CPVT: Arrhythmogenesis, Therapeutic Management, and Future Perspectives. A Brief Review of the Literature.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a primary electrical disease characterized by a normal resting electrocardiogram and induction of malignant arrhythmias during adrenergic stress leading to syncope or sudden cardiac death (SCD). CPVT is caused by mutations in the cardiac ryanodine receptor (RyR2) or in the sarcoplasmic reticulum protein calsequestrin 2 genes (CASQ2). The RyR2 mutations are responsible for the autosomal dominant form of CPVT, while CASQ2 mutations are rare and account for the recessive form. These mutations cause a substantial inballance in the homeostasis of intracellular calcium resulting in polymorphic ventricular tachycardia through triggered activity. Beta blockers were for years the cornerstone of therapy in these patients. Sodium channel blockers, especially flecainide, have an additive role in those not responding in beta blockade. Implantation of defibrillators needs a meticulous evaluation since inappropriate shocks may lead to electrical storm. Finally, cardiac sympathetic denervation might also be an alternative therapeutic option. Early identification and risk stratification is of major importance in patients with CPVT. The aim of the present review is to present the arrhythmogenic mechanisms of the disease, the current therapies applied and potential future perspectives.

Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.

Long-term prognosis of drug-induced Brugada syndrome.

BACKGROUND: Patients with drug-induced Brugada syndrome (BS) are considered at a lower risk than those with a spontaneous type I pattern. Nevertheless, they can present arrhythmic events. OBJECTIVE: The purpose of this study was to investigate their clinical characteristics, long-term prognosis and risk factors. METHODS: A consecutive cohort of 343 patients with drug-induced BS was included and compared with 78 patients with a spontaneous type I pattern. RESULTS: The mean age was 40.7 ± 18.3 years. Sudden cardiac death (SCD) was the clinical presentation in 13 (3.8%) and syncope in 86 (25.1%); 244 (71.1%) were asymptomatic. Patients with drug-induced BS were less frequently men (180 (52.5%) vs 63 (80.8%); P < .01), were more frequently asymptomatic (244 (71.1%) vs 44 (56.4%); P < .01), and had less ventricular arrhythmias (VAs) induced during electrophysiology study (41 (13.2%) vs 31 (42.4%); P < .01). An implantable cardioverter-defibrillator was implanted in 128 patients (37.3%). During a median follow-up of 62.5 months (interquartile range 28.9-115.6 months), 34 patients presented arrhythmic events. The event rate was 1.1% person-year (vs 2.3% person-year in patients with a spontaneous type I pattern; P < .01). Presentation as SCD and inducible VAs were independent risk factors significantly associated with arrhythmic events (adjusted hazard ratio 22.0 and 3.5). Drug-induced BS was related to a better prognosis only in asymptomatic individuals. CONCLUSION: Drug-induced BS has a good prognosis if asymptomatic; however, SCD is possible. Clinical presentation as SCD and inducible VAs during electrophysiology study are independent risk factors for arrhythmic events. In asymptomatic patients, proband status and inducible VAs can help to identify patients at higher risk, but further evidence is needed.

A score model to predict risk of events in patients with Brugada Syndrome.

AIMS: Risk stratification in Brugada Syndrome (BS) remains challenging. Arrhythmic events can occur life-long and studies with long follow-ups are sparse. The aim of our study was to investigate long-term prognosis and risk stratification of BS patients. METHODS AND RESULTS: A single centre consecutive cohort of 400 BS patients was included and analysed. Mean age was 41.1 years, 78 patients (19.5%) had a spontaneous type I electrocardiogram (ECG). Clinical presentation was aborted sudden cardiac death (SCD) in 20 patients (5.0%), syncope in 111 (27.8%) and asymptomatic in 269 (67.3%). Familial antecedents of SCD were found in 184 individuals (46.0%), in 31 (7.8%) occurred in first-degree relatives younger than 35 years. An implantable cardioverter defibrillator (ICD) was placed in 176 (44.0%). During a mean follow-up of 80.7 months, 34 arrhythmic events occurred (event rate: 1.4% year). Variables significantly associated to events were: presentation as aborted SCD (Hazard risk [HR] 20.0), syncope (HR 3.7), spontaneous type I (HR 2.7), male gender (HR 2.7), early SCD in first-degree relatives (HR 2.9), SND (HR 5.0), inducible VA (HR 4.7) and proband status (HR 2.1). A score including ECG pattern, early familial SCD antecedents, inducible electrophysiological study, presentation as syncope or as aborted SCD and SND had a predictive performance of 0.82. A score greater than 2 conferred a 5-year event probability of 9.2%. CONCLUSIONS: BS patients remain at risk many years after diagnosis. Early SCD in first-degree relatives and SND are risk factors for arrhythmic events. A simple risk score might help in the stratification and management of BS patients.

Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms.

Prevalence and Clinical Impact of Early Repolarization Pattern and QRS-Fragmentation in High-Risk Patients With Brugada Syndrome.

BACKGROUND: The phenotypic heterogeneity of Brugada syndrome (BrS) can lead some patients to show an additional inferolateral early repolarization pattern (ERP), or fragmented QRS (f-QRS). The aim of the study was to investigate the prevalence and clinical impact of f-QRS, ERP or combined f-QRS/ERP in high-risk patients with BrS. METHODS AND RESULTS: Patients with spontaneous or drug-induced BrS and an indication to receive an implantable cardioverter-defibrillator (ICD) were considered eligible for this study. From 1992 to 2012, a total of 176 consecutive patients with BrS underwent ICD implantation. Among them, 48 subjects (27.3%) presented with additional depolarization and/or repolarization abnormalities. f-QRS was found in 29 (16.5%), ERP in 15 (8.5%), and combined f-QRS/ERP in 4 patients (2.3%). After a mean follow-up of 95.2±51.9 months, spontaneous sustained ventricular arrhythmias were documented in 8 patients (16.7%). No significant difference was found in the rate of appropriate shocks between patients presenting with f-QRS or ERP and those without abnormalities. Patients with both f-QRS and ERP had a significantly higher rate of appropriate shocks (HR: 4.1; 95% CI: 1.1-19.7; P=0.04). CONCLUSIONS: Fragmented QRS and ERP are common ECG findings in high-risk BrS patients, occurring in up to 27% of cases. When combined, f-QRS and ERP confer a higher risk of appropriate ICD interventions during a very long-term follow-up. (Circ J 2016; 80: 2109-2116).

Single 3-Minute versus Double 4-Minute Freeze Strategy for Second-Generation Cryoballoon Ablation: A Single-Center Experience.

INTRODUCTION: Second-generation cryoballoon (CB-Adv) ablation is highly effective in achieving pulmonary vein isolation (PVI) with promising mid-term clinical outcome. However, the ideal freezing strategy is still under debate. The aim of this study was to assess the efficacy of a single 3-minute approach compared to the conventional 4-minute plus bonus application using CB-Adv. METHODS AND RESULTS: One hundred and sixty patients (67% male; mean age 58.0 ± 13.3 years) underwent PVI using CB-Adv for paroxysmal atrial fibrillation (PAF). Among 160 patients, 80 received a single 3-minute approach (3-mns group), while the remaining 80 conventional 4-minute plus bonus-freeze (4-mns group). Mean procedure and fluoroscopy times were 90.6 ± 15.8 and 18.3 ± 6.9 in the 4-mns group, 75.2 ± 17.1 and 13.5 ± 8.7 in the 3-mns group (P < 0.001, respectively). First-freeze isolation rate was 91.6% in the 4- versus 90.6% in the 3-mns group (P = 0.78). Persistent phrenic nerve palsy (PNP) occurred in 6/80 (3.5%) in the 4-mns group and 4/80 in the 3-mns group (P = 0.75). The overall freedom from ATas 2 years after the procedure was 78.1% (125/160): 77.5% (62/80 patients) in the 3-mns and 78.8% (63/80 patients) in the 4-mns group (P = 0.82). In multivariate analysis, time to PVI and nadir temperature independently predicted ATa recurrences (P < 0.001). CONCLUSIONS: CB-Adv ablation for PAF is highly effective, resulting in 78% 2-year freedom from arrhythmic recurrences. A "single 3-minute strategy" showed equal efficacy as compared to the conventional 4-minute plus bonus freeze approach at 2-year follow-up, providing shorter procedure and fluoroscopy time. Nadir temperature and time to PVI were predictors of arrhythmic recurrences. "Bonus-freeze" strategy might be unnecessary.

Clinical characterisation and long-term prognosis of women with Brugada syndrome.

OBJECTIVES: Brugada syndrome (BS) in women is considered an infrequent condition with a more favourable prognosis than in men. Nevertheless, arrhythmic events and sudden cardiac death (SCD) also occur in this population. Long-term follow-up data of this group are sparse. The purpose of the present study was to investigate the clinical characteristics and long-term prognosis of women with BS. METHODS: A consecutive cohort of 228 women presenting with spontaneous or drug-induced Brugada type I ECG at our institution were included and compared with 314 men with the same diagnosis. RESULTS: Mean age was 41.5±17.3 years. Clinical presentation was SCD in 6 (2.6%), syncope in 51 (22.4%) and the remaining 171 (75.0%) were asymptomatic. As compared with men, spontaneous type I ECG was less common (7.9% vs 23.2%, p<0.01) and less ventricular arrhythmias were induced during programmed electrical stimulation (5.5% vs 22.3%, p<0.01). An implantable cardioverter defibrillator (ICD) was implanted in 64 women (28.1%). During a mean follow-up of 73.2±56.2 months, seven patients developed arrhythmic events, constituting an event rate of 0.7% per year (as compared with 1.9% per year in men, p=0.02). Presentation as SCD or sinus node dysfunction (SND) was risk factor significantly associated with arrhythmic events (hazard risk (HR) 25.4 and 9.1). CONCLUSION: BS is common in women, representing 42% of patients in our database. Clinical presentation is less severe than men, with more asymptomatic status and less spontaneous type I ECG and prognosis is more favourable, with an event rate of 0.7% year. However, women with SCD or previous SND are at higher risk of arrhythmic events.

'The role of novel oral anticoagulants in patients undergoing cryoballoon ablation for atrial fibrillation'.

AIM: Peri-procedural thromboembolic (TE) and hemorrhagic events are complications of major concern for patients undergoing cryoballoon (CB) ablation for atrial fibrillation (AF). While peri-procedural anticoagulation management could decrease the incidence of these complications, data on CB ablation are scarce. The role of novel oral anticoagulants (NOACs) has not been thoroughly tested in this population. METHODS: In the present study, we sought to assess acute peri-procedural complications in patients undergoing CB ablation for AF under different anticoagulation regimens; anticoagulation administration was performed according to the CHA2DS2-VASc score guidelines. To the best of our knowledge, this is the first study that compares 1) uninterrupted warfarin, 2) bridging therapy with low molecular weight heparin (LMWH), 3) aspirin and 4) NOACs in this subgroup of patients. RESULTS: NOACs were as effective as uninterrupted warfarin in terms of bleeding complications and TE events. Surprisingly, the aspirin group had more hemorrhagic complications than both the warfarin and NOACs groups. CONCLUSION: In the current study, the use of NOACs was an effective and safe approach in CB ablation.

Electrophysiological findings following pulmonary vein isolation using radiofrequency catheter guided by contact-force and second-generation cryoballoon: lessons from repeat ablation procedures.

AIMS: To assess the incidence of late pulmonary vein (PV) reconnection following index PV isolation (PVI) procedure initially achieved with radiofrequency contact-force catheter ablation (CFCA) and second-generation cryoballoon ablation (CB-AdvA). METHODS AND RESULTS: A total of 56 consecutive patients (41 male, 73.2%; mean age 60.8 ± 11.8 years) underwent a repeat ablation because of recurrent atrial tachyarrhythmias (ATas) after index PVI achieved with CFCA (30 patients) or CB-AdvA (26 patients). All repeat procedures were performed by the means of CFCA. In the CFCA group, among 119 PVs, 43 (36.1%) showed conduction gaps in 24 patients (1.8 per patient), whereas in the CB-AdvA group among 103 veins, 21 (20.4%) showed a PV reconnection in 18 patients (1.2 per patient) (P = 0.01). The left superior pulmonary vein was less frequently reconnected following CB-AdvA when compared with CFCA (2/25, 8% vs. 11/29, 37.9%; P = 0.01). In the CFCA group, the mean CF per-vein was lower in reconnecting veins when compared with those persistently isolated (10.9 ± 2.7 vs. 18.6 ± 3.1 g; P < 0.001). In the CB-AdvA group, late PV reconnection was associated with warmer nadir temperature (-48.9 ± 5.1 vs. -51.2 ± 4.7°C; P = 0.05) and longer time-to-isolation (71.1 ± 20.2 vs. 50.2 ± 32.9 s; P = 0.03). CONCLUSION: The rate of late PV reconnection is significantly lower following CB-AdvA when compared with CFCA as index procedure. Lower CF values and warmer nadir temperature with longer time to effect were more frequently associated with PV reconnections in the setting of CFCA and CB-AdvA.

Effects of central sympathetic activation on repolarization-dispersion during short-term myocardial ischemia in anesthetized rats.

AIMS: Sympathetic activation during myocardial ischemia enhances arrhythmogenesis, but the underlying pathophysiologic mechanisms remain unclear. We investigated the central sympathetic effects on ventricular repolarization during the early-period post-coronary artery occlusion. MAIN METHODS: We studied 12 Wistar rats (254±2 g) for 30 min following left coronary artery ligation, with (n=6) or without (n=6) pretreatment with the central sympatholytic agent clonidine. Mapping of left and right ventricular epicardial electrograms was performed with a 32-electrode array. As an index of sympathetic activation, heart rate variability in the frequency domain was calculated. Heart rate and repolarization duration were measured with a custom-made recording and analysis software, followed by calculation of intra- and inter-ventricular dispersion of repolarization. KEY FINDINGS: Heart rate and heart rate variability indicated lower sympathetic activation in clonidine-treated rats during ischemia. Repolarization duration in the left ventricle prolonged after clonidine at baseline, independently of heart rate, but no differences were present 30 min post-ligation. Dispersion of repolarization in the right ventricle remained stable during ischemia, whereas it increased in the left ventricle, equally in both groups. A similar trend was observed for inter-ventricular dispersion, without differences between groups. SIGNIFICANCE: In addition to intra-ventricular repolarization-dispersion, anterior-wall myocardial ischemia may also increase inter-ventricular repolarization-dispersion. Progressive central sympathetic activation occurs during myocardial ischemia, but it does not affect intra- or inter-ventricular dispersion of ventricular repolarization during the early phase. Further research is warranted on the potential effects during subsequent time-periods.

P-wave indices as predictors of atrial fibrillation recurrence after pulmonary vein isolation in normal left atrial size.

AIMS: Prolonged P-wave duration and dispersion are universally accepted noninvasive markers for atrial electrical remodeling. Our aim was to analyze P-wave indices as predictors of atrial fibrillation recurrence after pulmonary vein isolation in patients with normal left atrial size. METHODS: From January 2008 to December 2011, 426 patients with drug-resistant symptomatic paroxysmal atrial fibrillation underwent pulmonary vein isolation as an index procedure by conventional radiofrequency or cryoballoon ablation in our center. Patients with left atrial dilatation, poor-quality electrocardiograms, atrial pacemaker stimulation, and those undergoing repeat procedures were excluded. A total of 201 patients were analyzed during a mean follow-up of 22 ±â€Š16 months. RESULTS: Patients with prolonged P-wave duration had higher rates of atrial fibrillation recurrences compared with those without prolonged P-wave duration (49 vs. 14%; P < 0.001). Atrial fibrillation recurrence was significantly associated with prolonged P-wave duration (129 ±â€Š13 vs. 119 ±â€Š11 ms; P < 0.001) and P-wave dispersion (54 ±â€Š12 vs. 42 ±â€Š10 ms; P < 0.001) compared with those who remained in sinus rhythm. P-wave duration and dispersion were independently associated with atrial fibrillation recurrence (hazard ratio 1.045, 95% confidence interval 1.027-1.063, P < 0.001; and hazard ratio 1.049, 95% confidence interval 1.022-1.078, P < 0.001, respectively), after adjusting for left atrial size and age. CONCLUSION: Prolonged P-wave duration and dispersion were found to be independently associated with higher recurrence rates of atrial fibrillation after pulmonary vein isolation in patients with normal left atrial dimension. Therefore, a prolongation of P-wave indices may help to identify those patients in whom electrical remodeling has already occurred and a more extensive ablation may be indicated.

Central Sympathetic Activation and Arrhythmogenesis during Acute Myocardial Infarction: Modulating Effects of Endothelin-B Receptors.

Sympathetic activation during acute myocardial infarction (MI) is an important arrhythmogenic mechanism, but the role of central autonomic inputs and their modulating factors remain unclear. Using the in vivo rat-model, we examined the effects of clonidine, a centrally acting sympatholytic agent, in the presence or absence of myocardial endothelin-B (ETB) receptors. We studied wild-type (n = 20) and ETB-deficient rats (n = 20) after permanent coronary ligation, with or without pretreatment with clonidine. Cardiac rhythm was continuously recorded for 24 h by implantable telemetry devices, coupled by the assessment of autonomic and heart failure indices. Sympathetic activation and arrhythmogenesis were more prominent in ETB-deficient rats during the early phase post-ligation. Clonidine improved these outcomes throughout the observation period in ETB-deficient rats, but only during the delayed phase in wild-type rats. However, this benefit was counterbalanced by atrioventricular conduction abnormalities and by higher incidence of heart failure, the latter particularly evident in ETB-deficient rats. Myocardial ETB-receptors attenuate the arrhythmogenic effects of central sympathetic activation during acute MI. ETB-receptor deficiency potentiates the sympatholytic effects of clonidine and aggravates heart failure. The interaction between endothelin and sympathetic responses during myocardial ischemia/infarction and its impact on arrhythmogenesis and left ventricular dysfunction merits further investigation.

On the Quest for the Best Freeze: Predictors of Late Pulmonary Vein Reconnections After Second-Generation Cryoballoon Ablation.

BACKGROUND: The second-generation cryoballoon is effective in achieving acute pulmonary vein isolation (PVI) and favorable clinical outcome. To date, no data are available on factors affecting late PV reconnection after second-generation cryoballoon ablation. METHODS AND RESULTS: A total of 29 consecutive patients (25 male, 86.2%; mean age 57.8±13.8 years) underwent a repeat procedure, after a mean 11.6±4.5 months (range, 3.5-19.7 months), after index ablation using the 28-mm second-generation cryoballoon. All repeat ablations were performed using a 3-dimensional electroanatomical mapping system. Among all 115 PVs, including 1 left common ostiums (LCOs), 25 (21.7%) showed a PV reconnection in 20 patients (1.25 per patient). Persistent PVI could be documented in 90 of 115 PVs (78.2%). In 9 of 29 patients (31%), all PVs were electrically isolated. In the multivariable analysis, time to PVI (P=0.03) and failure to achieve -40°C within 60 s (P=0.05) independently predicted late PV reconnection. At receiver-operator curve analysis, time to PVI <60 s identified the absence of PV reconduction (sensitivity, 86.7%; specificity, 86.2%; positive predictive value, 59.1%; and negative predictive value, 96.4%; area under the curve, 0.85; confidence interval, 0.73-0.97; P<0.001). CONCLUSIONS: The rate of late PV reconnection after second-generation cryoballoon ablation is low (1.25 PVs/patient). Faster time to isolation and achievement of -40°C within 60 s independently predict durable PVI. In addition, 60-s cut-off for time to PVI indicates persistent isolation with 96.4% negative predictive value. These parameters might guide the operator whether to perform further applications to ensure a long-lasting PVI.