Abstract P333: The Vascular Barrier: A Common Anti-arrhythmic Target In Atrial Fibrillation And Myocardial Infarction

Vascular leak is a major sequela of inflammation, which is associated with arrhythmic pathologies such as atrial fibrillation (AF) and myocardial infarction (MI). We recently demonstrated that the vascular leak-inducing cytokine vascular endothelial growth factor (VEGF; 90-580 pg/ml - levels found in AF patients) induces acute remodeling (30-60 minutes) of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains, disrupting their ultrastructure and prompting translocation of Na V 1.5 from these sites. This in turn disrupted impulse propagation and promoted arrhythmias in murine atria. Here, we tested the hypotheses that i) similar acute pro-arrhythmic remodeling occurs in the ventricles of MI patients, and ii) protecting the vascular barrier may prevent arrhythmias following an acute inflammatory insult. First, we examined myocardial samples from five human MI patients. VEGF was overexpressed in both cardiomyocytes and vascular endothelium in the border zone surrounding <6 month-old infarcts. Notably, co-localization analysis showed significantly reduced Na V 1.5 near both connexin43 and N-cadherin within the border zone in 1-, 3-, and 9-day-old infarcts, paralleling our observations in mouse atria. Next, we returned to our murine model of AF induced by acute inflammatory insult (100 pg/ml VEGF for 60 minutes) to test the antiarrhythmic efficacy of protecting the vascular endothelial barrier. Overall, median in vivo arrhythmia burden was higher in VEGF-treated mice relative to vehicle controls (7.5±11 vs. 0±6 s/hr). We tested two strategies shown to prevent vascular barrier breakdown: Blocking connexin43 hemichannels (αCT11 peptide) decreased in vivo arrhythmia burden to 0 ± 6.07 s/hr. Panx1-IL2 (a peptide inhibitor of Panx1 channels) treatment decreased also in vivo arrhythmia burden (0 ± 15.57 s/hr with 1.6 μM Panx1-IL2). Similar antiarrhythmic efficacy was also achieved with small molecule inhibitors of Cx43 and Panx1. These results highlight VEGF-induced vascular leak as a novel mechanism for acute arrhythmias both in the early stage AF and following MI. Indeed, this mechanism may contribute to post-MI AF. Importantly, vascular-barrier protection may be a viable strategy to prevent these arrhythmias.

Frequency of Arrhythmias and Conduction and Antiarrhythmic Efficacy of Upstream Therapy in Patients with Acute Myocardial Infarction with Comorbid Metabolic Syndrome and Vascular Endothelial Dysfunction

Context. Cardiac arrhythmias and conduction disorders are the most common reperfusion complications in patients with myocardial infarction (MI) in both acute and late postinfarction periods, which significantly complicates the course of the disease and often leads to an unfavorable prognosis for the early and distant periods. Objective. To evaluate the frequency of arrhythmias and conduction and the antiarrhythmic efficacy of upstream therapy in patients with acute MI with comorbid metabolic syndrome (MS) and endothelial vascular dysfunction. Materials and methods. The experimental group consisted of 42 patients with acute myocardial infarction in combination with MS, who underwent urgent coronary angiography followed by balloon angioplasty and stenting of the infarct-dependent coronary artery, as well as standard drug therapy according to the MOH protocol. Patients in the experimental group also received 5 intravenous infusions of arginine-carnitine mixture (4.2 g and 2.0 g, respectively) in 100 ml of solvent. The nature of the clinical course of MI was compared with that in 38 patients with MI in combination with MS (control group), who did not receive additional treatment and were comparable in age (56.64 ± 0.91 and 54.85 ± 0.76 years, respectively). Results. It was found that patients with MI with comorbid MS on percutaneous coronary intervention most often developed reperfusion syndrome with manifestations of arrhythmias and conduction. Under the influence of standard drug treatment in patients of the control group there was a significant clinical and functional improvement, though sinus tachycardia, ventricular extrasystole of high grades and supraventricular extrasystole remained resistant to treatment. There was also a pronounced endothelial vascular dysfunction, which in the process of standard treatment in patients of the control group did not reach the level of healthy individuals (p-value less than 0.05). Conclusions. In patients with acute MI with comorbid MS, who underwent balloon angioplasty and stenting of the infarct-dependent coronary artery, a pronounced vascular endothelial dysfunction and electrical instability is observed, accompanied by reperfusion arrhythmias and arrhythmias. The use of arginine-carnitine mixture as upstream therapy helped to restore endothelial function and showed a pronounced antiarrhythmic effect, which significantly reduced the incidence and severity of complications of acute MI such as reperfusion arrhythmias.

The place of sotalol in the treatment of extrasystole in patients with hypertension

Annotation. The spread of hypertension in the world encourages the search for new methods for its diagnosis and treatment. And the problem of treating patients with cardiac arrhythmias is that antiarrhythmic drugs of various classes used by doctors of practical health care have proarrhythmogenic properties. And this increases the possibility of the development of lethal cardiovascular events. From this perspective, the parameters for the effect on the morphofunctional parameters of the myocardium, highlighted in this article, when using the antiarrhythmic drug III sotalol, which has the properties of a beta-blocker, are relevant and justified. The purpose of the study was to study the effect of sotalol on the morphological and functional parameters of the myocardium with a combination of stage II hypertension and extrasystole of various topics in patients of different age groups and gender content. We examined 120 people with stage II hypertension (42 men and 78 women) aged 27 to 81 years (average age 59.8 years) and extrasystole of various topics and 30 people (13 men and 17 women) aged 30 to 76 years old (average age — 56.4) with stage II hypertension, in accordance with the Recommendations of the Ukrainian Association of Cardiology, without signs of extrasystole. The first clinical group was formed by 54 (45%) patients with supraventricular extrasystoles, the second — 42 (35%) patients with ventricular extrasystoles, the third — 24 (20%) with combined supraventricular and ventricular extrasystoles. Statistical analysis of the results of the study was performed using methods of variational statistics using the programs MicroSoft Exel 2003 and StatSoft “Statistica” v. 10.0. The regularities of such indicators of structural and geometric remodeling of the left ventricle in patients with isolated hypertension, hypertension and extrasystole of various topics, the nature of remodeling of the left ventricle, analysis of changes in intracardiac hemodynamics over 6 months of taking sotalol by the above-mentioned patients are established. It was established that in patients with hypertension and with hypertension and supraventricular extrasystole concentric hypertrophy of the left ventricle predominates, in patients with hypertension and ventricular extrasystole eccentric remodeling, in patients with hypertension and combined extrasystole, is eccentric concentric remodeling of the left ventricle. It was established that the anti-remodeling effect of sotalol was reflected in the effect on the structural-geometric state of the left ventricle, and the analysis of the antiarrhythmic efficacy of sotalol allows us to recommend it as a basic treatment for patients with hypertension combined with extrasystole. The results demonstrated the effect of sotalol on the structural and functional state of the myocardium in patients with isolated hypertension and hypertension, combined with extrasystole.

Pharmacological Evaluation of the Effects of Phenylcarbamic Acid Derivatives on Cardiovascular Functions in Rats

Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity

Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayedantiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p&lt;0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p&lt;0.01), and the number of rats that maintained sinus rhythm for more than 20 minutes (p&lt;0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50=59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.