KCNQ1 p.D446E Variant as a Risk Allele for Arrhythmogenic Phenotypes: Electrophysiological Characterization Reveals a Complex Phenotype Affecting the Slow Delayed Rectifier Potassium Current (IKs) Voltage Dependence by Causing a Hyperpolarizing Shift and a Lack of Response to Protein Kinase A Activation.

Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the ß-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele.

Diagnostic challenges of Brugada Syndrome in pediatric patients.

Although most cases of Brugada syndrome have been described in adults, pediatric patients with the disease have been reported since the original article from Josep and Pedro Brugada. Herein is presented the case series of Brugada syndrome in pediatric population of the National Institute of Cardiology Ignacio Chavez. One boy and two adolescent males had palpitations as clinical presentation of the disease. Atrial arrhythmias were documented in two, in the third case there was a high clinical suspicion and quinidine abolished symptoms. The aim of this report is to highlight the importance of performing a detailed clinical history as well as the usefulness of high precordial leads for the diagnosis of this entity.

The relevance of looking for right bundle branch block in catheter ablation of Ebstein's anomaly.

INTRODUCTION: Ebstein's anomaly is the most commonly occurring congenital defect associated with the Wolff-Parkinson-White syndrome. In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of right bundle branch block (RBBB) in sinus rhythm is a highly sensitive and specific indicator of the presence of an ipsilateral accessory AP. CASE: We present an electrophysiology case of a patient with Ebstein's anomaly and 3 ipsilateral accessory pathways. After ablation was performed, RBBB was evident. CONCLUSION: In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of a RBBB pattern in the surface ECG after RFCA should raise suspicion for the presence of multiple accessory pathways.

Reuse of pacemakers: comparison of short and long-term performance.

BACKGROUND: In developing economies, there are patients in whom pacemaker implantation is delayed because they cannot afford one. Reused devices have been a solution. To address concerns about safety, a cohort of consecutive patients implanted with a reused pacemaker was compared with a control group. METHODS AND RESULTS: A cohort of 603 consecutive patients from 2000 to 2010 was studied in an ambispective noninferiority study. The study group patients (n=307) received resterilized pacemakers, and the control group patients (n=296) received a new pacemaker. A combined end point of 3 major outcomes-unexpected battery depletion, infection, and device dysfunction-was analyzed. A total of 85 pacemakers had to be explanted, 31 in the control group (10.5%) and 54 in the study group (17.6%; relative risk, 1.68; 95% confidence interval, 1.1-2.5; P=0.02). Forty-three reached the primary end point, 16 in the control group (5.5%) and 27 in the study group (7.2%; relative risk, 1.3; 95% confidence interval, 0.70-2.45; P=0.794). In terms of individual outcomes, 5 new pacemakers (1.7%) and 11 resterilized pacemakers (3.6%) had unexpected battery depletion (relative risk, 2.12; 95% confidence interval, 0.75-6; P=0.116); 3.7% new pacemakers and 3.2% reused pacemakers had a procedure-related infection (relative risk, 0.87; 95% confidence interval, 0.38-2.03; P=0.46); and 1 pacemaker in the study group malfunctioned. CONCLUSIONS: Pacemaker reuse is feasible and safe and is a viable option for patient with bradyarrhythmias. Other than the expected shorter battery life, reuse of pacemaker generators is not inferior to the use of new devices.

Electrocardiographic manifestation of the middle fibers/septal fascicle block: a consensus report.

There are fibers in the left ventricle (LV) (LV middle network) that in around one third of cases may be considered a true septal fascicle that arises from the common left bundle. Its presence and the evidence that there are 3 points of activation onset in the LV favor the quadrifascicular theory of the intraventricular activation of both ventricles. Since the 70s, different authors have suggested that the block of the left middle fibers (MS)/left septal fascicle may explain different electrocardiographic (ECG) patterns. The 2 hypothetically based criteria that are in some sense contradictory include: a) the lack of septal "q" wave due to first left and later posteriorly shifting of the horizontal plane loop and b) the presence of RS in lead V(2) (V(1)-V(2)) due to some anterior shifting of the horizontal plane vectorcardiogram loop. However, there are many evidence that the lack of septal q waves can be also explained by predivisional first-degree left bundle-branch block and that the RS pattern in the right precordial leads may be also explained by first-degree right bundle-branch block. The transient nature of these patterns favor the concept that some type of intraventricular conduction disturbance exists but a doubt remains about its location. Furthermore, the RS pattern could be explained by many different normal variants. To improve our understanding whether these patterns are due to MF/left septal fascicle block or other ventricular conduction disturbances (or both), it would be advisable: 1) To perform more histologic studies (heart transplant and necropsy) of the ventricular conduction system; 2) To repeat prior experimental studies using new methodology/technology to isolate the MF; and 3) To change the paradigm: do not try to demonstrate if the block of the fibers produces an ECG change but to study with new electroanatomical imaging techniques, if these ECG criteria previously described correlate or not with a delay of activation in the zone of the LV that receives the activation through these fibers or in other zones.

[Corrected QT interval and GRACE score relationship in patients with non-ST segment elevation myocardial infarction]. / Relación del intervalo QT corregido con la escala GRACE en pacientes con infarto de miocardio sin elevación del segmento ST.

Background: The Global Registry of Acute Coronary Events (GRACE) prediction model stratifies patients with non-ST-segment elevation myocardial infarction (NSTEMI). Corrected QT interval (QTc) is not considered in this model. Objective: To evaluate the relationship between the QTc interval and the GRACE score in patients with NSTEMI. Materials and methods: An observational, retrospective study was carried between 2016 and 2019. We included patients with diagnosis of NSTEMI, QTc intervals were calculated with Bazett's formula, and they were classified into 2 groups: a normal QTc interval (<440 ms) and prolonged (≥440 ms). According to the GRACE score they were classified in three ranges: low risk (≤109 points), intermedium (110 - 139 points) and high (≥140 points), we determined if there were a correlation between QTc interval and the GRACE score. Results: A total of 940 patients with a diagnosis of NSTEMI were admitted in our institution, 634 met the inclusion criteria, there were 390 patients with normal QTc interval and 244 with a prolonged QTc interval. Patients with prolonged QTc were older (65.5 vs 61, p=0.001) with a lower proportion of males (71.7% vs 82.8%, p=0.001). An association was found between the GRACE score and the QTC interval, subjects with a normal QTc had a greater proportion of low and intermediate risk than those with a prolonged QTc (p=0.001). Conclusions. In NSTEMI patients, a normal QTc interval (<440 ms) is associated with a GRACE risk score of low or intermediate risk.

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Compound Heterozygous KCNQ1 Mutations Causing Recessive Romano-Ward Syndrome: Functional Characterization by Mutant Co-expression.

Next Generation Sequencing has identified many KCNQ1 genetic variants associated with type 1 long QT or Romano-Ward syndrome, most frequently inherited in an autosomal dominant fashion, although recessive forms have been reported. Particularly in the case of missense variants, functional studies of mutants are of aid to establish variant pathogenicity and to understand the mechanistic basis of disease. Two compound heterozygous KCNQ1 mutations (p.A300T and p.P535T) were previously found in a child who suffered sudden death. To provide further insight into the clinical significance and basis for pathogenicity of these variants, different combinations of wildtype, A300T and P535T alleles were co-expressed with the accessory ß-subunit minK in HEK293 cells, to analyze colocalization with the plasma membrane and some biophysical phenotypes of homo and heterotetrameric channels using the patch-clamp technique. A300T homotetrameric channels showed left-shifted activation V1/2 as previously observed in Xenopus oocytes, decreased maximum conductance density, slow rise-time300ms, and a characteristic use-dependent response. A300T slow rise-time300ms and use-dependent response behaved as dominant biophysical traits for all allele combinations. The P535T variant significantly decreased maximum conductance density and Kv7.1-minK-plasma membrane colocalization. P535T/A300T heterotetrameric channels showed decreased colocalization with plasma membrane, slow rise-time300ms and the A300T characteristic use-dependent response. While A300T left shifted activation voltage dependence behaved as a recessive trait when co-expressed with WT alleles, it was dominant when co-expressed with P535T alleles. Conclusions: The combination of P535T/A300T channel biophysical properties is compatible with recessive Romano Ward syndrome. Further analysis of other biophysical traits may identify other mechanisms involved in the pathophysiology of this disease.

[Clinical predictors of ventricular arrhythmia storms in Chagas cardiomyopathy patients with implantable defibrillators]. / Predictores clínicos de tormenta arrítmica en pacientes con cardiomiopatía Chagásica con un desfibrilador automático implantable.

OBJECTIVES: To define the predictive factors of electrical storm (ES) in patients with Chronic Chagas Heart Disease (CCh) with an implantable cardioverter defibrillator (ICD). MATERIAL AND METHODS: We retrospectively studied 21 consecutive patients with CCh in whom an ICD was implanted between April 2005 and December 2008, with a mean follow up of 867 days. Patients were classified into two groups according to the presence of electrical storm episodes. We compared baseline characteristics, medical treatment and determinants of ventricular function. P values less than 0.05 were considered statistically significant. RESULTS: Of the 21 patients with CCh there were eight women (37%), mean age 61 years and an EF of 30%. It was noted at least one episode of arrhythmic storm in 9 cases (incidence of 43%). The total number of episodes of arrhythmic storm was 13 and the number of ventricular arrhythmias in each episode of arrhythmic storm was 15.6 (range 3-61). A trigger was identified in only two cases (pulmonary infectious process and decompensation of chronic heart failure). After analyzing the possible predictors of arrhythmic storm was found that a greater percentage of subjects with this complication had an EF <35% (89% vs. 50%, p = 0.01) and NYHA functional class III (66% vs. 8.3%, p = 0.001). In contrast, a lower percentage of subjects with arrhythmic storm were under beta-blocker treatment (55% vs. 100%, p = 0.01). CONCLUSIONS: In subjects with CCh with an ICD, the following variables are predictive of arrhythmic storm: EF <35%, NYHA functional class III-IV and absence of beta-blocker treatment.

Association between premature ventricular complexes during exercise, long-term occurrence of life-threatening arrhythmia and mortality.

OBJECTIVE: Exercise-induced premature ventricular complexes (EiPVCs) are often considered as benign arrhythmias, although they are associated with a high risk of all-cause death in the general healthy population. However, an intermediate pathophysiological process remains unclear, particularly in patients with known cardiovascular disease. The aim of this study was to find an association between EiPVCs, the occurrence of life-threatening ventricular arrhythmias (LACO), and all-cause mortality in patients with cardiovascular disease. METHODS: This was an observational study of a cohort of patients with coronary artery disease (CAD) or idiopathic cardiomyopathy (ICM). Stress testing was performed as a part of the routine cardiovascular evaluation. The occurrence of EiPVCs was evaluated during exercise testing (ET). At follow-up, long-term occurrence of LACO was evaluated. A bivariate and multivariate analysis was performed. RESULTS: Out of the total of 1442 patients analysed, 700 (49%) had EiPVCs. During 14 years of following-up after ET, 106 LACO outcomes were observed. Long-term all-cause mortality was 4% (n=61). A bivariate analysis showed that patients with EiPVCs had an increased risk for LACO (RR=2.81, 95% CI; 1.9-4.3, P<.001), and for mortality (RR=2.1, CI95% 1.2-3.4, P<.01). Occurrence of LACO was also associated with a higher mortality risk (RR=5.7, 95% CI; 3.4-9.4, P<.001). After a post hoc analysis, LACO remained as a highly predictive variable for mortality. CONCLUSION: Patients with EiPVCs have a high risk of LACO and all-cause mortality. The presence of LACO could be an intermediate stage between EiPVCs and mortality in subjects with cardiovascular disease.

Postintervention Dyspnea after Radiofrequency Catheter Ablation: Think of a Phrenic Nerve Injury.

Phrenic nerve injury (PNI) is a rare complication of catheter ablation therapy, most commonly observed in cryoablation of the right side pulmonary veins. We present a case of PNI after radiofrequency catheter ablation that developed acute dyspnea 24 hours after the intervention. Dyspnea is the main symptom of PNI, so the diagnosis should always be suspected if it appears after any type of catheter ablation involving the trajectory of the phrenic nerve. There is no specific treatment for PNI. The only maneuver that has been reported to accelerate the recovery of PNI is early stopping of the ablation therapy.

Idiopathic Lead Migration: Concept and Variants of an Uncommon Cause of Cardiac Implantable Electronic Device Dysfunction.

OBJECTIVES: This cumulative case study was performed to properly address the possible mechanisms, forms, and consequences of "twiddler's," "reel," and "ratchet" syndromes. BACKGROUND: Twiddler's, reel, and ratchet syndromes are rare entities responsible for lead displacement of cardiac implantable electronic devices (CIED). METHODS: From 2007 to 2012, 1,472 CIED were implanted at our center. Eighty-nine cases were reviewed for failure of pacing circuit integrity. Only 9 met the inclusion criteria for idiopathic lead migration (ILM) and were grouped as ILM (twiddler) or ILM (reel). For a pooled analysis of cases, a review of the literature from 1990 to 2012 was performed, and the authors identified 78 cases from 64 publications. RESULTS: The study population consisted of 87 cases (45 women; median age, 66 years; 46 with ILM [twiddler] and 41 with ILM [reel]). Migration affected only 1 lead in 65% of 46 devices with more than 1 lead. None of the previously reported risk factors-manual manipulation of the device, elderly age, obesity, oversized pocket, and psychiatric history-correlated with the risk of ILM. CONCLUSIONS: Neither manual manipulation of the device nor the other traditional risk factors reported in the literature for ILM syndrome correlated with the risk of ILM.

Electrocardiographic characteristics of patients with Ebstein's anomaly before and after ablation of an accessory atrioventricular pathway.

UNLABELLED: The abnormal development of the tricuspid valve in patients with Ebstein's anomaly results in several activation abnormalities including delayed intraatrial conduction, right bundle branch block (RBBB), and ventricular preexcitation. The aim of the present study was to define the ECG characteristics before and after ablation of an accessory A-V pathway (AP) in patients with Ebstein's anomaly. METHODS: A series of 226 consecutive patients with Ebstein's anomaly was studied. Sixty-four patients (28%) had documented tachycardia. Thirty-three patients with recurrent tachycardia were found to have a single right-sided AP that was successfully ablated (study group). Thirty patients without tachycardia served as the control group. RESULTS: Only 21 of 33 patients (62%) had a typical ECG pattern of preexcitation. In addition, none of the patients had an ECG pattern of RBBB during sinus rhythm. In contrast, 28 of 30 (93%) patients in the control group had RBBB (P < 0.001). Radiofrequency catheter ablation resulted in appearance of RBBB in 31 of 33 (94%) patients. The absence of RBBB in patients with Ebstein's anomaly and recurrent tachycardia had a 98% sensitivity and 92% specificity for the diagnosis of an AP. The positive predictive value was 91% (0.77, 0.97 CI 95%) and the negative predictive value was 98% (0.85, 0.99 CI 95%). CONCLUSION: One-third of patients with Ebstein's anomaly and symptomatic tachyarrhythmias have minimal or absent ECG features of ventricular preexcitation. In these patients, the absence of RBBB pattern is a strong predictor of an AP.

[On the ventricular arrhythmias in Chagasic chronic cardiomyopathy]. / En torno a las arritmias ventriculares en la miocardiopatía chagásica crónica.

Some authors have shown a high prevalence of electric circuits localized in the epicardium in Chagasic cardiomyopathy. Other authors have found in these patients, during electric mapping, mid-diastolic potentials and earlier myocardial activation in epicardial regions than in the endocardium. In a previous study, we found electrocardiographic signs of subepicardial ischemia in 66% of seropositive Chagasic patients against 16% of seronegative Chagasic ones. In the case presented here, a Chagasic dilated cardiomyopathy, we found electrocardiographic signs of subepicardial injury in the left free ventricular wall, related with histological findings of lymphocytic inflammation in these regions. In contrast, the endocardium was completely free from inflammation foci.

[Cardiac involvement in Kearns-Sayre syndrome]. / Afección cardíaca en el síndrome de Kearns-Sayre.

The mitochondrial cytopathies or oxidative-phosphorylation diseases are a diverse group of disorders that result from the structural, biochemical, or genetic derangement of mitochondria. Because mitochondrial dysfunction can affect the most highly energy-dependent organs, cardiac involvement is frequent in these diseases. To identify the clinical features of Kearns-Sayre syndrome, an entity associated with this group of diseases, we evaluated cardiac structure and function in 5 patients with Kearns-Sayre syndrome and followed the clinical course of these patients for 5 years.

[Surgical radiofrequency catheter ablation of accessory pathways in Ebstein's anomaly]. / Ablación transquirúrgica de vía accesoria atrioventricular en anomalía de Ebstein.

Thirteen patients with Ebstein anomaly and atrioventricular reentrant tachycardia and at least one accessory pathway were included in this study. One accessory pathway in 7 (53.8%) patients and multiple accessory pathways in 6 (46.1%) were found. Mahaim accessory pathway was observed in 5 (38.4%) patients. A total of 22 accessory pathways was found, 2 (9%) were concealed. In all (100%), the accessory pathways were located in the tricuspid ring. The most frequent regions were right lateral free wall with 11 (50%) and 5 right posteroseptal (22.7%). Ten patients underwent surgical radiofrequency catheter ablation and three subjected to surgical section. We obtained success in 100%. No complications were observed during the procedures. In conclusion, surgical ablation therapy in patients with accessory pathways and Ebstein's anomaly is safe and effective.

[Direct cryothermal ablation eliminates conduction of the slow pathway without inducing ectopic rhythms]. / La ablación criotérmica percutánea directa elimina la conducción a través de la vía lenta intranodal sin inducir ritmos ectópicos.

Radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia is based on the elimination of conduction of slow or fast intranodal pathway. To avoid potential atrioventricular (AV) block, a new technology has been developed, cryothermal ablation. We report a case of AV nodal reentrant tachycardia in whom direct cryoablation, without previous ice mapping, was successfully performed. Interestingly and as previously described, cryotherapy did not induce ectopic rhythms, the conventional surrogate during radiofrequency ablation.

[Cardiology in the Morgagni's anatomo pathological work]. / La cardiología en la obra anatomopatológica de G.B. Morgagni.

In the XVIII century, under the influence of the "systematic spirit", characteristic of the Enlightenment age, pathological anatomy was systematized in the Morgagni's fundamental treatise De sedibus et causis morborum per anatomen indagatis, published as letters in 1761. Certain biographical data of the author are reported here as well as some his more important contributions to cardiology such as the Morgagni's, Adams', Stokes' syndrome. His points of view on sudden death and his observations on post-infarct myocardial rupture, are related also. In his global evaluation of these facts, the speculative approach always predominates. Indeed, in these anatomist's works, we find a good example of the application of epistemologic principles to the medical field.

Common electrocardiographic artifacts mimicking arrhythmias in ambulatory monitoring.

BACKGROUND: Ambulatory electrocardiographic monitoring is used in clinical practice as a means of detecting cardiac arrhythmias during daily activities. Current equipment provides analysis for the detection of arrhythmias, ST-segment deviation, and more sophisticated analyses (late potentials, Q-T behavior, and heart-rate variability). However, despite the system used, a number of artifacts could mislead diagnosis. METHODS AND RESULTS: We prospectively searched for artifacts during ambulatory electrocardiography in patients referred for monitoring to our institution, a tertiary referral center. Patients were ambulatory at home, work, school, or within the hospital. We divided artifacts according to Krasnow and Bloomfield's classification (pseudoarrhythmia, nonarrhythmia), and we added a new category, artifacts in patients with pacemakers. Artifacts encountered mimicked sinus arrest, supraventricular arrhythmias, ventricular arrhythmias, and aberrancy. Examples of each one and diagnostic clues are provided to recognize these artifacts properly. CONCLUSIONS: A substantial amount of invalid data (false-positive findings because of electrocardiographic artifacts) were identified during ambulatory electrocardiographic monitoring that can lead to inappropriate interpretation and may result in severe diagnostic errors.