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bioRxiv · 10.1101/773218

SCAR FORMATION AND DECREASED CARDIAC FUNCTION FOLLOWING ISCHEMIA/REPERFUSION INJURY IN 1-MONTH-OLD SWINE

Agnew, E. J.·Velayutham, N.·Matos Ortiz, G.·Alfieri, C. M.·Moore, V.·Riggs, K. W.·Baker, R. S.·Gibson, A. M.·Ponny, S. R.·Alsaied, T.·Zafar, F.·Yutzey, K. E.
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Abstract

Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation. Less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs, to assess regenerative repair in young large mammals. Female and male P30 pigs were subjected to cardiac ischemia (1 hour) by occlusion of the left anterior descending artery followed by reperfusion, or to sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 hours post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated cardiomyocyte (CM) cell cycling at 2-months-of-age in multinucleated CMs in both sham-operated and IR pigs. Regional scar formation and inflammation in the epicardial region proximal to injury were observed 4 weeks post-IR. Sex differences were found, suggestive of females creating a greater fibrotic response with worse cardiac function, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in P30 swine, at a time when CMs are still cycling. Pigs subjected to IR show myocardial damage with a prolonged decrease in cardiac function, formation of a small, regional scar with increased inflammation. These data demonstrate that P30 pigs do not regenerate myocardium, even in the presence of CM mitotic activity, but form a scar after transient IR injury.\n\nNEW & NOTEWORTHYHere, we report for the first time ischemia/reperfusion (IR) cardiac injury in 1-month-old (P30) pigs. This model of IR injury highlights lack of cardiac regeneration, even in the presence of cardiomyocyte (CM) cell cycling in young swine. An effective injury approach is described for use in large mammals to investigate cardiac function, CM cell cycling, extracellular matrix (ECM) remodeling, and gene expression changes, while highlighting the importance of studying both sexes.

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Agnew, E. J., Velayutham, N., Matos Ortiz, G., Alfieri, C. M., Moore, V., Riggs, K. W., Baker, R. S., Gibson, A. M., Ponny, S. R., Alsaied, T., Zafar, F., Yutzey, K. E.. 2019-09-18. SCAR FORMATION AND DECREASED CARDIAC FUNCTION FOLLOWING ISCHEMIA/REPERFUSION INJURY IN 1-MONTH-OLD SWINE. https://doi.org/10.1101/773218

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