The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update.

BACKGROUND: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. AIM: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. METHODS: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. DISCUSSION: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.

Clinical characterisation and risk stratification of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy ≥50 years of age.

PURPOSE: With the increased use of genetic testing for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), this disease is being increasingly recognised among elderly patients. However, elderly ARVD/C patients were underrepresented in prior cohorts. We aimed to describe the phenotypical characteristics and outcomes among ARVD/C patients surviving ≥50 years. METHODS: We assessed detailed phenotypical data of 29 patients who (1) presented at ≥50 years of age; and (2) fulfilled 2010 Task Force Criteria (TFC) for ARVD/C by last follow-up. Primary outcome was the occurrence of a major ventricular arrhythmia (sudden cardiac death, resuscitated sudden cardiac arrest or sustained ventricular tachycardia). RESULTS: The majority (55 %) of elderly ARVD/C subjects were male, with a mean age of 59.0 ± 5.8 years at presentation. Study participants fulfilled a median of six (IQR 5-8) TFC criteria by last follow-up, of which arrhythmia criteria were most frequent (97 %), followed by structural criteria (83 %), depolarisation criteria (72 %) and repolarisation criteria (69 %). By last follow-up, 15 (52 %) patients had experienced major ventricular arrhythmias. Most patients (n = 12) presented with this arrhythmia, while three experienced the event during 5.4 ± 3.2 years of follow-up. Compared with patients without an arrhythmic event, patients with major arrhythmias were more likely to be proband (p < 0.001) and male (p = 0.042). Likewise, survival free from sustained ventricular arrhythmia was lower among probands and males. CONCLUSION: Phenotypic characteristics of elderly ARVD/C patients are characterised by depolarisation abnormalities and structural cardiac changes. Ventricular arrhythmias in this elderly cohort are associated with male gender and proband status.

Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management.

Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.

Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.

BACKGROUND: Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death. METHODS: Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation. RESULTS: By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents' places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %). CONCLUSION: The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.

Haplotype sharing test maps genes for familial cardiomyopathies.

Identifying a mutation in a heterogeneous disease such as inherited cardiomyopathy is a challenge because classical methods, like linkage analysis, can often not be applied as there are too few meioses between affected individuals. However, if affected individuals share the same causal mutation, they will also share a genomic region surrounding it. High-density genotyping arrays are able to identify such regions shared among affected individuals. We hypothesize that the longest shared haplotype is most likely to contain the disease-causing mutation. We applied this method to two pedigrees: one with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one with dilated cardiomyopathy (DCM), using high-density genome-wide SNP arrays. In the ARVC pedigree, the largest haplotype was on chromosome 12 and contained a causative PKP2 mutation. In the DCM pedigree, a causative MYH7 mutation was present on a large shared haplotype on chromosome 14. We calculated that a pedigree containing at least seven meioses has a high chance of correctly detecting the mutation-containing haplotype as the largest. Our data show that haplotype sharing analysis can assist in identifying causative genes in families with low penetrance Mendelian diseases, in which standard tools cannot be used due to lack of sufficient pedigree information.

Arrhythmogenic right ventricular cardiomyopathy: asymptomatic to life threatening as illustrated by the cases of two sisters.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder of unknown cause that is characterised by fibrofatty replacement, primarily of the right ventricular myocardium, which can lead to life-threatening arrhythmias. It is a disease with a very diverse phenotype. In the present article we describe two sisters, each with a different manifestation of this disorder. The first patient died suddenly at the age of 18 during exercise. Her 17-year-old sister did not have any abnormalities at first cardiac consultation, but a few years later she met several diagnostic criteria for ARVC and an internal cardioverter defibrillator was implanted. Genetic analysis identified a mutation in the plakophilin- 2 (PKP2) gene. Cardiac evaluation of a third sister did not reveal any abnormalities and no mutation in the PKP2 gene was found. Thus, ARVC can vary in its clinical presentation, not only between siblings but also in time. This raises difficulties for the physician for diagnosis, treatment and followup. It is important for the physician involved to consider this disease in patients with palpitations and syncope, especially when there is a family history of ARVC or unexplained sudden death. (Neth Heart J 2007;15:348-53.).

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.

Identification of the substrate of atrial vulnerability in patients with idiopathic atrial fibrillation.

BACKGROUND: Experimental studies have shown that atrial fibrillation (AF) causes remodeling, which facilitates AF perpetuation. AF may also, however, occur in patients without remodeling and underlying structural cardiac disease. The substrate for enhanced vulnerability in these patients is unknown. METHODS AND RESULTS: We studied 43 patients without structural heart disease: 18 patients with documented sporadic paroxysmal AF and 25 control patients without AF. In each patient, a decapolar catheter was positioned against the right atrial free wall, and a quadripolar catheter was positioned in the right atrial appendage. Unipolar electrograms were recorded. Atrial vulnerability was assessed according to an increasingly aggressive stimulation protocol. Mean local fibrillatory interval (FI) was used as an index of local refractoriness. Spatial dispersion of refractoriness was assessed through the calculation of the coefficient of dispersion (CD), which was defined as the SD of mean local FI expressed as a percentage of the mean FI. In the AF group, AF was induced with a single extrastimulus in 16 of 18 patients; the CD was 5.4+/-2.6, and the mean FI was 164+/-29 ms. In the control group, AF could be induced only with more aggressive pacing in 23 of the 25 patients; the CD was 1.4+/-0.7 (P<0.0001), and the mean FI was 175+/-26 ms (NS). CONCLUSIONS: Patients with idiopathic AF showed increased dispersion of refractoriness, which may be the substrate for the observed enhanced inducibility and spontaneous occurrence of AF.

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.

Proarrhythmic effects of ventricular electrical catheter ablation in dogs.

Electrical catheter ablation of arrhythmogenic sites is a new therapy for ventricular tachycardia that is still being investigated. Recent studies have shown, however, that the procedure itself can provoke serious ventricular arrhythmias. The incidence, course and mechanism of these arrhythmias were studied in 10 beagles treated with a single R wave-synchronized cathodal shock delivered to the endocardial ventricular wall (5 dogs left ventricular, 5 dogs right ventricular). Shocks were delivered at 30 (four dogs), 80 (two dogs) or 250 J (four dogs). Each dog underwent programmed electrical stimulation at or near the ablation site before, within 1 hour after and 1 week after the shock. Holter electrocardiographic monitoring (24 hours) was performed during day 1 and 7 after the shock in all the dogs, and extended Holter monitoring was done during the first 5 days in four dogs. All dogs survived for 1 week. Within 10 minutes after the shock, a sustained ventricular tachycardia was recorded in nine dogs; deterioration into ventricular fibrillation occurred in two dogs. In nine dogs, 60 to 169 monomorphic ventricular tachycardia episodes (mean 101) occurred on day 1 and 0 to 11 (mean 3) occurred on day 7; Holter monitoring failed for technical reasons in one dog. Extended Holter monitoring showed a marked decline in the incidence of tachycardia during the first 3 days. Early activation during ventricular tachycardia was always derived at or near the ablation site, and the QRS configuration during pre- and postablation pacing at this site was identical to the tachycardia configuration. Ventricular tachycardia was never inducible with programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrical catheter ablation in the left and right ventricular wall in dogs: relation between delivered energy and histopathologic changes.

Electrical catheter ablation of arrhythmogenic sites is now being used for the treatment of ventricular tachycardias. However, the extent and type of the ablation lesion in relation to energy level are controversial and not well known. In 10 beagles, single cathodal shocks of 30 (4 dogs), 80 (2 dogs) or 250 J (4 dogs) were delivered to the endocardial ventricular wall (5 dogs left ventricular, 5 dogs right ventricular). One week after ablation the dogs were killed for histopathologic examination. In the left ventricular wall, ablation lesion volumes calculated from measured extensions in three perpendicular directions were 0.4 and 0.9 cc at 30 J, 1.9 cc at 80 J and 2.8 and 3.4 cc at 250 J; in the right ventricular wall they were 0.4 and 0.5 cc at 30 J, 1.3 cc at 80 J and 2.5 and 4.2 cc at 250 J. In the right ventricular wall all 30 to 250 J lesions were transmural, whereas in the left ventricular wall only 250 J lesions were transmural. All lesions showed a necrotic area surrounded by granulation tissue with degenerated myofibrils. Thus, the size of the ablation lesion depends on delivered energy, whereas the pattern of histopathologic change is identical in the 30 to 250 J energy range. These results suggest that with accurate localization of the arrhythmogenic site one low energy shock may be successful with less myocardial damage.

Effects of heating on impulse propagation in superfused canine myocardium.

OBJECTIVES: The goal of the study was to quantify the response of myocardial impulse propagation to hyperthermia and identify the temperatures required for transient and permanent block in conduction. BACKGROUND: Although it is generally accepted that the effects of radiofrequency ablation are thermally mediated, the precise response of myocardial impulse conduction to heating remains to be quantified. METHODS: Twenty-three preparations of ventricular myocardium from 10 beagle dogs were superfused at 36.5 to 37.5 degrees C and paced at a cycle length of 600 ms. Heating was performed for 30 s at 5-min intervals by an independent flow of heated superfusate. A 16-electrode grid was used to record extracellular electrograms directly before each heating episode (control value) and at 10, 20 and 30 s. RESULTS: Between 38.5 and 45.4 degrees C, conduction velocity was higher than that at the directly preceding control value (p < 0.05), reaching a maximum of 114% between 41.5 and 42.5 degrees C. Above 45.4 degrees C, a gradual decrease occurred, with transient block (absence of impulse conduction for < or = 5 min) after heating to 49.5 to 51.5 degrees C. This was followed by tachycardia in 69% of all cases immediately after cessation of heating. Permanent block occurred after a significantly higher temperature of 51.7 to 54.4 degrees C had been reached. Pacing at sites allowing preferential conduction either parallel or perpendicular to fiber orientation caused no difference in reaction to heating. Repeated heating of some preparations to 47.0 to 50.5 degrees C revealed no cumulative effects on conduction velocity. CONCLUSIONS: Transient and permanent block in impulse conduction occurred at 49.5 to 51.5 degrees C and 51.7 to 54.4 degrees C, respectively, in superfused canine myocardium, the former frequently being followed directly by tachycardia. Reaction of conduction velocity to hyperthermia was independent of myocardial fiber orientation and number of preceding heating episodes. Results may contribute to a better understanding of electrophysiologic phenomena observed during radiofrequency ablation procedures.

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.

Electrocardiographic identification of abnormal ventricular depolarization and repolarization in patients with idiopathic ventricular fibrillation.

OBJECTIVES: We sought to gain more insight into the arrhythmogenic etiology of idiopathic ventricular fibrillation (VF) by assessing ventricular depolarization and repolarization properties by means of various electrocardiographic (ECG) techniques. BACKGROUND: Idiopathic VF occurs in the absence of demonstrable structural heart disease. Abnormalities in ventricular depolarization or repolarization have been related to increased vulnerability to VF in various cardiac disorders and are possibly also present in patients with idiopathic VF. METHODS: In 17 patients with a first episode of idiopathic VF, 62-lead body surface QRST integral maps, QT dispersion on the 12-lead ECG and XYZ-lead signal-averaged ECGs were computed. RESULTS: All subjects of a healthy control group had a normal dipolar QRST integral map. In patients with idiopathic VF, either a normal dipolar map (29%,), a dipolar map with an abnormally large negative area on the right side of the thorax (24%) or a nondipolar map (47%) were recorded. Only four patients (24%) had increased QT dispersion on the 12-lead ECG and late potentials could be recorded in 6 (38%) of 16 patients. During a median follow-up duration of 56 months (range 9 to 136), a recurrent arrhythmic event occurred in 7 patients (41%), all of whom had an abnormal QRST integral map. Five of these patients had late potentials, and three showed increased QT dispersion on the 12-lead ECG. CONCLUSIONS: In patients with idiopathic VF, ventricular areas of slow conduction, regionally delayed repolarization or dispersion in repolarization can be identified. Therefore, various electrophysiologic conditions, alone or in combination, may be responsible for the occurrence of idiopathic VF. Body surface QRST integral mapping may be a promising method to identify those patients who do not show a recurrent episode of VF.

