Arrhythmogenic substrate elimination for safe testosterone therapy in symptomatic Brugada syndrome patients.

BACKGROUND: Brugada Syndrome (BrS) is a cardiogenetic disease known for its association with sudden cardiac death (SCD) in individuals with structurally normal hearts. The prevalence of BrS is higher in males, who also face a greater risk of SCD. Its higher prevalence and worse outcome in male subjects may be due to testosterone effects on ion channels expression and function. The influence of testosterone on cardiac action potentials, both genomically and non-genomically, underscores its potential role in unmasking the syndrome and triggering life-threatening arrhythmias. Notably, testosterone replacement therapy (TRT), used for hypogonadism and gender reassignment, has been linked to BrS unmasking. The role of epicardial ablation in symptomatic BrS patients where hormonal therapy cannot be discontinued is unknown. METHODS AND RESULTS: In this study we describe the first two cases of substrate mapping and ablation in BrS patients experiencing arrhythmic events while on TRT. In both cases, high-density epicardial mapping revealed abnormal areas of prolonged and fragmented electrograms in the right ventricular (RV) outflow tract and anterior wall. These abnormalities were completely abolished by radiofrequency ablation (RFA). After ablation, both patients showed a persistent normalization of the ECG and were free from ventricular arrhythmias at follow-up, despite ongoing TRT. CONCLUSION: RFA can be considered as a therapeutic option in symptomatic BrS patients with a high-risk profile who cannot discontinue TRT, being essential for restoring their normal physiology or preserving their sexual identity. As testosterone use is increasing, further studies are warranted to define a standardized diagnostic and therapeutic strategy in this specific subset of BrS patients.

Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.

AIMS: The long-QT syndrome (LQTS) represents a leading cause of sudden cardiac death (SCD). The aim of this study was to assess the presence of an underlying electroanatomical arrhythmogenic substrate in high-risk LQTS patients. METHODS AND RESULTS: The present study enrolled 11 consecutive LQTS patients who had experienced frequent implantable cardioverter-defibrillator (ICD discharges triggered by ventricular fibrillation (VF). We acquired electroanatomical biventricular maps of both endo and epicardial regions for all patients and analyzed electrograms sampled from several myocardial regions. Abnormal electrical activities were targeted and eliminated by the means of radiofrequency catheter ablation. VF episodes caused a median of four ICD discharges in eleven patients (6 male, 54.5%; mean age 44.0 ± 7.8 years, range 22-53) prior to our mapping and ablation procedures. The average QTc interval was 500.0 ± 30.2 ms. Endo-epicardial biventricular maps displayed abnormally fragmented, low-voltage (0.9 ± 0.2 mV) and prolonged electrograms (89.9 ± 24.1 ms) exclusively localized in the right ventricular epicardium. We found electrical abnormalities extending over a mean epicardial area of 15.7 ± 3.1 cm2. Catheter ablation of the abnormal epicardial area completely suppressed malignant arrhythmias over a mean 12 months of follow-up (median VF episodes before vs. after ablation, 4 vs. 0; P = 0.003). After the procedure, the QTc interval measured in a 12-lead ECG analysis shortened to a mean of 461.8 ± 23.6 ms (P = 0.004). CONCLUSION: This study reveals that, among high-risk LQTS patients, regions localized in the epicardium of the right ventricle harbour structural electrophysiological abnormalities. Elimination of these abnormal electrical activities successfully prevented malignant ventricular arrhythmia recurrences.

High-risk Brugada syndrome: factors associated with arrhythmia recurrence and benefits of epicardial ablation in addition to implantable cardioverter defibrillator implantation.

