Editorial

A Potential Role for Endothelinin Congestive Heart Failure

The endothelin family of peptides has recently been charac­terized. Endothelin-l and endothelin-3 are released by endo­thelial cells.' Infusion of either of these endothelins inanimals causes pronounced vasoconstriction, decreased car­diac output, and increased blood pressure.P Whether endo­thelin acts solely as a local mediator of vasoconstriction oralso as a circulating hormone has been controversial. Recentdata also support a role for endothelin in mitogenesis invascular smooth muscle.' The main stimuli for release ofendothelin are beginning to be elucidated. The study byRodeheffer and associates reported in this issue of the MayoClinic Proceedings (pages 719 to 724) demonstrates thatcirculating levels of endothelin are increased in patients withcongestive heart failure and also that circulating levels ofendothelin are higher in patients with severe congestive heartfailure than in those with mild congestive heart failure. Thisstudy poses several interesting questions about the role ofendothelin in heart failure and the potential mechanisms ofrelease of endothelin.

Relationship With Hypotension.-Preliminary studieshave demonstrated that hemorrhage-related hypotension,'infusion of endotoxin," cardiogenic shock, myocardial in­farction, orthostatic hypotension," and hypoxias-e-like con­gestive heart failure-are associated with increased.circulat­ing levels of endothelin. This observed association betweenhypotensive states and increased circulating levels of endo­thelin may suggest that baroreceptor unloading inhypoten­sion enhances release of endothelin. Alternatively, tissuehypoxia caused by hypotension or congestive heart failuremay stimulate release of endothelin. Indeed, Oparil andcolleagues" demonstrated that hypoxia can stimulate releaseof endothelin. Therefore, hypoxia may be one of the physi­ologic links that result in release of endothelin in all theseconditions.

Relationship With CoronaryArtery Disease.-A recentstudy by Lerman and co-workers7 demonstrated that endo­thelin is also increased in patients with atherosclerosis­perhaps because of injury of endothelial cells. This effectmay, in part, be responsible for the increase in endothelinobserved in the current cohort of patients, inasmuch as 55%

Address reprint requests to Dr. R. S. Zimmerman, Section of Endo­crinology, Ochsner Clinic, 1514 Jefferson Highway, New Orleans,LA 70121.

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of these patients had coronary artery disease. Because 45%of patients had no evidence ofcoronary artery disease, how­ever, the current study indicates that congestive heart failuremay independently be responsible for the increase in endo­thelin. It would be interesting to know whether levels ofendothelin are significantly different in patients who haveheart failure with and without associated coronary arterydisease. Another comparative study that would help segre­gate the effect of atherosclerosis from the effect of heartfailure would be an assessment of patients without coronaryartery disease who have heart failure in comparison withcontrol subjects.

Effects on Cardiac Output.-The role of endothelin inheart failure is complex; endothelin has effects on eachcomponent of cardiac output, including blood volume, ve­nous capacitance, cardiac contractility, coronary artery tone,and cardiac afterload. The effects of endothelin on thesecomponents of cardiac output are dependent on the dose andmay often influence cardiac output in opposing ways. Inaddition to understanding the role of endothelin on compo­nents of cardiac output, examining the role of endothelin onthe sequelae of heart failure, including peripheral edema andpulmonary edema, would be of interest. Finally, understand­ing endothelin in the context of other factors and hormonesreleased during heart failure is important.

Endothelin affects cardiac preload in opposing ways bydecreasing blood volume and by decreasing venous capaci­tance. Studies in 'our laboratory have evaluated the effectsof infusion of endothelin on vascular volume and escape ofalbumin in the nephrectomized rat." These studies demon­strated that endothelin causes a profound loss of plasmavolume, independent of renal excretion, by enhancing tran­sudation of fluid into the extrapulmonary interstitial spacepresumably by increasing hydrostatic pressure. This effectdecreases preload, enhances formation of peripheral edema,and protects the lung from volume overload. Endothelinalso affects cardiac preload by causing venoconstriction,which produces increased venous return by decreasing ve­nous capacitance.'? The ultimate effect of endothelin onpreload is based on the additive effects ofthese two opposingactions.

Endothelin enhances cardiac contractility in isolated car­diac atrial and ventricular tissue in vivo and in vitro. Fur­thermore, removal of endocardium in isolated papillarymuscles in the rat depresses contractilityY Thus, perhapslocal or systemic release of endothelin can help cardiacoutput by enhancing contractility. Because high doses ofendothelin can also cause coronary vasoconstriction and

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myocardial infarction, endothelin-I can cause decreasedcontractility at high doses.

Infusion of endothelin substantially increases cardiac af­terload by causing profound arterial vasoconstriction, andthe result is increased systemic vascular resistance.s-' Al­though systemic vascular resistance was notmeasured in thecurrent study by Rodeheffer and associates reported in thisissue of the Proceedings, numerous studies have substanti­ated an increase in systemic vascular resistance in heartfailure. Increased systemic vascular resistance during heartfailure may be caused by increased sympathetic outflow,increased catecholarnines, angiotensin, or vasopressin, orincreased endothelin. Furthermore, infusion studies in ratsand dogs-" have demonstrated that minimal changes in cir­culating levels of endothelin, such as those found in thecurrent study, can be associated with increased blood pres­sure and increased systemic vascular resistance. Thus, onthe basis of these observations, release of endothelin duringcongestive heart failure may, in part, be responsible for theincreased systemic vascular resistance. Nevertheless, previ­ous studies have been unable to show a significant correla­tion between systemic vascular resistance and circulatinglevels of endothelin in a dog model of congestive heartfailure produced by rapid ventricular pacing."

Effects on Blood Pressure and the Lungs.-Bumett andcolleagues" have identified two peptides-atrial natriureticfactor and endothelin-that are increased in congestive heartfailure. This finding may seem perplexing because thesepeptides have vastly different physiologic actions. Indeed,atrial natriuretic factor decreases blood pressure by decreas­ing venous return," whereas endothelin substantially in­creases blood pressure by causing vasoconstriction.P Per­haps the release of endothelin-l during heart failure mayenhance atrial stretch-induced release of atrial natriureticfactor because endothelin-l has been shown to be one factorthat causes release of atrial natriuretic factor.P Although thesystemic effects of these peptides on blood pressure differ,their pulmonary protective effects may be similar. Bothagents decrease the escape of albumin in the lungs. Atrialnatriuretic factor increases the peripheral escape of albumin,most likely by increasing the permeability of peripheral cap­illaries,15 whereas endothelin increases transudation of bloodout of the nonpulmonary circulation by increasing capillaryhydrostatic pressure in peripheral areas. Both effects mayincrease peripheral edema but protect the lungs from pulmo­nary edema.

Future Issues.-With the current study by Rodehefferand colleagues as a foundation, future studies should addressseveral questions prompted by this investigation. First, whateffect do medications for heart failure have on release ofendothelin? Many patients were taking several drugs thatmay have affected release of endothelin, and studies of the

Mayo Clio Proc, August 1992, Vol 67

effects of such drugs on release of endothelin have not beenpublished. Second, measurement of circulating levels ofendothelin does not distinguish between enhanced release ofendothelin and diminished clearance of endothelin. Thelatter is particularly likely in the setting of congestive heartfailure because it is commonly associated with a decreasedglomerular filtration rate. A study in which the effects ofdecreased glomerular filtration rates on circulating levels ofendothelin are measured would help distinguish betweenenhanced release and diminished clearance as a cause ofincreased circulating levels of endothelin in heart failure.Third, the assay used to measure endothelin cross-reactswith proendothelin. Therefore, the measured endothelinmay be inactive proendothelin, which would have no effecton systemic vascular resistance. This issue could be ad­dressed by using an assay that does not cross-react withproendothelin for investigating the effects of heart failure onlevels of endothelin. Finally, a study in which systemicvascular resistance is measured in patients with heart failureand in control subjects would help determine whetherchanges in endothelin correlate with changes in systemicvascular resistance. The current study by Rodeheffer and co­workers adds a new dimension to our understanding of thepathophysiologic changes in heart failure and provides use­ful information for future studies of the role of endothelin inheart failure.

