急性心肌梗死的猪模型主要成果评估
Summary
可靠和准确的结果评价是临床前的疗法转化为临床治疗的关键。目前的论文描述了如何评估猪急性心肌梗死模型的心脏功能和损坏3临床相关的主要成果参数。
Abstract
Mortality after acute myocardial infarction remains substantial and is associated with significant morbidity, like heart failure. Novel therapeutics are therefore required to confine cardiac damage, promote survival and reduce the disease burden of heart failure. Large animal experiments are an essential part in the translational process from experimental to clinical therapies. To optimize clinical translation, robust and representative outcome measures are mandatory. The present manuscript aims to address this need by describing the assessment of three clinically relevant outcome modalities in a pig acute myocardial infarction (AMI) model: infarct size in relation to area at risk (IS/AAR) staining, 3-dimensional transesophageal echocardiography (TEE) and admittance-based pressure-volume (PV) loops. Infarct size is the main determinant driving the transition from AMI to heart failure and can be quantified by IS/AAR staining. Echocardiography is a reliable and robust tool in the assessment of global and regional cardiac function in clinical cardiology. Here, a method for three-dimensional transesophageal echocardiography (3D-TEE) in pigs is provided. Extensive insight into cardiac performance can be obtained by admittance-based pressure-volume (PV) loops, including intrinsic parameters of myocardial function that are pre- and afterload independent. Combined with a clinically feasible experimental study protocol, these outcome measures provide researchers with essential information to determine whether novel therapeutic strategies could yield promising targets for future testing in clinical studies.
Introduction
减少射血分数（HFREF）心脏衰竭占所有心脏衰竭病例的50％，估计影响1 -人的2％，在西方世界1。其最常见的病因是急性心肌梗死（AMI）。由于AMI后急性死亡率，由于认识的提高和改进的治疗方案显著下降，重点已经转向了慢性后遗症;其中最突出的HFREF 2,3。连同增加的医疗费用4，心脏衰竭的日益流行强调需要新颖的诊断和治疗方法，它可以在不利的重构的高度平移猪模型如前所述5进行研究AMI后。
不利的重塑两者，决定因素（ 例如，梗死大小）和功能评估（ 例如 ，超声心动图）经常用于新疗法功效测试，指示相对的需要iable和相对便宜的方法。目前本文的目的是通过引入重要和可靠结果的措施为在急性心肌梗死的猪模型中的功效的测试，以满足这一需要。这些措施包括在风险（AAR），3D食管超声心动图（3D-TEE）和详细的基于准入压量（PV）循环收购涉及面积心肌梗死面积（IS）。
梗塞面积是不利的重塑和生存的AMI后6的主要决定因素。尽管缺血心肌可能挽救可逆损伤的心肌细胞，并限制梗塞尺寸的及时再灌注，灌注本身导致通过氧化应力的产生和不成比例的炎症反应的其他损害（缺血再灌注损伤（IRI））7。因此，IRI已被鉴定为有希望的治疗靶标。新的治疗的减小梗塞尺寸的能力是通过相对于评估梗死大小量化在风险（AAR）的区域。 AAR量化是强制性的，以校正在动物模型中的冠状动脉解剖的个体间变异性，作为较大AAR导致较大的绝对梗塞大小。因为梗塞大小，直接关系到心脏功能和心肌收缩力，在AAR变化可以影响无关研究治疗方式8的结果的措施。
三维食管超声心动图（3D-TEE）是测量心脏功能非侵入性安全，可靠，最重要的是，在临床应用廉价的方法。而经胸超声心动图（TTE）的图像不限于猪9 2D胸骨旁长期和短轴视图，3D-TEE可以用来获得左心室的完整的三维图像。因此，它不需要左心室（LV）卷的数学近似，如修改后的辛普森的第10条。后者达不到科尔的ectly估计左室重构后左室容积由于缺乏圆柱形几何11。此外，3D-TEE超过心外膜超声优选，因为它不要求手术干预，其中已经观察到施加在本模型12的心脏保护作用。虽然对于心肌功能的评估使用2D-TEE的已13,14之前进行了说明，关于心室几何限制是类似于在2D-TTE观察取决于LV重塑的程度。因此，较大的梗塞（因而心脏衰竭的可能性越高），越容易二维测量成为由不正确的几何假设有缺陷和需要3D技术越高。
尽管如此，大多数成像方式在他们的评估心肌的固有功能特性的能力的限制。环光伏提供此类相关的其他信息，因此他们的收购在下面详细描述。
Protocol
Representative Results
Discussion
心脏重塑在很大程度上取决于心肌梗死面积和心肌梗死的质量修复6,26。评估以标准化的方式前，本手稿提供伊文思蓝与体外 TTC染色，已验证和广泛使用8,16,27,28联合体内输注优雅方法。这种方法允许在危险中（AAR）就AAR 16的区域的量化和梗塞大小。目前的做法降低了染料扩散到AAR，梗塞区域或风险 – 与malpositioning – 乳头肌的，因为它不要求心肌穿刺。此外，?…
Disclosures
The authors have nothing to disclose.
