Effect of cyclosporine on plasma endothelin levels in humans after cardiac transplantation

thesehypothesesdefinitively, the study would have to be repeatedprospectively(so that meantransvalvular gradiFrom the aforementionedfindings we conclude that entsat rest would be recordedin all cases)in patientswith aortic dilatation is presentin patients with a functionally BAV who do not exhibit eccentric cusp excursion (apnormal or minimally stenotic BAV when comparedwith proximately 22%5)and who meet the criteria for funcage- and sex-matchedcontrol subjects.It might be ar- tional normality. In the absenceof such an onerousungued that lesser (<25 mm Hg) transvalvular pressure dertaking, we feel that our data provide further evidence gradients or eccentric left ventricular stroke volume ex- that aortic dilatation (a clinical correlate of aortic medial pulsion in the absenceof a pressuregradient could cause fragility) is presentin patients with a functionally normal aortic root dilatation. This is unlikely to account for the or minimally stenotic BAV. observeddifferences,becausedisturbancesof flow at the valvular level tend to causeaortic root changesdistal to the sinotubular junction. Our measurementswere pur- 1. Roberts WC. The congenitally bicuspidaortic valve. Am J Cardiol 1970;26: 72-82. posefully taken proximally, at the sinuslevel, to avoid this 2. Lindsay J Jr. Coarctation of the aorta, biscupid aortic valve and abnormal problem. Mean transvalvular pressuregradients <25 mm ascendingaortic wall. Am J Cardiol 1988;61:182-184. Abbott ME. Coarctation of the aorta of the adult type. Am Heart J Hg at rest were recordedtoo infrequently (<5 patients) 3.1928;3:381-421. in our sampleto attempt any reliable correlation between 4. McKusick VA. Associationof congenitalbicuspidaortic valve and Erdheim’s gradient magnitude and aortic root dimension. Cardiac cystic medial necrosis.Lancet 1972;1:1~26&1027. BrandenburgRO Jr, Tajik AJ, EdwardsWD, ReederGS, Shub C, SewardJB. catheterization data were not available. Although valve 5. Accuracy of two-dimensionalechocardiographicdiagnosisof congenitally bicuscusp eccentricity is acknowledgedto occur in approxi- pid aortic valve: echocardiographic-anatomiccorrelation in 115 patients.Am J mately 78% of BAV patients,5 it is not clear that the Cardiol 1983;51:1469-1473. 6. Triulzi M, Gillam LD, Gentile F, Newell JB, Weyman AE. Normal adult degreeof cusp excursion eccentricity is sufficient to alter cross-sectionalechocardiographicvalues: linear dimensionsand chamber areas. the direction of transvalvular blood flow. To disprove Echocardiography 1984;1:403-415. ters >34 mm, a conventionally accepted upper limit of normal for the aortic root at the sinus level in adults6

Effect of Cyclosporine on Plasma Endothelin Cardiac Transplantation

Levels in Humans After

Brooks S. Edwards, MD, Sharon A. Hunt, MD. Michael B. Fowler, MD, Hannah A. Valantine, MD, Lisbeth M. Anderson, and Amir Lerman, MD creasein renal vascular resistance.Administration of endothelin antisera reversedthe renal vasoconstriction.The effect of clinically relevant dosesof cyclosporineon the cyclosporine,considerablemorbidity remains associated activation of circulating endothelin in humans has not Smithits use. Renal insufficiency characterized by renal been evaluated. The current study was designed to (1) investigate vasoconstriction occurs frequently and limits the use of the drug.2 Hypertension occursin >90% of cyclosporine- whether plasma endothelin is activated in cyclosporine- and non-cyclosporine-treatedpatients after cardiac treated cardiac transplant recipients.3 In vitro cyclosporinedamagesendothelial cells,result- transplantation, and (2) to determine if a correlation ing in cell lysis and detachment.4Endothelin representsa exists between plasma endothelin and systemic arterial newly recognizedpolypeptideproducedby vascularendo- pressureor serum creatinine after transplantation. Studies were performed in 27 stable cardiac transthelium. Exogenousadministration of endothelin results in intenserenal and systemicvasoconstriction.5Recently, plant recipients. Group I comprised 21 subjects who investigatorsspeculatedthat endothelin may mediatecy- have undergone cardiac transplantation since 1980 and closporine-inducedhypertensionand renal insufficiency.‘j who were being treated with a cyclosporine-based immuRecent studies in the rat7 using superpharmacologic nosuppressive regimen. Group 2 comprised 6 patients dosesof cyclosporine demonstratecyclosporine-induced transplanted before the introduction of cyclosporine who activation of plasma endothelin with an associatedin- were receiving only prednisone and azathioprine’ as imince the introduction of cyclosporinein 1980,the lyear survival rate after cardiac transplantation is now S in excessof 80%.’ Despite the successexperiencedwith

