A ligação permanente da artéria coronária descendente anterior esquerda em Ratos: Um Modelo de Remodelação pós-infarto do miocárdio e insuficiência cardíaca
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
A insuficiência cardíaca é uma síndrome em que o coração não consegue bombear o sangue a uma taxa proporcional aos requisitos celulares de oxigênio em repouso ou durante o estresse. É caracterizada pela retenção de líquidos, falta de ar e fadiga, em particular no esforço. A insuficiência cardíaca é um problema crescente de saúde pública, a principal causa de hospitalização, e uma das principais causas de mortalidade. Doença isquêmica do coração é a principal causa de insuficiência cardíaca.
A remodelação ventricular refere-se a alterações na estrutura, tamanho e forma do ventrículo esquerdo. Esta remodelação arquitetônica do ventrículo esquerdo é induzida por lesão (por exemplo, infarto do miocárdio), por sobrecarga de pressão (por exemplo, hipertensão arterial sistêmica ou estenose aórtica), ou por sobrecarga de volume. Uma vez que a remodelação ventricular afecta o stress da parede, que tem um profundo impacto sobre a função cardíaca e no desenvolvimento de insuficiência cardíaca. Um modelo de ligadura permanente da descendin anterior esquerdag artéria coronária em ratos é usado para investigar o remodelamento ventricular e função cardíaca pós-infarto do miocárdio. Este modelo é fundamentalmente diferente, em termos de objetivos e relevância fisiopatológica em comparação com o modelo de ligadura transiente da artéria descendente anterior coronária. Neste último modelo de lesão de isquemia / reperfusão, o grau inicial do enfarte pode ser modulado por factores que afectam o salvamento do miocárdio após a reperfusão. Em contraste, a área de enfarte em 24 horas após a ligação permanente da artéria coronária descendente anterior da artéria coronária é fixo. A função cardíaca neste modelo será afetado por 1) o processo de expansão do infarto, a cura do infarto, e formação de cicatriz; e 2) o desenvolvimento concomitante de dilatação do ventrículo esquerdo, hipertrofia cardíaca, e remodelamento ventricular.
Além do modelo de ligadura permanente da artéria coronária descendente anterior da artéria coronária, a técnica de mea hemodinâmica invasivame- em ratinhos é apresentado em pormenor.
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
Alterações crônicas na estrutura e função do miocárdio, o desenvolvimento de disfunção ventricular esquerda, e progressão para insuficiência cardíaca pode ser investigado em vários modelos de murino 12. A remodelação cardíaca e disfunção pode ser induzida pela lesão do miocárdio ou por pressão sobrecarregar secundário para transversal constrição da aorta, ou podem ser investigados em modelos genéticos de cardiomiopatia dilatada 12. Obviamente, o benefício mais pronunciado d…
Disclosures
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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