AIMS: This study aims to evaluate the prognostic impact of the arrhythmogenic substrate size in symptomatic Brugada syndrome (BrS) as well as to validate the long-term safety and effectiveness of epicardial radiofrequency ablation (RFA) compared with no-RFA group. METHODS AND RESULTS: In this prospective investigational long-term registry study, 257 selected symptomatic BrS patients with implantable cardioverter defibrillator (ICD) implantation were included. Among them, 206 patients underwent epicardial RFA and were monitored for over 5 years post-ablation (RFA group), while 51 patients received only ICD implantation declining RFA. Primary endpoints included risk factors for ventricular fibrillation (VF) events pre-ablation and freedom from VF events post-ablation. In the RFA group, BrS substrates were identified in the epicardial surface of the right ventricle. During the pre-RFA follow-up period (median 27 months), VF episodes and VF storms were experienced by 53 patients. Independent risk factors included substrate size [hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.08-1.18; P < 0.001], aborted cardiac arrest (HR, 2.98; 95% CI, 1.68-5.28; P < 0.001), and SCN5A variants (HR, 2.22; 95% CI, 1.15-4.27; P = 0.017). In the post-RFA follow-up (median 40 months), the RFA group demonstrated superior outcomes compared with no-RFA (P < 0.001) without major procedure-related complications. CONCLUSION: Our study underscores the role of BrS substrate extent as a crucial prognostic factor for recurrent VF and validates the safety and efficacy of RFA when compared with a no-RFA group. Our findings highlight the importance of ajmaline in guiding epicardial mapping/ablation in symptomatic BrS patients, laying the groundwork for further exploration of non-invasive methods to guide informed clinical decision-making.

Brugada syndrome genetics is associated with phenotype severity.

AIMS: Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS. METHODS AND RESULTS: Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area. CONCLUSION: In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths.

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

Non-paroxysmal atrial fibrillation mapping: characterization of the electrophysiological substrate using a novel integrated mapping technique.

AIMS: Clinical outcomes after radiofrequency catheter ablation (RFCA) remain suboptimal in the treatment of non-paroxysmal atrial fibrillation (AF). Electrophysiological mapping may improve understanding of the underlying mechanisms. To describe the arrhythmia substrate in patients with persistent (Pers) and long-standing persistent (LSPers) AF, undergoing RFCA, using an integrated mechanism mapping technique. METHODS AND RESULTS: Patients underwent high-density electroanatomical mapping before and after catheter ablation. Integrated maps characterized electrogram (EGM) cycle length (CL) in regions with repetitive-regular (RR) activations, stable wavefront propagation, fragmentation, and peak-to-peak bipolar voltage. Among 83 patients (72% male, 60 ± 11 years old), RR activations were identified in 376 regions (mean CL 180 ± 31 ms). PersAF patients (n = 43) showed more RR sites per patient (5.3 ± 2.4 vs. 3.7 ± 2.1, P = 0.002) with faster CL (166 ± 29 vs. 190 ± 29 ms; P < 0.001) and smaller surface area of fragmented EGMs (15 ± 14% vs. 27 ± 17%, P < 0.001) compared with LSPersAF. The post-ablation map in 50 patients remaining in AF, documented reduction of the RR activities per patient (1.5 ± 0.7 vs. 3.7 ± 1.4, P < 0.001) and area of fragmentation (22 ± 17% vs. 8 ± 9%, P < 0.001). Atrial fibrillation termination during ablation occurred at RR sites (0.48 ± 0.24 mV; 170.5 ± 20.2 ms CL) in 31/33 patients (94%). At the latest follow-up, arrhythmia freedom was higher among patients receiving ablation >75% of RR sites (Q4 82.6%, Q3 63.1%, Q2 35.1%, and Q1 0%; P < 0.001). CONCLUSION: The integrated mapping technique allowed characterization of multiple arrhythmic substrates in non-paroxysmal AF patients. This technique might serve as tool for a substrate-targeted ablation approach.

Non-invasive assessment of the arrhythmogenic substrate in Brugada syndrome using signal-averaged electrocardiogram: clinical implications from a prospective clinical trial.

