Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells.

BACKGROUND: Telethonin (TCAP) is a Z-disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. TCAP is shown to modulate α-subunit of the human cardiac sodium channel (hNav 1.5) by direct interactions. Several TCAP variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes. METHODS: Mutational analyses for TCAP were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J-wave pattern ECG. Using patch-clamp techniques, electrophysiological characteristics of hNav 1.5 were studied in HEK-293 cells stably expressing hNav 1.5 and transiently transfected with wild-type (WT) or variant TCAP. RESULTS: We identified two TCAP variants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J-wave pattern ECG. No patient had variant hNav 1.5. Patch-clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT-TCAP (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward-shifted by 5 mV in cells expressing p.E49K compared with WT-TCAP. Voltage dependency of activation was not leftward-shifted by p.R153H, while voltage dependency of steady-state inactivation was leftward-shifted by p.E49K. CONCLUSIONS: We found two TCAP variants in the patients with BrS, J-wave pattern ECG, and ARVC that can cause loss-of-function of the hNav 1.5 in heterologous expression systems. Our observation suggests that these variants might impair INa and be associated with the patients' electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.

Correlation between asymptomatic gastroesophageal excessive transmural injury after pulmonary vein isolation and a bonus freeze protocol using the second-generation 28-mm cryoballoon for paroxysmal atrial fibrillation.

BACKGROUND: Second-generation cryoballoon (2G-CB) ablation is highly effective for achieving pulmonary vein isolation (PVI) with a promising clinical outcome. However, the ideal freezing strategy for preventing gastroesophageal excessive transmural injury (ETI) remains under debate. This study aimed to clarify the correlation between gastroesophageal ETI and a bonus-freeze protocol after PVI using 2G-CBs. METHOD: This study included 100 patients who underwent PVI using 2G-CB followed by an endoscopic examination. The freeze-cycle duration was set at 180s. In the first 33 patients a 120s bonus-freeze was applied after successful PVI (bonus group), while in the following 67 the bonus freeze was omitted (non-bonus group). Early freezing interruption was performed when the esophageal temperature reached 25°C. Gastroesophageal ETI was defined as any injury that resulted from the PVI, including esophageal damage or periesophageal nerve injury. RESULTS: Gastroesophageal ETIs were observed in 9 (27.3%) and 6 (9.0%) patients and were all asymptomatic, esophageal damage in 3 and 0, and periesophageal nerve injury in the remaining 6 and 6 in the bonus group and non-bonus group, respectively (p=0.033). In the multivariate analysis, the bonus freeze protocol (odds ratio 3.527; 95% confidence interval 1.110-11.208; p=0.033) was the sole independent predictor of gastroesophageal ETI. During a one-year follow-up 26 of 33 bonus group patients (78.8%) and 52 of 67 (77.6%) non-bonus group patients remained in stable sinus rhythm without any differences between the groups. CONCLUSIONS: In the patients with a bonus-freeze protocol using the 2G-CB, gastroesophageal ETIs were detected more often than in those with the non-bonus freeze protocol. In contrast, freedom from atrial fibrillation after the 2G-CB based PVI was comparable when applying either a bonus or non-bonus freeze protocol.

Lactococcus lactis cholangitis and bacteremia identified by MALDI-TOF mass spectrometry: A case report and review of the literature on Lactococcus lactis infection.

Lactococcus lactis is a rare causative organism in humans. Cases of L. lactis infection have only rarely been reported. However, because it is often difficult to identify by conventional commercially available methods, its incidence may be underestimated. We herein report the case of a 70-year-old man with cholangiocarcinoma who developed L. lactis cholangitis and review previously reported cases of L. lactis infection. Our case was confirmed by matrix-assisted desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). This case shows L. lactis is a potential causative pathogen of cholangitis and that MALDI-TOF MS can be useful for the rapid and accurate identification of L. lactis infection. We searched the literature for published case reports on cholangitis and any other infections caused by L. lactis, and thereby identified 36 cases, including our case. At least 66.7% (n = 24) of the cases had significant underlying conditions; 15 of the cases involved patients with an immunocompromised status. At least 41.7% (n = 15) had a significant food consumption history, such as the consumption of unpasteurized dairy products. The clinical sources of L. lactis were diverse and endocarditis was the most common diagnosis (n = 8), followed by hepatobiliary infection (n = 6), central nervous system infection (n = 5), and peritonitis (n = 4). The prognosis was favorable in most cases.

Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction.

BACKGROUND: Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep. OBJECTIVE: The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels. METHODS: LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system. RESULTS: We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation. CONCLUSION: We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.

Gain-of-function KCNH2 mutations in patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated. METHODS AND RESULTS: We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations. CONCLUSIONS: All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients.

Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30-40s, the age-dependent clinical and genetic differences remain unknown. METHODS AND RESULTS: A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers. CONCLUSIONS: The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.

Theophylline attenuates hippocampal blood flow responses induced by tooth pulp stimulation in rats.

In this study, we performed tests to determine whether tooth pulp stimulation (TPS) increases hippocampal blood flow (HBF), and if so, to investigate whether the increase in HBF is mediated via the activation of adenosine receptors. We measured HBF in urethane-anesthetized rats using laser Doppler flowmetry (LDF) and examined the effect of theophylline, a nonselective adenosine receptor antagonist, on TPS-induced HBF responses. TPS increased HBF, and its response was significantly attenuated by the intraperitoneal administration of theophylline (20 mg/kg). These results suggest that the HBF response induced by TPS may be, at least in part, produced through adenosine receptors.

Novel mutation of plakophilin-2 associated with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterized by dilatation and akinesis of the right ventricle, and causes life-threatening ventricular arrhythmia. Mutations of plakophilin-2 (PKP2) have recently been identified as one causative abnormality in ARVC. A case of ARVC with a mutation of PKP2 is reported here. Direct sequencing of the patient's DNA revealed an insertion mutation in exon 8 of PKP2 (1728_1729insGATG). The mutation caused the frameshift and the premature termination of translation (R577DfsX5). This is the first case report of PKP2 mutation found in Japanese ARVC patients.

La prevalencia de la fibrilación auricular aumenta con la edad avanzada: cambios histológicos y electrofisiológicos del miocardio auricular inducidos por la senectud en pacientes con Fibrilación Auricular Paroxística / The prevalence of atrial fibrillation increases with advancing age: age induced histological and electrophysiological changes of the atrial muscle in patients with Paraoxysmal Atrial Fibrillation

En un estudio reciente, hemos encontrado una correlación significativamente positiva entre la edad y el número de electrogramas auriculares endocárdicos anormales en el hombre 32). Los pacientes con más de 60 años de edad tenían un número promedio significativamente mayor de electrogramas auriculares anormales que los pacientes más jóvenes. Adicionalmente, la duración más larga y el máximo número de deflecciones fragmentadas de los electrogramas auriculares entre los 12 sitios de la aurícula derecha también mostraron una correlación significativamente positiva con la edad. Nuestros resultados demuestran un incremento progresivo en la extensión de la alteración electrofisiológica del miocardio auricular en el hombre anciano. Un electrograma auricular prolongado y fraccionado puede reflejar una actividad eléctrica focal desincronizada relacionada a una conducción anisotrópica y no uniforme a través de un miocardio auricular enfermo. Por lo tanto, electrogramas anormales indican áreas de anatomía y conducción alteradas que son sustratos propicios para las arritmias de reentrada (16). Teniendo en cuenta que los electrogramas auriculares anormales aumentan con la edad avanzada, estos cambios electrofisiológicos predisponen a la facilidad de desarrollar fibrilación auricular en pacientes ancianos. Las bases fisiopatológicas precisas para el inicio y mantenimiento de la FA no han sido resueltas. Con el surgimiento de la más novedosa y más sofisticada tecnología disponible en nuestros días, han re-emergido las controversias acerca de la génesis de la FA. Los nuevos avances y descubrimientos pueden ser relevantes para el mejor entendimiento de los mecanismos de inicio de la FA por interacción de las ondas frontales de propagación con obstáculos anatómicos o funcionales en su camino de despolarización

