History of arrhythmias.

A historical overview is given on the techniques to record the electrical activity of the heart, some anatomical aspects relevant for the understanding of arrhythmias, general mechanisms of arrhythmias, mechanisms of some specific arrhythmias and nonpharmacological forms of therapy. The unravelling of arrhythmia mechanisms depends, of course, on the ability to record the electrical activity of the heart. It is therefore no surprise that following the construction of the string galvanometer by Einthoven in 1901, which allowed high-fidelity recording of the body surface electrocardiogram, the study of arrhythmias developed in an explosive way. Still, papers from McWilliam (1887), Garrey (1914) and Mines (1913, 1914) in which neither mechanical nor electrical activity was recorded provided crucial insights into re-entry as a mechanism for atrial and ventricular fibrillation, atrioventricular nodal re-entry and atrioventricular re-entrant tachycardia in hearts with an accessory atrioventricular connection. The components of the electrocardiogram, and of extracellular electrograms directly recorded from the heart, could only be well understood by comparing such registrations with recordings of transmembrane potentials. The first intracellular potentials were recorded with microelectrodes in 1949 by Coraboeuf and Weidmann. It is remarkable that the interpretation of extracellular electrograms was still controversial in the 1950s, and it was not until 1962 that Dower showed that the transmembrane action potential upstroke coincided with the steep negative deflection in the electrogram. For many decades, mapping of the spread of activation during an arrhythmia was performed with a "roving" electrode that was subsequently placed on different sites on the cardiac surface with a simultaneous recording of another signal as time reference. This method could only provide reliable information if the arrhythmia was strictly regular. When multiplexing systems became available in the late 1970s, and optical mapping in the 1980s, simultaneous registrations could be made from many sites. The analysis of atrial and ventricular fibrillation then became much more precise. The old question whether an arrhythmia is due to a focal or a re-entrant mechanism could be answered, and for atrial fibrillation, for instance, the answer is that both mechanisms may be operative. The road from understanding the mechanism of an arrhythmia to its successful therapy has been long: the studies of Mines in 1913 and 1914, microelectrode studies in animal preparations in the 1960s and 1970s, experimental and clinical demonstrations of initiation and termination of tachycardias by premature stimuli in the 1960s and 1970s, successful surgery in the 1980s, the development of external and implantable defibrillators in the 1960s and 1980s, and finally catheter ablation at the end of the previous century, with success rates that approach 99% for supraventricular tachycardias.

Changes in sinus node function in a rabbit model of heart failure with ventricular arrhythmias and sudden death.

BACKGROUND: Heart failure is associated with profound changes in the balance of the autonomic nervous system, such as vagal withdrawal and increased catecholamine levels. It is not known whether the intrinsic sinus node function changes during the progression of heart failure. METHODS AND RESULTS: We implanted transmitters for Holter recording in an established rabbit model of heart failure (n=9) and observed changes in sinus cycle length and the occurrence of arrhythmias during the progression of heart failure. The in vitro sinus cycle length and the responses to acetylcholine and norepinephrine in the isolated right atria were analyzed in 12 rabbits with heart failure and in 6 control rabbits. In vivo cycle length increased in some animals and decreased in others. Sudden death occurred in 3 of 9 rabbits. These rabbits had developed a shorter cycle length than the surviving rabbits. Ventricular tachycardias developed in all but 1 rabbit. The in vitro sinus cycle length increased in heart failure. The response to acetylcholine also increased in heart failure, whereas the response to norepinephrine was unchanged. CONCLUSIONS: Changes in intrinsic sinus node function during the progression of heart failure cannot explain the observed decreases in heart rate variability and/or baroreflex sensitivity in this disease, because increased responsiveness to acetylcholine would be expected to cause the opposite.

Reentrant pathway during ventricular echoes is confined to the atrioventricular node : high-resolution mapping and dissection of the triangle of koch in isolated, perfused canine hearts.

