Domenico Potenza

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation

Ventricular fibrillation causes more than 300, 000 sudden deaths each year in the USA alone,. In approximately 5–12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

Sodium Channel Blockers Identify Risk for Sudden Death in Patients With ST-Segment Elevation and Right Bundle Branch Block but Structurally Normal Hearts

BACKGROUND A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Pulmonary-Vein Isolation for Atrial Fibrillation in Patients with Heart Failure

BACKGROUND Pulmonary-vein isolation is increasingly being used to treat atrial fibrillation in patients with heart failure. METHODS In this prospective, multicenter clinical trial, we randomly assigned patients with symptomatic, drug-resistant atrial fibrillation, an ejection fraction of 40% or less, and New York Heart Association class II or III heart failure to undergo either pulmonary-vein isolation or atrioventricular-node ablation with biventricular pacing. All patients completed the Minnesota Living with Heart Failure questionnaire (scores range from 0 to 105, with a higher score indicating a worse quality of life) and underwent echocardiography and a 6-minute walk test (the composite primary end point). Over a 6-month period, patients were monitored for both symptomatic and asymptomatic episodes of atrial fibrillation. RESULTS In all, 41 patients underwent pulmonary-vein isolation, and 40 underwent atrioventricular-node ablation with biventricular pacing; none were lost to follow-up at 6 months. The composite primary end point favored the group that underwent pulmonary-vein isolation, with an improved questionnaire score at 6 months (60, vs. 82 in the group that underwent atrioventricular-node ablation with biventricular pacing; P<0.001), a longer 6-minute-walk distance (340 m vs. 297 m, P<0.001), and a higher ejection fraction (35% vs. 28%, P<0.001). In the group that underwent pulmonary-vein isolation, 88% of patients receiving antiarrhythmic drugs and 71% of those not receiving such drugs were free of atrial fibrillation at 6 months. In the group that underwent pulmonary-vein isolation, pulmonary-vein stenosis developed in two patients, pericardial effusion in one, and pulmonary edema in another; in the group that underwent atrioventricular-node ablation with biventricular pacing, lead dislodgment was found in one patient and pneumothorax in another. CONCLUSIONS Pulmonary-vein isolation was superior to atrioventricular-node ablation with biventricular pacing in patients with heart failure who had drug-refractory atrial fibrillation. (ClinicalTrials.gov number, NCT00599976.)

Pulmonary Vein Stenosis After Radiofrequency Ablation of Atrial Fibrillation Functional Characterization, Evolution, and Influence of the Ablation Strategy

Background—Pulmonary vein (PV) stenosis is a complication of ablation for atrial fibrillation. The impact of different ablation strategies on the incidence of PV stenosis and its functional characterization has not been described. Methods and Results—PV isolation was performed in 608 patients. An electroanatomic approach was used in 71 and circular mapping in 537 (distal isolation, 25; ostial isolation based on PV angiography, 102; guided by intracardiac echocardiography, 140; with energy delivery based on visualization of microbubbles, 270). Severe (≥70%) narrowing was detected in 21 patients (3.4%), and moderate (50% to 69%) and mild (<50%) narrowing occurred in 27 (4.4%) and 47 (7.7%), respectively. Severe stenosis occurred in 15.5%, 20%, 2.9%, 1.4%, and 0%, respectively. Development of symptoms was correlated with involvement of >1 PV with severe narrowing (P =0.01), whereas all patients with mild and moderate narrowing were asymptomatic. In the latter group, lung perfusion (V/Q) scans were normal in all but 4 patients. All patients with severe stenosis had abnormal perfusion scans. Conclusions—V/Q scans are useful to assess the functional significance of PV stenosis. Mild and moderate degrees of PV narrowing are not associated with development of symptoms and seem to have no or minimal detrimental effect on pulmonary flow. The incidence of severe PV stenosis seems to be declining with better imaging techniques to ensure ostial isolation and to guide power titration. Mild narrowing 3 months after ablation does not preclude future development of severe stenosis and should be assessed with repeat imaging studies.

Response of Atrial Fibrillation to Pulmonary Vein Antrum Isolation Is Directly Related to Resumption and Delay of Pulmonary Vein Conduction

