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Comparison of Neuroendocrine Activation inPatients With Left Ventricular DysfunctionWith and Without Congestive Heart Failure

A Substudy of the Studies ofLeft Ventricular Dysfunction (SOLVD)

Gary S. Francis, MD, Claude Benedict, MD, DPhil, David E. Johnstone, MD,Philip C. Kirlin, MD, John Nicklas, MD, Chang-seng Liang, MD, PhD,

Spencer H. Kubo, MD, Elizabeth Rudin-Toretsky, MS, and Salim Yusuf, MRCP, DPhil,for the SOLVD Investigators

Neuroendocrine activation is known to occur in patients with congestive heart failure, but thereis uncertainty as to whether this occurs before or after the presence of overt symptoms. In theStudies of Left Ventricular Dysfunction (SOLVD), a multicenter study of patients with ejectionfractions of 35% or less, we compared baseline plasma norepinephrine, plasma renin activity,plasma atrial natriuretic factor, and plasma arginine vasopressin in 56 control subjects, 151patients with left ventricular dysfunction (no overt heart failure), and 81 patients with overtheart failure before randomization. Median values for plasma norepinephrine (p=9.0001),plasma atrial natriuretic factor (p<0.0001), plasma arginine vasopressin (p=0.006), andplasma renin activity (p=0.03) were significantly higher in patients with left ventriculardysfunction than in normal control subjects. Neuroendocrine values were highest in patientswith overt heart failure. Plasma renin activity was normal in patients with left ventriculardysfunction without heart failure who were not receiving diuretics and was significantlyincreased (p<0.05) in patients on diuretic therapy. We conclude that neuroendocrineactivation occurs in patients with left ventricular dysfunction and no heart failure. Neuroen-docrine activation is further increased as overt heart failure ensues and diuretics are added totherapy. (Circulation 1990;82:1724-1729)

C ongestive heart failure is a complex clinicalsyndrome with varying pathophysiology andclinical expression. It is well known that

overt heart failure is characterized by activation ofseveral neuroendocrine systems.' Plasma norepi-nephrine (PNE)2 and plasma atrial natriuretic factor(ANF)3 are increased and known to be prognosticfactors in patients with heart failure. Activation ofthe renin-angiotensin system is common in patientswith advanced heart failure. Angiotensin convertingenzyme inhibitor therapy improves survival inpatients with advanced heart failure,4 suggesting that

Supported by the National Heart, Lung, and Blood Institute,National Institutes of Health, Bethesda, Md.Address for reprints: Salim Yusuf, MRCP, DPhil, SOLVD

Project Officer, Division of Epidemiology and Clinical Applica-tions, Clinical Trials Branch, National Heart, Lung, and BloodInstitute, National Institutes of Health, Federal Building, Room5C10, 2550 Wisconsin Avenue, Bethesda, MD 20892.

Received February 27, 1990; revision accepted June 26, 1990.

the renin-angiotensin system plays an important rolein the pathogenesis of symptomatic heart failure. Ithas been unclear, however, whether neuroendocrineactivation occurs in response to the clinical featuresof heart failure or in patients with asymptomatic leftventricular dysfunction. The identification of veryearly neuroendocrine activation has important ther-apeutic implications because early introduction oftreatment designed to block certain neuroendocrineactivation may prevent progression of ventriculardilatation5'6 and may prevent development of clinicalheart failure. Studies in animals have demonstratedthat converting enzyme inhibitor therapy introducedearly in the course of left ventricular dysfunction mayprevent progressive neuroendocrine activation7 andleft ventricular remodeling8 and improve survival.9The first purpose of our study was to determine ifpatients with left ventricular dysfunction who wereasymptomatic or only mildly symptomatic (no overtheart failure) have neuroendocrine activation. Sec-

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Francis et al Neuroendocrine Activity and Heart Failure 1725

ond, we compared neuroendocrine levels in patientswith left ventricular dysfunction with values inpatients with overt congestive heart failure.

