Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032904.33237.8E
N. Chanani, Douglas B. Cowan, K. Takeuchi, D. Poutias, L. M. Garcia, P. D. del Nido, F. McGowan
BackgroundMounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses. Methods and ResultsPrimary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-&agr; (TNF-&agr;), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NF&kgr;B), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-&agr; induced significant NF&kgr;B activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 &mgr;mol/L. In contrast, milrinone increased nuclear NF&kgr;B translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1&bgr;. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells. ConclusionsBoth amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NF&kgr;B and limits the production of pro-inflammatory cytokines, whereas milrinone does not.
{"title":"Differential Effects of Amrinone and Milrinone Upon Myocardial Inflammatory Signaling","authors":"N. Chanani, Douglas B. Cowan, K. Takeuchi, D. Poutias, L. M. Garcia, P. D. del Nido, F. McGowan","doi":"10.1161/01.CIR.0000032904.33237.8E","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032904.33237.8E","url":null,"abstract":"BackgroundMounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses. Methods and ResultsPrimary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-&agr; (TNF-&agr;), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NF&kgr;B), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-&agr; induced significant NF&kgr;B activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 &mgr;mol/L. In contrast, milrinone increased nuclear NF&kgr;B translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1&bgr;. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells. ConclusionsBoth amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NF&kgr;B and limits the production of pro-inflammatory cytokines, whereas milrinone does not.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"429 1-2 1","pages":"I-284-I-289"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76306399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032885.55215.CE
S. Kuki, K. Taniguchi, T. Masai, T. Yokota, Kiyoshi Yoshida, Keiji Yamamoto, H. Matsuda
BackgroundAlthough a staged elephant trunk procedure has been widely used, the early mortality of the first stage operation as well as the interval mortality between operations remains unsatisfactory. We developed an alternative elephant trunk procedure to reduce mortality and morbidity. Methods and Results Ascending aorta and arch vessels were minimally dissected. During systemic cooling, a four-branched arch graft with a sewing “collar” and a long “elephant trunk” was prepared. The ascending aorta was opened under selective brain perfusion with moderate hypothermia (25°C), and the elephant trunk was then pulled down into the descending aorta using the catching catheter introduced via a femoral artery. The elephant trunk anastomosis using the collar was made at the base of the innominate artery. The arch vessels were divided and closed at aortic stump, and grafted separately as a consequence of the very proximal site for the elephant trunk anastomosis. Between October 1998 and September 2001, 17 patients, ranging in age from 25 to 79 years (mean 67 years) with extensive aortic aneurysm underwent this operation. Preoperative cardiac complications included coronary artery disease in 5, aortic regurgitation in 3, and 3 of these 8 patients had poor left ventricular function with an ejection fraction less than 40%. Nine patients underwent a second stage operation, in 1 of them the permanent elephant trunk procedure was initially attempted but the second stage procedure was done because of increasing endo-leakage. The mean interval between operations was 8 days (range 1 to 14 days) in the remaining 8 patients. In 5 of 6 patients who underwent the permanent elephant trunk procedure, a decrease in the size of the aneurysm based on thromboexclusion was observed using serial computed tomography scans. A single stage repair was performed in 1 patient. The 30-day survival rate of all operations was 100%, however, there was 1 in-hospital death (6%) after the second operation. There was no stroke, however, paraplegia occurred after the first operation in 1 patient (6%) of the in-hospital death. No new phrenic or recurrent laryngeal nerve palsy occurred as a result of surgery. ConclusionsThe present technique using a modification of the elephant trunk technique for extensive aortic aneurysm provides acceptable mortality and morbidity. The present strategy would be an alternative for the standard elephant trunk procedure in some high-risk patients with advanced age and comorbidities.
