Kensuke Ihara

Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation

BACKGROUND Recent experimental studies have demonstrated that several microRNAs (miRNAs) expressed in atrial tissue promote a substrate of atrial fibrillation (AF). However, because it has not been fully elucidated whether these experimental data contribute to identifying circulating miRNAs as biomarkers for AF, we used a combined analysis of human serum and murine atrial samples with the aim of identifying these biomarkers for predicting AF.Methods and Results:Comprehensive analyses were performed to screen 733 miRNAs in serum from 10 AF patients and 5 controls, and 672 miRNAs in atrial tissue from 6 inducible atrial tachycardia model mice and 3 controls. We selected miRNAs for which expression was detected in both analyses, and their expression levels were changed in the human analyses, the murine analyses, or both. This screening identified 11 candidate miRNAs. Next, we quantified the selected miRNAs using a quantitative RT-PCR in 50 AF and 50 non-AF subjects. The individual assessment revealed that 4 miRNAs (miR-99a-5p, miR-192-5p, miR-214-3p, and miR-342-5p) were significantly upregulated in AF patients. A receiver-operating characteristics curve indicated that miR-214-3p and miR-342-5p had the highest accuracy. The combination of the 4 miRNAs modestly improved the predictive accuracy for AF (76% sensitivity, 80% specificity). CONCLUSIONS Novel circulating miRNAs were upregulated in the serum of AF patients and might be potential biomarkers of AF.

Seasonal, weekly, and circadian distribution of ventricular fibrillation in patients with J-wave syndrome from the J-PREVENT registry

Ventricular fibrillation (VF) in Brugada syndrome (BrS) is known to occur more frequently during nighttime and from spring to early summer. In this study, we investigated whether early repolarization syndrome (ERS) has the same seasonal, weekly, and circadian distribution of VF events as BrS using data from the “J‐wave associated with prior cardiac event” (J‐PREVENT) registry.

Severe iatrogenic bradycardia related to the combined use of beta-blocking agents and sodium channel blockers

Purpose Drug-induced bradycardia is common during antiarrhythmic therapy; the major culprits are beta-blockers. However, whether other antiarrhythmic drugs are also a significant cause of this, alone or in combination with beta-blockers, is not well known. Methods We retrospectively investigated the records of all patients hospitalized at our institution for drug-related bradycardia from the years 2004 to 2012. Patients with cardiac disease and electrolytic or hormonal abnormalities that could cause bradyarrhythmias were excluded. Results Eight patients were identified (mean age, 79±5 years; range, 71–85 years; 6 women). Three patients were taking only beta-blockers (hereafter referred to as the BB group), while five patients were on both beta-blockers and Na channel blockers (hereafter referred to as the BB + Na group). Heart rates ranged from 20∼49 beats/minute on arrival. The initial electrocardiogram showed sinus bradycardia (n=6) or sinus arrest with escape beats (n=2). QRS duration was 80–100 ms. The clinical presentation of the BB + Na group was considerably worse than that of the BB group, and included cardiogenic shock and heart failure. Four of the BB + Na patients had been on their medications for over 300 days. The BB group recovered solely with drug discontinuation, while 4 of the 5 patients in the BB + Na group needed additional treatments, such as intravenous administration of atropine or adrenergic agonist and temporary pacing. Bradycardia did not recur during follow-up (median, 687 days). Conclusion Although wide QRS ventricular tachyarrhythmia is a better known proarrhythmic effect of Na channel blockers, life-threatening bradycardia may also occur in combination with beta-blockers in the elderly, even months after the start of medication, and at plasma concentrations that do not prolong QRS width.

High Atrial Defibrillation Threshold With Internal Cardioversion Indicates Arrhythmogenicity of Superior Vena Cava in Non-Long-Standing Persistent Atrial Fibrillation.

BACKGROUND The purpose of this study was to clarify the relation between atrial defibrillation threshold (ADFT) for internal cardioversion (IC) and arrhythmogenicity of the superior vena cava (SVC). METHODS AND RESULTS A total of 159 consecutive patients (139 male, age 59.9±10.3 years) who underwent radiofrequency catheter ablation of atrial fibrillation (AF) were assessed. IC was performed in 50 patients with non-long-standing persistent AF (non-LSAF) with a purpose-built cardioversion catheter in which direct current is delivered between the right atrium and the coronary sinus. SVC arrhythmogenicity was defined as SVC firing initiating AF, SVC associated with maintenance of AF, or frequent ectopy in the SVC. In all 50 non-LSAF patients, AF termination was obtained on IC during the procedure except in 1 patient with SVC AF. In the patients with ADFT >10 J (n=10), SVC arrhythmogenicity was observed more often than in those with ADFT ≤10 J (n=40; 60% vs. 13%; P=0.004). There were no significant differences between the 2 groups in left atrial diameter (40.8±7.6 vs. 40.6±6.3 mm; P=0.92), persistent AF (33% vs. 50%; P=0.46), or other clinical parameters. The patients who underwent SVC isolation, however, had higher ADFT before SVC isolation than those who did not (15.5±8.8 vs. 9.2±4.4 J; P=0.01). CONCLUSIONS High IC ADFT is associated with SVC arrhythmogenicity in non-LSAF patients.

Atrial tachycardia originating from the hepatic segment of inferior vena cava in interruption of inferior vena cava with azygos continuation.

Interruption of inferior vena cava (IVC) with azygos continuation is a rare venous anomaly, and arrhythmogenic IVC is also rarely reported. Arrhythmogenicity of the hepatic segment of IVC in interruption of IVC has never been reported. We describe the case of a 37-year-old female with interrupted left IVC with azygos continuation to right superior vena cava and atrial tachycardia originating from the hepatic segment of IVC.

Coexistence of Left-Sided Atrioventricular Accessory Pathways With a Common Inferior Pulmonary Vein Ostium

Background—As the technique for radiofrequency catheter ablation for atrial fibrillation (AF) has progressed, so has our knowledge of both normal and abnormal anatomy of the left atrium and pulmonary veins (PV). We treated several AF patients with accessory conduction pathways (ACP) who were also found to have a common ostium of inferior PVs (CIPV), a relatively rare PV anomaly. No relation between ACP and PV anomalies has ever been reported, and the aim of our study was to study this association. Methods and Results—This study included 137 consecutive patients (104 men; mean age, 60±9 years) who underwent AF ablation for paroxysmal and persistent AF at our institution from March 2009 to August 2010. We analyzed coexisting supraventricular tachycardias and left atrium and PV morphology by multidetector row CT. Thirty-eight of 137 patients (27.7%) were found to have some PV anomaly, consisting of 13 with a common trunk of left PV, 19 with right additional PV, 3 with a common trunk of right PV, and 3 with CIPV. Thirty-one patients (22.6%) had supraventricular tachycardias. They were 26 cases of atrial flutter, 4 of Wolff-Parkinson-White syndrome, and 3 of atrioventricular nodal reentrant tachycardia. The prevalence of a coexisting ACP was significantly higher in patients with CIPV than in those without CIPV (3 of 3 [100%] versus 1 in 134 [0.7%]; P<0.0001). All ACPs with CIPV were located in the left side. The other supraventricular tachycardias were not associated with any PV anomalies. Conclusions—There is a possible association between CIPV and left-sided ACP in AF patients. This suggests that there is a likelihood of developmental association between them.

Coronary Endothelial Dysfunction and Impaired Microcirculation Response to Atrial Natriuretic Peptide in Hyperinsulinemia

Endothelial dysfunction occurs in hyperinsulinemia (HI). Coronary microcirculation responses to vasoactive agents are examined in 57 patients with angiographically normal coronary arteries. Patients were divided into 2 groups, 37 with normoinsulinemia (NI) and 20 with HI based on results of a 75-g oral glucose tolerance test. Epicardial artery vasoactivity in response to acetylcholine chloride is measured to assess endothelial function. Coronary microcirculation function is evaluated by intracoronary administration of 50 µg of adenosine triphosphate, 1 mg of isosorbide dinitrate, and 0.05 mg/kg of atrial natriuretic peptide. Epicardial artery vasoconstriction in response to 100 µg of acetylcholine is mildly reduced in HI (P = .04). Coronary flow reserve in response to adenosine triphosphate in NI is similar to that in HI. In NI, the resting mean (SD) peak velocity in response to isosorbide dinitrate (40.7 [10.9] cm/s) vs atrial natriuretic peptide (39.6 [10.9] cm/s) is similar. In contrast, the resting mean (SD) peak velocity in response to atrial natriuretic peptide (31.3 [9.3] cm/s) vs isosorbide dinitrate (43.5 [10.0] cm/s) in HI is statistically significantly blunted (P < .001). Atrial natriuretic peptide may have a pathologic effect on coronary microcirculation even in mild endothelial dysfunction among patients with HI.