MethodsStudy DesignThe Studies of Left Ventricular Dysfunction

(SOLVD) is a multicenter study encompassing twotrials. First, the prevention trial is designed to test thehypothesis that enalapril, a converting enzyme inhib-itor, will prevent the development of clinical heartfailure and reduce mortality in patients with leftventricular dysfunction (ejection fraction, c35%)who do not yet require digitalis or diuretics forcontrol of signs or symptoms of congestion (preven-tion group). Patients in the prevention group mayreceive diuretics for the treatment of hypertensionand digitalis for control of ventricular heart rate inatrial fibrillation. The treatment trial is designed totest the hypothesis that enalapril will reduce mortal-ity in patients with left ventricular dysfunction (ejec-tion fraction, <35%) and symptomatic heart failurerequiring therapy with digitalis, diuretics, and/ornonconverting enzyme inhibitor vasodilators (treat-ment group). Both trials contain a placebo controlgroup. It was decided in advance to measure PNE,plasma renin activity (PRA), plasma ANF, andplasma arginine vasopressin (AVP) in a subset of atleast 200 patients before their randomization toplacebo or enalapril in both the prevention andtreatment trials of SOLVD and to compare thesevalues with those from a group of control subjectswithout cardiovascular disease. Collaboration wasinvited from all 23 participating SOLVD centers, and17 centers agreed to collaborate (see "Appendix").

Patient SelectionPatients were selected for SOLVD if they were not

receiving angiotensin converting enzyme inhibitorsand had a left ventricular ejection fraction of 35% orless by radionuclide ventriculography, contrast ven-triculography, or two-dimensional echocardiographywithin the previous 3 months. Patients were excludedif they had acute myocardial infarction within 30days, valvular or outflow tract obstruction requiringsurgery, constrictive pericarditis, complex congenitalheart disease, planned cardiac surgery, advancedpulmonary disease or cor pulmonale, uncontrolledhypertension (> 140/95 mm Hg), significant liver dis-ease, or other life-threatening disorders. Data collec-tion for the neuroendocrine substudy began in 1987and continued until November 1988. All consecutivepatients who were willing to participate wereenrolled.One-hundred fifty-one patients recruited for the

prevention group had neurohormones measured(Table 1). Average age was 59±+11 (+SD) years andranged from 21 to 79 years. Twenty percent ofpatients were taking diuretics for hypertension, and13% were taking digitalis for control of arrhythmias,

TABLE 1. Patient Characteristics

nAge (yr)Sex (% male)Ejection fraction (%)Ischemic heart disease (%)Diuretic use (%)Digitalis use (%)Serum sodium (meq/l)Serum potassium (meq/l)Blood urea nitrogen (mg%)Serum creatinine (mg%)Hematocrit (%)

Control56

56.4±11.670

Group

Prevention

15159.2±10.6

8729±5822013

140±2.54.3±0.617.3±5.01.1±0.3

42.5±4.1

Treatment

8162.7+9.4

7926±6858959

140+3.14.2+0.519.9±6.51.2+0.3

41.5±4.6

usually atrial fibrillation. Men composed 87% of thegroup. Underlying ischemic heart disease was pres-ent in 82%. Average left ventricular ejection fractionin the prevention group was 29+±5%.

Eighty-one patients recruited for the treatmentgroup of SOLVD had neurohormones measuredbefore randomization. Average age was 63±9 yearsand ranged from 34 to 79 years. Mean ejectionfraction was 26±6%. Diuretics and digitalis werebeing used by 89% and 59%, respectively. Underlyingischemic heart disease was present in 85% ofpatients. Men composed 79% of the group. Thesubset of patients participating in the neuroendo-crine substudy is broadly comparable to the largergroup of patients entering SOLVD, except for asomewhat higher rate of coronary artery disease andlower use of digitalis in the treatment group ofsubstudy patients.