{"title":"An Alternative Approach Using Long Elephant Trunk for Extensive Aortic Aneurysm: Elephant Trunk Anastomosis at the Base of the Innominate Artery","authors":"S. Kuki, K. Taniguchi, T. Masai, T. Yokota, Kiyoshi Yoshida, Keiji Yamamoto, H. Matsuda","doi":"10.1161/01.CIR.0000032885.55215.CE","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032885.55215.CE","url":null,"abstract":"BackgroundAlthough a staged elephant trunk procedure has been widely used, the early mortality of the first stage operation as well as the interval mortality between operations remains unsatisfactory. We developed an alternative elephant trunk procedure to reduce mortality and morbidity. Methods and Results Ascending aorta and arch vessels were minimally dissected. During systemic cooling, a four-branched arch graft with a sewing “collar” and a long “elephant trunk” was prepared. The ascending aorta was opened under selective brain perfusion with moderate hypothermia (25°C), and the elephant trunk was then pulled down into the descending aorta using the catching catheter introduced via a femoral artery. The elephant trunk anastomosis using the collar was made at the base of the innominate artery. The arch vessels were divided and closed at aortic stump, and grafted separately as a consequence of the very proximal site for the elephant trunk anastomosis. Between October 1998 and September 2001, 17 patients, ranging in age from 25 to 79 years (mean 67 years) with extensive aortic aneurysm underwent this operation. Preoperative cardiac complications included coronary artery disease in 5, aortic regurgitation in 3, and 3 of these 8 patients had poor left ventricular function with an ejection fraction less than 40%. Nine patients underwent a second stage operation, in 1 of them the permanent elephant trunk procedure was initially attempted but the second stage procedure was done because of increasing endo-leakage. The mean interval between operations was 8 days (range 1 to 14 days) in the remaining 8 patients. In 5 of 6 patients who underwent the permanent elephant trunk procedure, a decrease in the size of the aneurysm based on thromboexclusion was observed using serial computed tomography scans. A single stage repair was performed in 1 patient. The 30-day survival rate of all operations was 100%, however, there was 1 in-hospital death (6%) after the second operation. There was no stroke, however, paraplegia occurred after the first operation in 1 patient (6%) of the in-hospital death. No new phrenic or recurrent laryngeal nerve palsy occurred as a result of surgery. ConclusionsThe present technique using a modification of the elephant trunk technique for extensive aortic aneurysm provides acceptable mortality and morbidity. The present strategy would be an alternative for the standard elephant trunk procedure in some high-risk patients with advanced age and comorbidities.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"36 1","pages":"I-253-I-258"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85936829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032913.33237.F5
M. Rothenburger, M. Wilhelm, D. Hammel, C. Schmidt, T. D. Tjan, D. Böcker, H. Scheld, Ç. Schmid
BackgroundThe latest generation of left ventricular assist devices consists of nonpulsatile impeller pumps. In these small pumps, thrombus formation inside the device does not lead to thromboembolic end-organ dysfunction but may dramatically impair pump flow. We report on our experience with thrombus-related pump dysfunctions of the MicroMed DeBakey left ventricular assist device and its treatment. MethodsEight of 22 patients with a MicroMed DeBakey VAD presented with a critically reduced pump flow. In 7 cases, an increased power demand indicative of progressive thrombus formation associated with the device was evident, whereas 1 case presented with thrombus formation within the inflow conduit associated with a very low power demand. Brief spontaneously resolving pump stops had been noted in 6 patients. All 8 patients were treated with 100 mg of recombinant tissue plasminogen activator (rt-PA), administered via an IV line. ResultsRt-PA lysis led to an increase of pump flow along with a reduction of power demand within a short time in all patients. No severe bleeding complications occurred. However, 4 patients experienced transient epistaxis. All patients could be discharged from intensive care immediately after discontinuation of thrombolytic therapy. ConclusionRt-PA lysis is a very effective tool for thrombus-related pump dysfunction in patients with impeller pumps, which renders emergency surgical exchange unnecessary in most cases.
{"title":"Treatment of Thrombus Formation Associated With the MicroMed DeBakey VAD Using Recombinant Tissue Plasminogen Activator","authors":"M. Rothenburger, M. Wilhelm, D. Hammel, C. Schmidt, T. D. Tjan, D. Böcker, H. Scheld, Ç. Schmid","doi":"10.1161/01.CIR.0000032913.33237.F5","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032913.33237.F5","url":null,"abstract":"BackgroundThe latest generation of left ventricular assist devices consists of nonpulsatile impeller pumps. In these small pumps, thrombus formation inside the device does not lead to thromboembolic end-organ dysfunction but may dramatically impair pump flow. We report on our experience with thrombus-related pump dysfunctions of the MicroMed DeBakey left ventricular assist device and its treatment. MethodsEight of 22 patients with a MicroMed DeBakey VAD presented with a critically reduced pump flow. In 7 cases, an increased power demand indicative of progressive thrombus formation associated with the device was evident, whereas 1 case presented with thrombus formation within the inflow conduit associated with a very low power demand. Brief spontaneously resolving pump stops had been noted in 6 patients. All 8 patients were treated with 100 mg of recombinant tissue plasminogen activator (rt-PA), administered via an IV line. ResultsRt-PA lysis led to an increase of pump flow along with a reduction of power demand within a short time in all patients. No severe bleeding complications occurred. However, 4 patients experienced transient epistaxis. All patients could be discharged from intensive care immediately after discontinuation of thrombolytic therapy. ConclusionRt-PA lysis is a very effective tool for thrombus-related pump dysfunction in patients with impeller pumps, which renders emergency surgical exchange unnecessary in most cases.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"18 1","pages":"I-189-I-192"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82019100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032882.55215.00
A. Scheule, G. Zimmerman, J. Johnston, A. Razzouk, S. Gundry, L. Bailey
BackgroundUtilizing donor hearts with prolonged graft ischemia may extend the donor pool. Methods and ResultsThe medical records of 363 infants and children, aged 1 day to 17 years, transplanted at Loma Linda University between November 1985 and March 2001, were retrospectively reviewed. Fourteen children received organs with prolonged ischemic times (>8 hours)(PIT) compared with 14 with short ischemic times (≤90 minutes)(SIT). There were no significant differences when comparing donors for gender, age, weight, cause of death, or duration of cardiopulmonary resuscitation. Preoperative donor shortening fraction (%), as determined by echocardiography, was significantly higher in the SIT group (44.5 versus 36.5%;P =0.006). There were no significant differences between PIT and SIT recipients when comparing age at transplant, weight at transplant, waiting time, weight mismatch, postoperative days on ventilator, duration of inotropic support, and hospital stay. Cardiopulmonary bypass time was significantly longer in the PIT group (140.5 versus 80.5 minute;P =0.001). Median length of follow-up for both groups was approximately 5 years. Five grafts were lost in the PIT group; 7 were lost in the SIT group, with 1 early graft loss in each group. Significant posttransplant coronary artery disease was diagnosed in 2 recipients in each group (PIT: 80 and 42; SIT: 84 and 67 months posttransplant). There was no significant difference between groups in actuarial graft survival. Number of rejection episodes and hospital readmissions during the first posttransplantation year did not differ significantly between groups. ConclusionLate outcomes were not adversely affected by donor hearts preserved by single dose cold crystalloid cardioplegia with greater than 8 hours of cold ischemia.
