Favourable mid-term outcome after heart transplantation for late Fontan failure.

OBJECTIVES Fontan failure (FF) represents a growing and challenging indication for paediatric orthotopic heart transplantation (OHT). The aim of this study was to identify predictors of the best mid-term outcome in OHT after FF. METHODS Twenty-year multi-institutional retrospective analysis on OHT for FF. RESULTS Between 1991 and 2011, 61 patients, mean age 15.0 ± 9.7 years, underwent OHT for failing atriopulmonary connection (17 patients = 27.8%) or total cavopulmonary connection (44 patients = 72.2%). Modality of FF included arrhythmia (14.8%), complex obstructions in the Fontan circuit (16.4%), protein-losing enteropathy (PLE) (22.9%), impaired ventricular function (31.1%) or a combination of the above (14.8%). The mean time interval between Fontan completion and OHT was 10.7 ± 6.6 years. Early FF occurred in 18%, requiring OHT 0.8 ± 0.5 years after Fontan. The hospital mortality rate was 18.3%, mainly secondary to infection (36.4%) and graft failure (27.3%). The mean follow-up was 66.8 ± 54.2 months. The overall Kaplan-Meier survival estimate was 81.9 ± 1.8% at 1 year, 73 ± 2.7% at 5 years and 56.8 ± 4.3% at 10 years. The Kaplan-Meier 5-year survival estimate was 82.3 ± 5.9% in late FF and 32.7 ± 15.0% in early FF (P = 0.0007). Late FF with poor ventricular function exhibited a 91.5 ± 5.8% 5-year OHT survival. PLE was cured in 77.7% of hospital survivors, but the 5-year Kaplan-Meier survival estimate in PLE was 46.3 ± 14.4 vs 84.3 ± 5.5% in non-PLE (P = 0.0147). Cox proportional hazards identified early FF (P = 0.0005), complex Fontan pathway obstruction (P = 0.0043) and PLE (P = 0.0033) as independent predictors of 5-year mortality. CONCLUSIONS OHT is an excellent surgical option for late FF with impaired ventricular function. Protein dispersion improves with OHT, but PLE negatively affects the mid-term OHT outcome, mainly for early infective complications.

The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network.

Pulmonary Vein Isolation Versus Defragmentation: The CHASE-AF Clinical Trial

BACKGROUND Long-term success rates using ablation for persistent atrial fibrillation (AF) are disappointing and usually do not exceed 60%. OBJECTIVES This study sought to compare arrhythmia-free survival between pulmonary vein isolation (PVI) and a stepwise approach (full defrag) consisting of PVI, ablation of complex fractionated electrograms, and additional linear ablation lines in the setting of atrial tachycardias (AT) in patients with persistent AF after PVI. METHODS From November 2010 to February 2013, 205 patients (151 men; 61.7 ± 10.2 years of age) underwent de novo ablation for persistent AF. Subsequently, patients were prospectively randomized to either PVI alone (n = 78) or full defrag (n = 75), with 52 patients not randomized due to AF termination with the original PVI. The primary endpoint was recurrence of any AT after a blanking period of 3 months. RESULTS During the entire study, 241 ablations were performed (mean: 1.59 in the PVI-alone group, 1.55 in the full-defrag group). With the stepwise approach, termination of AF occurred in 45 (60%) patients. However, arrhythmia-free survival did not differ whether patients underwent single or multiple procedures (p = 0.468). Procedure duration, fluoroscopy time, and radiofrequency duration were significantly longer in the full-defrag group (all p < 0.001). CONCLUSIONS A stepwise approach aimed at AF termination does not seem to provide additional benefit over PVI alone in patients with persistent AF, but it is associated with significantly longer procedural and fluoroscopic duration as well as radiofrequency application time. (The Randomized Catheter Ablation of Persist End Atrial Fibrillation Study [CHASE-AF]; NCT01580124).

Use of antiarrhythmic drugs during ablation of persistent atrial fibrillation: observations from a large single-centre cohort

Catheter ablation of complex fractionated atrial electrograms (CFAE), also known as defragmentation ablation, may be considered for the treatment of persistent atrial fibrillation (AF) beyond pulmonary vein isolation (PVI). Concomitant antiarrhythmic drug (AAD) therapy is common, but the relevance of AAD administration and its optimal timing during ablation remain unclear. Therefore, we investigated the use and timing of AADs during defragmentation ablation and their possible implications for AF termination and ablation success in a large cohort of patients. Retrospectively, we included 200 consecutive patients (age: 61 ± 12 years, LA diameter: 47 ± 8 mm) with persistent AF (episode duration 47 ± 72 weeks) who underwent de novo ablation including CFAE ablation. In all patients, PVI was performed prior to CFAE ablation. The use and timing of AADs were registered. The follow-ups consisted of Holter ECGs and clinical visits. Termination of AF was achieved in 132 patients (66 %). Intraprocedural AADs were administered in 168/200 patients (84 %) 45 ± 27 min after completion of PVI. Amiodarone was used in the majority of the patients (160/168). The timing of AAD administration was predicted by the atrial fibrillation cycle length (AFCL). At follow-up, 88 patients (46 %) were free from atrial arrhythmia. Multivariate logistic regression analysis revealed that administration of AAD early after PVI, LA size, duration of AF history, sex and AFCL were predictors of AF termination. The administration of AAD and its timing were not predictive of outcome, and age was the sole independent predictor of AF recurrence. The administration of AAD during ablation was common in this large cohort of persistent AF patients. The choice to administer AAD therapy and the timing of the administration during ablation were influenced by AFCL, and these factors did not significantly influence the moderate single procedure success rate in this retrospective analysis.

Interventional management of recurrent paroxysmal atrial fibrillation despite isolated pulmonary veins: impact of an ablation strategy targeting inducible atrial tachyarrhythmias

AIMS Pulmonary vein isolation (PVI) is an effective treatment option for paroxysmal atrial fibrillation (PAF). Reconnection of pulmonary veins (PVs) is the predominant cause for recurrence of PAF. However, treatment of patients with recurrence of PAF despite isolated PV in the absence of extra-PV foci remains challenging. METHODS AND RESULTS Of 265 patients undergoing repeat catheter ablation (CA) for recurrence of PAF 21 (8%) patients (14 men, age 58 ± 14 years) showed no reconnection of PV. Therefore, inducibility of sustained atrial arrhythmias was tested. If sustained atrial fibrillation (AF) or sustained atrial tachycardia (AT) was induced, patients underwent CA. During follow-up (FU), Holter- and Tele-electrocardiogram were performed. In 19 (91%) of 21 patients, sustained atrial arrhythmias [16 (84%) AF; 3 (15%) patients AT] were induced. One patient showed PAF. Eighteen patients underwent CA aiming for termination of induced arrhythmia. In 14 (77%) patients, termination into sinus rhythm was achieved. Despite extensive CA, three (16%) patients were externally cardioverted. No periprocedural complications occurred. During 21.2 ± 6.8-month FU, 10 (53%) patients were free of any arrhythmia. Paroxysmal atrial fibrillation recurred in 4 (21%) and AT in 5 (26%) patients. One patient showed persistent AF. Repeat CA was scheduled and successfully performed for these patients. CONCLUSION In patients with recurrence of PAF despite isolated PV, termination of induced atrial arrhythmias can be achieved in most patients by defragmentation and AT ablation. Moreover, this ablation strategy results in favourable mid-term outcome results.

Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success

BACKGROUND In the meantime, catheter ablation is widely used for the treatment of persistent atrial fibrillation (AF). There is a paucity of data about long-term outcomes. This study evaluates (1) 5-year single and multiple procedure success and (2) prognostic factors for arrhythmia recurrences after catheter ablation of persistent AF using the stepwise approach aiming at AF termination. METHODS AND RESULTS A total of 549 patients with persistent AF underwent de novo catheter ablation using the stepwise approach (2007-2009). A total of 493 patients were included (Holter ECGs ≥ every 6 months). Mean follow-up was 59 ± 16 months with 2.1 ± 1.1 procedures per patient. Single and multiple procedure success rates were 20.1% and 55.9%, respectively (80% off antiarrhythmic drug). Antiarrhythmic drug-free multiple procedure success was 46%. Long-term recurrences (n=171) were paroxysmal AF in 48 patients (28%) and persistent AF/atrial tachycardia in 123 patients (72%). Multivariable recurrent event analysis revealed the following factors favoring arrhythmia recurrence: failure to terminate AF during index procedure (hazard ratio [HR], 1.279; 95% confidence interval [CI], 1.093-1.497; P = 0.002), number of procedures (HR, 1.154; 95% CI, 1.051-1.267; P = 0.003), female sex (HR, 1.263; 95% CI, 1.027-1.553; P = 0.027), and the presence of structural heart disease (HR, 1.236; 95% CI, 1.003-1.524; P = 0.047). AF termination was correlated with a higher rate of consecutive procedures because of atrial tachycardia recurrences (P = 0.003; HR, 1.71; 95% CI, 1.20-2.43). CONCLUSIONS Catheter ablation of persistent AF using the stepwise approach provides limited long-term freedom of arrhythmias often requiring multiple procedures. AF termination, the number of procedures, sex, and the presence of structural heart disease correlate with outcome success. AF termination is associated with consecutive atrial tachycardia procedures.

Utility of electrophysiological studies to predict arrhythmic events

AIM To evaluate the prognostic value of electrophysiological stimulation (EPS) in the risk stratification for tachyarrhythmic events and sudden cardiac death (SCD). METHODS We conducted a prospective cohort study and analyzed the long-term follow-up of 265 consecutive patients who underwent programmed ventricular stimulation at the Luzerner Kantonsspital (Lucerne, Switzerland) between October 2003 and April 2012. Patients underwent EPS for SCD risk evaluation because of structural or functional heart disease and/or electrical conduction abnormality and/or after syncope/cardiac arrest. EPS was considered abnormal, if a sustained ventricular tachycardia (VT) was inducible. The primary endpoint of the study was SCD or, in implanted patients, adequate ICD-activation. RESULTS During EPS, sustained VT was induced in 125 patients (47.2%) and non-sustained VT in 60 patients (22.6%); in 80 patients (30.2%) no arrhythmia could be induced. In our cohort, 153 patients (57.7%) underwent ICD implantation after the EPS. During follow-up (mean duration 4.8 ± 2.3 years), a primary endpoint event occurred in 49 patients (18.5%). The area under the receiver operating characteristic curve (AUROC) was 0.593 (95%CI: 0.515-0.670) for a left ventricular ejection fraction (LVEF) < 35% and 0.636 (95%CI: 0.563-0.709) for inducible sustained VT during EPS. The AUROC of EPS was higher in the subgroup of patients with LVEF ≥ 35% (0.681, 95%CI: 0.578-0.785). Cox regression analysis showed that both, sustained VT during EPS (HR: 2.26, 95%CI: 1.22-4.19, P = 0.009) and LVEF < 35% (HR: 2.00, 95%CI: 1.13-3.54, P = 0.018) were independent predictors of primary endpoint events. CONCLUSION EPS provides a benefit in risk stratification for future tachyarrhythmic events and SCD and should especially be considered in patients with LVEF ≥ 35%.

Complex genetic background in a large family with Brugada syndrome.

The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant.

Fibrilación auricular y terapéutica anticoagulante

La fibrilación auricular es la taquiarritmia más frecuente en la población general. La frecuencia de dicha arritmia aumenta con la edad, presentándose en un 1.5% de los 50 a 59 años a 8-10% de los 80 a 89 años. La fibrilación auricular incrementa el riesgo de sufrir un evento cerebrovascular isquémico cardioembólico en 5 veces y causa el 15% de todos los accidentes cerebrovasculares isquémicos. El manejo de la fibrilación auricular se enfoca, principalmente, en la prevención de los fenómenos tromboembólicos y en el control de la frecuencia y ritmo cardiaco. La anticoagulación, ha demostrado ser la principal herramienta en la prevención de eventos cardioembólicos. Aunque las complicaciones hemorrágicas por el tratamiento son esperables, y aumentan con la edad, sobrepasa por mucho, el beneficio de usar anticoagulación, al riesgo de sangrados. Precisamente debido a la heterogeneidad clínica de esta arritmia y a la dificultad de establecer un tratamiento adecuado para cada caso en particular, el American College of Cardiology, la American Heart Association, la European Society of Cardiology y el American College of Chest Physicians han establecido unas guías para mejorar el manejo de los pacientes. La revisión de esta patología y de estas directrices propuestas pueden facilitar y mejorar notablemente el tratamiento de los pacientes con fibrilación auricular.

New diagnostic and therapeutic approaches to treat ventricular tachycardias originating at the summit of the left ventricle role of merged hemodynamic-MRI and alternative ablation sources

The left ventricular (LV) summit is the most common site of idiopathic epicardial LV arrhythmias and frequently represents a diagnostic and a therapeutic challenge.1 We present a case of sustained monomorphic ventricular tachycardia (SMVT) originating at the LV summit that underwent failed cryosurgical epicardial ablation and was successfully treated with the aid of merged hemodynamic and contrast-enhanced MRI (CE-MRI).

Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome

The voltage-dependent K+ channel responsible for the slowly activating delayed K+ current IKs is composed of pore-forming KCNQ1 and regulatory KCNE1 subunits, which are mutated in familial forms of cardiac long QT syndrome. Because KCNQ1 and KCNE1 genes also are expressed in epithelial tissues, such as the kidneys and the intestine, we have investigated the adaptation of KCNE1-deficient mice to different K+ and Na+ intakes. On a normal K+ diet, homozygous kcne1−/− mice exhibit signs of chronic volume depletion associated with fecal Na+ and K+ wasting and have lower plasma K+ concentration and higher levels of aldosterone than wild-type mice. Although plasma aldosterone can be suppressed by low K+ diets or stimulated by low Na+ diets, a high K+ diet provokes a tremendous increase of plasma aldosterone levels in kcne1−/− mice as compared with wild-type mice (7.1-fold vs. 1.8-fold) despite lower plasma K+ in kcne1−/− mice. This exacerbated aldosterone production in kcne1−/− mice is accompanied by an abnormally high plasma renin concentration, which could partly explain the hyperaldosteronism. In addition, we found that KCNE1 and KCNQ1 mRNAs are expressed in the zona glomerulosa of adrenal glands where IKs may directly participate in the control of aldosterone production by plasma K+. These results, which show that KCNE1 and IKs are involved in K+ homeostasis, might have important implications for patients with IKs-related long QT syndrome, because hypokalemia is a well known risk factor for the occurrence of torsades de pointes ventricular arrhythmia.

Iontophoresis for modulation of cardiac drug delivery in dogs.

Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional antiarrhythmia therapy involving oral or intravenous medication is often ineffective and complicated by drug-associated side effects. Previous studies from our laboratory have demonstrated the advantages of cardiac drug-polymer implants for enhanced efficacy for cardiac arrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed release rate. Modulation of the drug delivery rate has the advantage of regulating the amount of the drug delivered depending upon the disease state of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery. In this study, we report our investigations of a cardiac drug implant in dogs that is capable of iontophoretic modulation of the administration of the antiarrhythmic agent sotalol. We used a heterogeneous cation-exchange membrane (HCM) as an electrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is passed only through the HCM and not the myocardium. The iontophoretic cardiac implant demonstrated in vitro drug release rates that were responsive to current modulation. In vivo results in dogs have confirmed that iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We also observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to regional drug administration. In 30-day dog experiments, iontophoretic cardiac implants demonstrated robust sustained function and reproducible modulation of drug delivery kinetics.

Computational Methods for Identifying Hypertrophic Cardiomyopathy using 12-lead ECG

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease where the heart muscle is partially thickened and blood flow is - potentially fatally - obstructed. It is one of the leading causes of sudden cardiac death in young people. Electrocardiography (ECG) and Echocardiography (Echo) are the standard tests for identifying HCM and other cardiac abnormalities. The American Heart Association has recommended using a pre-participation questionnaire for young athletes instead of ECG or Echo tests due to considerations of cost and time involved in interpreting the results of these tests by an expert cardiologist. Initially we set out to develop a classifier for automated prediction of young athletes’ heart conditions based on the answers to the questionnaire. Classification results and further in-depth analysis using computational and statistical methods indicated significant shortcomings of the questionnaire in predicting cardiac abnormalities. Automated methods for analyzing ECG signals can help reduce cost and save time in the pre-participation screening process by detecting HCM and other cardiac abnormalities. Therefore, the main goal of this dissertation work is to identify HCM through computational analysis of 12-lead ECG. ECG signals recorded on one or two leads have been analyzed in the past for classifying individual heartbeats into different types of arrhythmia as annotated primarily in the MIT-BIH database. In contrast, we classify complete sequences of 12-lead ECGs to assign patients into two groups: HCM vs. non-HCM. The challenges and issues we address include missing ECG waves in one or more leads and the dimensionality of a large feature-set. We address these by proposing imputation and feature-selection methods. We develop heartbeat-classifiers by employing Random Forests and Support Vector Machines, and propose a method to classify full 12-lead ECGs based on the proportion of heartbeats classified as HCM. The results from our experiments show that the classifiers developed using our methods perform well in identifying HCM. Thus the two contributions of this thesis are the utilization of computational and statistical methods for discovering shortcomings in a current screening procedure and the development of methods to identify HCM through computational analysis of 12-lead ECG signals.

Os inibidores orais do fator Xa na prevenção de eventos cerebrovasculares em doentes com fibrilhação auricular não-reumática

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014