Alteraciones electrofisiológicas diferentes en pacientes con fibrilación auricular paroxística dependiendo de la enfermedad subyacente: implicancia clínica para el desarrollo futuo de nuevos fármacos antiarrítmicos / Different electrophysiological alterations in patients with paroxysmal atrial fibrillation depending on the underlying disorder: Clinical implications for future developments of novel antiarrhythmic drugs

En conclusión, la Fibrilación Auricular Paroxística (PAF) es causada por varias enfermedades subyacentes. Varios estudios indican que las propiedades electrofisiológicas de la AF son diferentes por los tipos diferentes de enfermedades subyacentes. A pesar de que la elección de un fármaco antiarrítmico debería estar basada en las propiedades electrofisiológicas de la arritmia en cuestión, las características electrofisiológicas de la aurícula en la PAF en cada una de las enfermedades subyacentes son poco claras aún. Los pacientes con PAF exhiben una diversidad electrofisiológica de la aurícula en conjunción con la cardiopatía de base, y un mejor entendimiento de las anormalidades electrofisiológicas ayudaría a determinar una mayor efectividad de las drogas antiarrítmicas en estos pacientes. Se requiere una mayor investigación en el futuro sobre las propiedades electrofisiológicas de la AF para poder contribuir al futuro desarrollo de un tratamiento apropiado

Attitudes of Japanese cardiologists toward anticoagulation for nonvalvular atrial fibrillation and reasons for its underuse.

BACKGROUND: Although warfarin reduces embolic events in patients with nonvalvular atrial fibrillation (NVAF), it is used less frequently in Japan and so the aim of the present study was to determine the attitudes of Japanese cardiologists toward antithrombotic therapy for NVAF patients. METHODS AND RESULTS: Subjects were NVAF patients enrolled in a prospective study in 1999. Clinical characteristics, type of NVAF and antithrombotic therapy, risk factors for embolism, and contraindications to warfarin were analyzed. Risk factors included advanced age (>75 years), hypertension, diabetes mellitus, congestive heart failure, and prior embolic events. Contraindications to warfarin included bleeding tendency, malignant tumors and others. Among 509 patients (66.6+/-10.3 years old), 359 had at least one risk factor for embolism and of these 359 patients, 200 (55.7%) received warfarin (ie, modest adherence to the guideline for antithrombotic therapy). There were 159 patients who had at least one risk factor but did not receive warfarin; 70.4% of these received antiplatelet drugs. Contraindications were found in only 22.6% and paroxysmal nature of NVAF seemed a possible reason for non-use of warfarin in 47.2% of 159 patients. CONCLUSIONS: In Japan warfarin is not used extensively for treatment of NVAF patients having risk factors and the reasons for not using antithrombotic therapy seemed inappropriate in most of patients.

Vulnerabilidad auricular aumentada: implicancia clínica de los parámetros electrofisiológicos inducidos por estimulación auricular programada en la enfermedad del nódulo sinusal asociada a fibrilación auricular paroxística / Augmented atrial vulnerability: clinical implications of the electrophysiological parameters induced by programmed atrial stimulation in the sick sinus syndrome associated to paroxysmal atrial fibrillation