Association of intramural fat deposition in the interatrial septum with focal atrial tachyarrhythmias originating near the atrioventricular node

We describe a case with three focal atrial tachycardias (ATs) and focal atrial fibrillation (AF) originating from the interatrial septum (IAS) near the atrioventricular node (AVN). Contrast-enhanced computed tomography demonstrated the association of fat deposition within the anterior IAS near the AVN with successful ablation sites of these ATs and AF. This is the first report that the intramural fat deposition in the IAS could be associated with the formation of AT and AF re-entry circuits originating near the AVN.

Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping

Recent genome-wide association studies targeting atrial fibrillation (AF) have indicated a strong association between the genotype and electrophysiological phenotype in the atria. That encourages us to utilize a genetically-engineered mouse model to elucidate the mechanism of AF. However, it is difficult to evaluate the electrophysiological properties in murine atria due to their small size. This protocol describes the electrophysiological evaluation of atria using an optical mapping system with a high temporal and spatial resolution in Langendorff perfused murine hearts. The optical mapping system is assembled with dual high-speed complementary metal oxide semiconductor cameras and high magnification objective lenses, to detect the fluorescence of a voltage-sensitive dye and Ca2+ indicator. To focus on the assessment of murine atria, optical mapping is performed with an area of 2 mm × 2 mm or 10 mm x 10 mm, with a 100 × 100 resolution (20 µm/pixel or 100 µm/pixel) and sampling rate of up to 10 kHz (0.1 ms) at maximum. A 1-French size quadripolar electrode pacing catheter is placed into the right atrium through the superior vena cava avoiding any mechanical damage to the atrium, and pacing stimulation is delivered through the catheter. An electrophysiological study is performed with programmed stimulation including constant pacing, burst pacing, and up to triple extrastimuli pacing. Under a spontaneous or pacing rhythm, the optical mapping recorded the action potential duration, activation map, conduction velocity, and Ca2+ transient individually in the right and left atria. In addition, the programmed stimulation also determines the inducibility of atrial tachyarrhythmias. Precise activation mapping is performed to identify the propagation of the excitation in the atrium during an induced atrial tachyarrhythmia. Optical mapping with a specialized setting enables a thorough electrophysiological evaluation of the atrium in murine pathological models.

Radiofrequency Catheter Ablation from the Epicardial Sites for Ventricular Arrhythmias Originating from the Left Ventricular Summit—Two Case-Reports—

Introduction: We report 2 cases of ventricular arrhythmias (VAs) originating from the left ventricular summit (LVS) which required radiofrequency energy (RF) application in the great cardiac vein (GCV) and/or the epicardium for treating VAs. Case 1: Sixty-five year-old female with idiopathic VAs underwent RF-catheter ablation (CA). The earliest activation site of VAs was observed in GCV, to which left descending coronary artery (LAD) run close. Sufficient RF delivery could not be performed due to the concerns about the injury to LAD, and the procedure resulted in a transient therapeutic effect. Case 2: Fifty-one year-old male suffering from VAs associated with non-ischemic cardiomyopathy underwent RF-CA. In 1st session, the earliest activation site of VAs was recognized in GCV, however, RF-CA application in GCV failed to abolish VAs. In 2nd session with the subxiphoidal pericardial approach, the earliest site was located at LVS extremely close to LAD. Despite the multiple RF applications in the vicinity sites of that portion, we were unable to abolish VAs. Conclusion: In sporadic cases, epicardial approach is required to eliminate VAs. However, the discretion and attention have to be paid in order to avoid the serious complications for treating VAs originating from LVS.