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.

Increased dispersion and shortened refractoriness caused by verapamil in chronic atrial fibrillation.

OBJECTIVES: The objective was to assess the effect ofverapamil on atrial fibrillation (AF) cycle length and spatial dispersion of refractoriness in patients with chronic AF. BACKGROUND: Previous studies have suggested that verapamil prevents acute remodeling by AF. The effects of verapamil in chronic AF are unknown. METHODS: During electrophysiologic study in 15 patients with chronic AF (duration >1 year), 12 unipolar electrograms were recorded from right atrial free wall, right atrial appendage and coronary sinus, along with monophasic action potential recordings from the right atrial appendage. The mean fibrillatory interval at each atrial recording site was used as an index for local refractoriness. Dispersion of refractoriness was calculated as the standard deviation of all local mean fibrillatory intervals expressed as a percentage of the overall mean fibrillatory interval. After baseline measurements, verapamil (0.075 mg/kg intravenous in 10 min) was infused and the measurements were repeated. RESULTS: After administration ofverapamil, mean fibrillatory intervals shortened by a mean of 16.6 +/- 3.3 ms (p < 0.001) at the right free wall, 15.0 +/- 3.5 ms (p < 0.001) at the appendage and 17.1 +/- 3.2 ms (p < 0.01) in the coronary sinus. Monophasic action potential duration decreased by 15.9 +/- 4.0 ms (p < 0.01). Dispersion of refractoriness increased in all patients from 3.8 +/- 0.8 to 5.1 +/- 1.8 (p < 0.001). A strong correlation between mean fibrillatory intervals and action potential duration was found, both before and after verapamil. CONCLUSIONS: Verapamil caused shortening of refractoriness and increase in spatial dispersion of refractoriness in patients with chronic AF. This implies that verapamil is not useful in reversing the remodeling process in these patients.

Role of atrial fibrillation and atrioventricular conduction (including Wolff-Parkinson-White syndrome) in sudden death.

A short refractory period of the accessory pathway is considered a major threat for sudden death in patients with Wolff-Parkinson-White syndrome and atrial fibrillation. RR interval and QRS signal analysis together with signal analysis of a bipolar high right atrial electrogram were obtained in six patients with Wolff-Parkinson-White syndrome and either induced or spontaneous atrial fibrillation. A record of a sufficiently long episode of atrioventricular (AV) conduction by way of the bypass tract that could be used for satisfactory RR interval sequence and QRS analysis was obtained from only one patient. The results were compared with those of a representative patient with atrial fibrillation and normal AV nodal-His conduction. In a patient with Wolff-Parkinson-White syndrome, atrial fibrillation and AV conduction by way of the bypass tract may exhibit high ventricular rates (median RR intervals of about 300 ms) and long/short RR interval ratios of just over 1 (RR intervals not exceeding 400 ms). The right atrial electrogram showed a noiselike excitation pattern. This study suggests that rather than a short refractory period of the bypass tract, it is lack of concealed conduction, responsible for the presence of long RR intervals, that allows the ventricles to reach very high ventricular rates and at times to fibrillate. The normal AV nodal-His system seems to protect the heart against high ventricular rates and ventricular fibrillation during atrial fibrillation by its relatively long refractory period and capacity to induce long RR intervals by means of concealed conduction.

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.