AIMS: Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs. METHODS AND RESULTS: Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P < 0.001) with more delayed potentials (220.4 ± 46.0 vs. 186.7 ± 42.3 ms, P < 0.001). Late potentials were present in 82/96 (85.4%) Group 1 and in 31/154 (20.1%) Group 2 individuals (P < 0.001). Patients exhibiting LPs had more frequently a spontaneous Type 1 pattern (30.1% vs. 10.9%, P < 0.001), SCN5A mutation (34.5% vs. 21.2%, P = 0.02), and exhibited a larger AS with longer potentials (5.8 ± 2.7 vs. 2.2 ± 1.7 cm2; 231.2 ± 37.3 vs. 213.8 ± 39.0 ms; P < 0.001, respectively). Arrhythmogenic substrate dimension was the strongest predictor of the presence of LPs (odds ratio 1.9; P < 0.001). An AS area of at least 3.5 cm2 identified patients with LPs (area under the curve 0.88, 95% confidence interval 0.843-0.931; P < 0.001) with a sensitivity of 86%, specificity 88%, positive predictive value 85%, and negative predictive value 89%. CONCLUSION: The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity.ClinicalTrials.gov number (NCT02641431; NCT03106701).

Multipoint pacing improves peripheral hemodynamic response: Noninvasive assessment using radial artery tonometry.

BACKGROUND: Multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], Abbott, Sylmar, CA, USA) improves the response rate to cardiac resynchronization therapy (CRT). We evaluated the feasibility of noninvasive radial artery tonometry (RAT) to characterize arterial pressure morphology changes (pre-ejection period [PEP] and ejection duration [ED]) between conventional CRT and MPP pacing interventions. METHODS: Patients with a MPP-enabled CRT device (Quadra Assura MP™, Abbott) underwent noninvasive RAT assessment (SphygmoCor CVMS, AtCor Medical Inc., Itasca, IL, USA) at 3-6 months after implantation. A pacing protocol was performed in a randomized order including one optimized conventional biventricular CRT (CONV) configuration using the distal electrode and five MPP configurations. The PEP, ED, and PEP/ED ratio were determined for each intervention from the RAT pressure waveform and electrocardiogram. RESULTS: Pressure waveforms were successfully recorded in 19 patients (89% male, QRS 147 ± 16 ms, 63% ischemic). In 17/19 (89%) patients, at least one MPP intervention resulted in improved PEP, ED, and PEP/ED compared to CONV. The MPP intervention with greatest separation of LV cathodes and minimum intra-LV delay significantly improved PEP (mean PEP -15 ± 33% vs -8 ± 32% [CONV], P = 0.04) and ED (mean ED +8 ± 8% [MPP] vs +4 ± 7% [CONV], P = 0.02), and PEP/ED (-0.07 ± 0.14 [MPP] vs -0.04 ± 0.13 [CONV], P = 0.02) compared with CONV. CONCLUSIONS: Noninvasive RAT efficiently characterizes changes in PEP and ED between CONV and MPP interventions. MPP configurations using the widest separation among LV cathodes and minimum intra-LV delay may significantly improve RAT-derived parameters as compared to conventional CRT.

Atrial fibrillation detection using a novel three-vector cardiac implantable monitor: the atrial fibrillation detect study.

AIMS: Continuous rhythm monitoring is valuable for adequate atrial fibrillation (AF) management in the clinical setting. Subcutaneous leadless implantable cardiac monitors (ICMs) yield an improved AF detection, overcoming the intrinsic limitations of the currently available external recording systems, thus resulting in a more accurate patient treatment. The study purpose was to assess the detection performance of a novel three-vector ICM device equipped with a dedicated AF algorithm. METHODS AND RESULTS: Sixty-six patients (86.4% males; mean age 60.4 ± 9.4 years) at risk to present AF episodes, having undergone the novel ICM implant (BioMonitor, Biotronik SE&Co. KG, Berlin, Germany), were enrolled. External 48-h ECG Holter was performed 4 weeks after the device implantation. The automatic ICM AF classification was compared with the manual Holter arrhythmia recordings. Of the overall study population, 63/66 (95.5%) had analysable Holter data, 39/63 (62%) showed at least one true AF episode. All these patients had at least one AF episode stored in the ICM. On Holter monitoring, 24/63 (38%) patients did not show AF episodes, in 16 of them (16/24, 67%), the ICM confirmed the absence of AF. The AF detection sensitivity and positive predictive value for episodes' analysis were 95.4 and 76.3%, respectively. CONCLUSION: Continuous monitoring using this novel device, equipped with a dedicated detection algorithm, yields an accurate and reliable detection of AF episodes. The ICM is a promising tool for tailoring individual AF patient management. Further long-term prospective studies are necessary to confirm these encouraging results.

Wolff-Parkinson-White syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.

BACKGROUND: The management of Wolff-Parkinson-White is based on the distinction between asymptomatic and symptomatic presentations, but evidence is limited in the asymptomatic population. METHODS AND RESULTS: The Wolff-Parkinson-White registry was an 8-year prospective study of either symptomatic or asymptomatic Wolff-Parkinson-White patients referred to our Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-RFA group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-RFA group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (P<0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation (P<0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P<0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds. CONCLUSIONS: The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes.

Multipoint left ventricular pacing in a single coronary sinus branch improves mid-term echocardiographic and clinical response to cardiac resynchronization therapy.

INTRODUCTION: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing in a single coronary sinus branch improves acute LV function. We hypothesized that multipoint pacing (MPP) can improve midterm echocardiographic and clinical response compared with conventional CRT. METHODS AND RESULTS: Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical, Sylmar, CA, USA) were randomized to receive biventricular (BiV) pacing with either conventional LV pacing (CONV group) or MPP (MPP group). For each patient, an optimal pacing configuration for the assigned pacing mode was programmed based on intraoperative pressure-volume (PV) loop measurements. A clinical evaluation and transthoracic echocardiogram were performed before implant (BASELINE) and at 3 months postimplant and analyzed by a blinded observer. A reduction in end-systolic volume (ESV) of ≥15% relative to BASELINE was prospectively defined as response to CRT. Forty-four patients (NYHA Class III, EF 29 ± 6%, QRS duration 152 ± 17 milliseconds) were enrolled and randomized. One patient in the MPP group was lost to follow-up and excluded from further analysis. After 3 months, 11 of 22 (50%) CONV patients and 16 of 21 (76%) MPP patients were classified as responders. ESV reduction, EF increase, and NYHA class reduction relative to BASELINE were significantly greater in the MPP group than in the CONV group (ESV: -21.0 ± 13.9 vs. -12.6 ± 11.1%, P = 0.03; EF: +9.8 ± 5.1 vs. +2.0 ± 7.8 percentage points, P < 0.001; ΔNYHA: -1.05 ± 0.22 vs. -0.72 ± 0.46 functional classes, P = 0.006). CONCLUSION: PV loop optimized BiV pacing with MPP resulted in an improved rate of response to CRT.

Risk of malignant arrhythmias in initially symptomatic patients with Wolff-Parkinson-White syndrome: results of a prospective long-term electrophysiological follow-up study.

BACKGROUND: The available amount of detailed long-term data in patients with Wolff-Parkinson-White syndrome is limited, and no prospective electrophysiological studies looking at predictors of malignant arrhythmia are available. METHODS AND RESULTS: Among 8575 symptomatic Wolff-Parkinson-White patients with atrioventricular reentrant tachycardia referred for electrophysiological test, 369 (mean age, 23±12.5 years) declined catheter ablation and were followed up. The primary end point of the study was to evaluate over a 5-year follow-up the predictors and characteristics of patients who develop malignant arrhythmias. After a mean follow-up of 42.1±10 months, malignant arrhythmias developed in 29 patients (mean age, 13.9±5.6 years; 26 male), resulting in presyncope/syncope (25 patients), hemodynamic collapse (3 patients), or cardiac arrest caused by ventricular fibrillation (1 patient). Of the remaining 340 patients, 168 (mean age, 34.2±9.0 years) remained asymptomatic up to 5 years, and 172 (mean age, 13.6±5.1 years) had benign recurrence, including sustained atrioventricular reentrant tachycardia (132 patients) or atrial fibrillation (40 patients). Compared with the group with no malignant arrhythmias, the group with malignant arrhythmias showed shorter accessory-pathway effective refractory period (P<0.001) and more often exhibited multiple accessory pathways (P<0.001), and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation was more frequently inducible (P<0.001). Multivariable analysis demonstrated that short accessory-pathway effective refractory period (P<0.001) and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation (P<0.001) were independent predictors of malignant arrhythmias. CONCLUSIONS: Symptomatic patients with Wolff-Parkinson-White syndrome generally have a good outcome, and predictors of malignant arrhythmias are similar to those reported for asymptomatic patients with ventricular pre-excitation.

Electrocardiographic temporo-spatial assessment of depolarization and repolarization changes after epicardial arrhythmogenic substrate ablation in Brugada syndrome.

Aims: In Brugada syndrome (BrS), with spontaneous or ajmaline-induced coved ST elevation, epicardial electro-anatomic potential duration maps (epi-PDMs) were detected on a right ventricle (RV) outflow tract (RVOT), an arrhythmogenic substrate area (AS area), abolished by epicardial-radiofrequency ablation (EPI-AS-RFA). Novel CineECG, projecting 12-lead electrocardiogram (ECG) waveforms on a 3D heart model, previously localized depolarization forces in RV/RVOT in BrS patients. We evaluate 12-lead ECG and CineECG depolarization/repolarization changes in spontaneous type-1 BrS patients before/after EPI-AS-RFA, compared with normal controls. Methods and results: In 30 high-risk BrS patients (93% males, age 37 + 9 years), 12-lead ECGs and epi-PDMs were obtained at baseline, early after EPI-AS-RFA, and late follow-up (FU) (2.7-16.1 months). CineECG estimates temporo-spatial localization during depolarization (Early-QRS and Terminal-QRS) and repolarization (ST-Tpeak, Tpeak-Tend). Differences within BrS patients (baseline vs. early after EPI-AS-RFA vs. late FU) were analysed by Wilcoxon signed-rank test, while differences between BrS patients and 60 age-sex-matched normal controls were analysed by the Mann-Whitney test. In BrS patients, baseline QRS and QTc durations were longer and normalized after EPI-AS-ATC (151 ± 15 vs. 102 ± 13 ms, P < 0.001; 454 ± 40 vs. 421 ± 27 ms, P < 0.000). Baseline QRS amplitude was lower and increased at late FU (0.63 ± 0.26 vs. 0.84 ± 13 ms, P < 0.000), while Terminal-QRS amplitude decreased (0.24 ± 0.07 vs. 0.08 ± 0.03 ms, P < 0.000). At baseline, CineECG depolarization/repolarization wavefront prevalently localized in RV/RVOT (Terminal-QRS, 57%; ST-Tpeak, 100%; and Tpeak-Tend, 61%), congruent with the AS area on epi-PDM. Early after EPI-AS-RFA, RV/RVOT localization during depolarization disappeared, as Terminal-QRS prevalently localized in the left ventricle (LV, 76%), while repolarization still localized on RV/RVOT [ST-Tpeak (44%) and Tpeak-Tend (98%)]. At late FU, depolarization/repolarization forces prevalently localized in the LV (Terminal-QRS, 94%; ST-Tpeak, 63%; Tpeak-Tend, 86%), like normal controls. Conclusion: CineECG and 12-lead ECG showed a complex temporo-spatial perturbation of both depolarization and repolarization in BrS patients, prevalently localized in RV/RVOT, progressively normalizing after epicardial ablation.

Prediction of a good response to cardiac resynchronization therapy in patients with severe dilated cardyomyopathy: could conventional echocardiography be the answer after all?

OBJECTIVES: The aim of this study was to assess the performance of echocardiographic parameters to predict response to cardiac resynchronization therapy (CRT). BACKGROUND: CRT reduces morbidity and mortality due to the proper selection of candidates for CRT. METHODS: The 12-month trial was performed on 70 optimally medicated patients with standard inclusion criteria: NYHA class III or IV heart failure, left ventricular ejection fraction (LVEF) ≤ 35%, and QRS ≥ 120 ms. All parameters were evaluated by conventional and tissue Doppler-based methods. Indicator of positive CRT response was more than 20% in improvement of LVEF. RESULTS: LVEF increased >20% in 42 patients. Out of 43 tested baseline echocardiographic parameters, 12 showed statistical difference between responders and nonresponders. Out of these 12 parameters, six (LVSV, LVSI, LVFS, RVd, VPMR, and PISA) had modest to moderately good ability to predict LVEF response with sensitivity ranging from 62.2% to 82.4%, and specificity ranging from 56.5% to 81.2%. For those parameters, the area under the receiver-operating characteristic curve for positive response to CRT was ≤0.76. Multivariate regression analysis resulted in selection of LVSI and LVFS as possible predictive independent parameters for a good response. The cutoff value for LVSI was 38.7 mL/m(2) (P = 0.045) and for LVFS was 13% (P = 0.032). CONCLUSIONS: Contribution of LVSI and LVFS is to be confirmed in larger trials. Simplicity of their assessment by conventional echocardiography could be an argument for adding them to the inclusion criteria for CRT in severe heart failure patients.

Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.

BACKGROUND: In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS. METHODS: The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined. RESULTS: In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results. CONCLUSIONS: In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.

New electromechanical substrate abnormalities in high-risk patients with Brugada syndrome.

BACKGROUND: The relationship between the typical electrocardiographic pattern and electromechanical abnormalities has never been systematically explored in Brugada syndrome (BrS). OBJECTIVES: The aims of this study were to characterize the electromechanical substrate in patients with BrS and to evaluate the relationship between electrical and mechanical abnormalities. METHODS: We enrolled 50 consecutive high-risk patients with BrS (mean age 42 ± 7.2 years), with implantable cardioverter-defibrillator implantation for primary or secondary prevention of ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]), undergoing substrate mapping and ablation. Patients underwent 3-dimensional (3D) echocardiography with 3D wall motion/deformation quantification and electroanatomic mapping before and after ajmaline administration (1 mg/kg in 5 minutes); 3D mechanical changes were compared with 50 age- and sex-matched controls. The effect of substrate ablation on electromechanical abnormalities was also assessed. RESULTS: In all patients, ajmaline administration induced Brugada type 1 pattern, with a significant increase in the electrical substrate (P < .001), particularly in patients with previous spontaneous VT/VF (P = .007). Induction of Brugada pattern was associated with lowering of right ventricular (RV) ejection fraction (P < .001) and worsening of 3D RV mechanical function (P < .001), particularly in the anterior free wall of the RV outflow tract, without changes in controls. RV electrical and mechanical abnormalities were highly correlated (r = 0.728, P < .001). By multivariate analysis, only the area of RV dysfunction was an independent predictor of spontaneous VT/VF (odds ratio 1.480; 95% confidence interval 1.159-1.889; P = .002). Substrate ablation abolished both BrS-electrocardiographic pattern and mechanical abnormalities, despite ajmaline rechallenge. CONCLUSION: BrS is an electromechanical disease affecting the RV. The typical BrS pattern reflects an extensive RV arrhythmic substrate, driving consistent RV mechanical abnormalities. Substrate ablation abolished both Brugada pattern and mechanical abnormalities.

Multipoint left ventricular pacing improves response to cardiac resynchronization therapy with and without pressure-volume loop optimization: comparison of the long-term efficacy of two different programming strategies.