Acknowledgements
The authors gratefully acknowledge Marlijn Jansen, Joyce Visser, Grace Croft, Martijn van Nieuwburg, Danny Elbersen and Evelyn Velema for their excellent technical support during the animal experiments.
Materials
| 3-dimensional transesophageal echocardiography | |||
| iE33 ultrasound device | Philips | – | |
| X7-2t transducer | Philips | – | |
| Aquasonic® 100 ultrasound transmission gel | Parker Laboratories Inc. | 01-34 | Alternative product can be used |
| Battery handle type C (laryngoscope handle) | Riester | 12303 | |
| Ri-Standard Miller blade MIL 4 (laryngoscope blade) | Riester | 12225 | |
| Qlab 10.0 (3DQ Advanced) analysis software | Philips | – | |
| Name | Company | Catalog Number | Comments |
| Pressure-volume loop acquisition | |||
| Cardiac defibrillator | Philips | ||
| 0.9% saline | Braun | ||
| 8F Percutaneous Sheath Introducer Set | Arrow | CP-08803 | Alternative product can be used |
| 9F Radifocus® Introducer II Standard Kit | Terumo | RS*A90K10SQ | Alternative product can be used |
| 8F Fogarty catheter | Edward Life Sciences | 62080814F | Alternative product can be used |
| 7F Criticath™ SP5107H TD catheter (Swan-Ganz) | Becton Dickinson (BD) | 680078 | Alternative product can be used |
| Ultraview SL Patient Monitor and Invasive Command Module (external cardiac output device) | Spacelabs Healthcare | 91387 | Alternative product can be used |
| ADVantage system™ | Transonic SciSense | – | |
| 7F tetra-polar admittance catheter (7.0 VSL Pigtail / no lumen) | Transonic SciSense | – | |
| Multi-channel acquisition system (Iworx 404) | Iworx | – | |
| Labscribe V2.0 analysis software | Iworx | – | Alternative product can be used |
| Name | Company | Catalog Number | Comments |
| Infarct size / area-at-risk quantification | |||
| Diathermy | – | Alternative product can be used | |
| Lebsch knife | – | Alternative product can be used | |
| Hammer | – | Alternative product can be used | |
| Bone marrow wax | Syneture | Alternative product can be used | |
| Klinkenberg scissors | – | Alternative product can be used | |
| Retractor | – | Alternative product can be used | |
| Surgical scissors | – | ||
| 7F Percutaneous Sheath Introducer Set | Arrow | CP-08703 | Alternative product can be used |
| 8F Percutaneous Sheath Introducer Set | Arrow | CP-08803 | Alternative product can be used |
| 7F JL4 guiding catheter | Boston Scientific | H749 34357-662 | Alternative product can be used |
| 8F JL4 guiding catheter | Boston Scientific | H749 34358-662 | Alternative product can be used |
| COPILOT Bleedback Control Valves | Abbott Vascular | 1003331 | Alternative product can be used |
| BD Connecta™ | Franklin Lakes | 394995 | Alternative product can be used |
| Contrast agent | Telebrix | ||
| Persuader 9 Steerable Guidewire 9 (0.014", 180 cm, straight tip), hydrophilic coating | Medtronic Inc. | 9PSDR180HS | Alternative product can be used |
| SAPPHIRE™ Coronary Dilatation Catheter (PTCA balloon suitable for the size of the particular coronary artery (2.75 – 3.25 mm)) | OrbusNeich | 103-3015 | Alternative product can be used |
| Evans Blue | Sigma-Aldrich | E2129-100G | Toxic. Alternative product can be used |
| 2,3,5-triphenyl-tetrazolium chloride (TTC) | Sigma-Aldrich | T8877-100G | Irritant. Alternative product can be used |
| 9V battery | – | – | |
| Ruler | – | – | |
| Photocamera | Sony | – | |
| ImageJ | National Institutes of Health | – | Alternative product can be used |
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