Fifty-six control subjects were also studied. Controlsubjects were recruited by each clinic and wereeligible if there were no historical or physical findingsof heart disease or hypertension. Friends and rela-tives of patients frequently participated as controlsubjects if they were clinically free of heart disease orhypertension. None was taking medications known toinfluence neurohormones. Men composed 70% ofthe control group. The average age was 56±12 yearsand ranged from 37 to 80 years.The protocol was approved by the local hospital

review boards. All control subjects and patientsprovided written informed consent to participate inthe study.

Neuroendocrine MeasurementsAn intravenous cannula (short 18- or 20-gauge

plastic catheter connected to a three-way stopcock)was inserted. The catheter was filled with diluteheparinized saline, and samples were obtained after30 minutes of supine rest. After we aspirated anddiscarded the catheter dead space, blood was with-drawn into a plastic syringe. Five milliliters were

-

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1726 Circulation Vol 82, No 5, November 1990

placed into a prechilled tube containing reducedglutathione and calcium chelator EGTA preservativefor PNE analysis. The sample was centrifuged within1 hour at 40 C at 2,500 rpm for 12 minutes. Plasmawas then transferred to a polypropylene tube andstored at -20° C or colder temperature. Five millili-ters for PRA analysis were placed into an evacuatedtube containing liquid potassium and EGTA. Thetube was inverted several times and centrifugedwithin 1 hour of collection at 40 C at 2,500 rpm for 12minutes. Plasma AVP and ANF samples were placedin evacuated, prechilled EGTA tubes. Centrifuge,transfer, and storage were similar to those for PNEand PRA. Collection of blood samples occurredbetween approximately 8:00 AM and 5:00 PM.

Samples were shipped on dry ice for analysis to theSOLVD Neuroendocrine Core Laboratory at theUniversity of Texas at Galveston.

Neuroendocrine AssaysPNE levels were measured by a radioenzymatic

method using the enzyme catechol-o-methyltransferase.10 PRA was measured using the modifiedradioimmunoassay technique of Sealey and Laragh.1"Plasma AVP and ANF were measured by a simplifiedradioimmunoassay using commercially availableantibodies.'2 All samples were analyzed withoutknowledge of the patient's clinical condition.

Sensitivity and Reproducibility ofAssaysThe radioenzymatic assay for PNE has a sensitivity

of 1 pg/ml, which yields a sample-to-blank radioac-tivity count ratio of more than 2. In addition, theinterassay coefficient of variation is 6.1% (calculatedfrom 20 different assays done consecutively on 20different days). The radioimmunoassay for PRA isdependent on the sensitivity of the antibody used inthe assay, which can reliably detect 2 pg angiotensinI (sample-to-blank ratio, 2). This assay can detectvery low PRA (0.1 ng/ml/hr). The interassay coeffi-cient of variation for PRA is 13.6% The radioimmu-noassay for ANF has a sensitivity of 2 pg/ml, and thesensitivity for AVP is 0.22 pg/ml. The interassaycoefficients of variation for ANF and AVP are 13.7%and 11.6%, respectively.

Additionally, previously assayed test samples ofPNE were mailed from the core laboratory to theclinics where they were stored and then returned andreanalyzed to assess the stability of the samplesduring transportation. There was no significant dif-ference in the PNE values (278±+28 versus 269±+32pg/ml,p=NS) in 123 samples studied in this fashion.

StatisticsAlthough mean values are presented, neuroendo-

crine data are also expressed in median values andtheir interquartile intervals (25% and 75% percen-tile) because the values were not normally distrib-uted. The Wilcoxon rank-sum test was used to makecomparisons between any two groups, and the

Kruskal-Wallis test was used to compare the data forall three groups.

