The local repolarization heterogeneity in the murine pulmonary veins myocardium contributes to the spatial distribution of the adrenergically induced ectopic foci.

An atrial tachyarrhythmias is predominantly triggered by a proarrhythmic activity originate from the pulmonary veins (PV) myocardial sleeves; sympathetic or adrenergic stimulation facilitates PV proarrhythmia. In the present study the electrophysiological inhomogeneity, spatiotemporal characteristics of the adrenergically induced ectopic firing and sympathetic nerves distribution have been investigated in a murine PV myocardium to clarify mechanisms of adrenergic PV ectopy. Electrically paced murine PV demonstrate atrial-like pattern of conduction and atrial-like action potentials (AP) with longest duration in the mouth of PV. The application of norepinephrine (NE), agonists of α- and ß-adrenergic receptors (ARs) or intracardiac nerves stimulation induced spontaneous AP in a form of periodical bursts or continuous firing. NE- or ARs agonists-induced SAP originated from unifocal ectopic foci with predominant localization in the region surrounding PV mouth, but not in the distal portions of a murine PV myocardium. A higher level of catecholamine content and catecholamine fiber network density was revealed in the PV myocardial sleeves relative to LA appendage. However, no significant local variation of catecholamine content and fiber density was observed in the murine PV. In conclusion, PV mouth region appear to be a most susceptible to adrenergic proarrhythmia in mice. Intrinsic spatial heterogeneity of AP duration can be considered as a factor influencing localization of the ectopic foci in PV.

[Electrhopysiological Effect of the Polyamine Spermine in Normoxic and Ischemic Ventricular Myocardium].

Cytoplasmic polyamines (PA) are involved in control of many cellular functions and are well known as regulators of so called inward-rectifier potassium ion channels. Nevertheless, functional significance of extracellular PA in the heart is poorly elucidated. Aim of this study was to study effects of endogenous PA spermine in the ventricular myocardium. Effects of the extracellular spermine were investigated in isolated multicellular preparations of rabbit and rat ventricular myocardium. Langendorff-perfused  isolated rat and rabbit hearts were also used. Action potential (APs) duration and pattern of excitation in ventricular myocardium were estimated using standard microelectrode technique and optical mapping. Functional refractory periods were assessed in Langendorff perfused hearts with the help of programmedelectrical stimulation of the ventricle. In this study extracellular PA spermine (0.1-5 mM) induced shortening of the APs in multicellular preparations of rat ventricular myocardium registered using sharp microelectrode technique. However, spermine caused only weak effect in preparations of ventricular myocardium from rabbit heart: highest tested concentration of spermine (5 mM) induced 4.7 % APs shortening. Similarly, 0.1-1 mM of spermine was unable to alter substantially ventricular effective refractory periods in isolated perfused rabbit hearts. In two animal species tested (rat and rabbit) 0.1-1 mM of spermine failed to affect conduction velocity and activation pattern in ventricles of isolated Langendorff-perfused hearts under normoxia. However, in the rat no-flow model of ischemia-reperfusion extracellular spermine improved conduction of excitation in ventricles. Our results allow suggesting that extracellular spermine can prevent ischemia-induced proarrhythmic changes in ventricular myocardium probably due to reduction of calcium accumulation, but this effect is significant only when PA is applied in millimolar concentrations. Also, potential anti-ischemic effect of the PA may be species specific.

[Types of Conduction Disturbances in Pulmonary Veins].

Recently, the notion that in 60-80 % of cases the origin of the pulmonary veins (PV) is the place of origin of atrial fibrillation (AF) has become widespread. It has been shown that in this area, under the action of norepinephrine (HA), in the absence of stimulation, an intrinsic rhythm appears. Using two-channel microelectrode leads (from the mouth and distal part of the PV) in rats weighing 350-450 grams, it was found that: 1) in the distal part of PV there are cells with depolarized resting potential (RP) up to -50 mV, which under normal conditions are not excitable; 2) in 17 experiments out of 23, various blocks of excitation conduction along PV were revealed; 3) in 8 experiments out of 23, a reflected excitation wave - echo from PV - was recorded. Myocardium of PV is an extremely heterogeneous medium with a strong variance in the duration of the action potential and variable rate of conduction, which contributes to the occurrence of different types of conduction blocks and causes echoes and other rhythm disturbances.

[Intracellular Molecular Mechanisms of Adrenergic Regulation of Pulmonary Vein Myocardium Membrane Potential].

Pulmonary vein (PV) myocardium is characterized by numerous electrophysiological properties which make this tissue highly prone to spontaneous, ectopic activity partially due to resting potential (RP) instability. PV derived ectopy frequently underlies supraventricular arrhythmias, including atrial fibrillation. It has also been demonstrated that adrenergic stimulation causes proarrhythmic alterations in PV. Selective α1- and ß-adrenoreceptors stimulation causes RP depolarization and hyperpolarization, respectively, at least in rats. The intracellular mechanisms of α1- and ß-adrenoreceptors-dependent RP drifts are not investigated. Adenylate cyclase (AC) activator forscolin similarly to selective ß-adrenoreceptors agonist isoproterenol (ISO) induced strong hyperpolarization in quiescent isolated perfused multicellular preparations of rat PV. Maximal value of hyperpolarization in PV was equal after application of both compounds. Proteinkinase A (PKA) inhibitors КТ5720, H-89 and Rp-adenosine-cAMP suppressed ISO-induced hyperpolarization in PV. Inhibitors of phospholipase C (U73122) or D (FIPI), similarly to proteinkinase C (PKC) inhibitor chelerythrine, failed to suppress α-adrenoreceptors-dependent phenylephrine-induced depolarization in rat PV myocardium. These results allow us to suggest that ß-adrenoreceptors-dependent RP hyperpolarization in quiescent rat PV myocardium is only partially mediated by cAMP-dependent signal transduction pathway and by PKA. Besides, PKA-independent mechanisms also contribute to ß-agonists effects in PV. In addition, α-adrenoreceptors-dependent depolarization in rat PV myocardium could be independent on PLC and PKC.

[Restoration of Sinus Rhythm in Patients With Persistent Atrial Fibrillation and Obesity: New Possibilities of Pharmacological Cardioversion].

We present in this article 2 cases of successful pharmacological restoration of sinus rhythm by a new class III antiarrhythmic drug refralon in patients with obesity and persistent atrial fibrillation. In both cases, the effective use of refralon was preceded by repeated ineffective attempts of electrical cardioversion. In the article we discuss the role of obesity as the factor leading to a substantial increase of transthoracic electrical resistance, and thus significantly reducing the probability of sinus rhythm restoration by means of electrical cardioversion. The clinical examples described in this article clearly show that the use of refralon may represent a unique clinical alternative to electrical cardioversion for sinus rhythm restoration in patients with persistent atrial fibrillation, and in some cases where the success of electrical cardioversion is obviously questionable, like in patients with severe obesity, the use of refralon seems preferable.

The role of cytoplasmic calcium in the regulation of the resting potential in the pulmonary veins myocardium in rats and mice.

We have demonstrated the phenomenon of Са(2+)-induced hyperpolarization in the myocardium of pulmonary veins (PVs) in rats. An increase in cytoplasmic calcium [Са(2+)] i was shown to shift the resting potential (RP) in the PVs towards more negative values. The compounds inducing an increase in [Са(2+)] i , such as isoproterenol (10 µM), caffeine (5 mM), and ryanodine (0.01 µM), caused hyperpolarization of 10 ± 2, 9 ± 1.3, and 4.1 ± 2 mV, respectively. The inhibition of calcium-dependent potassium currents (IKCa) did not change RP of PVs under the control conditions and did not affect the Са(2+)-induced hyperpolarization.

[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.

[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.

[Electrophysiological mechanisms of heart rate stability of the hibernating mammals during hypothermia].

Despite more than 100 years of study, the mechanisms of natural resistance of the hibernator heart to cardiac arrhythmias during hypothermia has remained unknown. Renewed optimism in this area of research comes with recent methodological advances which enable to shed light on the hidden secrets of the hibernator's heart. This review discusses basic mechanisms of hypothermic ventricular arrhythmias and highlights some recent findings from the hibernator's heart electrophysiology, which may have an antiarrhythmic potential for the human heart as well.