PURPOSE: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. METHODS: Patients undergoing CRT implant (Quadra Assura MP™ CRT-D and Quartet™ LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of ≥ 15% relative to baseline at 6 months as determined by a blinded observer. RESULTS: Patient characteristics at baseline (NYHA II-III, ejection fraction [EF] 27 ± 6%, QRS 151 ± 17 ms) were not significantly different between the PVL-OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p = 0.53). After 6 months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV - 20 ± 11 vs. - 22 ± 11%, p = 0.59; EF + 10 ± 4 vs. + 9 ± 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction ≥ 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). CONCLUSIONS: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization.

Permanent endovenous pediatric pacing: absence of lead failure--20 years follow-up study.

BACKGROUND: The aim of the study was to analyze endovenous pacing lead survival in pediatric population implanted by cephalic cut down, or by axillary vein puncture. METHODS: All implantations were performed in total endotracheal anesthesia, by the same surgeon. Implantations of ventricular leads were performed by cephalic vein cut down or by external jugular vein preparation. In dual-chamber pacing, atrial leads were implanted via cephalic vein (along with ventricular lead), by axillary vein puncture or via external jugular vein. All implanted leads were secured by resorbable suture. RESULTS: Over the 20-year follow-up period, 105 children of 5.7 years average age (range 1 day-15 years) were implanted with a permanent endovenous pacing system for congenital or postsurgical complete atrioventricular block or sinus node disease. Within the group, 27 patients (25.7%) weighed less than 10 kg on implantation. A total of 121 endovenous leads were implanted. All ventricular leads were with a passive fixation mechanism, and most of them unipolar (87.6%) and steroid eluting (94.2%). Leads implanted in atrial position were 82% bipolar, predominantly with active fixation (94%), and all steroid eluting. The most frequently used mode of stimulation was VVIR (66.6%). No acute or chronic lead displacement, exit block, sensing problem, lead conductor fracture, insulation defect or infections were observed during the total follow-up of 709 pacing years (average 6.9, range 0-20 years). CONCLUSION: Implantation of the endovenous leads by preparation of the cephalic or puncture of the axillary vein, with lead fixation by resorbable suture represents a method of choice.

Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome.

BACKGROUND: Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it. OBJECTIVES: This prospective registry study was designed to explore clinical and electrophysiological predictors of malignant ventricular tachyarrhythmia inducibility in Brugada syndrome. METHODS: A total of 191 consecutive selected patients with (group 1; n = 88) and without (group 2; n = 103) Brugada syndrome-related symptoms were prospectively enrolled in the registry. Patients underwent electrophysiological study and substrate mapping or ablation before and after ajmaline testing (1 mg/kg/5 min). RESULTS: Overall, before ajmaline testing, 53.4% of patients had ventricular tachyarrhythmia inducibility, which was more frequent in group 1 (65.9%) than in group 2 (42.7%; p < 0.001). Regardless of clinical presentation, larger substrates with more fragmented long-duration ventricular potentials were found in patients with inducible arrhythmias than in patients without inducible arrhythmias (p < 0.001). One extrastimulus was used in more extensive substrates (median 13 cm2; p < 0.001), and ventricular fibrillation was the more frequently induced rhythm (p < 0.001). After ajmaline, patients without arrhythmia inducibility had arrhythmia inducibility without a difference in substrate characteristics between the 2 groups. The substrate size was the only independent predictor of inducibility (odds ratio: 4.51; 95% confidence interval: 2.51 to 8.09; p < 0.001). A substrate size of 4 cm2 best identified patients with inducible arrhythmias (area under the curve: 0.98; p < 0.001). Substrate ablation prevented ventricular tachyarrhythmia reinducibility. CONCLUSIONS: In Brugada syndrome dynamic substrate variability represents the pathophysiological basis of lethal ventricular tachyarrhythmias. Substrate size is independently associated with arrhythmia inducibility, and its determination after ajmaline identifies high-risk patients missed by clinical criteria. Substrate ablation is associated with electrocardiogram normalization and not arrhythmia reinducibility. (Epicardial Ablation in Brugada Syndrome [BRUGADA_I]; NCT02641431; Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701).