Yuhi Hasebe

Low-Intensity Pulsed Ultrasound Induces Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia

Background Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD. Methods and Results We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm2 for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm2, P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group. Conclusions These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.

Delayed enhancement on cardiac magnetic resonance imaging is a poor prognostic factor in patients with cardiac sarcoidosis

BACKGROUND Predictors of ventricular arrhythmias (VA) in patients with cardiac sarcoidosis (CS) remain unclear. METHODS AND RESULTS We examined 61 consecutive CS patients who were admitted to our hospital from April 2002 to March 2012 with a mean follow-up period of 45 ± 31 months for the relationship between delayed enhancement on cardiac magnetic resonance imaging (DE-MRI) and VA or a composite endpoint, including VA, heart failure hospitalization, and cardiovascular mortality. Although there was no significant difference in baseline clinical characteristics between patients with VA and those without it, the former group was characterized as compared with the latter by lower left ventricular (LV) ejection fraction (p<0.05), larger LV systolic/diastolic dimensions (both p<0.05), and a significant association with DE-MRI (p<0.05). Furthermore, the patients with DE-MRI (n=26), as compared with those without it (n=11), had a significantly higher composite endpoint event rate (41% vs. 0%, p<0.05) and a trend toward higher VA (29% vs. 0%, p=0.12). Univariate analysis also showed that impaired LV systolic function was significantly associated with composite events on follow-up. CONCLUSIONS These results indicate that the presence of DE-MRI is a significant predictor of VA events and poor outcome in CS patients.

Current Status of Primary Prevention of Sudden Cardiac Death With Implantable Cardioverter Defibrillator in Patients With Chronic Heart Failure

BACKGROUND The current status of primary prevention of sudden cardiac death (SCD) with implantable cardioverter defibrillator (ICD) in patients with heart failure with reduced ejection fraction remains to be fully elucidated in Japan. METHODS AND RESULTS In the chronic heart failure (CHF) cohort study, the CHART-2 Study, we enrolled 2,778 consecutive patients with NYHA class II-III. According to the Japanese Circulation Society guideline of prophylactic ICD, we divided them into 3 groups: group A, class I indication; B, class IIa; and C, no indication. During the (median) 3.2-year follow-up, 79 fatal arrhythmic events (FAE), defined as composite of sudden cardiac/arrhythmic death, ventricular tachycardia/fibrillation and appropriate ICD therapy, occurred. In the groups A, B and C, the prevalence of FAE was 16.1%, 8.9% and 1.9%, respectively; the use of prophylactic ICD among those with FAE, however, was only 44%, 9% and 6%, respectively. In the groups A and B combined, chronic atrial fibrillation (cAF) and left ventricular end-diastolic dimension (LVDd) ≥ 65 mm were independent predictors of FAE, and, when combined, their prognostic impact was highly significant (hazard ratio, 7.01; P<0.001). CONCLUSIONS Primary prevention of SCD with ICD in CHF patients is validated but is still underused in Japan, and the combination of cAF and LVDd ≥ 65 mm may be a useful indication of prophylactic ICD implantation.

Association of Adventitial Vasa Vasorum and Inflammation With Coronary Hyperconstriction After Drug-Eluting Stent Implantation in Pigs In Vivo

BACKGROUND The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges. CONCLUSIONS The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo.

Accuracy of Optical Frequency Domain Imaging for Evaluation of Coronary Adventitial Vasa Vasorum Formation After Stent Implantation in Pigs and Humans – A Validation Study –

BACKGROUND Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Development of a Novel Shock Wave Catheter Ablation System -The First Feasibility Study in Pigs-

