) peptide agonist DPDPE (0.5 mg/kg, i.v.) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The delta 2-OR agonist DSLET did not affect arrhythmias upon the coronary artery occlusion and reperfusion. Pretreatment with the selective delta-antagonists ICI 174,864 (2.5 mg/kg) or TIPP[psi] (0.5 mg/kg) completely eliminated the antiarrhythmic effect of DPDPE. Uncapable of crossing the blood brain barrier, the nonselective OR antagonist naloxone methiodide (5 mg/kg) also abolished this effect. At the same time, hexametonium (10 mg/kg) did not antagonize the antiarrhythmic effect of DPDPE. Pretreatment with the KATP channel blocker glibenclamide (0.3 mg/kg) completely eliminated the protective effect of the delta 1-OR stimulation. It was concluded that the delta 1-OR stimulation prevents the ischemic and reperfusion arrhythmias by means of the KATP channel activation.

[The anesthesiological procedure for correcting preloading in the surgery of acquired mitral valve defects]. / Anesteziologicheskaia taktika korrektsii prednagruzki v khirurgii priobretennykh porokov mitral'nogo klapana.

Intraoperative correction of preload in patients with acquired valvular disease (AVD) complicated by right-ventricular failure and severe pulmonary hypertension necessitates search for pathogenetically based algorithms of anesthesiological strategy. The objective of this study was to develop a strategy of assessing and treating the preload at the stage of induction anesthesia in patients with right-ventricular failure. During surgery central hemodynamic parameters and their response to a short head-down-tilt (15-20 degrees) were evaluated in patients (n = 42) with cardiac index (CI) less than 2 l/min/m2 after induction anesthesia. The patients were divided into 2 groups with different severity of preoperative status. Group 1 (main) included 24 patients with stages II-III cardiac failure (according to N. Strazhesko and B. Vasilenko) and group 2 (control) consisted of 18 patients with stage IIA cardiac failure. Progressing preoperative cardiac failure resulted in decrease of cardiac index and failure of compensatory hemodynamic mechanisms in AVD patients. The level of right-ventricular preload, pulmonary resistance, and stroke index were lower in group 1 than in the controls; however, 8% of group 1 patients responded positively to increased preload. In the control group 50% responded favorably to head-down-tilt. Hence, comprehensive assessment of cardiac index, central hemodynamic parameters and their response to head-down tilt help individually choose the anesthesiological strategy.

[The effect of hemodilution on the indices of aerobic metabolism and water metabolism in children with congenital heart defects operated on under artificial circulation]. / Vliianie gemodiliutsii na pokazateli aérobnogo metabolizma i vodnogo obmena u detei s vrizhdennymi porokami serdtsa, operirovannykh v usloviiakh iskusstvennogo krovoobrashcheniia.

The majority of pediatric cardiosurgery centers make use of cardiopulmonary bypass (CPB) with low hematocrit, and therefore we deemed it interesting to investigate the pathological effects of hemodilution on patients. Specifically, we studied the effect of hemodilution on aerobic and water metabolism in children with congenital heart disease subjected to CPB. Two groups of patients were examined. In the studied group (n = 12, mean age 7.1 +/- 1.1 years) the blood-fluid ratio in primary filling of the CPB device was 1:6.2 +/- 0.7 and minimal hematocrit during myocardial ischemia 18 +/- 0.7%. Control group consisted of 7 patients aged 8.3 +/- 0.6 years, with the above values 1:2.8 +/- 0.4 and 22 +/- 1.6%, respectively. The groups were similar as regards the initial status of patients, level of hypothermia, and duration of myocardial ischemia. Gas content in venous blood was the criterion of aerobic metabolism. Fluid accumulation in the extravasal space during and after surgery was assessed by bioelectroimpedance measurements of the total extracellular extravasal fluid (EEF). Monitoring showed a decrease of hematocrit during CPB to 18 +/- 0.7%, saturation of venous blood with oxygen within 70-75%, and oxygen content 37-43 mm Hg. In the main group a manifest increase of EEF was observed as early as during the early postperfusion period; this increase is probably one of the main components in the detrimental effect of hemodilution. Redistribution of fluid after CPB leads to expressed interstitial edemas and impairs the function of vital organs. That is why signs of cardiorespiratory failure were observed in the main group. Thus, one of the main problems in CPB with low hematocrit is fluid accumulation in the extravasal space.

[Surgical treatment of paroxysmal cardiac arrhythmias with extracorporeal circulation and deep hypothermic protection]. / Khirurgicheskoe lechenie proksizmal'nykh narushenii ritma serdtsa v usloviiakh iskusstvennogo krovoobrashcheniia i uglublennoi gipotermicheskoi zashchity.

The paper analyzes the results of surgical management of the Wolff-Parkinson-White syndrome in 29 patients. Evidence is provided that it is not necessary to perform an intracardiac electrophysiological study in all patients in the preoperative period. A method for pacing mapping is proposed, which is advisable to be used in conduction block by the accessory pathway during an operation. Surgical policy is also discussed in the paper in relation to the site of accessory pathway. The paper provides the results of surgical management of cardiac fibrillation in patients with the Wolff-Parkinson-White syndrome in deep hypothermic protection.

[Function of the heart conduction system in patients with progressive muscular dystrophy]. / Sostoianie provodiashchei sistemy serdtsa u bol'nykh s progressiruiushchei myshechnoi distrofiei.

Intracardiac electrophysiologic studies were carried out in 9 patients with progressive muscular dystrophy. Diagnostic stimulation of the heart demonstrated no sinus mode dysfunction. The intra-atrial conduction time increased to 72 +/- 7.1 ms (p less than 0.05), and the interatrial conduction time, to 97 +/- 12.5 ms (p greater than 0.05) in response to shortened testing stimulus delay in 3 patients. All 9 patients showed great variation in the duration of effective refractory atrial and atrioventricular periods (97.0 +/- 12.5 ms). The H-V interval increased from 43.9 +/- 4.3 to 73.9 +/- 7.6 ms (p less than 0.01) in response to shortened delay in 7 of 9 patients. Atrial pre-excitation resulted in a block of the right and left limbs of the His bundle in 5 of 7 patients. Third-degree atrioventricular block was recorded by continuous ECG monitoring in 7 patient. It is suggested that an apparent or latent intraventricular conductivity disorder may be present in most cases of progressive muscular dystrophy.