Role of abnormal repolarization in the mechanism of cardiac arrhythmia.

In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K+ currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca2+ handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na+ channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K+ channel (dofetilide).

Impaired epicardial activation-repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles.

AIM: Activation-repolarization coupling refers to the inverse relationship between action potential duration and activation time in myocardial regions along the path of ventricular excitation. This study examined whether the activation-repolarization coupling plays a role in coordinating repolarization times between the right ventricular (RV) and left ventricular (LV) chambers, and if impaired coordination contributes to electrical instability produced by hypokalaemia or dofetilide, a blocker of the delayed rectifier K(+) current. METHODS: In Langendorff-perfused, isolated guinea pig hearts, six monophasic action potential recording electrodes were attached to RV and LV epicardium. Local activation time and action potential duration (APD90 ) were determined during spontaneous beating, regular pacing and extrasystolic excitation. RESULTS: In regularly beating hearts, the RV epicardial sites had longer APD90 , but exhibited earlier activation times, as compared to LV sites, which minimized the interventricular difference in repolarization time. Upon extrasystolic stimulation, the APD90 was reduced to a greater extent in RV compared with LV, which translated to a reversed slope of APD90 -to-activation time relationship, and increased spatial repolarization gradients. Hypokalaemia and dofetilide prolonged APD90 , with the effect being greater in LV compared with RV. In hypokalaemic hearts, LV activation was delayed. These changes contributed to increased asynchrony in repolarization times in the LV and RV in both regular and extrasystolic beats, and enhanced susceptibility to tachyarrhythmia. CONCLUSION: Impaired RV-to-LV activation-repolarization coupling is an important determinant of electrical instability in the setting of non-uniformly prolonged epicardial APD90 or slowed interventricular conduction.

Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart.

AIM: Endocardial pacing instituted to treat symptomatic bradycardia may nevertheless promote tachyarrhythmia in some pacemaker-implanted patients. We sought to determine the contributing electrophysiological mechanisms. METHODS: Left ventricular (LV) monophasic action potential duration (APD(90)) and effective refractory periods were determined in perfused guinea-pig hearts along with volume-conducted ECG recordings during epicardial and endocardial stimulations. RESULTS: Consistent with electrotonic modulation of repolarization, APD(90) at a given (either epicardial or endocardial) recording site tended to be longer while pacing from the ipsilateral LV site as compared to stimulations applied at the opposite side of ventricular wall. As a result, the intrinsic transmural repolarization gradient was amplified during endocardial pacing while being significantly reduced upon epicardial stimulations. The maximum slope of APD(90) restitution was greater upon endocardial than epicardial pacing. The excitability was found to recur at earlier repolarization time point at endocardium than epicardium, thereby contributing to increased endocardial critical intervals for re-excitation. Premature extrasystolic beats could have been elicited at shorter coupling stimulation intervals and propagated with greater transmural conduction delay upon endocardial than epicardial stimulations. Endocardial site exhibited lower ventricular fibrillation thresholds and greater inducibility of tachyarrhythmia upon extrasystolic stimulations as compared to epicardium. CONCLUSION: Arrhythmic susceptibility in guinea-pig heart is greater during endocardial than epicardial pacing because of greater transmural APD(90) dispersion, steeper electrical restitution slopes, greater critical intervals for LV re-excitation and slower transmural conduction of the earliest premature ectopic beats. Further studies are warranted to determine whether these effects may contribute to proarrhythmia in paced human patients.

Electrophysiological determinants of hypokalaemia-induced arrhythmogenicity in the guinea-pig heart.

AIM: Hypokalaemia is an independent risk factor contributing to arrhythmic death in cardiac patients. In the present study, we explored the mechanisms of hypokalaemia-induced tachyarrhythmias by measuring ventricular refractoriness, spatial repolarization gradients, and ventricular conduction time in isolated, perfused guinea-pig heart preparations. METHODS: Epicardial and endocardial monophasic action potentials from distinct left ventricular (LV) and right ventricular (RV) recording sites were monitored simultaneously with volume-conducted electrocardiogram (ECG) during steady-state pacing and following a premature extrastimulus application at progressively reducing coupling stimulation intervals in normokalaemic and hypokalaemic conditions. RESULTS: Hypokalaemic perfusion (2.5 mm K(+) for 30 min) markedly increased the inducibility of tachyarrhythmias by programmed ventricular stimulation and rapid pacing, prolonged ventricular repolarization and shortened LV epicardial and endocardial effective refractory periods, thereby increasing the critical interval for LV re-excitation. Hypokalaemia increased the RV-to-LV transepicardial repolarization gradients but had no effect on transmural dispersion of APD(90) and refractoriness across the LV wall. As determined by local activation time recordings, the LV-to-RV transepicardial conduction and the LV transmural (epicardial-to-endocardial) conduction were slowed in hypokalaemic heart preparations. This change was attributed to depressed diastolic excitability as evidenced by increased ventricular pacing thresholds. CONCLUSION: These findings suggest that hypokalaemia-induced arrhythmogenicity is attributed to shortened LV refractoriness, increased critical intervals for LV re-excitation, amplified RV-to-LV transepicardial repolarization gradients and slowed ventricular conduction in the guinea-pig heart.

