Kojiro Tanimoto

Pulsatile Cardiac Tissue Grafts Using a Novel Three-Dimensional Cell Sheet Manipulation Technique Functionally Integrates With the Host Heart, In Vivo

We devised a method of fabricating easily transplantable scaffoldless 3D heart tissue, made with a novel cell-sheet (CS) technology from cultured cardiomyocytes using a fibrin polymer coated dish. In the present study, we tested in vivo electrical communication which is essential for improving heart function between the host heart and the grafted CS. The epicardial surface of the ventricle of an anesthetized open-chest nude rat was ablated by applying a heated metal. Bilayered CS was obtained from neonatal rat primary culture. CS was transplanted onto the injured myocardial surface (sMI) (sMI+sheet group). The rats were allowed to recover for 1 to 4 weeks, to stabilize the grafts. Action potentials (APs) from the excised perfused heart were monitored by the fluorescence signal of di-4ANEPPS with a high speed charge-coupled device camera. The APs were observed under epicardial pacing of the host heart or the CS grafts. The pacing threshold of the current output was measured in the sMI+sheet group and in the nongrafted sMI group at the center of the sMI and in the normal zone (Nz). Bidirectional AP propagation between the sMI and Nz was observed in the sMI+sheet group (n=14), but was blocked at the marginal area of the sMI in the sMI group (n=9). The ratio of the pacing threshold (sMI/Nz) was significantly lower in the sMI+sheet than in the sMI group (3.0±0.7, 19.0±6.1 respectively P<0.05). There were neither spontaneous nor pacing-induced arrhythmias in these two groups. Bidirectional smooth AP propagation between the host heart and the grafted CS was observed. This finding suggested functional integration of this CS graft with the host heart without serious arrhythmia.

A comparison between calcium channel blocking drugs with different potencies for T- and L-type channels in preventing atrial electrical remodeling

Calcium overload plays a key role in the development of atrial electrical remodeling. The effect of an L-type Ca channel blocker in preventing this remodeling has been reported to be short lasting, partly due to down-regulation of this channel and persisting Ca entry through the T-type Ca channel. To prove if efonidipine, a dual L- and T-type Ca channel blocker exerts a greater effect than an L-type Ca channel blocker verapamil, 21 dogs underwent rapid atrial pacing at 400 bpm for 14 days, pretreatment with efonidipine in 7 (E), verapamil in 7 (V), and none in 7 (C). We measured the atrial effective refractory period (ERP) serially during 14 days of rapid pacing. In response to rapid pacing, ERP decreased progressively in C. In contrast, in E and V, ERP remained greater than ERP in C (P < 0.01) on days 2 through 7. However, on the 14th day, ERP in V decreased to the level seen in C, whereas ERP in E remained significantly longer than ERPs in C or V (P < 0.01). The blockade L-type Ca channel alone is not sufficient, but the addition of a T-type Ca channel blockade shows a more sustained effect to prevent atrial electrical remodeling.

Brugada Syndrome Behind Complete Right Bundle-Branch Block

Background— The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers. Methods and Results— The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V2 or V3 in 3 patients. In 2 patients, new ST-segment elevation was induced by class IC drugs. The QRS duration was more prolonged in patients with BS and CRBBB compared with age- and sex-matched controls: 170±13 versus 145±15 milliseconds in V1 and 144±19 versus 128±7 milliseconds in V5 (both P<0.0001). The amplitude of R in V1 was larger in the BS patients than in the control subjects (P=0.0323), but that of R′ was similar (P=0.0560). Conclusions— BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST-segment elevation. The prevalence, mechanism, and clinical significance of a combination of CRBBB and BS are yet to be determined.

