La ligadura permanente de la arteria coronaria descendente anterior en ratones: un modelo de remodelación post infarto de miocardio e insuficiencia cardiaca
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
La insuficiencia cardíaca es un síndrome en el que el corazón deja de bombear sangre a un ritmo acorde con las necesidades de oxígeno celular en reposo o durante el estrés. Se caracteriza por la retención de líquidos, falta de aliento, y la fatiga, en particular en el esfuerzo. La insuficiencia cardiaca es un problema creciente de salud pública, la principal causa de hospitalización, y una causa importante de mortalidad. La cardiopatía isquémica es la principal causa de insuficiencia cardíaca.
Remodelación ventricular se refiere a cambios en la estructura, el tamaño, y la forma del ventrículo izquierdo. Esta remodelación arquitectónica del ventrículo izquierdo es inducida por lesión (por ejemplo, infarto de miocardio), por sobrecarga de presión (por ejemplo, hipertensión arterial sistémica o estenosis aórtica), o por sobrecarga de volumen. Desde la remodelación ventricular afecta el estrés de pared, tiene un profundo impacto en la función cardiaca y en el desarrollo de insuficiencia cardíaca. Un modelo de ligadura permanente de la descendin anterior izquierdag arteria coronaria en ratones se utiliza para investigar el remodelado ventricular y la función cardiaca después de un infarto de miocardio. Este modelo es fundamentalmente diferente en términos de objetivos y relevancia fisiopatológica en comparación con el modelo de la ligadura transitoria de la arteria descendente anterior coronaria. En este último modelo de lesión por isquemia / reperfusión, la medida inicial del infarto puede ser modulada por factores que afectan recuperación miocárdica después de la reperfusión. En contraste, la zona del infarto a las 24 horas después de la ligadura permanente de la arteria descendente anterior coronaria es fijo. La función cardiaca en este modelo se verá afectado por 1) el proceso de expansión del infarto, la curación del infarto, y la formación de cicatrices; y 2) el desarrollo concomitante de la dilatación ventricular izquierda, hipertrofia cardiaca, y remodelación ventricular.
Además del modelo de ligadura permanente de la arteria descendente anterior coronaria, la técnica de mea hemodinámica invasivamedicio- en ratones se presenta en detalle.
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
Cambios crónicos en la estructura y la función miocárdica, el desarrollo de la disfunción ventricular izquierda, y la progresión a la insuficiencia cardíaca pueden ser investigados en varios modelos murinos 12. La remodelación cardiaca y la disfunción puede ser inducida por lesión miocárdica o por sobrecarga de presión secundaria a la constricción de la aorta transversal, o pueden ser investigados en modelos genéticos de la miocardiopatía dilatada 12. Obviamente, el beneficio más pro…
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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