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.
Hjertesvikt er et syndrom der hjertet ikke klarer å pumpe blod med en hastighet i samsvar med mobilnettet oksygenbehov ved hvile eller under stress. Det er preget av væskeretensjon, kortpustethet, og tretthet, særlig ved anstrengelse. Hjertesvikt er et økende folkehelseproblem, den ledende årsak til sykehusinnleggelse, og en viktig årsak til dødelighet. Iskemisk hjertesykdom er den viktigste årsaken til hjertesvikt.
Ventrikulær ombygging refererer til endringer i strukturen, størrelsen og formen av den venstre ventrikkel. Dette arkitektoniske ombygging av venstre ventrikkel indusert av skade (for eksempel hjerteinfarkt), ved hjelp av trykk overbelastning (for eksempel, systemisk arteriell hypertensjon eller aortastenose), eller ved væskeoverskudd. Siden ventrikkel ombygging påvirker vegg stress, har det en betydelig innflytelse på hjertefunksjon og på utvikling av hjertesvikt. En modell med permanent ligering av den venstre fremre descending koronar i mus brukes til å undersøke ventrikkel ombygging og hjertefunksjon etter hjerteinfarkt. Denne modellen er fundamentalt annerledes i form av mål og patofysiologisk relevans i forhold til modellen av forbigående ligation av venstre fremre nedstigende coronary artery. I denne sistnevnte modell av iskemi / reperfusjonsskade, kan den initiale grad av infarkt bli modulert ved faktorene som påvirker myokardial berging etter reperfusjon. I motsetning til dette er det infarktområdet på 24 timer etter permanent ligering av den venstre fremre nedadstigende koronararterie fast. Hjertefunksjon i denne modellen vil bli påvirket av 1) prosessen med infarkt ekspansjon, infarktet healing, og arrdannelse; og 2) samtidig utvikling av venstre ventrikkel dilatasjon, hjertehypertrofi, og ventrikkel ombygging.
Foruten den modell med permanent ligering av den venstre fremre nedadstigende koronararterie, teknikken for invasiv hemodynamisk measurements i mus er presentert i detalj.
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.
Kroniske endringer i myocardial struktur og funksjon, kan utviklingen av venstre ventrikkel dysfunksjon, og progresjon til hjertesvikt bli undersøkt i flere murine modeller 12. Cardiac ombygging og dysfunksjon kan være forårsaket av skade på hjertet eller ved trykk overbelastning sekundært til tverrgående aorta innsnevring, eller kan bli undersøkt i genetiske modeller av dilatert kardiomyopati 12. Selvsagt, den mest uttalt fordel for murine modeller er tilgjengeligheten av et stort antall tr…
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. |