Early initiation of anti-relapse antiarrhythmic therapy in patients with atrial fibrillation and flutter after pharmacological cardioversion with refralon.

Aim      Evaluating the efficacy and safety of early administration of antirecurrence antiarrhythmic therapy (AAT) following restoration of sinus rhythm (SR) with refralon.Aim      Evaluating the efficacy and safety of early administration of antirecurrence antiarrhythmic therapy (AAT) following restoration of sinus rhythm (SR) with refralon.Material and methods  The study included 247 patients with atrial fibrillation/atrial flutter (AF/AFL) (142 men) who underwent pharmacological cardioversion (PCV) with refralon. A 4-step schedule of drug administration was used (successive intravenous infusions at doses of 5, 5, 10, and 10 µg/kg; maximum total dose was 30 µg/kg). Patients who recovered SR and had no contraindications were prescribed antirecurrence AAT in the early (≤24 h; n=101) or delayed (≥24 h; n=95) period. Lappaconitine hydrobromide, propafenone, and sotalol were administered orally as the antirecurrence therapy. The decision on the time of initiating ATT and the choice of the drug and its dose was taken by the attending physician individually. The safety criteria included a prolonged PQ interval >200 ms; second- or third-degree atrioventricular block; QRS complex duration >120 ms; QT prolongation >500 ms; and heartbeat pauses >3 s. The efficacy criteria included the absence of sustained recurrence of AF/AFL after initiation of AAT and the duration of hospitalization after PCV. Patients were followed up during the study until they were discharged from the hospital.Results SR was recovered in 229 (92.7 %) patients. In the group of early AAT initiation, a PQ duration >200 ms was observed in 8 (7.9 %) patients, whereas in the group of delayed AAT initiation, in 7 patients (7.4 %; p=1.000). A wide QRS complex >120 ms was recorded in 1 (1.1 %) patient of the delayed AAT initiation group and in none of the patients of the early AAT initiation group (p=0.485). Ventricular arrhythmogenic effects and QT prolongation >500 ms were not detected in any patient. Numbers of early AF recurrence did not differ in the groups of early and delayed AAT initiation: 6 (5.9 %) vs. 5 (5.3 %), respectively (p=1.000). Median duration of hospitalization after PCV was 4 days in the group of early AAT initiation and 5 days in the group of delayed AAT initiation (р=0.009).Conclusion      Early initiation of the refralon AAT does not increase the risk of drug adverse effects and reduces the duration of stay in the hospital.

The Dependence of the Electrophysiological Effects of Class III Antiarrhythmic Drug Refralon on the Frequency of Myocardium Activation.

We studied the frequency dependence of the effects of the novel Russian class III antiarrhythmic drug refralon on the duration of action potentials (AP) in rabbit ventricular myocardium. The absence of an inverse frequency dependence of AP prolongation was demonstrated: the effects of refralon at stimulation frequency of 1 Hz were stronger than at 0.1 Hz. The patch-clamp experiments with recording of rapid delayed rectifier potassium current IKr in a heterologous expression system showed that the blocking effect of refralon developed significantly faster at 2 Hz depolarization frequency than at 0.2 Hz. This feature of refralon distinguishes it among the majority of other class III drugs (sotalol, dofetilide, E-4031) and explains the relatively high safety of this drug together with its high efficacy.

[Potential risk factors of atrial fibrillation recurrence after cryoballoon ablation].

