Stem cells and cardiac arrhythmias.

Recent discoveries in the physiology and pathology of myocardial progenitor cells have allowed researchers to better understand a variety of cardiac pathologies and look at the pathophysiology of arrhythmias from a different perspective. Since the myocardium is composed of a syncytium of electrically interconnected cells, the process of incorporation of newly formed or imported cells into its structure is particularly important. Progenitor cells are stimulated by spontaneous electrical activity, a lengthy action potential, and easily induced triggering activity. All these can lead to arrhythmias development via the three classical mechanisms (reentrancy, automatism, or triggering activity). Transplanted stem cells can influence the electrophysiological properties of cardiomyocytes, thus creating a proarrhythmic substrate. The islets of unbound cells can form an anatomical block, causing unidirectional blockages and recurrent arrhythmias. Similarly, stem cells are capable of establishing heterotopic excitation foci with cardiac stimulatory activity. Finally, the paracrine factors produced by stem cells can also cause proarrhythmic effects. The review examines the factors that influence the proarrhythmic properties of administered stem cells and the mechanisms of arrhythmia development. The results indicate that further research should be carried out to establish the possible impact of stem cells on the development of arrhythmias.

Intermittent Hypoxic Conditioning Alleviates Post-Traumatic Stress Disorder-Induced Damage and Dysfunction of Rat Visceral Organs and Brain.

Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC's ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC's reduction of oxidative stress.

Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction.

This review focuses on the biological action of the compounds from the group of substituted 1,3,4-thiadiazines on stress response and myocardial infarction. The aim of this review is to propose the possible mechanisms of action of 1,3,4-thiadiazines and offer prospectives in the development of new derivatives as therapeutic agents. It is known, that compounds that have biological effects similar to those used as antidepressants can down-regulate the secretion of proinflammatory cytokines, up-regulate the release of anti-inflammatory ones and affect cell recruitment, which allows them to be considered immunomodulators as well. The results of pharmacological evaluation, in silico studies, and in vivo experiments of several compounds from the group of substituted 1,3,4-thiadiazines with antidepressant properties are presented. It is proposed that the cardioprotective effects of substituted 1,3,4-thiadiazines might be explained by the peculiarities of their multi-target action: the ability of the compounds to interact with various types of receptors and transporters of dopaminergic, serotonergic and acetylcholinergic systems and to block the kinase signal pathway PI3K-AKT. The described effects of substituted 1,3,4-thiadiazines suggest that it is necessary to search for a new agents for limiting the peripheral inflammatory/ischemic damage through the entral mechanisms of stress reaction and modifying pro-inflammatory cytokine signaling pathways in the brain.

Cardiac injury in rats with experimental posttraumatic stress disorder and mechanisms of its limitation in experimental posttraumatic stress disorder-resistant rats.

Traumatic stress causes posttraumatic stress disorder (PTSD). PTSD is associated with cardiovascular diseases and risk of sudden cardiac death in some subjects. We compared effects of predator stress (PS, cat urine scent, 10 days) on mechanisms of cardiac injury and protection in experimental PTSD-vulnerable (PTSD) and -resistant (PTSDr) rats. Fourteen days post-stress, rats were evaluated with an elevated plus-maze test, and assigned to PTSD and PTSDr groups according to an anxiety index calculated from the test results. Cardiac injury was evaluated by: 1) exercise tolerance; 2) ECG; 3) myocardial histomorphology; 4) oxidative stress; 5) pro- and anti-inflammatory cytokines. Myocardial heat shock protein 70 (HSP70) was also measured. Experimental PTSD developed in 40% of rats exposed to PS. Exercise tolerance of PTSD rats was 25% less than control rats and 21% less than PTSDr rats. ECG QRS, QT, and OTc intervals were significantly longer in PTSD rats than in control and PTSDr rats. Only cardiomyocytes of PTSD rats had histomorphological signs of metabolic and hypoxic injury and impaired contractility. Oxidative stress markers were higher in PTSD than in PTSDr rats. Pro-inflammatory IL-6 was higher in PTSD rats than in control and PTSDr rats, and anti-inflammatory IL-4 was lower in PTSD than in control and PTSDr rats. Myocardial HSP70 was lower in PTSD rats than in PTSDr and control rats. Our conclusion was that rats with PTSD developed multiple signs of cardiac injury. PTSDr rats were resistant also to cardiac injury. Factors that limit cardiac damage in PS rats include reduced inflammation and oxidative stress and increased protective HSP70.NEW & NOTEWORTHY For the first time, rats exposed to stress were segregated into experimental PTSD (ePTSD)-susceptible and ePTSD-resistant rats. Cardiac injury, ECG changes, and impaired exercise tolerance were more pronounced in ePTSD-susceptible rats. Resistance to ePTSD was associated with decreased inflammation and oxidative stress and with increased protective heat shock protein 70. Results may help identify individuals at high risk of PTSD and also provide a foundation for developing preventive and therapeutic means to restrict PTSD-associated cardiac morbidity.

Stress cardiomyopathy: Is it limited to Takotsubo syndrome? Problems of definition.

In 2006, Takotsubo syndrome (TTC) was described as a distinct type of stress-induced cardiomyopathy (stress cardiomyopathy). However, when thinking about Takotsubo cardiomyopathy from the viewpoints of the AHA and ESC classifications, 2 possible problems may arise. The first potential problem is that a forecast of disease outcome is lacking in the ESC classification, whereas the AHA only states that 'outcome is favorable with appropriate medical therapy'. However, based on the literature data, one can make a general conclusion that occurrence of myocardial lesions in TTC (i.e., myocardial fibrosis and contraction-band necrosis) causes the same effects as in other diseases with similar levels of myocardial damage and should not be considered to have a lesser impact on mortality. To summarise, TTC can cause not only severe complications such as pulmonary oedema, cardiogenic shock, and dangerous ventricular arrhythmias, but also damage to the myocardium, which can result in the development of potentially fatal conditions even after the disappearance of LV apical ballooning. The second potential problem arises from the definition of TTC as a stress cardiomyopathy in the AHA classification. In fact, the main factors leading to TTC are stress and microvascular anginas, since, as has been already discussed, coronary spasm can cause myocardium stunning, resulting in persistent apical ballooning. Thus, based on this review, 3 distinct types of stress cardiomyopathies exist (variant angina, microvascular angina, and TTC), with poor prognosis. Adding these diseases to the classification of cardiomyopathies will facilitate diagnosis and preventive prolonged treatment, which should include intensive anti-stress therapy.

Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide.

Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.

Effect of a new class of compounds of the group of substituted 5R1, 6H2-1,3,4-thiadiazine-2-amines on the inflammatory and cytokine response in experimental myocardial infarction.

This study investigated the effects of the L-17 compound of the group of substituted 5R1, 6H2- 1,3,4-thiadiazine-2-amines on the immune response and the plasma level of circulating cytokines in acute myocardial infarction (MI) in rats. The study was based upon experimental work which demonstrated the role of local and systemic inflammatory reactions in MI. Acute MI in rats was induced by left coronary artery coagulation. Histological study of the myocardium sections has been carried out at the 1(th) and 7(th) days of the experimental myocardial infarction. Serum activity of creatine phosphokinase (CPK), aspartate aminotransferase (AST), isoenzymes 1 and 2 and lactate dehydroge nase (LDH1-2) were investigated at days 1(st)and 7(th). ELISA analysis for plasma cytokine levels was performed using commercially available test kits following the manufacturer's instructions. Biochemical analysis in animals with the administration of the L-17 compound after MI showed that the AST and CPK levels at days 5 and 7 of experiments did not differ significantly from the values of intact animals. In animals of the group with MI without the administration of the L-17 compound, the IL-1 level 8 times and the TNF level 7.8 times exceeded the normal indicators, while the use of L-17 compound in the therapy resulted in only 1.8 times increase of IL-1 level and 4.7 times increase of TNF level in comparison with the norm. Thus, the introduction of L-17 compound in case of experimental MI delays exudative/alternative phase of inflammation, accelerates granulocytic and decreased the inflammation and anti-inflammation interleukins level.