J. M. T. de Bakker

Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation.

In this report we describe electrophysiologic and histologic findings in hearts and endocardially resected preparations from patients with sustained ventricular tachycardias in the chronic phase of myocardial infarction. We recorded simultaneously from 64 endocardial sites during tachycardia in 72 patients that were operated on for medically intractable ventricular tachycardias. Two other patients underwent heart transplantation, and mapping was performed on the explanted isolated heart connected to a Langendorff perfusion set-up. During operation 139 tachycardias with different morphologies could be induced. Although the majority of evidence supports the concept of a reentrant mechanism for these tachycardias, we found that 105 tachycardias appeared to arise at a focal area of less than 1.4 cm2. In only three cases macroreentry around the infarction scar could be detected. Of 21 tachycardias in which the origin appeared to be focal, earliest subendocardial activation was preceded by discrete electrograms of low amplitude (presystolic activity). In three tachycardias presystolic activity was detected at several sites, permitting reconstruction of its route. Histology of the endocardial resected preparation in one of these cases revealed separate zones of viable myocardial fibers in areas in which presystolic activity was recorded. These zones were located intramurally and subendocardially, supporting the concept that reentry occurred via isolated bundles of surviving myocytes at the border of the infarct and the larger subendocardial muscle mass. Conduction velocity through the isolated tracts was on the order of 25 cm/sec. Similar reentrant pathways were found in the two isolated hearts. Extracellular and intracellular recordings were made from 20 endocardial preparations that were excised from areas in which tachycardia originated. Preparations were superfused in a tissue bath. These experiments showed that action potentials were usually close to normal, but occasionally action potentials with reduced amplitude and slow upstrokes were found. In addition, there were cells that exhibited both fast and slow upstrokes, depending on the direction of the wavefront. Histology of seven resected preparations and the isolated hearts showed subendocardially as well as intramurally located zones of viable myocardium. Fractionation of extracellular electrograms and slow conduction were found in areas where surviving muscle fibers and strands of fibrous tissue were interwoven, and in zones where muscle fibers were oriented in parallel but isolated by strands of connective tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Slow conduction in the infarcted human heart. 'Zigzag' course of activation.

BACKGROUNDnVentricular tachycardias occurring in the chronic phase of myocardial infarction are caused by reentry. Areas of slow conduction, facilitating reentry, are often found in the infarcted zone. The purpose of this study was to elucidate the mechanism of slow conduction in the chronic infarcted human heart.nnnMETHODS AND RESULTSnSpread of activation was studied in infarcted papillary muscles from hearts of patients who underwent heart transplantation because of infarction. Recordings were carried out on 10 papillary muscles that were superfused in a tissue bath. High-resolution mapping was performed in areas revealing slow conduction. Activation delay between sites perpendicular to the fiber direction and 1.4 mm apart could be as long as 45 milliseconds. Analysis of activation times revealed that activation spread in tracts parallel to the fiber direction. Conduction velocity in the tracts was between 0.6 and 1 m/s. Although tracts were separated from each other over distances up to 8 mm, they often connected with each other at one or more sites, forming a complex network of connected tracts. In this network, wave fronts could travel perpendicular to the fiber direction. Separation of tracts was due to collagenous septa. At sites where tracts were interconnected, the collagenous barriers were interrupted.nnnCONCLUSIONSnSlow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by a zigzag course of activation at high speed. Activation proceeds along pathways lengthened by branching and merging bundles of surviving myocytes ensheathed by collagenous septa.

Origin and significance of double potentials near the atrioventricular node. Correlation of extracellular potentials, intracellular potentials, and histology.

BACKGROUNDnAtrioventricular junctional (AV nodal) reentrant tachycardia can be cured by catheter ablation of the slow pathway, which is part of the reentrant circuit. Previous work has suggested that extracellular double potentials may help identify the site of the slow pathway, but the origin and significance of these potentials are controversial. The aim of this study was to identify the source of these potentials.nnnMETHODS AND RESULTSnStudies were performed in isolated, blood-perfused porcine (n = 8) and canine (n = 4) hearts. Several methods were used to identify the origin of potentials: microelectrode recording, extracellular mapping, pacing from multiple sites, and light microscopy. Two types of double potentials, similar to those found in humans, were found in all hearts. LH potentials consisted of a low-frequency deflection followed by a high-frequency deflection during sinus rhythm or anterior septal pacing. HL potentials consisted of a high-frequency deflection followed by a low-frequency deflection. LH potentials were found close to the coronary sinus orifice. They were caused by asynchronous activation of the sinus septum and the region between the coronary sinus orifice and tricuspid annulus. HL double potentials were found along the tricuspid annulus. They were caused by asynchronous activation of two cell layers. The high-frequency component was caused by depolarization of atrial-type cells in the deep subendocardial layer. The low-frequency component was caused by depolarization of cells with nodal characteristics close to the endocardium. These cells were present around the entire tricuspid annulus, were not part of the compact AV node, and could be dissociated from the bulk of the atria by rapid atrial pacing.nnnCONCLUSIONSnLH potentials are caused by asynchronous activation of muscle bundles above and below the coronary sinus orifice. Their proximity to the site of the slow pathway is probably serendipity. HL double potentials are caused by asynchronous activation of atrial cells and a band of nodal-type cells close to the tricuspid annulus. The band of nodal-type cells is not part of the compact AV node and may represent the substrate of the slow AV nodal pathway.

