Endothelin and heart transplantation

Time for primary review 28 days. Endothelins are 21-amino-acid peptides that are produced ubiquitously by vascular endothelial and smooth muscle cells, but also by numerous other cells in many different organs. Endothelin-1 (ET-1) appears to be the predominantly produced isoform and to be responsible for most of the physiological and pathophysiological changes seen in humans. As suggested by its mitogenic properties, by its potent and long-lasting vasoconstrictor effects and by its origin in vasculature, ET-1 is thought to be mainly a cardiovascular hormone and/or paracrine factor that may play a key role in cardiovascular diseases such as systemic hypertension, atherogenesis, cardiac hypertrophy, heart and circulatory failures [1–5]. To date, although increased circulating ET-1 levels have been reported in heart-transplant recipients (Htx), suggesting a role for ET-1 in the cardiovascular and renal adaptation to human heart transplantation [6, 7], no attempt has been made to review the available literature concerning ET-1 after heart transplantation. We will thus discuss first the factors modulating ET-1 levels in Htx and will then investigate an eventual ET-1 pathophysiological role, addressing more particularly ET-1's participation in accelerated coronary artery disease, acute graft rejection, systemic hypertension and renal impairment after heart transplantation. Although already increased in patients with heart failure, circulating ET-1 has generally been reported to be elevated after heart transplantation (Tables 1 and 2). Such an increase may result from decreased pulmonary or renal clearance and/or from enhanced ET-1 production. Mean values of endothelin-1 plasma levels in controls, in patients with heart failure and in heart transplant recipients early and late after transplantation Results are expressed as means±SEM. For each group, the means were obtained from the literature data for which both controls and patients' values were available, including our unpublished data. For all groups, patients' data differed significantly from controls; ANOVA, P<0.01. Mean values of endothelin-1 plasma levels in controls, in patients with heart failure and in heart transplant recipients early and late after transplantation Results are expressed as means±SEM. For each group, the means were obtained from the literature data for which both controls and patients' values were available, including our unpublished data. For all groups, patients' data differed significantly from controls; ANOVA, P<0.01. Endothelin-1 plasma levels in normal subjects, in patients with heart failure and in heart transplant recipients early and late after transplantation Results are expressed as means±SEM or as the range of values. Htx, heart transplant recipients; Delay, delay after transplantation; Cyclo, cyclosporinemia; Endoth, plasma endothelin levels; MSBP, mean systemic blood pressure; Creatin, plasma creatinine levels; M, male. Where necessary, MSBPs were calculated from the formula: MSBM=diastolic blood pressure+(systolic−diastolic blood pressure)/3. Unit conversion: cyclosporine, 1 ng/ml=0.83 nmol/l; endothelin, 1 pg/ml=0.401 pmol/l; creatinine, 1 mg/dl=88.4 μmol/l. Cyclo: a4.7 (2.02 to 9.1) mg/kg; b200±80 mg/day. Endothelin-1 plasma levels in normal subjects, in patients with heart failure and in heart transplant recipients early and late after transplantation Results are expressed as means±SEM or as the range of values. Htx, heart transplant recipients; Delay, delay after transplantation; Cyclo, cyclosporinemia; Endoth, plasma endothelin levels; MSBP, mean systemic blood pressure; Creatin, plasma creatinine levels; M, male. Where necessary, MSBPs were calculated from the formula: MSBM=diastolic blood pressure+(systolic−diastolic blood pressure)/3. Unit conversion: cyclosporine, 1 ng/ml=0.83 nmol/l; endothelin, 1 pg/ml=0.401 pmol/l; creatinine, 1 mg/dl=88.4 μmol/l. Cyclo: a4.7 (2.02 to 9.1) mg/kg; b200±80 mg/day. In the range of its plasma concentrations in Htx, pulmonary clearance is thought to contribute more than renal clearance to ET-1 circulating levels [8]. However, ET-1 pulmonary clearance after heart transplantation remains to be investigated, since about half of 21 Htx showed a fall in ET-1 levels across the lungs, the other half having an increase across the pulmonary vascular bed [9]. On the other hand, it has been proposed that a decreased renal clearance may participate in a plasma ET-1 increase in Htx. Accordingly, positive correlations were reported between ET-1 plasma levels and serum creatinine levels in Htx [7, 9–11]. Nonetheless, although statistically significant, the relationships between both parameters were weak and such an association was not observed by all authors [12, 13]. It suggests