Background—The role of pulmonary vein (PV) isolation in ablative treatment of atrial fibrillation (AF) has been debated in conflicting reports. We sought to compare PV conduction in patients who had no AF recurrence (group I), patients who could maintain sinus rhythm on antiarrhythmic medication (group II), and patients who had recurrent AF despite antiarrhythmic medication (group III) after PV antrum isolation (PVAI). Methods and Results—PV conduction was examined in consecutive patients undergoing second PVAI for AF recurrence. We also recruited some patients cured of AF to undergo a repeat, limited electrophysiological study at >3 months after PVAI. All patients underwent PVAI with an intracardiac echocardiography (ICE)–guided approach with complete isolation of all 4 PV antra (PVA). The number of PVs with recurrent conduction and the shortest atrial to PV (A-PV) conduction delay was measured with the use of consistent Lasso positions defined by ICE. Late AF recurrence was defined as AF >2 months after PVAI with the patient off medications. Patients in groups I (n=26), II (n=37), and III (n=44) did not differ at baseline (38% permanent AF; ejection fraction 53±6%). Recurrence of PV–left atrial (LA) conduction was seen in 1.7±0.8 and 2.2±0.8 PVAs for groups II and III but only in 0.2±0.4 for group I (P=0.02). In patients with recurrent PV-LA conduction, the A-PV delay increased from the first to second procedure by 69±47% for group III, 267±110% for group II, and 473±71% for group I (P<0.001). When pacing was at a faster rate, A-PV block developed in all 5 of the group I patients with recurrent PV-LA conduction. Conclusions—The majority of patients with drug-free cure show no PV-LA conduction recurrence. Substantial A-PV delay is seen in patients able to maintain sinus rhythm on antiarrhythmic medication or cured of AF compared with patients who fail PVAI.

Ablation for longstanding permanent atrial fibrillation: Results from a randomized study comparing three different strategies

BACKGROUND This prospective multicenter randomized study aimed to compare the efficacy of 3 common ablation methods used for longstanding permanent atrial fibrillation (AF). METHODS A total of 144 patients with longstanding permanent AF (median duration 28 months) were randomly assigned to circumferential pulmonary vein ablation (CPVA, group 1, n = 47), to pulmonary vein antrum isolation (PVAI, group 2, n = 48) or to a hybrid strategy combining ablation of complex fractionated or rapid atrial electrograms (CFAE) in both atria followed by a pulmonary vein antrum isolation (CFAE + PVAI, group 3, n = 49). RESULTS Scarring in the left atrium and structural heart disease/hypertension were present in most patients (65%). After a mean follow-up of 16 months, 11% of patients in group 1, 40% of patients in group 2 and 61% of patients in group 3 were in sinus rhythm after one procedure and with no antiarrhythmic drugs (P < .001). Sinus rhythm maintenance would increase respectively to 28% (group 1), 83% (group 2), and 94% (group 3) after 2 procedures and with antiarrhythmic drugs (AADs, P < .001). The AF terminated during ablation, either by conversion to sinus rhythm or organization into an atrial tachyarrhythmia, in 13% of patients (group 1), 44% (group 2), and 74% (group 3) respectively. CFAE alone, performed as the first step of the ablation in group 3, organized AF in only 1 patient. CONCLUSION In this study, the hybrid AF ablation strategy including antrum isolation and CFAE ablation had the highest likelihood of maintaining sinus rhythm in patients with longstanding permanent AF. Electrical isolation of the PVs, although inadequate if performed alone, is relevant to achieve long-term sinus rhythm maintenance after ablation. Bi-atrial CFAE ablation had a minimal impact on AF termination during ablation.

First Human Experience With Pulmonary Vein Isolation Using a Through-the-Balloon Circumferential Ultrasound Ablation System for Recurrent Atrial Fibrillation

BackgroundStandard mapping and ablation of focal sources of atrial fibrillation are associated with very long procedure times and low efficacy. An anatomic approach to complete pulmonary vein isolation could overcome these limitations. Methods and ResultsFifteen patients with atrial fibrillation refractory to medication underwent circumferential isolation of the pulmonary veins by using a novel catheter, with an ultrasound transducer (8-MHz) mounted near the tip, in a saline-filled balloon. Twelve atrial foci and/or atrial fibrillation triggers were identified in 9 patients (pulmonary vein locations: left upper, 3; right upper, 6; right middle, 1; right lower, 1; and left inferior, 1). In 5 patients, lesions were placed in the absence of any mapped triggers. Irrespective of trigger mapping, circumferential isolation of both upper pulmonary veins was attempted in all patients. The lower pulmonary veins were ablated when sinus rhythm activation mapping revealed evidence of a sleeve of atrial muscle in the vein. The median number of lesions per patient required to isolate 1 pulmonary vein was 4 (range, 1 to 29). After ablation, no evidence of narrowing was seen with repeat venography or follow-up computed tomography scan. After a mean follow-up of 35±6 weeks, 5 patients had recurrence of atrial fibrillation. Three responded to drugs that were previously ineffective, and 2 remained in atrial fibrillation. ConclusionsThis novel ultrasound ablation system can successfully isolate multiple pulmonary veins. At early follow-up, this approach seems to be effective in preventing recurrent atrial fibrillation in a significant number of patients.

