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BASIC SCIENCE

Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction

new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant–coronary ligation rat model

Hiroshi Nakamura, MD, PhD^*,*, Seiji Umemoto, MD, PhD^*, George Naik, BSc, Gordon Moe, MD, FACC, Satoko Takata, MD^*, Peter Liu, MD, FACC and Masunori Matsuzaki, MD, PhD, FACC^*

^* Department of Cardiovascular Medicine, Yamaguchi University School of Medicine, Ube, Japan
St. Michael’s Hospital, Toronto, Canada
Centre for Cardiovascular Research, The Toronto Hospital, and University of Toronto, Toronto, Canada

Manuscript received October 29, 2002; revised manuscript received March 22, 2003, accepted March 27, 2003.

^* Reprint requests and correspondence: Dr. Hiroshi Nakamura, Department of Cardiovascular Medicine, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505 Japan.
nahirosi{at}yamaguchi-u.ac.jp

OBJECTIVES: The present study investigated the effects of tumor necrosis factor (TNF)-alpha and angiotensin II (ANG II) on cardiac remodeling and dysfunction at the early stage of acute myocardial infarction (MI) by using a novel heterotopic cardiac transplantation–coronary ligation model.

BACKGROUND: A recent clinical study has demonstrated a possible role of monocytosis in the development of left ventricular (LV) remodeling in patients with acute MI reperfusion.

METHODS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce MI in the donor heart and to evaluate the hearts of both donors and recipients in Lewis rats.

RESULTS: A significant decrease in LV fractional shortening and positive rate of rise in LV pressure and a significant increase in LV end-diastolic dimension/body weight and LV end-diastolic pressure were observed in the recipient hearts in the ligation group on day 7. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group. In contrast, ANG II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Furthermore, the recipients’ transient LV remodeling and dysfunction were completely abolished by the intravenous administration of a TNF-alpha antagonist.

CONCLUSIONS: We developed a novel cardiac transplantation–coronary ligation model capable of inducing MI in the absence of downstream hemodynamic effects and allowing differential quantification of indexes of cardiac remodeling in vivo, including the local and remote effects of ANG II and TNF-alpha on cardiac remodeling.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   ANG II   angiotensin II   dP/dt   rate of rise in left ventricular pressure   FS   fractional shortening   HF   heart failure   HR   heart rate   LV   left ventricular   LVEDD   left ventricular end-diastolic dimension   LVEDP   left ventricular end-diastolic pressure   LVESD   left ventricular end-systolic dimension   MCP   monocyte chemoattractant protein   MI   myocardial infarction   TNF   tumor necrosis factor   TNFR:Fc   tumor necrosis factor-alpha receptor antagonist   WBC   white blood cell

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