[Hypothermia induced alteration of refractoriness in the ventricular myocardium of ground souirrel Citellus undulatus].

Bioelectrical activity and refractoriness in ventricular myocardium of the hibernator--ground squirrel Citellus undulatus were investigated during hypothermia. Experiments were performed with use of isolated, perfused preparations of papillary muscle from right ventricular. Preparations were obtained from hibernating (HS), summer active (SAS) squirrels and from rats. Bioelectrical activity was registered using the standard microelectrode technique at 37-17 degrees C. Action potentials duration (APD), refractoriness duration (RD) and the velocity of the action potential wave front (dV/dt) were estimated. Hypothermia induced APD and RD prolongation were demonstrated in all groups of experimental animals. However, normalized RD was significantly longer in the HS group during hypothermia than in SAS and rats. Ratio of RD to APD in HS group exceeds unity at 17 degrees C, which allows to suggest so called "postrepolarization refractoriness" during hypothermia. Also, HS reveal more prominent preservation of dV/dt during hypothermia than SAS and rat. Significant prolongation of RD and maintenance of normal excitation conduction during hypothermia probably plays essential role in hibernators resistivity to cold induced arrhythmias.

[Influence of new III class antiarrhythmic drug Niferidil (RG-2) on bioelectrical activity of rat pulmonary veins myocardium].

Myocardial cells in pulmonary veins are thought to play a major role in the initiation and maintenance of atrial arrhythmias, including atrial fibrillation. In experiments on rat pulmonary veins, antiarrhythmic drug niferidil (RG-2) produced increase of APD90% and functional refractory period and decrease of action potential amplitude and slope of APD restitution curve. Thus niferidil (RG-2) exerts stronger action on pulmonary veins than left atrium. This can take important part in Niferidil (RG-2) antiarrhythmic activity.

[Excitation conduction in the rat pulmonary veins myocardium assessed by the optical mapping].

In this study, conduction of excitation in the rat left atrial and pulmonary veins myocardium was assessed by the optical mapping technique. Rat atrial myocardium and pulmonary vein myocardium demonstrated weak differences in the activation time and conduction velocity. Maximal conduction velocity in atrial myocardium estimated by the optical mapping was 84 +/- 14 cm/s, the same parameter in pulmonary vein myocardium was 71 +/- 11 cm/s. Period of refractoriness in the atria was significantly shorter (44 +/- 3 ms) than in pulmonary vein myocardium (60 +/- 3 ms). Despite the differences in the period of refractoriness excitation wavelength in the pulmonary veins and atrial myocardium was very similar (43 +/- 7 and 37 +/- 5 mm, respectively). Conduction of excitation in rat atria was characterized by high level of "linearity". Regions with essential decrease of conduction velocity and complete abruption of conduction (conduction blocks) were observed in pulmonary vein myocardium. It was suggested that high histological heterogeneity and intercellular electrical resistance played an important role in conduction abnormalities in rat pulmonary veins.

[First experience of clinical use of new class III antiarrhythmic agent niferidil in patients with persistent atrial fibrillation and flutter].

The aim of the study was to evaluate the efficacy and safety of administered intravenously niferidil in doses 10, 20 and 30 mkg per kg in patients with persistent atrial fibrillation (AF) and flutter (AFL) for pharmacological cardioversion. The study included 30 patients (22 male) with persistent AF (n = 28) and AFL (n = 2) without structural heart diseases with median arrhythmia duration 6.1 +/- 4.8 months (2 weeks to 24 months). Niferidil was administered as 3 bolus injections (10 mkg per kg each) performed with the interval of 15 minutes. Antiarrhythmic efficacy of niferidil in dose of 10 mkg per kg was 60%, in dose of 20 mkg per kg it was 70%, and in dose of 30 mkg per kg reached 90% prespectively. The part of the patients, in whom QTc prolongation exceeded potentionally dangerous value of 500 mc, was 22.2% (6 of 27). None of the patients developed proarrhythmic side effect as torsade de pointes.

[Ionic mechanisms of action of class III antiarrhythmic drugs].

In this review we discuss mechanisms of antiarrhythmic and adverse proarrhythmic action of class III drugs. Special attention is given to ionic currents and channels which determine specific features of their effects (IKr, IKa, IKur). We consider general patterns of changes of bioelectrical activity in atria and ventricles leading to development of arrhythmias or stabilization of rhythm. We also discuss value of QT interval as predictor of torsade de pointes. Perspectives and limitations of development of novel class III antiarrhythmic drugs are discussed as well. We present consideration of efficacy and mechanisms of action of such compounds as dronedarone and vernacalant suggested for termination of atrial fibrillation and maintenance of sinus rhythm. Special attention is given to RG 2 - a novel compound with class III activity.

[Investigation of pacemaker shift in the rabbit sinoatrial node using the optical mapping technique].

Changes of the activation sequence in the rabbit sinoatrial node under the influence of low temperature and I(f) selective blocker ivabradine have been studied using the optical mapping technique. Both factors caused a shift of the pacemaker within the sinoatrial node region. These results are compared with the data obtained recently in the investigation of pacemaker shift under the influence of cholinergic and adrenergic factors. Possible mechanisms of the pacemaker shift are discussed. The suppression of electric activity in the central part of the sinoatrial node during the action of acetylcholine, which is called cholinergic inexcitability, may be considered as one of the mechanisms of the pacemaker shift. It is shown that the main cause of cholinergic inexcitability is the activation of potassium acetylcholine-dependent current I(KACh).

[Modern conceptions of the atrial fibrillation development. The role of the myocardial sleeves in the pulmonary veins].

Atrial fibrillation (AF) is the most common supraventricular cardiac arrhythmia. In this review several conceptions focused on the mechanisms of the AF initiation are discussed. At present time viewpoint that the ectopical activity in the pulmonary vien myocardial sleeves (PVs) account for AF in prevailing. PVs myocardium has been the subject of many anatomical and physiological investigations. PVs myocardium differs from left atria tissue and has many moprhological properties that make in convenient substrate for AF initiation and maintenance. PVs cardiomyocytes were shown to have great variability of electrophysiological properties (action potential duration, resting potential, upstroke velocity, etc.). Attempt to discuss afterdepolarization, triggered activity and abnormal automaticity as initiators of AF in PVs was made. It was shown that as in experimental condition, as in vivo in PVs can exist er-entry. Possibly, re-entry from PVs could be the one mechanism by which AF is initiated. In review big attention to the innervations of PVs and role of the sympathetic and the parasympathetic nerves in PVs ectopical activity is paid. Combined influence of autonomic nerves may be critical to initiating AF in PVs. Pharmacological intervention as a possible way to suppress or prevent the activity in the PVs that leads to AF is discussed.

[Mechanisms of functioning and regulation of mammalian sinoatrial node].

Actual data concerning mechanisms of automaticity in sinoatrial node, which acts as a primary pacemaker in mammalian heart, is reviewed. Studies dealing with ionic currents, maintaining automatic generation of excitation in the sinoatrial cells, and possible role of intracellular calcium turnover are discussed. Special attention is given to the differences between the central and peripheral parts of sinoatrial node, phenomenon of intranodal pacemaker shift resulting from that differences and possible role of pacemaker shift in the modulation of the sinus rhythm. Mechanisms of sinus rhythm regulation under the action of acetylcholine and noradrenalin are also discussed in detail.

[Changes in the activation sequence in the rabbit sinoatrial node induced by adrenergic stimulation].

We used high resolution optical mapping for the study of changes of activation sequence of a rabbit sinoatrial node induced by adrenergic stimulation during natural and paced rhythm. Activation of adrenoreceptors with isoproterenol (10, 100 nanoM, 1 microM) as well as stimulation of intramural postganglionic sympathetic nerves caused pacemaker migration within sinoatrial node and increase of the rate of generation of excitation. Pacemaker migration in cases of pronounced acceleration of rhythm could proceed in two stages. Termination of adrenergic influences has been followed by restoration of initial chronotopography of excitation of sinoatrial node.