En model af Cardiac Remodeling Gennem Sammensnøring af den abdominale aorta i rotter
Summary
A rat model of abdominal aortic constriction that induces cardiac hypertrophy and remodeling is described. An efficient, highly-reproducible, and minimally-invasive method is used to provide a simple yet useful platform for research in myocardial hypertrophy and dysfunction.
Abstract
Heart failure is one of the leading causes of death worldwide. It is a complex clinical syndromethat includes fatigue, dyspnea, exercise intolerance, and fluid retention. Changes in myocardial structure, electrical conduction, and energy metabolism develop with heart failure, leading to contractile dysfunction, increased risk of arrhythmias, and sudden death. Hypertensive heart disease is one of the key contributing factors of cardiac remodeling associated with heart failure. The most commonly-used animal model mimicking hypertensive heart disease is created via surgical interventions, such as by narrowing the aorta. Abdominal aortic constriction is a useful experimental technique to induce a pressure overload, which leads to heart failure. The surgery can be easily performed, without the need for chest opening or mechanical ventilation. Abdominal aortic constriction-induced cardiac pathology progresses gradually, making this model relevant to clinical hypertensive heart failure. Cardiac injury and remodeling can be observed 10 weeks after the surgery. The method described here provides a simple and effective approach to produce a hypertensive heart disease animal model that is suitable for studying disease mechanisms and for testing novel therapeutics.
Introduction
Hjertesvigt er et komplekst klinisk syndrom, hvor symptomerne omfatter træthed, dyspnø, motion intolerance, og væskeretention i perifere væv. Det er den hyppigste dødsårsag i de udviklede lande 1. Bortset fra nedarvet kardiomyopati forårsaget af mutationer i sarkomeret proteiner eller ionkanaler 2, kan myokardiedysfunktion være forårsaget af en række medicinske tilstande, herunder hypertension, valvulær hjertesygdomme, fedme og diabetes 3. Ændringer i myokardie struktur, elektrisk ledning, og energi stofskifte fører til utilstrækkelig hjertefunktion pumpekapacitet for at imødekomme kredsløbssygdomme krav, hvilket i sidste ende resulterer i hjertesvigt 3,4. Undersøge mekanismerne bag hjertesvigt, derfor er kritisk inden for kardiovaskulær forskning. Identifikation molekylære mekanismer, der fører til hjertesvigt progression kan i sidste ende hjælpe med opdagelsen af nye terapeutiske mål eller nyttige biomarkører <sup> 1. Det er derfor vigtigt at udvikle hjertesvigt dyremodeller, der deler vigtige kliniske funktioner med hjerteinsufficiens hos mennesker 5.
Hjertehypertrofi og remodellering spiller en kritisk rolle i udviklingen af hjertesvigt. Hypertensive hjertesygdomme er den vigtigste medvirkende faktor af hjertehypertrofi og utilpasset remodeling ses i humane patienter 1. For at efterligne disse menneskelige betingelser, er dyremodeller ofte etableret gennem kirurgiske procedurer. Navnlig kan den tværgående eller abdominale aorta indsnævres til at øge modstanden mod den venstre ventrikel, hvilket i sidste ende fører til en trykoverbelastning i hjertet. Dette fænomen resulterer sædvanligvis i hjertehypertrofi, til en fysiologisk erstatning af cardiomyocytter opfylde den funktionelle efterspørgsel af det kardiovaskulære system. tilsidesætter dog den funktionelle efterspørgsel de normale fysiologiske kompenserende mekanismer, der fører til hjerte-fibrose og entrepflise værdiforringelse. Tværgående pulsåresammensnøring (TAC) kirurgi indebærer ofte komplicerede procedurer, herunder torakotomi, mekanisk ventilation, og adskillelse af thymus og fedtvæv fra aortabuen. I modsætning hertil abdominale aorta indsnævring kræver enklere eksperimentelle teknikker 6-8. Den abdominale aorta, mellem venstre og højre renale arterier, er indsnævret under operationen. Hjertehypertrofi og remodellering kan iagttages adskillige uger efter den abdominale aorta indsnævring kirurgi 6-8; de producerer robust hypertensiv hjertesygdom svarende til den, der genereres af den tværgående pulsåresammensnøring kirurgi 9,10. Her beskriver vi en protokol til at udføre abdominal aorta indsnævring i rotter under anvendelse af en effektiv, højt reproducerbar, og minimalt invasiv metode. Den abdominale aorta støder op til de renale arterier er indsnævret af en 0,72 mm løkke dannet af en 4-0 silketråd. Ti uger efter operationen, hjertehypertrofi og remodeling kan observeres. Rottemodellen af abdominal aorta konstriktion-induceret hjertehypertrofi tilvejebringer en platform for at studere sygdomsmekanismer og patofysiologi samt udviklingen af potentielle lægemidler.
Protocol
Representative Results
Discussion
Hypertensive heart disease, a major health problem that contributes greatly to morbidity and mortality, can lead to cardiac hypertrophy and heart failure5. The pathogenesis and progression of hypertensive heart disease in humans is complex, so an appropriate animal model is critical to investigate the underlying mechanisms and to test novel therapeutics that aim to improve cardiac structure and function5. The abdominal aortic constriction model, which simulates chronic heart disease, is an effective…
Disclosures
The authors have nothing to disclose.
Acknowledgements
The authors’ work was supported by a grant from Ministry of Science and Technology (MOST 103-2320-B-002-068-MY2), the National Health Research Institute (NHRI-EX104-10418SC), and National Taiwan University (NTU 104R4000).
Materials
| 22-Gauge syringe needle | BD Biosciences | 309572 | |
| EDTA Blood Collection Tubes | BD Biosciences | REF365974 | |
| 4-0 silk suture | Sharpoint™ Products | DC-2515N | |
| 6-0 silk suture | Sharpoint™ Products | DC-2150N | |
| Pentobarbital | Sigma Aldrich | 1507002 | |
| Paraformaldehyde | Sigma Aldrich | 441244 | |
| Acetaminophen | Sigma Aldrich | A7085 | |
| Picrosirius red solution | Abcam | ab150681 | |
| Cardiac troponin kit | Abcam | ab200016 | |
| Imagequant | Molecular Dynamics | ||
| Langendorff | ADInstruments | ML870B2 |
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