The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium.

Cardiac sodium channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of sodium channel expression and function in the myocardium. Sodium channel Scn5a mRNA and Nav1.5 protein distribution was investigated in adult and embryonic mouse heart through immunohistochemistry and in situ hybridization. Functional sodium channel availability in subepicardial and subendocardial myocytes was assessed using patch-clamp technique. Adult and embryonic (ED14.5) mouse heart sections showed low expression of Nav1.5 in the HCN4-positive sinoatrial and atrioventricular nodes. In contrast, high expression levels of Nav1.5 were observed in the HCN4-positive and Cx43-negative AV or His bundle, bundle branches and Purkinje fibers. In both ventricles, a transmural gradient was observed, with a low Nav1.5 labeling intensity in the subepicardium as compared to the subendocardium. Similar Scn5a mRNA expression patterns were observed on in situ hybridization of embryonic and adult tissue. Maximal action potential upstroke velocity was significantly lower in subepicardial myocytes (meanxa0±xa0SEM 309xa0±xa032xa0V/s; nxa0=xa014) compared to subendocardial myocytes (394xa0±xa032xa0V/s; nxa0=xa011; Pxa0<xa00.05), indicating decreased sodium channel availability in subepicardium compared to subendocardium. Scn5a and Nav1.5 show heterogeneous distribution patterns within the cardiac conduction system and across the ventricular wall. This differential distribution of the cardiac sodium channel may have profound consequences for conduction disease phenotypes and arrhythmogenesis in the setting of sodium channel disease.

Localization of the site of origin of postinfarction ventricular tachycardia by endocardial pace mapping. Body surface mapping compared with the 12-lead electrocardiogram

BackgroundThe purpose of this study was to assess the value of body surface mapping and the standard 12-lead ECG in localizing the site of origin of postinfarction ventricular tachycardia (VT) during endocardial pace mapping of the left ventricle. summary Background. The purpose of this study was to assess the value of body surface mapping and the standard 12-lead ECG in localizing the site of origin of postinfarction ventricular tachycardia (VT) during endocardial pace mapping of the left ventricle. Methods and ResultsSimultaneous recordings of 62-lead body surface QRS integral maps and scalar 12-lead ECG tracings were obtained in 16 patients with prior myocardial infarction during a total of 26 distinct VT configurations and during subsequent left ventricular catheter pace mapping at 9 to 24 different endocardial sites. Anatomic pacing site locations were computed by means of a biplane cineradiographic method and plotted on a polar projection of the left ventricle. The QRS integral map and the QRS complexes of the 12 standard leads of eachVT morphology obtained in a particular patient were compared independently with the different paced QRS integral maps and paced QRS complexes of the 12-lead ECG generated in that same patient. The stimulus site locations of the best matching paced QRS integral map and paced QRS complexes of the 12-lead ECG were indicated on the polar projection and subsequently compared with the endocardial location of the corresponding site ofVT origin identified during intraoperative (surgical ablation) or catheter activation sequence mapping (catheter ablation). The localization resolution of pace mapping was established separately for each electrocardiographic technique by computing the size of endocardial areas with similar morphological features of the QRS complex. Pace mapping advocated with body surface mapping or the 12-lead ECG enabled adequate reproduction of the VT QRS morphology in 24 of 26 VTs (92%) and 25 of 26 VTs (96%), respectively. Activation sequence mapping identified the site of origin in 12 of 26 previously observedVT configurations (46%). Ten and 11 VTs were localized by activation sequence mapping and pace mapping combined with body surface mapping or the 12-lead ECG, respectively. Pace mapping applied with body surface mapping identified the site of origin correctly (distance .2 cm) in 8 of 10 compared VTs (80%); an adjacent site (distance between 2 and 4 cm) or a disparate site (distance >4 cm) was identified in the remaining 2 of 10 VTs (20%). Pace mapping used with the 12-lead ECG localized the site of origin correctly in 2 of 11 VTs (18%); the site of origin was identified correctly next to an additional adjacent site in 5 of 11 VTs (55%); and an adjacent site or a disparate site was found in 1 of 11 VTs (9%vo) and 2 of 11 VTs (18%), respectively. The difference in localization accuracy of both electrocardiographic techniques was statistically significant (P=.02). The mean size of endocardial areas where a comparable QRS morphology was obtained during pace mapping was 6.0±4.5 cm2 with the application of body surface mapping and 15.1±12.0 cm2 with the use of the 12-lead ECG. ConclusionsThese results demonstrate that application of the 62-lead instead of the 12-lead ECG during endocardial pace mapping enhances the localization resolution of this mapping technique and enables more precise identification of the site of arrhythmogenesis in the majority of compared postinfarctionVT episodes.