ResultsDetailed history and physical examination indi-

cated that the majority (>80%) of the patients in theprevention group had no signs or symptoms of heartfailure. On the contrary, the majority (>90%) of thepatients in the treatment group had signs and symp-toms of heart failure. Ischemic heart disease was thedominant etiology in both groups. There was nosignificant difference between the prevention andtreatment groups regarding the time from acutemyocardial infarction to randomization. The overallresults of the baseline neuroendocrine values for thethree groups are shown in Table 2 and Figure 1. Bothmean and median values, as well as overall signifi-cance, are shown in Table 2. Also shown is theinterquartile range (25% to 75%). The median PNEwas 317 pg/ml (242-450 pg/ml) in the control groupcompared with 422 pg/ml (312-566 pg/ml) in theprevention group and 507 pg/ml (368-644 pg/ml) inthe treatment group. The median PRA was 0.60ng/ml/hr (0.3-0.9 ng/ml/hr) in the control groupcompared with 0.7 ng/ml/hr (0.3-1.6 ng/ml/hr) in theprevention group and 1.4 ng/ml/hr (0.5-3.8 ng/ml/hr) in the treatment group. The median ANF levelwas 48 pg/ml (31-65 pg/ml) in the control groupcompared with 103 pg/ml (69-139 pg/ml) in theprevention group and 146 pg/ml (91-203 pg/ml) inthe treatment group. The median plasma AVP was1.8 pg/ml (1.4-2.3 pg/ml) in the control group com-pared with 2.2 pg/ml (1.7-3.0 pg/ml) in the preven-tion group and 3.0 pg/ml (2.3-4.4 pg/ml) in thetreatment group.The median values in the prevention group are all

significantly greater than those in the control group,and the values in the treatment group are all signifi-cantly greater than those in the prevention group(Figure 1). However, PRA was only marginallyincreased in the prevention group compared with con-trol subjects (p=0.03); this could be accounted for bythe fact that 20% of these patients were taking diureticsfor hypertension. The data were therefore reanalyzedaccording to diuretic use. The values for PNE, ANF,and AVP were still significantly elevated in both pre-vention and treatment groups. However, PRA was notsignificantly elevated in prevention patients not ondiuretics (Table 3). This implies that virtually all of theincrease in PRA is accounted for by diuretic use. Themedian value for PRA, with or without diuretic ther-apy, is within the normal range in the prevention group.The patients in the treatment group who are not ondiuretics also have a normal PRA, but the number ofsuch patients is very small (n=9).

DiscussionThis study demonstrates that patients with a left

ventricular ejection fraction of 35% or less who havebeen judged by their physician to not need treatment

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Francis et al Neuroendocrine Activity and Heart Failure

TABLE 2. Mean and Median Neuroendocrine Levels in Prevention Patients, Treatment Patients, and Control Subjects

Neuroendocrine Interquartile rangemeasurement Trial n Mean Median (25% to 75%) p

PNE Control 54 346 317 242-450 0.0001(pg/mi) Prevention 151 468 422 312-566

Treatment 81 576 507 368-644

PRA Control 56 0.7 0.6 0.3-0.9 0.0001(ng/ml/hr) Prevention 151 1.4 0.7 0.3-1.6

Treatment 80 2.6 1.4 0.5-3.8

AVP Control 54 2.0 1.8 1.4-2.3 0.0001(pg/ml) Prevention 147 2.6 2.2 1.7-3.0

Treatment 80 3.5 3.0 2.3-4.4

ANF Control 54 51.4 48.3 31-65 0.0001(pg/mi) Prevention 147 117.3 102.8 69-139

Treatment 80 154.9 145.7 91-203

PNE, plasma norepinephrine; PRA, plasma renin activity; AVP, arginine vasopressin; ANF, atrial natriuretic factor.

with digitalis, diuretics, or vasodilators for signs andsymptoms of heart failure have neuroendocrineactivation. There is a highly significant increase inthe median values for PNE, plasma ANF, andplasma AVP compared with those for control sub-jects. The median value for PRA is only marginallyincreased in this group of patients and is probablydue to diuretic therapy. There is an additionalsignificant increment in PNE, PRA, ANF, and AVPin patients with overt signs and symptoms of con-gestive heart failure compared with patients withleft ventricular dysfunction in the prevention group.The above trends were observed for all neurohor-mones other than PRA when analyses were con-fined to those not on diuretics.

