clinical cardiodynamic effects of adrenocortical steroids...

Clinical and Cardiodynamic Effects of AdrenocorticalSteroids in Congestive Heart FailureBy MURRAY A. GREENE, AI.D., ARTHUR GORDON, AI.D., AND

ADOLPH J. BOLTAX, AI.D.

T HE TENDENCY of adrenocortical ste-roids and corticotrophin (ACTH) to

promote salt and water retention, resultingin an inereased extracellular fluid volume, hasbeen established by many investigators.1-'Studies have also demonstrated the impor-tance of excessive activity of the adrenal cor-tex in the pathogenesis of fluid retention andedema formation in various disease states,including heart failure.6 In contrast, so-dium and water diuresis and an improved re-sponse to mercurial diuretics, accompanied byclinical improvement, were reported in somepatients with congestive heart failure duringor following the administration of cortico-steroids and ACTH.12-19 The need to eluci-date the problem of the effects of these agentsin heart failure and the role of adrenal corti-coids in the formation of edema are the basisfor the present study of the effects of corti-costeroids upon the clinical status, electrolytebalances, and cardiovascular dynamics in agroup of subjects having heart disease ofvaried etiologies and congestive failure ofvarying severity.

Materials and MethodsNine patients, 4 female and 5 male, with con-

gestive heart failure are the subjects of this study(table 1). Ages ranged from 17 to 65 vears. Thepatients are further classified according to etiology,functional capacity (New York Heart Associa-tion), and clinical status in table 1. Varied etiolo-gies and mild to severe degrees of heart failureare represented.

The patients were hospitalized throughout thestudy and were semi-aimbulatory or restricted tobed rest according to their functional capacities.

From the Department of MIedicine, The BronxHospital, New York, N. Y.

Supported in part by a grant from The JohnPolachek Foundation for Medical Research and inpart by a grant (H-4344) from the National Insti-tutes of Health, U. S. Public Health Service.

Circulation, Volume XXI, May 1960

A steady clinical state of at least 5 to 7 days' dura-tion was required as a control period prior tophysiologic testing. This state was maintained bythe usual therapy for congestive heart failure andincluded a standard lowv-salt diet (less than 2 to 3Gm. of sodium ehloride daily). Mercurial diureticswere not given during this control period althoughmost patients had received this therapy during thecourse of their previous illness.During the control period, routine clinical ob-

servations were made and pertinent laboratory dataobtained. Radioiodine uptakes by the thyroidgland were measured in order to evaluate the pos-sibility that depression of thyroid function bysteroids may secondarily affect clinical states andcardiodynaiies. Phenolsulfonphthalein excretionsand urea clearances were measured as gross indicesof renal function. Fluid balances were evaluatedaccording to daily fasting weights, daily urine out-puts, and frequent determinations of serum andurine electrolytes.

Physiologic studies of cardiovascular hemody-namics by the standard technic of right heartcatheterization were then performed (tables 2Aand 2B). The patients were in the resting recum-bent positions and were not given premedication.Duplicate measurements of cardiac output (directFick) were made. Pressures were obtained with theuse of Statham strain-gage transducers (P23A)and recorded on a multichannel oscillographic pho-tographic recorder. Mean pressures were obtainedby electrical integration of the pressure pulses.Since flow and pressure miieasuremiients did not varysignificantly during single studies, olnly averagevalues are tabulated. Total pulmonary vascular,pulmonary "arteriolar," and total peripheral arte-rial resistances were calculated according to stand-ard formulas (Poiseuille). Resistance is expressedas dynes see. ci.-5 by the use of conversion fac-tors.: Total plasma volumiies were determined bythe I131-labeled human serum albumin methodand converted to total blood volumes by the useof peripheral hematocrit values. Predicted plasmavolumes for either sex were based on the studiesof Samet et al.20 These values are essentially simi-lar to those reported by other investigators. Pul-

*1,332 = conversion factor fronm mmn. Hg to clynescm.4

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STEROIDS IN CONGESTIVE FAILURE

monary vital capacities and maximum breathingcapacities were obtained the day prior to cathe-terization with the modified Benedict-Roth spirom-eter.