Background-During ventricular echoes, reentrant excitation is supposed to involve 2 functionally distinct pathways in the atrioventricular (AV) nodal area. The exact pathway of reentrant excitation is unknown. The objectives of this study were to analyze electrical activity in the AV nodal area after ventricular stimulation and during ventricular echoes and to assess the role of perinodal atrial tissue in AV nodal reentry. Methods and Results-In 16 isolated, blood-perfused canine hearts, multiterminal electrodes were used to map electrical activity in Koch's triangle after ventricular stimulation and during ventricular echoes. The subendocardial cell layers were chemically destroyed in 3 hearts. Incisions in the posterior approach to the compact node were made in 6 hearts. The apex of the triangle of Koch was surgically dissociated from the perinodal atrial tissue in 5 hearts. Retrograde atrial activation occurred via 2 distinct endocardial exit sites. Ventricular echoes could be induced in all hearts irrespective of the atrial activation pattern. Simultaneous retrograde activation of both exit sites often preceded reciprocation. Ventricular echoes were demonstrable after chemical destruction of the endocardium and after surgical dissociation of the perinodal atrial tissue from the AV node. Conclusions-Our data show that the reentrant pathway during ventricular echoes is confined to the AV node. The tissue that connects the node to the endocardial exit sites has to be excluded from the reentrant circuit responsible for single echoes.

Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators.

BACKGROUND: Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. METHODS AND RESULTS: A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. CONCLUSIONS: These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.

Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis.

BACKGROUND: Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. METHODS AND RESULTS: High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. CONCLUSIONS: The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

Endocardial mapping by simultaneous recording of endocardial electrograms during cardiac surgery for ventricular aneurysm.

A technique was developed for the simultaneous recording of 30 endocardial electrograms during cardiac surgery in patients undergoing aneurysmectomy or endocardial resection, or both, for medically intractable ventricular tachycardia. An inflatable balloon covered with 30 terminals at distances of 1.5 to 2 cm was used to record from the entire endocardial surface; a smaller silicone rubber sheet with 30 terminals at distances of 0.7 cm was used to obtain a better spatial resolution. The multielectrodes were inserted into the left ventricular cavity by way of an incision in the aneurysm. A transportable minicomputer was used for the acquisition and analysis of the signals. After initiation of ventricular tachycardia by programmed stimulation, signals of a 1.5 second period were stored and analyzed. The earliest activated terminal could be determined within 2 to 5 minutes. The technique was applied in 32 patients and proved especially useful in those patients in whom sustained tachycardia could not be evoked and in whom conventional mapping with a roving electrode would have been impossible or very time consuming. In all patients, the isochronic maps showed that the ectopic impulses originated from a rather localized area and no evidence was found for large endocardial circus movements, thereby excluding these as a mechanism underlying the tachycardia. Isochronic maps, depicting activation sequences during consecutive ectopic beats with the same QRS morphologic features, showed the same site of origin in all but six patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial).