背景:利用移植物长时间缺血的供体心脏可以扩大供体池。方法与结果对1985年11月至2001年3月在美国洛马林达大学(Loma Linda University)进行移植手术的363例1天~ 17岁婴幼儿的病历进行回顾性分析。14例患儿接受了缺血时间延长(>8小时)(PIT)， 14例患儿接受了缺血时间短(≤90分钟)(SIT)。在比较供者的性别、年龄、体重、死亡原因或心肺复苏持续时间时，没有显著差异。超声心动图显示，SIT组术前供体缩短率(%)明显高于对照组(44.5 vs 36.5%;P =0.006)。在比较移植时的年龄、移植时的体重、等待时间、体重不匹配、术后使用呼吸机天数、肌力支持持续时间和住院时间时，PIT和SIT受者之间没有显著差异。PIT组体外循环时间明显更长(140.5分钟vs 80.5分钟;P =0.001)。两组的中位随访时间约为5年。PIT组丢失5个移植物;SIT组丢失7例，每组1例早期移植物丢失。两组分别有2例移植后冠脉病变(PIT: 80和42;SIT:移植后84和67个月)。精算移植存活率组间无显著差异。移植后第一年内的排斥事件和再入院次数在两组之间没有显著差异。结论单剂量冷晶体心脏停跳保存供体心脏超过8小时，对晚期预后无不良影响。
{"title":"Duration of Graft Cold Ischemia Does Not Affect Outcomes in Pediatric Heart Transplant Recipients","authors":"A. Scheule, G. Zimmerman, J. Johnston, A. Razzouk, S. Gundry, L. Bailey","doi":"10.1161/01.CIR.0000032882.55215.00","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032882.55215.00","url":null,"abstract":"BackgroundUtilizing donor hearts with prolonged graft ischemia may extend the donor pool. Methods and ResultsThe medical records of 363 infants and children, aged 1 day to 17 years, transplanted at Loma Linda University between November 1985 and March 2001, were retrospectively reviewed. Fourteen children received organs with prolonged ischemic times (>8 hours)(PIT) compared with 14 with short ischemic times (≤90 minutes)(SIT). There were no significant differences when comparing donors for gender, age, weight, cause of death, or duration of cardiopulmonary resuscitation. Preoperative donor shortening fraction (%), as determined by echocardiography, was significantly higher in the SIT group (44.5 versus 36.5%;P =0.006). There were no significant differences between PIT and SIT recipients when comparing age at transplant, weight at transplant, waiting time, weight mismatch, postoperative days on ventilator, duration of inotropic support, and hospital stay. Cardiopulmonary bypass time was significantly longer in the PIT group (140.5 versus 80.5 minute;P =0.001). Median length of follow-up for both groups was approximately 5 years. Five grafts were lost in the PIT group; 7 were lost in the SIT group, with 1 early graft loss in each group. Significant posttransplant coronary artery disease was diagnosed in 2 recipients in each group (PIT: 80 and 42; SIT: 84 and 67 months posttransplant). There was no significant difference between groups in actuarial graft survival. Number of rejection episodes and hospital readmissions during the first posttransplantation year did not differ significantly between groups. ConclusionLate outcomes were not adversely affected by donor hearts preserved by single dose cold crystalloid cardioplegia with greater than 8 hours of cold ischemia.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"26 1","pages":"I-163-I-167"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83919276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032899.55215.44
V. Jeevanandam, D. Jayakar, A. Anderson, S. Martin, W. Piccione, A. Heroux, J. Wynne, L. Stephenson, J. Hsu, P. Freed, A. Kantrowitz
PurposeThe Kantrowitz CardioVADTM (KCV) is an electrically powered, pneumatically driven circulatory assist device which provides diastolic augmentation and systolic unloading to the failing heart. It consists of a 60cc-pumping chamber, a percutaneous access device (PAD), and an external controller. The pumping chamber, is surgically implanted in the descending thoracic aorta with the patient on cardiopulmonary bypass. Its physiologic function is analogous to that of the intra-aortic balloon pump (IABP). MethodsBetween 1997 and 2000, 5 men (age 59 to 73) with end-stage cardiomyopathy refractory to maximal drug treatment and with documented hemodynamic improvement on an IABP were enrolled in a feasibility study. ResultsMean bypass time was 157 minute (range 120 to 196 minute); mean cross-clamp time was 101 minute (range 69 to 144). Patient 1 died intra-operatively. Compared with preoperative values, at 1 month, cardiac index increased (1.7 to 2.6 L/min/m2) and there were significant decreases in creatinine (2.6 to 1.5 mg/dL), pulmonary capillary wedge pressure (PCWP) (32 to 14 mm Hg), and right atrial pressure (RA) (19 to 9 mm Hg). NYHA class improved (IV to II). The mean increase in cardiac index with the KCV OFF to ON was 0.53 L/min/m2 (36%). Two patients were discharged home. The device was used intermittently without thromboembolic complications. The only device related complications were attributed to PAD design and have been corrected. ConclusionOur initial human trial demonstrates successful implantation of the KCV in end-stage patients, the ability of the device to be used intermittently without anticoagulation, and documents hemodynamic and functional improvement in the status of these patients.