Left atrial strain is a powerful predictor of atrial fibrillation recurrence after catheter ablation: study of a heterogeneous population with sinus rhythm or atrial fibrillation

AIMS Accumulating data show the efficacy of catheter ablation (CA) for atrial fibrillation (AF); however, postoperative recurrence is not uncommon. The aim of this study was to identify predictors of AF recurrence in patients undergoing CA. METHODS AND RESULTS We studied 100 patients with symptomatic paroxysmal (68) or persistent (32) AF who underwent CA preceded by transthoracic echocardiographic examination. Of these, 50 had sinus rhythm during echocardiography (Group NSR) and 50 had AF rhythm (Group AF). The left atrial (LA) strain was measured by two-dimensional speckle tracking echocardiography. Echocardiographic parameters were compared between the patients with AF recurrence and no recurrence. During 12 months of follow-up, 26 of 100 patients (11 in Group NSR and 15 in Group AF) had AF recurrence; these patients had significantly longer AF duration, a lower LA global strain (LA-GS), lower LA lateral total strain (LA-LS), and larger maximum LA volume index (LAVImax) than those who maintained sinus rhythm. Multivariate logistic regression identified basal LA-LS and LAVImax as independent predictors of AF recurrence. Furthermore, receiver operating characteristic analyses revealed that basal LA-LS was the most useful parameter for predicting AF recurrence [area under the curve (AUC): 0.84 vs. 0.74 in LAVImax]. Subanalyses showed that LAVImax was another independent predictor of AF recurrence in Group AF, but not in Group NSR, while basal LA-LS was a significant predictor in both groups. CONCLUSION LA myocardial function assessed by basal LA-LS could predict AF recurrence after CA. Notably, such an assessment could be applicable even during AF rhythm, suggesting its convenience in the clinical setting without defibrillation before analysis.

A case of vagally mediated idiopathic ventricular fibrillation

Background A 25-year-old woman experienced three episodes of syncope over the course of 2 years. The attacks all occurred just after she had sat down, and two were accompanied by convulsions. She had no obvious prodromes and no personal or family history of cardiovascular disease.Investigations Electrocardiography, chest radiography, echocardiography, cerebral and cardiac MRI, electroencephalography, 24 h Holter monitoring, electrophysiological study with drug provocation testing and heart-rate variability analysis.Diagnosis Vagally mediated ventricular fibrillation initiated by premature ventricular complexes arising from the right ventricular outflow tract.Management Catheter ablation was performed at the right ventricular outflow tract and an implantable cardioverter-defibrillator was fitted.

Ventricular fibrillation associated with complete right bundle branch block.

BACKGROUND A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings. OBJECTIVE To evaluate complete right bundle branch block (RBBB) in patients with IVF. METHODS Patients with IVF showing complete RBBB were included in the present study. Structural and primary electrical diseases were excluded, and provocation tests were performed to exclude the presence of spastic angina or Brugada syndrome (BrS). The prevalence of complete RBBB and the clinical and ECG parameters were compared either in patients with IVF who did not show RBBB or in the general population and age and sex comparable controls with RBBB. RESULTS Of 96 patients with IVF, 9 patients were excluded for the presence of BrS. Of 87 patients studied, 10 (11.5%) patients showed complete RBBB. None had structural heart diseases, BrS, or coronary spasms. The mean age was 44 ± 15 years, and 8 of 10 patients were men. Among the ECG parameters, only the QRS duration was different from that of the other patients with IVF who did not show complete RBBB. Ventricular fibrillation recurred in 3:2 in the form of storms, which were well suppressed by isoproterenol. Complete RBBB was found less often in control subjects (1.37%; P < .0001), and the QRS duration was more prolonged in patients with IVF: 139 ± 10ms vs 150 ± 14ms (P = .0061). CONCLUSIONS Complete RBBB exists more often in patients with IVF than in controls. A prolonged QRS complex suggests a conduction abnormality. Our findings warrant further investigation of the role of RBBB in the development of arrhythmias in patients with IVF.

Serum inflammation markers predicting successful initial catheter ablation for atrial fibrillation.