OBJECTIVES: This substudy tested a prospective hypothesis that European Myocardial Infarct Amiodarone Trial (EMIAT) patients with depressed heart rate variability (HRV) benefit from amiodarone treatment. BACKGROUND: The EMIAT randomized 1,486 survivors of acute myocardial infarction (MI) aged < or =75 years with left ventricular ejection fraction (LVEF) < or =40% to amiodarone or placebo. Despite a reduction of arrhythmic mortality on amiodarone, all-cause mortality was not changed. METHODS: Heart rate variability was assessed from prerandomization 24-h Holter tapes in 1,216 patients (606 on amiodarone). Two definitions of depressed HRV were used: standard deviation of normal to normal intervals (SDNN) < or =50 ms and HRV index < or =20 units. The survival of patients with depressed HRV was compared in the placebo and amiodarone arms. A retrospective analysis investigated the prospective dichotomy limits. All tests were repeated in five subpopulations: patients with first MI, patients on beta-adrenergic blocking agents, patients with LVEF < or =30%, patients with Holter arrhythmia and patients with baseline heart rate > or =75 beats/min. RESULTS: Centralized Holter processing produced artificially high SDNN but accurate HRV index values. Heart rate variability index was < or =20 U in 363 (29.9%) patients (183 on amiodarone) with all-cause mortality 22.8% on placebo and 17.5% on amiodarone (23.2% reduction, p = 0.24) and cardiac arrhythmic mortality 12.8% on placebo and 4.4% on amiodarone (66% reduction, p = 0.0054). Among patients with prospectively defined depressed HRV, the largest reduction of all-cause mortality was in patients with first MI (placebo 17.9%, amiodarone 10.3%, 42.5% reduction, p = 0.079) and in patients with heart rate < or =75 beats/min (placebo 29.0%, amiodarone 19.3%, 33.7% reduction, p = 0.075). Among patients with first MI and depressed HRV, amiodarone treatment was an independent predictor of survival in a multivariate Cox analysis. The retrospective analysis found a larger reduction of mortality on amiodarone in 313 (25.7%) patients with HRV index < or =19 U: 23.9% on placebo and 17.1% on amiodarone (28.4% reduction, p = 0.15). This was more expressed in patients with first MI: 49.4% mortality reduction on amiodarone (p = 0.046), on beta-blockers: 69.0% reduction (p = 0.047) and with heart rate > or =75 beats/min: 37.9% reduction (p = 0.054). CONCLUSION: Measurement of HRV in a large set of centrally processed Holter recordings is feasible with robust methods of assessment. Patients with LVEF < or =40% and depressed HRV benefit from prophylactic antiarrhythmic treatment with amiodarone. However, this finding needs confirmation in an independent data set before clinical practice is changed.

Double component action potentials in the posterior approach to the atrioventricular node: do they reflect activation delay in the slow pathway?

OBJECTIVES: The aim of the study was to elucidate the mechanism of double component action potentials in the posterior approach to the atrioventricular (AV) junctional area. BACKGROUND: Double component action potentials are often associated with activation delay and therefore might be a marker of the location of the so-called slow pathway. METHODS: The AV junction was scanned for double component action potentials in Langendorff perfused pig and dog hearts, using conventional microelectrode recordings. Characteristics of these action potentials were investigated during basic and premature stimulation and cooling of the anterior approach to the node. RESULTS: During basic stimulation, double component action potentials were recorded in 19 out of 20 hearts. In 74% of these cases, the second component occurred before the His deflection. During premature stimulation this percentage was 50%, while delay between the two components always increased. In 80% of the cases, the amplitude of the two components became <20 mV during progressive shortening of the coupling interval. The first component was generated by activation in superficial layers, the second one by activation in deeper layers. Cooling of the anterior region revealed that the second component was caused by activation arriving from the anterior region. CONCLUSIONS: Double component action potentials in the posterior approach to the AV node are generated by the asynchronous arrival of wave fronts in different, weakly coupled layers or by the summation of asynchronously arriving wave fronts. They are not always associated with activation delay in the slow pathway.

Fractionated electrograms in dilated cardiomyopathy: origin and relation to abnormal conduction.

OBJECTIVES: We sought to investigate the origin of the fractionated electrogram and its relations to abnormal conduction in cardiomyopathic myocardium. BACKGROUND: Patients with dilated cardiomyopathy have a high incidence of ventricular tachycardias. Electrograms recorded in these patients are often fractionated. METHODS: High resolution mapping (200-microM interelectrode distance) of the electrical activity was carried out in 11 superfused papillary muscles and 6 trabeculae from 7 patients who underwent heart transplantation because of dilated cardiomyopathy. Similar measurements were taken in four papillary muscles from dog hearts in which electrical barriers had been artificially made. Ten human preparations were studied histologically. RESULTS: All preparations revealed sites with fractionated electrograms. In three human preparations, activation patterns showed a discernible line of activation block running parallel to the fiber direction. Fractionated electrograms were recorded at sites contiguous to the line of block. In five preparations, fractionated electrograms were recorded at sites where lines of block were not identified. In these preparations, electrical barriers consisted of short stretches of fibrous tissue. In the remaining nine preparations, fractionated electrograms were recorded, both from sites contiguous to distinct obstacles and sites without evidence of a barrier. CONCLUSIONS: Our observations showed that fractionated electrograms recorded in myocardium damaged by cardiomyopathy were due to both distinct, long strands and short stretches of fibrous tissue. Delayed conduction was caused by curvation of activation around the distinct lines of block and by the wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy.