目的Kantrowitz心血管辅助装置(KCV)是一种电动、气动驱动的循环辅助装置，为衰竭的心脏提供舒张增强和收缩卸载。它由一个60cc的泵腔、一个经皮通路装置(PAD)和一个外部控制器组成。泵腔，手术植入胸降主动脉与病人在体外循环。其生理功能类似于主动脉内球囊泵(IABP)。方法:在1997年至2000年期间，5名终末期心肌病患者(59岁至73岁)对最大药物治疗难治性，经IABP治疗后血流动力学改善，纳入可行性研究。结果平均旁路时间157 min (120 ~ 196 min);平均交叉夹钳时间为101分钟(范围69 ~ 144分钟)。患者1在术中死亡。与术前相比，1个月时心脏指数升高(1.7 ~ 2.6 L/min/m2)，肌酐(2.6 ~ 1.5 mg/dL)、肺毛细血管楔压(PCWP) (32 ~ 14 mm Hg)、右房压(RA) (19 ~ 9 mm Hg)显著降低。NYHA分级提高(IV至II)。KCV OFF至ON时心脏指数平均增加0.53 L/min/m2(36%)。两名病人出院回家。该装置间歇性使用，无血栓栓塞并发症。唯一与器械相关的并发症归因于PAD设计，并已得到纠正。我们的初步人体试验表明，KCV在终末期患者中成功植入，该装置能够在不抗凝的情况下间歇性使用，并记录了这些患者血液动力学和功能的改善。
{"title":"Circulatory Assistance With a Permanent Implantable IABP: Initial Human Experience","authors":"V. Jeevanandam, D. Jayakar, A. Anderson, S. Martin, W. Piccione, A. Heroux, J. Wynne, L. Stephenson, J. Hsu, P. Freed, A. Kantrowitz","doi":"10.1161/01.CIR.0000032899.55215.44","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032899.55215.44","url":null,"abstract":"PurposeThe Kantrowitz CardioVADTM (KCV) is an electrically powered, pneumatically driven circulatory assist device which provides diastolic augmentation and systolic unloading to the failing heart. It consists of a 60cc-pumping chamber, a percutaneous access device (PAD), and an external controller. The pumping chamber, is surgically implanted in the descending thoracic aorta with the patient on cardiopulmonary bypass. Its physiologic function is analogous to that of the intra-aortic balloon pump (IABP). MethodsBetween 1997 and 2000, 5 men (age 59 to 73) with end-stage cardiomyopathy refractory to maximal drug treatment and with documented hemodynamic improvement on an IABP were enrolled in a feasibility study. ResultsMean bypass time was 157 minute (range 120 to 196 minute); mean cross-clamp time was 101 minute (range 69 to 144). Patient 1 died intra-operatively. Compared with preoperative values, at 1 month, cardiac index increased (1.7 to 2.6 L/min/m2) and there were significant decreases in creatinine (2.6 to 1.5 mg/dL), pulmonary capillary wedge pressure (PCWP) (32 to 14 mm Hg), and right atrial pressure (RA) (19 to 9 mm Hg). NYHA class improved (IV to II). The mean increase in cardiac index with the KCV OFF to ON was 0.53 L/min/m2 (36%). Two patients were discharged home. The device was used intermittently without thromboembolic complications. The only device related complications were attributed to PAD design and have been corrected. ConclusionOur initial human trial demonstrates successful implantation of the KCV in end-stage patients, the ability of the device to be used intermittently without anticoagulation, and documents hemodynamic and functional improvement in the status of these patients.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"205 1","pages":"I-183-I-188"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72656527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032918.33237.04
A. Kaza, I. Kron, Shari M Leuwerke, C. Tribble, V. Laubach
BackgroundKeratinocyte growth factor (KGF) has been shown to play an important role in pneumocyte proliferation and lung development. We hypothesized that exogenous KGF would enhance postpneumonectomy compensatory lung growth through alveolar proliferation. Methods and ResultsAdult Sprague–Dawley rats were used. Left pneumonectomy was performed in group P, sham thoracotomy in group S, and left pneumonectomy with administration of KGF (6.25 mg/week, intraperitoneally) in group PK. Lung weight index (LWI), lung volume index (LVI), and alveolar cell proliferation index (CPI) were measured in the right lung at 10 and 21 days after surgery. Morphometric analysis was used to determine alveolar surface density (Sv) and total volume of respiratory region (TVvr). As expected, LWI, LVI, and CPI were significantly increased after pneumonectomy at both time points in group P. The administration of KGF resulted in further significant enhancements of LWI, LVI, and CPI in group PK. TVvr was significantly increased in group P and further enhanced in group PK. Interestingly, Sv was not altered in group P but was significantly elevated in group PK. Administration of KGF to sham-operated animals did not alter LWI, LVI, or CPI. ConclusionsKGF enhances compensatory lung growth after pneumonectomy in adult rats as indicated by increased LWI, LVI, and CPI. KGF induces new alveolar formation, as indicated by increases in Sv and TVvr. We believe that this is the first evidence that KGF can induce new alveolar formation in mature lungs.
