Pier D. Lambiase

Prevalence of J-point elevation in sudden arrhythmic death syndrome families.

OBJECTIVES The purpose of this study was to assess the prevalence of J-point elevation among the relatives of sudden arrhythmic death syndrome (SADS) probands. BACKGROUND J-point elevation is now known to be associated with idiopathic ventricular fibrillation. We hypothesized that this early repolarization phenomenon is an inherited trait responsible for a proportion of otherwise unexplained SADS cases. METHODS Families of SADS probands were evaluated in an inherited arrhythmia clinic. Twelve-lead electrocardiograms were analyzed for J-point elevation defined as >0.1 mV from baseline present in 2 or more of the inferior (II, III, and aVF) or lateral (1, aVL, V(4) to V(6)) leads. Electrocardiographic data were compared with those of 359 controls of a similar age, sex, and ethnic distribution. RESULTS A total of 363 first-degree relatives from 144 families were evaluated. J-point elevation in the inferolateral leads was present in 23% of relatives and 11% of control subjects (odds ratio: 2.54, 95% confidence interval: 1.66 to 3.90; p < 0.001). CONCLUSIONS J-point elevation is more prevalent in the relatives of SADS probands than in controls. This indicates that early repolarization is an important potentially inheritable pro-arrhythmic trait or marker of pro-arrhythmia in SADS.

Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation.

AIMS To establish clinical factors affecting success in persistent atrial fibrillation (AF) ablation. METHODS AND RESULTS Wide area circumferential ablation with linear and electrogram-based left atrial (LA) ablation was performed in 191 consecutive patients for persistent AF. After mean follow-up of 13.0 ± 8.9 months, overall success was 64% requiring a mean of 1.5 procedures. Single procedure success rate was 32%. Left atrial size was a univariate predictor of recurrence after a single procedure (P =0.04). Only LA size [hazard ratio (HR) 1.05/mm with 95% confidential interval (CI) 1.02-1.08] was an independent predictor of recurrence after a single procedure. Only LA size was a univariate predictor of recurrence after multiple procedures (P < 0.01). Left atrial size (HR 1.07/mm with 95% CI 1.02-1.11) and hypertrophic cardiomyopathy (HCM; HR 2.42 with 95% CI 1.06-5.55) were independent predictors of recurrence after multiple procedures. Ablation strategy did not affect success after a single procedure. Left atrial size of <43 mm predicted long-term success with a sensitivity of 92%, specificity 52%, positive predictive value 49%, and negative predictive value 93%. With LA size >43 mm, HCM (HR 3.09 with 95% CI 1.70-7.5) and AF duration (HR 1.07/year with 95% CI 1.00-1.13) were independent predictors of recurrence. CONCLUSION Left atrial size is the major independent determinant of AF recurrence after ablation for persistent AF. This has important implications for patient selection for persistent AF ablation and the evaluation of AF ablation clinical trial results.

Incidence of left atrial thrombus prior to atrial fibrillation ablation: is pre-procedural transoesophageal echocardiography mandatory?

AIMS The exact role of transoesphageal echo (TOE) prior to atrial fibrillation (AF) ablation remains unclear. This study examines the incidence and predictors of left atrial (LA) thrombus in patients undergoing AF ablation. METHODS AND RESULTS Patients were treated with warfarin for at least 4 weeks prior to ablation. This was substituted with therapeutic dalteparin 3 days before the procedure. All patients underwent TOE to exclude LA thrombus. Six clinical risk factors for thrombus were defined, known to be risk factors for stroke in AF: age>75, diabetes, hypertension, valve disease, prior stroke, or transient ischaemic attack and cardiomyopathy. A total of 635 procedures were performed. The incidence of thrombus was 12/635 (1.9%) despite therapeutic anti-coagulation. Patients with thrombus had larger LA diameter, mean 50.6+/-6.2 mm vs. 44.2+/-7.6 (P=0.006). In univariate analysis, persistent AF [odds ratio (OR)=10.4 with 95% CI 1.8-19.1], hypertension [OR=11.7 with 95% CI 2.5-54.1], age>75 (OR=4.5 with 95% CI 1.2-17.2), and cardiomyopathy (OR 5.9 with 95% CI 1.8-19.1) were significantly associated with thrombus. In multivariate analysis, hypertension (OR=14.2 with 95% CI 2.6-77.5), age>75 (OR=8.1, 95% CI 1.5-44.9), and cardiomyopathy (OR=10.5 with 95% CI 2.6-77.5) were independently associated with thrombus. There was no thrombus in patients without clinical risk factors. CONCLUSION In patients presenting for AF ablation, LA thrombus is only seen in those with clinical risk factors. TOE is indicated in this group but may be unnecessary in patients without clinical risk factors.