We have shown that neuroendocrine activationoccurs at a symptomless or mildly symptomatic stageof left ventricular dysfunction and therefore is notlikely to be a simple consequence of worseningcongestion. Our data suggest that there is additionalprogressive neuroendocrine activation as patientsprogress from early asymptomatic or mildly symp-tomatic left ventricular dysfunction to symptomaticheart failure. Similar findings have been observed inthe pacing animal model of heart failure.7"13Although patients in both the prevention and

treatment groups have left ventricular dysfunction,the left ventricular ejection fraction in the samplefrom the treatment group (26+6%) was significantlylower than that for the prevention group (29+±5%).

Median Plasma Norepinephrine(pg/mi)

P-.0001

(242-450)

Median Plasma ANF(pg/mi)

P-O.

rPC0.00015

2.0

1.0

0

4

2-

1 -

Median Plasma Renin Activity(ng/ml/hr)

jP-0.0003l

Contro Preventon Treat(0.3-0.9) (0.3-1.6) (0.5-3.8)

Median Plasma AVP(pg/mi)

P-O.OO00

FP-O.OO6

0 -

FIGURE 1. Bar graphs of incre-mental and significant increase inplasma norepinephrine, plasmarenin activity, plasma arginine vaso-pressin (AlP), and plasma atrialnatriuretic factor (ANF) in controlsubjects, prevention patients, andtreatment patients. Treatment val-ues are higher than control valuesfor each neurohormone. Medianvalues and interquartile ranges,25% to 75%.

(91-203)

600

500400 -

300 -

200 -

100

0

200 -

100 -

0 J1L- I

1

1727

L;onuo(31-B5)

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1728 Circulation Vol 82, No 5, November 1990

TABLE 3. Plasma Neuroendocrine Levels in Prevention Patients, Treatment Patients, and Control SubjectsMedian and interquartile ranges

Neurohumoral Prevention patients Treatment patientsmeasurement Control No diuretics On diuretics No diuretics On diureticsPNE 316.5 (242-450) 422.0 (309-548) 416.5 (341-625.8) 473.0 (330-553) 507.5 (366-669.5)

(pg/mi) (n=54) (n= 121) (n=30) (n=9) (n=72)PRA 0.6 (0.3-0.9) 0.7 (0.3-1.5) 1.0 (0.5-2.4) 0.7 (0.4-1.6) 1.7 (0.5-4.3)

(ng/ml/hr) (n=56) (n = 121) (n =30) (n=9) (n=71)

AVP 1.8 (1.4-2.3) 2.3 (1.7-3.0) 2.2 (1.7-2.8) 2.9 (2.1-3.5) 3.0 (2.3-4.5)(pg/mi) (n=54) (n=117) (n=30) (n=9) (n=71)

ANF 48.3 (30.6-64.8) 102.8 (68.5-133.3) 103.9 (73.6-180.2) 105.5 (65.1-209.1) 148.0 (96.7-202.3)(pg/mi) (n=54) (n= 117) (n=30) (n=9) (n=71)

PNE, plasma norepinephrine; PRA, plasma renin activity; AVP, plasma arginine vasopressin; ANF, plasma atrial natriuretic factor.Comparisons of PNE, AVP, and ANF between controls and prevention patients not on diuretics are significant atp=0.0002,p=0.007, and

p=O.OOOl, respectively. PRA levels are not significantly different between the two groups. The addition of diuretics is associated with amarked increase in PRA.

