成年绵羊模型中自体心包经导管肺动脉瓣置换术，使用自扩展镍钛诺支架
1Department of Pediatric Cardiology and Congenital Heart Disease,Charité University Medicine Berlin, 2Department of Pediatric Cardiology and Congenital Heart Disease,Deutsches Herzzentrum Berlin, 3DZHK (German Centre for Cardiovascular Research) and BMBF (German Ministry of Education and Research), 4BIH (Berlin Institute of Health), 5BCRT (BIH Center of Regenerative Therapies)
Summary
本研究证明了通过在成年绵羊模型中使用自膨胀镍钛诺支架来开发自体肺动脉瓣植入原体肺动脉瓣位置的可行性和安全性。这是为右心室流出道功能障碍患者开发经导管肺动脉瓣置换术的一步。
Abstract
经导管肺动脉瓣置换术已被确立为右心室流出道或生物人工瓣膜功能障碍患者的可行替代方法，具有良好的早期和晚期临床结局。然而，必须解决诸如支架式心脏瓣膜恶化、冠状动脉阻塞、心内膜炎和其他并发症等临床挑战，以终生应用，特别是在儿科患者中。为了促进为患者开发终身解决方案，在成年绵羊模型中进行了经导管自体肺动脉瓣置换术。自体心包在通气麻醉下 ，通过 左前外侧切开术从绵羊身上收获。将心包置于3D定形心脏瓣膜模型上进行无毒交联2天21 h。进行心内超声心动图（ICE）和血管造影以评估天然肺动脉瓣（NPV）的位置，形态，功能和尺寸。修剪后，将交联的心包缝合到可自膨胀的镍钛诺支架上，并压接到自我设计的输送系统中。 通过 左颈静脉导管插入术将自体肺动脉瓣（APV）植入NPV位置。重复ICE和血管造影以评估APV的位置，形态，功能和尺寸。APV成功植入绵羊J体内。本文选取绵羊J获得具有代表性的结果。将带有镍钛诺支架的30 mm APV精确植入NPV位置，无任何显着的血流动力学变化。无瓣膜旁渗漏、无新发肺动脉瓣功能不全或肺动脉瓣移位移。该研究在长期随访中证明了在成年绵羊模型中 开发 一种用于在NPV位置植入自膨胀镍钛诺支架的可行性和安全性。
Introduction
朋霍费尔等人1 标志着2000年经导管肺动脉瓣置换术（TPVR）的开始，这是一项快速创新，在尽量减少并发症和提供替代治疗方法方面取得了重大进展。此后，使用TPVR治疗右心室流出道（RVOT）或生物假体瓣膜功能障碍迅速增加2，3。迄今为止，目前市场上可用的TPVR设备已经为RVOT功能障碍患者提供了令人满意的长期和短期结果4，5，6。此外，正在开发和评估各种类型的TPVR瓣膜，包括去细胞心脏瓣膜和干细胞驱动的心脏瓣膜，其可行性已在临床前大型动物模型7，8中得到证明。Duran博士首次报道了使用自体心包进行主动脉瓣重建，其中以三个不同大小的连续凸起为模板，根据主动脉环的尺寸指导心包的形成，随访60个月9时存活率为84.53%。Ozaki手术被认为是瓣膜修复程序而不是瓣膜置换程序，涉及用戊二醛处理的自体心包替换主动脉瓣叶;然而，与Duran博士的程序相比，它在用模板测量患病瓣膜以切割固定心包10 方面显着改善，并且不仅从成人病例中获得了令人满意的结果，而且在儿科病例11中也取得了令人满意的结果。目前，只有Ross手术可以为患有主动脉瓣疾病的患者提供活瓣替代品，在避免长期抗凝，生长潜力和心内膜炎12风险低方面具有明显优势。但是，在如此复杂的外科手术后，肺自体移植物和右心室至肺动脉导管可能需要重新干预。
目前可用于临床的生物假体瓣膜由于对显性猪或牛组织的移植物抗宿主反应而不可避免地随着时间的推移而降解13.瓣膜相关的钙化，降解和功能不全可能需要在几年后重复干预，特别是在年轻患者中，由于缺乏瓣膜生长，需要在其一生中接受多次肺动脉瓣置换术，这是当前生物假体材料固有的特性14。此外，目前可用的基本上是非再生的TPVR瓣膜具有重大局限性，例如血栓栓塞和出血并发症，以及由于不良组织重塑而导致的耐久性有限，这可能导致小叶回缩和普遍瓣膜功能障碍15，16。
据推测，开发一种具有自我修复、再生和生长能力特征的自膨胀镍钛诺支架上的天然自体肺动脉瓣（APV）将确保生理性能和长期功能。而无毒交联剂处理的自体心包可以从收获和制造过程中唤醒。为此，这项临床前试验在成年绵羊模型中植入支架自体肺动脉瓣，目的是开发理想的介入性瓣膜替代品和低风险的程序方法来改善RVOT功能障碍的经导管治疗。本文选取绵羊J来说明全面的TPVR手术，包括心包切除术和经颈静脉植入自体心脏瓣膜。
Protocol
这项临床前研究由柏林卫生和社会事务区域办事处（LAGeSo）的法律和伦理委员会批准。所有动物（绵羊）都按照欧洲和德国实验动物科学学会（FELASA，GV-SOLAS）的指导方针得到了人道的照顾。该手术通过对一只3岁，47公斤的雌性绵羊J进行自体肺动脉瓣置换来说明。 1. 术前管理 从抵达当天到心包切除术日，将所有实验性绵羊安置在同一个装有稻草的?…
Representative Results
在绵羊J中，APV（直径30毫米）被成功植入RVOT的“着陆区”。 在绵羊J中，在通气的全身麻醉下，以及后续MRI和ICE中，血液动力学在整个左前外侧小胸切开术中保持稳定（表1，表2和表3）。收获测量9 cm x 9 cm的自体心包，并通过去除多余的组织进行修剪（图3A-C）。将自体心包置于3D成型模具上…
Discussion
这项研究是开发用于TPVR的活肺动脉瓣的重要一步。在成年绵羊模型中，该方法能够证明， 通过 颈静脉导管插入，可以将来自绵羊自身心包的APV植入自膨胀镍钛诺支架。在绵羊J中，使用自行设计的通用输送系统，支架自体肺动脉瓣成功地植入正确的肺部位置。植入后，绵羊J的心脏瓣膜在长达21个月的时间内显示出良好的功能，不仅为未来未成熟绵羊自体肺动脉瓣的临床前试验提供了安全有…
Declarações
The authors have nothing to disclose.
Acknowledgements
我们衷心感谢所有为这项工作作出贡献的人，包括过去和现在的成员。这项工作得到了德国联邦经济事务和能源部的资助，存在 – 研究转移（03EFIBE103）。郝义萌得到了中国留学基金委（CSC：202008450028）的支持。
Materials
| 10 % Magnesium | Inresa Arzneimittel GmbH | PZN: 00091126 | 0.02 mol/ L, 10X10 ml |
| 10 Fr Ultrasound catheter | Siemens Healthcare GmbH | SKU 10043342RH | ACUSON AcuNav™ ultrasound catheter |
| 3D Slicer | Slicer | Slicer 4.13.0-2021-08-13 | Software: 3D Slicer image computing platform |
| Adobe Illustrator | Adobe | Adobe Illustrator 2021 | Software |
| Amiodarone | Sanofi-Aventis Deutschland GmbH | PZN: 4599382 | 3- 5 mg/ kg, 150 mg/ 3 ml |
| Amplatz ultra-stiff guidewire | COOK MEDICAL LLC, USA | Reference Part Number:THSF-35-145-AUS | 0.035 inch, 145 cm |
| Anesthetic device platform | Drägerwerk AG & Co. KGaA | 8621500 | Dräger Atlan A350 |
| ARROW Berman Angiographic Balloon Catheter | Teleflex Medical Europe Ltd | LOT: 16F16M0070 | 5Fr, 80cm (X) |
| Butorphanol | Richter Pharma AG | Vnr531943 | 0.4mg/kg |
| C-Arm | BV Pulsera, Philips Heathcare, Eindhoven, The Netherlands | CAN/CSA-C22.2 NO.601.1-M90 | Medical electral wquipment |
| Crimping tool | Edwards Lifesciences, Irvine, CA, USA | 9600CR | Crimper |
| CT | Siemens Healthcare GmbH | − | CT platform |
| Dilator | Edwards Lifesciences, Irvine, CA, USA | 9100DKSA | 14- 22 Fr |
| Ethicon Suture | Ethicon | LOT:MKH259 | 4- 0 smooth monophilic thread, non-resorbable |
| Ethicon Suture | Ethicon | LOT:DEE274 | 3-0, 45 cm |
| Fast cath hemostasis introducer | ST. JUDE MEDICAL Minnetonka MN | LOT Number: 3458297 | 11 Fr |
| Fentanyl | Janssen-Cilag Pharma GmbH | DE/H/1047/001-002 | 0.01mg/kg |
| Fragmin | Pfizer Pharma GmbH, Berlin, Germany | PZN: 5746520 | Dalteparin 5000 IU/ d |
| Functional screen | BV Pulsera, Philips Heathcare, Eindhoven, The Netherlands | System ID: 44350921 | Medical electral wquipment |
| Glycopyrroniumbromid | Accord Healthcare B.V | PZN11649123 | 0.011mg/kg |
| Guide Wire M | TERUMO COPORATION JAPAN | REF*GA35183M | 0.89 mm, 180 cm |
| Hemochron Celite ACT | International Technidyne Corporation, Edison, USA | NJ 08820-2419 | ACT |
| Heparin | Merckle GmbH | PZN: 3190573 | Heparin-Natrium 5.000 I.E./0,2 ml |
| Hydroxyethyl starch (Haes-steril 10 %) | Fresenius Kabi Deutschland GmbH | ATC Code: B05A | 500 ml, 30 ml/h |
| Imeron 400 MCT | Bracco Imaging | PZN00229978 | 2.0–2.5 ml/kg, Contrast agent |
| Isoflurane | CP-Pharma Handelsges. GmbH | ATCvet Code: QN01AB06 | 250 ml, MAC: 1 % |
| Jonosteril Infusionslösung | Fresenius Kabi Deutschland GmbH | PZN: 541612 | 1000 ml |
| Ketamine | Actavis Group PTC EHF | ART.-Nr. 799-762 | 2–5 mg/kg/h |
| Meloxicam | Boehringer Ingelheim Vetmedica GmbH | M21020A-09 | 20 mg/ mL, 50 ml |
| Midazolam | Hameln pharma plus GMBH | MIDAZ50100 | 0.4mg/kg |
| MRI | Philips Healthcare | − | Ingenia Elition X, 3.0T |
| Natriumchloride (NaCl) | B. Braun Melsungen AG | PZN /EAN:04499344 / 4030539077361 | 0.9 %, 500 ml |
| Pigtail catheter | Cordis, Miami Lakes, FL, USA | REF: 533-534A | 5.2 Fr 145 °, 110 cm |
| Propofol | B. Braun Melsungen AG | PZN 11164495 | 20mg/ml, 1–2.5 mg/kg |
| Propofol | B. Braun Melsungen AG | PZN 11164443 | 10mg/ml, 2.5–8.0 mg/kg/h |
| Safety IV Catheter with Injection port | B. Braun Melsungen AG | LOT: 20D03G8346 | 18 G Catheter with Injection port |
| Sulbactam- ampicillin | Pfizer Pharma GmbH, Berlin, Germany | PZN: 4843132 | 3 g, 2.000 mg/ 1.000 mg |
| Sulbactam/ ampicillin | Instituto Biochimico Italiano G Lorenzini S.p.A. – Via Fossignano 2, Aprilia (LT) – Italien | ATC Code: J01CR01 | 20 mg/kg, 2 g/1 g |
| Surgical Blade | Brinkmann Medical ein Unternehmen der Dr. Junghans Medical GmbH | PZN: 354844 | 15 # |
| Surgical Blade | Brinkmann Medical ein Unternehmen der Dr. Junghans Medical GmbH | PZN: 354844 | 11 # |
| Suture | Johnson & Johnson | Hersteller Artikel Nr. EH7284H | 5-0 polypropylene |
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Citar este artigo
Hao, Y., Sun, X., Kiekenap, J. F. S., Emeis, J., Steitz, M., Breitenstein-Attach, A., Berger, F., Schmitt, B. Transcatheter Pulmonary Valve Replacement from Autologous Pericardium with a Self-Expandable Nitinol Stent in an Adult Sheep Model. J. Vis. Exp. (184), e63661, doi:10.3791/63661 (2022).