A randomized double-blind crossover trial of triventricular versus biventricular pacing in heart failure

A significant proportion of patients implanted with biventricular (BiV) devices fail to respond. Clinical response may be improved by additional ventricular stimulation sites. This single‐centre, double‐blinded randomized crossover trial aimed to determine whether long‐term multisite ventricular pacing is superior to conventional BiV pacing in heart failure patients.

The prognostic significance of premature ventricular complexes in adults without clinically apparent heart disease: a meta-analysis and systematic review

Aims Meta-analysis and systematic review to determine the long-term prognostic significance of premature ventricular complexes (PVCs) in adults without clinically apparent heart disease. Methods Relevant studies were searched on MEDLINE and EMBASE. Inclusion criteria: controlled studies on adults without clinically apparent heart disease comparing the prognosis of the presence against the absence of PVCs. Endpoints: all-cause mortality, cardiovascular mortality, sudden cardiac death or development of ischaemic heart disease. OR of endpoints were analysed with random effects model. Relationships between study outcomes and study characteristics were assessed by meta-regression and sensitivity analysis. Results Eight studies satisfied the inclusion criteria. Meta-analysis shows that in adults without clinically apparent heart disease, PVCs on ECG recording are associated with a pooled OR of 1.72 (95% CI 1.28 to 2.31) of endpoints compared with those without PVCs. However, only one study used echocardiogram or stress test to rule out heart disease. Meta-regression identified mean sample age (p=0.001), diabetes (p=0.005) and hypertension (p=0.005) as predictors of events. Only studies that used 100% male, not 100% female or mixed gender, found increased events. Conclusions Most studies on PVC prognosis in ‘normal hearts’ did not use advanced tests to rule out structural heart disease. Among these patients, PVCs are associated with a worse cardiovascular outcome if patients are older and have higher cardiovascular risk, suggesting that the poor prognosis studies may have inadvertently included patients with occult structural heart disease, the population in which PVCs are known to confer adverse outcomes.

Safety and efficacy of multipolar pulmonary vein ablation catheter vs. irrigated radiofrequency ablation for paroxysmal atrial fibrillation: a randomized multicentre trial.

Aims The current challenge in atrial fibrillation (AF) treatment is to develop effective, efficient, and safe ablation strategies. This randomized controlled trial assesses the medium-term efficacy of duty-cycled radiofrequency ablation via the circular pulmonary vein ablation catheter (PVAC) vs. conventional electro-anatomically guided wide-area circumferential ablation (WACA). Methods and results One hundred and eighty-eight patients (mean age 62 ± 12 years, 116 M : 72 F) with paroxysmal AF were prospectively randomized to PVAC or WACA strategies and sequentially followed for 12 months. The primary endpoint was freedom from symptomatic or documented >30 s AF off medications for 7 days at 12 months post-procedure. One hundred and eighty-three patients completed 12 m follow-up. Ninety-four patients underwent PVAC PV isolation with 372 of 376 pulmonary veins (PVs) successfully isolated and all PVs isolated in 92 WACA patients. Three WACA and no PVAC patients developed tamponade. Fifty-six percent of WACA and 60% of PVAC patients were free of AF at 12 months post-procedure (P = ns) with a significant attrition rate from 77 to 78%, respectively, at 6 months. The mean procedure (140 ± 43 vs. 167 ± 42 min, P<0.0001), fluoroscopy (35 ± 16 vs. 42 ± 20 min, P<0.05) times were significantly shorter for PVAC than for WACA. Two patients developed strokes within 72 h of the procedure in the PVAC group, one possibly related directly to PVAC ablation in a high-risk patient and none in the WACA group (P = ns). Two of the 47 patients in the PVAC group who underwent repeat ablation had sub-clinical mild PV stenoses of 25–50% and 1 WACA patient developed delayed severe PV stenosis requiring venoplasty. Conclusion The pulmonary vein ablation catheter is equivalent in efficacy to WACA with reduced procedural and fluoroscopy times. However, there is a risk of thrombo-embolic and pulmonary stenosis complications which needs to be addressed and prospectively monitored. ClinicalTrials.gov Identifier NCT00678340.

