急性心筋梗塞の豚モデルにおける主要アウトカム評価
Summary
信頼できる正確なアウトカム評価は、臨床治療への臨床前治療の翻訳のための鍵です。現在の用紙は、ブタ急性心筋梗塞モデルにおける心機能および損傷の3つの臨床的に関連する主要な結果パラメータを評価する方法を説明します。
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
西部の世界1の人々の2％ -の減少駆出率（HFrEF）と心不全は、推定1に影響を与え、すべての心不全症例の約50％を占めます。その最も一般的な原因は、急性心筋梗塞（AMI）です。 AMI後の急性死亡率が増加による認識と改善された治療選択肢に大幅に減少しているように、重点はその慢性後遺症の方にシフトしています。最も顕著なのはHFrEF 2,3です。一緒に医療費4の増加に伴って、心不全の成長流行は、以前5に記載されているように 、AMI後の有害なリモデリングの高度に並進ブタモデルで試験することができる新規な診断および治療の必要性を強調しています。
どちらも、決定（ 例えば、梗塞サイズ）と有害なリモデリングの機能評価（ 例えば 、心エコー検査）は、多くの場合、RELの必要性を示す、新たな治療法の有効性試験のために使用されていますiableと比較的安価な方法。現在の論文の目的は、急性心筋梗塞のブタモデルにおける有効性試験のための重要かつ信頼性の高いアウトカム指標を導入することにより、このニーズに対処することです。これらは、リスク（AAR）の領域に関連した梗塞サイズ（IS）、3D経食道心エコー検査（3D-TEE）と詳細なアドミッタンスベースの圧力 – 容積（PV）ループ取得を含みます。
梗塞サイズは、AMI 6の後に不利なリモデリングおよび生存の主要な決定因子です。虚血性心筋のタイムリーな再灌流が可逆的に負傷した心筋細胞を回収し、梗塞サイズが制限される場合がありますが、再灌流自体は、酸化ストレスと不均衡な炎症反応（虚血再灌流障害（IRI））7の世代を通じて追加の損傷を引き起こします。したがって、IRIは、有望な治療標的として同定されています。梗塞サイズを減少させる新規治療薬の能力は関連して梗塞サイズを評価することによって定量化されますリスク領域（AAR）へ。より大きなAARが大きく、絶対梗塞サイズにつながるとしてAARの定量化は、動物モデルの冠状動脈の解剖学における個体間変動を補正することが必須です。梗塞サイズは、心臓の性能や心筋の収縮に直接関係しているので、AARの変動にかかわらず治療法8の研究のアウトカム指標に影響を与えることができます。
三次元経食道心エコー検査（3D-TEE）は、心機能を非侵襲的に測定するための臨床応用可能な、最も重要なのは、安全で信頼性が高く、安価な方法です。経胸壁心エコー図（TTE）画像は、ブタ9 2D胸骨傍の長短軸のビューに制限され、一方、3D-TEEは、左心室の完全な3次元画像を得るために使用することができます。したがって、そのような変更されたシンプソンのルール10と左心室（LV）ボリュームの数学的な近似を必要としません。後者は、CORRを下回りますectlyによる円筒形状11の不足のためにLVリモデリング後のLV容積を推定します。それが本モデル12における心臓保護効果を発揮することが観察されている外科的介入を必要としないようにまた、3D-TEEは、心外膜の心エコー検査上好ましいです。心筋機能の評価のための2D-TEEの使用が13,14の前に記載されているが、心室の幾何学的形状に関する制限は、2D-TTEで観察されたものと類似しており、LVリモデリングの程度に依存します。したがって、より大きな梗塞（したがって、心不全の可能性が高い）、より多くの可能性が高い2次元測定が不正確な幾何学的な仮定による不良になっおよび3D技術に対する高い必要性。
それにもかかわらず、ほとんどのイメージングモダリティは、心筋の固有の機能的特性を評価する能力が制限されています。 PVループは、関連する追加情報を提供し、その取得はことです以下に詳細に説明。
Protocol
Representative Results
Discussion
心臓リモデリングは、主に心筋梗塞サイズおよび心筋梗塞修復6,26の品質に依存します。標準化された方法で、前者を評価するために、本原稿が検証され、広範囲に8,16,27,28を使用されてきたex vivoでの TTC染色と組み合わせたエバンスブルーのin vivo注入のエレガントな方法を提供します。この方法は、AAR 16に関連するリスク（AAR）の領域の定量および梗塞?…
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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