Aim      To identify risk factors for recurrence of atrial fibrillation (AF) following cryoballoon ablation (CBA).Material and methods  This prospective study included patients with paroxysmal AF who had undergone CBA (141 patients, median age 60 years, 3% men). The evaluation prior to CBA included clinical instrumental parameters (electrocardiography (ECG), 24-h ECG monitoring, echocardiography, contrast-enhanced cardiac multispiral computed tomography). Also, possible intraoperative indexes that could affect the CBA effectivity, were evaluated. The postoperative follow-up duration was 12 months. Effectivity was assessed during in-person visits at 3, 6, and 12 months, when questioning of patients and 24-h ECG monitoring were performed. CBA was considered ineffective if the patient had recurrences of any atrial tachyarrhythmia longer than 30 sec after the end of the 3-month "blind" period.Results During the 12-month follow-up, recurrences of atrial tachyarrhythmia were observed in 46 (32.6 %) patients. Patients with ineffective CBA more frequently had AF during the first 3 months (71.7 % vs. 11.6 %; р<0.001). Such patients had a history of multiple ineffective treatments with antiarrhythmic drugs (AAD), common pulmonary venous (PV) collector (41.3 % vs. 20.0 %; р=0.008), and stroke/recurrent ischemic attacks (15.2 % vs. 5.2 %; р=0.047). Multifactorial regression analysis showed that the factors of AF recurrence included common PV collector (relative risk (RR) 2.35; 95 % confidence interval (CI) 1.29-4.25; р=0.005), multiple ineffective AADs (RR 1.42; 95 % CI 1.08-1.86; р=0.011), and early AF recurrence (RR 7.57; 95 % CI 3.84-14.90; р<0.001).Conclusion      Common PV collector and multiple ineffective AADs are risk factors of ineffective CBA. Early recurrences during the first 3 postoperative months are a significant risk factor of long-term AF recurrences.

[Efficiency and safety of using the modified protocol for the administration of the domestic class III antiarrhythmic drug for the relief of paroxysmal atrial fibrillation].

AIM: Evaluation of the efficacy and safety of the modified refralon administration protocol for the relief of paroxysmal atrial fibrillation (AF). MATERIALS AND METHODS: The study included 39 patients (19 men, mean age 6312.8 years). All patients, after excluding contraindications in the intensive care unit, were injected intravenously with refralon at an initial dose of 5 mg/kg. If AF was preserved and there were no contraindications, after 15 min, repeated administration was performed at a dose of 5 mg/kg (total dose of 10 mg/kg). After another 15 min, while maintaining AF and the absence of contraindications, the third injection of the drug was performed at a dose of 10 mg/kg (total dose of 20 mg/kg). In the absence of relief and the absence of contraindications, another injection of refralon at a dose of 10 mg/kg was performed after another 15 min (in this case, the maximum total dose of 30 mg/kg was reached). After each injected bolus and before the introduction of the next one, the ECG parameters and the general condition of the patient were assessed. The patient was monitored for 24 hours to exclude the arrhythmogenic effect and other possible adverse events. RESULTS: Restoration of sinus rhythm (SR) was noted in 37 patients out of 39 (95%). Of these, 19 people (48.7%) had SR recovery after the administration of a minimum dose of refralone of 5 mg/kg. The effectiveness of the total dose of 10 mg/kg was 76.9%, the dose of 20 mg/kg was 89.7%, and the dose of 30 mg/kg was 95%. Only two patients did not recover HR after administration of the maximum dose of refralon 30 mg/kg. Pathological prolongation of the QTc interval (500 ms) was recorded in 5% of patients. Not a single case of ventricular arrhythmogenic action (induction of Torsade de pointes) has been reported. Bradyarrhythmias (pauses, bradycardia) were registered in 13% of cases, were of a transient nature. CONCLUSION: Refralon has a high efficiency of relief (95%) of paroxysmal AF, while in almost half of cases (48.7%), SR recovery is achieved using the minimum dose of refralon 5 mg/kg. Despite the prolongation of the QTc500 ms recorded in 5% of cases, none of the patients developed Torsade de pointes after administration of the drug.

[Cardiac magnetic resonance imaging with contrast enhancement in treatment of atrial fibrillation].

Catheter ablation is presently the main method for interventional treatment of atrial fibrillation (AF). Despite improvements of the method and accumulation of personnel's experience, incidence of recurrent AF following catheter interventions remains high. This review addresses a possibility of using contrast-enhanced cardiac magnetic resonance imaging to increase the effectiveness of interventional treatment of arrhythmia.

Urokinase receptor regulates nerve regeneration through its interaction with α5ß1-integrin.

PURPOSE: Urokinase receptor (uPAR) promotes extracellular matrix proteolysis, regulates adhesion and cell migration, transduces intracellular signals through interactions with the lateral partners. The expression of uPAR and urokinase (uPA) is significantly upregulated in peripheral nerves after injury, however, little is known about uPAR function in nerve regeneration or the molecular mechanisms involved. The purpose of this study is to investigate the role of uPAR in nerve regeneration after traumatic injury of n. Peroneus communis in uPA-/-, uPAR-/- or control mice (WT) and in neuritogenesis in an in vitro Neuro 2A cell model. RESULTS: Electrophysiological analysis indicates that nerve recovery is significantly impaired in uPAR-/- mice, but not in uPA-/- mice. These data correlate with the reduced amount of NF200-positive axons in regenerating nerves from uPAR-/- mice compared to uPA-/- or control mice. There is an increase in uPAR expression and remarkable colocalization of uPAR with α5 and ß1 integrin in uPA-/- mice in recovering nerves, pointing to a potential link between uPAR and its lateral partner α5ß1-integrin. Using an in vitro model of neuritogenesis and α325 blocking peptide, which abrogates uPAR-α5ß1 interaction in Neuro 2A cells but has no effect on their function, we have further confirmed the significance of uPAR-α5ß1 interaction. CONCLUSION: Taken together, we report evidence pointing to an important role of uPAR, rather than uPA, in peripheral nerve recovery and neuritogenesis.

[Electrophysiological Cardiac Parameters and Results of Antiarrhythmic Treatment in Patients with Paroxysmal Atrial Fibrillation (Lone and Associated with Arterial Hypertension)].

PURPOSE: to assess cardiac electrophysiological parameters in patients with paroxysmal atrial fibrillation (AF), lone or with concomitant arterial hypertension (AH), and their prognostic significance relative to treatment effectiveness. MATERIALS AND METHODS: We included in this study 184 patients with paroxysmal AF (84 with concomitant AH and 100 with presumed lone AF). Cardiac electrophysiological study was performed in accordance with standardized protocol that included assessment of sinus node recovery time, sinoatrial, intraatrial and interatrial conduction time, and effective refractory periods (ERP) of right and left atria and atrioventricular node. Patients with inducible supraventricular reentrant arrhythmias that could potentially trigger AF underwent catheter radiofrequency ablation of those arrhythmias. Other patients received either antiarrhythmic drug therapy (AAD; n=79) or catheter cryo-ablation (CBA; n=81). Treatment was considered ineffective in case of any symptomatic or asymptomatic AF episode documented by ECG or Holter ECG within 12 months of follow-up. RESULTS: Patients with lone AF compared with those with AH had shorter ERP of the right atrium (219±21 ms vs. 253±44 ms, respectively, p<0.05) and more prominent dispersion of ERP of right and left atria (median 40 ms, interquartile range 10-50 ms vs. median 20 ms, interquartile range 10-22.5 ms, respectively, p<0.05). There was no statistically significant difference in other electrophysiology parameters between the groups. Sustained supraventricular reentrant arrhythmias were induced in 9% (9 of 100) patients with presumed lone AF and in 1.2% (1 of 84) patients with AH (p<0.05). All these arrhythmias were successfully ablated, and patients had no AF recurrence during 12-month follow-up. Among other patient treatment (CBA n=81, AAD n=79) was effective in 64% of those with lone AFib and in 34% - with AH (p<0.05). In multivariate multiple regression analysis, none of electrophysiological parameters could be assumed as a factor associated with the efficacy of CBA or AAD. CONCLUSION: Patients with lone AF had more prominent atrial electrophysiological inhomogeneity compared with patients with concomitant AH. Cardiac electrophysiological parameters had no influence on effectiveness of antiarrhythmic treatment.

[Recent advances in diagnosis and management of atrial fibrillation].

Alterations of heart rhythm are a common clinical event. They can be caused by almost any kind of heart disorder. Atrial fibrillation (AF) is the most common type of abnormal heart rhythm. Prevalence of AF in the general population is 1-2%, and given that AF incidence rate continues to increase it can be predicted that the number of patients will be doubled within the next 50 years. This review provides the most recent diagnostic and treatment methods, including both unique domestic antiarrhythmic drugs and non - drug methods for AF treatment which were developed and implemented in clinical practice at NMRC of Cardiology of the Ministry of Health of the Russian Federation.

Review of New American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death.

In this brief review we focus on major updates and key points of 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.

[Congenital Cardiac Conduction Abnormalities].

Abnormalities in cardiac conduction can occur due to a variety of factors. So called "idiopathic", conduction system degeneration develops without evident causes and may have hereditary basis. In the majority of cases it has no clinical manifestation, do not require treatment and have overall good prognosis. In this review we focus on congenital complete atrioventricular block and progressive cardiac conduction defect - rare but malignant and potentially lethal conditions that can be caused by genetic mutations and may be isolated or associated with structural heart disease. Cardiac involvement is relatively common in rare hereditary diseases - myodystrophies and mitochondrial cytopathies. Conduction abnormalities are among the most severe manifestations that may determine prognosis in these rare genetic disorders. These conditions deserve special consideration because of rapid progression of conduction defects and high prevalence of sudden cardiac death if no appropriate treatment applied.

[Refralon (niferidil) is a new class III antiarrhythmic agent for pharmacological cardioversion for persistent atrial fibrillation and atrial flutter].

AIM: To evaluate the efficacy and safety of refralon (niferidil), a new class III antiarrhythmic agent whose activity is related to the block of delayed rectifying potassium current and to the prolongation of atrial and ventricular action potential and refractory periods, when it is used as an agent for pharmacological cardioversion for atrial fibrillation (AF) and atrial flutter (AFL). SUBJECTS AND METHODS: The efficacy of the drug as 3 intravenous boluses of 10 µg/kg was evaluated in 134 patients (90 men; 57.8 ± 11 years) with a mean AF duration of 3 (1.5; 6) months. Its effect was controlled by 24-hour Holter ECG monitoring. The criterion for its antiarrhythmic effect was 24-hour sinus rhythm (SR) recovery. RESULTS: Niferidil restored SR in 47.7% of the patients with AF after administration of bolus 1, in 62% after bolus 2, and in 84.6% after bolus 3. SR was restored in all 100% patients with AFL. With the AF duration of less than 3 months, the efficacy of niferidil was 91.8%. There was nonsustained polymorphic ventricular tachycardia (VT) (torsade de pointes) in 1 (0.7%) patient and nonsustained monomorphic VT was stated in 5 (3.7%) patients. CONCLUSION> Pharmacological cardioversion with niferidil for persistent AF and VT may be regarded as a possible alternative to electrical cardioversion.

[Ventricular Tachycardia as a First Manifestation of Myotonic Dystrophy].

We report a case of bundle-branch reentrant ventricular tachycardia as a first and severe manifestation of myotonic dystrophy. Progressive cardiac conduction disturbances and cardiac arrhythmias are well-known features of myotonic dystrophy, although they are commonly found in late stage of disease in patients with established diagnosis. We review clinical manifestations, diagnostics, management, and prognostic value of cardiac involvement in myotonic dystrophy.

[Pharmacogenetic aspects of antiarrhythmic drug therapy].

It is known for a long time that individuals vary widely in their responses to therapy with different drugs. Variability in drug response may be due to variability in the relationship between drug dose and concentrations of the drug at target sites (pharmacokinetic variability). Another mechanism is that individuals vary in their response to identical exposures to a drug due to variability in the target molecule with which a drug interacts or in biological microenvironment in which the "drug-target" interaction occurs (pharmacodynamic variability). Variants (polymorphisms and mutations) of genes that encode proteins important for pharmacokinetics or for pharmacodynamics are described as important contributors to variable drug actions. In this article pharmacogenetic and pharmacogenomic aspects of antiarrhythmic drug therapy and genetic factors contributing to proarrhythmia are reviewed.

[Novel class III antiarrhythmic agent niferidile: review of experimental and clinical studies].

This article reviews experimental and clinical studies of a novel antiarrhythmic agent niferidile. Niferidile, a class III antiarrhythmic agent, blocks potassium outward currents, prolongs repolarization and refractory periods predominantly in atria than in ventricles. Intravenous Niferidile was efficient for interruption of AV-nodal and orthodromic re-entrant tachycardias with rates of 75% to 80%. Niferidile had a conversion rate of up to 87.3% in persistent atrial fibrillation and up to 100% in persistent atrial flutter. Proarrhythmic action of niferidil administration manifested as nonsustained torsade de pointes and monomorphic ventricular tachycardia in 1.2 and 3.7% of cases, respectively. Niferidile can be used for pharmacological cardioversion of persistent atrial fibrillation and flutter as an alternative to electrical cardioversion.

[Cardiac potassium channels: molecular structure, physiology, pathophysiology and therapeutic implications].

Potassium channels and currents play essential roles in cardiac repolarization. Potassium channel blockade by class III antiarrhythmic drugs prolongs cardiac repolarization and results in termination and prevention of cardiac arrhythmias. Excessive inhomogeneous repolarization prolongation may lead to electrical instability and proarrhythmia (Torsade de Pointes tachycardia). This review focuses on molecular structure, physiology, pathophysiology and therapeutic potential of potassium channels of cardiac conduction system and myocardium providing information on recent findings in pathogenesis of cardiac arrhythmias, including inherited genetic abnormalities, and future perspectives.

[Electrophysiological effects and antiarrhythmic activity of novel domestic class III antiarrhythmogenic drug niferidil administered in patients with paroxismal supraventricular tachycardia].

Intracardiac electrophysiological effects and antiarrhythmic activity of novel domestic class III antiarrhythmogenic drug niferidil has been studied in a group of 25 patients with paroxismal supraventricular tachycardia (PSVT) diagnosis. The drug was administered in a dose of 20 mg/kg (i.v.). Niferidil injections increased the refractory periods in both right and left atrium (by 22 and 20%, respectively, p < 0.001), right ventricle (12%, p < 0.01), and the His-Purkinje system (34%, p < 0.001) and improved additional anterograde and retrograde conduction (by 22 and 31%, respectively, p < 0.001), while not influencing the conduction via excitable cardiac tissues. Elongation of the QTc interval (22%, p <0.05) in one case was accompanied by an arrythmogenic effect (induction of short-term polymorphous ventricular tachycardia of the "torsade de pointes" type. Niferidil arrested PSVT in 78% cases and prevented PSVT development in response to endocardial stimulation in 86% of patients.

[Vanilloid receptors: structure, regulatory functions, pharmacology, therapeutic potential].

Transient receptor potential vanilloid (TRPV1), representing ion channel family, is activated in human and animal organism by capsaicin and some other factors such as heat, acidosis, and ion dysbalance. TRPV1 is a component of the endogenous system regulating various functions and participating in some pathologic processes. The structure, regulatory functions, mechanisms of activation, and chemistry of vanilloid receptors are reviewed and the mechanisms of their agonists and antagonists (including endogenous ligands) are considered. The results of experiments and clinical tests showing the therapeutic potential of vanilloids are considered.

Homotropic cooperative binding of organic solvent vapors by solid trypsin.

Homotropic cooperative binding was observed at vapor sorption of organic solvents (acetonitrile, propionitrile, ethanol, 1-propanol, 2-propanol, nitroethane) by dried solid trypsin from porcine pancreas (0.05 g H2O/g protein). The vapor sorption isotherms were obtained by the static method of gas chromatographic headspace analysis at 298 K for 'vapor solvent+solid trypsin' systems in the absence of the liquid phase. All isotherms have a sigmoidal shape with significant sorbate uptake only above the threshold of sorbate thermodynamic activity. On the sorption isotherms of non-hydroxylic sorbates the saturation of trypsin by organic solvent was observed above the sorbate threshold activity. The formation of inclusion compounds with phase transition between solvent-free and solvent-saturated trypsin is supposed. Approximation of obtained isotherms by the Hill equation gives the inclusion stoichiometry S, inclusion free energy, and the Hill constant N of clathrates. The inclusion stoichiometry S depends significantly on the size and shape of sorbate molecules and changes from S=31 mol of sorbate per mol of trypsin for ethanol to S=6 for nitroethane. The inclusion free energies determined for the standard states of pure liquid sorbate and infinitely dilute solution in toluene are in the range from -0.5 to -1.2 kJ/mol and from -3.1 to -8.1 kJ/mol, respectively, per 1 mol of sorbate. The Hill constants are relatively high: from N=5.6 for 1-propanol to N approximately equal to 10(3) for nitroethane. The implication of the obtained results for the interpretation of solvent effects on the enzyme activity and stability in low-water medium is discussed.

Second primary glioblastoma.

Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.