Periods Of Myocardial Ischemia Research Articles

0576 Impact of Obstructive Sleep Apnea on In-Hospital Mortality Due to Acute Myocardial Infarction - A Large Retrospective National Study of Veterans

Abstract Introduction Ischemic preconditioning (IPC) is a phenomenon that refers to multiple, brief periods of myocardial ischemia followed by reperfusion. This counterintuitive preconditioning is thought to provide cardioprotection from subsequent prolonged ischemic events. Obstructive sleep apnea (OSA) may lead to IPC by frequent, recurrent short episodes of hypoxia and sympathetic stimulation. We hypothesized in patients who were admitted with acute myocardial infarction (MI), the presence of OSA was associated with improved survival during the hospitalization, likely due to IPC. Methods This is a retrospective cohort study utilizing national Veterans Health Administration (VHA) records. The cohort includes patients from 1999-2020 with a hospitalization for MI as the principal diagnosis. We confirm the OSA diagnosis using ICD9/10 codes. The primary outcome was in-hospital mortality during the index admission for acute MI. We reported the odds ratio (OR) of in-hospital mortality between with-OSA and without-OSA using logistic regression. We adjusted the OR (aOR) by age, gender, race, ethnicity, BMI, and Charlson Comorbidity index. Results Out of 4,237,444 veterans with any sleep diagnosis, 76,359 patients were hospitalized with a diagnosis of MI. We observed 30,116 with OSA (age, 64±10; BMI, 33±7) and 43,480 without OSA (age, 68±12; BMI, 29±6). The aOR of in-patient mortality was lower in with-OSA (n = 333[1.1%]; aOR, 1.86; 95% CI, 1.63 to 2.12) compared to without-OSA (n = 1,102[2.5%]; aOR, 2.02; 95% CI, 1.78 to 2.30). After stratifying the patients based on previous history of MI, the results remained the same. Conclusion We found that in patients admitted with acute MI, the OSA cohort was associated with lower mortality when compared to non-OSA cohort. We speculate that these differences may be attributed to IPC likely due to repetitive, chronic episodes of hypoxia in obstructive sleep apnea. Further research is warranted to elicit the clinical implications of ischemic preconditioning and OSA. Support (If Any) Culebras, A. Exploring the trail between cerebral ischemic aggravation and ischemic preconditioning. Obstructive sleep apnea leads the way. Sleep Medicine, Volume 67 ,2020, p 276-277Salman LA, Shulman R, Cohen JB. Obstructive sleep apnea, hypertension, and cardiovascular risk: epidemiology, pathophysiology, and management. Curr Cardiol Rep 2020;22(2):6

Аналіз застосування Мексикору у хворих із гострим коронарним синдромом

Матеріали та методи. Під спостереженням знаходилися дві групи хворих із гострим коронарним синдромом. Перша група включала 48 хворих із нестабільною стенокардією (НС) віком 58,5 ± 3,8 року. Діагноз НС верифікований на підставі скарг хворих і змін на електрокардіограмі — підйому або депресії інтервалу на 1 мм тривалістю не більше 3 діб, відсутності зон гіпокінезії при УЗД серця, негативного тропонінового тесту. Другу групу становили 45 хворих із гострим інфарктом міокарда. Діагноз верифіковано за допомогою тропонінового тесту і змін на ЕКГ. У цю групу включалися хворі з Q-позитивним гострим інфарктом міокарда (ГІМ). Чоловіки — 83,2 %, жінки — 16,8 %. Середній вік хворих становив 60,3 ± 1,2 року. Задньобазальна локалізація виявлена у 40,2 %, передня — у 59,8 %. В анамнезі у 70 % хворих гіпертонічна хвороба ІІ ст. «Стаж» ішемічної хвороби серця становив у середньому 10,8 ± 4,5 року. 80 % хворих цієї групи неодноразово лікувалися в кардіологічних стаціонарах із приводу загострень ішемічної хвороби серця. У 38,5 % хворих на момент надходження відзначені надшлуночкові і шлуночкові (екстрасистолія) порушення ритму. Результати. Застосування Мексикору у хворих із ГІМ значно покращувало систолічну функцію серця, що проявлялося у вірогідній різниці основних показників, що її відображають (фракція викиду, швидкість циркуляторного скорочення волокон, серцевого викиду), і відповідних показників у хворих контрольної групи. Подібні сприятливі зміни були виявлені і при вивченні в динаміці показників діастолічної функції серця, що визначаються за швидкістю трансмітрального потоку. Обговорення. Зазначені зміни ми пов’язуємо з відновленням або поліпшенням скоротливості ішемізованого міокарда та функціонального стану так званих інтактних відділів серця, що компенсують своєю діяльністю втрату скоротливості некротизованих ділянок. Це підтверджується динамікою стану зон акінезії і дискінезії у хворих на ІМ, де відстежується відновлення скоротливості окремих ділянок серця на фоні застосування Мексикору (перехід граничних із зонами інфаркту сегментів зі стану акінезії в гіпокінез, гіпокинезу — в нормокінез), і практично зворотною динамікою у хворих контрольної групи. Мексикор сприяв поліпшенню клінічного перебігу ІМ, що проявлялося в обмеженні величини вогнища некрозу і стимуляції репаративних процесів, поліпшенні скорочувальної функції серця і газообміну, зменшенні частоти пролонгованого і рецидивного перебігу, ймовірності розвитку аневризми серця і випадків серцевої недостатності, порушень ритму і провідності, недостатності кровообігу і в кінцевому підсумку летальності. За результатами холтерівського моніторування у хворих на НС Мексикор прискорював стабілізацію стенокардії і зменшував, порівняно з контрольною групою, добову частоту і тривалість періодів ішемії міокарда, епізодів порушень ритму, сприятливо впливав на зміну інтеграла зміщення ST і співвідношення больових/безбольових періодів ішемії. Висновки. Включення Мексикору в традиційну терапію гострого коронарного синдрому вже на догоспітальному етапі дозволяє істотно зменшити прояви окислювального стресу, сприяє нормалізації діяльності серцево-судинної системи і покращує клінічний перебіг захворювань.

Efficacy of Histidine-Tryptophan-Ketoglutarate Solution Versus Blood Cardioplegia in Cardiac Surgical Procedures: A Randomized Controlled | Parallel Group Study.

In cardiac surgery, myocardial protection is required during cross-clamping followed by reperfusion. The use of cardioplegic solutions helps preserve myocardial energy stores, hindering electrolyte disturbances and acidosis during periods of myocardial ischaemia. This study aimed to compare the efficacy and safety between the histidine-tryptophan-ketoglutarate (HTK) solution and blood cardioplegia in various cardiac surgeries. Three-hundred-twenty patients aged 30-70 years old undergoing various cardiac surgeries were randomized into the HTK group and the blood cardioplegia group. The ventilation time, total bypass time, cross-clamp time, length of intensive care unit (ICU) or hospital stay, and postoperative complications were analyzed. The total bypass time and cross-clamp time were significantly shorter in the HTK group than in the blood cardioplegia group (P < 0.001). Segmental wall motion abnormalities (SWMA) at postoperative echocardiography were significantly higher in in the blood cardioplegia group (P = 0.008). The number of patients requiring DC Shock was significantly higher in the HTK group (P < 0.001). The number of patients requiring inotropic support was significantly higher in the blood cardioplegia group (P < 0.001). The length of ICU, hospital stay, and ventilation time were significantly longer in the blood cardioplegia group than in the HTK group (P = 0.004, P < 0.001, P < 0.001, respectively). The number of patients requiring prolonged ventilation was significantly higher in the blood cardioplegia group compared with the HTK group (P = 0.022). There was no significant difference between the study groups regarding electrocardiographic changes, 30-day mortality, and 30-day readmission. The use of HTK cardioplegia was associated with significantly shorter cross-clamp time, bypass time, duration of mechanical ventilation, length of ICU stay, and length of hospital stay. It is associated with less incidence of postoperative segmental wall abnormalities and less need for inotropic support than blood cardioplegia. Custodiol cardioplegia is a safe and feasible option that can be used as an effective substitute for blood cardioplegia to enhance myocardial protection.

Characterization of novel lncRNAs in upper thoracic spinal cords of rats with myocardial ischemia-reperfusion injuries.

Myocardial ischemia-reperfusion injury (MIRI) is a significant problem in clinical cardiology, and refers to a more serious myocardial injury caused by blood recanalization after a period of myocardial ischemia, as compared with injury caused by vascular occlusion. The spinal cord, as the primary afferent and efferent center of cardiac sensory and sympathetic nerve fibres, has received increased attention in recent years with regards to the regulation of MIRIs. Previous studies have revealed that MIRI has a strong correlation with the abnormal expression of long non-coding (lnc)RNAs in the myocardium; however, there are limited reports on the effects of the altered expression of lncRNAs in the spinal cord following MIRI. To investigate the expression patterns of lncRNAs in the spinal cord after MIRI and their potential role in the early stage of reperfusion, a MIRI model was established in rats. After 30 min of myocardial ischemia and 2 h of reperfusion, the upper thoracic spinal cord tissues were immediately dissected and isolated. lncRNAs and mRNAs in spinal cord tissues were screened using transcriptome sequencing technology, and the expression of several highly deregulated mRNAs, including Frs3, Zfp52, Dnajc6, Nedd4l, Tep1, Myef2, Tgfbr1, Fgf12, Mef2c, Tfdp1 and lncRNA, including ENSRNOT00000080713, ENSRNOT00000090564, ENSRNOT00000082588, ENSRNOT00000091080, ENSRNOT00000091570, ENSRNOT00000087777, ENSRNOT00000082061, ENSRNOT00000091108, ENSRNOT00000087028, ENSRNOT00000086475, were further validated via reverse transcription-quantitative PCR. The number of altered expressed lncRNAs was 126, among which there were 41 upregulated probe sets and 85 downregulated sets. A total of 470 mRNAs were differentially expressed, in which 231 probe sets were upregulated and 239 were downregulated. Gene Ontology analysis indicated that dysregulated transcripts related to biological processes were mainly associated with ‘cell-cell signaling’. Moreover, pathway analysis demonstrated significant changes in the ‘PI3K/Akt signaling pathway’ and the ‘p53 signaling pathway’. Thus, the altered expression of lncRNAs in the spinal cord may be of considerable importance in the process of MIRI. The present results could provide an insight into the potential roles and mechanism of lncRNAs during the early stage of reperfusion.

PGC-1α protects from myocardial ischaemia-reperfusion injury by regulating mitonuclear communication.

The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia‐reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia‐reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator‐activated receptor gamma co‐activator 1α (PGC‐1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC‐1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like ‐1 and ‐2 (NRF‐1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.

Results of Minimally Invasive Valve-Sparing Aortic Root Valve Surgery: Propensity Score Matching Analysis.

Aim Evaluation of efficacy and safety of minimally invasive, valve-sparing interventions on the aortic root and a comparative analysis of outcomes versus a group of patients with a complete sternotomy intervention using the method of propensity score matching (PSM).Materials and methods From 2016 through 2019, 458 interventions on the aortic root were performed, including 160 (36.6 %) interventions with mini-sternotomy. The study included 106 patients with the valve-sparing surgery (David procedure). Two groups of 30 patients each were formed using PSMC: group 1, complete sternotomy (CS) and group 2, J-shaped mini-sternotomy (MS). Immediate and long-term outcomes were evaluated at 13.8±10.3 (1-38 months (min-max) in the MS group and 42±21 (1-61 months (min-max) in the CS group.Results Statistically significant differences in death rate, echocardiographic indexes, absence of reoperations and complications in the postoperative period were not observed. In group 2, durations of extracorporeal circulation (p=0.04) and period of myocardial ischemia (p=0.004) were increased. The same group showed decreased intraoperative blood loss (p=0.001), postoperative drainage losses (p=0.0001), extubation time (р=0.0001), duration of stay in resuscitation and intensive care units and in the department of reconstructive recovery cardiovascular surgery (p=0,005).Conclusion The David procedure with mini-sternotomy is a safe and effective alternative to the traditional approach. This technique significantly reduces the time of rehabilitation and duration of patients' stay in the hospital without significant differences in the long-term period, which suggests advantages of this method. However, despite these promising results, the retrospective nature of this study, a small sample of patients, and a short follow-up period warrant further study.

Novel cardioprotection strategies for the aged heart: evidence from pre-clinical studies.

The incidence of cardiovascular disease is rising as the population ages. This has led to an increase in the need to perform cardiac surgery in older patients. However, aged hearts are particularly susceptible to reperfusion injury following periods of myocardial ischaemia that occur during cardiac surgery. Indeed, older adults experience myocardial dysfunction and reduced survival post-surgery compared to younger people and certain groups, including older women and frail older adults, are at particular risk. This highlights the need to design cardioprotective strategies specifically for the ageing heart. Cardioprotection during surgery is often accomplished by perfusing the heart with chemical arresting agents, known as cardioplegic solutions. New protective strategies have been developed and tested in animal models, where cardioplegic solutions have been modified by changing their temperature, chemical components and/or the frequency of delivery. In addition, drugs designed to activate cardioprotective mechanisms or to inhibit mechanisms involved in injury have been added to improve the efficacy of these solutions. However, most experimental studies have developed and optimized cardioplegic solutions in hearts from younger male animals. This review discusses pre-clinical models used to optimize cardioplegic solutions, with an emphasis on the few studies that have used hearts from older animals. Pharmacologic agents that have been shown to enhance the benefits of cardioplegia in younger hearts and could, in theory, protect vulnerable older hearts are also considered. We emphasize the need to conduct studies in frail older animals of both sexes to facilitate translation of laboratory-based observations to the clinic.

Metabolism changes and the role of the free radicals on myocardial ischemia

Myocardial ischemic results from severe impairment of coronary blood supply and produces a spectrum of clinical syndromes. It results in a characteristic pattern of metabolic and structural changes that leads to extremely complex situations, which have been extensively studied in recent years. A detailed understanding is now available of the complexity of the response of the myocardium to an ischemic insult. Reperfusion is the most effective way to treat the ischaemic myocardial. But, restoration of flow, however, might result in numerous other negative consequences, thus directly influencing the degree of recovery. Much evidence shows that during the period of myocardial ischemia and reperfusion can occur various changes both in terms of metabolic, electrical, histology, structural, and physiological. Pathological changes in the form of metabolic changes and the role of free radicals on the condition of ischemia and reperfusion injury will be discussed. There are several potential manifestations and outcomes associated with myocardial ischemia and reperfusion.

The protective effect of AT1-antibody against myocardial ischemia-reperfusion injury through inhibition of inflammation and apoptosis

Myocardial ischemia and reperfusion (I/R) injury is known to occur on restoration of coronary flow after a period of myocardial ischemia. Angiotensin II (Ang II) is the most important bioactive substance of the renin-angioensin system (RAS), and exerts its physiological actions through AT1 receptors by regulating vascular tension and blood flow, and promoting cell growth and proliferation. The aim of the present study is to investigate the effects and its possible underlying mechanisms of AT1-AB on myocardial ischemia/reperfusion (I/R) injury. To test this hypothesis, we randomly assigned four groups (six mice per group) for experiment. To produce myocardial injury, the left anterior coronary artery (LAD) was occluded for 30 min, followed by 120 min of reperfusion in anesthetized mice. In the mice heart subjected to I/R injury, pretreatment AT1-AB (1mcg/gm) decreased the pathological scores of myocardium, and significantly attenuated I/R-induced increases of myocardial TNFα, IL-1β, IL-6. Further, 1mcg/gm AT1-AB significantly attenuated cTn-I and reduced apoptosis index of cardiac muscle cell of mice subjected to I/R injury. Therefore, these results demonstrate that AT1-AB exhibits significant protective effect against myocardial I/R injury which is related to inhibition of the release of inflammatory cytokines and the apoptosis of cardiac muscle cell.

Electrical alternans induced by a brief period of myocardial ischemia during percutaneous coronary intervention: The characteristic ECG morphology and relationship to mechanical alternans

Electrical alternans (EA) has not been fully studied in the current percutaneous coronary intervention (PCI) procedure. The purpose of this study was to evaluate visible EA and the morphology of ST segment during PCI. The incidence of visible EA and ST-segment morphology were studied while the coronary artery was occluded for 20 seconds. When data were available, the relationship between EA and blood pressure was analyzed. The clinical and electrocardiographic data were compared with those of the age- and sex-matched controls. During balloon inflation, visible EA was observed in 5 of 306 patients (1.6%) in the last 2 years. EA was limited to PCI in the proximal left anterior descending artery. The ST segment elevated to 10.1 ± 3.2 mm, followed by an alternating QRS complex with a lower ST segment (5.6 ± 1.9 mm; P = .0047) with characteristic ST-segment morphology, which is known as lambda pattern. The mean age of the 5 patients was 68 ± 20 years, and 4(80%). were men. After the release of inflation, the ST-segment level returned rapidly to baseline, followed by normalization of J point. Compared with controls, the maximal elevated ST segment was significantly higher in patients with EA (5.7 ± 2.7 mm; P = .0028). The occlusion of the proximal left anterior descending artery with more severe ischemia seemed to be a prerequisite for developing EA. A higher ST segment was associated with a lower blood pressure and vice versa. A short period of ischemia during PCI may induce visible EA and alternating QRS complexes with a characteristic ST-segment morphology. A higher ST segment was associated with a lower blood pressure and vice versa.

Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning

Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism.

Hypotheses, rationale, design, and methods for evaluation of ischemic preconditioning assessed by sequential exercise tests in diabetic and non-diabetic patients with stable coronary artery disease--a prospective study.

BackgroundIschemic preconditioning is a powerful mechanism of myocardial protection and in humans it can be evaluated by sequential exercise tests. Coronary Artery Disease in the presence of diabetes mellitus may be associated with worse outcomes. In addition, some studies have shown that diabetes interferes negatively with the development of ischemic preconditioning. However, it is still unknown whether diabetes may influence the expression of ischemic preconditioning in patients with stable multivessel coronary artery disease.Methods/DesignThis study will include 140 diabetic and non-diabetic patients with chronic, stable coronary artery disease and preserved left ventricular systolic function. The patients will be submitted to two sequential exercise tests with 30-minutes interval between them. Ischemic parameters will be compared between diabetic and non-diabetic patients. Ischemic preconditioning will be considered present when time to 1.0 mm ST-segment deviation is greater in the second of two sequential exercise tests. Exercise tests will be analyzed by two independent cardiologists.DiscussionIschemic preconditioning was first demonstrated by Murry et al. in dog’s hearts. Its work was reproduced by other authors, clearly demonstrating that brief periods of myocardial ischemia followed by reperfusion triggers cardioprotective mechanisms against subsequent and severe ischemia. On the other hand, the demonstration of ischemic preconditioning in humans requires the presence of clinical symptoms or physiological changes difficult to be measured. One methodology largely accepted are the sequential exercise tests, in which, the improvement in the time to 1.0 mm ST depression in the second of two sequential tests is considered manifestation of ischemic preconditioning.Diabetes is an important and independent determinant of clinical prognosis. It's a major risk factor for coronary artery disease. Furthermore, the association of diabetes with stable coronary artery disease imposes worse prognosis, irrespective of treatment strategy. It’s still not clearly known the mechanisms responsible by these worse outcomes. Impairment in the mechanisms of ischemic preconditioning may be one major cause of this worse prognosis, but, in the clinical setting, this is not known.The present study aims to evaluate how diabetes mellitus interferes with ischemic preconditioning in patients with stable, multivessel coronary artery disease and preserved systolic ventricular function.

A2B or not 2B: that is the question: AUTHORS' RETROSPECTIVE

This editorial refers to an article by S. Philipp et al. [1][1] published in Cardiovascular Research in 2006 (see [Box 1][2]). It is accompanied by an editorial by K. Przyklenk, pp. 195–197, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . Our interest in adenosine A2B receptors is based on studies reported in a paper we published in this journal in 2006.1 Below we describe the largely unplanned and serendipitous events that led us to conclude that the A2B receptor was an important player. There are four known adenosine receptor subtypes: A1, A2A, A2B, and A3. Interestingly, all four have been proposed to be involved in protecting the heart against ischaemic injury. All subtypes are G protein-coupled receptors of the serpentine 7 family. The A1 and A3 receptors are clearly Gi-coupled, whereas the A2A receptor is Gs-coupled. The A2B receptor is also Gs-coupled, but a Gi (or Go) coupling can also be demonstrated.2 The A2B receptor also has a much lower affinity for adenosine than the other three subtypes. The cardiomyocyte expresses all four subtypes, but their physiological effects are diverse. A1 receptor occupation reduces the heart rate by modulating sinoatrial node activity and depresses conduction through the AV node. A2A agonists are powerful vasodilators in most organs because of their Gs coupling. On the other hand, these agonists have a negligible effect on contractility in the heart, probably a reflection of their fairly low density relative to β-adrenergic receptors. A2B agonists have little haemodynamic effect. In 1986 Murry et al .3 discovered ischaemic preconditioning. This is a phenomenon whereby a brief period of myocardial ischaemia … [1]: #ref-1 [2]: #F1

Endogenous endothelin stimulates cardiac sympathetic afferents during ischaemia

Myocardial ischaemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Previous studies have shown that a brief period of myocardial ischaemia increases endothelin in cardiac venous plasma draining ischaemic myocardium and that exogenous endothelin excites cutaneous group III and IV sensory nerve fibres. The present study tested the hypothesis that endogenous endothelin stimulates cardiac afferents during ischaemia through direct activation of endothelin A receptors (ET(A)Rs). Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicates (T(2)-T(5)) in anaesthetized cats. Single fields of 38 afferents (CV = 0.25-3.86 m s(-1)) were identified in the left or right ventricle with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 38 cardiac afferents (8 Adelta, 30 C-fibres) and the responses of these 38 afferents to chemical stimuli were further studied in the following protocols. In the first protocol, injection of endothelin 1 (ET-1, 1, 2 and 4 microg) into the left atrium (LA) stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BQ-123, a selective ET(A)R antagonist, abolished the responses of nine afferents to 2 microg of ET-1 injected into the left atrium and attenuated the ischaemia-related increase in activity of eight other afferents by 51%. In contrast, blockade of ET(B) receptors caused inconsistent responses to exogenous ET-1 as well as to ischaemia. Furthermore, in the absence of ET(A)R blockade, cardiac afferents responded consistently to repeated administration of ET-1 (n = 7) and to recurrent myocardial ischaemia (n = 7). Finally, using an immunocytochemical staining approach, we observed that ET(A) receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous endothelin contributes to activation of cardiac afferents during myocardial ischaemia through direct stimulation of ET(A) receptors likely to be located in the cardiac sensory nervous system.

Man Overboard!

Man Overboard!

Ways of Improving the Results of Treatment for Pulmonary Thromboembolism

Objective: to reveal the predictors of clinically significant deterioration of cardiac pump function resulting from alveolar opening maneuver (AOM) (mobilization) made early after extracorporeal circulation during standard cardiosurgery. Subjects and methods. Hemodynamic, clinical, and laboratory parameters were analyzed in 20 cardiosurgical patients who had undergone AOM in the early postperfusion period. The study inclusion criteria were a PaO2/FiO2 ratio of less than 350 mm Hg, a cardiac index (CI) of more than 2.5 l/min/m2, a dosage of dopamine and/or dobutamine of not more than 10 ^g/kg/min, and standard AOM performance (Pmax, 30—35 cm H2O; end-expiratory pressure (PEEP), 13—15 cm H2O). Regression analysis was used to identify the predictors of a clinically significant reduction in CI (less than 2.5 l/min/m2). Results. Before and after AOM, CI was 3.1±0.1 and 2.9±0.1 l/min/m2, respectively (p&gt;0.05); however, CI was less than 2.5 l/min/m2 (2.16±0.09 l/min/m2) in 25% of cases. After AOM, CI values were significantly related to those recorded prior to a respiratory procedure (p=0.039), total peripheral vascular resistance index (TPVRI) (p=0.00039), and intrapulmonary blood shunt fraction (Qs/Qt) (p=0.041). There were no relationships to other recorded and estimated hemodynamic parameters (p&gt;0.1). &#8211; After AOM, CI values were unrelated (p&gt;0.1) to the duration of extracorporeal circulation, the period of myocardial ischemia, and the used dosages of inotropic agents. The predictor of a clinically significant CI reduction after AOM was the only index TPVRI (p=0.00025) recorded before a respiratory procedure. Following AOM, the probability of a significant CI reduction substantially increased (the approximation coefficient R2=0.75) at TPVRI values of 2000 din^sec^cm-5^m2 or more. Conclusion. After AOM performed in the early period after extracorporeal circulation, CI values are related to the baseline level of CI, TPVRI, and Qs/Qt; however, after this procedure only the value of TPVRI is a reliable predictor of clinically significantly depressed cardiac pump function. The risk of persistent car-diodepression is highest at TPVRI values of 2000 din^sec^cm-5^m2 or more. AOM should be carried out early after extra-corporeal circulation in cardiosurgical patients, by making an invasive monitoring that makes it possible to maximally correctly evaluate central hemodynamics, including CI and TPVRI. Key words: alveolar opening maneuver (mobilization), lung recruitment, recruiting maneuver in cardiosurgical patients, central hemodynamics during lung recruitment, cardiodepression during lung recruitment.

Predictors of the Cardiodepressive Effect of Alveolar Opening Maneuver (Mobilization) in Cardiosurgical Patients

Objective : to reveal the predictors of clinically significant deterioration of cardiac pump function resulting from alveolar opening maneuver (AOM) (mobilization) made early after extracorporeal circulation during standard cardiosurgery. Subjects and methods. Hemodynamic, clinical, and laboratory parameters were analyzed in 20 cardiosurgical patients who had undergone AOM in the early postperfusion period. The study inclusion criteria were a PaO 2 /FiO 2 ratio of less than 350 mm Hg, a cardiac index (CI) of more than 2.5 l/min/m 2 , a dosage of dopamine and/or dobutamine of not more than 10 μg/kg/min, and standard AOM performance (P max , 30—35 cm H 2 O; endexpiratory pressure (PEEP), 13—15 cm H 2 O). Regression analysis was used to identify the predictors of a clinically significant reduction in CI (less than 2.5 l/min/m 2 ). Results . Before and after AOM, CI was 3.1±0.1 and 2.9±0.1 l/min/m 2 , respectively ( p >0.05); however, CI was less than 2.5 l/min/m 2 (2.16±0.09 l/min/m 2 ) in 25% of cases. After AOM, CI values were significantly related to those recorded prior to a respiratory procedure ( p =0.039), total peripheral vascular resistance index (TPVRI) ( p =0.00039), and intrapulmonary blood shunt fraction (Qs/Qt) ( p =0.041). There were no relationships to other record ed and estimated hemodynamic parameters (p>0.1). After AOM, CI values were unrelated (p>0.1) to the duration of extracorporeal circulation, the period of myocardial ischemia, and the used dosages of inotropic agents. The predictor of a clinically significant CI reduction after AOM was the only index TPVRI (p=0.00025) recorded before a respiratory procedure. Following AOM, the probability of a significant CI reduction substantially increased (the approximation coefficient R2=0.75) at TPVRI values of 2000 din•sec•cm-5•m2 or more. Conclusion. After AOM performed in the early period after extracorporeal circulation, CI values are related to the baseline level of CI, TPVRI, and Qs/Qt; however, after this procedure only the value of TPVRI is a reliable predictor of clinically significantly depressed cardiac pump function. The risk of persistent cardiodepression is highest at TPVRI values of 2000 din•sec•cm-5•m2 or more. AOM should be carried out early after extracorporeal circulation in cardiosurgical patients, by making an invasive monitoring that makes it possible to maximally correctly evaluate central hemodynamics, including CI and TPVRI.

Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents

Ischemic preconditioning (IPC) constitutes an endogenous protective mechanism in which one or more brief periods of myocardial ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. Pharmacological preconditioning represents an ideal alternative of IPC. We now describe the design and synthesis of indole, quinoline, and purine systems with an attached pharmacophoric nitrate ester group. The indole and quinoline derivatives 4 and 5 possess structural features of the nitrate containing K ATP channel openers. Purine analogues 11 and 12, substituted at the position 6 by a piperidine moiety and at position 9 by an alkyl nitrate, could combine the effects of the nitrate containing K ATP channel openers and those of adenosine. Compound 13 bears the nicotinamide moiety of nicorandil instead of nitrate ester. Compounds 4, 5, and 11 reduced infarction and the levels of malondialdehyde (MDA) at reperfusion in anesthetized rabbits. Compounds 12 and 13 did not significantly reduce the infarct size. Analogues 4 and 5 increased cGMP and MDA during ischemia, while combined analogue 4 and mitoK ATP blocker 5-hydroxydecanoic acid (5-HD) abrogated this benefit suggesting an action through mitoK ATP channel opening. Treatment with derivative 11 combined with 5-HD as well as treatment with 11 and adenosine receptor blocker 8-( p-sulfophenyl)theophylline (SPT) did not abrogate cardioprotection. Compound 11 is a lead molecule for the synthesis of novel analogues possessing a dual mode of action through cGMP–mitoK ATP channel opening-free radicals and through adenosine receptors.

Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4

Reactive oxygen species (ROS) generated during ischemia-reperfusion (I/R) enhance myocardial injury, but brief periods of myocardial ischemia followed by reperfusion [ischemic preconditioning (IP)] induce cardioprotection. Ischemia is reported to stimulate glucose uptake through the translocation of GLUT-4 from the intracellular vesicles to the sarcolemma. In the present study we demonstrated involvement of ROS in IP-mediated GLUT-4 translocation along with increased expression of caveolin (Cav)-3, phospho (p)-endothelial nitric oxide synthase (eNOS), p-Akt, and decreased expression of Cav-1. The rats were divided into the following groups: 1) control sham, 2) N-acetyl-L-cysteine (NAC, free radical scavenger) sham (NS), 3) I/R, 4) IP + I/R (IP), and 5) NAC + IP (IPN). IP was performed by four cycles of 4 min of ischemia and 4 min of reperfusion followed by 30 min of ischemia and 3, 24, 48 h of reperfusion, depending on the protocol. Increased mRNA expression of GLUT-4 and Cav-3 was observed after 3 h of reperfusion in the IP group compared with other groups. IP increased expression of GLUT-4, Cav-3, and p-AKT and p-eNOS compared with I/R. Coimmunoprecipitation demonstrated decreased association of Cav-1/eNOS in the IP group compared with the I/R group. Significant GLUT-4 and Cav-3 association was also observed in the IP group. This association was disrupted when NAC was used in conjunction with IP. It clearly documents a significant role of ROS signaling in Akt/eNOS/Cav-3-mediated GLUT-4 translocation and association in IP myocardium. In conclusion, we demonstrated a novel redox mechanism in IP-induced eNOS and GLUT-4 translocation and the role of caveolar paradox in making the heart euglycemic during the process of ischemia, leading to myocardial protection in a clinically relevant rat ischemic model.

Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.