Increased dispersion of "refractoriness" in patients with idiopathic paroxysmal atrial fibrillation.

The average interval between local depolarizations during atrial fibrillation, the so-called atrial fibrillation interval, was used as an index for local "refractoriness." This was based on the assumption that during fibrillation, cells are reexcited as soon as their refractory period ends. A very good correlation was found between refractory periods determined with the extrastimulus technique at a basic cycle length of 400 ms and atrial fibrillation intervals measured at the same epicardial sites of the right atrium. This new technique was used to assess dispersion in atrial fibrillation intervals in 10 patients with idiopathic paroxysmal atrial fibrillation and in a control group of 6 patients who were undergoing cardiac surgery. After a routine median sternotomy a multiterminal grid with up to 40 electrodes was placed over the right atrium, and atrial fibrillation was induced by premature stimulation. The average fibrillation interval in the test group, recorded at 247 sites, was 152 +/- 3 ms and that in the control group, recorded at 118 sites, was 176 +/- 8.1 ms (p less than 0.05). Dispersion in atrial fibrillation intervals, defined as the variance of the fibrillation intervals at all the recording sites, was three times larger in the group with paroxysmal atrial fibrillation than in the control group. This study suggests that both a shorter refractory period and a larger dispersion in refractoriness are responsible for the recurrence of atrial fibrillation.

Value of body surface mapping in localizing the site of origin of ventricular tachycardia in patients with previous myocardial infarction.

OBJECTIVES: This study examined the performance of the 62-lead body surface electrocardiogram (ECG) in identifying the site of origin of ventricular tachycardia in patients with a previous myocardial infarction. BACKGROUND: Because the accuracy of ECG localization of ventricular tachycardia using standard 12-lead recordings is restricted to the identification of rather large ventricular areas, application of multiple torso lead recordings may augment the resolving power of the surface ECG and result in more discrete localization of arrhythmogenic foci. METHODS: Thirty-two patients were selected for electrophysiologically guided ablative therapy for drug-resistant postinfarction ventricular tachycardia. In these patients, QRS integral maps of distinct monomorphic ventricular tachycardia configurations were correlated with a previously generated infarct-specific reference data base of paced QRS integral maps. Each paced pattern in the data base corresponded with ectopic endocardial impulse formation at 1 of 18 or 22 discrete segments of the left ventricle with a previous anterior or inferior myocardial infarction, respectively. Electrocardiographic localization was compared with the results obtained during intraoperative or catheter endocardial activation sequence mapping. RESULTS: Body surface mapping was performed during 101 distinct ventricular tachycardia configurations. Compared with the activation mapping data that were acquired in 64 of 101 ventricular tachycardias, body surface mapping identified the correct segment of origin in 40 (62%) of 64 tachycardias, a segment adjacent to the segment where the arrhythmia actually originated in 19 (30%) of 64 tachycardias and a segment disparate from the actual segment of origin in 5 (8%) of 64 tachycardias. With respect to infarct location, the segment of origin was correctly identified in 28 (60%) of 47 ventricular tachycardias in patients with anterior, 7 (70%) of 10 tachycardias in patients with inferior and 5 (71%) of 7 tachycardias in patients with combined anterior and inferior myocardial infarction. CONCLUSIONS: This study shows that body surface mapping enables precise localization of the origin of postinfarction ventricular tachycardia in 62% and regional approximation in 30% of tachycardias. The multiple-lead ECG may be used to guide and shorten catheter-based mapping procedures during ventricular tachycardia and to provide relevant information on the origin of tachycardias that cannot be mapped with conventional single-site mapping techniques because of unfavorable characteristics.

Anisotropic conduction in the triangle of Koch of mammalian hearts: electrophysiologic and anatomic correlations.