After the control clinical and physiologic studieswere completed, adrenocortical steroids were ad-ministered for 13 to 16 days (table 1). Six pa-tients received prednisone and 3 received triameino-lone." These agents were selected because of theirdiminished tendency to cause soduim and waterretention, edema, and potassium depletion as com-pared to other agents.21-25 None of the other usualcontraindications to steroid therapy was present.

Clinical status, routine laboratory data, and fluidbalances were evaluated throughout the phase ofsteroid therapy. Radioiodine uptakes by the thy-roid gland were measured prior to repeat cardiaccatheterization. The previously stabilized cardiacregimen was continued during this period. Mer-curial diuretics were given whenever warranted bythe development of appreciable aggravation of elin-ical heart failure. Supplementary potassium ther-apy was not given.

Right heart catheterization and blood volumedeterminations were then performed on the lastday of steroid administration; vital capacities andmaximum breathing capacities were determined onthe day prior to catheterization (tables 2A and2B).

Clinical status and fluid balances were observedin some patients for several days following steroidwithdrawal.

Changes in cardiovascular hemodynamics as aresult of drug administration were evaluated interms of statistical probabilities. In order to de-termine whether these changes may have been dueto chance variation, or due to the action of anintroduced variable (steroids in this study), 29consecutive right heart catheterizations in this lab-oratory in adults with varied types of heart diseaseand with varying degrees of conlgestive failure were

**The authors wish to thank The Squibb Institutefor Medical Researeh, New Jersey, for their supplyof triameinolone, (Kenaeort ®).

*S. Tinie periods are denoted in this column.

analyzed. In each of these studies at least 2 con-trol "resting" cardiac output deternminations (directFick), multiple pressure measurements, and resist-ance calculations were performed at intervals of22 to 143 nminutes (average 41 minutes), while thepatients' states were considered to be constant.Chance or expected variations in terms of 95 percent confidence limits (2 standard deviations fromthe mean variation) were established on this basisfor the various measures of cardiovascular hemo-dynamics. A wide range of abnormalities in cardio-dynamics was present in this control group, aswould be expected in any series of patients withheart disease and congestive failure. It was there-fore thought that greater reliability in an evalua-tion of the results would exist if these confidencelimits were expressed in terms of percentage varia-tions rather than changes in absolute values. Twoexceptions are pulmonary "wedge" and right ven-

tricular end-diastolic pressures. These parametersare expressed in terms of absolute changes becauseonly mininmal variations usually occur during a

''resting" state and because small variations intheir usually low num-lerical values frequently re-

sult in inordinately high percentage changes.Changes in cardiovascular dynamics in the pres-

ent series of 9 patients who received steroids were

then evaluated in terms of statistical significanceat the 5-per cent level. Changes that are consid-ered to be statistically significant are appropriatelyindicated in tables 2A and 2B. It is appreciatedthat appraisals of the 2 sets of data in these sub-jects may not be strictly comiiparable with those ofthe control group because of the differences in timeintervals. The possibility of greater variations in"resting" states may exist when studies are sep-arated by greater time intervals. This factor doesnot appear to represent a major difficulty, how-ever, since miietabolic states could be studied andcompared on the basis of oxygen consumptionsand respiratory quotients.

ResultsThree types of responses to steroid adminis-

tration occurred in this series of patients:

I, control observation period prior to initialphysiologic studies; II, during the period of steroid administration (maximal changes andtheir time of occurrence are indicated); III, immediately prior to the repeat physiologicstudies.

tDyspilea. Severe if at rest, moderate if during mild effort, and slight if only duringmoderate effort.

+Edema. Marked if involving more than lower extremities (presacral, abdominal wall),slight, if involving ankles.

AI, aortic insufficiency; AS, aortic stenosis; CHF, congestive heart failure; CP, cor pul-monale; E, emphysema; HHD, hypertensive heart disease; IMH, idiopathic myocardial hyper-trophy; MI, mitral insufficiency; MS, mitral stenosis; PF, pulmonary fibrosis; RHD, rheu-inatic heart disease.


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Increases in congestive heart failure (5 pa-tients), no significant changes in clinical states(3 patients), and improvement in clinicalstate and in cardiodynamics (1 patient).