Improving safety in the electrophysiology laboratory using a simple radiation dose reduction strategy: a study of 1007 radiofrequency ablation procedures

Background The use of fluoroscopic screening involves exposure to ionising radiation for both patients and operators. Objective To assess the effects of radiation dose reduction manoeuvres (DRM) during radiofrequency ablation (RFA) procedures. Design Prospective study of DRM. Setting Tertiary cardiac centre. Interventions Two DRM were combined: removal of the secondary radiation grid and programming an ultra-low pulsed fluoroscopy rate. These methods were assessed using an anthropomorphic phantom model to measure skin entrance dose rates. Procedures were classified as complex (ablation of atrial fibrillation, ventricular tachycardia or complex congenital heart disease arrhythmias) or simple (all other RFA). Main outcome measures Dose area product and screening times were compared for ablations performed before and after DRM. Equivalent doses to organs and malignancy risk were determined by computer modelling. Results Over a 39-month period, 1007 ablation procedures were performed (631 simple, 376 complex). Radiation dose was significantly reduced after DRM for both simple (20.4±26.9 Gycm2 vs 8.0±10.3 Gycm2, p<0.00001) and complex ablations (63.3±50.1 Gycm2 vs 32.8±31.7 Gycm2, p<0.00001) with no difference in screening times. The mean lifetime risk of fatal cancer attributable to radiation exposure per million procedures was reduced from 182 to 68 for simple ablations and from 440 to 155 for complex ablations. Conclusions Significant reductions in radiation exposure during RFA were achieved using simple DRM, corresponding to a two-thirds reduction of the risk of excess fatal malignancy.

Right atrial angiography facilitates transseptal puncture for complex ablation in patients with unusual anatomy

ObjectiveThe number of transseptal punctures performed worldwide has increased exponentially with the development of ablation therapies for atrial arrhythmias. Safe access into the left atrium in these procedures is often complicated by abnormal anatomy. We assessed the potential of right atrial angiography to facilitate transseptal puncture for atrial ablation.Methods and resultsWe examined all transseptal punctures performed for complex left atrial ablation in our centre over a 29-month period. In cases where conventional transseptal techniques failed, we performed orthogonal right atrial angiography to define cardiac anatomy and orientation. During the study period, 255 transseptal procedures were performed. Of these, 16 cases were complicated by distorted atrial anatomy, extreme cardiac rotation or unexpected location of the atria in relation to the diaphragm, preventing left atrial access using conventional fluoroscopy. The application of right atrial angiography facilitated successful transseptal puncture in all patients when use of conventional mapping catheters and fluoroscopy proved unhelpful. There were no complications relating to right atrial angiography.ConclusionThese cases highlight a number of difficulties encountered when performing transseptal punctures. Previously reported adjunctive techniques require specialised equipment, general anaesthesia or multiple catheters that may be unavailable or impede the procedure. Right atrial angiography is a simple and safe adjunct to conventional techniques to facilitate complex transseptal procedures.

Tpeak – Tend interval and Tpeak – Tend /QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype

resonance imaging data suggesting right ventricular outflow tract dilatation in patients with Brugada syndrome as the resolution of imaging modalities has improved. 5 This fibrotic process would promote conduction delay in the right ventricle and may explain the presence of a coved ST-segment elevation pattern independent of specific ion channel mutations promoting transmural repolarization gradients. Invasive mapping studies of the right ventricle in patients with Brugada syndrome have confirmed the presence of significant conduction delay, and computer simulations incorporating these delays can reproduce the characteristic surface ECG features. 3,6 These conduction abnormalities could also increase arrhythmogenicity of the substrate through promoting conduction block and re-entry or causing destabilization of VT into VFn. This may help to explain significant variations in presentations and risk of sudden death in this condition. Letsas et al. 7 presented data addressing the problem of refining non-invasive risk stratification in patients with Brugada syndrome. They demonstrated that an increased Tpeak–Tend interval in leads V2 and V6 and Tpeak–Tend/QT ratio in lead V2 were associated with VT/VF inducibility in patients with Brugada syndrome with spontaneous or ajmaline-induced type 1 ECG patterns. The Tpeak–Tend interval-related repolarization parameters were measured in all precordial leads. The Tpeak–Tend/QT ratio now arrives in the context of the recent description of the fragmented QRS and late potentials as other high-risk markers in Brugada syndrome. 8 These surface ECG parameters may reflect common features of the arrhythmogenic substrate and may have the advantage of being non-invasive and capable of tracking progressive changes in the Brugada heart over time. However, there is some controversy as to what the Tpeak–Tend measurements actually represent. Although experiments using left ventricular wedge preparations have shown that the Tpeak–Tend interval was associated with transmural dispersion of repolarization, a study using an in vivo model questioned this. Opthof et al. 9 have demonstrated that the Tpeak–Tend interval represented

The investigation of sudden arrhythmic death syndrome (SADS)—the current approach to family screening and the future role of genomics and stem cell technology

SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon.