RNA-methylation-dependent RNA processing controls the speed of the circadian clock.

The eukaryotic biological clock involves a negative transcription-translation feedback loop in which clock genes regulate their own transcription and that of output genes of metabolic significance. While around 10% of the liver transcriptome is rhythmic, only about a fifth is driven by de novo transcription, indicating mRNA processing is a major circadian component. Here, we report that inhibition of transmethylation reactions elongates the circadian period. RNA sequencing then reveals methylation inhibition causes widespread changes in the transcription of the RNA processing machinery, associated with m(6)A-RNA methylation. We identify m(6)A sites on many clock gene transcripts and show that specific inhibition of m(6)A methylation by silencing of the m(6)A methylase Mettl3 is sufficient to elicit circadian period elongation and RNA processing delay. Analysis of the circadian nucleocytoplasmic distribution of clock genes Per2 and Arntl then revealed an uncoupling between steady-state pre-mRNA and cytoplasmic mRNA rhythms when m(6)A methylation is inhibited.

An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.

The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.

Pathological and Comprehensive Genetic Investigation of Autopsy Cases of Idiopathic Bradyarrhythmia.

BACKGROUND: Idiopathic bradyarrhythmia is considered to be due to pathological degeneration of the cardiac conduction system (CCS) during aging. There appears to have been no comprehensive genetic investigations in patients with idiopathic bradyarrhythmia.Methods and Results: Ten autopsy cases with advanced bradyarrhythmia (6 men and 4 women; age: 70-94 years, 81.5±6.9 years; 5 cases each of sinus node dysfunction [SND] and complete atrioventricular block [CAVB]) were genetically investigated by using whole-exome sequencing. Morphometric analysis of the CCS was performed with sex-, age- and comorbidity-matched control cases. As a result, severe loss of nodal cells and distal atrioventricular conduction system were found in SND and CAVB, respectively. However, the conduction tissue loss was not significant in either the atrioventricular node or the proximal bundle of His in CAVB cases. A total of 13 heterozygous potential variants were found in 3 CAVB and 2 SND cases. Of these 13 variants, 4 were missense in the known progressive cardiac conduction disease-related genes: GATA4 and RYR2. In the remaining 9 variants, 5 were loss-of-function mutation with highly possible pathogenicity. CONCLUSIONS: In addition to degenerative changes of selectively vulnerable areas in the heart during advancing age, the vulnerability of the CCS, which may be associated with "rare variants of small effect," may also be a contributing factor to the degeneration of CCS, leading to "idiopathic" bradyarrhythmia.

Nmu/Nms/Gpr176 Triple-Deficient Mice Show Enhanced Light-Resetting of Circadian Locomotor Activity.

The suprachiasmatic nucleus (SCN) is the master circadian clock in mammals and is properly entrained by environmental light cycle. However, the molecular mechanism(s) determining the magnitude of phase shift by light is still not fully understood. The orphan G-protein-coupled receptor Gpr176 is enriched in the SCN, controls the pace (period) of the circadian rhythm in behavior but is not apparently involved in the light entrainment; Gpr176-/- animals display a shortened circadian period in constant darkness but their phase-resetting responses to light are normal. Here, we performed microarray analysis and identified enhanced mRNA expression of neuromedin U (Nmu) and neuromedin S (Nms) in the SCN of Gpr176-/- mice. By generating C57BL/6J-backcrossed Nmu/Nms/Gpr176 triple knockout mice, we noted that the mutant mice had a greater magnitude of phase shift in response to early subjective night light than wildtype mice, while Nmu/Nms double knockout mice as well as Gpr176 knockout mice are normal in the phase shifts induced by light. At the molecular level, Nmu-/-Nms-/-Gpr176-/- mice had a reduced induction of Per1 and cFos mRNA expression in the SCN by light and mildly upregulated circadian expression of Per2, Prok2, Rgs16, and Rasl11b. These expressional changes may underlie the phenotype of the Nmu/Nms/Gpr176 knockout mice. Our data argue that there is a mechanism requiring Nmu, Nms, and Gpr176 for the proper modulation of light-induced phase shift in mice. Simultaneous modulation of Nmu/Nms/Gpr176 may provide a potential target option for modulating the circadian clock.

Cardiac vagus nerve denervation by pulmonary vein isolation was effective for swallowing-induced atrial tachycardia.

Swallowing-induced atrial tachycardia (SIAT) is a relatively rare arrhythmia. A 56-year-old woman was admitted to treat atrial tachycardia that occurs by not only eating and drinking but also yawning. Both the right and left upper pulmonary veins were suspected as the earliest activation site of the tachycardia and the abnormal activation of ectopies themselves were suppressed after pulmonary vein isolation (PVI). In a 24-hour Holter electrocardiogram, the HF component of the analysis of heart rate variability was suppressed both at 1 day and at 2 years after ablation. In this case, cardiac vagal nerve denervation by PVI was effective for SIAT.

Paradoxical delayed capture proved the dual-loop tachycardia mechanism of a cavotricuspid isthmus-dependent atrial flutter.

A 37-year-old man underwent catheter ablation for a cavotricuspid isthmus-dependent atrial flutter. Two 20-pole deflectable electrode catheters were placed in a parallel position on the tricuspid annulus and right atrial lateral wall. The dual-loop tachycardia mechanism of the atrial flutter was suggested by paradoxical delayed capture of the lateral wall of the right atrium during entrainment pacing from the lateral tricuspid annulus.

Ripple map guided catheter ablation targeting abnormal atrial potentials during sinus rhythm for non-paroxysmal atrial fibrillation.

BACKGROUND: Abnormal atrial potential (AAP) during sinus rhythm may be a critical ablation target for atrial fibrillation. However, the assessment of local electrograms throughout the left atrium is difficult. Thus, we sought to investigate the effectiveness of Ripple map guided AAP ablation. METHODS AND RESULTS: AAP areas were determined by Ripple mapping on the CARTO system in 35 patients (Ripple group) by marking the area where small deflections persisted after the first deflection wavefront had passed. Following pulmonary vein isolation, AAP areas were ablated. If AAP areas were located on the left atrial posterior wall, the posterior wall was isolated. The outcome of this approach was compared with that of 66 patients who underwent an empirical linear ablation approach (control group). There were no differences in patient characteristics between the groups. The total radiofrequency application time and procedure time were shorter in the Ripple group than in the control group (radiofrequency application time, 48 ± 14 minutes vs 61 ± 13 minutes, P < .001; procedure time, 205 ± 30 minutes vs 221 ± 27 minutes, P = .013). Gastroparesis occurred in one patient in each group (P = .645), but in both cases this was relieved with conservative therapy. Kaplan-Meier analysis revealed that rate of freedom from atrial arrhythmia was higher in the Ripple group than in the control group (91% vs 74% during the 12 months' follow up; P = .040). CONCLUSION: Ripple map guided AAP ablation effectively suppressed atrial arrhythmia in patients with non-paroxysmal AF.

P-wave vector magnitude predicts the left atrial low-voltage area in patients with paroxysmal atrial fibrillation.

BACKGROUND: P-wave amplitude (PWA) parameters can be the surrogate measures of the left atrial low-voltage areas (LVAs). METHODS: We measured PWAs using an automated system in 50 patients with paroxysmal atrial fibrillation (AF). We examined the relationships between left atrial LVAs and PWA parameters, including P-wave vector magnitude, calculated as the square root of the sum of lead II PWA squared, lead V6 PWA squared, and a one-half lead V2 PWA squared. RESULTS: Lead I PWA was most strongly correlated with LVAs in the anterior wall and appendage (anterior wall, R = -0.391, P = 0.006; appendage, R = -0.342, P = 0.016), whereas lead II PWA was most strongly correlated with LVAs in the septum, posterior wall, and bottom wall (septum, R = -0.413, P = 0.003; posterior wall, R = -0.297, P = 0.039; bottom wall; R = -0.288, P = 0.045). Although maximum, minimum, mean, and lead I PWAs were not correlated with total LVA, P-wave vector magnitude and lead II PWA were significantly correlated with total LVA (P-wave vector magnitude, R = -0.430, P = 0.002; lead II PWA, R = -0.323, P = 0.023). P-wave vector magnitude achieved the highest accuracy for predicting significant LVA (total LVA > 10%) with an area under the curve of 0.772; sensitivity, specificity, and positive and negative predictive values were 64%, 88%, 85%, and 69%, respectively, for the cutoff value of 0.130 mV. CONCLUSION: P-wave vector magnitude is a useful electrocardiographic predictor of left atrial LVAs.

Minimal inflammatory foci of unknown etiology may be a tentative sign of early stage inherited cardiomyopathy.

Although relatively uncommon, pathologists may encounter minimal inflammatory foci in the absence of typical structural heart disease; however, the clinicopathological significance of minimal inflammatory foci, including correlation with sudden unexpected death, is unexplored. From 1072 serial autopsy subjects, cases with unexplained minimal inflammatory foci, the extent of which was under 1% of the whole examined ventricle, were extracted to exclude cases with borderline/focal myocarditis resulting from local, systemic infection, or autoimmune mechanisms. Immunohistochemistry and genetic analysis targeting viral genomes and heart disease-related genes using next generation sequencing were performed. We detected 10 cases with unexplained minimal inflammatory foci (five males, five females, aged 15-68 years). The cause and/or manner of death were sudden unexpected death (6 cases, 60%), sudden unexpected death with epilepsy (1 case, 10%), drowning in a hot bath (1 case, 10%), and suicide (2 cases, 20%). In none of these cases was pathogen-derived DNA or RNA detected. In 8 of the 10 cases (80%), 17 possible pathogenic genetic variants causative for arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy; DSP was the most frequently involved gene (three cases with two different variants), followed by LAMA4 and MYBPC3 (two cases, two variants for each gene), LDB3 (two cases, one variant), and the remaining 10 variants occurred in seven cases (DSC2, RYR2, SOS1, SCN5A, SGCD, LPL, PKP2, MYH11, GATA6, and DSG2). All mutations were missense mutations. DSP_Lys1581Glu and DSC2_p.Thr275Met were classified according to American College of Medical Genetics and Genomics consensus statement guidelines as pathogenic or likely pathogenic for arrhythmogenic cardiomyopathy in three patients (30%). The remaining 15 variants were classified as potentially pathogenic variants. Unexplained minimal inflammatory foci may be an early sign of inherited cardiomyopathy, and such cases might already have arrhythmogenic potential that can lead to sudden unexpected death. Detection of minimal inflammatory foci by careful pathological examination may indicate the value of conducting comprehensive genetic analysis, even if significant structural abnormalities are not evident.

Edoxaban suppresses the progression of atrial fibrosis and atrial fibrillation in a canine congestive heart failure model.

Coagulation factor Xa activates the protease-activated receptor 2 (PAR2) and causes tissue fibrosis; however, the effects of Xa inhibitor edoxaban on atrial fibrosis and atrial fibrillation (AF) have not been investigated. We examined the effect of edoxaban on the progression of atrial fibrosis in a canine congestive heart failure (CHF) model. Beagle dogs were assigned to sham, placebo, and edoxaban groups (n = 6/group). Dogs of the placebo or edoxaban groups received 19 days of medication with daily oral placebo or edoxaban, respectively, followed by 14 days of ventricular tachypacing. Dogs of the sham group had no medication or pacing. Ventricular tachypacing prolonged AF duration in dogs of the placebo group (159 ± 41 s, p < 0.01 vs. sham); however, this effect was suppressed by edoxaban treatment. Compared with the sham group, tachypacing alone also significantly increased the atrial fibrotic area (2.9 ± 0.1% vs. 7.8 ± 0.4%, p < 0.01), PAR2 expression (1.0 ± 0.1 vs. 1.8 ± 0.3, p < 0.05), and atrial fibronectin expression (1.0 ± 0.2 vs. 2.0 ± 0.2, p < 0.01). These responses were suppressed by edoxaban treatment (area 5.9 ± 0.4%, p < 0.01; PAR2 1.1 ± 0.1, p < 0.05; fibronectin 1.2 ± 0.2, p < 0.05 vs. placebo). Edoxaban showed suppressive effects on atrial remodeling, AF progression, and excessive expressions of PAR2 and fibronectin in a canine CHF model. The suppression of the Xa/PAR2 pathway might be a potential pharmacological target of edoxaban.

Impacts of the body size on the left atrial wall thickness and atrial fibrillation recurrence after catheter ablation.

The increased body size correlates with the occurrence of atrial fibrillation (AF); however, the impact of the body size on the AF recurrence after ablation remains unclear. We enrolled 283 AF patients (179 paroxysmal, 51 persistent, and 53 long-standing persistent) who received ablation and assessed the correlation between the body surface area (BSA) and the AF recurrence. Furthermore, we measured the left atrial wall thickness using computed tomography. During the 12-month follow-up period, the AF freedom rates for patients with paroxysmal AF, persistent AF, and long-standing persistent AF were 83%, 76%, and 77%, respectively. The left atrial dimension, BSA, and body mass index (BMI) were higher in the AF-recurrent group compared with the AF-free group (left atrial dimension: 44.1 ± 7.5 mm vs. 41.7 ± 6.5 mm, P = 0.019; BSA: 1.81 ± 0.20 m2 vs. 1.72 ± 0.19 m2, P = 0.002; BMI 25.0 ± 3.2 kg/m2 vs. 24.0 ± 3.2 kg/m2, P = 0.035). The multivariate analysis revealed that only the BSA was an independent predictor of the AF recurrence after ablation (hazard ratio 6.843; 95% confidence interval 1.523-30.759, P = 0.012). The BSA significantly correlated with the left atrial wall thickness (R = 0.306, P < 0.001), and the left atrial wall thickness was higher in the AF-recurrent group compared with the AF-free group (2.00 ± 0.20 mm vs. 1.87 ± 0.17 mm, P < 0.001). The large body size correlates with the AF recurrence after ablation, which could be attributed to an increase in the left atrial wall thickness.

P-wave vector magnitude predicts recurrence of atrial fibrillation after catheter ablation in patients with persistent atrial fibrillation.

BACKGROUND: The predictive efficacies of parameters related to P-wave amplitude (PWA) for atrial fibrillation (AF) recurrence after catheter ablation are unclear. METHODS: We measured multiple PWA parameters using an automated system in 126 consecutive patients with persistent and long-standing persistent AF who underwent catheter ablation. The relationships between AF recurrence and various PWA parameters were examined, including the association with P-wave vector magnitude (calculated as the square root of the sum of lead II PWA squared, lead V6 PWA squared, and a one-half lead V2 PWA squared). RESULTS: Atrial fibrillation did not recur in 87 patients (69%) during 32 ± 15 months of follow-up. The maximum PWA, mean PWA, and P-wave vector magnitude were lower in patients with AF recurrence than those without (maximum PWA, 0.14 ± 0.05 mV vs. 0.16 ± 0.05 mV, p = 0.017; mean PWA, 0.05 ± 0.02 mV vs. 0.06 ± 0.02 mV, p = 0.003; P-wave vector magnitude, 0.09 ± 0.03 mV vs. 0.13 ± 0.04 mV, p < 0.001). A multivariate Cox regression analysis revealed that the predictive ability of P-wave vector magnitude for AF recurrence was independent of other clinical properties (hazard ratio: 0.153, 95% confidence interval: 0.046-0.507, p = 0.002). Atrial fibrillation freedom rates of patients with P-wave vector magnitude higher and lower than 0.13 mV were 93% and 57%, respectively. P-wave vector magnitude weakly correlated with left atrial dimension (R = -0.280, p = 0.004). CONCLUSIONS: P-wave vector magnitude can predict AF recurrence after catheter ablation in patients with persistent AF.

Coefficient of variation of P-wave duration measured using an automated measurement system predicts recurrence of atrial fibrillation.

BACKGROUND: P-wave parameters representing atrial conduction heterogeneity are associated with recurrence of atrial fibrillation (AF) after catheter ablation. However, intra- and inter-observer variabilities are unavoidable during manual measurement of P-wave parameters. METHODS: The study included 201 patients with paroxysmal AF who underwent catheter ablation. P-wave duration (PWD) was measured using a computerized automated measurement system with a surface 12-lead electrocardiogram. The coefficient of variation of PWD (CV-PWD) across the 12 electrocardiographic leads was determined as an index of atrial conduction heterogeneity. RESULTS: AF did not recur in 157 (78%) patients during a 12-month follow-up period. CV-PWD assessed before catheter ablation was not different between the AF-recurrent and AF-free groups (0.069 ±â€¯0.023 vs. 0.069 ±â€¯0.023, P = 0.090). However, CV-PWD measured after catheter ablation was significantly larger in the AF-recurrent group than in the AF-free group (0.090 ±â€¯0.037 vs. 0.073 ±â€¯0.024, P < 0.001). In receiver operating curve analysis, CV-PWD assessed after catheter ablation achieved an area under the curve of 0.702; the sensitivity, specificity, and positive and negative predictive values were 68%, 69%, 38%, and 88%, respectively, for the cut-off value of 0.080. During the follow-up period, AF freedom rates of high CV-PWD patients (CV-PWD ≥ 0.080) and low CV-PWD patients (CV-PWD < 0.080) were 65% and 88%, respectively. CONCLUSIONS: CV-PWD determined using an automated measurement system was associated with AF recurrence after catheter ablation in patients with paroxysmal AF.

[A Case of Trigeminal Neuralgia Treated with Microvascular Decompression 10 years after Gamma Knife Radiosurgery].

We report a case of trigeminal neuralgia treated with microvascular decompression 10 years after We report a case of trigeminal neuralgia treated with microvascular decompression 10 years after Gamma Knife radiosurgery was performed. The patient was a 65-year-old female. The root entry zone of the trigeminal nerve received irradiation:a 4-mm shot, with a maximum dose of 80 Gy. The symptoms improved following treatment, however pain recurred five and a half years later. The pain gradually increased over time, to the point where the patient was unable to eat solid food. Carbamazepine was prescribed and the dosage increased. However, side effects such as dizziness and drowsiness manifested. Microvascular decompression was performed, revealing that the trigeminal nerve was markedly atrophied and being pressed upon by the superior cerebellar artery. The superior cerebellar artery was transpositioned with Teflon braided tape to the cerebellar tent. There were no abnormal findings such as arachnoid thickening, adhesions between vessels and nerves, or atherosclerotic plaque in the affected vessels. Pain completely abated following surgery, and side effects such as numbness of the face have not been observed at the time of writing this report.

Improvement of Hemodynamic Parameters in Patients With Preserved Left Ventricular Systolic Function by Catheter Ablation of Atrial Fibrillation　- A Prospective Study Using Impedance Cardiography.

BACKGROUND: The effects of catheter ablation for atrial fibrillation (AF) on hemodynamic parameters in patients with preserved left ventricular (LV) systolic function are unclear. Methods and Results: We enrolled 178 patients with AF (paroxysmal, 108; persistent, 70) with preserved LV systolic function who underwent AF ablation. The stroke volume index (SVI) was repeatedly measured using impedance cardiography. Reduced SVI (SVI, <33 mL/m2) was observed in 55% of patients before ablation. In patients with paroxysmal AF, the SVI did not change immediately after ablation (from 35±6 mL/m2to 35±5 mL/m2; P=0.652); however, it increased 1 month after ablation and further increased 6 months after ablation (1 month, 37±6 mL/m2, P<0.001; 6 months, 38±6 mL/m2, P<0.001). In patients with persistent AF, the SVI increased immediately after ablation (from 30±5 mL/m2to 36±6 mL/m2; P<0.001) and further increased until 6 months after ablation (1 month, 37±6 mL, P<0.001; 6 months, 38±5 mL/m2, P<0.001). The baseline SVI was the strongest predictor of the cardiac function improvement with an area under the curve of 0.828. CONCLUSIONS: The restoration and maintenance of sinus rhythm using catheter ablation increased the SVI in patients with preserved LV systolic function.

Atmospheric Activity Concentration of 90Sr and 137Cs after the Fukushima Daiichi Nuclear Accident.

On March 11, 2011, the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident occurred and large amounts of radionuclides were discharged into the atmosphere. We have operated continuous aerosol samplings at four locations in Japan from the accident until the end of 2011. The activities of 90Sr and 137Cs in the aerosol samples were measured using low background liquid scintillation counters and high-purity germanium detectors, respectively. The atmospheric 90Sr and 137Cs concentrations decreased exponentially during 2011. The time variation of the 90Sr/137Cs ratio was obtained, and we found that the ratio rose from 1.2 × 10-3 in March to 1.3 × 10-1 in August 2011. One reason for the increase in the 90Sr/137Cs ratio could be the change in the primary emission source of activity at the FDNPP, which occurred near June 2011.

Heterogeneity in the left atrial wall thickness contributes to atrial fibrillation recurrence after catheter ablation.

Influence of left atrial wall thickness on outcome of catheter ablation for atrial fibrillation (AF) is unclear. Overall, 213 patients with AF (128 paroxysmal and 85 persistent) received ablation. We measured the wall thickness of 16 and 19 areas in the pulmonary vein antrum (PVWT) and left atrial body (LAWT), respectively. Coefficient of variation of wall thickness (CV-WT) was calculated to assess heterogeneity in the left atrial wall thickness. In patients with paroxysmal AF, maximum PVWT, mean PVWT, maximum LAWT, and CV-WT were higher in AF recurrent group than in AF-free group (maximum PVWT, 2.85 ± 0.52 vs. 2.50 ± 0.45 mm, P = 0.003; mean PVWT, 1.59 ± 0.13 vs. 1.50 ± 0.15 mm, P = 0.018; maximum LAWT, 3.85 ± 0.77 vs. 3.41 ± 0.61 mm, P = 0.005; CV-WT, 0.34 ± 0.06 vs. 0.32 ± 0.05, P = 0.039). In patients with persistent AF, maximum PVWT, mean PVWT, maximum LAWT, mean LAWT, and CV-WT were higher in the AF-recurrent group than in the AF-free group (maximum PVWT, 2.52 ± 0.36 vs. 2.31 ± 0.36 mm, P = 0.031; mean PVWT, 1.53 ± 0.12 vs. 1.45 ± 0.14 mm, P = 0.036; maximum LAWT, 3.68 ± 0.75 vs. 3.11 ± 0.50 mm, P < 0.001; mean LAWT, 2.34 ± 0.35 vs. 2.13 ± 0.21 mm, P = 0.002; CV-WT, 0.35 ± 0.06 vs. 0.31 ± 0.05, P = 0.005). Thick and heterogeneous left atrial wall contributes to AF recurrence after ablation.

Vasovagal syncope is associated with poor prognosis in patients with left ventricular dysfunction.

Vasovagal syncope (VVS) is known to have a benign prognosis and be associated with enhanced contraction and activation of the left ventricular (LV) mechanoreceptors. However, a little is known about VVS in patients with LV dysfunction. The present study aimed to investigate the prevalence and prognosis of VVS in patients with LV dysfunction. We enrolled 368 patients with unexplained syncope. In 7 of these patients, LV ejection fraction was lower than 40%. The results of a head-up tilt test (HUT) and the recurrence of syncope were compared between these 7 patients with LV dysfunction and the remaining patients. Positive HUT was obtained in the 6 patients (86%) with LV dysfunction; this rate tended to be higher as compared with normal cardiac function (192/361, 53%, P = 0.069). In patients with LV dysfunction, response in HUT was mostly vasodepressor type (62%); however, most of HUT responses were mixed type in patients with normal LV function (67%). Among patients with positive HUT, the recurrent rate of syncope after HUT was higher in those with LV dysfunction than in those with normal LV function (67 vs. 21%, P = 0.008). VVS in patients with LV dysfunction may be refractory to treatment and could be associated with poor prognosis.

Citrus fruits induced swallow syncope with atrioventricular block or sinus arrest.

Swallow syncope is a relatively rare syndrome and caused by various foods and drinks. A 76-year-old man was admitted with frequent syncope while eating. Holter electrocardiogram revealed frequent occurrence of atrioventricular block during meals. Both atrioventricular block and sinus arrest were induced by only eating citrus fruits, citrus jelly, and acidic foods but not by other drinks and foods. These arrhythmias were suppressed after administration of atropine. No further episodes of syncope recurred after the implantation of a DDD pacemaker. This case indicated that acidic stimulation of citrus induced a vasovagal reflex via esophageal nociceptors leading to syncope.

Latent pathogenicity of the G38S polymorphism of KCNE1 K+ channel modulator.

KCNE1 encodes a modulator of KCNQ1 and KCNH2 channels. Although KCNE1(G38S), a single-nucleotide polymorphism (SNP) causing a G38S substitution in KCNE1, is found frequently, whether and how this SNP causes long QT syndrome (LQTS) remains unclear. We evaluated rate-dependent repolarization dynamics using Holter electrocardiogram (ECG) to assess the pathogenicity of KCNE1(G38S). Forty-five patients exhibiting long QT intervals, as assessed by their baseline ECGs, and 16 control subjects were enrolled. KCNE1(G38S) carriers were identified using genome sequencing. LQTS patients were classified into LQT1 or LQT2 using genetic analysis or epinephrine test. QT-RR relations were determined using 24-h Holter ECG recordings. Among the 15 patients (33.3 %) with KCNE1(G38S), four patients without any mutations or amino acid changes in other major cardiac ion channels were categorized as KCNE1(G38S) carriers. In the QT-RR regression lines, the QT-RR slope was greater in the KCNE1(G38S) carriers and the LQT2 patients (0.215 ± 0.021 and 0.207 ± 0.032, respectively) than in the LQT1 patients (0.163 ± 0.014, P < 0.05) and the control subjects (0.135 ± 0.025, P < 0.001). The calculated QT intervals at an RR interval of 1200 ms were longer in the KCNE1(G38S) carriers and LQT1 and LQT2 patients than in the control subjects. Patients with KCNE1(G38S) had a rate-dependent repolarization abnormality similar to patients with LQT2 and, therefore, may have a potential risk to develop lethal arrhythmias.