Randomized Study Comparing Combined Pulmonary Vein–Left Atrial Junction Disconnection and Cavotricuspid Isthmus Ablation Versus Pulmonary Vein–Left Atrial Junction Disconnection Alone in Patients Presenting With Typical Atrial Flutter and Atrial Fibrillation

Background—Atrial flutter (AFL) and atrial fibrillation (AF) frequently coexist in the same patient. Recently it has been demonstrated that the triggers for both AF and AFL may originate in the pulmonary veins (PVs). We hypothesized that in patients with both AF and typical AFL, pulmonary vein–left atrial junction (PV-LAJ) disconnection may eliminate both arrhythmias. Methods and Results—Consecutive patients with documented symptomatic AF and typical AFL were randomly assigned to have PV-LAJ disconnection combined with cavotricuspid isthmus (CTI) ablation (group 1, n=49) or PV-LAJ disconnection alone (group 2, n=59). Within the first 8 weeks after ablation, 32 of the group 2 patients had typical AFL documented, whereas none was seen in group 1. Twenty of these 32 converted to sinus rhythm after initiating antiarrhythmic drugs (AADs). Twelve were cardioverted, and AADs were started. After 8 weeks, all AADS were stopped, and only 3 patients continued to have recurrent sustained typical AFL that was eliminated by CTI ablation. Beyond 8 weeks of follow-up, 7 patients in group 1 and 6 patients in group 2 (14% and 11%, respectively) continued to have AF. Ten of these 13 patients underwent a repeat PV-LAJ disconnection procedure and were cured. The remaining 3 remained in normal sinus rhythm while taking AADs. Conclusions—In patients with both AFL and AF, PV-LAJ disconnection alone may be sufficient to control both arrhythmias. CTI block reduced early postablation recurrence of arrhythmias, which in the majority of patients reflects a short-term clinical problem.

Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.

Background—The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial. Methods and Results—We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier. Conclusions—In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.

Atrial Fibrillation Ablation Strategies for Paroxysmal Patients: randomized comparison between different techniques.

Background— Whether different ablation strategies affect paroxysmal atrial fibrillation (AF) long-term freedom from AF/atrial tachyarrhythmia is unclear. We sought to compare the effect of 3 different ablation approaches on the long-term success in patients with paroxysmal AF. Methods and Results— One hundred three consecutive patients with paroxysmal AF scheduled for ablation and presenting in the electrophysiology laboratory in AF were selected for this study. Patients were randomized to pulmonary vein antrum isolation (PVAI; n=35) versus biatrial ablation of the complex fractionated atrial electrograms (CFAEs; n=34) versus PVAI followed by CFAEs (n=34). Patients were given event recorders and followed up at 3, 6, 9, 12, and 15 months postablation. There was no statistical significant difference between the groups in term of sex, age, AF duration, left atrial size, and ejection fraction. At 1 year follow-up, freedom from AF/atrial tachyarrhythmia was documented in 89% of patients in the PVAI group, 91% in the PVAI plus CFAEs group, and 23% in the CFAEs group ( P <0.001) after a single procedure and with antiarrhythmic drugs. Conclusion— No difference in terms of success rate was seen between PVAI alone and PVAI associated with defragmentation. CFAEs ablation alone had the smallest impact on AF recurrences at 1-year follow-up. These results suggest that antral isolation is sufficient to treat most patients with paroxysmal AF. Received March 19, 2008; accepted February 11, 2009. # CLINICAL PERSPECTIVE {#article-title-2}Background—Whether different ablation strategies affect paroxysmal atrial fibrillation (AF) long-term freedom from AF/atrial tachyarrhythmia is unclear. We sought to compare the effect of 3 different ablation approaches on the long-term success in patients with paroxysmal AF. Methods and Results—One hundred three consecutive patients with paroxysmal AF scheduled for ablation and presenting in the electrophysiology laboratory in AF were selected for this study. Patients were randomized to pulmonary vein antrum isolation (PVAI; n=35) versus biatrial ablation of the complex fractionated atrial electrograms (CFAEs; n=34) versus PVAI followed by CFAEs (n=34). Patients were given event recorders and followed up at 3, 6, 9, 12, and 15 months postablation. There was no statistical significant difference between the groups in term of sex, age, AF duration, left atrial size, and ejection fraction. At 1 year follow-up, freedom from AF/atrial tachyarrhythmia was documented in 89% of patients in the PVAI group, 91% in the PVAI plus CFAEs group, and 23% in the CFAEs group (P<0.001) after a single procedure and with antiarrhythmic drugs. Conclusion—No difference in terms of success rate was seen between PVAI alone and PVAI associated with defragmentation. CFAEs ablation alone had the smallest impact on AF recurrences at 1-year follow-up. These results suggest that antral isolation is sufficient to treat most patients with paroxysmal AF.