Robert S. Zimmerman, M.D.Section of EndocrinologyOchsner ClinicNew Orleans, Louisiana

REFERENCES1. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T,

Goto K, Masaki T: The human endothelin family: threestructurally and pharmacologically distinct isopeptides pre­dicted by three separate genes. Proc Nat! Acad Sci USA86:2863-2867, 1989

2. Miller WL, Redfield MM, Burnett JC Jr: Integrated cardiac,renal, and endocrine actions of endothelin. J Clin Invest83:317-320,1989

3. Zimmerman RS, Martinez AJ, MacPhee AA, Barbee RW:Cardio-renal effects of endothelin-3 in the rat. Life Sci47:2323-2332, 1990

4. Dubin D, Pratt RE, Cooke JP, Dzau VJ: Endothelin, a potentvasoconstrictor, is a vascular smooth muscle mitogen. J VaseMed BioI 1 (No. 3):150-154, 1989

5. ZimmermanRs, Mayrnind M, Barbee RW: The role ofendothelin in hemorrhagic shock (abstract). Am J Hypertens5 (No.5, Part 2):102A, 1992

6. Vemulapalli S, Chiu PJS, Rivelli M, Cedeno K, Coleman W,Sybertz EJ: Tumor necrosis factor and hemorrhage produceelevation of plasma endothelin in rats (abstract). FASEB J4:A456, 1990

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7. Lerman A, Edwards BS, Hallett JW, Heublein DM, SandbergSM, Burnett JC Jr: Circulating and tissue endothelin im­munoreactivity in advanced atherosclerosis. N Engl J Med325:997-1001, 1991

8. Oparil S, Chen Y-F, Hicks P, Elton TS: Normobaric hypoxiastimulates endothelin-l gene expression in the rat (abstract).Am J Hypertens 5 (No.5, Part 2):3A, 1992

9. Zimmerman RS, Martinez AJ, Maymind M, Barbee RW:Effect of endothelin on plasma volume and albumin escape.Circ Res 70: 1027-1034, 1992

10. Miller VM, Komori K, Burnett JC Jr, Vanhoutte PM: Differ­ential sensitivity to endothelin in canine arteries and veins.AmJ Physiol 257:H1l27-H1131,1989

II. Moravec CS, Reynolds EE, Stewart RW, Bond M: Endothe­lin is a positive inotropic agent in human and rat heart in vitro.Biochem Biophys Res Commun 159:14-18,1989

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12. Margulies KB, Hildebrand FL Jr, Lerman A, Perrella MA,Burnett JC Jr: Increased endothelin in experimental heartfailure. Circulation 82:2226-2230, 1990

13. Burnett JC Jr, Kao PC, Hu DC, Heser DW, Heublein D,Granger JP, Opgenorth TJ, Reeder GS: Atrial natriureticpeptide elevation in congestive heart failure in the human.Science 231:1145-1147,1986

14. Edwards BS, Schwab TR, Zimmerman RS, HeubleinDM, Jiang N-S, Burnett JC Jr: Cardiovascular, renal,and endocrine response to atrial natriuretic peptide in an­giotensin II mediated hypertension. Circ Res 59:663-667,1986

15. Zimmerman RS, Trippodo NC, MacPhee AA, Martinez AJ,Barbee RW: High-dose atrial natriuretic factor enhancesalbumin escape from the systemic but not the pulmonarycirculation. Circ Res 67:461-468, 1990