Control subjects versus prevention patients on no diuretics: PNE, p=0.0002; PRA,p=0.1; AVP,p=0.007; ANF, p=0.0001.Prevention patients on no diuretics versus prevention patients on diuretics: PNE, p=0.6; PRA, p =0.02; AVP, p=0.9; ANF, p=0.6.Prevention patients on diuretics versus treatment patients on diuretics: PNE, p=0.3; PRA, p=0.3; AVP, p=0.005; ANF, p=0.04.Treatment patients on diuretics versus treatment patients on no diuretics: PNE, p=0.4; PRA, p=0.05; AVP, p=0.4; ANF, p=0.3.

This small difference was not unexpected, as thetreatment group members had symptomatic heartfailure and were probably more advanced in thenatural course of their disease. The treatment groupwas also older (62.7 years) than the prevention group(59.2 years), which was in turn older than the controlgroup (56.4 years). Despite these differences, thepatient groups were similar for other variables,including a preponderance of men, a high prevalenceof ischemic heart disease, and electrolytes, hemato-crit, serum creatinine, and blood urea nitrogen levels.Reanalysis of the data after stratifying for the smalldifferences in age and ejection fraction did not alterthe results.PRA was normal among those patients not on

diuretics in both the prevention and treatment trials.It is therefore likely that activation of the circulatingrenin-angiotensin system in patients with left ventric-ular dysfunction as well as in those with symptomaticheart failure is a phenomenon that is in part relatedto diuretic use. Diuretics and sodium-restrictive dietsare well known to increase PRA in patients withheart failure.14-16 It is possible that the tissue-boundrenin-angiotensin system is active in patients withasymptomatic or mildly symptomatic left ventriculardysfunction despite only marginal increases in circu-lating renin activity, but we have no data on tissue-bound angiotensin activity.There are several other important limitations of

this study. These patients were not followed sequen-tially but rather represent two distinct groups studiedat different points in their natural histories. Directproof of incremental neuroendocrine activationwould require follow-up and sequential measure-ments in patients from the asymptomatic stage to theovert symptomatic heart failure stage. Such studiesare currently being carried out. It is also likely thatthere is some overlap in the prevention and treat-ment groups. Although both groups had definite left

ventricular dysfunction, the use of digitalis anddiuretics to treat symptoms of congestion was basedon clinician judgment. It is possible that a fewpatients in the prevention group had mild heartfailure not detected clinically and that some patientsin the overtly symptomatic group did not have heartfailure. Although this overlap in clinical spectrummight tend to decrease any real differences betweenthe prevention and treatment patients, detailed his-tory and physical examination revealed none of thesymptoms or signs of heart failure in the majority(>80%) of the patients in the prevention group. Themajority of patients in the treatment group (>90%)had these signs and symptoms. The neuroendocrinevalues were essentially unchanged when accountingfor these factors.The main findings of this study are that both

vasoconstrictor and vasodilator systems are activatedin the very early stages of left ventricular dysfunctionbefore the onset of overtly symptomatic congestiveheart failure. The implications of these observationsare currently speculative but may offer a rationale forthe very early introduction of therapy designed toalter neuroendocrine activation before the onset ofovert symptoms of congestive heart failure. However,the lack of an observed increase in circulating PRAin patients with left ventricular dysfunction suggeststhat sympathetic nervous system activation andrelease of ANF and AVP may precede activation ofthe renin-angiotensin system.

SummaryWe have demonstrated in a large group of patients

with left ventricular dysfunction that there is activa-tion of the sympathetic nervous system, as measuredby PNE, as well as the release of AVP and ANF.Circulating renin activity is within normal limits.Patients requiring therapy for symptomatic conges-tive heart failure have evidence of even greater

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Francis et al Neuroendocrine Activity and Heart Failure 1729

neuroendocrine activation, with significant increasesin PNE, plasma AVP, and plasma ANF. Neuroendo-crine activation appears to precede overtly symp-

tomatic heart failure and may therefore contribute toits development.

