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.

[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.

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 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.

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.

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.

Association between premature ventricular complexes during exercise, long-term occurrence of life-threatening arrhythmia and mortality / Asociación entre ectopia ventricular en ejercicio, la ocurrencia de arritmias potencialmente mortales y mortalidad a largo plazo

Abstract 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.

Resumen Objetivo: La extrasistolia ventricular inducida por ejercicio (EVIE) suele considerarse una arritmia benigna, sin embargo, ha sido asociada a mayor mortalidad en población general. Hasta hoy no se ha encontrado el proceso fisiopatológico involucrado, particularmente en pacientes con enfermedad cardiovascular. El objetivo del estudio fue establecer una asociación entre EVIE con la ocurrencia de arritmias ventriculares potencialmente malignas (APM) y letalidad a largo plazo, en sujetos con enfermedad cardiovascular. Método: Estudiamos una cohorte de pacientes con enfermedad coronaria o miocardiopatía dilatada, que realizaron una prueba de ejercicio al inicio del estudio. Inicialmente evaluamos la ocurrencia de EVIE, APM y letalidad a largo plazo y posteriormente se realizó un estudio bivariable y multivariable. Resultados: Se incluyeron 1,442 pacientes de los cuales 700 presentaron EVIE (49%). Durante 14 an˜os de seguimiento, 106 sujetos presentaron APM y la mortalidad total fue de 61 casos (4%). El estudio bivariable mostró que aquellos pacientes con EVIE tuvieron un riesgo de presentar APM de 2.81 (IC95% de 1.9 a 4.3, p < 0.001) y de mortalidad de 2.1 (IC95% de 1.2 a 3.4, p < 0.01). Los individuos con APM tuvieron mayor riesgo de mortalidad (RR= 5.7, IC95% de 3.4 a 9.4, p < 0.001). Después de un análisis multivariable, la APM continuó siendo una variable altamente predictiva de mortalidad. Conclusión: Los pacientes con EVIE tienen un riesgo elevado de presentar APM y de mortalidad a largo plazo. Los resultados sugieren que las APM podrían representar un estado intermedio entre la presencia de EVIE y la mortalidad en pacientes con enfermedad cardiovascular.

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.

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.

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.

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

En el siglo XVIII, bajo el influjo del <

In the XVIII century, under the influence of the <

[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.

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.

Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverter-defibrillator: a case series and literature review.

BACKGROUND: To prevent the recurrence of ventricular arrhythmias (VA) in Brugada syndrome (BrS), only quinidine has been consistently reported to have a beneficial effect. Recommended doses are ≥ 1 g/d. The efficacy of lower doses of quinidine has been suggested on the basis of a few isolated experiences. OBJECTIVES: To describe the efficacy and safety of doses ≤ 600 mg/d of quinidine after cardioverter-defibrillator implantation in BrS at 2 referral centers and to compare those results with a comprehensive review of the literature. METHODS: In a retrospective analysis of medical records from the 2 centers, 6 men with BrS who received ≤ 600 mg/d of quinidine sulfate or hydroquinidine after cardioverter-defibrillator implantation were identified. Quinidine was initiated after arrhythmic syncope or appropriate shocks, including arrhythmic storm in 4. A literature search was performed to find previous cases with symptomatic BrS reported as having received ≤ 600 mg/d of quinidine. RESULTS: Quinidine prevented recurrence of VA in all patients from our series without side effects during a median follow-up of 4 years (from 2 to 8 years). In the literature review, 14 additional adults were found. With the exception of 3, quinidine effectively suppressed arrhythmic events in all of them. Four subjects who discontinued the medication experienced VA recurrence, successfully treated by restarting quinidine. CONCLUSIONS: Low doses of quinidine were well tolerated and effective to prevent the recurrence of VA, including arrhythmic storm, in subjects with BrS with an implantable cardioverter-defibrillator. Effectiveness of quinidine or hydroquinidine in doses ≤ 600 mg/d is 85%.

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.

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

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.

Doença de Ebstein: ausência de bloqueio de ramo direito como preditor de via anômala manifestada / Ebstein disease: absence of right branch block as a predictor of manifested anomalous way

O desenvolvimento anormal da válvula tricúspide na doença de Ebstein resulta em uma série de anormalidades na ativação, que inclui condução intra-atrial demorada, bloqueio de ramo direito(BRG) e pré-excitação ventricular. O objetivo desse tabalho era definir as características do ECG antes e depois da ablação de uma via anômala atrioventricular. De 226 pacientes consecutivos com anomalia de Ebstein, 64 apresentavam taquicardia documentada...