Long-term results of the corridor operation for atrial fibrillation.

OBJECTIVE--To investigate the long-term results of the corridor operation in the treatment of symptomatic atrial fibrillation refractory to drug treatment. BACKGROUND--The corridor operation is designed to isolate from the left and right atrium a conduit of atrial tissue connecting the sinus node area with the atrioventricular node region in order to preserve physiological ventricular drive. The excluded atria can fibrillate without affecting the ventricular rhythm. This surgical method offers an alternative treatment when atrial fibrillation becomes refractory to drug treatment. PATIENTS--From 1987 to 1993, 36 patients with drug refractory symptomatic paroxysmal atrial fibrillation underwent surgery. The in hospital rhythm was followed thereafter by continuous rhythm monitoring and with epicardial electrograms. After discharge Holter recording and stress testing were regularly carried out to evaluate the sinus node function and to detect arrhythmias; whereas Doppler echocardiography was used to measure atrial contraction and size. MAIN OUTCOME MEASURES--Maintained absence of atrial fibrillation without drug treatment after operation; preservation of normal chronotropic response in the sinus node. RESULTS--The corridor procedure was successful in 31 (86%) of the 36 patients. After a mean (SD) follow up of 41 (16) months 25 (69%) of the 36 patients were free of arrhythmias without taking drugs (mean (SE) actuarial freedom at four years 72 (9)%)). Paroxysmal atrial fibrillation recurred in three patients; paroxysmal atrial flutter (two patients) and atrial tachycardia (one patient) developed in the corridor in three others. Among the 31 patients in whom the operation was successful sinus node function at rest and during exercise remained undisturbed in 26 and 25 patients respectively (mean (SE) actuarial freedom of sinus node dysfunction at four years (81(7)%)). Pacemakers were needed in five (16%) of the 31 patients for insufficient sinus node rhythm at rest only. Doppler echocardiography showed maintenance of right atrial contribution to right ventricle filling in 26 of the 31 patients after operation in contrast to the left atrium, which never showed such contribution. His bundle ablation was performed and a pacemaker implanted in the five patients in whom the corridor operation was unsuccessful. CONCLUSION--These results substantiate the idea of this surgical procedure. Modification of the technique is, however, needed to achieve a reliable isolation between left atrium and corridor, which would make this experimental surgery widely applicable in the treatment of drug refractory atrial fibrillation.

Endocardial catheter mapping: wire skeleton technique for representation of computed arrhythmogenic sites compared with intraoperative mapping.

Guiding surgical therapy of ventricular tachycardia by preoperative endocardial catheter mapping necessitates improvement of the accuracy of localization of the arrhythmogenic site. We therefore used a new mathematical cineradiographic method during catheter mapping to compute the position of left ventricular arrhythmogenic sites relative to three anatomic reference points: the centers of aortic and mitral valve ostia and the left ventricular apex. To enable the surgeon to identify the position of the computed sites, a wire skeleton (one for each patient) representing a single or multiple arrhythmogenic site(s) relative to the anatomic reference points was constructed. This wire skeleton was inserted into the left ventricular cavity during surgery. Side branches of the device indicated preoperatively localized arrhythmogenic sites. Results in eight consecutive patients were compared with those of intraoperative simultaneous mapping of 64 endocardial sites. Sixteen morphologically distinct monomorphic ventricular tachycardias were mapped by catheter and 15 by intraoperative mapping. In 12 ventricular tachycardias an identical morphology was recorded during both techniques. The distance between arrhythmogenic sites localized with both methods was 1 cm or less in 11 of these 12 ventricular tachycardias and 2 cm in one ventricular tachycardia. These results indicate that endocardial catheter mapping combined with wire skeleton representation of computed positions of arrhythmogenic sites is reliable for guiding surgical therapy of ventricular tachycardia and since some of the ventricular tachycardias were inducible only during either preoperative or intraoperative mapping, both techniques have an additive value. In addition, the wire skeleton proved convenient during surgery by identifying the arrhythmogenic sites.

Single Cells Isolated from Human Sinoatrial Node: Action Potentials and Numerical Reconstruction of Pacemaker Current

Pacemaker activity of the sinoatrial node has extensively been studied in laboratory animals of various species, but is virtually unexplored in man. Most experimental data have been obtained from rabbit, where the hyper- polarization-activated funny current (If), also known as the pacemaker current, plays an important role in diastolic depolarization and thus in setting pacing rate. Recently, we isolated pacemaker cells from excised human sinoatrial node tissue, and recorded action potentials and If using the whole- cell patch-clamp technique in current clamp and voltage clamp mode, respectively. Single sinoatrial node pacemaker cells showed a spontaneous beating rate of 73 plusmn 3 beats/min (mean plusmn SEM, n = 3) with a remarkably slow diastolic depolarization. If was identified in voltage clamp experiments as the 2 mmol/L Cs+-sensitive inward current activating upon 2-s hyper- polarizing voltage clamp steps. The If reversal potential and (de)activation kinetics were similar to those in rabbit. However, the fully-activated If conductance was 3-4 times smaller than typically found in rabbit. Furthermore, the half-maximal activation voltage was ~20 mV more negative than in rabbit. These differences would both act to reduce the functional role of If in human pacemaker cells. To assess this functional role, we carried out a numerical reconstruction of the If time course during an experimentally recorded human sinoatrial node action potential, based on the obtained data on If amplitude and kinetics. This reconstruction revealed that If provides a small but significant inward current in the voltage range of diastolic depolarization. We conclude that human sinoatrial node pacemaker cells functionally express If and that this If contributes to pacemaking in human sinoatrial node.

Fever-triggered ventricular arrhythmias in Brugada syndrome and type 2 long-Qt syndrome

The risk for lethal ventricular arrhythmias is increased in individuals who carry mutations in genes that encode cardiac ion channels. Loss-of-function mutations in SCN5A, the gene encoding the cardiac sodium channel, are linked to Brugada syndrome (BrS). Arrhythmias in BrS are often preceded by coved-type ST-segment elevation in the right-precordial leads V1 and V2. Loss-of-function mutations in KCNH2, the gene encoding the cardiac ion channel that is responsible for the rapidly activating delayed rectifying potassium current, are linked to long-QT syndrome type 2 (LQT-2). LQT-2 is characterised by delayed cardiac repolarisation and rate-corrected QT interval (QTc) prolongation. Here, we report that the risk for ventricular arrhythmias in BrS and LQT-2 is further increased during fever. Moreover, we demonstrate that fever may aggravate coved-type ST-segment elevation in BrS, and cause QTc lengthening in LQT-2. Finally, we describe molecular mechanisms that may underlie the proarrhythmic effects of fever in BrS and LQT-2. (Neth Heart J 2010;18:165-9.)

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Introduction. Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure due to adverse electrical remodelling. To establish whether abnormal conduction is responsible for arrhythmogenic remodelling in progressed stages of heart failure, we have monitored functional, structural and electrical remodelling in a murine model of heart failure, induced by longstanding pressure overload.Methods. Mice were subjected to transverse aortic constriction (TAC; n=18) or sham operated (n=19) and monitored biweekly by echocardiography and electrocardiography. At the 16-week endpoint, electrical mapping was performed to measure epicardial conduction velocity and susceptibility to arrhythmias. Finally, tissue sections were stained for Cx43 and fibrosis.Results. In TAC mice, fractional shortening decreased gradually and was significantly lower compared with sham at 16 weeks. Left ventricular hypertrophy was significant after six weeks. TAC mice developed PQ prolongation after 12 weeks, QT prolongation after 16 weeks and QRS prolongation after two weeks. Right ventricular conduction velocity was slowed parallel to fibre orientation. In 8/18 TAC hearts, polymorphic ventricular tachyarrhythmias were provoked and none in sham hearts. TAC mice had more interstitial fibrosis than sham. Immunohistology showed that Cx43 levels were similar but highly heterogeneous in TAC mice. All parameters were comparable in TAC mice with and without arrhythmias, except for Cx43 heterogeneity, which was significantly higher in arrhythmogenic TAC mice.Conclusion. Chronic pressure overload resulted in rapid structural and electrical remodelling. Arrhythmias were related to heterogeneous expression of Cx43. This may lead to functional block and unstable reentry, giving rise to polymorphic ventricular tachyarrhythmias. (Neth Heart J 2010;18:509-15.)