Takehiro Kimura

Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis.

To improve the modest efficacy of mesenchymal stem cell (MSC) transplantation, the treatment of human MSCs with angiotensin receptor blockers (ARBs) was investigated. MSCs were cultured with or without the medium containing 3 μmol/l of ARBs before cardiomyogenic induction. After cardiomyogenic induction in vitro, cardiomyogenic transdifferentiation efficiency (CTE) was calculated by immunocytochemistry using anticardiac troponin‐I antibody. In the nude rat chronic myocardial infarction model, we injected MSCs pretreated with candesartan (A‐BM; n = 18) or injected MSCs without pretreatment of candesartan (BM; n = 25), each having survived for 2 weeks. The left ventricular function, as measured by echocardiogram, was compared with cardiomyogenic transdifferentiation in vivo, as determined by immunohistochemistry. Pretreatment with ARBs significantly increased the CTE in vitro (10.1 ± 0.8 n = 12 vs. 4.6 ± 0.3% n = 25, p < .05). Transplantation of candesartan‐pretreated MSCs significantly improved the change in left ventricular ejection fraction (BM; −7.2 ± 2.0 vs. A‐BM; 3.3 ± 2.3%). Immunohistochemistry revealed significant improvement of cardiomyogenic transdifferentiation in A‐BM in vivo (BM; 0 ± 0 vs. A‐BM; 0.014 ± 0.006%). Transplantation of ARB‐pretreated MSCs significantly improved cardiac function and can be a promising cardiac stem cell source from which to expect cardiomyogenesis. STEM CELLS 2011;29:1405–1414

Nonthermal Cardiac Catheter Ablation Using Photodynamic Therapy

Background— Radiofrequency ablation has limitations, largely related to creation of lesions by heating. Here, we report the first nonthermal ablation by applying photodynamic therapy (PDT) to cardiac tissues using a custom-made deflectable laser catheter. The present study investigated the feasibility of PDT for cavotricuspid isthmus ablation in a canine model. Methods and Results— We evaluated the pharmacokinetic profiles of 17 canines after administration of a photosensitizer (talaporfin sodium) by various protocols. We succeeded in maintaining the photosensitizer concentration at a level in excess of the clinically effective dose for humans. Using a 4-polar 7-French deflectable laser catheter, we performed PDT-mediated cavotricuspid isthmus ablation in 8 canines. PDT caused oxidative injury only to the irradiated area and successfully produced a persistent electric conduction block. No acute, gross changes such as edematous degeneration, thrombus formation, steam pops, or traumatic injury were observed after irradiation. Hematoxylin and eosin staining of tissues samples also showed well-preserved endothelial layers. Testing of the blood samples taken before and after the procedure revealed no remarkable changes. Lesion size at 2 weeks after the procedure and the temperature data collected during irradiation were compared between the PDT and irrigated radiofrequency ablation procedures. A ventricular cross-section revealed a solid PDT lesion, which was as deep as a radiofrequency lesion. In addition, endocardial, surficial, and intramural temperature monitoring during the PDT irradiation clearly demonstrated the nonthermal nature of the ablation technique. Conclusions— Nonthermal PDT-mediated catheter ablation is a potentially novel treatment for cardiac arrhythmias.

Myocardial electrical conduction block induced by photosensitization reaction in exposed porcine hearts in vivo

This study proposes photosensitization reaction for non‐thermal cardiac ablation in arrhythmia therapy. Acute and chronic phase experiments were conducted in exposed porcine hearts to demonstrate the photosensitization reaction‐induced myocardial electrical conduction block in vivo.

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.

Photosensitization reaction-induced acute electrophysiological cell response of rat myocardial cells in short loading periods of talaporfin sodium or porfimer sodium

Electrophysiological responses of rat myocardial cells to exogenous photosensitization reactions for a short period of incubation with two photosensitizers, talaporfin sodium or porfimer sodium, were measured in a subsecond time scale. The loading period of the photosensitizer when the photosensitizer might not be taken up by the cells was selected as 15 min, which was determined by the fluorescence microscopic observation. We measured the intracellular Ca2+ concentration ([Ca2+]in) by using a fluorescent Ca2+ indicator, Fluo‐4 AM, under a high‐speed confocal laser microscope to evaluate the acute electrophysiological cell response to the photosensitization reaction. The measured temporal change in Fluo‐4 fluorescence intensity indicated that the response to the photosensitization reaction might be divided into two phases in both photosensitizers. The first phase is acute response: disappearance of Ca2+ oscillation when irradiation starts, which might be caused by ion channel dysfunction. The second phase is slow response: [Ca2+]in elevation indicating influx of Ca2+ due to the concentration gradient. The continuous Ca2+ influx followed by changes in cell morphology suggested micropore formation on the surface of the cell membrane, resulting in necrotic cell death.

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.

Optimal conditions for cardiac catheter ablation using photodynamic therapy

AIMS Photodynamic therapy (PDT) is based on non-thermal injury mediated by singlet oxygen species and is used clinically in cancer therapy. In our continuing efforts to apply this technology to cardiac catheter ablation, we clarified the optimal condition for creating PDT-mediated lesions using a laser catheter. METHODS AND RESULTS In a total of 35 canines, we applied a laser directly to the epicardium of the beating heart during open-chest surgery at 15 min after administration of a photosensitizer, talaporfin sodium. We evaluated the lesion size (depth and width) using hematoxylin-eosin staining under varying conditions as follows: laser output (5, 10, 20 W/cm(2)), irradiation time (0-60 s), photosensitizer concentration (0, 2.5, 5 mg/kg), blood oxygen concentration (103.5 ± 2.1 vs. 548.0 ± 18.4 torr), and contact force applied during irradiations (low: <20 g, high: >20 g). A laser irradiation at 20 W/cm(2) for 60 s under 5 mg/kg (29 µg/mL) of photosensitizer induced a lesion 8.7 ± 0.8 mm deep and 5.2 ± 0.2 mm wide. The lesion size was thus positively correlated to the laser power, irradiation time, and photosensitizer concentration, and was independent of the applied contact force and oxygen concentration. In addition, the concentration of the photosensitizer strongly correlated with the changes in the pulse oximetry data and fluorescence of the backscattering laser, suggesting that a clinically appropriate condition could be estimated in real time. CONCLUSION Photodynamic therapy-mediated cardiac lesions might be controllable by regulating the photosensitizer concentration, laser output, and irradiation time.