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.
L'insuffisance cardiaque est un syndrome dans lequel le cœur ne parvient pas à pomper le sang à un taux correspondant aux exigences d'oxygène cellulaires au repos ou lors d'un stress. Elle est caractérisée par la rétention d'eau, de l'essoufflement et de la fatigue, en particulier à l'effort. L'insuffisance cardiaque est un problème croissant de santé publique, la principale cause d'hospitalisation, et une cause majeure de mortalité. La cardiopathie ischémique est la principale cause de l'insuffisance cardiaque.
Remodelage ventriculaire se réfère à des changements dans la structure, la taille et la forme du ventricule gauche. Ce remodelage architectural du ventricule gauche est induit par une blessure (par exemple, infarctus du myocarde), par une surcharge de pression (par exemple, hypertension artérielle systémique ou une sténose aortique), ou par une surcharge de volume. Depuis le remodelage ventriculaire affecte stress de la paroi, il a un impact profond sur la fonction cardiaque et sur le développement de l'insuffisance cardiaque. Un modèle de ligature permanente de la descendin antérieure gaucheg artère coronaire chez la souris est utilisée pour étudier le remodelage ventriculaire et la fonction cardiaque post-infarctus du myocarde. Ce modèle est fondamentalement différente en termes d'objectifs et la pertinence physiopathologique par rapport au modèle de ligature transitoire de l'artère interventriculaire antérieure coronaire. Dans ce dernier modèle de lésion d'ischémie / reperfusion, l'étendue de l'infarctus initial peut être modulée par des facteurs qui affectent le sauvetage myocardique suivant reperfusion. En revanche, la zone de l'infarctus à 24 h après la ligature permanente de l'artère interventriculaire antérieure coronaire est fixe. La fonction cardiaque dans ce modèle sera affectée par 1) le processus d'expansion de l'infarctus, infarctus guérison, et la formation de cicatrices; et 2) le développement concomitant de la dilatation ventriculaire gauche, hypertrophie cardiaque et le remodelage ventriculaire.
Outre le modèle de ligature permanente de la descendante antérieure gauche artère coronaire, la technique de mea hémodynamique invasiveme- chez la souris est présenté en détail.
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.
Changements chroniques dans la structure et la fonction du myocarde, le développement d'une dysfonction ventriculaire gauche, et la progression de l'insuffisance cardiaque peuvent être étudiés dans plusieurs modèles murins 12. Le remodelage cardiaque et un dysfonctionnement peut être induite par une lésion myocardique ou par la pression secondaire à une surcharge constriction aortique transverse, ou peuvent être étudiés dans des modèles génétiques de 12 cardiomyopathie dilaté…
The authors have nothing to disclose.
This work was supported by Onderzoekstoelagen grant OT/13/090 of the KU Leuven and by grant G0A3114N of the FWO-Vlaanderen.
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. |