Patterns of Myocardial Endothelin-1 Expression and Outcome After Cardiac Transplantation

Abstract

Background-Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy. Methods and Results-Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (Pϭ0.02). Compared with patients with negative interstitial ET-1 expression (nϭ22), patients with positive interstitial ET-1 expression (nϭ25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, Pϭ0.002), lower mean episodes of acute rejection (Ն grade 2) during the first 3 months of transplant (1.09Ϯ0.66 versus 1.86Ϯ1.6, Pϭ0.048), and more common vasculopathy at 2 years (50% versus 15%, Pϭ0.02), and they tended to have worse survival (83.2% versus 100%, Pϭ0.058). Conclusions-Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.

Heart Preservation Using Continuous Ex Vivo Perfusion Improves Viability and Functional Recovery

“…Our data corroborate the relationship between heightened perioperative levels of ET-1 and early myocardial dysfunction. In addition, ET-1 has been suggested to play a role in late CAV, and reduced overall survival [25][26][27][28] in clinical cardiac transplantation. ET-1 antagonists improve systolic function in animal models of cardiac transplantation.…”

Cardiac Allograft Vasculopathy: An Ongoing Challenge in the Care of Heart Transplant Recipients

“…Endothelial cell dysfunction resulting from inflammatory injury predisposes to thrombosis, vasoconstriction, and vascular smooth muscle cell proliferation. Reperfusion injury increases expression of endothelin 1, which is associated with posttransplant ischemic fibrosis and subsequent development of arteriopathy, in addition to generating free radicals that promote the expression of such inflammatory adhesion molecules and subsequent leukocyte recruitment (Ferri et al, 2002). More research is needed in the field of organ preservation, possibly targeting specific cellular processes to minimize reperfusion injury.…”

Endothelin-1 Is a Key Mediator of Coronary Vasoconstriction in Patients With Transplant Coronary Arteriosclerosis

“…7 Interstitial ET-1 expression in human cardiac biopsies at 3 months after transplantation is associated with the subsequent development of angiographic TCA. 38 However, the findings of ET-1 mRNA or peptide in cardiac biopsies do not provide information about its biological activity. Although the presence of ET-1 in cardiac biopsies suggests an association between ET-1 and TCA, these observations cannot determine whether there is a causal relationship between ET-1, development of TCA and subsequent clinical outcomes.…”

“…Although the presence of ET-1 in cardiac biopsies suggests an association between ET-1 and TCA, these observations cannot determine whether there is a causal relationship between ET-1, development of TCA and subsequent clinical outcomes. 38 Furthermore, plasma ET-1 levels (which are elevated in cardiac transplant recipients) do not correlate with the presence of TCA, 39 partly because ET-1 is produced at many sites outside of the transplanted organ and partly because the majority of endothelin is released abluminally not luminally. 40 Thus, data about the biological activity of ET-1 in human coronary arteries after cardiac transplantation and the relationship of any biologically active ET-1 to the presence of TCA are needed.…”