High density intramural mapping of post-infarct premature ventricular contractions and ventricular tachycardia.

BACKGROUND: Spontaneous ventricular premature contractions (PVCs) and ventricular tachycardia (VT) in the acute post infarct milieu is assumed to be due to automaticity. However, the mechanism has not been studied with intramural mapping. OBJECTIVE: To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, and to test the hypothesis that post-infarct PVCs and VT are due to re-entry rather than automaticity. METHODS: In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 20 min of stabilization, recordings were made during the first 10 min of ischemia, and activation maps of individual beats were constructed. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch. RESULTS: In all experiments ST-T alternans was present. Spontaneous ventricular beats occurred in five of 15 dogs where the earliest ectopic activity was manifested in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo-to epicardial spread along the non-ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In three dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. A similar sequence was observed in VT that followed. CONCLUSION: Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium are the mechanism of PVCs and VT in post-infarct myocardium.

Brief history of arrhythmia in the WPW syndrome - the contribution of George Ralph Mines.

George Ralph Mines studied the basic principles of reentry and published his data in The Journal of Physiology in 1913. Exactly 100 years later we discuss his first electrophysiological experiments and how his results lead to the insight that was the basis for the treatment of the clinical arrhythmias seen in Wolff-Parkinson-White syndrome.

Mechanism of ventricular premature beats elicited by left stellate ganglion stimulation during acute ischaemia of the anterior left ventricle.

AIMS: Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This 'injury' current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the 'injury' current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion. METHODS AND RESULTS: In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization. CONCLUSION: LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.

Concept of the vulnerable parameter: the Sicilian Gambit revisited.

Why consider the concept of the vulnerable parameter in a series on "Noninvasive Risk Assessment in Guiding Therapy for Prevention of Sudden Death?" Preceding that question might be, "what is the vulnerable parameter?" In the following pages, we shall review the history behind the concept of the vulnerable parameter, its evolution after its initial identification, where it stands today, and finally, why the vulnerable parameter is important to our consideration of risk factors.

Stellate ganglion stimulation causes spatiotemporal changes in ventricular repolarization in pig.

BACKGROUND: Dispersion in ventricular repolarization is relevant for arrhythmogenesis. OBJECTIVE: The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization. METHODS: In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5-10 mg/h) administration. RESULTS: LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at ∼5 seconds (10 ± 1.5 ms) and shortening at 20-30 seconds of stimulation (-28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2 of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS. CONCLUSION: LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls.

Long-term cardiac memory in canine heart is associated with the evolution of a transmural repolarization gradient.

OBJECTIVE: The contribution of regional electrophysiologic heterogeneity to the T-wave changes of long-term cardiac memory (CM) is not known. We mapped activation and repolarization in dogs after induction of CM and in sham animals. METHODS AND RESULTS: CM was induced by three weeks of AV-sequential pacing at the anterior free wall of the left ventricle (LV), midway between apex and base in 5 dogs. In 4 sham controls a pacemaker was implanted but ventricular pacing was not performed. At 3 weeks, unipolar electrograms were recorded (98 epicardial, 120 intramural and endocardial electrodes) during atrial stimulation (cycle length 450 ms). Activation times (AT) and repolarization times (RT) were measured and activation recovery intervals (ARIs) calculated. CM was associated with 1) deeper T waves on ECG, with no change in QT interval; 2) longer activation time at the site of stimulation in CM (29.7+/-1.0, X+/-SEM) than sham (23.9+/-1.3 ms p<0.01); 3) an LV transmural gradient in repolarization time such that repolarization at the epicardium terminated 12.4+/-2.4 ms later than at the endocardium p<0.01), in contrast to no gradient in shams (2.7+/-4.2 ms); in memory dogs, the repolarization time gradient was greatest at sites around the pacing electrode varying from 13.1+/-2.3 ms to 25.5+/-3.8 ms; 4) more negative left ventricular potentials at the peak of the body surface T wave (-4.9+/-0.8 vs -2.2+/-0.4 mV; p<0.05) but no altered right ventricular epicardial T-wave potentials. ARIs did not differ between groups. Right ventricular activation was delayed but was not associated with altered repolarization because of compensatory shortening of the right ventricular ARIs. CONCLUSION: CM-induced T-wave changes are caused by evolution of transmural repolarization gradients manifested during atrial stimulation that are maximal near the site of ventricular pacing.

Dispersion of repolarization in canine ventricle and the electrocardiographic T wave: Tp-e interval does not reflect transmural dispersion.