that the slight renal impairment that is usually observed after heart transplantation is unlikely to contribute predominantly to the increased plasma ET-1 levels found in Htx. In this view, ET-1, being a potent renal vasoconstrictor, the decrease in renal function in Htx may also be a result rather than a cause of the elevated plasma ET-1 concentrations [1–6]. Proinflammatory cytokines, which are responsible for both the primary host response to a bacterial infection, as well as initiating the repair of tissue after injury [14–16], strongly stimulate ET-1 synthesis and release [17–19]. Since they are increased, both early and late, after heart transplantation [16, 20, 21], proinflammatory cytokines may play a role in ET-1 elevation in Htx. Thus, both cardiopulmonary bypass-induced systemic inflammatory response and impaired peripheral circulation, local ischemia or hypoxia, which are also observed during other major surgical procedures, may participate in the early ET-1 increase observed during the first days after heart transplantation [7, 22, 23]. Simultaneously, and continuing thereafter, the immunologically mediated inflammatory process might also enhance ET-1 release in Htx. Indeed, although, to the best of our knowledge, a relationship between endothelin and cytokines remains to be shown in Htx, the numerous experimental studies performed so far in animals and humans suggest that proinflammatory cytokines are likely to participate in ET-1 elevation after heart transplantation [16–21]. In agreement with this hypothesis, increased cytokines, together with increased ET-1 levels, have been observed recently in kidney and simultaneous pancreas–kidney transplant recipients during progression of microangiopathy [24]. As previously stated, numerous cells in many different organs can secrete ET-1, but one may expect that vascular endothelial and smooth muscle cells may be major sites of ET-1 production after heart transplantation. The contribution of the transplanted heart to the ET-1 increase may, however, be modest. Indeed, although the transplanted heart is submitted to repeated ischemic and inflammatory injuries, which are well known to stimulate ET-1 release, a transcardiac release of ET-1 has not been consistently observed in Htx [9, 25, 26]. ET-1 uptake has even been reported after heart transplantation [9, 26]. As proposed by the authors, rather then a lack of ET-1 release by the graft, this result might support the theory that ET-1 is bound rapidly to its cardiac receptors [26]. Supporting this hypothesis, ET-1 immunoreactivity has been localized to endothelial cells of blood vessels and endocardium as well as to cardiac myofibers after heart transplantation [26, 27]. The sustained increase in plasma ET-1 levels in Htx may therefore be related to elevated pretransplantation levels, arising from all vascular cells of the body [12]. This preexistant vascular dysfunction may be associated with, or responsible for, the pretransplantation heart and/or circulatory failures [12]. Accordingly, increased ET-1 levels and vascular dysfunction are associated, and several studies have demonstrated that reversal of impaired vasodilation in congestive heart failure is delayed after heart transplantation [28, 29]. In this view, although more controversial, the immunosuppressive therapy could participate in the ET-1 elevation after heart transplantation. Thus, cyclosporine A (CsA) and corticoids, through induction of hypercholesterolemia, have been shown to increase both plasma and tissue ET-1 levels [30, 31]. On the other hand, dexamethasone significantly reduces both basal and cytokine-stimulated release of ET-1 in cultured cells [32]. However, thymoglobulin transiently stimulates proinflammatory cytokine release [33]and tacrolimus is known to damage endothelial cells. CsA, which is generally introduced as early as the third day after heart transplantation, may participate in ET-1 hypersecretion in Htx. Indeed, CsA stimulates cytokine expression and, through endothelial cell injury, induces ET-1 synthesis by human endothelial and smooth muscle cells [34–37]. Accordingly, Grieff et al. [38]showed a temporary rise in ET-1 plasma levels, 6 h after CsA administration in organ transplant recipients on chronic therapy. Nevertheless, to date, most reports failed to demonstrate a relationship between CsA medication and plasma ET-1 levels in Htx [6, 7, 12, 13, 39]. These studies may have missed a transient ET-1 increase. Indeed, ET-1 was generally measured prior to CsA administration, at a time when CsA levels should be close to their nadir. However, circulating ET-1 was recently monitored in Htx for 2.5 and 6 h, respectively, after the oral administration of CsA, and no CsA-induced ET-1 increase was observed ([40], unpublished data). Furthermore, it