Hirofumi Mitsuyama

Conduction and refractory disorders in the diabetic atrium

Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control (n = 26) and DM (n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P < 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD(80)) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P < 0.01), and the coefficient of variation of APD(80) was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P < 0.05). The ratio of APD(80) at PCL shorter than 200 ms to that at 200 ms was smaller (P < 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P < 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.

Ca2+/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats

Action potential duration alternans (APD-ALT), defined as long-short-long repetitive pattern of APD, potentially leads to lethal ventricular arrhythmia. However, the mechanisms of APD-ALT in the arrhythmogenesis of cardiac hypertrophy remain undetermined. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca(2+) cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart. APD was measured by high-resolution optical mapping in left ventricular (LV) anterior wall from normotensive Wistar-Kyoto (WKY; n = 10) and spontaneously hypertensive rats (SHR; n = 10) during rapid ventricular pacing. APD-ALT was evoked at significantly lower pacing rate in SHR compared with WKY (382 ± 43 vs. 465 ± 45 beats/min, P < 0.01). These changes in APD-ALT in SHR were completely reversed by KN-93 (1 μmol/l; n = 5), an inhibitor of CaMKII, but not its inactive analog, KN-92 (1 μmol/l; n = 5). The magnitude of APD-ALT was also significantly greater in SHR than WKY and was completely normalized by KN-93. Ventricular fibrillation (VF) was induced by rapid pacing more frequently in SHR than in WKY (60 vs. 10%; P < 0.05), which was also abolished by KN-93 (0%, P < 0.05). Western blot analyses indicated that the CaMKII autophosphorylation at Thr287 was significantly increased in SHR compared with WKY. The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was prevented by KN-93. CaMKII could be an important mechanism of arrhythmogenesis in cardiac hypertrophy.

Swallowing-induced multifocal atrial tachycardia originating from right pulmonary veins

A 64-year-old woman experienced reproducible palpitation caused by irregular atrial tachycardia (AT) while swallowing. This tachycardia was resistant to multiple antiarrhythmic drugs and β-blockers. Catheter mapping revealed right pulmonary vein (PV) firings with different activation sequences, thereby producing multifocal AT. Extensive encircling isolation of ipsilateral right PVs abolished the multifocal AT. Although isolated right PVs were captured by pacing, dissociated PV firings were not induced by swallowing after radiofrequency catheter ablation.

Predictors of high defibrillation threshold in patients with implantable cardioverter-defibillator using a transvenous dual-coil lead.

BACKGROUND Defibrillation testing (DT) is considered a standard procedure during implantable cardioverter-defibrillator (ICD) implantation. However, little is known about the factors that are significantly related to patients with high defibrillation threshold (DFT) using the present triad system. METHODS AND RESULTS We examined 286 consecutive patients who underwent ICD implantation with a transvenous dual-coil lead and DT from December 2000 to December 2011. We defined patients who required 25 J or more by the implanted device as the high DFT group, and those who required less than 25 J as the normal DFT group. For each patient, assessment parameters included underlying disease, comorbidities, NYHA functional class, drugs, and echocardiographic measures. The high DFT group consisted of 12 patients (4.2%). Multivariate analysis identified 3 independent predictors for high DFT: atrial fibrillation (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.24-22.33, P=0.023), hypertension (OR 4.01, 95% CI 1.08-15.96, P=0.039), thickness of interventricular septum (IVS) >12 mm (OR 4.82, 95% CI 1.17-20.31, P=0.030). CONCLUSIONS Atrial fibrillation, hypertension and IVS hypertrophy were significantly associated with high DFT. Identification of such patients could help to lower the risk of complications with DT.

Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats.

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K(+) current (IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.

Suppression of ventricular fibrillation by electrical modification of the Purkinje system in hypertrophic cardiomyopathy

A 56-year-old man in hypertrophic cardiomyopathy had an electrical storm caused by ventricular fibrillation (VF). Mapping during the initiation of the VF triggered by a premature ventricular contraction (PVC1), with right bundle branch block (RBBB)-like morphology and superior axis, demonstrated a prominent Purkinje–muscle junction (PMJ) delay at the distal portion of the left posterior fascicle. Delivery of radiofrequency (RF) energy to this area abolished the VF triggered by the PVC1. However, VF emerged by triggering another PVC (PVC2) with RBBB-like morphology and inferior axis. Similarly, the initiation of VF was associated with the PMJ delay at the peripheral left anterior fascicle, where RF delivery completely suppressed the VF. The PMJ delay and subsequent Purkinje–muscle reentry-like activity could be essential for the initiation of the Purkinje-related VF.