{"title":"Keratinocyte Growth Factor Enhances Post-Pneumonectomy Lung Growth by Alveolar Proliferation","authors":"A. Kaza, I. Kron, Shari M Leuwerke, C. Tribble, V. Laubach","doi":"10.1161/01.CIR.0000032918.33237.04","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032918.33237.04","url":null,"abstract":"BackgroundKeratinocyte growth factor (KGF) has been shown to play an important role in pneumocyte proliferation and lung development. We hypothesized that exogenous KGF would enhance postpneumonectomy compensatory lung growth through alveolar proliferation. Methods and ResultsAdult Sprague–Dawley rats were used. Left pneumonectomy was performed in group P, sham thoracotomy in group S, and left pneumonectomy with administration of KGF (6.25 mg/week, intraperitoneally) in group PK. Lung weight index (LWI), lung volume index (LVI), and alveolar cell proliferation index (CPI) were measured in the right lung at 10 and 21 days after surgery. Morphometric analysis was used to determine alveolar surface density (Sv) and total volume of respiratory region (TVvr). As expected, LWI, LVI, and CPI were significantly increased after pneumonectomy at both time points in group P. The administration of KGF resulted in further significant enhancements of LWI, LVI, and CPI in group PK. TVvr was significantly increased in group P and further enhanced in group PK. Interestingly, Sv was not altered in group P but was significantly elevated in group PK. Administration of KGF to sham-operated animals did not alter LWI, LVI, or CPI. ConclusionsKGF enhances compensatory lung growth after pneumonectomy in adult rats as indicated by increased LWI, LVI, and CPI. KGF induces new alveolar formation, as indicated by increases in Sv and TVvr. We believe that this is the first evidence that KGF can induce new alveolar formation in mature lungs.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"46 1","pages":"I-120-I-124"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73005230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032914.33237.3B
Y. Sakomura, H. Nagashima, Y. Aoka, K. Uto, Akiko Sakuta, S. Aomi, H. Kurosawa, T. Nishikawa, H. Kasanuki
BackgroundCystic medial degeneration (CMD) is a histological abnormality that is common in annuloaortic ectasia (AAE) and aortic dissection with Marfan syndrome. Apoptosis and loss of vascular smooth muscle cells (VSMCs) is one of the features of CMD, but little is known about its pathogenesis. Peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), a transcription factor of the nuclear receptor superfamily, has been reported to show antiproliferative effects on VSMCs as well as anti-inflammatory effects on macrophages. PPAR&ggr; agonist has been recently reported to induce apoptosis of cultured VSMCs. MethodsWe examined the histopathology of ascending aortas in AAE of Marfan patients (n=21) and control patients (n=6) at surgery. RT-PCR was performed to demonstrate expression of PPAR&ggr; in CMD. Localization of PPAR&ggr; was determined by double immunostaining using antibodies against PPAR&ggr; and cell-specific markers (ie, SMCs, macrophages, and T lymphocytes). ResultsPPAR&ggr; expression was upregulated in AAE samples but minimal in control samples by RT-PCR (P =0.07). Immunoreactivity against PPAR&ggr; in numerous nuclei of VSMCs was observed in CMD lesions. Severity of CMD correlated with positive immunoreactivity of PPAR&ggr; in medial VSMCs (P =0.03). No inflammatory cells (ie, macrophages or T lymphocytes) were detected in CMD lesions. ConclusionPPAR&ggr; expression is upregulated in SMCs of CMD without any inflammatory response. Activated PPAR&ggr; in VSMCs might be involved in the pathogenesis of CMD in Marfan’s aortas. Regulation of PPAR&ggr; might lead to clinical implication in protection against progression of AAE.
{"title":"Expression of Peroxisome Proliferator-Activated Receptor-&ggr; in Vascular Smooth Muscle Cells Is Upregulated in Cystic Medial Degeneration of Annuloaortic Ectasia in Marfan Syndrome","authors":"Y. Sakomura, H. Nagashima, Y. Aoka, K. Uto, Akiko Sakuta, S. Aomi, H. Kurosawa, T. Nishikawa, H. Kasanuki","doi":"10.1161/01.CIR.0000032914.33237.3B","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032914.33237.3B","url":null,"abstract":"BackgroundCystic medial degeneration (CMD) is a histological abnormality that is common in annuloaortic ectasia (AAE) and aortic dissection with Marfan syndrome. Apoptosis and loss of vascular smooth muscle cells (VSMCs) is one of the features of CMD, but little is known about its pathogenesis. Peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), a transcription factor of the nuclear receptor superfamily, has been reported to show antiproliferative effects on VSMCs as well as anti-inflammatory effects on macrophages. PPAR&ggr; agonist has been recently reported to induce apoptosis of cultured VSMCs. MethodsWe examined the histopathology of ascending aortas in AAE of Marfan patients (n=21) and control patients (n=6) at surgery. RT-PCR was performed to demonstrate expression of PPAR&ggr; in CMD. Localization of PPAR&ggr; was determined by double immunostaining using antibodies against PPAR&ggr; and cell-specific markers (ie, SMCs, macrophages, and T lymphocytes). ResultsPPAR&ggr; expression was upregulated in AAE samples but minimal in control samples by RT-PCR (P =0.07). Immunoreactivity against PPAR&ggr; in numerous nuclei of VSMCs was observed in CMD lesions. Severity of CMD correlated with positive immunoreactivity of PPAR&ggr; in medial VSMCs (P =0.03). No inflammatory cells (ie, macrophages or T lymphocytes) were detected in CMD lesions. ConclusionPPAR&ggr; expression is upregulated in SMCs of CMD without any inflammatory response. Activated PPAR&ggr; in VSMCs might be involved in the pathogenesis of CMD in Marfan’s aortas. Regulation of PPAR&ggr; might lead to clinical implication in protection against progression of AAE.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"54 1","pages":"I-259-I-263"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78668375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032901.55215.CC
T. Ozawa, Donald A. G. Mickle, R. Weisel, N. Koyama, S. Ozawa, Ren-Ke Li
BackgroundThe optimal cardiac graft for the repair of congenital heart defects will be composed of autologous cells and will grow with the child. The biodegradable material should permit rapid cellular growth and delayed degradation with minimal inflammation. We compared a new material, &egr;-caprolactone-co-l-lactide sponge reinforced with knitted poly-l-lactide fabric (PCLA), to gelatin (GEL) and polyglycolic acid (PGA), which are previously evaluated materials. MethodsSyngenic rat aortic smooth muscle cells (SMCs, 2×106) were seeded onto GEL, PGA, and PCLA patches and cultured (n=11 per group). The DNA content in each patch was measured at 1, 2, and 3 weeks after seeding. Histological examination was performed 2 weeks after seeding. Cell-seeded patches were employed to replace a surgically created defect in the right ventricular outflow tract (RVOT) of rats (n=5 per group). Histology was studied at 8 weeks following implantation. ResultsIn vitro studies showed that the DNA content increased significantly (P <0.05) in all patches between 1 and 3 weeks after seeding. Histology and staining SMCs for anti-&agr;-smooth muscle actin (&agr;SMA) revealed better growth of cells in the interstices of the grafts with GEL and PCLA than the PGA graft. In vivo studies demonstrated that seeded SMCs survived at least 8 weeks after the patch implantation in all groups. PCLA scaffolds were replaced by more cells with larger &agr;SMA-positive areas and by more extracellular matrix with larger elastin-positive areas than with GEL and PGA. The patch did not thin and expanded significantly. The GEL and PGA patches thinned and expanded. All grafts had complete endothelialization on the endocardial surface. ConclusionsSMC-seeded biodegradable materials can be employed to repair the RVOT. The novel PCLA patches permitted better cellular penetration in vitro and did not thin or dilate in vivo and did not produce an inflammatory response. The cell-seeded PCLA patch may permit the construction of an autologous patch to repair congenital heart defects.
