Maurizio Gasparini

Clinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Background—Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined. Methods and Results—Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart entered the study. The clinical phenotype of the 30 probands and of 118 family members was evaluated, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia, 12 of 30 polymorphic ventricular tachycardia, and 4 of 30 catecholaminergic idiopathic ventricular fibrillation;RyR2 mutations were identified in 14 of 30 probands (36% bidirectional ventricular tachycardia, 58% polymorphic ventricular tachycardia, 50% catecholaminergic idiopathic ventricular fibrillation) and in 9 family members (4 silent gene carriers). Genotype-phenotype analysis showed that patients with RyR2 CPVT have events at a younger age than do patients with nongenotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative risk=4.2). Conclusions—CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. &bgr;-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: Patients with nongenotyped CPVT are predominantly women and become symptomatic later in life; patients with RyR2 CPVT become symptomatic earlier, and men are at higher risk of cardiac events. These data provide a rationale for prompt evaluation and treatment of young men with RyR2 mutations.

Clinical and Genetic Heterogeneity of Right Bundle Branch Block and ST-Segment Elevation Syndrome A Prospective Evaluation of 52 Families

BackgroundThe ECG pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups. Methods and ResultsSixty patients (45 males aged 40±15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33±38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%). ConclusionsAt variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.

Risk Stratification in Brugada Syndrome: Results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) Registry

OBJECTIVES The PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) prospective registry was designed to assess the predictive accuracy of sustained ventricular tachycardia/ventricular fibrillation (VTs/VF) inducibility and to identify additional predictors of arrhythmic events in Brugada syndrome patients without history of VT/VF. BACKGROUND Brugada syndrome is a genetic disease associated with increased risk of sudden cardiac death. Even though its value has been questioned, inducibility of VTs/VF is widely used to select candidates to receive a prophylactic implantable defibrillator, and its accuracy has never been addressed in prospective studies with homogeneous enrolling criteria. METHODS Patients with a spontaneous or drug-induced type I electrocardiogram (ECG) and without history of cardiac arrest were enrolled. The registry included 308 consecutive individuals (247 men, 80%; median age 44 years, range 18 to 72 years). Programmed electrical stimulation was performed at enrollment, and patients were followed-up every 6 months. RESULTS During a median follow-up of 34 months, 14 arrhythmic events (4.5%) occurred (13 appropriate shocks of the implantable defibrillator, and 1 cardiac arrest). Programmed electrical stimulation performed with a uniform and pre-specified protocol induced ventricular tachyarrhythmias in 40% of patients: arrhythmia inducibility was not a predictor of events at follow-up (9 of 14 events occurred in noninducible patients). History of syncope and spontaneous type I ECG (hazard ratio [HR]: 4.20), ventricular refractory period <200 ms (HR: 3.91), and QRS fragmentation (HR: 4.94) were significant predictors of arrhythmias. CONCLUSIONS Our data show that VT/VF inducibility is unable to identify high-risk patients, whereas the presence of a spontaneous type I ECG, history of syncope, ventricular effective refractory period <200 ms, and QRS fragmentation seem useful to identify candidates for prophylactic implantable cardioverter defibrillator.

Assessment of Atrioventricular Junction Ablation and DDDR Mode-Switching Pacemaker Versus Pharmacological Treatment in Patients With Severely Symptomatic Paroxysmal Atrial Fibrillation A Randomized Controlled Study

BACKGROUND The purpose of the study was to evaluate the effect of AV junction ablation and pacemaker implantation on quality of life and specific symptoms in patients with paroxysmal atrial fibrillation (AF) not controlled by drugs. METHODS AND RESULTS We performed a multicenter, randomized, 6-month evaluation of the clinical effects of AV junction ablation and DDDR mode-switching pacemaker (Abl+Pm) versus pharmacological treatment in 43 patients with intolerable, recurrent paroxysmal AF of three or more episodes in the previous 6 months not controlled with three or more antiarrhythmic drugs. Before completion of the study, 3 patients in the drug group withdrew because of the severity of their symptoms and 1 patient assigned to the Abl+Pm group in whom the ablation procedure failed. At the end of the 6 months, the 21 patients of the Abl+Pm group who completed the study showed, in comparison with the 18 of the drug group, lower scores in the Living with Heart Failure Questionnaire (-51%, P=.0006), palpitations (-71%, P=.0000), effort dyspnea (-36%, P=.04), exercise intolerance score (-46%, P=.001), and easy fatigue (-51%, P=.02). The scores for rest dyspnea, chest discomfort, and NYHA functional classification were also lower (-56%, -50%, and -17%, respectively) in the Abl+Pm group, although not significantly. At the end of the study, palpitations were no longer present in 81% of the Abl+Pm group and in 11% of the drug group (P=.0000). AF was documented in 31 of 122 visits (25%) in the Abl+Pm group and in 9 of 107 examinations (8%) in the drug group (P=.0005); chronic AF developed in 5 (24%) and 0 (0%) in the two groups, respectively (P=.04). CONCLUSIONS In patients with paroxysmal AF not controlled by pharmacological therapy, Abl+Pm treatment is highly effective and superior to drug therapy in controlling symptoms and improving quality of life. The discontinuation of drug therapy exposes patients to further recurrences of paroxysmal AF and the risk of developing permanent AF.

Effect of Long-Detection Interval vs Standard-Detection Interval for Implantable Cardioverter-Defibrillators on Antitachycardia Pacing and Shock Delivery: The ADVANCE III Randomized Clinical Trial

IMPORTANCE Using more intervals to detect ventricular tachyarrhythmias has been associated with reducing unnecessary implantable cardioverter-defibrillator (ICD) therapies. OBJECTIVE To determine whether using 30 of 40 intervals to detect ventricular arrhythmias (VT) (long detection) during spontaneous fast VT episodes reduces antitachycardia pacing (ATP) and shock delivery more than 18 of 24 intervals (standard detection). DESIGN, SETTING, AND PARTICIPANTS Randomized, single-blind, parallel-group trial that enrolled 1902 primary and secondary prevention patients (mean [SD] age, 65 [11] years; 84% men; 75% primary prevention ICD) with ischemic and nonischemic etiology undergoing first ICD implant at 1 of 94 international centers (March 2008-December 2010). INTERVENTIONS Patients were randomized 1:1 to programming with long- (n = 948) or standard-detection (n = 954) intervals. MAIN OUTCOMES AND MEASURES Total number of ATPs and shocks delivered for all episodes (primary outcomes) and inappropriate shocks, mortality, and syncopal rate (secondary outcomes). RESULTS During a median follow-up of 12 months (interquartile range, 11-13), long-detection group had 346 delivered therapies (42 therapies per 100 person-years, 95% CI, 38-47) vs 557 in the standard-detection group (67 therapies per 100 person-years [95% CI, 62-73]; incident rate ratio [IRR], 0.63 [95% CI, 0.51-0.78]; P < .001). The long- vs the standard-detection group experienced 23 ATPs per 100 person-years (95% CI, 20-27) vs 37 ATPs per 100 person-years (95% CI, 33-41; IRR, 0.58 [95% CI, 0.47-0.72]; P < .001); 19 shocks per 100 person-years (95% CI, 16-22) vs 30 shocks per 100 person-years (95% CI, 26-34; IRR, 0.77 [95% CI, 0.59-1.01]; P = .06), with a significant difference in the probability of therapy occurrence (P < .001); and a reduction in first occurrence of inappropriate shock (5.1 per 100 patient-years [95% CI, 3.7-6.9] vs 11.6 [95% CI, 9.4-14.1]; IRR, 0.55 [95% CI, 0.36-0.85]; P = .008). Mortality (5.5 [95% CI, 4.0-7.2] vs 6.3 [95% CI, 4.8-8.2] per 100 patient-years; HR, 0.87; P = .50) and arrhythmic syncope rates (3.1 [95% CI, 2.6-4.6] vs 1.9 [95% CI, 1.1-3.1] per 100 patient-years; IRR, 1.60 [95% CI, 0.76-3.41]; P = .22) did not differ significantly between groups. CONCLUSIONS AND RELEVANCE Among patients receiving an ICD, the use of a long- vs standard-detection interval resulted in a lower rate of ATP and shocks, and inappropriate shocks. This programming strategy may be an appropriate alternative. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00617175.

Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation

Aims To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. Methods and results Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57–1.42), P = 0.64 and 1.00 (0.60–1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09–0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10–0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03–0.70, P = 0.016) for HF mortality. Conclusion Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death.

Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: Data from the European Long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry

Background— A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results— The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age 500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions— Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary. # Clinical Perspective {#article-title-18}Background— A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results— The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age <20 years at implantation, a QTc >500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions— Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary.

Device-detected atrial fibrillation and risk for stroke: an analysis of >10 000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices)

Objective The aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke. Background Cardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden. Design, setting, and patients A pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed. Results During a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3–14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22–3.64, P = 0.008). Conclusions Device-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.

Pretreatment with verapamil in patients with persistent or chronic atrial fibrillation who underwent electrical cardioversion

OBJECTIVES To evaluate, in a prospective and randomized fashion, the efficacy of a pretreatment with verapamil (V) in reducing recurrences of atrial fibrillation (AF) after electrical cardioversion (C). BACKGROUND The increased vulnerability for AF recurrence is probably due to AF-induced changes in the electrophysiologic properties of the atria. This electrical remodeling seems to be due to intracellular calcium overload. METHODS One hundred seven patients with persistent or chronic AF underwent external and/or internal C. All patients received oral propafenone (P) (900 mg/day) three days before and during the entire period of follow-up (three months). In the first group, patients received only the P. In the second group, in adjunct to P, oral V (240 mg/day) was initiated three days before C and continued during the follow-up. Finally, in the third group, oral V was administered three days before and continued only for three days after electrical C. RESULTS During the three months of follow-up, 23 patients (23.7%) had AF recurrence. Mantel-Haenszel cumulative chi-square reached a significant level only when comparing AF free survival curves of group I versus group II and group III (chi-square = 5.2 and 4, respectively; p < 0.05). Significantly, 15 (65.2%) AF relapses occurred during the first week after cardioversion with a higher incidence in group I (10/33 patients, 30.3%) than group II (2/34 patients, 5.9%; p = 0.01) and group III (3/30 patients, 10%; p = 0.04). CONCLUSIONS Six days of oral V administration centered on the C day, combined with P, significantly reduce the incidence of early recurrences of AF compared with P alone.

Investigation of a novel algorithm for synchronized left-ventricular pacing and ambulatory optimization of cardiac resynchronization therapy: Results of the adaptive CRT trial

BACKGROUND In patients with sinus rhythm and normal atrioventricular conduction, pacing only the left ventricle with appropriate atrioventricular delays can result in superior left ventricular and right ventricular function compared with standard biventricular (BiV) pacing. OBJECTIVE To evaluate a novel adaptive cardiac resynchronization therapy ((aCRT) algorithm for CRT pacing that provides automatic ambulatory selection between synchronized left ventricular or BiV pacing with dynamic optimization of atrioventricular and interventricular delays. METHODS Patients (n = 522) indicated for a CRT-defibrillator were randomized to aCRT vs echo-optimized BiV pacing (Echo) in a 2:1 ratio and followed at 1-, 3-, and 6-month postrandomization. RESULTS The study met all 3 noninferiority primary objectives: (1) the percentage of aCRT patients who improved in their clinical composite score at 6 months was at least as high in the aCRT arm as in the Echo arm (73.6% vs 72.5%, with a noninferiority margin of 12%; P = .0007); (2) aCRT and echo-optimized settings resulted in similar cardiac performance, as demonstrated by a high concordance correlation coefficient between aortic velocity time integrals at aCRT and Echo settings at randomization (concordance correlation coefficient = 0.93; 95% confidence interval 0.91-0.94) and at 6-month postrandomization (concordance correlation coefficient = 0.90; 95% confidence interval 0.87-0.92); and (3) aCRT did not result in inappropriate device settings. There were no significant differences between the arms with respect to heart failure events or ventricular arrhythmia episodes. Secondary end points showed similar benefit, and right-ventricular pacing was reduced by 44% in the aCRT arm. CONCLUSIONS The aCRT algorithm is safe and at least as effective as BiV pacing with comprehensive echocardiographic optimization.