BACKGROUND We investigated various serum inflammatory markers to predict ablation responders who have no atrial fibrillation (AF) relapse after the initial ablation. METHODS Forty-four consecutive AF patients (age: 59 ± 8 years, paroxysmal: 31, CHADS₂: 1.1 ± 1.1) who underwent an initial pulmonary vein isolation were investigated. Various serum inflammatory markers, such as adiponectin, ANP, BNP, 1CTP, F1+2, hs-CRP, IL-6, intact P1NP, MDA-LDL, MMP-2, TGF-β, TIMP-2, and TNF-α, were evaluated prior to ablation. AF relapse was defined as AF documented in telemonitoring electrocardiograms twice a day during 9.7 ± 2.4 months of follow-up with three months of a blanking-period. RESULTS A total of 29 patients (paroxysmal: 21) maintained sinus rhythm after the initial catheter ablation. These ablation responders had significantly lower MMP-2 (Sinus vs. Relapsed: 748 ± 132.7 vs. 841.2 ± 152.4 ng/mL, P=0.042) and TNF-α (1.1 ± 0.4 vs. 1.8 ± 1.7 pg/mL, P=0.046) levels prior to ablation. A BNP-adjusted Cox multivariate regression analysis revealed that the independent predictive factor for AF recurrence was high MMP-2 levels (>766 ng/mL) accompanied by high TNF-α levels (>1.2 pg/mL). CONCLUSIONS The levels of MMP-2 and TNF-α might be useful for predicting initial AF catheter ablation responders.

Safety and efficacy of pericardial endoscopy by percutaneous subxyphoid approach in swine heart in vivo.

OBJECTIVE A nonsurgical approach from the epicardial surface is useful for various cardiac interventions, such as positioning of the left ventricular lead for cardiac resynchronization therapy and epicardial ablation. Stem cell delivery on the epicardial surface can be considered in the future if good quality of visualization can be obtained. However, because the pericardial space is limited, hemodynamic conditions may deteriorate with pericardial endoscopy. Therefore, the feasibility and efficacy of pericardial endoscopy were examined by using ready-made endoscopes. METHODS Anesthetized swines (26-61 kg; n = 6) were used for the experiment. Electrocardiogram, femoral artery blood pressure, and oxygen saturation by pulse oximetry were continuously monitored during the procedures. Guided by the fluoroscopy, sheaths were advanced to the pericardial space using the modified Seldinger technique from the subxyphoid space. RESULTS After insertion of an endoscope with a maximum diameter of 6.9 mm, hemodynamic parameters were stable during the procedure with atropine. Stable and acceptable endoscopic images were obtained. Minor operations can be performed with pericardial endoscopic-guided laparoscopic forceps with no complications. CONCLUSIONS The endoscopic pericardial procedure is effective and feasible. This procedure can increase the possibility and efficacy of nonsurgical treatment for cardiac diseases.

Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs.

Abstract: The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3–5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3–3 µg·kg−1·min−1) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 µg·kg−1·min−1) and flecainide (0.13 mg·kg−1·min−1) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling.

The effectiveness of rigid pericardial endoscopy for minimally invasive minor surgeries: cell transplantation, epicardial pacemaker lead implantation, and epicardial ablation

BackgroundThe efficacy and safety of rigid pericardial endoscopy as the promising minimally invasive approach to the pericardial space was evaluated. Techniques for cell transplantation, epicardial pacemaker lead implantation, and epicardial ablation were developed.MethodsTwo swine and 5 canines were studied to evaluate the safety and efficacy of rigid pericardial endoscopy. After a double pericardiocentesis, a transurethral rigid endoscope was inserted into the pericardial space. The technique to obtain a clear visual field was examined, and acute complications such as hemodynamic changes and the effects on intra-pericardial pressure were evaluated. Using custom-made needles, pacemaker leads, and forceps, the applications for cell transplantation, epicardial pacemaker lead implantation, and epicardial ablation were also evaluated.ResultsThe use of air, the detention of a stiff guide wire in the pericardial space, and the stretching of the pericardium with the rigid endoscope were all useful to obtain a clear visual field. A side-lying position also aided observation of the posterior side of the heart. As a cell transplantation methodology, we developed an ultrasonography-guided needle, which allows for the safe visualization of transplantation without major complications. Pacemaker leads were safely and properly implanted, which provides a better outcome for cardiac resynchronizing therapy. Furthermore, the success of clear visualization of the pulmonary veins enabled us to perform epicardial ablation.ConclusionsRigid pericardial endoscopy holds promise as a safe method for minimally invasive cell transplantation, epicardial pacemaker lead implantation, and epicardial ablation by allowing clear visualization of the pericardial space.