LETTER TO THE EDITOR
Coronary endothelial dysfunction in the early months after heart transplantation
Guy Berkenboom, MD, FESCa,
Vincent Crasset, MDa and
Philippe Unger, MDa
a Department of Cardiology, Erasme Hospital, Lennik Road 808, Brussels 1070, Belgium
gberkenb{at}ulb.ac.be
We read with interest the report by Aptecar et al. (1) that early after heart transplantation, coronary vasodilator effects of bradykinin are preserved despite abnormal response to intracoronary injection of acetylcholine. This absence of alterations to the vasodilator action of bradykinin is neither a new nor an unexpected finding. In cardiac transplant recipients with normal angiography, this preservation of the coronary response to endogenous vasodilator peptides has already been reported not only for substance P (2), as mentioned by Aptecar et al. (1), but also for bradykinin (3). In contrast to acetylcholine and serotonin, bradykinin and substance P are potent endothelium-dependent vasodilators. Their endothelial vasodilator effects are not counterbalanced by a direct constriction mediated by the stimulation of smooth muscle receptors.
As pointed out in our previous study (3) also performed in the early months following transplantation, the hypersensitivity to the vasoconstrictor effect of serotonin is not directly related to a decrease in endothelium-derived nitric oxide (NO) availability. Indeed, acute L-arginine supplementation in transplant recipients, as compared to hyperlipidemic patients, did not modify the hypersensitivity to serotonin (3).
Immune processes such as cytokines produced by activated macrophages and T cells play a major role in these abnormal responses, probably even in the absence of rejection episodes (4). First, this inflammatory response may promote the release of endothelin, an endothelium-derived contracting factor (EDCF) able to potentiate the vasoconstriction to various amines (5) and seems to play a major role in the development of the graft vasculopathy (6,7). Second, cytokines may also activate the inducible isoform of nitric oxide synthase (iNOS), promoting the release of potent oxidants such as superoxide anion and peroxynitrite (8). In line with this hypothesis, the coronary vasoconstriction to acetylcholine was enhanced in patients with rejection episodes cited in Aptecar et al. (1).
Hence, from available data, it is unlikely that the coronary endothelial NO synthase pathway is impaired early after heart transplantation. The abnormal responses to serotonin and acetylcholine are probably related to the presence of EDCF and/or changes in smooth muscle receptors. Therefore, a direct action on the endothelial NO synthase via an enhanced bradykinin availability by long-term angiotensin-converting enzyme (ACE) inhibition, as suggested by Aptecar et al. (1), should not markedly improve the endothelial function.
Furthermore, according to animal studies (9), NO formation is already enhanced by activation of iNOS in the early months after transplantation. This enhanced NO availability may explain the elevated resting coronary blood flow observed in the transplant recipients of Aptecar et al. (1), which is congruent with previous studies (10).
Therefore, therapeutical approaches, aiming at counteracting these abnormalities, with endothelin antagonists or/and antioxidants, seem more appealing than with ACE inhibitors, which may worsen cyclosporine-induced nephrotoxicity.
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References
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- Aptecar E, Teiger E, Dupouy P, et al. Effects of bradykinin on coronary blood flow and vasomotion in transplant patients. J Am Coll Cardiol. 2000;35:1607–1615[Abstract/Free Full Text]
- Kushwaha SS, Crossman DC, Bustami M, et al. Substance P for evaluation of coronary endothelial function after cardiac transplantation. J Am Coll Cardiol. 1991;17:1537–1544[Abstract]
- Berkenboom G, Crasset V, Unger P, Vachiery J-L, LeClerc J-L. Absence of L-arginine effect on coronary hypersensitivity to serotonin in cardiac transplant recipients. Am J Cardiol. 1999;84:1182–1186[Medline]
- Ventura HO, Mehra MR, Smart FW, Stapleton DD. Cardiac allograft vasculopathy: current concepts. Am Heart J. 1995;129:791–798[CrossRef][Medline]
- Yang Z, Richard V, von Segesser L, et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. Circulation. 1990;82:188–195[Abstract/Free Full Text]
- Ravalli S, Szabolics M, Albala A, Michler RE, Cannon PJ. Increased immunoreactive endothelin-1 in human transplant coronary artery disease. Circulation. 1996;94:2096–2102[Abstract/Free Full Text]
- Geny B, Piquard F, Lonsdorfer J, Haberey P. Endothelin and heart transplantation. Cardiovasc Res. 1998;38:556–562
- Buttery LDK, Springall DR, Chester AH, et al. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest. 1996;75:77–85[Medline]
- Akyurek LM, Fellstrom BC, Yan ZQ, Hansson GK, Funa K, Larsson E. Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts. Am J Pathol. 1996;149:1981–1990[Abstract]
- Rechavia E, Araujo L, DeSilva R, et al. Dipyridamole vasodilator response after human orthotopic heart transplantation: quantification by oxygen-15 labelled water and positron emission tomography. J Am Coll Cardiol. 1992;19:100–106[Abstract]
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