{"title":"Optimal Biomaterial for Creation of Autologous Cardiac Grafts","authors":"T. Ozawa, Donald A. G. Mickle, R. Weisel, N. Koyama, S. Ozawa, Ren-Ke Li","doi":"10.1161/01.CIR.0000032901.55215.CC","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032901.55215.CC","url":null,"abstract":"BackgroundThe optimal cardiac graft for the repair of congenital heart defects will be composed of autologous cells and will grow with the child. The biodegradable material should permit rapid cellular growth and delayed degradation with minimal inflammation. We compared a new material, &egr;-caprolactone-co-l-lactide sponge reinforced with knitted poly-l-lactide fabric (PCLA), to gelatin (GEL) and polyglycolic acid (PGA), which are previously evaluated materials. MethodsSyngenic rat aortic smooth muscle cells (SMCs, 2×106) were seeded onto GEL, PGA, and PCLA patches and cultured (n=11 per group). The DNA content in each patch was measured at 1, 2, and 3 weeks after seeding. Histological examination was performed 2 weeks after seeding. Cell-seeded patches were employed to replace a surgically created defect in the right ventricular outflow tract (RVOT) of rats (n=5 per group). Histology was studied at 8 weeks following implantation. ResultsIn vitro studies showed that the DNA content increased significantly (P <0.05) in all patches between 1 and 3 weeks after seeding. Histology and staining SMCs for anti-&agr;-smooth muscle actin (&agr;SMA) revealed better growth of cells in the interstices of the grafts with GEL and PCLA than the PGA graft. In vivo studies demonstrated that seeded SMCs survived at least 8 weeks after the patch implantation in all groups. PCLA scaffolds were replaced by more cells with larger &agr;SMA-positive areas and by more extracellular matrix with larger elastin-positive areas than with GEL and PGA. The patch did not thin and expanded significantly. The GEL and PGA patches thinned and expanded. All grafts had complete endothelialization on the endocardial surface. ConclusionsSMC-seeded biodegradable materials can be employed to repair the RVOT. The novel PCLA patches permitted better cellular penetration in vitro and did not thin or dilate in vivo and did not produce an inflammatory response. The cell-seeded PCLA patch may permit the construction of an autologous patch to repair congenital heart defects.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"10 1","pages":"I-176-I-182"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80381877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032872.55215.05
S. Hoerstrup, A. Kadner, S. Melnitchouk, A. Trojan, K. Eid, Jay Tracy, R. Sodian, J. Visjager, S. Kolb, J. Grunenfelder, G. Zund, M. Turina
BackgroundWe previously demonstrated the successful tissue engineering and implantation of functioning autologous heart valves based on vascular-derived cells. Human marrow stromal cells (MSC) exhibit the potential to differentiate into multiple cell-lineages and can be easily obtained clinically. The feasibility of creating tissue engineered heart valves (TEHV) from MSC as an alternative cell source, and the impact of a biomimetic in vitro environment on tissue differentiation was investigated. Methods and ResultsHuman MSC were isolated, expanded in culture, and characterized by flow-cytometry and immunohistochemistry. Trileaflet heart valves fabricated from rapidly bioabsorbable polymers were seeded with MSC and grown in vitro in a pulsatile-flow-bioreactor. Morphological characterization included histology and electron microscopy (EM). Extracellular matrix (ECM)-formation was analyzed by immunohistochemistry, ECM protein content (collagen, glycosaminoglycan) and cell proliferation (DNA) were biochemically quantified. Biomechanical evaluation was performed using Instron™. In all valves synchronous opening and closing was observed in the bioreactor. Flow-cytometry of MSC pre-seeding was positive for ASMA, vimentin, negative for CD 31, LDL, CD 14. Histology of the TEHV-leaflets demonstrated viable tissue and ECM formation. EM demonstrated cell elements typical of viable, secretionally active myofibroblasts (actin/myosin filaments, collagen fibrils, elastin) and confluent, homogenous tissue surfaces. Collagen types I, III, ASMA, and vimentin were detected in the TEHV-leaflets. Mechanical properties of the TEHV-leaflets were comparable to native tissue. ConclusionGeneration of functional TEHV from human MSC was feasible utilizing a biomimetic in vitro environment. The neo-tissue showed morphological features and mechanical properties of human native-heart-valve tissue. The human MSC demonstrated characteristics of myofibroblast differentiation.