Introduction Radio-frequency catheter ablation (RFCA) using Joule heat has two fundamental weaknesses: the limited depth of treatment and the risk of thrombus formation. In contrast, focused shock wave (SW) therapy could damage tissues at arbitrary depths without heat generation. Thus, we aimed to develop a SW catheter ablation (SWCA) system that could compensate for the weaknesses of RFCA therapy. Methods and Results We developed a SWCA system where the SW generated by a Q-switched Holmium: yttrium aluminum garnet (YAG) laser beam was reflected by a reflector attached to 14-Fr catheter tip and then was converged onto the focus. We examined the feasibility of our system on pigs in vivo. When applied using the epicardial approach, the SWCA caused persistent spheroidal lesions with mild superficial injury than the RFCA. The lesions were created to a depth based on the focal length (2.0 mm) [2.36 ± 0.45 (SD) mm immediately after procedure, n = 16]. When applied to the atrioventricular (AV) node using the endocardial approach, the SWCA caused junctional escape rhythms in 2 pigs and AV block in 12 pigs (complete AV block in 9) in acute phase (n = 14). Nine of the 14 pigs survived with pacemakers for the long-term study, and the AV block persisted for 12.6 ± 3.9 (SD) days in all surviving pigs. Histological examination showed AV nodal cell body atrophy in the acute phase and fibrotic lesions in the chronic phase. Importantly, no acute or chronic fatal complications were noted. Conclusions Our novel SWCA system could be a promising modality as a non-thermal ablation method to compensate for the weaknesses of RFCA therapy. However, further research and development will be necessary as the current prototype still exhibited the presence of micro-thrombus formation in the animal studies.

Usefulness of the Noncontact Mapping System to Elucidate the Conduction Property for the Treatment of Common Atrial Flutter

Background: The functional role of the cavotricuspid isthmus (CTI) for common atrial flutter (cAFL) remains to be elucidated. In the present study, we examined whether the EnSite system (St. Jude Medical, St. Paul, MN, USA), a noncontact mapping system, is useful to evaluate the conduction properties of CTI to minimize radiofrequency (RF) ablation applications for cAFL.

Development of a novel shock wave catheter ablation system—A validation study in pigs in vivo

Aims Although the radiofrequency catheter ablation (RFCA) is widely used for the treatment of tachyarrhythmias, it has three fundamental weaknesses as a thermal ablation system, including a limited lesion depth, myoendocardial injury linking to thromboembolism, and prolonged inflammation followed by subsequent recurrences. In order to overcome these limitations, we have been developing a shock wave (SW) catheter ablation (SWCA) system as a novel non-thermal therapy. In the present study, we validated our new SWCA system with increased SW intensity. Methods and results In a total of 36 pigs, we applied our new SWCA to ventricular muscle in vivo for the following protocols. (i) Epicardial approach (n = 17): The lesion depth achieved by the SWCA from the epicardium was examined. High intensity SW achieved 5.2 ± 0.9 mm lesions (35 applications), where there was a strong correlation between SW intensity and lesion depth (R = 0.80, P < 0.001, 54 applications). (ii) Endocardial approach (n = 6): The extent of endocardial injury with the two energy sources was examined by electron microscopy (8 applications each). Shock wave catheter ablation markedly reduced myoendothelial injury compared with RFCA (4.3 ± 1.2 vs. 79.6 ± 4.8%, P < 0.01). The electrophysiological effects on the SW lesions were also confirmed using three-dimensional mapping system. (iii) Time-course study (n = 6 each): The healing process after ablation therapy was examined. We found transient inflammatory responses and accelerated reparative process with preserved blood flow in the SWCA group. Conclusion These results indicate that our SWCA system is characterized, as compared with RFCA, by deeper lesion depth, markedly less myoendocardial injury and accelerated tissue repair process.

Development of a Novel Shock Wave Catheter Ablation System

Although radio-frequency catheter ablation (RFCA) is quite effective for the treatment tachyarrhythmias, it possesses two fundamental limitations, including limited efficacy for the treatment of ventricular tachyarrhythmias of epicardial origin and the risk of thromboembolism. Consequently, new method is required, which can eradicate arrhythmia source in deep part of cardiac muscle without heating. On the other hand, for a medical application of shock waves, extracorporeal shock wave lithotripter (ESWL) has been established [1]. It was demonstrated that the underwater shock focusing is one of most efficient method to generate a controlled high pressure in a small region [2]. In order to overcome limitations of existing methods, we aimed to develop a new catheter ablation system with underwater shock waves that can treat myocardium at arbitrary depth without causing heat.