Se desconoce la utilidad de ciertos parámetros electrofisiológicos de vulnerabilidad auricular como indicadores clínicos del desarrollo de fibrilación auricular paroxística, en un grupo más homogéneo de pacientes como es el de la enfermedad del nódulo sinusal. Se realizó una estimulación auricular programada con extraestímulos simples en 56 pacientes, de los cuales 32 pacientes tenían buena función del nódulo sinusal y no presentaban fibrilación auricular paroxística (Grupo I) y 24 pacientes con enfermedad del nódulo sinusal y fibrilación auricular paroxística (Grupo II). La incidencia de inducción de la actividad auricular repetitiva (71 por ciento vs 38 por ciento; p<0.02), actividad auricular fragmentada (88 por ciento vs 50 por ciento; p<0.005) y fibrilación auricular sostenida (46 por ciento vs 6 por ciento; p<0.001) fue significativamente mayor en el Grupo II comparado al Grupo control. Las zonas respectivas de inducción de RAF (36±37 vs 11±18 ms;p<0.005), zona de FAA (52±43 vs 14±18 ms; p<0.001), zona de IACD (52±36 vs 29±25 ms; p<0.02) fueron significativamente más amplias en los pacientes del Grupo II comparados al Grupo control. Los parámetros electrofisiológicos indicadores de vulnerabilidad auricular aumentada se encuentran significativamente alterados en los pacientes con enfermedad del nódulo sinusal asociado a fibrilación auricular paroxística. Los datos obtenidos en esta investigación prospectiva sugieren que existe una mayor predisposición para el desarrollo de episodios de fibrilación auricular en pacientes con enfermedad del nódulo sinusal, porque poseen una vulnerabilidad auricular significativamente mayor

Pericarditis estéril, un modelo de fibrilación auricular: ¿Qué hemos aprendido de los experimentos en animales? / Sterile pericarditis modells of atrial fibrillation: what have we learned from animal experiments?

El mecanismo electrofisiológico de la fibrilación auricular no está aún bien comprendido. Por un largo tiempo ha existido controversia con respecto a si la arritmia se debía a un foco unico de despolarización rápida o a una excitación de reentrada. Esta arritmia puede ser el resultado de una combinación de los mecanismos. Actualmente, esta aceptado en forma general que focos ectópicos en las venas pulmonares pueden iniciar fibrilación auricular y a su vez pueden actuar en la mantención de la arritmia. Sin embargo, no todos los pacientes con arritmias auriculares presentan fibrilación auricular. Se requiere un sustrato anatómico auricular que predisponga al inicio y mantenimiento de la fibrilación auricular. Esta arritmia resulta de un número crítico de ondas pequeñas circulantes en forma simultánea, la llamada hipótesis de las ondas pequeñas multiples propuesta por Moe y Col. Los estudios de fibrilación auricular con mapeo multisitios de Allessie y col. con una preparación auricular canina perfundida con Langendorff y con inducción mediante estimulación rápida y sostenida con infusión de acetilcolina, han proveído una clara evidencia para corroborar la hipotésis propuesta por Moe y col. como base de inicio de fibrilación auricular. Allessie y col. enfatizaron la importancia de un número crítico de ondas pequeñas circulantes en forma simultánea en un tipo de reentrada randomizada y la importancia de activación de ambas auriculas por ondas pequeñas provenientes de la otra aurícula. El modelo de fibrilación auricular de pericarditis estéril es uno de los modelos experimentales nuevos para el flutter auricular y también para la fibrilación auricular. En este modelo, la fibrilación auricular es inducida por estimulación rápida auricular. Este artículo fue diseñado para investigar que hemos aprendido de la fibrilación auricular inducida en animales de experimentación con el modelo de pericarditis estéril

Estimulación auricular programada con extraestímulos: vulnerabilidad auricular aumentada en pacientes con enfermedad del nódulo sinusal sin taquiarritmias / Programmed atrial stimulation with extrastimuli: augmented atrial vulnerability in patients with sick sinus syndrome without tachyarrhythmias