BACKGROUND: The concept that the interval between the peak (T(peak)) and the end (T(end)) of the T wave (T(p-e)) is a measure of transmural dispersion of repolarization time is widely accepted but has not been tested rigorously by transmural mapping of the intact heart. OBJECTIVES: The purpose of this study was to test the relationship of T(p-e) to transmural dispersion of repolarization by correlating local repolarization times at endocardial, midmural, and epicardial sites in the left and right ventricles with the T wave of the ECG. METHODS: Local activation times, activation-recovery intervals, and repolarization times were measured at 98 epicardial sites and up to 120 midmural and endocardial sites in eight open-chest dogs. In four of the dogs, long-term cardiac memory was induced by 3 weeks of ventricular pacing at 130 bpm because previous data suggest that, in this setting, delayed epicardial repolarization increases transmural dispersion. The other four dogs were sham operated. RESULTS: In sham dogs, T(p-e) was 41 +/- 2.2 ms (X +/- SEM), whereas the transmural dispersion of repolarization time was 2.7 +/- 4.2 ms (not significant between endocardium and epicardium). Cardiac memory was associated with evolution of a transmural gradient of 14.5 +/- 1.9 ms (P <.02), with epicardium repolarizing later than endocardium. The corresponding T(p-e) was 43 +/- 2.3 ms (not different from sham). In combined sham and memory dogs, T(p-e) intervals did not correlate with transmural dispersion of repolarization times. In contrast, dispersion of repolarization of the whole heart (measured as the difference between the earliest and the latest moment of repolarization from all left and right ventricular, endocardial, intramural, and epicardial recording sites) did correlate with T(p-e) (P <.0005, r = 0.98), although the latter underestimated total repolarization time by approximately 35%. The explanation for this finding is that parts of the heart fully repolarize before the moment of T(peak). CONCLUSION: T(p-e) does not correlate with transmural dispersion of repolarization but is an index of total dispersion of repolarization.

Local transmural action potential gradients are absent in the isolated, intact dog heart but present in the corresponding coronary-perfused wedge.

The left ventricular (LV) coronary-perfused canine wedge preparation is a model commonly used for studying cardiac repolarization. In wedge studies, transmembrane potentials typically are recorded; whereas, extracellular electrical recordings are commonly used in intact hearts. We compared electrically measured activation recovery interval (ARI) patterns in the intact heart with those recorded at the same location in the LV wedge preparation. We also compared electrically recorded and optically obtained ARIs in the LV wedge preparation. Five Langendorff-perfused canine hearts were paced from the right atrium. Local activation and repolarization times were measured with eight transmural needle electrodes. Subsequently, left ventricular coronary-perfused wedge preparations were prepared from these hearts while the electrodes remained in place. Three electrodes remained at identical positions as in the intact heart. Both electrograms and optical action potentials were recorded (pacing cycle length 400-4000 msec) and activation and repolarization patterns were analyzed. ARIs found in the subepicardium were shorter than in the subendocardium in the LV wedge preparation but not in the intact heart. The transmural ARI gradient recorded at the cut surface of the wedge was not different from that recorded internally. ARIs recorded internally and at the cut surface in the LV wedge preparation, both correlated with optically recorded action potentials. ARI and RT gradients in the LV wedge preparation differed from those in the intact canine heart, implying that those observations in human LV wedge preparations also should be extrapolated to the intact human heart with caution.

Repolarization gradients in the canine left ventricle before and after induction of short-term cardiac memory.

BACKGROUND: Questions remain about the contributions of transmural versus apicobasal repolarization gradients to the configuration of the T wave in control settings and after the induction of short-term cardiac memory. METHODS AND RESULTS: Short-term cardiac memory is seen as T-wave changes induced by altered ventricular activation that persists after restoration of sinus rhythm. We studied cardiac memory in anesthetized, open-chest dogs paced from the ventricle for 2 hours. Unipolar electrograms were recorded from as many as 98 epicardial and 144 intramural sites, and activation times and activation-recovery intervals (ARIs) were measured. In separate experiments, epicardial monophasic action potentials were recorded. We found no appreciable left ventricular intramural gradients in repolarization times (activation time+ARI) in either control conditions or after the induction of memory. In controls, there was a left ventricular apicobasal gradient, with the shortest repolarization times in anterobasal regions and longest repolarization times posteroapically. After induction of memory, repolarization times shortened uniformly throughout the ventricular wall. Monophasic action potential duration at 90% repolarization decreased by approximately 10 ms after induction of memory. CONCLUSIONS: In the intact canine left ventricle at physiological rates, there is no transmural gradient in repolarization. Apicobasal gradients in repolarization time, with shortest repolarization times in anterobasal areas and longest repolarization times in posteroapical regions, are important in the genesis of the T wave. Repolarization times and monophasic action potentials at the 90% repolarization level shorten after the induction of memory. The deeper T wave in the ECG after induction of memory may be explained by the more rapid phase 3 of the action potential.

Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: experimental evidence to resolve some controversies.

BACKGROUND: Activation recovery intervals (ARIs) and monophasic action potential (MAP) duration are used as measures of action potential duration in beating hearts. However, controversies exist concerning the correct way to record MAPs or calculate ARIs. We have addressed these issues experimentally. OBJECTIVES: To experimentally address the controversies concerning the correct way to record MAPs or calculate ARIs. METHODS: Left ventricular local electrograms were recorded in isolated pig hearts with an exploring electrode grid, with a KCl reference electrode on the left ventricular myocardium, the aortic root, or the left atrium. Local activation was determined from calculated Laplacian electrograms. RESULTS: With the KCl electrode on the aortic root, local electrograms represented local activation. However, with the KCl electrode on the myocardium remote from the exploring electrode, a combined electrogram emerged consisting of local activation recorded from the grid and remote activation recorded from the reference electrode. The remote, inverted monophasic component did not show propagation and did not correlate with the Laplacian complex. When the KCl electrode was placed on the atrium during AV block, remote atrial monophasic components were completely dissociated from local, ventricular deflections. At left ventricular sites with a positive T wave, the Laplacian signal showed that the end of the T wave was caused by remote repolarization. During cooling-induced regional action potential prolongation, the T wave became negative, whereby the positive flank of the T wave remained correlated with repolarization (recorded with a MAP at the same site). CONCLUSIONS: MAPs are recorded from the depolarizing electrode. In both negative and positive T waves, the moment of maximum dV/dt corresponds to local repolarization.

Region-specific, pacing-induced changes in repolarization in rabbit atrium: an example of sensitivity to the rare.

OBJECTIVE: In subsets of patients paroxysmal firing of ectopic foci in pulmonary veins or coronary sinus is an important cause of atrial fibrillation. This appears to represent a rare event overriding a dominant sinus mechanism to alter the rhythmic firing of the atrium. Hence, we tested the hypothesis that a rare stimulation pattern might alter the myocardial substrate, making it more susceptible to the initiation of arrhythmias. METHODS: In isolated right and left rabbit atria, a "rare" burst pacing protocol (BPP) was applied as follows: over 3 h, preparations were driven for 4.5 min from sinus node (SN) or Bachmann's bundle (BB) regions at cycle length (CL)=400 ms followed by 30 s of stimulation from coronary sinus (CS) or pulmonary vein (PV) at CL=200 ms. Microelectrodes were used to record action potentials at the end of 4.5 min of pacing at CL=400 ms. We then intervened with 5-min bigeminal pacing to probe atrial vulnerability to arrhythmias: S1 was delivered from SN or BB and S2 from CS or PV, respectively. S1-S2 interval was the shortest eliciting a propagated response. RESULTS: BPP shortened repolarization in CS and PV regions but not in SN or BB, resulting in increased dispersion of repolarization in right and decreased in left atria. Propranolol, atropine and losartan failed to alter the decrease in repolarization induced by BPP whereas apamin, nifedipine and ryanodine prevented BPP effects. Before BPP, bigeminy did not induce arrhythmias in either atrium, but after BPP, bigeminy significantly increased the incidence of arrhythmias in the right atrium. CONCLUSIONS: BPP from foci outside the regions of dominant activation alters dispersion of atrial repolarization. Modulation of apamin-sensitive channels may contribute to the shortening of repolarization in CS and PV regions. Alterations of atrial repolarization gradient create an arrhythmogenic substrate and may be an early step in atrial electrophysiologic remodeling.

Dispersion in ventricular repolarization in the human, canine and porcine heart.

Dispersion in repolarization is important for the genesis of the T wave, and for the induction of reentrant arrhtyhmias. Because the T wave differs across species our intent here is to review the epicardial, endocardial and transmural repolarization patterns contributing to repolarization in whole hearts from man, dog and pig. The major points we emphasize are: transmural repolarization time gradients are small and are directed from endocardium (early) to epicardium (late) in dog and human and from epicardium to endocardium in pig; the right ventricle tends to repolarize before the left ventricle and this difference is larger in dog than in pig; a negative relation between the activation times and the repolarization times is rare in man, and absent in dog and pig. Given the above, a large dispersion in repolarization between two myocardial areas does not lead to arrhythmias without a premature beat. Moreover, an arrhythmic substrate can be identified by a metric composed of activation times and repolarization times, the reentry vulnerability index, RVI.

Increased Late Sodium Current Contributes to the Electrophysiological Effects of Chronic, but Not Acute, Dofetilide Administration.

BACKGROUND: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. METHODS AND RESULTS: We continuously infused dofetilide (6-9 µg/kg bolus+6-9 µg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. CONCLUSIONS: Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.

Reentrant circuits in the canine atrioventricular node during atrial and ventricular echoes: electrophysiological and histological correlation.

BACKGROUND: The anatomic-electrophysiological correlation of AV nodal reentry is unclear. To localize reentrant circuits during atrial and ventricular echoes and to characterize sites of slow conduction and block, we correlated histology with electrophysiology of the AV node. METHODS AND RESULTS: In 10 isolated dog hearts, extracellular electrical activity was recorded in Koch's triangle at 208 or 247 sites (interelectrode distance, 0.5 and 0.3 mm) after removal of 0.7 to 1.5 mm of overlying atrial tissue. Resection did not affect refractory periods. Five hearts were subjected to histology. Complete atrial echoes were induced in 1 heart, incomplete atrial echoes in 5 hearts. Unidirectional conduction block occurred at the atrial-transitional cell junction in the superior area. Zones of slow conduction arose at the atrial-transitional or the transitional-compact node junction in the inferior area. Complete reentrant circuits of ventricular echoes were obtained in 5 hearts. Unidirectional conduction block occurred at the compact node-transitional cell junction in the superior area. Localized zones of slow conduction arose at the junctions between the different types of tissue in the inferior area. CONCLUSIONS: In the dog heart, tissue architecture and functional dissociation between the inferior and the superior region of the AV node enable dual physiology and reentry. Slow conduction and functional conduction block occur at the junctions between the different types of tissue in the AV nodal area. Atrial echoes were enabled by conduction block at the atrial-transitional cell junction, whereas during ventricular echoes conduction block occurred at the compact node-transitional cell junction.

Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation.

BACKGROUND: Paroxysmal atrial fibrillation in patients is often initiated by foci in the pulmonary veins. The mechanism of these initiating arrhythmias is unknown. The aim of this study was to determine electrophysiological characteristics of canine pulmonary veins that may predispose to initiating arrhythmias. METHODS AND RESULTS: Extracellular recordings were obtained from the luminal side of 9 pulmonary veins in 6 Langendorff-perfused dog hearts after the veins were incised from the severed end to the ostium. Pulmonary veins were paced at the distal end, the ostium, and an intermediate site. During basic and premature stimulation, extracellular electrical activity was recorded with a grid electrode that harbored 247 electrode terminals. In 4 hearts, intracellular electrograms were recorded with microelectrodes. Myocyte arrangement immediately beneath the venous walls was determined by histological analysis in 3 hearts. Extracellular mapping revealed slow and complex conduction in all pulmonary veins. Activation delay after premature stimulation could be as long as 96 ms over a distance of 3 mm. Action potential duration was shorter at the distal end of the veins than at the orifice. No evidence for automaticity or triggered activity was found. Histological investigation revealed complex arrangements of myocardial fibers that often showed abrupt changes in fiber direction and short fibers arranged in mixed direction. CONCLUSIONS: Zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation. This architecture of muscular sleeves in the pulmonary veins may facilitate reentry and arrhythmias associated with ectopic activity.

Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates.

BACKGROUND: We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates. METHODS AND RESULTS: An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2. CONCLUSIONS: A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.

A brief history of sudden cardiac death and its therapy.

At the end of the 19th century, there was both experimental and clinical evidence that coronary artery obstruction causes ventricular fibrillation and sudden death and that fibrillation could be terminated by electric shocks. The dominant figure at that time was McWilliam, who in 1923 complained that "little attention was given to the new view for many years." This remained so for many decades. It was not until the 1960s that the medical profession became aware of the magnitude of the problem of sudden death and began to install coronary care units where arrhythmias could be monitored and prompt defibrillation could be delivered. This approach was pioneered by Julian in 1961. Milestones that allowed this development were open-chest defibrillation by Beck, closed-chest defibrillation by Zoll, cardiac massage by Kouwenhoven et al., and development of the DC defibrillator by Lown. In 1980, Mirowski et al. implanted the first implantable cardioverter defibrillator (ICD) in a patient. Thereafter, the use of the ICD increased exponentially. Several randomized trials, largely in patients with coronary artery disease and left ventricular dysfunction or in patients with documented lethal arrhythmias, showed beyond doubt that the ICD is superior to antiarrhythmic drug therapy in preventing sudden death, although a number of trials showed no effect. Trials on antiarrhythmic drugs were disappointing. Sodium channel blockers and "pure" potassium channel blockers actually increase mortality, calcium channel blockers have no effect, and, although amiodarone reduces arrhythmic death, it had no effect on total mortality in the 2 largest trials. Only the beta-blockers have been proven to reduce the incidence of sudden death, but their effect appears not to be related to the suppression of arrhythmias but rather to the reduction in sinus rate. Drugs that prevent ischemic events, or lessen their impact, such as anticoagulants, statins, angiotensin-converting enzyme inhibitors, and aldosteron antagonists, all reduce the incidence of sudden death.

Mechanical effects on arrhythmogenesis: from pipette to patient.

Mechanical stimuli delivered to the precordium can, if strong enough and timed at the beginning of the T-wave, induce ventricular premature beats or runs of ventricular tachycardia and even fibrillation. On the other hand, there are reports that a properly timed "chest thump" can terminate ventricular tachycardia, or can act as pacemaker stimuli during an episode of asystole. It is likely that in these cases mechanical energy is translated to an electrical stimulus. There are more subtle ways in which mechanical stimuli, mediated by stretch, can exert electrophysiological effects, and the most common name to describe these effects is mechanoelectrical feedback. Most studies have concentrated on acute stretch or dilatation, while the effects of chronic stretch, which may clinically be more important, are difficult to evaluate since they are accompanied by other factors, such as hypertrophy, heart failure, fibrosis, neurohumeral disturbances, and electrolyte abnormalities, all of which have arrhythmogenic effects. There are a number of ion channels that are activated following stretch. Stretch during diastole usually leads to a depolarization, resembling a delayed afterdepolarization, which may reach threshold and initiate a ventricular premature beat. Stretch during systole usually shortens the action potential, but action potential prolongation, resulting in early afterdepolarizations has been described as well. The arrhythmias during acute myocardial ischaemia occur in two phases: the 1A phase between 2 and 10 min following coronary artery occlusion, and the 1B phase between 18 and 30 min. Experiments will be described, indicating that the ventricular premature beats of the 1B phase, which may induce ventricular fibrillation, are caused by stretch of the border between ischaemic and normal myocardium. Briefly, 1B arrhythmias are much less frequent in the isolated perfused heart than in the heart in situ, but in working, ejecting isolated hearts, the number of 1B arrhythmias is similar to those in the in situ heart. The ventricular premature beats have a focal origin at the border, and they occur more often after a pause-induced potentiated contraction.

Electrophysiological changes in heart failure and their relationship to arrhythmogenesis.

This review focuses mainly on studies in non-ischemic animal models of heart failure. These animals develop ventricular arrhythmias, mostly non-sustained ventricular tachycardia, and often die suddenly. Clinical studies suggest that sudden death is due to ventricular tachycardia or fibrillation in about 50% of cases, the other half to bradyarrhythmias or electromechanical dissociation. Electrophysiologic changes in heart failure are not confined to the ventricles: the intrinsic sinus rate is reduced due to a downregulation of If and sensitivity to acetylcholine is enhanced by upregulation of the muscarinic receptor. Reduction of heart rate may be a protective mechanism since at rapid rates contractility is reduced and the likelihood for triggered activity due to delayed afterdepolarizations is enhanced. The beneficial effect of beta-adrenergic blockade in patients may be partly due to the reduction in sinus rate. Although the results of different studies often vary, the most consistent electrophysiological changes in the ventricles are prolongation of the action potential, especially at slow rates, a reduction in the transient outward current Ito, the rapid and slow components of the delayed rectifier Ikr and Iks, and the inward rectifier Ik1. Abnormalities in intracellular calcium handling play a major role in the genesis of delayed afterdepolarizations. Triggered activity based on delayed afterdepolarizations has been demonstrated in failing myocardium and are caused by spontaneous release of calcium from the sarcoplasmic reticulum (SR), especially in the presence of noradrenaline. Three factors combine to the enhanced propensity for the occurrence of delayed afterdepolarizations: (1) increased activity of the Na/Ca exchanger, (2) a reduced inward rectifier, (3) residual beta-adrenergic responsiveness required to raise the reduced sarcoplasmic calcium content to a level where spontaneous calcium release occurs. Early afterdepolarizations have also been demonstrated, especially in human myocytes from failing hearts in the presence of noradrenaline. Mapping experiments have shown that the ventricular arrhythmias are mainly due to non-reentrant mechanisms, most likely triggered activity based on delayed afterdepolarizations.