A Murine Model of Ischemic Cardiomyopathy Induced by Repetitive Ischemia and Reperfusion[*]

Abstract

Background: Repetitive brief myocardial ischemia has been implicated in the pathogenesis of the ventricular dysfunction associated with ischemic cardiomyopathy and myocardial hibernation. In this study we examine the effects of repetitive ischemia and reperfusion (I/R) on murine myocardium. Methods: C57/BL6 mice underwent daily 15 min left anterior descending coronary occlusions followed by reperfusion. After 3, 5, 7, 14, 21 and 28 days, echocardiographic studies were performed, and hearts of I/R and sham-operated animals were processed for histological examination. Results: Histological studies showed no evidence of myocardial necrosis in the ischemic region. Quantitative assessment of collagen revealed a marked persistent interstitial deposition of collagen after seven days I/R in the anterior left ventricular wall (sham 4.6 ± 2.0 %, I/R 21.5 ± 6.5 %, p < 0.05). Echocardiographic studies showed persistent regional anterior wall dysfunction in I/R animals. Histological evaluation showed absence of neovessel formation. After discontinuation of the I/R protocol, fibrosis and regional ventricular dysfunction decreased within 60 days. Conclusions: Repetitive brief murine myocardial I/R induces reversible fibrotic remodeling and ventricular dysfunction, without myocardial infarction and necrosis, and may play a role in the pathogenesis of ischemic cardiomyopathy and myocardial hibernation.

Key words

Ischemia - reperfusion - myocardium - hibernation

1 Ernst Derra Award at the 4th Joint Meeting of German, Austrian, and Swiss Society for Thoracic and Cardiovascular Surgery, Hamburg, February 15 - 18, 2004

References

• 1 Rahimtoola S H. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina.  Circulation. 1985;  72 123-135
• 2 Kloner R A, Bolli R, Marban E, Reinlib L, Braunwald E. Medical and cellular implications of stunning, hibernation, and preconditioning: an NHLBI workshop.  Circulation. 1998;  97 1848-1867
• 3 Vanoverschelde J L, Wijns W, Borgers M. et al . Chronic myocardial hibernation in humans. From bedside to bench.  Circulation. 1997;  95 1961-1971
• 4 Elsasser A, Schlepper M, Klovekorn W P. et al . Hibernating myocardium: an incomplete adaptation to ischemia.  Circulation. 1997;  96 2920-2931
• 5 Frangogiannis N G, Shimoni S, Chang Su Min. et al . Evidence for an active inflammatory process in the hibernating human myocardium.  Am J Pathol. 2002;  160 1425-1433
• 6 Weihrauch D, Tessmer J, Warltier D C, Chilian W M. Repetitive coronary artery occlusions induce release of growth factors into the myocardial interstitium.  Am J Physiol. 1998;  275 969-976
• 7 Dewald O, Frangogiannis N G, Zoerlein M. et al . Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species.  Proc Natl Acad Sci USA. 2003;  100 2700-2705
• 8 Nossuli T O, Lakshminarayanan V, Baumgarten G. et al . A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies.  Am J Physiol Heart Circ Physiol. 2000;  278 1049-1055
• 9 Frangogiannis N G, Perrard J L, Mendoza L H. et al . Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion.  Circulation. 1998;  98 687-698
• 10 Heusch G. Hibernating myocardium.  Physiol Rev. 1998;  78 1055-1085
• 11 Nagueh S F, Mikati I, Weilbaecher D. et al . Relation of the contractile reserve of hibernating myocardium to myocardial structure in humans.  Circulation. 1999;  100 490-496
• 12 Elsasser A, Schlepper M, Zimmermann R. et al . The extracellular matrix in hibernating myocardium - a significant factor causing structural defects and cardiac dysfunction.  Mol Cell Biochem. 1998;  186 147-158
• 13 Ausma J, Cleutjens J, Thone F, Flameng W, Ramaekers F, Borgers M. Chronic hibernating myocardium: interstitial changes.  Mol Cell Biochem. 1995;  147 35-42

1 Ernst Derra Award at the 4th Joint Meeting of German, Austrian, and Swiss Society for Thoracic and Cardiovascular Surgery, Hamburg, February 15 - 18, 2004