Aproximadamente un 15-40 por ciento de los pacientes con enfermedad del nódulo sinusal desarrollan fibrilación auricular mientras que los restantes no la desarrollan. Por ende, pensamos que la presencia de anormalidades electrofisiológicas del miocardio auricular podrían explicar estas diferencias en la génesis de la fibrilación auricular en pacientes con enfermedad del nódulo sinusal. Como parte del estudio electrofisiológico se realizó una estimulación auricular programada con extraestímulos simples en 58 pacientes, de los cuales, 32 pacientes tenían buena función del nódulo sinusal y no presentaban fibrilación auricular paroxística (Grupo I), y 26 pacientes con enfermedad del nódulo sinusal sin taquicardias (Grupo II). La mayoría de los parámetros electrofisiológicos indicadores de vulnerabilidad auricular aumentada no se encuentran significativamente alterados en los pacientes con enfermedad del nódulo sinusal sin taquicardias. La inducción de fibrilación auricular y actividad auricular repetitiva no es significativamente diferente que el grupo control. Solamente la incidencia de inducción de la actividad auricular fragmentada su respectiva zona de inducción, así como la zona de inducción del retardo en la conducción interauricular son significativamente mayores en los pacientes con enfermedad del nódulo sinusal sin taquicardias. Por ende, existe una tendencia significativa a desarrollar un retardo en la conducción de las extrasístoles pero sin la capacidad necesaria para desencadenar despolarizaciones repetitivas ni fibrilación auricular

Ritmo sinusal o fibrilación auricular: ¿latido sinusal o sin latido?. Editorial / Sinus rhythm or atrial fibrillation?: sinus beat or not to beat?. Editorial

El aumento en el entendimiento de la fibrilación auricular como una enfermedad más que una alternativa aceptable al ritmo sinusal ha llevado a la búsqueda de claros argumentos para aceptar a una determinada estrategia como tratamiento gold standard. En este aspecto, la decisión de restaurar el ritmo sinusal o de controlar la respuesta ventricular y dejar que la fibrilación persista es de importancia crucial. Los resultados recientes de ensayos controlados y randomizados que estudiaron este aspecto y que han proporcionado adecuada iluminación en la manera apropiada de tratar a estos pacientes, serán tratados en este artículo

Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm.

An abnormal distribution of the gap junction occurs in chronic atrial fibrillation (AF). There are conflicting data regarding changes in connexins (Cxs) in experimental models of AF. We examined whether patients with chronic AF have alterations in atrial Cxs. We analyzed the expression of Cx40 and Cx43 in the right atrial myocardium from 10 patients with mitral valvular disease (MVD) who had AF (MVD/AF), 10 patients with MVD who were in normal sinus rhythm (MVD/NSR), and 10 control patients in NSR (tissue obtained during coronary artery bypass surgery). Hemodynamic and echocardiographic data were obtained before surgery, and an electrophysiologic examination was performed during the operation. An immunohistochemical study was performed on atrial tissue. The relative expression level of Cx40 protein was significantly lower in MVD/AF patients (6.5 +/- 4.6) than in either MVD/NSR patients (17.7 +/- 8.9, p <0.05) or controls (24.7 +/- 11.1, p <0.01). The relative expression level of Cx40 messenger ribonucleic acid was also significantly lower in MVD/AF patients (0.23 +/- 0.13) than in MVD/NSR patients (0.47 +/- 0.26, p <0.01) or controls (0.47 +/- 0.17, p <0.01). For Cx43 protein and messenger ribonucleic acid, there was no significant difference in relative expression levels among the 3 groups. Interestingly, the level of serine-phosphorylated Cx40 was approximately 52% greater in MVD/AF patients than in controls. In MVD/AF patients, the immunoreactive signal of Cx40 was significantly lower than in controls. There was no significant difference in the connective tissue-volume fraction among the groups. Thus, downregulation of Cx40 and abnormal phosphorylation of Cx40 may result in abnormal cell-to-cell communication and alteration in the electrophysiologic properties of the atrium, leading to the initiation and/or perpetuation of AF.