Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation.

[Figure: see text].

Interrelationships between interventricular electrical delays in cardiac resynchronization therapy.

INTRODUCTION: In cardiac resynchronization therapy, pacing the left ventricle (LV) at sites of prolonged electrical delay is associated with better outcomes. We sought to characterize the interrelationships between intrinsic, right-ventricular (RV)-paced, and LV-paced interventricular delays. METHODS AND RESULTS: The following electrical timings were measured at implantation for all electrodes of the LV quadripolar leads: QLV, interventricular delay in intrinsic rhythm (RVs-LVs), in RV-paced rhythm (RVp-LVs), and in LV-paced rhythm (LVp-RVs). We included 32 patients (78% men, age 72 years, LV ejection fraction 29%, left bundle branch block 84%). QLV and RVs-LVs were correlated (R2 = .72, p < .0001), as were RVs-LVs and RVp-LVs (R2 = .27, p = .002) and RVp-LVs and LVp-RVs (R2 = .60, p < .001). Direction of activation along the four LV lead electrodes was concordant between RVs-LVs and RVp-LVs in only 17 (53%) patients. The latest-activated electrodes in RVs-LVs and RVp-LVs were concordant in 26 (81%) patients, adjacent in 3 (9%) patients, and remote in 3 (9%) patients. Biventricular-paced QRS duration varied by more than 10 ms between the two electrodes in half of the patients with dissimilar latest electrodes. Among the seven echocardiographic nonresponders at 6 months, the programmed electrode was remote from the latest electrode in RVs-LVs in five patients and in RVp-LVs in three patients. CONCLUSION: Intrinsic and RV-paced interventricular electrical delays are correlated, but there is substantial heterogeneity between patients. The latest-activated electrode may be different between RVs-LVs and RVp-LVs, and this might have important implications in selecting the optimal LV vector.

Single-catheter simplified stepwise approach to persistent atrial fibrillation ablation: A feasibility study.

BACKGROUND: The strategy for atrial fibrillation ablation in persistent atrial fibrillation remains controversial. A single-catheter approach was recently validated for pulmonary vein isolation. AIM: To evaluate the feasibility of this approach to performing persistent atrial fibrillation ablation, including pulmonary vein isolation and atrial lines, if needed. METHODS: We prospectively included 159 consecutive patients referred to our centre for a first persistent atrial fibrillation ablation between January 2018 and December 2018. All patients underwent pulmonary vein isolation. If the patient was still in atrial fibrillation (spontaneously or inducible), we subsequently performed a stepwise approach, including roof line, anterior mitral line, posterior box lesion and cavotricuspid isthmus line. Finally, if patient remained in atrial fibrillation at the end of the procedure, a synchronized direct-current cardioversion was applied to restore sinus rhythm. RESULTS: At baseline, 54 patients were in sinus rhythm and underwent pulmonary vein isolation. For patients in atrial fibrillation, after pulmonary vein isolation and ablation of additional lines, if needed, 18 patients were converted to atrial tachycardia and one directly to sinus rhythm; 96 were still in atrial fibrillation and underwent direct-current cardioversion. After a mean follow-up of 17±6 months, 57 patients (36%) experienced atrial arrhythmia recurrence. No deaths, tamponades or phrenic nerve injuries were observed following the procedure. The main mode of arrhythmia recurrence was atrial fibrillation in 75% of cases and atrial tachycardia in 25% of cases. CONCLUSION: A single-catheter approach, including pulmonary vein isolation and atrial lines, is feasible and safe in patients undergoing persistent atrial fibrillation ablation, with an acceptable success rate of 64% at mid-term follow-up.

Definition of success criteria for ablation of typical right atrial flutter with a single-catheter approach: A pilot study.

BACKGROUND: The success rate of cavotricuspid isthmus ablation to treat right common flutter is high (up to 95%), but needs bidirectional block confirmation, requiring two or three catheters. AIM: To describe a new pacing technique using a single catheter to ablate and confirm cavotricuspid isthmus block with differential PR interval measurements. METHODS: We included 61 patients from five centres, who were referred for cavotricuspid isthmus ablation. All patients had cavotricuspid isthmus ablation, and the cavotricuspid isthmus block was confirmed by differential pacing using two or three catheters. The new method consisted of measuring the PR interval on the surface electrocardiogram using pacing from the tip of the ablation catheter on the lateral side (lateral delay) and the septal side (coronary sinus ostium) of the cavotricuspid isthmus line (difference=delta PR interval), before and after cavotricuspid isthmus ablation. We analysed the value of the delta PR interval in predicting bidirectional cavotricuspid isthmus block as confirmed by standard methods. RESULTS: Among our patient population (mean age 63±12 years), 39 patients were ablated during sinus rhythm, and 22 during common flutter. Cavotricuspid isthmus block was achieved in all patients but one. Lateral delay and delta PR interval increased significantly after validation of cavotricuspid isthmus block (257±42 vs. 318±50ms and 32±23 vs. 96±22ms, respectively; P<0.0001). A delta PR interval cut-off of ≥70ms had 100% sensitivity and specificity to predict bidirectional cavotricuspid isthmus block. CONCLUSIONS: A single-catheter ablation approach to performing cavotricuspid isthmus line based on surface electrocardiogram PR interval measurement is feasible. After ablation, cavotricuspid isthmus block was systematically obtained when the delta PR interval was>70ms.

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (If ). The L-type Ca2+ current was reduced in KI SAN cells in a [Ca2+]i-dependent way, suggesting that bradycardia was due to disrupted crosstalk between the "voltage" and "Ca2+" clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR2- dependent Ca2+ release. This finding was consistent with a higher Ca2+ leak during diastolic periods produced by long-lasting Ca2+ sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR2 N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca2+ clock may slow the heart rhythm by disturbing the coupling between Ca2+ and voltage clocks.

Causes of Death and Influencing Factors in Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrillation is associated with a higher mortality, but causes of death of atrial fibrillation patients and their specific predictors have been less well defined. We aimed to identify the causes of death among atrial fibrillation patients and secondly, clinical predictors for the different modes of deaths. METHODS: Patients diagnosed with atrial fibrillation in a four-hospital institution between 2000 and 2010 were identified. During a follow-up of 929 ± 1082 days (median 456, interquartile 10-1584), 1253 deaths were recorded (yearly rate 5.5%). RESULTS: Cardiovascular deaths accounted for 54% and noncardiovascular for 43%. The three main causes of death were heart failure (29%), infection (18%), and cancer (12%). Fatal stroke or fatal bleeding each accounted for 7% of all deaths. On multivariate analysis, the strongest predictors of death were permanent atrial fibrillation, heart failure (whether with decreased or with preserved ejection fraction), previous bleeding, and renal failure, which were independently associated with an increase in the risk of all-cause mortality (35%, 78%, 42%, and 79%, respectively), cardiovascular mortality (43%, 129%, 46%, and 93%, respectively), and noncardiovascular mortality (21%, 45%, 40%, and 50%, respectively). Oral anticoagulant use was independently associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.62; 95% confidence interval [CI], 0.54-0.71; P <.0001), cardiovascular mortality (HR 0.60; 95% CI, 0.49-0.72; P <.0001), and noncardiovascular mortality (HR 0.60; 95% CI, 0.49-0.74; P <.0001). CONCLUSIONS: The majority of deaths were related to a cardiovascular origin, and heart failure was the most common cause of death in atrial fibrillation patients. Despite the high risk of stroke associated with atrial fibrillation, only 7% died from stroke. Optimization of management of any underlying heart disease and associated comorbidities should be a relevant therapeutic target to reduce total mortality in atrial fibrillation patients.

Effect of Active Smoking on Comparative Efficacy of Antithrombotic Therapy in Patients With Atrial Fibrillation: The Loire Valley Atrial Fibrillation Project.

BACKGROUND: Active smoking is associated with elevated thrombotic risk. Smoking status has recently been incorporated into the SAMe-TT2R2 (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]) score that can help predict poor international normalized ratio control in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs). The clinical benefit of antiplatelet therapy (APT) has been seen primarily in smokers. We hypothesized that active smoking may differently influence the risks of stroke and bleeding in patients with AF treated with VKAs or with APT. METHODS: We examined the clinical course of 7,809 consecutive patients with AF seen between 2000 and 2010. Outcomes in patients who were active smokers were compared with those in other patients. RESULTS: Among 7,809 patients with AF, 1,034 (13%) were active smokers. APT was prescribed on an individual basis for 2,761 patients (35%) and VKAs for 4,534 (57%). After a follow-up of 929 ± 1,082 days (median = 463 days, interquartile range = 1,564 days), smoking was not independently associated with a higher risk of stroke/thromboembolic event in patients with AF (hazard ratio [HR], 0.95; 95% CI, 0.78-1.22; P = .66). On multivariate analysis, smoking was independently associated with a worse prognosis for the risk of severe bleeding (HR, 1.23; 95% CI, 1.01-1.49; P = .04) and for the risk of major Bleeding Academic Research Consortium bleeding (HR, 1.40; 95% CI, 1.02-1.90; P = .03). Smoking was independently associated with a higher risk of bleeding in patients treated with VKAs (HR, 1.32; 95% CI, 1.04-1.67; P = .02), whereas the risk was nonsignificant in patients treated with APT (HR, 1.28; 95% CI, 0.94-1.74; P = .11). CONCLUSIONS: In AF, there was a higher risk of severe bleeding in smokers, mainly in those treated with VKAs.