OBJECTIVES: The purpose of this study was to characterize anisotropy in the triangle of Koch by relating electrophysiology with anatomy. BACKGROUND: Atrioventricular (AV) node fast and slow pathway characteristics have been suggested to be due to nonuniform anisotropy in the triangle of Koch. METHODS: During atrial pacing, we determined the electrical activity within the triangle of Koch by multichannel mapping in 11 isolated hearts from pigs and dogs. Orientation of fibers was determined in nine hearts. RESULTS: Fibers were parallel to the tricuspid valve annulus (TVA) in the posterior part of the triangle of Koch. In the midjunctional area, the direction of the fibers changed to an orientation perpendicular to the TVA. During stimulation from posterior and anterior sites, activation proceeded parallel to the TVA at a high conduction velocity (0.5 to 0.6 m/s). During stimulation from sites near the coronary sinus, a narrow zone of slow conduction occurred in the posterior part of the triangle of Koch where activation proceeded perpendicular to the fiber orientation. Above and below this zone, conduction was fast and parallel to the annulus. After premature stimulation, conduction delay in the triangle of Koch increased by 4 to 21 ms; in contrast, the AH interval increased by 80 to 210 ms. CONCLUSIONS: Data support the concept of anisotropic conduction in the triangle of Koch. Activation maps correlated well with the arrangement of superficial atrial fibers. Comparison of conduction delay in the triangle of Koch and AH delay after premature stimulation disproves that anisotropy in the superficial layers plays an important role in slow AV conduction.

Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: role of the arrangement of surviving cardiac fibers.

Electrophysiologic and histologic studies were performed on Langendorff-perfused human hearts from patients who underwent heart transplantation because of extensive infarction. In nine hearts, 15 sustained ventricular tachycardias could be induced by programmed stimulation. In all hearts, mapping of epicardial and endocardial electrical activity during tachycardia was carried out. Histologic examination of the infarcted area between the site of latest activation of one cycle and the site of earliest activation of the next cycle revealed zones of viable myocardial tissue. In two hearts in which the time gap between latest and earliest activation was small, surviving myocardial tissue constituted a continuous tract that traversed the infarct. In three other hearts in which the time gap was large, surviving tissue consisted of parallel bundles that coursed separately over a few hundred micrometers, then merged into a single bundle and finally branched again. The direction of the fibers within the bundles was perpendicular to the direction of the activation front in that area. A similar type of inhomogeneous anisotrophy and activation delay was found in an infarcted papillary muscle removed from one of the explanted hearts and studied in a tissue bath during basic stimulation. Histologic examination of this preparation revealed that the delay was caused by a zigzag route of activation over branching and merging bundles of surviving myocytes separated by connective tissue.

Effects of intracavitary blood flow and electrode-target distance on radiofrequency power required for transient conduction block in a Langendorff-perfused canine model.

OBJECTIVES: We sought to quantify the effects of electrode-target distance and intracavitary blood flow on radiofrequency (RF) power required to induce transient conduction block, using a Langendorff-perfused canine ablation model. BACKGROUND: Given the thermally mediated nature of RF catheter ablation, cooling effects of intracavitary blood flow and electrode-target distance will influence lesion extension and geometry and electrophysiologic effects. METHODS: In eight Langendorff-perfused canine hearts, the right ventricular free wall was opened, and the right bundle branch (RBB) carefully localized by multielectrode activation mapping. The right atrium was paced at cycle length of 500 ms. Proximal and distal electrodes were attached at the endocardial aspect of the RBB, and the perfused heart was submerged in heparinized blood at 37 degrees C. A standard 4-mm tip ablation electrode was positioned at a constant contact pressure of 5 g between the two electrodes at the site of maximal RBB potential (0 mm) and 2 and 4 mm distant from this site along a line perpendicular to the RBB. RF pulses (500 kHz) were delivered for 30 s at 0.5-W increments until transient bundle branch block. In four hearts, intracavitary flow was simulated by directing a 30-cm/s jet of blood parallel to the septum at the ablation site, and the protocol was repeated to assess the effects on power required for block. In one heart, the effect of variable flow was assessed (0, 15 and 30 cm/s). RESULTS: An exponential distance-related increase was seen in power required for block, from 1.8 +/- 0.9 W (mean +/- SD) at 0 mm to 5.4 +/- 1.1 W at 4 mm. In the presence of 30-cm/s flow, an increase to 3.9 +/- 0.8 W at 0 mm and 13.1 +/- 2.4 W at 2 mm was seen. At 4 mm, coagulum formation invariably occurred before block could be induced. For 15-cm/s flow, less power was required: 3 and 7 W at 0 and 2 mm, respectively. CONCLUSIONS: Increasing the ablation electrode-target distance causes an exponential increase in power required for conduction block; this relation is profoundly influenced by intracavitary flow. Given the geometry of endomyocardial RF lesions, these findings are particularly relevant for directly subendocardial ablation targets.

