Induction of left ventricular remodeling and dysfunction in the recipient heart following donor heart myocardial infarction: new insights into the pathological role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation model

BACKGROUND: Neurohormonal and cytokine activation after acute myocardial infarction contribute to cardiac remodeling. This study aimed to examine the effects of tumor necrotic factor (TNF)-alpha and angiotensin II on cardiac remodeling and dysfunction after acute myocardial infarction. METHODS AND RESULTS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce myocardial infarction in the donor heart, and to evaluate the hearts of both donors and recipients in Lewis rats. The recipients in the ligation group showed significant body-weight loss, hyperthermia, tachycardia, hypotension and leukocytosis at day 7. A significant decrease in left ventricular fractional shortening and + dP/dt, and a significant increase in left ventricular enddiastolic dimension/body weight and left ventricular enddiastolic pressure were also observed in the recipient hearts in the ligation group at day 7. With the exception of the increased perivascular fibrosis, these recipient responses were no longer seen at day 21. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group at day 7. In contrast, angiotensin II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Further, the recipients' transient left ventricular remodeling and dysfunction were completely abolished by the intravenous administration of chimeric TNF-alpha soluble receptor. CONCLUSIONS: We developed a novel heterotopic cardiac transplantation-coronary ligation model capable of inducing myocardial infarction in the absence of downstream hemodynamic effects, and allowing differential quantification of indexes of cardiac remodeling in vivo, such as the local and remote effects of angiotensin II and TNF-alpha on cardiac remodeling. Modification of activated cytokines, such as TNF-alpha induced by cardiac ischemic stress, might be a beneficial strategy for the treatment of cardiac dysfunction and subsequent cardiac remodeling after acute myocardial infarction.