Cardiac resynchronization therapy in ischemic and non-ischemic cardiomyopathy

Cardiac resynchronization therapy (CRT) using a biventricular pacing system has been an effective therapeutic strategy in patients with symptomatic heart failure with a reduced left ventricular ejection fraction (LVEF) of 35% or less and a QRS duration of 130 ms or more. The etiology of heart failure can be classified as either ischemic or non‐ischemic cardiomyopathy. Ischemic etiology of patients receiving CRT is prevalent predominantly in North America, moderately in Europe, and less so in Japan. CRT reduces mortality similarly in both ischemic and non‐ischemic cardiomyopathy, whereas reverse structural left ventricular remodeling occurs more favorably in non‐ischemic cardiomyopathy. Because the substrate for ventricular arrhythmias appears to be more severe in cases of ischemic as compared with non‐ischemic cardiomyopathy, the use of an implantable cardioverter‐defibrillator (ICD) backup method could prolong the long‐term survival, especially of patients with ischemic cardiomyopathy, even in the presence of CRT. The aim of this review article is to summarize the effects of CRT on outcomes and the role of ICD backup in ischemic and non‐ischemic cardiomyopathy.

Successful termination of recurrent ventricular arrhythmias by adaptive servo-ventilation in a patient with heart failure

A 60-year-old woman who underwent operation due to severe aortic stenosis with left ventricular dysfunction had frequent nonsustained ventricular tachycardia (NSVT) at night. She had an increased apnea-hypopnea index and a reduction in minimum O2 saturation during sleep, which was closely associated with the frequency of NSVT. Adaptive servo-ventilation (ASV) therapy improved sleep disorder breathing (SDB) and also reduced ventricular arrhythmias. These effects were associated with the attenuation of the sympathetic nerve activities by the analysis of heart rate variability. ASV is expected to be effective in the treatment of ventricular tachyarrhythmias in patients with heart failure and SDB.

Pleomorphic ventricular tachycardia originating from Purkinje fiber network of left anterior fascicle

A 55-year-old woman with recurrent syncope and palpitation experienced polymorphic ventricular tachycardia (VT) and more than 3 monomorphic VTs with a right bundle branch block configuration as inferior, middle, and superior axis. During the pleomorphic VT, the diastolic potential (dp) was recorded at the anterolateral left ventricle. Changes in the QRS morphology were associated with the time between dp and onset of QRS complex (dp-V interval), and prolongation of dp-V interval terminated the VT. In addition, the delayed potentials were seen during sinus rhythm around this area. Delivery of radiofrequency current targeting the delayed potentials abolished all the VTs. Different exits from relatively large area of slow conduction in the left anterior fascicle might have produced the pleomorphic VTs.

Predictors and proarrhythmic consequences of inappropriate implantable cardioverter-defibrillator therapy

BACKGROUND Despite the benefits of implantable cardioverter-defibrillator (ICD) therapy, inappropriate shocks can lead to multiple adverse effects. The aim of this study was to clarify the predictors of inappropriate ICD shocks and their proarrhythmic consequences. METHODSANDRESULTS We retrospectively studied 316 consecutive patients who underwent ICD implantation from December 2000 to December 2011. Of them, 70 (22%) experienced inappropriate ICD shocks without proarrhythmia requiring some intervention; 2 patients (0.6%) had proarrhythmic inappropriate ICD therapy by antitachycardia pacing (ATP), thereby calculated to be 0.18% of patients per year. However, they did not have syncope from this inappropriate ATP. Multivariate analysis identified younger age (≤56 years: hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.02-2.77, P=0.043), paroxysmal atrial fibrillation (HR 3.00, 95% CI 1.64-5.31, P=0.0002), stroke (HR 2.23, 95% CI 1.11-4.47, P=0.024), and no diuretic use (HR 1.72, 95% CI 1.03-2.93, P=0.039) as independent predictors of the occurrence of inappropriate ICD shocks. CONCLUSIONS Young age, paroxysmal atrial fibrillation, stroke, and no use of diuretics were independently associated with inappropriate ICD shocks. Proarrhythmic inappropriate ICD therapy was observed with an annual incidence of 0.18% by ATP.