This review discusses the effects of amiodarone on thyroid function and summarises the results of international studies and the evidence obtained by the researchers from the A.L. Myasnikov Research Institute of Clinical Cardiology and Endocrinology Research Centre. The guidelines on thyroid dysfunction diagnostics and therapy, as well as the follow-up of amiodarone-treated patients, are presented.

AIM:To study prevalence of obstructive sleep apnea syndrome (OSAS) in patients with nocturnal asystoles, and assess therapeutic efficiency of constant positive air pressure (CPAP) applied to upper respiratory tract in this category of patients.METHODS:The study incorporated 37 patients (33 men and 4 women, average age 50+/-11 years) with nocturnal heart beat interruptions of over 3 seconds. Baseline examination revealed grade II-III arterial hypertension in 67.5%, coronary heart disease - in 19%, diabetes mellitus in 8% and no cardiovascular disease - in 5.5% of patients. Sinus rhythm was registered in 30 (81%) of patients, 7 (19%) patients had permanent atrial fibrillation. Causes of deteriorated cardiac conduction were as follows: sinoatrial blocks and sinoatrial arrests (n=18), grade II-III atrio ventricular block (n=10), combination of these forms of bradyarrhythmias (n=2) and block of conduction to ventricles in permanent atrial fibrillation (n=7). According to intra esophageal cardiac pacing, the function of sinus node and atrio ventricular conduction appeared to be undisturbed in all patients with sinus rhythm. All patients have undergone polysomnographic (PSG) examination. For patients with OSAS, an individual selection of therapeutic pressure was carried out using the CPAP apparatuses. CPAP therapy was considered effective against OSAS if normalization of apnea/hypopnea index (AHI) was observed.RESULTS:OSAS was registered in 25 cases (68%) (mean AHI 54.9+/-28.7), 20 patients (80%) had severe grade of the syndrome. CPAP therapy appeared to be effective in all patients. At the background of treatment AHI decreased from 60.7 to 5.5 episodes per hour of sleep, mean oxygen saturation of arterial blood rose from 74 to 90%. Effect of CPAP therapy relative to cardiac conduction abnormalities was attained in all 19 patients with sinus rhythm and only in one patient with permanent atrial fibrillation.CONCLUSION:OSAS was revealed in 68% of patients with nocturnal bradyarrhythmias. Individually selected therapy with constant positive pressure in patients with nocturnal asystoles and OSAS efficiently eliminated in sleep asystoles and made it possible to avoid pacemaker implantation in some patients.

To study complex of pathogenetic changes arising during VVI mode single chamber ventricular pacing we temporarily (for 1 hour) switched pacing mode from dual (DDD) to single (VVI) chamber stimulation in 11 patients. Parameters studied were cardiac output (CO), total peripheral vascular resistance (TPVR), levels of precursors of atrial and inactive fragment of brain natriuretic peptides (pro-ANP and NT-pro-BNP, respectively), noradrenaline, aldosterone, and renin activity in blood plasma. Reprogramming of pacing mode was associated with 21.4% lowering of CO and 11.4% elevation of TPVR according to impedance cardiography data, and augmentation of pro-ANP secretion from 429.79 to 620.22 fmol/l. At the background of VVI pacing there was a tendency to increase of noradrenaline blood concentration without significant changes of aldosterone concentration and plasma renin activity.

In order to assess concentration of C-reactive protein (CRP) and prevalence of autoantibodies against beta(1)-adrenoreceptors (abeta(1)-AR) in patients with cardiac supraventricular arrhythmias we studied 53 patients with arrhythmias and 20 healthy control subjects. Patients with idiopathic arrhythmias (atrial fibrillation or flutter and atrial tachycardia, n=35) comprised group I. Group II was formed of 15 patients with supraventricular arrhythmias and dilated cardiomyopathy (DCM) or chronic myocarditis. Patients of group III (n=23) had supraventricular arrhythmias and arterial hypertension (AH). CRP concentration was determined by recently developed well standardized high sensitivity method. abeta(1)-AR were detected in blood serum by direct immunoassay. Synthetic fragment containing 26 amino acids of abeta(1)-AR second loop was used as antigen. Patients with supraventricular arrhythmias and DCM or chronic myocarditis had higher median CRP (8.0 mg/1) than patients with idiopathic arrhythmias (0.78 mg/l), with supraventricular arrhythmias and AH (1.57 mg/l), or control group (0.6 mg/l). Groups I, II and III showed similar prevalence of ab1-AR (51.4, 40.0, 52.2%, respectively), that was significantly higher than in control subjects (10%) (p<0.005). These results provide evidence of the possible presence of autoimmune and/or inflammatory processes that may be involved in the genesis of supraventricular arrhythmias.

In order to assess parameters of heart rate variability (HRV) and prevalence of autoantibodies against the beta(1)-adrenoreceptors in patients with cardiac arrhythmias we studied 42 patients with arrhythmias and 20 healthy control subjects. Thirty one patients with idiopathic arrhythmias were included in group I: with paroxysmal atrial fibrillation or flutter (n=13), paroxysmal atrial tachycardia (n=2) and paroxysmal ventricular tachycardia (n=16). Group II was formed of 11 patients with paroxysmal ventricular tachycardia and dilated cardiomyopathy or chronic myocarditis. ab1-AR were determined in blood serum by direct immunoassay. Synthetic fragment containing 26 amino acids of ab1-AR second loop was used as antigen. Groups I (54.8%) and II (63.6%) showed similar prevalence of ab1-AR, which was significantly higher than in control subjects (10%) (p<0.005). HRV parameters in I group were lower in ab1-AR-positive compared with ab1-AR-negative patients. At the same time HRV parameters in ab1-AR-positive patients were significantly different from those in controls (p<0.05). In group II HRV parameters of ab1-AR-positive and ab1-AR-negative patients were significantly lower than in control subjects (p<0.05). We suppose, that ab1-AR could participate in dysfunction of chronotropic heart regulation and contribute to development of arrhythmias in patients with structurally normal hearts.

During 1 year of amiodarone intake development of amiodarone-associated thyroid dysfunction was observed in 25% of patients (hypothyroidism and thyrotoxicosis in 19.2 and 5.8%, respectively). Development of hypothyroidism was not accompanied with loss of antiarrhythmic efficacy of amiodarone and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. in all patients with clinical and in less than one half (47.6%) of patients with subclinical forms of hypothyroidism replacement therapy with L-thyroxin was carried out. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. in all patients with thyrotoxicosis which developed during amiodarone intake thyrostatic therapy with mercasolil was carried out and in case of its inefficacy prednisolone was added. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been prescribed because of life saving indications. Achievement of euthyroid state was followed by restoration of antiarrhythmic efficacy of amiodarone. Amiodarone was discontinued just in 1 patient with ventricular extrasystole as correction of thyroid status and restoration of euthyroidosis enabled effective use of other antiarrhythmic drugs.

In experiments on isolated rat and rabbit right atrium, a new class III antiarrhythmic drug RG-2 (0,01-1 microM) was shown to have anticholinergic action competing with 0.2-1 mM carbachol. RG-2 (0.1-1 microM) produced dose-dependent increase of APD90% in rat and rabbit atrial cells and had no effects on other action potential parameters. In presence of carbachol RG-2 produced significantly greater increase of APD90% and caused significant increase of APD50%. Thus RG-2 exerts anticholinergic action, which can take important part in RG-2 antiarrhythmic activity.

A perforated patch-clamp analysis of the effect of a novel class III antiarrhythmic agent RG-2, on voltage-dependent currents was made in rat ventricular myocytes. In these cells, RG-2 decreased delayed rectifier outward K(+) current, I(k), in concentration dependent manner with threshold concentration 0.1 microM/l. In contrast, the drug did not have significant effects on the transient outward and inward rectifier K(+) current. RG-2 in concentration dependent manner decreased Ca(2+) current (I(Ca,L)) with threshold concentration 1 microM/l, tenfold higher than threshold concentration for I(k). We can conclude that decreasing of I(k) may explain prolongation of cardiac repolarization induced by RG-2, and contribute to its antiarrhythmic action.

The electrophysiologic effects of a new drug, RG-2 were studied on anesthetized open-chest dogs and on rabbit right atrial tissue. RG-2 was manufactured in Chemical-Pharmaceutical Institute in Moscow. Dogs (n=12) were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). An ECG lead II, arterial blood pressure, His bundle electrogram, atrial and ventricular bipolar electrograms were continuously monitored, recorded and then analyzed by a computerized complex for electrophysiological study. Electrophysiological variables, ECG parameters, atrioventricular conduction (His electrogram) and blood pressure were determined after sequential i.v. administration of 1, 5, 10, 20, 40 and 80 ug/kg of RG-2. Interval between injections was 60 min. RG-2 had no significant effect on PQ, QRS, S-A, A-H and H-V intervals, but the drug caused dose-dependent increase of R-R and QT intervals. Moreover, RG-2 dose-dependently increased the atrial and ventricular effective refractory periods (AERP and VERP). Maximal increases of AERP and VERP registered at 5 min after administration of RG-2 (40 microg/kg) were 46+/-2% (p<0.001 vs control) and 23+/-6% (p<0.05 vs control), respectively. In the isolated rabbit right atrial tissue RG-2 (0.01 to 1 microM) had no effects on maximal diastolic potential, action potential amplitude and Vmax, but revealed concentration-dependent increase of action potential duration at 90% repolarization level (APD90%). The maximal effects on APD90% obtained after RG superfusion at 1 microM were 26+/-7% (p<0.001 vs control). We conclude that RG-2 has significant effects of class III antiarrhythmic drugs in vivo and in vitro.

Aim. To assess effect of radio frequency catheter ablation (RFCA) on heart rate variability (HRV) in patients with supraventricular tachyarrhythmias (SVT). Methods. Spectral analysis of HRV on 5-minute ECG strips was carried out in 19 patients with SVT before and 2 days after RFCA. Results: Both total and high frequency power significantly decreased (p<0,05) after RFCA in supine and orthostatic positions. Significant decrease of low frequency power occurred after RFCA in orthostatic position. Conclusion: In patients with SVT RFCA alters autonomic regulation of chronotropic function of the heart. Sympathetic and parasympathetic influences on the chronotropic function of the heart are attenuated in early period after the procedure.

Electrophysiological abnormalities of the heart conduction system and their role in development of different forms of supraventricular tachycardias, are discussed. Electrophysiological mechanisms and diagnostic criteria of the supraventricular tachycardias with wide QRS complex, are described.

According to results of testing of antiarrhythmic drugs which included electrophysiological study and 24-hour ECG monitoring 109 patients with proven malignant ventricular tachyarrhythmias were divided into 2 groups: 63 patients (60%) for whom effective antiarrhythmic therapy was found and 45 patients (40%) resistant to any antiarrhythmic therapy. Twenty two parameters including history, clinical data, results of electro-, echocardiography and radionuclide ventriculography, ets. were used for comparison of these groups. According to stepwise discriminant analysis the following parameters were independently related to results of drug tests: heart failure NYHA class II or higher, age, QRS duration in sinus rhythm, possibility to terminate attack of tachycardia medically, sex, presence of left ventricular aneurysm, left ventricular ejection fraction. Mathematical model of assessment of probability of positive or negative results of antiarrhythmic therapy was created. The use of this model before drug testing allowed to predict with probability of 80,3% possibility to work out effective antiarrhythmic therapy. The model also allowed to select patients who needed nondrug treatment.

The ability of quinidine to block alpha(1)-adrenoreceptors and M-2-cholinergic receptors suggests that in line with increasing heart rate the drug is capable to decrease the power of both high-frequency (respiratory) variations of heart rate which is determined by parasympathetic influences on the sinus node and low-frequency (vasomotor) variations which are determined by combined influences of both divisions of the autonomic nervous system on this node. This suggestion was tested by analyzing 5-min ECG recordings from 22 patients (mean age 36+/-16 years) with various arrhythmias but without organic heart disease. ECG was recorded in supine position during free and paced breathing and during active orthostatic test before and after 3 days of oral quinidine (1 g/day). Both at rest and during tests 60-70% of patients responded to quinidine by tachycardia while low-frequency variations power decreased in 80-100% and high-frequency variations power decreased in 45-75% of patients. A simultaneous spectral analysis of amplitudes of successive QRS complexes which allowed to estimate frequency, amplitude and regularity of respiratory cycles showed that increase in low-frequency and/or high-frequency power was associated with respiratory changes. In some patients the rise in low-frequency power may result from increased power of so-called very slow variations of heart rate. There was no relationship between quinidine-induced decrease in low-frequency or high-frequency powers and age of patients or type of arrhythmia. Based on the literature analysis and our data we have concluded that the decrease in heart rate induced by quinidine in 40% of patients with arrhythmias is determined by the predominance of direct inhibition by the drug of the sinus node automaticity over its tachycardia-inducing neurotropic action. The possibility that this action attenuates the neurotropic component of the drug effect, i.e. stimulatory effect of the sympathetic nervous system on the sinus node, which is caused by blockade of vascular alpha(1)-adrenoreceptors and reduction in blood pressure, can not be excluded.

Efficacy, safety and tolerability of a short term course treatments with propafenone and quinidine were compared in 34 patients (22 men, 12 women, mean age 48+/-11 years) with ECG confirmed attacks of ventricular tachycardia and various cardiovascular pathology. Propafenone and quinidine were used orally in 27 and 28 patients, respectively. Holter ECG monitoring and intracardiac electrophysiological study were used for control of therapy. Propafenone and quinidine caused pronounced side effects in 11% and 18% of patients, respectively. According to results of both methods of control propafenone produced antiarrhythmic effect in 48%, quinidine - in 39% of patients. Proarrhythmic effects at the stage of drug testing were registered in 16% and 4,4% of patients during tests with propafenone and quinidine respectively. Propafenone was not effective in all 6 while quinidine was effective in 5 out of 10 patients (50%) with ventricular tachycardia and previous myocardial infarction. Arrhythmogenic effects were observed in 3 of 6 (50%) and in 1 of 10 (10%) propafenone and quinidine treated patients, respectively Patients in whom antiarrhythmic effect was achieved during short term inhospital therapy continued to take the drug as outpatients. During long-term (up to 39 months) treatment there were no cases of sudden cardiac death. Recurrences of attacks of tachycardia occurred in 4 (44%) of 9 patients receiving propafenone and in 1 (11%) of 9 patients receiving quinidine.

Efficacy and tolerability of propafenone (450 - 900 mg/day) and verapamil (240 - 480 mg/day) were assessed in 74 patients with paroxysmal supraventricular tachycardias including 35 patients with atrioventricular nodal reciprocal tachycardia and 39 patients with paroxysmal orthodromic reciprocal tachycardia. Extracardiac and cardiac adverse affects were observed in 35 (47,3%) and 6 patients (12,5%) during therapy with propafenone and verapamil, respectively. Cessation of therapy due to adverse reactions was required in 2(2,7%) patients during treatment with propafenone and 2 (4,2%) patients during treatment with verapamil. Propafenone was effective in 30 (85,7%) and 28 (75,7%), verapamil - in 21 (72,4%) and 8 (47,1%) patients with atrioventricular nodal reciprocal and orthodromic reciprocal tachycardia, respectively. Patients who continued to take propafenone were followed-up up to 36 months. In atrioventricular nodal reciprocal tachycardia frequency of recurrent attacks decreased by 87% while 13 patients (54,2%) had no recurrences at all. In patients with paroxysmal orthodromic reciprocal tachycardia frequency of attacks decreased by 81% and 14 patients (50%) had no attacks during follow-up.

Effects of beta-adrenergic receptor blockade on heart rate variability demonstrate 2 phenomena which seem to be paradoxical. First, it has been claimed that low frequency power significantly rises although beta-blockers are expected to decrease its sympathetic component. Second, high frequency power has also been shown to rise. The nature of this phenomenon is not clear because high frequency heart rate fluctuations reflect parasympathetic influences on the sinus node. Effects of a short course of propranolol an low and high power components were investigated in 17 patients with different forms of cardiac arrhythmias without organic heart disease. Spectra of variability of heart rate and of amplitudes of QRS complexes were calculated from 5 min ECG recordings obtained in supine and standing positions. Spectra of amplitudes of QRS complexes reflected individual breathing patterns. No relation was found between the type of arrhythmia and values of heart rate, low or high frequency power neither before nor after propranolol. Propranolol decreased low frequency power in supine position by 50+/-18% in 82% of patients and in standing position by 61+/-17% in 87% of patients. The increase of low frequency power in some patients was determined by changes of breathing rate or by short non-periodical "jumps" of heart rate which had no relation to regular low frequency changes of heart rate. High frequency power increased at rest by 145% in 70% of patients. its decrease in other cases was related to slowing of breathing or reduction of tidal volume. According to the literature, beta-adrenergic blockers penetrating into the brain release norandrenaline from central noradrenergic neurons. The latter by activating alpha(1)-adrenoreceptors of medullary cardiomotor parasympathetic neurons increases their excitability and thereby enhances sinus respiratory arrhythmias and hence law frequency power of heart rate variability.