[Neurotensin: reception and intracellular mechanisms of signaling].

The review coveres the features of neurotensin receptor, functional role ot its structural elements, nature of conjugation with effectoral cell systems, and mechanisms of receptor decensitization developing as results of prolonged effect of agonist. The author provides pharmacological description of neurotensin antagonists and special features of three subtypes of its receptors. The author reviews the research results establishing a correlation between structural modification of various section of neurotensin molecula and manifestations of its physiological activity. Special focus is mage on discussion of neurotensin's physiological effects developing as results of its modulating impact on discharge of other biologically active substances.

[Peripheral mechanisms of vagal sinus arrhythmia: a role of typical affiliation of cardiac M-cholinoreceptors].

Salvo impulses on the vagus nerve of a cat with a varying in each cardiocycle interval after ECG P wave led to recurrent variations of ECG interval P-P manifesting as sinus arrhythmia. A chronotropic effect of the vagus nerve experienced moderate changes in dislocation of the vagus stimulus position in the beginning of cardiocycle lasting about 200 ms after ECG P wave and in ECG segment T-P. Distinct (in the range 100-300 ms) variations of the interval ECG P-P lengthening took place in the change of the vagus stimulus generation moment in the narrow zone of cardiocycle of 40-70 ms duration. The zone location corresponded to the end of ECG T wave. Metoctramine or gallamine block of M2-cholinoreceptors reduced maximal lengthening of the interval P-P and severity of cycle changes of P-P interval in arrhythmia and its variation amplitude under changing moment of vagus stimulus generation in the zone of cardiocycle showing marked shifts of a chronotropic effect. M1-cholinoreceptor block with pirenzepin or receptors of M3-subtype in the action of 4-DAMP produced an opposite effect enhancing these parameters.

[Neurotensin: physiological properties and role in the regulation of organism function]. / Neirotenzin: fiziologicheskie svoistva i rol' v reguliatsii funktsii organizma.

In review one can find summarized data about neurotensin structure, properties and physiological activity, presented in publications of last 30 years, from the time when this peptide has been discovered. The article contains data about neurotensin blood plasma level and its distribution in various organs and tissues in humans and different animal species. Main manifestations of neurotensin physiological activity are discussed as its participation in regulation of cardiovascular, digestive and endocrine systems and also in regulation of immunity and cell growth. From clinical point of view, obvious interest represents neurotensin ability to produce neuroleptical and antipsychotie effects after injecting into the brain ventricles.

[Dynamics of the vagus effect on the cardiac rhythm during blockade of various subtypes of M-cholinoreceptors in cats]. / Dinamika vagusnogo vliianiia na ritm serdtsa koshki pri blokade otdel'nykh podtipov M-kholinoretseptorov.

While single vagus bursts were used in cats with an incremental time delay following P-wave of the ECG, two zones were identified within the cardiac cycle differing from each other by their chronotropic responses. At the initial (approximately 120-130 ms) part of the cardiac cycle, an increase in the P-stimulus interval evoked a "moderate" (+8-16%) increment of the chronotropic response up to its maximal amplitude. Further increase of that interval provoked an "abrupt" (-80-90%) decrease of the vagus response. Block of M1-(pirenzepine), M2-(metoctramine and gallamine) or M3-(DAMP) cholinoreceptors diminished vagally-induced minimal and maximal prolongation of the ECG P-P interval and decreased the amplitude of its alterations associated with varying the position of vagus stimulus within the cardiac cycle. The coefficient delineating magnitude of the vagus effect over a zone with "moderate" changes of the chronotropic response was decreased after blocking the M1- and M2-cholinoreceptors, whereas duration of that zone was shortened following blockade of the M1- and M3-receptors. Velocity of the original vagus response and the rate of its subsequent decline decreased following blockade of the M1- and M2-subtypes of cholinoreceptors.

[Protective electrophysiological effects of somatostatin in patients with paroxysmal atrioventricular reciprocal tachycardias]. / Kupiruiushchee deistvie i élektrofiziologicheskie éffekty somatostatina u bol'nykh s paroksizmal'nymi atrioventrikuliarnymi retsiproknymi takhikardiiami.

Within 30 seconds after intravenous injection of somatostatin (sandostatin, 0.1 mg) we observed restoration of sinus rhythm in patients with atrioventricular (AV) junctional or orthodromic reciprocal tachycardias. This action was associated with interruption of re-entry on anterograde direction of AV conductivity. Somatostatin elicited pronounced cardiac electrophysiological effects which were due to activation of parasympathetic nervous system. Besides, it evoked transient elevation of systolic (+12.6%) and diastolic (+13.5%) blood pressures. High efficacy and good tolerance of somatostatin allow to consider this peptide as an alternative to adenosine and verapamil in the treatment of AV reciprocal tachycardias.

[Effect of regulatory peptides on the effect of cardiorespiratory synchronization in patients with heart diseases]. / Deistvie reguliatornykh peptidov na éffekt kardiorespiratornyi sinkhronizatsii u bol'nykh s patologiei serdtsa.

A long-acting somatostatin analogue (sandostatin) and synthetic opioid dalargin were examined for the effect on the heart rhythm under the cardiorespiratory synchronization test in patients with heart disease. In high-frequency respiration synchronized with photostimulator flashes the patients exhibited cardiorespiratory synchronism when heart rate corresponds exactly to respiration rate. A spontaneous change of the respiration rate entailed corresponding changes in the heart rate. This allowed regulation of the heart rhythm. Intravenous injection of sandostatin or dalargin extended the range of the cardiorespiratory synchronization. The latter points to involvement of peptides in mechanisms of heart taking of the control signals coming from the central nervous system.

Cardiotropic effects of Met-enkephalin and somatostatin under conditions of neurotensin receptor blockade.

Pretreatment with the neurotensin receptor antagonist decreased the severity and time of Met-enkephalin-induced inhibition of vagal chronotropic effects in cats. The opiate receptor antagonist naloxone produced a delayed inhibitory effect on the synchronizing component of the vagal chronotropic effect under conditions of neurotensin receptor blockade. Cardiotropic effects of somatostatin remained unchanged during neurotensin receptor blockade. These data indicate one-way and two-way interactions between peptides modulating parasympathetic cardiac regulation.

[The regulatory effects of opioid peptides--enkephalins--in controlling the activities of the cardiovascular system]. / Reguliatornye éffekty opioidnykh peptidov--énkefalinov v kontrole deiatel'nosti serdechno-sosudistoi sistemy.

In this review we analyse the experimental and clinical findings demonstrating important regulatory significance of met-enkephalin, leu-enkephalin and their derivatives in the control of cardiovascular system activity. Enkephalin-positive immunoreactivity is revealed in the heart of different species of animals, and their cardiovascular effects are established in numerous investigations. It is determined that cardiac effects of enkephalins are essentially associated with modulatory influence at the presynaptic and postsynaptic levels on the activity of extracardiac neural regulation. Cardiovascular effects of endogenous opioid system are extremely important in developing of myocardial ischemia, cardiac arrhythmias and congestive heart failure. The cellular mechanisms of opioid effects are associated with stimulation of mu- and delta-subtypes of opiate receptors which stimulation of mu- and delta-subtypes of opiate receptors which are coupled with conductivity of ion channels, adenylate cyclase activity, phosphoinositide turnover and calcium-calmodulin-dependent protein kynases.

[The dynamics of the chronotropic effect of a single vagal stimulus in cats under the action of met-enkephalin and neurotensin]. / Dinamika khronotropnogo éffekta odinochnogo vagusnogo stimula u koshek pri deistvii met-énkefalina i neirotenzina.

Following a burst of pulses applied to the vagus nerve with progressively incremental delay after the P wave of the ECG, the narrow zone of the cardiac cycle was identified where even a small shift of the vagal burst position evoked an abrupt alteration of the chronotropic effect magnitude. Met-enkephalin potentiated the phase-dependent vagal chronotropic effect, whereas neurotensin moved its limits toward the initial part of the P-P interval.

[The role of different mechanisms of cholinergic regulation in controlled bradycardia evoked by vagal stimulation]. / Rol' razlichnykh zven'ev kholinergicheskoi reguliatsii v razvitii upravliaemoi bradikardii pri razdrazhenii bluzhdaiushchego nerva.

In experiments on anesthetised cats we investigated functional significance of different cholinergic mechanisms regulating the magnitude of vagal chronotropic effect components, inhibitory tonic and synchronizing. It was established that inhibitory tonic vagal component is determined by intensity of acetylcholine hydrolysis and total amount of excited cardiac M-cholinoreceptors. The magnitude of synchronizing vagal component depended on subtypes of cholinoreceptors selectively excited by acetylcholine released from vagal terminals. In particular, the blockade of M1- or M3-cholinoreceptors potentiated the synchronizing vagal component, whereas the blockade of M2-cholinoreceptors inhibited it.

[The contribution of the mu- and delta-opiate receptors to the realization of the vagotropic action of met-enkephalin]. / Vklad mu- i del'ta-opiatnykh retseptorov v realizatsiiu vagotropnogo deistviia met-énkefalina.

In cat experiments the effect of methenkephalin on the heart rate, on the chronotropic effect of the vagus and its components--tonic and synchronizing was compared with the influence of the selective agonists and antagonists mu- and delta-opiate receptors. The influence of methenkephalin on the initial heart rate and the synchronizing component of the vagal chronotropic effect was found to be realized through excitation of the delta-opiate receptors. The modulating effect of methenkephalin on the expression of the inhibiting tonic action of the vagus was mediated both by the mu- and delta-opiate receptors.