AppendixThe following individuals (listed by centers) con-

tributed importantly to the conduct of the study.University ofMichigan, Ann Arbor. Principal Inves-

tigator, J. Nicklas; L. Quain.University of Alabama, Birmingham. Principal

Investigator, W.J. Rogers; M.J. Henzlova, F. Atkins,and N. Lambert.Harvard University/West Roxbury Veterans Affairs

Medical Center, Boston. Principal Investigator, K.M.McIntyre; P.A. Woods.Mont Godinne Hospital, Belgium. B. Marchandise,

E. Schroeder, C. Libois.Buffalo University, Buffalo, N.E Principal Investi-

gator, R.M. Kohn; L.D. Banks, J.A. Celano.University of Illinois, Chicago. Principal Investiga-

tor, J.G. Shanes; J. Ghali, B.J. Dierenfeldt.University of Florida, Gainesville. Principal Investi-

gator, C.J. Pepine; C. Kohuth, G. Ruby.Dalhousie University, Halifax, Nova Scotia. Princi-

pal Investigator, D.E. Johnstone; S. Black.Baylor University, Houston. Principal Investigator,

J.B. Young; D. Gibson, C. Kingry.Michigan State University, East Lansing. Principal

Investigator, P.C. Kirlin; L. Blankenship, H. Boichot.University of Minnesota, Minneapolis. Principal

Investigator, J.N. Cohn; I. Goldenberg, G.K. Bjerken,S. Holmer, B.J. O'Toole-Brehm, L. Mensing, K.Monson.

Vanderbilt University, Nashville, Tenn. PrincipalInvestigator, M.W. Kronenberg; T.R. Edens, D.M.Howe.

Robert Wood Johnson Medical School, New Bruns-wick N.J. Principal Investigator, J.B. Kostis; D.M.Shindler, S. Karstensen.

Oregon Health Sciences University, Portland, Ore.Principal Investigator, B.H. Greenberg; D.K. Dutton.Brown University, Providence. R.I. Principal Inves-

tigator, R.J. Capone; L. Erikson.University of Rochester, Rochester, N.E Principal

Investigator, W.B. Hood, Jr.; C. Liang, K. Miller, M.Farrell.New York Medical College, Valhalla. R.H. Kay, M.

Reid.Neurohumoral Core Laboratory, University of Texas,

Galveston. Principal Investigator, C.R. Benedict;D.W. Cappolino, S. Chakravarthy.Data Coordinating Center, University ofNorth Caro-

lina, Chapel Hill. Principal Investigator, E. Davis; E.Rudin-Toretsky, J. Hosking, G.D. Williams.

Study Chairman. B. Pitt, University of Michigan,Ann Arbor.

Project Office (SOLVD). Clinical Trials Branch,National Heart, Lung, and Blood Institute, National

Institutes of Health. Project Officer, S. Yusuf; J.Probstfield.

AcknowledgmentsThe secretarial assistance of Mrs. Sandy Thiesse

and the statistical programming of George D. Wil-liams are greatly appreciated. There were many

members of the SOLVD group who contributedimportantly by drawing blood samples and participat-ing during discussions of the project, and their help isgratefully acknowledged.

References1. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN:

The neurohumoral axis in congestive heart failure. Ann InternMed 1984;101:370-377

2. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, FrancisGS, Simon AB, Rector T: Plasma norepinephrine as a guide toprognosis in patients with chronic congestive heart failure. NEngl J Med 1984;311:819-823

3. Gottlieb SS, Kukin ML, Ahern D, Packer M: Prognosticimportance of atrial natriuretic peptide in patients withchronic heart failure. JAm Coil Cardiol 1989;13:1534-1539

4. The CONSENSUS Trial Study Group: Effect of enalapril onmortality in severe congestive heart failure. N Engl J Med1987;316:1429-1435

5. Sharpe N, Smith H, Murphy J, Hannan S: Treatment ofpatients with symptomless left ventricular dysfunction aftermyocardial infarction. Lancet 1988;1:255-259

6. Pfeffer MA, Lamas GL, Vaughan DE, