Prolonged Myocardial Ischemia Research Articles

Impact of the new coronavirus infection pandemic on the course of coronary heart disease

ABSTRACT. This study analyzes the impact of the new coronavirus infection pandemic on the course of coronary heart disease. It highlights the role of factors such as endothelial dysfunction, microvascular hypoperfusion, thrombosis, and systemic inflammation in worsening cardiovascular pathology, including coronary heart disease. The paper also explores additional causes for the deterioration of coronary heart disease during the peak of the pandemic. Despite recommendations advocating for percutaneous intervention in all patients with acute coronary syndrome and ST-segment elevation, there has been a notable decrease in the number of percutaneous intervention procedures performed during the peak of the pandemic. This decline is observed in patients with both ST-segment elevation and those without (reductions of 21% and 37%, respectively). Despite the recommendations advocating for percutaneous intervention in all patients with acute coronary syndrome and ST-segment elevation, there has been a notable decrease in the number of percutaneous intervention procedures performed during the peak of pandemic. This decline is observed in patients with both ST-segment elevation and those without (reductions of 21% and 37%, respectively). Furthermore, there has been an increase in the time interval between ambulance contact and the execution of percutaneous procedures, resulting in prolonged myocardial ischemia and subsequently poorer patient prognosis. Moreover, due to limitations in the ability to provide inpatient examination and treatment for individuals with chronic heart failure, there has been a pronounced exacerbation of the condition and an increase in mortality rates. Similarly, the provision of cardiac rehabilitation after myocardial infarction has been significantly restricted. Given the extensive number of patients who have been affected or continue to suffer from new coronavirus infection, it is of utmost importance to develop predictive models that account for the development of post-new coronavirus infection syndrome and the emergence of early and late complications of a new coronavirus infection, including coronary artery disease, and comorbidities. The current risk assessment models, aimed at predicting mortality and guiding the treatment of patients with new coronavirus infection or post-infection, do not comprehensively consider all the necessary parameters nor do they predict the emergence of long-term complications. Therefore, further prospective studies are required to address these limitations.

Tumor Necrosis Factor Family Members and Myocardial Ischemia-Reperfusion Injury: State of the Art and Therapeutic Implications

Ischemic heart disease is the principal cause of death worldwide and clinically manifests as myocardial infarction (MI), stable angina, and ischemic cardiomyopathy. Myocardial infarction is defined as an irreversible injury due to severe and prolonged myocardial ischemia inducing myocardial cell death. Revascularization is helpful in reducing loss of contractile myocardium and improving clinical outcome. Reperfusion rescues myocardium from cell death but also induces an additional injury called ischemia-reperfusion injury. Multiple mechanisms are involved in ischemia-reperfusion injury, such as oxidative stress, intracellular calcium overload, apoptosis, necroptosis, pyroptosis, and inflammation. Various members of the tumor necrosis factor family play a key role in myocardial ischemia-reperfusion injury. In this article, the role of TNFα, CD95L/CD95, TRAIL, and the RANK/RANKL/OPG axis in the regulation of myocardial tissue damage is reviewed together with their potential use as a therapeutic target.

Gene expression patterns and related pathways in the hearts of rhesus monkeys subjected to prolonged myocardial ischemia.

After myocardial infarction (MI) occurs, progressive pathological cardiac remodeling results in heart dysfunction and even heart failure during the following months or years. The present study explored the molecular mechanisms underlying the late phase of MI at the global transcript level. A rhesus monkey model of myocardial ischemia induced by left anterior descending (LAD) artery ligation was established, and the heart tissue was collected eight weeks after ligation for transcriptome analysis by DNA microarray technology. Differentially expressed genes in the core infarcted area and remote infarcted area of the ischemic heart were detected with significance analysis of microarray (SAM), and related pathways were detected by Gene Ontology (GO)/pathway analysis. We found that compared to the sham condition, prolonged ischemia increased the levels of 941 transcripts, decreased the levels of 380 transcripts in the core infarcted area, and decreased the levels of 8 transcripts in the remote area in monkey heart tissue. Loss of coordination between the expression of genes, including natriuretic peptide A (NPPA), NPPB, and corin (Corin, serine peptidase), may aggravate cardiac remodeling. Furthermore, imbalance in the enriched significantly changed pathways, including fibrosis-related pathways, cardioprotective pathways, and the cardiac systolic pathway, likely also plays a key role in regulating the development of heart remodeling.

Cardiac Rehabilitation of Patients Following Myocardial Infarction

Abstract Myocardial infarction (MI) - represents cardiomyocytes necrosis due to prolonged myocardial ischemia, occurring in the context of an imbalance between myocardial oxygen supply and consumption. According to the National Bureau of Statistics, in 2017, mortality from cardiovascular diseases made up 58.4% of all deaths, of which ischemic heart disease (IHD) constituted 52.5% and 8.5% were due to acute myocardial infarction. Cardiovascular rehabilitation is used to optimize the physical, psychological and social functioning of the patient who suffered a myocardial infarction. The session includes 3 phases: the warm-up, the actual training and the recovery (relaxation) phase. The program is individualized, so it is necessary to correctly select the type, intensity, duration and frequency for maximum therapeutic effect. Exercise-based medical rehabilitation is a supplement to drug therapy and post-infarction interventional surgery, as it improves cardiopulmonary function, optimizes drug therapy, decreases risk factors, increases exercise tolerance, improves mental status, reduces the risk of repeated heart attack and cardiac mortality. There are fewer complications due to bed rest and increased performance as a result of improved hemodynamic and metabolic function. As part of a cardiac rehabilitation program, physical activity helps with psychological adaptation and contributes to a successful return to work.

Effects of ferroptosis in myocardial ischemia/reperfusion model of rat and its association with Sestrin 1.

Ferroptosis is a type of iron-dependent programmed cell death. The inhibition of ferroptosis has been reported to alleviate myocardial ischemia/reperfusion injury (IRI). However, it is unknown whether this protective effect occurs in the ischemia or reperfusion phase. Sestrin 1 (Sesn1) possesses remarkable cytoprotective functions to diverse cellular stresses. However, whether Sesn1 is involved in the regulatory process of ferroptosis during myocardial IRI is unknown. This study aimed to simulate an acute myocardial infarction (AMI) that occurs in rats within 6 h, verify the occurrence and effects of ferroptosis in the phases of ischemia and reperfusion, and further explore the relationship between ferroptosis, IRI and Sesn1. The hearts of Sprague Dawley (SD) rats undergoing ischemia for varying lengths of time or having undergone ischemia followed by varying lengths of reperfusion were examined. The occurrence of ferroptosis was verified by detecting changes in ferroptosis biomarkers. In addition, ferrstatin-1 (Fer-1) was administered to demonstrate the effect of ferroptosis in myocardial IRI and to detect changes in Sesn1. The results showed that the myocardial damage was more severe with more prolonged myocardial ischemia. There were no significant changes in ferroptosis biomarkers in cardiac tissues during the ischemia phase, the levels of iron and malondialdehyde (MDA) were elevated, and the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) were decreased after myocardial IRI. Compared to the ischemia/reperfusion (I/R) group, the treatment with Fer-1 before reperfusion can attenuate myocardial IRI, reverse the decrease in GPX4 and FTH1 expression, and decrease the rise in iron content and MDA. In addition, we found that the expression of Sesn1 was reduced in hearts that suffered IRI; however, the treatment with Fer-1 can reverse this situation. Ferroptosis occurred during the myocardial reperfusion phase but not ischemia. The inhibition of ferroptosis exerted beneficial effects on myocardial IRI, providing a theoretical basis for targeted therapy in patients with AMI. Sestrin 1, regulated by ferroptosis, may play an important role in myocardial IRI.

Andrographolide protects against isoproterenol-induced myocardial infarction in rats through inhibition of L-type Ca2+ and increase of cardiac transient outward K+ currents

Myocardial infarction (MI) is the irreversible injury of the myocardium caused by prolonged myocardial ischemia and is a major cause of heart failure and eventual death among ischemic patients. The present study assessed the protective potentials of andrographolide against isoproterenol-induced myocardial infarction in rats. Animals were randomly divided into four groups: Control (Ctr) group received 0.9% saline solution once daily for 21 days, Isoproterenol (Iso) group received 0.9% saline solution once daily for 19 days followed by 80 mg/kg/day of isoproterenol hydrochloride solution on day 20 and 21, Andrographolide (Andro) group received 20 mg/kg/day of andrographolide for 21 days, and Andrographolide plus Isoproterenol (Andro + Iso) group received 20 mg/kg/day of andrographolide for 21 days with co-administration of 80 mg/kg/day of isoproterenol hydrochloride solution on day 20 and 21. After all treatments, cardiac-specific parameters that define cardiac health and early subacute MI were measured in all groups using both biophysical and pharmacological assay methods. Isoproterenol administration significantly (P < 0.05) increased cardiac mass indexes, systemic cardiac biomarkers, infarct size and caused cardiac histological alterations; significantly (P < 0.05) increased heart rate, QRS & QTc intervals and caused ST-segment elevation; significantly (P < 0.05) increased myocytes shortening, action potential duration (APD), L-type Ca2+ current (ICa,L) density and significantly (P < 0.05) decreased transient outward K+ current (Ito) density typical of the early subacute MI. Interestingly, pretreatment with andrographolide prevented and or minimized these anomalies, notably, by reducing ICa,L density and increasing Ito density significantly. Therefore, andrographolide could be seen as a promising therapeutic agent capable of making the heart resistant to early subacute infarction and it could be used as template for the development of semisynthetic drug(s) for cardiac protection against MI.

Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes

Ischemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo’s cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3’s impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200–380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100–500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3’s cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3’s protection is a cardiomyocyte phenomenon and targets mitochondria.

PROSPECTIVE ANALYSIS OF IMPACT OF PHARMCOTHERAPY ADHERENCE ON TREATMENT EFFECTIVENESS IN POST OPERATIVE HEART PATIENTS

Myocardial infarction is the irreversible damage of myocardial tissue caused by prolonged ischemia and hypoxia. This most commonly occurs when a coronary artery becomese blocked following the rupture of an atherosclerotic plaque, which then leads to the formation of a blood clot (coronary thrombosis). This event can also trigger coronary vasospasm. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart.&#x0D; This prospective, pilot, observational study performed confirmed the hypothesis that systematic identifications and interventions administered through continued physician follow-up and patients counselling will improve adherence to therapy and therefore improvement in treatment effectiveness by lowering especially Troponin level ,CPK and quality of life in MI patients.&#x0D; Study was shown that lack of proper knowledge about disease and patients counseling and chronic treatment, most of patients takes disease and its treatment lightly and shows lower adherence attitude. The study analysis shown that female are generally more aware than males for adherence. Study analysis concluded that there was significant reduction in their Troponin level and CPK values in different comparison groups after each level of follow up.&#x0D; Statistical analysis concluded that patients with adherence ˃ 95% showed significant reduction in Troponin level and CPK values and patients with age group ≤50 shows more adherence than older.&#x0D; Most heart patients recorded with hypertension and Coronary Artery Diseases only few ones with diabetic complications. During study patients shows good control over their blood pressure and only few adverse events but no complications occur during study period.

Role of Renin Angiotensin System in Isoproterenol-Induced Myocardial Infarction in Male Rats

Background: Myocardial infarction (MI) is a necrosis of cardiomyocytes due to prolonged myocardial ischemia, the injured heart characterized by activation of the renin-angiotensin system (RAS). The cardiac effect of enalapril and losartan was determined in Isoproterenol (ISO) induced MI rat model. Methods: Twenty-four adult male rats were randomly divided into four groups of six rats each, Group-I- Normal rats, group II-ISO (150 mg/kg once daily for two successive days), Group-III-Enalapril pretreated, and Group-IV-Losartan pretreated rats. Enalapril and losartan were given by gavage at dose 10 mg/kg and 30 mg/kg, respectively the treatment started 3 days before ISO injection and continue for 5 days after 2nd ISO dose. Results: ISO-induced group showed significant increase in the cardiac enzymes lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), accompanied with marked decrease in the catalase (CAT) and glutathione (GSH) and Bcl2. Both enalapril and losartan induce significant reduction of cardiac enzymes and systolic blood pressure and improve oxidative stress which confirmed by reduction of Malondialdehyde (MDA) and elevation of antioxidant enzymes and markedly upregulated the expression of Bcl2, Nrf-2 and HO-1. Moreover, Both enalapril and losartan reversed the histopathological changes induce by ISO and thus exhibits its cardioprotective activity. Moreover, treated rats partially minimize myocardial necrosis and interstitial edema. In conclusion: Enalapril and losartan ameliorates oxidative stress, inhibit apoptosis and improve cardiac dysfunction by alteration of Nrf2/HO-1 signaling pathway. It also reduces cardiac enzymes and improves blood pressure without affection of serum K on short term therapy in MI.

Diazoxide preserves myocardial function in a swine model of hypothermic cardioplegic arrest and prolonged global ischemia

ObjectiveAdenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model. MethodsTwelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 μmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared. ResultsFour pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O2/min, P = .12). ConclusionsDiazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.

Autonomic neurocardiogenic syndrome is stonewalled by the universal definition of myocardial infarction.

Myocardial infarction (MI) is defined as myocardial cell death due to prolonged myocardial ischemia. Clinically, troponin rise and/or fall have become the “defining feature of MI” according to the universal definition of MI (UD-MI). Takotsubo syndrome (TS) and TS-related disease conditions also cause troponin elevation with typical rise and/or fall pattern but through a mechanism other than coronary ischemia. By strict application of the clinical diagnostic criteria for type-1 MI, type-2 MI, type-3 MI, and MI with non-obstructive coronary arteries according to the UD-MI including the fourth one published recently, TS and most of the 26 other causes of troponin elevation mentioned in the fourth UD-MI may erroneously be classified as MI. The existing evidence argues for the case that TS by itself is not a MI. Hyper-activation of the autonomic-sympathetic nervous system including local cardiac sympathetic hyper-activation and disruption with nor-epinephrine churn and spillover is the most probable cause of TS. This autonomic neuro-cardiogenic (ANCA) mechanism results in myocardial “cramp” (stunning), the severity and duration of which depend on the degree of the sympathetic-hyperactivation and nor-epinephrine spillover. The myocardial cramp may squeeze the cytosolic free troponin pools causing mild to moderate troponin elevation in TS and TS-related disease conditions. This ANCA syndrome, which has hitherto been enveloped by the UD-MI over more than one decade, may occur in acute, recurrent, and chronic forms. In this critical review, the controversies of UD-MI, evidence for ANCA syndrome, and a hypothetical mechanism for the troponin elevation in ANCA syndrome are provided.

Automating detection and localization of myocardial infarction using shallow and end-to-end deep neural networks

Myocardial infarction (MI), also known as a heart attack, is one of the common cardiac disorders caused by prolonged myocardial ischemia. For MI patients, specifying the exact location of a heart muscle suffering from blood shortage or stoppage is of crucial importance. Automatic localization systems can support physicians for better decisions in emergency situations. Using 12-lead electrocardiogram, in this paper, two MI detection and localization methods are proposed with classic and end-to-end deep machine learning techniques. For the feature extraction phase, the classic approach performs a Discrete Wavelet Transform (DWT) and Principal Component Analysis (PCA) on the pre-processed signals followed by a shallow neural network (NN) for the classification phase. However, in the end-to-end residual deep learning technique, a Convolutional Neural Network (CNN) is directly employed on the pre-processed input signals. For specifying the infarcted region of myocardium, 6 classes of subdiagnosis are considered. Proposed models are verified with the Physikalisch-Technische Bundesanstalt (PTB) dataset, where the data of each patient is first grouped and then carefully partitioned to training, validation, and test datasets. The results of K-fold cross-validation indicate that the general model achieves over 98% accuracy for both MI detection and localization with fewer number of feature sets compared to previous studies. Moreover, the end-to-end CNN model shows superior performance by achieving perfect results. Thus, with the larger size of CNN models, one may choose a perfect system that requires larger memory compared to another system that requires less computational power and accepts nearly 2% of false positives and/or false negatives.

A Surprising Evolution of Myocardial Infarction in Young Adults

Abstract Introduction. Ischemic heart disease is the leading cause of death with increasing prevalence. Acute myocardial infarction is a consequence of prolonged acute myocardial ischemia, which appears secondary to an imbalance between oxygen consumption and intake at this level. Case report. We present the case of a male patient, aged 53 years old, admitted in the Cardiovascular Recovery Clinic for moderate dyspnea, intermittent dizziness and muscle pain predominantly in the lower limbs. Regarding his medical history, he suffered an antero-lateral myocardial infarction due to excessive physical effort, which was trombolysed. Following the remission of the acute episode, the evolution over the next 6-12 months was towards heart failure clinically manifested by dyspnea. Considering the presence of heart failure associated with severely diminished ejection fraction, the medication is adjusted and Sacubitril/Valsartan is introduced at a dose of 49/51 mg twice a day, under which our patient presents with both clinical and echocardiography improvement. Cardio-pulmonary stress testing is the most accurate as it provides the best information regarding functional capabilities, beyond the ejection fraction of the left ventricle. Following the treatment with RNAi (angiotensin receptor-neprilysin inhibitor), the parameters evaluated during the stress test were improved, which is clinically transposed by improving the quality of life and implicitly the long-term prognosis. Conclusion. The particularity of this case consists in the occurrence of myocardial infarction at a young age (36 years) in a patient without a heredocolateral history or associated risk factors at that time. The association of ARNI (Sacubitril / Valsartan) in the therapeutic scheme has determined a clinical improvement, as well as paraclinical especially regarding the echocardiographic parameters (the ejection fraction increased from 25% to 40% at the end of the evaluation).

Temporal dynamics of immune response following prolonged myocardial ischemia/reperfusion with and without cyclosporine A

Understanding the dynamics of the immune response following late myocardial reperfusion is critical for the development of immunomodulatory therapy for myocardial infarction (MI). Cyclosporine A (CSA) possesses multiple therapeutic applications for MI, but its effects on the inflammation caused by acute MI are not clear. This study aimed to determine the dynamics of the immune response following myocardial ischemia/reperfusion (I/R) and the effects of CSA in a mouse model of prolonged myocardial ischemia designated to represent the human condition of late reperfusion. Adult C57BL/6 mice were subjected to 90 min of closed-chest myocardial I/R, which induced severe myocardial injury and excessive inflammation in the heart. Multicomponent analysis of the immune response caused by prolonged I/R revealed that the peak of cytokines/chemokines in the systemic circulation was synchronized with the maximal influx of neutrophils and T-cells in the heart 1 day after MI. The peak of cytokine/chemokine secretion in the infarcted heart coincided with the maximal macrophage and natural killer cell infiltration on day 3 after MI. The cellular composition of the mediastinal lymph nodes changed similarly to that of the infarcted hearts. CSA (10 mg/kg/day) given after prolonged I/R impaired heart function, enlarged the resulting scar, and reduced heart vascularization. It did not change the content of immune cells in hearts exposed to prolonged I/R, but the levels of MCP-1 and MIP-1α (hearts) and IL-12 (hearts and serum) were significantly reduced in the CSA-treated group in comparison to the untreated group, indicating alterations in immune cell function. Our findings provide new knowledge necessary for the development of immunomodulatory therapy targeting the immune response after prolonged myocardial ischemia/reperfusion.

The flavonoid 4,4\u2032-dimethoxychalcone promotes autophagy-dependent longevity across species

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.

Cyclosporine-insensitive mode of cell death after prolonged myocardial ischemia: Evidence for sarcolemmal permeabilization as the pivotal step.

A prominent theory of cell death in myocardial ischemia/reperfusion (I/R) posits that the primary and pivotal step of irreversible cell injury is the opening of the mitochondrial permeability transition (MPT) pore. However, the predominantly positive evidence of protection against infarct afforded by the MPT inhibitor, Cyclosporine A (CsA), in experimental studies is in stark contrast with the overall lack of benefit found in clinical trials of CsA. One reason for the discrepancy might be the fact that relatively short experimental ischemic episodes (<1 hour) do not represent clinically-realistic durations, usually exceeding one hour. Here we tested the hypothesis that MPT is not the primary event of cell death after prolonged (60–80 min) episodes of global ischemia. We used confocal microcopy in Langendorff-perfused rabbit hearts treated with the electromechanical uncoupler, 2,3-Butanedione monoxime (BDM, 20 mM) to allow tracking of MPT and sarcolemmal permeabilization (SP) in individual ventricular myocytes. The time of the steepest drop in fluorescence of mitochondrial membrane potential (ΔΨm)-sensitive dye, TMRM, was used as the time of MPT (TMPT). The time of 20% uptake of the normally cell-impermeable dye, YO-PRO1, was used as the time of SP (TSP). We found that during reperfusion MPT and SP were tightly coupled, with MPT trending slightly ahead of SP (TSP-TMPT = 0.76±1.31 min; p = 0.07). These coupled MPT/SP events occurred in discrete myocytes without crossing cell boundaries. CsA (0.2 μM) did not reduce the infarct size, but separated SP and MPT events, such that detectable SP was significantly ahead of MPT (TSP -TMPT = -1.75±1.28 min, p = 0.006). Mild permeabilization of cells with digitonin (2.5–20 μM) caused coupled MPT/SP events which occurred in discrete myocytes similar to those observed in Control and CsA groups. In contrast, deliberate induction of MPT by titration with H2O2 (200–800 μM), caused propagating waves of MPT which crossed cell boundaries and were uncoupled from SP. Taken together, these findings suggest that after prolonged episodes of ischemia, SP is the primary step in myocyte death, of which MPT is an immediate and unavoidable consequence.

Aortic arch reconstruction in surgical treatment of ascending aortic aneurysms and dissections

Aim. The study focused on the analysis of short-term results of aortic arch reconstruction in patients undergoing open heart surgery for ascending aortic aneurysms and dissections, comparison of intra-operative brain protection methods and verification of predictors of complications.Methods. 84 patients (mean age 55.5 ± 11.5 years, 72.6 % (61) males) with ascending aortic aneurysms and Stanford type A ascending aortic and arch dissections underwent surgery over a period from January, 2013, to March, 2015. Patients were divided into 3 groups. The 1st group included patients with ascending aortic aneurysm combined with aortic dilatation at the level of innominate artery &gt;4.0 cm (n = 41). The 2nd group consisted of patients with Stanford type A acute ascending aortic and arch dissection (n = 25). In the 3rd group there were patients with type A chronic ascending aortic and arch dissection (n = 18). No significant differences between the groups were observed. Mean values of the maximum ascending aortic diameter did not differ significantly and were 59.6, 58.4 and 62.4 mm in the 1st, 2nd and 3rd groups, respectively. 3 patients from the 2nd group presented with acute heart failure, 6 – acute myocardial infarction, and 3 – stroke. Higher values of pressure gradient on the aortic valve were registered in the 1st group, as compared to those in the 2nd and 3rd groups (mean value of the peak gradient was 4.5, 8.1 and 12.4 mm Hg, respectively). EuroSCORE II value in the 1st , 2nd and 3rd groups was 9.4 %, 17.7 % and 5.8 %, respectively. Results. Overall hospital mortality was 1.2 %: 1 patient with acute type A aortic dissection and later dissection of innominate artery developed stroke and died due to multiple organ failure. More prolonged cardiopulmonary bypass time and aortic cross-clamp time were required for patients with acute ascending aortic dissections, but the total surgery time and circulatory arrest time differed significantly only in the 2nd and 3rd groups. Lengthy inotropic support, ventilation time and total ICU stay, as well as a higher rate of neurologic disorders in patients with aortic dissections in comparison with patients with aneurysms were observed. We verified correlation of the urgent type of surgery, acute type A aortic dissection, including arch and descending thoracic aortic dissection, also with dissection of cervicocerebral arteries, with a more complicated hospital period, increased inotropic support and prolonged duration of stay in the intensive care unit.Conclusion. Hemiarch repair of aortic arch dilatation in case of ascending aortic replacement is an effective and safe method of treatment of extended ascending aortic aneurysms and dissections. Unilateral anterograde cerebral perfusion with simultaneous crossclamping of contralateral common carotid artery allows to maintain effective cerebral protection in conditions of moderate hypothermia and duration of circulatory arrest for at least 30-40 minutes. Adverse prognostic factors are urgent surgery, ascending aortic, arch and descending thoracic aortic dissection, prolonged extracorporeal circulation and myocardial ischemia, and disuse of the axillary artery for cannulation.Received 6 October 2016. Accepted 24 November 2016.Funding: The study was carried out within the government’s task for 2015-2017, “Cardiovascular pathologies”, theme No. 4 “Research on genome and cellular mechanisms of formation of aorta and aortic valve pathology and development of new methods for its treatment including hybrid technologies”.Conflict of interest: The authors declare no conflict of interest.Author contributionsMaterial acquisition and analysis: Gordeev M.L., Uspenskiy V.E., Bakanov A.Y., Volkov V.V., Ibragimov A.N., Scherbinin T.S., Irtyuga O.B., Naimushin A.V. Article writing: Gordeev M.L., Uspenskiy V.E., Bakanov A.Y. Review &amp; editing: Gordeev M.L., Naimushin A.V.AcknowledgmentThe authors express their gratitude for support in diagnostics and management of patients with aortic abnormalities to I. V. Basek, PhD, Head of X-Ray CT Department, and to the employees of X-ray CT Department; to D.A. Zverev, PhD, Head of X-ray Endovascular Surgery Research Lab and the employees of X-ray Endovascular Surgery Departments; O.M. Moiseyeva, Doc. Sci. (Medicine), Head of Noncoronarogenic Heart Diseases Department and her employees, as well as to the employees of Anesthesiology &amp; Resuscitation and Cardiovascular Surgery Departments.

MYOCARDIAL INFARCTION TYPE 4TH: FEATURES OF THE COURSE, PREVENTION AND MANAGEMENT OF PATIENTS AFTER PERCUTANEOUS CORONARY INTERVENTIONS

To date, cardiovascular diseases occupy the first place in the structure of total morbidity and mortality in many countries. In 2013 in the Russian Federation from cardiovascular disease died 1 million 799 thousand people, from the bottom 529.8 thousand from coronary heart disease, the primary role belongs to myocardial infarction and its complications. Currently, the gold standard for the diagnosis of coronary heart disease, including myocardial infarction, remains coronary angiography; the main objectives of coronary angiography are to assess the features of the coronary anatomy, determination of the possibility of endovascular treatment of myocardial infarction and revascularization by stent implantation. Despite the constant improvement of technology and the progress made in relation to pharmacological support, percutaneous coronary intervention (PCI) is an invasive manipulation, which is associated with a certain risk. Diagnostic criteria for myocardial infarction 4a type include increasing the level of troponin above 5 rules of 99th the upper threshold reference values within 48 hours after the PCI procedure, in patients with normal troponin increased (≤ 99th the upper threshold reference values), or a level of troponin 20 % or more in patients with initial high level troponin combined with evidence of prolonged myocardial ischemia. Stent when performing percutaneous coronary interventions, accompanied by the activation of thrombogenic reactions, can lead to thrombosis and development 4b type. To the diagnostic signs of the myocardial infarction 4b type are the stent thrombosis, angiographic proven and/or at autopsy, in combination with increased troponin level at least one greater than the 99th the upper threshold reference values. Stent when performing PCI, accompanied by the activation of thrombogenic reactions, can lead to thrombosis and development myocardial infarction 4b type. The diagnostic signs myocardial infarction 4b type are the stent thrombosis, angiographic proven and/or at autopsy, in combination with increased troponin level at least one greater than the 99th the upper threshold reference values. You should consider the fact that the setting of drug-eluting stents increases the period of their endothelization after implantation, which in turn increases the likelihood of late thrombosis and is an indication for long-term dual antiplatelet therapy. The article describes the varieties of myocardial infarction associated with PCI, an algorithm for the diagnosis and management of patients in accordance with current clinical recommendations.

Abstract 18782: Cardiac-specific Ablation of Ulk1, but not of Atg7, Attenuates Mitochondrial Autophagy in the Heart in Response to Energy Stress (Best of Basic Science Abstract)

Rationale and Objective: During myocardial ischemia, mitochondria in cardiomyocytes undergo oxidative stress, develop protein damage/dysfunction, and trigger cell death. Dysfunctional mitochondria are eliminated through mitochondrial autophagy (MA). MA is mediated by both Atg7-dependent (conventional) and independent (alternative) mechanisms. We investigated the molecular mechanism mediating MA in response to prolonged myocardial ischemia. Methods and Results: We subjected wild-type, cardiac-specific atg7 KO, and cardiac-specific ulk1 KO mice (WT, atg7cKO, or ulk1cKO, respectively) to 48-hour fasting. The protein level of LC3-II was increased more than 5-fold in WT and ulk1cKO mouse hearts in response to starvation (p&lt;0.05), suggesting that conventional autophagy is induced. LC3-II was not detectable, and p62 was markedly accumulated in atg7cKO mouse hearts, indicating the complete absence of conventional autophagy in atg7cKO mouse hearts. Mitochondrial mass, as evaluated by the mitochondrial DNA content, was significantly increased in ulk1cKO mouse hearts (1.27-fold, p&lt;0.05) in response to fasting, but not in WT nor atg7cKO mouse hearts. Electron microscopic analyses indicated that autophagosomes containing mitochondria were easily detected in WT and atg7cKO, but not in ulk1cKO, mouse hearts after fasting. These results suggest that Ulk1, rather than Atg7, is essential for mediating MA in response to fasting. We also subjected them to prolonged ischemia (2 hours). The size of myocardial infarction/area at risk was significantly greater in ulk1KO mouse hearts (67%, p&lt;0.05) than in WT (37 %) and atg7cKO (40 %) mouse hearts. Although WT and atg7cKO mouse hearts exhibited a significant decrease in the protein level of COXI (0.81- and 0.82-fold, p&lt;0.05) in the ischemic region, ulk1cKO mouse hearts exhibited an increase (1.27-fold, p&lt;0.05). Through electron microscopy, MA was clearly observed at the ischemic area in WT and atg7cKO mouse hearts, but not in ulk1cKO mouse hearts. Conclusions: These results suggest that Ulk1, rather than Atg7, plays an important role in mediating protection of the heart against energy stress by mediating degradation of damaged mitochondria through MA.

Pathophysiology of Myocardial Infarction.

Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti-inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-β induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction.