Durable Physiological Changes and Decreased Syncope Burden 12 Months After Unifocal Right-Sided Ablation Under Computed Tomographic Guidance in Patients With Neurally Mediated Syncope or Functional Sinus Node Dysfunction.

[Figure: see text].

Unifocal Right-Sided Ablation Treatment for Neurally Mediated Syncope and Functional Sinus Node Dysfunction Under Computed Tomographic Guidance.

Background Biatrial, extensive, and complex ablation strategies have been published for the treatment of neurally mediated syncope, sinus node dysfunction, and functional atrioventricular block. We have developed a less extensive and more specific approach compared with previously published cardioneuroablation strategies, called cardio-neuromodulation. It is based on tailored vagolysis of the sinoatrial node through partial ablation of the anterior right-ganglionated plexus, preferentially through a right-sided approach. Methods Patients with syncope were enrolled between December 2016 and December 2017. They were assigned to group A if they had a positive head-up tilt test and to group B if they presented with a pause ≥3 seconds. The area to target during cardio-neuromodulation was designed offline on a computed tomographic scan. Slow heart rates and pauses were compared during 24-hour rhythm registration at baseline, at 1-month follow-up, and 6-month follow-up. Syncope burden was assessed before the procedure and at 3- and 6-month follow-up. Results Twenty patients underwent cardio-neuromodulation through a right-sided approach (12 in group A, 8 in group B). The first application of radiofrequency energy led to a P-P interval shortening >120 ms in all 20 patients. After a mean±SD ablation time of 7±4 minutes and mean ablated surface area of 11±6 mm2, the P-P interval shortened by 219±160 ms ( P<0.001). The number of beats <50/min during 24-hour rhythm registration was reduced by a median of 100% at 6-month follow-up ( P<0.001). Syncope burden was reduced by 95% at 6-month follow-up ( P<0.001). Conclusions These data indicate that cardio-neuromodulation, through a right-sided and computed tomographic-guided procedure, is safe, fast, and highly reproducible in preventing inappropriate functional sinus bradycardia and syncope recurrence.

Multielectrode Pulmonary Vein Isolation Versus Single Tip Wide Area Catheter Ablation for Paroxysmal Atrial Fibrillation: A Multinational Multicenter Randomized Clinical Trial.

BACKGROUND: Single-shot ablation techniques may facilitate safe and simple pulmonary vein isolation to treat paroxysmal atrial fibrillation. Multielectrode pulmonary vein isolation versus single tip wide area catheter ablation-paroxysmal atrial fibrillation is the first multinational, multicenter, prospective, noninferiority randomized clinical trial comparing multielectrode-phased radiofrequency ablation (MEA) to standard focal irrigated radiofrequency ablation (STA) using 3-dimensional navigation. METHODS AND RESULTS: Patients with paroxysmal atrial fibrillation were randomized to MEA (61 patients) or STA (59 patients). Preprocedure transesophageal echocardiogram and computed tomography/magnetic resonance imaging (also 6-month postprocedure) were performed. Mean age was 57 years, 25% female sex, BMI was 28, CHA2DS2-VASc score was 0 to 1 in 82%, 8% had previous right atrial ablation, whereas all had at least 1 antiarrhythmic drug failure. The MEA group had significantly shorter mean procedure time (96±36 versus 166±46 minutes, P<0.001) and fluoroscopy time (23±9 versus 27±9 minutes, P=0.023). The total radiofrequency energy duration was 22±8 minutes for MEA versus 36±13 minutes for STA (P<0.001) with confirmed pulmonary vein isolation in all patients. Hospital admission was 1 day in both groups, without major adverse events either during the procedure or during 30-day follow-up. Two patients in the STA group had 1 PV with asymptomatic narrowing >50%. Freedom of atrial fibrillation for MEA and STA was 86.4% and 89.7% at 6 months, dropping to 76.3% and 81.0% at 12 months. CONCLUSIONS: In this multicenter, randomized clinical trial, MEA and STA had similar rates of single-procedure acute pulmonary vein isolation without serious adverse events in the first 30 days. MEA had slightly lower long-term arrhythmia freedom, but showed marked and significantly shorter procedure, fluoroscopy, and radiofrequency energy times. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov; Unique identifier: NCT01696136.

Formation of thermal coagulum on multielectrode catheters during phased radiofrequency energy ablation of persistent atrial fibrillation.

BACKGROUND: Radiofrequency ablation (RFA) can unfavorably cause coagulum on the ablation electrode. The aim of this study was to assess this phenomenon on three different multielectrode catheters used to treat persistent atrial fibrillation with duty-cycled RFA. METHODS AND RESULTS: Twenty-six consecutive patients have been treated with the pulmonary vein ablation catheter (PVAC) and the multiarray ablation catheter (MAAC). In 13 patients, additional ablation with the multiarray septal catheter (MASC) has been performed. The multichannel RF generator GENius™ (Medtronic Inc., Minneapolis, MN, USA) independently delivered energy in a bipolar and unipolar mode (ratio of 4/1, 2/1, or 1/1) to any of the electrodes. Versions 14.2, 14.3, and 14.4 of the generator were used. Coagulum presence was determined postablation by careful visual inspection of the catheter electrodes. No coagulum formation was visualized on the PVACs. Coagulum formation was visualized in 59% of the electrodes of the MAACs using a 2/1 mode and the 14.2 software version versus 69% using the 14.4 version and a 2/1 mode (P = 0.7) versus 14% of the electrodes applying a 1/1 ratio and the 14.4 software version (P < 0.001). CONCLUSIONS: Duty-cycled RFA in 2/1 bipolar/unipolar ratio generates a substantial frequency of coagulum formation on the multielectrode catheters MAAC and MASC. The use of the 14.4 version of the software to drive the RF generator and the use of energy in the default 1/1 bipolar/unipolar ratio could significantly reduce the frequency of coagulum formation, but so far, could not completely overcome it. The PVAC did not form coagulum, regardless of generator version or energy ratio used.

Implantable cardioverter/defibrillator interventions in primary prevention: do current implantation criteria really predict ICD interventions?

BACKGROUND: Randomized controlled trials have proven the efficacy of implantable cardioverter/defibrillators (ICDs) to prevent sudden cardiac death (SCD) in primary prevention. However,long-term data on the incidence of appropriate and inappropriate interventions in real life and on the predictive value of commonly used clinical variables to guide patient selection are scarce. METHODS: We retrospectively studied 101 patients who received an ICD for primary prophylaxis of SCD: 63.4% with ischaemic heart disease (IHD) and 36.6% with idiopathic dilated cardiomyopathy (IDCM). The mean follow-up period was 26.2 (+/- 14.8; median 27.8; range 5.6-70.5) months. Age, left ventricular ejection fraction (LVEF), QRS duration, NYHA class and electrophysiological study (EPS) outcome were evaluated as predictors of ICD intervention. RESULTS: At 2 years the cumulative incidence of appropriate (17.5% in IHD; 28% in IDCM; P= 0.63) and inappropriate (12.8% in IHD, 15.4% in IDCM; P = 0.62) interventions was similar in both groups. Atrial fibrillation was the most common cause of inappropriate interventions in the IHD group, sinus tachycardia in the IDCM group. Advanced age was associated with less inappropriate interventions (HR: 0.96 (95% confidence interval (CI) 0.94-0.98); P < 0.01), and a better LVEF with less appropriate interventions (HR: 0.97 (95% Cl 0.94-0.99); P < 0.01). This amounted in a significant absolute difference in the number of appropriate interventions between the group with a LVEF < 25% and 25-34% after 3 years of follow-up of 42% in IHD (48% vs 6%). A prolonged QRS duration was associated with a slightly elevated risk for appropriate interventions only in the IHD group (HR: 1.01 (95% CI 1.00-1.03); P = 0.04). On the other hand, increased NYHA class was only associated with increased risk for appropriate interventions in the IDCM group (HR: 5.24 (95% CI1.11-24.74); P= 0.04). No significant statistical association was found between a positive EPS and appropriate or inappropriate interventions. CONCLUSIONS: In primary prevention, during a mean follow-up of 2 years, one in five patients had a possibly live-saving appropriate intervention. However, the incidence of inappropriate interventions was substantial. Predictors for appropriate interventions were: (i) LVEF in the total study group, (ii) NYHA class in the IDCM group and (iii) QRS duration in the IHD group.

Adenosine-induced ventricular asystole or rapid ventricular pacing to enhance three-dimensional rotational imaging during cardiac ablation procedures.

AIMS: Rotational angiography with digital three-dimensional reconstruction (3DRA) allows per-procedural 3D imaging to facilitate cardiac ablation procedures. We developed a new approach that allows per-procedural 3D imaging of the atria and ventricles with a single C-arm rotation, combining higher 3D image quality with a lower contrast and radiation dose. METHODS AND RESULTS: Forty patients underwent 3DRA of the left atrium (LA, n = 26), right atrium (RA, n = 11), left ventricle (LV, n = 2), or right ventricle (RV, n = 1) during ablation procedures performed under general anaesthesia. Contrast agent (60 +/- 12 mL) was diluted and injected directly in the chamber of interest, during adenosine-induced ventricular asystole (n = 31) or rapid RV pacing (n = 9, atrial imaging only) to reduce cardiac motion artefacts and enhance contrast opacification during rotational imaging. Reconstructed 3D data sets were graded according to predefined quality criteria (n = 40) and quantitatively compared with cardiac computed tomography (CT) (LA, n = 14). Adenosine-induced ventricular asystole and rapid pacing both allowed a sustained and homogeneous contrast opacification of target cardiac chambers, resulting in useful 3D data sets in 39 of 40 (98%) patients. Moreover, it was possible to achieve 'good' or 'optimal' 3D image quality in the majority of patients (adenosine: 61%, pacing 78%, P = 0.69). When compared with rapid pacing, the total elimination of cardiac motion artefacts with adenosine more frequently resulted in 'optimal' 3D image quality (42% vs. 11%, P = 0.01) and added the possibility for single-rotation 3D imaging of the ventricles. Quantitative analysis showed an excellent agreement between pulmonary vein diameters measured on cardiac CT and 3DRA images. Integration of 3DRA-based LA surfaces with real-time fluoroscopy was easy and highly accurate. CONCLUSION: Adenosine-induced ventricular asystole or rapid ventricular pacing allow acquisition of 3DRA with an excellent direct contrast opacification of any cardiac chamber and a reduction of cardiac motion artefacts, resulting in high-quality per-procedural 3D imaging with a single C-arm rotation.

High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics.

BACKGROUND: Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression. METHODS AND RESULTS: The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications. Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event. CONCLUSIONS: This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction disease.

Nuevas perspectivas en el síndrome de QT largo / New insights into the long-QT syndrome

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The Brugada syndrome.

PURPOSE OF REVIEW: The Brugada syndrome has been an area of intensive investigation since its earliest description in 1992, both on a clinical and on a basic research level. In this review, we will focus on recent achievements in the molecular dissection of the disease pathophysiology and on large multicenter studies dealing with prognostic markers and the natural history of the Brugada syndrome. RECENT FINDINGS: In the past year, two additional genetic pathways have been associated with the disease. Also, an inflammatory or infectious etiology has recently been linked with the Brugada syndrome. The debate on the predictive role of programmed electrical stimulation is still ongoing. Very recently, large follow-up studies questioned the prognostic role of programmed electrical stimulation in this disease. SUMMARY: Knowledge on the genetic determinants of the Brugada syndrome remains limited. Therefore, the management and the risk stratification of patients should be performed on a clinical basis. Sufficient evidence exists to reassure clinicians who feel reluctant to include programmed electrical stimulation in the risk stratification strategy of asymptomatic Brugada syndrome patients.

Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome.

BACKGROUND: It has been proposed that the highest risk for cardiac events in patients with long-QT syndrome subtype 2 (LQT2) is related to mutations in the pore region of the KCNH2 channel. It has also been suggested that a subpopulation of LQT2 patients may benefit from pharmacological therapy with modified KCNH2 channel-blocking drugs. METHODS AND RESULTS: In a large LQT2 family (n=33), we have identified a novel nonpore missense mutation (K28E) in the Per-Arnt-Sim (PAS) domain of the KCNH2 channel associated with a malignant phenotype: One third of the suspected gene carriers experienced a major cardiac event. Wild-type and K28E-KCNH2 channels were transiently transfected in HEK293 cells. For the mutant channel, whole-cell patch-clamp analysis showed a reduced current density, a negative shift of voltage-dependent channel availability, and an increased rate of deactivation. Western blot analysis and confocal imaging revealed a trafficking deficiency for the mutant channel that could be rescued by the K+ channel blocker E-4031. In cells containing both wild-type and mutant channels, deactivation kinetics were normal. In these cells, reduced current density was restored with E-4031. CONCLUSIONS: Our data suggest that besides pore mutations, mutations in the PAS domain may also exhibit a malignant outcome. Pharmacological restoration of current density is promising as a mutation-specific therapy for patients carrying this trafficking-defective mutant.

Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?

This study evaluated common clinical characteristics of patients with lamin A/C gene mutations that cause either isolated dilated cardiomyopathy or dilated cardiomyopathy in association with skeletal muscular dystrophy. We pooled clinical data of all published carriers of lamin A/C gene mutations as cause of skeletal and/or cardiac muscle disease and reviewed ECG findings. Cardiac dysrhythmias were reported in 92% of patients after the age of 30 years; heart failure was reported in 64% after the age of 50. Sudden death was the most frequently reported mode of death (46%) in both the cardiac and the neuromuscular phenotype. Carriers of lamin A/C gene mutations often received a pacemaker (28%). However, this intervention did not alter the rate of sudden death. Review of the ECG findings typically showed a low amplitude P wave and prolongation of the PR interval with a narrow QRS complex. This meta-analysis suggests that cardiomyopathy due to lamin A/C gene mutations portends a high risk of sudden death, and that this risk does not differ between subjects with predominantly cardiac or neuromuscular disease. This implies then that all carriers of a lamin A/C gene mutation need to be carefully screened with particular emphasis also on tachyarrhythmias. Prospective studies are needed to evaluate risk stratification and proper treatment strategies.

Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death.

OBJECTIVES: The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation. BACKGROUND: Brugada syndrome and isolated cardiac conduction defect have been linked to SCN5A mutations. METHODS: Eleven members of a western European family underwent electrophysiologic investigations and mutation analysis of the SCN5A gene. Wild-type and mutant SCN5A channels were expressed in HEK293 cells, and whole cell currents were studied using patch clamp procedures. RESULTS: A novel mutation, R376H, in the first pore segment of SCN5A variably causes Brugada syndrome and/or conduction disease in a single family. Biophysical analysis demonstrated a significant current reduction for the mutant, a pathophysiologic profile consistent with Brugada syndrome and isolated cardiac conduction defect. Among 11 family members, 9 were carriers of the mutation. The proband's initial presentation was a saddleback Brugada ECG, atrial flutter, and diffuse conduction disturbances. He had no inducible ventricular arrhythmias but experienced sudden cardiac death. His brother was affected by atrial flutter and had a clear conduction disorder, but he did not display baseline or evocable ECG signs of Brugada syndrome. He received an implantable cardioverter-defibrillator that delivered one appropriate shock after 1 year of follow-up. The phenotype in the family members was highly variable and ranged from noninducible and inducible asymptomatic carriers of the mutations to isolated conduction disease and to symptomatic Brugada syndrome. CONCLUSIONS: We describe the functional characterization of a novel SCN5A pore mutation, R376H, with variable clinical expression in the same family. Differentiating between electrophysiologic entities (Brugada syndrome-isolated cardiac conduction defect) is more challenging. Recognition of factors modifying the clinical presentation may be important for clinical decision making.

A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating.

Congenital long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A encoding the alpha-subunit of the cardiac Na(+) channel (Nav1.5). Functional studies of SCN5A mutations in the linker between domains III and IV, and more recently the C-terminus, have been shown to alter inactivation gating. Here we report a novel LQT3 mutation, L619F (LF), located in the domain I-II linker. In an infant with prolonged QTc intervals, mutational analysis identified a heterozygous missense mutation (L619F) in the domain I-II linker of the cardiac Na(+) channel. Wild-type (WT) and mutant channels were studied by whole-cell patch-clamp analysis in transiently expressed HEK cells. LF channels increase maintained Na(+) current (0.79 pA/pF for LF; 0.26 pA/pF for WT) during prolonged depolarization. We found a +5.8mV shift in steady state inactivation in LF channels compared to WT (WT, V(1/2)=-64.0 mV; LF, V(1/2)=-58.2 mV). The positive shift of inactivation, without a corresponding shift in activation, increases the overlap window current in LF relative to WT (1.09 vs. 0.58 pA/pF), as measured using a positive voltage ramp protocol (-100 to +50 mV in 2s). The increase in window current, combined with an increase in non-inactivating Na(+) current, may act to prolong the AP plateau and is consistent with the disease phenotype observed in patients. Moreover, the defective inactivation imposed by the L619F mutation implies a role for the I-II linker in the Na(+) channel inactivation process.

Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.

OBJECTIVE: It has been suggested that both pacing and treatment with mexiletine may reduce torsade de pointes (TdP) arrhythmias in patients with long QT syndrome 3 (LQT3), but it is not fully understood how these interventions could prevent TdP. We therefore studied the effects of pacing and mexiletine in mice with a heterozygous knock-in DeltaKPQ SCN5A(Delta/+) deletion (SCN5A-Tg), a murine LQT3 model. METHODS: Three right and left ventricular monophasic action potentials (MAPs) were simultaneously recorded in Langendorff-perfused hearts of SCN5A-Tg and wild type (WT) littermates. AV block was induced, and pacing was performed at baseline and during mexiletine infusion (4 microg/ml). MAP recordings were analysed for action potential duration (APD), APD dispersion, and early afterdepolarisations (EADs) and related to spontaneous arrhythmias. RESULTS: After inducing AV block, SCN5A-Tg hearts were bradycardic [SCN5A-Tg 532+/-60 vs. WT 284+/-48 ms cycle length (CL, mean+/-S.E.M., P<0.05(*))]. EADs occurred in 16/18, and polymorphic ventricular tachycardia (pVT) in 11/18 SCN5A-Tg but not in 19 WT. SCN5A-Tg had longer APD than WT hearts*. At CL of 200 ms and longer, APD dispersion was higher in SCN5A-Tg [dispersion (APD70): 12+/-3 ms vs. 5+/-2 ms at CL=200 ms*], and increased to 35+/-4 ms* directly prior to pVT episodes. Sudden rate accelerations initially increased APD dispersion due to EADs and APD alternans in SCN5A-Tg, but pacing then reduced APD dispersion. Pacing suppressed (n=9/9) and prevented (n=49/50) pVT. Mexiletine shortened APD at long CL*, and suppressed pVT (n=4/5*), but did not prevent pVT during normal rhythm. CONCLUSIONS: Bradycardia, increased dispersion of APD and EADs provoke ventricular ectopy and pVT in SCN5A-Tg hearts. Ventricular pacing reduces APD dispersion, suppresses EADs and prevents pVT in SCN5A-Tg hearts. These effects provide a pathophysiological rationale for pacing in LQT3.