Macroreentry in the infarcted human heart: the mechanism of ventricular tachycardias with a "focal" activation pattern.

Endocardial mapping of electrical activity was carried out in 150 patients to guide antiarrhythmic surgery for drug-resistant ventricular tachycardia in the chronic phase of myocardial infarction. In 20 of these patients, the activation pattern of 27 distinct tachycardias was focal and diastolic potentials were recorded at three or more sites. In 26 tachycardias, the sequence of diastolic potentials progressed from the area of latest activation of one cycle toward the "origin" of the next cycle. In two patients, the heart was stimulated during tachycardia, resulting in entrainment of the tachycardia in both. Late potentials were recorded during entrainment at sites where diastolic potentials occurred during tachycardia. In 11 of the 20 patients, endocardial mapping was performed during sinus rhythm. In four of these, late potentials were observed during sinus rhythm at sites where diastolic potentials were recorded during tachycardia. In two patients without late potentials during sinus rhythm, late potentials were observed during stimulation and induced ectopic beats. The results support the concept that the mechanism of several of these tachycardias is based on reentry in a macrocircuit comprising a tract of surviving tissue traversing the infarct and the remaining healthy tissue. They also indicate that the absence of late potentials during sinus rhythm does not guarantee the absence of arrhythmogenic pathways.

Determinants of prognosis in symptomatic ventricular tachycardia or ventricular fibrillation late after myocardial infarction. The Dutch Ventricular Tachycardia Study Group of the Interuniversity Cardiology Institute of The Netherlands.

In a multicenter study, 390 patients with sustained symptomatic ventricular tachycardia or ventricular fibrillation late after acute myocardial infarction were prospectively followed up to assess determinants of mortality and recurrence of arrhythmic events. Patients were given standard antiarrhythmic treatment, which consisted primarily of drug therapy. During a mean follow-up period of 1.9 years, 133 patients (34%) died; arrhythmic events and heart failure were the most common cause of death (41 patients [11%] died suddenly, 31 [8%] died because of recurrent ventricular tachycardia or ventricular fibrillation and 23 [6%] died of heart failure). One hundred ninety-two patients (49%) had at least one recurrent arrhythmic event; 85% of first recurrent arrhythmic events were nonfatal. Multivariate analysis of data from patients who developed the arrhythmia less than 6 weeks after infarction identified five variables as independent determinants of total mortality: 1) age greater than 70 years (risk ratio 4.5); 2) Killip class III or IV in the subacute phase of infarction (risk ratio 3.5); 3) cardiac arrest during the index arrhythmia (risk ratio 1.7); 4) anterior infarction (risk ratio 2.2); and 5) multiple previous infarctions (risk ratio 1.6). Multivariate analysis of data from patients developing the arrhythmia greater than 6 weeks after infarction identified four variables as independently predictive of total mortality: 1) Q wave infarction (risk ratio 2.1); 2) cardiac arrest during the index arrhythmia (risk ratio 1.7); 3) Killip class III or IV in the subacute phase of infarction (risk ratio 1.7); and 4) multiple previous infarctions (risk ratio 1.4). The results of the two multivariate analyses were used in a model for prediction of mortality at 1 year. The average predicted mortality rate varied considerably according to the model: for 243 patients (62%) with the lowest risk, it was 13%, corresponding to an observed mortality rate of 12%; for 92 patients (24%) with intermediate risk, it was 27%, corresponding to an observed rate of 28%; for 55 patients (14%) with the highest risk, it was 64%, corresponding to an observed rate of 54%. This study shows that patients with symptomatic ventricular tachycardia or ventricular fibrillation late after myocardial infarction who are given standard antiarrhythmic treatment have a high mortality rate. The predictive model presented identifies patients at low, intermediate and high risk of death and can be of help in designing the appropriate diagnostic and therapeutic strategy for the individual patient.

Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts.

OBJECTIVE: The aim of the study was to assess the occurrence of triggered activity and automaticity in ventricular trabeculae from failing human hearts and normal and failing rabbit hearts during exposure to a normal and altered extracellular environment. METHODS: Ventricular trabeculae were harvested from failing human hearts (from patients undergoing cardiac transplantation) and from normal and failing rabbit hearts (combined volume and pressure overload). Trabeculae were superfused with normal Tyrode solution followed by a modified Tyrode solution, which mimicked the extracellular milieu in patients with severe heart failure. Modified Tyrode solution contained low potassium (3.0 mM), low magnesium (0.4 mM), and noradrenaline (1 microM). RESULTS: During superfusion with normal Tyrode solution, early afterdepolarisations, delayed afterdepolarisations, and automaticity were not observed in trabeculae from failing hearts. In the modified Tyrode solution, early afterdepolarisations could be induced in 26% of control rabbit and 30% of failing rabbit trabeculae, but never in human trabeculae. During superfusion with the modified solution delayed afterdepolarisations or triggered activity could be induced in 50% of the human failing trabeculae, in 43% of the failing rabbit trabeculae, and in 9% of the normal rabbit trabeculae (p < 0.01); automaticity was observed in 44% of the human trabeculae, and in 7% of the failing rabbit trabeculae, but in none of the control rabbit trabeculae. In failing rabbit myocardium action potential duration was prolonged at cycle lengths > or = 350 ms, but not at shorter cycle lengths. CONCLUSIONS: Delayed afterdepolarisations and automaticity, but not early afterdepolarisations, occur more frequently in myocardium from failing hearts, but only during superfusion with a modified Tyrode solution. This emphasises that the extracellular environment is important with respect to arrhythmogenesis in heart failure, apart from the fixed cellular defect due to heart failure per se. Prolongation of the action potential in failing hearts does not occur at physiological and higher heart rates and therefore cannot be regarded as a protective factor in the prevention of reentrant arrhythmias. The rate of triggered and automatic rhythms was slow. Therefore these mechanisms cannot be responsible for clinical ventricular tachycardias or fibrillation, but may serve as triggers for reentrant arrhythmias.

Dispersion of refractoriness in normal and ischaemic canine ventricle: effects of sympathetic stimulation.

OBJECTIVE: Dispersion in refractoriness is considered a major factor in induction and persistence of cardiac arrhythmias. The sympathetic nervous system is known to modulate refractoriness. An index of refractoriness has therefore been assessed in normal and ischaemic myocardium simultaneously at multiple sites, with and without sympathetic stimulation. METHODS: In six dogs on total cardiopulmonary bypass the average interval between local activations was measured during artificially induced ventricular fibrillation from extracellular electrograms simultaneously recorded from 32 ventricular sites. These local ventricular fibrillation intervals may be used as an index of local refractoriness. RESULTS: During regional ischaemia, ventricular fibrillation intervals of ischaemic sites could prolong by up to 60% after 3 min following coronary occlusion. Left stellate ganglion stimulation during ischaemia produced either no response or prolonged the ventricular fibrillation intervals even further at ischaemic sites, whereas ventricular fibrillation intervals at non-ischaemic sites shortened. Dispersion in refractoriness across the ischaemic border increased by 14-59% in individual hearts following sympathetic stimulation during acute, regional ischaemia. CONCLUSIONS: Due to opposite effects on normal and ischaemic myocardium, sympathetic stimulation increases the difference in refractoriness over the ischaemic border. This may enhance the chance for regional conduction block and the propensity to re-entrant arrhythmias.

