Published Online
on February 27, 2006

A more recent version of this article appeared on March 7, 2006

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Submitted on May 27, 2005
Revised on December 16, 2005
Accepted on December 23, 2005

Factor XIII Deficiency Causes Cardiac Rupture, Impairs Wound Healing, and Aggravates Cardiac Remodeling in Mice With Myocardial Infarction

Matthias Nahrendorf MD, Kai Hu MD, Stefan Frantz MD, Farouc A. Jaffer MD, PhD, Ching-Hsuan Tung PhD, Karl-Heinz Hiller PhD, Sabine Voll; , Peter Nordbeck MD, David Sosnovik MD, Stefan Gattenlöhner MD, Mikhail Novikov MD, Gerhard Dickneite PhD, Guy L. Reed MD, Peter Jakob PhD, Anthony Rosenzweig MD, Wolfgang R. Bauer MD, PhD, Ralph Weissleder MD, PhD, and Georg Ertl MD^*

From the Medizinische Klinik und Poliklinik I, Universität Würzburg, Würzburg, Germany (M. Nahrendorf, K.H., S.F., P.N., S.G., W.R.B., G.E.); Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (M.N., F.A.J., C.T., D.S., R.W.); Physikalisches Institut (EP5), Universität Würzburg, Würzburg, Germany (K.H., S.V., P.J.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (M. Novikov, A.R.); ZLB Behring, Marburg, Germany (G.D.); and Cardiology Division, Department of Medicine, Medical College of Georgia, Augusta (G.L.R.).

^* To whom correspondence should be addressed. E-mail: Ertl_G{at}medizin.uni-wuerzburg.de.

Background--Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data.

Methods and Results--To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII^-/- and FXIII^-/+ (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII^-/- mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII^-/- mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII^-/- mice receiving supplemental FXIII than in FXIII^-/- mice (P<0.05). In FXIII^-/- but not in reconstituted FXIII^-/- mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII^-/- mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII^-/- mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII^-/- mice.

Conclusions--These data suggest that FXIII has an important role in murine myocardial healing after infarction.

Key words: factor XIII • healing • heart failure • myocardial infarction • remodeling

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