R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome.

Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.

Effects of right bundle branch block on the antidromic circus movement tachycardia in patients with presumed atriofascicular pathways.

BACKGROUND: The typical and most common tachycardia in patients with atriofascicular pathways is a macro reentrant tachycardia, with anterograde conduction over the decrementally conducting bypass tract and retrograde conduction over the right bundle branch-His-AV node axis resulting in a short V-right bundle branch and short V-H interval. OBJECTIVES: To report on changes in rate and QRS configuration when right bundle branch block (RBBB) develops spontaneously during antidromic tachycardia using an atriofascicular fiber. METHODS: Three of 25 patients with an antidromic circus movement tachycardia using a right-sided atriofascicular pathway showed episodes of right bundle branch block (RBBB) during ventriculo-atrial conduction. Effect of retrograde RBBB on tachycardia rate and QRS configuration was studied using intracardiac and extracardiac recordings. RESULTS: All 3 patients showed prolongation of their V-A interval when retrograde RBBB occurred during tachycardia, resulting in a longer tachycardia cycle length. The VA time increase ranged from 85 to 100 msec, with a mean 346 +/- 5 msec. Two of the 3 patients also showed a change in QRS configuration due to a more leftward shift of the frontal plane QRS axis. CONCLUSION: Rate changes in antidromic tachycardia in patients with atriofascicular fibers can be based on a shift in VA conduction from one bundle branch to the other. This may be accompanied by changes in the frontal plane QRS axis because of a change in ventricular activation sequence.

Short atrioventricular Mahaim fibers: observations on their clinical, electrocardiographic, and electrophysiologic profile.

UNLABELLED: Short A-V manheim fiber. INTRODUCTION: A short atrioventricular decrementally conducting accessory pathway is an uncommon variant of preexcitation. Available data from small series suggest that their decremental properties might not be caused by A-V nodal-like tissue. METHODS: We compared clinical, electrocardiographic and electrophysiologic parameters in two groups of patients: 8 patients with a short A-V Mahaim pathway (Group A), and 33 patients with atriofascicular pathways (Group B). Radiofrequency catheter ablation was carried out guided by activation mapping at the annulus in Group A patients and targeting the "M" potential in Group B patients. RESULTS: After ablation of all associated rapidly conducting bypass tracts, 7 of the 8 Group A patients showed clear preexcitation. In only 1 of 8 patients the short A-V Mahaim fiber was actively engaged in a reentrant tachycardia circuit. During radiofrequency catheter ablation an automatic rhythm occurred in 4 of 8 patients. Intravenous adenosine caused conduction a block in the Mahaim fiber in 3 of the 5 patients tested. In group B, no patient showed clear preexcitation (P<00001) while 72% had a minimal preexcitation pattern. Twenty-nine of the 33 patients had a circus movement tachycardia with AV conduction over the atriofascicular fiber. During radiofrequency catheter ablation 30 of 33 patients showed accessory pathway automaticity. Adenosine caused transient block at the atriofascicular pathway in 11 (92%) of the 12 patients tested. CONCLUSIONS: While short decrementally conducting right-sided accessory pathways show a typical ECG pattern different from atriofascicular pathways, their electrophysiologic properties do not seem to be uniform. Those pathways can be successfully interrupted by catheter ablation.

The electrocardiogram during sinus rhythm and tachycardia in patients with Mahaim fibers: the importance of an "rS" pattern in lead III.

OBJECTIVES: The purpose of the study was to identify the electrocardiographic (ECG) characteristics of the Mahaim fiber. BACKGROUND: Mahaim fibers are slowly conducting accessory pathways reaching into the right ventricle. They often play a role in tachycardias. METHODS: We retrospectively analyzed 40 patients with Mahaim fibers. Five patients had associated Wolff-Parkinson-White syndrome and were excluded from the study. Two patients had a short atrioventricular decremental accessory pathway and were also excluded. The remaining 33 patients had a tachycardia with anterograde conduction over a Mahaim fiber. Twenty were female. Their mean age was 24 +/- 10 years. RESULTS: The most common pattern of minimal preexcitation during sinus rhythm was an rS pattern in lead III. This was found in 20 patients. There was a match between the presence of rS in lead III during sinus rhythm and left axis deviation during tachycardia with anterograde conduction over the Mahaim fiber. After ablation, a different QRS pattern emerged in lead III, indicating the absence of conduction over the Mahaim fiber. To obtain information on the prevalence of an rS pattern in lead III in age-matched controls with palpitations and without structural heart disease, the 12-lead ECG of 200 young individuals were examined. An rS pattern in lead III was found in 6%. CONCLUSIONS: A narrow QRS with an rS pattern in lead III during sinus rhythm in a patient with a history of palpitations should alert the physician to the possibility of a Mahaim fiber. During tachycardia, these patients typically show a left bundle branch block-like QRS complex with left axis deviation.

Electrocardiogram during tachycardia in patients with anterograde conduction over a Mahaim fiber: old criteria revisited.

OBJECTIVES: The aim of this study was to prospectively evaluate the sensitivity, specificity, and positive and negative predictive values of previously described ECG criteria to identify preexcited tachycardia due to decrementally conducting accessory pathways (QRS axis between 0 and -75 degrees , QRS width < or = 0.15 seconds, an R wave in lead I, an rS pattern in lead V(1), RS > 1 QRS transition > V(4), and cycle length between 220 and 450 ms). BACKGROUND: Preexcited tachycardia associated with decrementally conducting right-sided accessory pathways usually shows a rather "narrow" QRS complex and can be difficult to differentiate from supraventricular tachycardia (SVT) with left bundle branch block (LBBB) aberrant conduction. METHODS: We analyzed three groups of patients: 32 patients with an atriofascicular pathway (group I); 8 patients with long (n = 3) or short (n = 5) decrementally conducting right-sided AV pathway (group II); and a control group that consisted of 35 patients with SVT and LBBB (group III). RESULTS: Presence of all six criteria had 87.5% sensitivity in group I and a 0% sensitivity in group II. There were four false negatives in group I. The negative predictive value was 82.5%, with six false positives in group III (five patients with an aberrant LBBB-shaped tachycardia with ventriculoatrial conduction over an accessory AV pathway). The criterion cycle length was not helpful. CONCLUSIONS: Criteria for identifying a tachycardia with anterograde conduction over a Mahaim fiber are helpful only in atriofascicular pathways, with a sensitivity of 87.5% and a negative predictive value of 82.5%. The major cause of false positives was a tachycardia with aberrant LBBB conduction and ventriculoatrial conduction over an accessory AV pathway.

Displasia ventricular direita arritmogênica: diagnóstico, prognóstico e tratamento / Arrhythmogenic right ventricular dysplasia: diagnosis, prognosis and treatment

Descritas as características anátomo-clínicas da displasia ventricular direita arritmogênica e discutidos os métodos diagnósticos e terapêuticos, é apresentada a Série de Maastricht constituída de 14 pacientes, com os dados clínicos, diagnósticos e terapêuticos num tempo médio de 4.2 anos de acompanhamento