{"title":"Tissue Engineering of Functional Trileaflet Heart Valves From Human Marrow Stromal Cells","authors":"S. Hoerstrup, A. Kadner, S. Melnitchouk, A. Trojan, K. Eid, Jay Tracy, R. Sodian, J. Visjager, S. Kolb, J. Grunenfelder, G. Zund, M. Turina","doi":"10.1161/01.CIR.0000032872.55215.05","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032872.55215.05","url":null,"abstract":"BackgroundWe previously demonstrated the successful tissue engineering and implantation of functioning autologous heart valves based on vascular-derived cells. Human marrow stromal cells (MSC) exhibit the potential to differentiate into multiple cell-lineages and can be easily obtained clinically. The feasibility of creating tissue engineered heart valves (TEHV) from MSC as an alternative cell source, and the impact of a biomimetic in vitro environment on tissue differentiation was investigated. Methods and ResultsHuman MSC were isolated, expanded in culture, and characterized by flow-cytometry and immunohistochemistry. Trileaflet heart valves fabricated from rapidly bioabsorbable polymers were seeded with MSC and grown in vitro in a pulsatile-flow-bioreactor. Morphological characterization included histology and electron microscopy (EM). Extracellular matrix (ECM)-formation was analyzed by immunohistochemistry, ECM protein content (collagen, glycosaminoglycan) and cell proliferation (DNA) were biochemically quantified. Biomechanical evaluation was performed using Instron™. In all valves synchronous opening and closing was observed in the bioreactor. Flow-cytometry of MSC pre-seeding was positive for ASMA, vimentin, negative for CD 31, LDL, CD 14. Histology of the TEHV-leaflets demonstrated viable tissue and ECM formation. EM demonstrated cell elements typical of viable, secretionally active myofibroblasts (actin/myosin filaments, collagen fibrils, elastin) and confluent, homogenous tissue surfaces. Collagen types I, III, ASMA, and vimentin were detected in the TEHV-leaflets. Mechanical properties of the TEHV-leaflets were comparable to native tissue. ConclusionGeneration of functional TEHV from human MSC was feasible utilizing a biomimetic in vitro environment. The neo-tissue showed morphological features and mechanical properties of human native-heart-valve tissue. The human MSC demonstrated characteristics of myofibroblast differentiation.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"46 1","pages":"I-143-I-150"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81791779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-09-24DOI: 10.1161/01.CIR.0000032875.55215.CB
D. Balzer, H. Kort, R. Day, H. Corneli, J. Kovalchin, B. Cannon, S. Kaine, D. Ivy, S. Webber, A. Rothman, R. Ross, S. Aggarwal, Masato Takahashi, J. Waldman
BackgroundThis study was performed to determine whether a preoperative hemodynamic evaluation with oxygen and inhaled nitric oxide identifies patients with pulmonary hypertension who are appropriate candidates for corrective cardiac surgery or transplantation more accurately than an evaluation with oxygen alone. Methods and ResultsAt 10 institutions, 124 patients with heart disease and severe pulmonary hypertension underwent cardiac catheterization to determine operability. The ratio of pulmonary and systemic vascular resistance (Rp:Rs) was determined at baseline while breathing ∼21% to 30% oxygen, and in ∼100% oxygen and ∼100% oxygen with 10 to 80 parts per million nitric oxide to evaluate pulmonary vascular reactivity. Surgery was performed in 74 patients. Twelve patients died or developed right heart failure secondary to pulmonary hypertension following surgery. Rp:Rs<0.33 and a 20% decrease in Rp:Rs from baseline were chosen as 2 criteria for operability to determine, in retrospect, the efficacy of preoperative testing in patient selection. In comparison to an evaluation with oxygen alone, sensitivity (64% versus 97%) and accuracy (68% versus 90%) were increased by an evaluation with oxygen and nitric oxide when Rp:Rs<0.33 was used as the criterion for operability. Specificity was only 8% when a 20% decrease in Rp:Rs from baseline was used as the criterion for operability. ConclusionBy using a combination of oxygen and inhaled nitric oxide, a greater number of appropriate candidates for corrective cardiac surgery or transplantation can be identified during preoperative testing when a specific value of Rp:Rs is used as a criterion for operability.
{"title":"Inhaled Nitric Oxide as a Preoperative Test (INOP Test I): The INOP Test Study Group","authors":"D. Balzer, H. Kort, R. Day, H. Corneli, J. Kovalchin, B. Cannon, S. Kaine, D. Ivy, S. Webber, A. Rothman, R. Ross, S. Aggarwal, Masato Takahashi, J. Waldman","doi":"10.1161/01.CIR.0000032875.55215.CB","DOIUrl":"https://doi.org/10.1161/01.CIR.0000032875.55215.CB","url":null,"abstract":"BackgroundThis study was performed to determine whether a preoperative hemodynamic evaluation with oxygen and inhaled nitric oxide identifies patients with pulmonary hypertension who are appropriate candidates for corrective cardiac surgery or transplantation more accurately than an evaluation with oxygen alone. Methods and ResultsAt 10 institutions, 124 patients with heart disease and severe pulmonary hypertension underwent cardiac catheterization to determine operability. The ratio of pulmonary and systemic vascular resistance (Rp:Rs) was determined at baseline while breathing ∼21% to 30% oxygen, and in ∼100% oxygen and ∼100% oxygen with 10 to 80 parts per million nitric oxide to evaluate pulmonary vascular reactivity. Surgery was performed in 74 patients. Twelve patients died or developed right heart failure secondary to pulmonary hypertension following surgery. Rp:Rs<0.33 and a 20% decrease in Rp:Rs from baseline were chosen as 2 criteria for operability to determine, in retrospect, the efficacy of preoperative testing in patient selection. In comparison to an evaluation with oxygen alone, sensitivity (64% versus 97%) and accuracy (68% versus 90%) were increased by an evaluation with oxygen and nitric oxide when Rp:Rs<0.33 was used as the criterion for operability. Specificity was only 8% when a 20% decrease in Rp:Rs from baseline was used as the criterion for operability. ConclusionBy using a combination of oxygen and inhaled nitric oxide, a greater number of appropriate candidates for corrective cardiac surgery or transplantation can be identified during preoperative testing when a specific value of Rp:Rs is used as a criterion for operability.","PeriodicalId":10194,"journal":{"name":"Circulation: Journal of the American Heart Association","volume":"24 1","pages":"I-76-I-81"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75047054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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