左冠状动脉前降支的小鼠结扎：对心肌梗死后重塑和心衰模型
Summary
Heart failure is the leading cause of hospitalization and a major cause of mortality. A model of permanent ligation of the left anterior descending coronary artery in mice is applied to investigate ventricular remodelling and cardiac dysfunction post-myocardial infarction. The technique of invasive hemodynamic measurements in mice is presented.
Abstract
心脏衰竭是其中心脏不能泵送血液的速率与在休息或应激期间蜂窝氧气要求相称的综合症。它的特征是液体潴留，气短，和疲劳，特别是在消耗。心脏衰竭是一个日益严重的公共健康问题，住院的主要原因，和死亡的一个主要原因。缺血性心脏疾病是心脏衰竭的主要原因。
心室重塑是指改变结构左心室，大小和形状。这种建筑的左心室重塑被损伤（ 例如，心肌梗塞）引起的，通过压力负荷（ 例如，全身性动脉高血压或主动脉瓣狭窄），或按体积超负荷。由于心室重构影响墙体的压力，但对心功能和心脏衰竭的发展产生深远的影响。左前descendin永久性结扎模型克冠状动脉小鼠被用来研究心室重构和心脏功能后心肌梗死。该模型是在目标和病理生理学的相关方面相比左前降冠状动脉的瞬态结扎模型根本的不同。在后一种缺血/再灌注损伤模型，梗死的初始程度可以通过影响心肌打捞再灌注因素进行调制。与此相反，在梗塞面积在左前降冠状动脉的永久结扎后24小时，是固定的。在此模型中的心功能会受1）梗塞扩展，梗塞愈合，和瘢痕形成的方法; 2）左心室扩张，心肌肥厚，心室重构伴随发展。
除了左前永久性结扎的下行冠状动脉，浸润性血液动力学MEA的技术中的模型小鼠surements中详细介绍。
Introduction
Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with the cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure1.
Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. In other words, ventricular remodelling concerns an alteration of the left ventricular architecture. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload (e.g., mitral insufficiency). Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure.
Loss of myocardial tissue following acute myocardial infarction results in a decreased systolic ejection and an increased left ventricular end-diastolic volume and pressure. The Frank-Starling mechanism, implying that an increased end-diastolic volume results in an increased pressure developed during systole, may help to restore cardiac output. However, the concomitant increased wall stress may induce regional hypertrophy in the non-infarcted segment, whereas in the infarcted area expansion and thinning may occur. Experimental animal studies show that the infarcted ventricle hypertrophies and that the degree of hypertrophy is dependent on the infarct size2.
The loss of myocardial tissue following acute myocardial infarction results in a sudden increase in loading conditions. Post-infarct remodelling occurs in the setting of volume overload, since the stretched and dilated infarcted tissue increases the left ventricular volume. An increased ventricular volume not only implies increased preload (passive ventricular wall stress at the end of diastole) but also increased afterload (total myocardial wall stress during systolic ejection). Afterload is increased since the systolic radius is increased. Therefore, ventricular remodelling post-myocardial infarction is characterized by mixed features of volume overload and pressure overload.
The myocardium consists of 3 integrated components: cardiomyocytes, extracellular matrix, and the capillary microcirculation. All 3 components are involved in the remodelling process. Matrix metalloproteinases produced by inflammatory cells induce degradation of intermyocyte collagen struts and cardiomyocyte slippage. This leads to infarct expansion characterized by the disproportionate thinning and dilatation of the infarct segment3. In later stages of remodelling, interstitial fibrosis is induced, which negatively affects the diastolic properties of the heart.
The vascular and cardiomyocyte compartment in the myocardium should remain balanced in the process of ventricular remodelling to avoid tissue hypoxia4,5. Whether hypertrophy progresses to heart failure or not may be critically dependent on this balance between the vascular and cardiomyocyte compartment in the myocardium.
A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion6. In contrast, the infarct area at 24 hours after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling.
Protocol
Representative Results
Discussion
在心肌的结构和功能的慢性变化，左心功能不全的发展，并进展到心脏衰竭可以几种鼠模型12进行调查。心脏重塑和功能障碍可以通过心肌损伤可诱发或压力过载继发于横向主动脉缩窄，或可在扩张型心肌病12的遗传模型进行研究。显然，小鼠模型的最显着优点是转基因和基因敲除菌株，包括细胞类型特异性和可诱导的转基因模型中的大量的可用性。评价在这些模型心脏重构的已?…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
This work was supported by Onderzoekstoelagen grant OT/13/090 of the KU Leuven and by grant G0A3114N of the FWO-Vlaanderen.
Materials
| Reagents | |||
| Buprenorphine (Buprenex®) | Bedford Laboratories | ||
| Sodium Pentobarbital (Nembutal®) | Ceva | ||
| Betadine® | VWR internationals | 200065-400 | |
| 5 – 0 silk suture | Ethicon, Johnson & Johnson Medical | K890H | |
| 6 – 0 prolene suture | Ethicon, Johnson & Johnson Medical | F1832 | |
| 6 – 0 Ti- Cron suture | Ethicon, Johnson & Johnson Medical | F1823 | |
| Urethane | Sigma | 94300 | |
| Alconox | Alconox Inc. | ||
| Equipment | |||
| Ventilator, MiniVent Model 845 | Hugo Sachs | 73-0043 | |
| Chest retractor or Thorax retractor | Kent Scientific corporation | INS600240 | ALM Self-retaining, serrated, 7cm long, 4 x 4 "L" shaped prongs, 3mm x 3mm |
| 1.0 French Millar pressure catheter | Millar Instruments | SPR – 1000/NR | |
| Powerlab | ADInstruments Pty Ltd. | ||
| LabChart® software | ADInstruments Pty Ltd. | ||
| Rectal probe | ADInstruments Pty Ltd. |
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