is a common observation that, despite CsA therapy similar to that performed in Htx, ET-1 plasma levels return to baseline after successful renal and liver transplantations [41, 42]. In summary, the sustained ET-1 increase observed after heart transplantation appears to be multifactorial, and is likely to be due to endothelial and vascular smooth cell dysfunction related mainly to renal impairment, proinflammatory cytokines and immunosuppressive therapy (Fig. 1). It may be interesting to study the few Htx presenting with relatively low ET-1 plasma levels ([39], unpublished data in Table 1) to further investigate the regulatory mechanism of ET-1 release and to determine if these patients show a low posttransplant rate of complications. Proposed regulatory mechanisms and effects of endothelin-1 after heart transplantation. Although most of the available information on ET-1 in Htx is confined to reports studying plasma levels, this may not accurately reflect the biological activity of ET-1 in situ. Indeed, ET-1 is rapidly cleared from the circulation and measurable plasma ET-1 levels may only be found if the produced peptide reaches concentrations that are high enough to escape the site of production [1, 2, 5, 39]. Thus, circulating plasma levels of ET-1 most probably reflect a spill-over from local secretion. In this respect, ET-1 urine excretion may represent an integrated 24-h ET-1 release and the increased urinary ET-1 levels in Htx [43]support the theory that ET-1 may play a significant pathophysiological role, even if its plasma levels are not elevated. Proliferative vasculopathy, called graft arteriosclerosis, is now the main limiting factor of long-term survival after heart transplantation. Thus, transplant coronary artery disease results in myocardial infarction, ventricular failure, malignant arrhythmias and sudden death [44]. Although the underlying mechanisms of graft arteriosclerosis are various and are not yet fully elucidated, immune-mediated endothelial injury may play a crucial role, resulting in endothelial dysfunction with abnormal vasodilation [45, 46]. In this respect, both the elevated circulating ET-1 level generally observed after heart transplantation and the increased immunoreactive ET-1 in human transplant coronary arteries favor a role for ET-1 in Htx's graft vasculopathy [47–50]. Indeed, Berkenboom et al. [47, 48]not only observed an abnormal coronary response to serotonin in cardiac transplant patients, but they demonstrated that the higher ET-1 plasma levels were associated with a greater decrease in coronary artery diameter (Table 3). Accordingly, coronary endothelial dysfunction after cardiac transplantation appears to be characterized by enhanced ET-1 uptake by the heart and is associated with increased myocardial ET-1 mRNA expression [26]. This is further supported in a rat heterotopic cardiac transplant model in which marked upregulation of ET mRNA was observed in arteriosclerotic coronary arteries of allografts, compared to the isograft controls [51]. Moreover, it has been demonstrated very recently that an endothelin antagonist significantly preserved the smooth muscle function and attenuated the development of chronic intimal hyperplasia in rat aortic allografts [52]. Abnormal serotonin-induced coronary vasoconstriction and endothelin-1 plasma levels after heart transplantation Results are expressed as means±SEM. Controls and Htx A and B, from Berkenboom et al. [47], differ from controls: aP<0.05, cP<0.02, different from group A; b and d, P<0.02. Htx C and D, from Berkenboom et al. [48], difference with group C, eP<0.01. Abnormal serotonin-induced coronary vasoconstriction and endothelin-1 plasma levels after heart transplantation Results are expressed as means±SEM. Controls and Htx A and B, from Berkenboom et al. [47], differ from controls: aP<0.05, cP<0.02, different from group A; b and d, P<0.02. Htx C and D, from Berkenboom et al. [48], difference with group C, eP<0.01. The mechanisms by which ET-1 participates in accelerated coronary artery disease in Htx may be similar to that observed in atherosclerosis. Indeed, there is evidence that the mitogenic and vasoconstrictive ET-1, immunostaining of which has been observed in human atherosclerotic arteries in endothelial cells, macrophages and intimal smooth muscle cells [53, 54], has an important role in the initiation and progression of cellular pathways leading to atherogenesis. In the early stage of coronary atherosclerosis, the release of ET-1 into vessel lumen activates circulating monocytes and macrophages, and the release of ET-1 into the vascular wall mediates smooth muscle cell proliferation and vasoconstriction. The potent coronary vasoconstrictive properties of ET-1 may thus potentiate the atherosclerotic process by reducing blood