Increases in Congestive Heart Failure

Clinical heart failure increased in severityin 5 (cases 1 to 5) of the 9 patients duringsteroid therapy (table 1). In 4 of these pa-tients (cases 1 to 4) slight to mnoderate reduc-tions in daily urine volumes occurred concomi-tant with increases in weight, indicating posi-tive fluid balances. Laboratory data suggest-ed worsening of hepatic function (increasedbromsulfalein retention) and renal function(increased blood urea nitrogen and decreasedurea clearance) in some patients of this group.All initially had normal 24-hour radioiodineuptakes (thyroid); no changes occurred dur-ing steroid therapy. Parenteral mercurialdiuretics were given to 4 patients (cases 2 to5) because it was considered hazardous to per-muit the deteriorated clinical conditions to per-sist. Responses to this therapy were poor.Hyponatremia and hypochloremia existed

in 2 patients in the control period, slight inone (case 1) and marked in the other (case 3).During steroid therapy slight depression ofserum sodium occurred in 2 patients (cases1 and 4) and of serum chloride in 2 (cases Iand 3). In all 5 patients daily urine sodiumand chloride exeretions were markedly de-pressed in the control period. During steroidtherapy excretion of these ions did not changeor decreased slightly in 4 patients, whereasani increase occurred in 1 (case 2).At the time of the second physiologic

studies, 1 patient (case 1) who did not re-ceive mercurials had a weight gain of 6pounds and considerable increase in heartfailure, and another (case 2) was somewhatimproved by mercurial therapy but was stillworse than his control state as well as 2pounds heavier. The others had resumed theircontrol clinical states after mercurial therapyalthough 2 (cases 3 and 5) were 2 and 4pounds lighter.

In 1 patient (case 3) the second catheteri-zation was unsuccessful. In the others very

few statistically significant changes in cardio-dynamics occurred (tables 2A and 2B). Thislack of change could be attributed to the ap-preciable neutralization of the clinically ob-vious detrimental effects of steroids by mer-curial therapy, which was administered untilclinical improvement was obtained.

Total plasma volumes were elevated ini-tially in all 5 patients, but they did not changemuch after steroid therapy. Slight falls inplasma volumes in 3 patients may well haveresulted froni mercurial diuretics used to com-bat congestive failure. No significant changesin vital capacities and maximum breathingcapacities occurred as a result of steroid ad-ministration. In 3 patients (cases 1 to 3) inwhom fluid balances were measured for sev-eral days following steroid withdrawal, nosignificant changes occurred in weights, urinevolumes, and urinary excretions of elec-trolytes.No Significant Changes in Clinical States

In 3 patients (cases 6 to 8) no changes inclinical heart failure occurred during steroicdadministration (table 1). A weight loss of 5pounds was noted in 1 patient (case 8). Mark-ed anorexia and diminished food intake aswell as a decline in urine output and in uiin-ary sodium and chloride exeretions suggestedthat this weight loss was due to a decreasein tissue mass rather than to a diuretic re-sponse. No changes occurred in laboratorydata or in 24-hour radioiodine uptake by thethyroid gland. In 2 patients (cases 6 and 7)control 24-hour urine sodium and chlorideexeretiolis were within normal limits; in theother patient excretions of these ions weredimninished. Moderate reductions in daily so-dium and chloride excretions occurred inthese 3 patients during steroid administration.No significant changes in cardiodynamics

occurred as a result of corticosteroid adminis-tration except for a decrease in right ventricu-lar end-diastolic pressure and pulnionary"arteriolar'" resistanee in 1 patielnt (case 7)(tables 2A and 2B).Total plasma volumes were elevated initial-

ly in all 3 patients. In 2 (eases 6 and 7)Circulation, Volume XXI, May 1960

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slight to moderate decreases occurred duringsteroid therapy; in 1 (case 8) a moderateincrease occurred.No significant changes in vital capacities

and maximum breathing capacities occurredas a result of steroid therapy. In 2 patients(cases 6 and 8) in whom fluid balances werestudied for several days following steroidwithdrawal, no changes occurred in bodyweights, urine volumes, and urine electrolyteexcretions.

Improvement in Clinical State and in Cardiody-namics

In the patient (case 9) with pulmonaryfibrosis and emphysema and cor pulmonaleas the basic disease, there was an improve-ment in dyspnea during steroid therapy (table1). However, a weight gain of 4 to 5 poundsand a slight decrease in daily urine outputoccurred concomitantly. There were nochanges in routine laboratory data or in radio-iodine uptake by the thyroid gland. A slightfall in serum chloride occurred.Improvement in cardiodynamics resulted

from administration of corticoids (tables 2Aand 2B). There were a significant increasein cardiac output and lowered pulmonaryartery systolic and mean pressures and rightventricular end-diastolic pressure. Althoughthese changes in pressures may have been dueto corresponding changes in intrathoraciepressure (which was not measured), the simi-larity of pulmonary "wedge" pressures inboth studies suggests that the decreases inpulmoonary artery and right ventricular pres-sures were due to decreases in effective intra-vascular pressures. Pulmonary vascular andpulmonary "arteriolar" resistances also de-creased significantly. Qxygen consumptionwas higher during the second study and mayhave indicated some change in metabolic state.Nevertheless, the data indicate improvementin dynamics. Total plasma volume increasedslightly with steroid therapy. Minimal, ifany, improvement in vital capacity and maxi-mum breathing capacity occurred.No changes in fluid balance occurred fol-

lowing steroid withdrawal.Circulation, Volume XXI, May 1960

Discussion

The effects of ACTH and adrenal corticalsteroids upon renal and cardiovascular sys-tems in man and experimental animals havebeen far from uniform, so that generaliza-tion about the specific activities of these hor-inones is most difficult. The tendency of thesehormones to promote salt and water retentionand, consequently, an increase in extracellu-lar fluid volume has been observed by manyinvestigators.1-5, 26 Corticoids that have prom-inent actions of this type include desoxy-corticosterone, cortisone, hydrocortisone, andaldosterone. Newer synthetic derivativeshave distinctly less tendency to cause saltand water retention although positive fluidbalance has been observed, especially withhigher dosages.2' 25 In contrast, some studiesdemonstrate that these hormones may possessdiuretic properties. Davis and Howell27 ob-served that both ACTH and cortisone pro-duced an initial loss of salt and water in theintact dog. Other authors have reportednatriuresis and chloruresis during the ad-ministration of ACTH in man28 and in therat.29 Gaunt, Birnie, and Eversole30 citedexperimental data indicating that corticalhormones may produce diuresis in animalswith normal water balance, in overhydratedones, and even in mildly dehydrated ones.

In view of this diversity of steroid actions,it is not difficult to understand the uncer-tainties regarding clinical applicabilities ofthese hormones in patients with diseases char-acterized by positive fluid balanees, particu-larly congestive heart failure. This difficultyis further compounded by studies that havedemnonstrated increased activity of endogenoussalt-retaining adrenal cortical hormone, aldo-sterone, in these diseases.7 T31-33 In gen-eral corticoids have been used with cautionin these conditions because of their tendeneyto promote salt and water retention. Vari-ous investigators, however, have reported fav-orable results following the administration ofthese hormones to patients with congestiveheart failure.12-19 Results, however, were notuniform in all studies. Some patients had

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cliniical and hemodynamic deterioration prob-ably due to renal retentioni of salt an-d water.12In another study'8 a small number of pa-tients demonstrated decreased urinary sodiuimexcretion, inerease in weight, and possiblyinerease in dyspnea.The present study was undertaken to eluci-

date the effects of adrenal cortieoids in conl-gestive heart failure. In the 5 of the 9 pa-tients in this series subjective anid objectiveclinical manifestations and laboratory dataindicated positive fluid balalnces with increas-ed fluid accumulationi anid inereased cardiacdeeompensation during the phase of steroidtherapy. Respolnses to mnercurial diureticswere poor. Heightened responsiveness dur-ing steroid therapy was lnot observed in anypatient in this study. An evaluation ofcardiodynamic changes is more difficult be-cause of the effects of additional diuretiemeasures given to 4 patients during steroidtherapy. These agents were givenl because ofthe development of precarious clinical condi-tions. It is therefore not surprising that 11osignificant changes in cardiodynamics andsome decreases in plasma volunmes were notedin those patients given miiercurial diureticsuntil clinical improvement occurred. In 1 pa-tient (case 2) who was clinically worse andhad an inerease in plasma volume (in spite of2 mercurial injections) at the time of thesecond cardiac catheterizationi significant in-creases occurred in pulmoonary artery anIdright ventricular end-diastolic pressures.

In 3 of the remaining 4 patients no changesin cliniical status occurred durinig steroidtherapy. Somue diminution in urinary sodiumand chloride excretions occurred in these pa-tients although the depressioln present in thefirst group was nlot observed. One patient(case 8) had a reduction in circulating volumneand a deeline in right venitricular elnd-diastolicpressure. A minimal inerease in daily urin-arv volunme in this patient would not appearto account completely for the diminution ineirculatilng volume although it could have con-tributed to it. Another possibility may bethat of internal fluid shifts.

In 1 patienlt (case 9') eliuiical symptoms

improved durinig steroid therapy. This wasthe only subject who had pulmonary fibrosisand emphysema with cor pulmionale. Thispatienlt had imnprovement in cardiodylnamicisdespite a positive fluid balanee. It wouLldbe difficult in this case to define the primarymode of action of the steroid frolm the limit-ed amount of data available concerniing pri-marv pulmoinary functions. Possibilities in-elude improvemieint in pulmonary iniflamma-tion, bronelhomotor tone, anid vascular resis-tance, causilng a decline in right heart workload and, conisequently, improvement in rightheart function. Other workers have describedfavorable clinical results and improvenmentsin pulmaonarv function following corticoster-oid therapy in patients with chronic pul-muonarv disease.34 This ease is of initerestin that clinical an-d hemodyniamie improve-mnent occurred onlv in that patient who didnot have uncomitplicated heart failure. Fac-tors were probably presenit that are kniowln tobe favorably affected by corticosteroids, e.g.,iniflammnatioin, and so forth. It is also prob-able that the additional fluid retained wasdistributed throughout the body compart-menets and any7 inierease in fluid that miighthave occurred in the right heart was nmorethan compensated bv the favorable primaryeffect on the cardiopulmonary systeuis.

It is difficult to delineate those factors thatmay favor fluid retention during steroidtherapy in some patients anid not in others.The patienits whose heart failure inereasedwere those who gelnerally seemed to haavegreater degrees of decompensation character-ized bv severe subjective maniifestations, co'n-siderable fluid accumnulationi, alnd marked de-pressionis in sodium. anid chloride exeretions.Comparisoln of cardiovascular dyianmics be-tween the first 2 groups reveals much overlap-ping in many of the mneasurements. However.the generally higher pulmonary "wedge" andright ventricular enid-diastolie pressures andtotal plasma volumes in those patients worsen-ed by steroids suggest that deteriorationi ismore likely to be produced in those patientswho already have conisiderable fluid accumula-tion. The addition of agents that can retaini


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salt and water simply increases the severityof the existing positive fluid balance.

It is difficult to explain the differences inresults in the present study from those re-

ported by others, 12-19 in which diuresis andclinical improvement were noted in many pa-

tients with congestive heart failure. Evalua-tion of the effects of prolonged administrationof various drugs in heart failure may be haz-ardous in view of the spontaneous variationsthat may occur in this state. Strict selectionof patient miaterial is also important. Sub-jects who are in a steady clinical state are beststudied; those who have had acute deteriora-tion in cardiac funetion prior to drug admin-istration may not be satisfactory subjects forthis way suggest variable extralneous adversefactors which by their presence or remittaneemay influence results. Concomitant therapythat nmay be detrimental to subjects with heartfailure should be avoided. One group of in-vestigators maintainied high levels of waterintake before anid during steroid administra-tion.'5-1' Leiter35 has reviewed data which in-dicate that subjects with congestive failuremay retain water excessively (resembling theeffects of excessive antidiuretic hormone),leading to a worseninig of elinical status. Ster-oids may have prevented overhydration inthese patientsl'5 16 as it does in water intoxi-cation aiid as an anitagonist to antidiuretichormone30' 36, 37 and niav niot have affectedany of the originally existing abnormal eardi-ovascular-renal hemodvnaniies.

Patients were selected for the presenit studywho were in a steady clinieal state and whohad heart disease of varied etiologies and ofvarying severity and no other condition thatcould be favorably affected bv steroids, espe-

cially infectious diseases and overt inflanmma-tory processes. The one exception was thepatient with pulmuonary fibrosis and emphy-sema. The results in this patient demonstratethe need for care in patient selection. Thephase of drug adminiistration was restrictedto 13 to 16 days to miinimize the possibility ofspontaneous change in disease states.Further work with agents that more spe-


cifically antagonize endogenous fluid-retainingfactors may prove fruitful in patients withcongestive heart failure. The prominent roleof endogenous adrenocortical hormones (espe-cially aldosterone) in retaining fluid and inpromoting formation of edema in patientswith heart failure has recently been empha-sized. Drugs that may antagonize these hor-mones would be most important.38

SummaryThis study is concerned with the effects of

adrenocortical steroids in patients with con-gestive heart failure.Nine adults with heart failure were studied

during a steady clinical state (5 to 7 days),during administration for 13 to 16 days ofprednisome (6 patients) or triameinolone (3patients) and in some subjects following ster-oid withdrawal. Daily determinations offluid balances were made. Standard rightheart catheterizations and inieasurements ofblood volumes were performed prior to andat the terminiation of therapy.

Three types of responses to steroids oc-curred. In 5 patients increases in subjectiveand objective manifestations of heart failureand increased fluid retention occurred. Fourof them developed precarious clinical condi-tions during steroid therapy, requiring mer-curial diuretics, but with poor results. Ingeneral, cardiodynamie status at the termin-ation of steroid therapy correlated well withclinical status. In 3 patients the clinicalstatus did not change. Some depression inurinary sodium and chloride excretions werenoted during therapy. Cardiodynamics wereunaltered, except for an unexplained decreasein right ventricular end-diastolic pressure in1 patient. In 1 patient elinical and cardio-dynlamic state improved, despite positive fluidbalance. This was the only subject withprimary lung disease (emphysema) and cor

pulmonale.These studies suggest that corticosteroids

are generally detrimental in uncomplicatedcongestive heart failure. Greater deteriora-tion appeared in subjects having the moresevere degrees of decompensation, suggesting

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that exogenous fluid-retaininig influences wereadded to endogenous fluid-retaining forces,resulting in further accumulation of fluid ina circulatory system already burdened by hy-pervolemia.

AcknowledgmentThe authors wish to express their appreciation to

Miss Olga Gallego and Mrs. Josephine Damsky fortheir valuable assistance in the conduct of this study,and to Dr. Aaron S. Goldberg, Chemistry Depart-ment, The Bronx Hospital, for supplying the bloodand urinary chemical analyses.

Summario in InterlinguaIste studio es coneernite con le effectos de steroides

adrenocortical in patientes con congestive disfalli-mento cardiac.Novem adultos con disfallimento cardiac esseva

studiate in un stabile stato clinic (pro periodos de 5 a7 dies), durante 13 a 16 dies de administration deprednisona (6 patientes) o triameinolona (3 pati-entes), e in certe casos post le finl del curso de medi-cation steroide. Esseva effectuate determinationesdiurne del balancias de liquido. Catheterismo dexterestandard e mesuration del volumine de sanguine essevaeffectuate ante le initiation del therapia e post sutermination.

Occurreva tres typos de responsa al administrationdel steroides. In 5 patientes il habeva subjective eobjective augmentos del manifestationes de disfalli-mento cardiac e augmentos del retention de liquido.Quatro del cinque disveloppava precari conditionesclinic durante le therapia steroide. Tlles requireva(liureticos mercurial, sed le resultatos non esseva bon.A generalmente parlar, le stato cardiodyniamic altermination del therapia steroide se monstrava bencorrelationate con le stato clinic. In 3 patientes lestato clinic non se alterava. IJn certe depression delexcretion urinari de niatrium e chloruro esseva notatedurante le therapia. Le cardiodynamnica remanevainalterate, con le exception del occurrentia de uninexplicate reduction del tension dextero-ventricularterinino-diastolic in 1 patiente. In 1 patiente le statoclinic e carcdiodynamic se meliorava in despecto de unpositive balanicia de liquido. Iste patiente esseva lesol con primari morbo pulmonar (emphysemna) e cordepulmonial.Le hie reportate studios suggere que corticosteroides

es generalmente detrimentose in non complicate casosde congestive disfallimento cardiac. In subjectos conplus sever grados de discompensationi le deteriorationesseva plus mareate. Isto pareva indicar que exogeneinfluentias liquido-retentori esseva addite, con le re-sultato de un accumulation additional de liquido inun systema eirculatori jam suffrente de hypervolemia.

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MURRAY A. GREENE, ARTHUR GORDON and ADOLPH J. BOLTAXHeart Failure

Clinical and Cardiodynamic Effects of Adrenocortical: Steroids in Congestive

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1960 American Heart Association, Inc. All rights reserved.

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