Ischaemic preconditioning delays ischaemia induced cellular electrical uncoupling in rabbit myocardium by activation of ATP sensitive potassium channels.

OBJECTIVE: The aim was to examine whether ischaemic preconditioning delays the onset of cellular electrical uncoupling during ischaemia, and whether the effect of preconditioning is mediated by the activation of ATP sensitive K+ channels (IK-ATP). METHODS: Onset of uncoupling, action potential duration (APD80), and conduction velocity were measured in an isolated perfused rabbit papillary muscle. Preconditioning consisted of 10 min occlusion and 10 min reperfusion prior to 40 min sustained ischaemia. Five groups were studied: (1) control (sustained ischaemia only); (2) preconditioning; (3) preconditioning with 20 microM glibenclamide, a blocker of IK-ATP, added for 10 min during the reperfusion period; (4) sustained ischaemia after 15 min perfusion with 20 microM cromakalim (BRL 34915), an opener of IK-ATP; (5) sustained ischaemia after 10 min perfusion with 20 microM glibenclamide without preconditioning. RESULTS: Uncoupling started at 15.0(SEM 0.7) min of ischaemia in the control group and at 22.8(1.5) min after preconditioning (p < 0.001 v control group). Blocking IK-ATP during the preconditioning protocol with glibenclamide abolished the delay of uncoupling: onset was at 14.7(1.2) min. Activation of IK-ATP with cromakalim resulted in uncoupling at 23.3(1.9) min (p < 0.002 v control). Glibenclamide without preconditioning had no effect on uncoupling: onset was at 15.6(1.0) min. APD80 during ischaemia was significantly shorter in the preconditioning and cromakalim groups than in the control group from 5 min of ischaemia onward. In the preconditioning+glibenclamide group and the glibenclamide group APD80 was at no point significantly different from the control group. Conduction velocity during ischaemia decreased to about 70% of baseline after 10 min and was not different between the five groups. CONCLUSIONS: (1) Preconditioning delays the onset of electrical uncoupling; (2) the protective effect of preconditioning may be caused by activation of the IK-ATP channel; (3) the protective effect is associated with reduction of action potential duration, but not with changes of conduction velocity.

Interaction of sympathetic and parasympathetic nervous system on ventricular refractoriness assessed by local fibrillation intervals in the canine heart.

OBJECTIVE: The aim was to assess the effects of autonomic nerve stimulation on local ventricular refractoriness by measuring local ventricular fibrillation intervals. METHODS: In 10 dogs on cardiopulmonary bypass, ventricular fibrillation intervals were recorded simultaneously at up to 32 sites before and after neural stimulation. In four dogs (group 1) the response to bilateral stellate ganglion stimulation was measured before and after bilateral cervical vagotomy. In three dogs (group 2) bilateral stellate ganglion stimulation, vagal nerve stimulation, and combined vagal and stellate ganglia stimulation were performed. In three dogs (group 3) the same protocol was applied after total decentralisation of the autonomic nervous system. RESULTS: Bilateral stellate ganglion stimulation shortened the ventricular fibrillation interval at 44-50% of myocardial sites before and after vagotomy, whereas prolongation of the interval was observed at 14-18% of the sites. At higher stimulus strength shortening of the interval was measured at 85% of the sites in the intact and decentralised groups. No prolongation was observed. The shortening was largest in the decentralised group (11.1 ms). Dispersion in refractoriness increased in hearts from all groups, but not in each individual heart. Left, right, or bilateral vagal stimulation was without effect at about 75% of the tested sites. The fact that the response to autonomic nerve stimulation varies from site to site warrants our approach of simultaneous recordings at multiple sites. Dispersion in refractoriness was not affected by vagal stimulation. Combined autonomic stimulation had approximately the same effect on dispersion in refractoriness as bilateral stellate ganglion stimulation alone. However, vagal stimulation attenuated the responses to bilateral stellate ganglion stimulation by some 20% in the decentralised group. CONCLUSIONS: Vagal stimulation has minor effects on ventricular refractoriness, but this is not due to sparse innervation, since vagal stimulation is able to mitigate the effects of sympathetic stimulation in decentralised hearts.