flow and subsequently enhancing platelet aggregation and thrombus formation. ET-1 then participates in the progression of atherosclerosis by interacting with other cytokines and growth factors to further stimulate smooth muscle cell proliferation, induce chemotaxis and replication of fibroblasts, and activate fibroblasts to secrete collagen matrix [5, 53–56]. Experimental data suggested that ET-1 may have a role in the pathogenesis of acute allograft rejection after organ transplantation. Thus, in animal studies, increased ET-1 tissue levels have been observed in acute rejection of renal, hepatic and pulmonary allografts. Similarly in human beings, some reports showed a transient increase in plasma ET-1 levels during acute renal and hepatic graft rejection, with normalization of plasma ET-1 occurring thereafter [11, 57–60]. Since both ET-1 plasma and tissue levels have been shown to be higher at the time of ongoing rejection [11, 60], whether or not ET-1 plasma levels may serve as a marker for noninvasive rejection diagnosis after heart transplantation was investigated. In Htx, no significant association of systemic ET-1 concentration with the severity of rejection was observed when comparing ET-1 plasma levels and histologic grade of acute cellular graft rejection [11]. However, the type of rejection process seems to influence changes in circulating ET-1 levels. Thus, interstitial cellular rejection, where the endothelial cell layer remains morphologically intact, induced no significant plasma ET-1 increase in renal-transplant patients. On the other hand, significant increases in ET-1 levels were found only during vascular rejection, which is associated with larger amounts of cell damage [41, 61]. Thus, it may be hypothesized that the type of acute rejection in Htx, which is generally interstitial, may explain the lack of an associated increase in ET-1 levels. However, no trend towards increased ET-1 was observed in Htx presenting with severe vasculitic and humoral rejection episodes, supporting the view that ET-1 is not a good marker for acute rejection after heart transplantation [11, 27]. Posttransplantation nephropathy and hypertension are very common after heart transplantation. Acute renal failure secondary to high doses of CsA can now generally be avoided, but Htx still experience a decline in renal function that is characterized by both a decrease in the glomerular filtration rate and in renal blood flow. Since this renal dysfunction could be prevented by selective infusion of an ET-1 blocking antibody or antagonist, it suggests a causal role for ET-1 in CsA-induced nephrotoxicity [62, 63]. Accordingly, ET-1 can affect all vascular beds, but renal circulation is particularly sensitive to its vasoconstrictor actions, which result in decreased renal plasma flow and glomerular filtration rates. Thus, it is likely that increased ET-1 may impair renal function after heart transplantation. Similarly, it has been shown in animals than a twofold increase in ET-1 levels is sufficient to increase systemic vascular resistances [3], suggesting that ET-1 may participate in the prevalence of high systemic hypertension in Htx, which is characterized by elevated systemic vascular resistance, normal cardiac output and a modest impairment of renal function. Again, CsA may play a role since its direct toxic effect on the vascular endothelium increases both plasma and urinary ET-1 levels [37, 62]. Accordingly, although an association between increases in plasma ET-1 levels and mean arterial pressure was rarely found, the lack of correlation between ET-1 and systemic blood pressure or peripheral resistance does not detract from ET as a possible mediator of CsA-associated hypertension, since ET-1 may activate other neurohormonal vasoactive systems, thus complicating further the relation between measured plasma ET-1 and its biologic effect [6, 12, 13, 64]. Therefore, the potent vasoconstrictor peptide, ET-1, may partly mediate posttransplant systemic hypertension [65]. In summary, it is likely that ET-1 participates in posttransplant complications, such as renal damage, hypertension and graft vasculopathy. Since there is growing evidence that blockade of ET-1 action by specific ET-1 receptor antagonists or ET-1 converting enzyme inhibitors is useful in animals and cardiovascular patients by decreasing systemic hypertension, renal impairment and cardiac failure [62, 63, 66–69], such therapeutic tools may be proposed in Htx in order to prevent renal impairment and hypertension. Furthermore, in view of the recently reported attenuation of neointimal formation in aortic rat allograft by an ET antagonist [52], ET-1 blockade might provide new opportunities to greatly improve the long-term prognosis and quality of life after heart transplantation.