From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905, and the Department of Internal Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305. This study was supported in part by a grant from The Mayo Foundation, Rochester, Minnesota. Manuscript received November 7. 1990; revised manuscript received December- 10, 1990, and accepted December 12.

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munosuppressive therapy. While subjects were in the seated position, 10 ml of venous blood was collected from the antecubital vein. Whole blood was centrifuged at 2,500 r.p.m. at 4°C. The plasma was stored in polypropylene tubes at -20°C until assayed. Extracted plasma endothelin was determined by specific radioimmunoassay using rabbit antiendothelin antisera (RAS6901, Peninsula Laborato-

ries, Belmont, California), as previously described.8 The Mean arterial blood pressure with therapy was 102 f 4 mm Hg in group 1 and 96 f 5 mm Hg in group 2 recovery of the extraction procedure was 81%. Interassay and intraassay variations were 9 and 5%, respective- (difference not signtjkant). Serum creatinine was greatly. The lower level of detectability of the assay is 0.5 pg,t er in group 1 (1.4 f 0.1 mg/dl) than in group 2 (1 .Of 0.1 mg/dl, p <0.05) (Figure IA). ’ ml, with a range of 0.5 to 400 pg/ml. Plasma endothelin was 3.2 f 0.3 pg/ml in group 1 Serum creatinine was assayed using a clinical creatinine analyzer. Arterial pressure was determined using a and 4.1 f 0.8 pg/ml in group 2 (Figure 1B). This value sphygmomanometer while the patient Was in the seated was not statistically different from that measured in 67 normal subjects (2.4 f 0.3 pg/ml) and the values beposition. tween the 2 transplant groups were not statistically difComparison between groups was performed by Student’s unpaired 2-tailed t test. Statistical significance ferent. Plasma endothelin did not correlate with blood was achieved at the p X0.0.5 level. Results are expressed pressure (Figure 2A) or serum creatinine (Figure 2B) in as mean f standard error. either group. The average age of subjects at the time pf study was In this seriesof stable cardiac transplant recipients, 45 f 3 years in group 1 and 41 f 6 years in group 2. The plasma endothelin was not different between cyclospoaverage time from transplant to study was 22 f 7 rine and non-cyclosporine-treatedpatients. Circulating months in group 1 and 147 & 17 months in group 2. endothelin did not correlate with arterial pressureor seNineteen of 21 subjects in group 1 were men, as were 5 rum creatinine. of 6 subjects in group 2. The ability to study endothelin in non-cyclosporineEighteen of 21 (86%) cyclosporine-treated patients treated cardiac transplant patients provides unique data and allows one the potential to separatecyclosporineef(group 1) and 1 of 6 (17%) non-cyclosporine-treated patients (group 2) required antihypertensive therapy. fects from more general changes that may occur after

Noncyclosporine treated

Cyclosporine treated

A

FYGURE 1. A, serum creatine (Cr), and B, plasma endothelin cardiac transptant recipients. NS = diffemm not significant.

Noncyclosporine treated

Cyclosporine treated

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90

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110

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was observed.

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783

cardiac transplantation. The fact that endotbelin wasnot different between cyclosporine- and non-cyclosporinetreated patients provides unique evidencedemonstrating that clinical levelsof cyclosporinedo not activate plasma endothelin. The inability to document activation of endothelin in this large group of normotensiveand hypertensivecardiac transplant recipients suggestsseveral possible explanations. Although endothelin may not participate asa mediator for posttransplant hypertension and renal insufficiency, there are alternative possibilities. The sensitivity of the vasculature to endothelin may be altered by cyclosporine. Garr and Pallergimportantly demonstratedthat cyclosporinemay enhancethe renal vascular responseto a variety of vasoconstrictors.Potentially, in the cardiac transplant recipient treated with cyclosporine,there may be an enhanced vascular responseto normal levels of endothelin. Furthermore, onecannot excludethe possibility of local endothelin action without significantly increasingcirculating concentrations.In preliminary studies,Lerman et allo observedthat very low-doseendothelin (1 ng/kg/min) may increase renal vascular resistance without increasing plasma endothelin. Perico et al” recently demonstratedthat cyclosporinemay increaseurinary endothelin excretion without altering plasmalevels, suggestingintrarenal endothelin production. The distal nephron is rich in endothelinr2and may potentially be a site for enhancedintrarenal endothelin production in the presenceof cyclosporine.Finally, this study doesnot addressthe possibility of diurnal changesin plasma endothelin. In a preliminary observation,Grieff et all3 reported activation of plasma endothelin, which occurs 4 to 12 hours after ingestion of oral cyclosporineand which returns toward baseline as cyclosporine levels decline. In the current study, plasmaendothelin wasdeterminedat a time when cyclosporine would be at a trough level. Unlike previousstudiesin the rat using superpharmacologic dosesof cyclosporine,*the current study in human

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cardiac transplant recipients demonstratesthat chronic cyclosporinetherapy is not associatedwith sustainedactivation of circulating endothelin. Furthermore, posttransplantation hypertension and renal insufficiency doesnot correlate with circulating endothelin and may occur in the absenceof an increasein circulating endothelin. Acknowledgment: We gratefully acknowledgethe assistanceof DeniseHeublein in performing the endothelin assay,John C. Burnett, Jr., MD, for reviewing the manuscript, and Shelly O’Groske for secretarial assistancein manuscript preparation.

1. Heck CF, Shumway SJ, Kaye MP. The registry of the International Society for Heart Transplantation: sixth official report 1989. J He& Transplant 1989;s: 211-216. 2. Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associatcd chronic nephropathy. N Engl J Med 1984;311:699-705. 3. Olivari MT, Antolick A, Ring WS. Arterial hypertension in heart transplant recipients treated with triple-drug immunosuppressive therapy. J Heart Traw plant 1989;8:34-39. 4. Zoja C, Furci L, Ghi+di F, Zilio P, Benigni A, Remuzzi G. Cyclosporininduced endothelial cell *Jury. &ab Inuest 1986;55:455-462. 5. Miller WL, Redfield MM, Burnett JC. Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Inuesr 1989;83:317-320. 6. Cairns HS, Rogerson M, Fairbanks LD, Westwick J, Neild GH. Endothelin 1988;2: 1496-1497. and cyclosporin nephrotoxicity. Lance? 7. Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL. Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int 199Q;37: 1487-1491. 8. Cavero PG, Miller WL, Heublein DM, Margulies KB, Burnett JC Jr. Endothelin in experimental congestive heart failure in the anesthetized dog. Am J Physiol 1990;259:F312-F317. 9. Garr MD, Paller MS. Cyclosporine augments renal but not systemic vascular reactivity. Am J Pbysiol 1990;258:F211-F217. 10. Lerman A, Hildebrand FL Jr, Burnett JC Jr. Endothelin has biologic action at physiologic and pathophysiologic concentrations (abstr). J Am Sot Nephrol 1990;1:419. 11. Perico N, Benigni A, Ladny JR, Imberti 0, Bellizzi L, Remuzzi G. Chronic cyclosporine A (CyA) administration to rats increases urinary excretion of bigendothelin and endothelin (abstr). J Am Sot Nephrol 1990;1:617. 12. Edwards BS, Anderson LA, Schwab TR, Burnett JC Jr. Presence of renal tubular endothelin in two animal species. Am J Hypertens 1990;3:64A\. 13. Grieff M, Shoheib SA, Loertscher R, Stewart DJ. Cvcloswrine A (CSA1 induces elevation in circulating endothelin-I (ET-l) following transplantation (abstr). J Am Sot Nephrol 1990;1:758. -

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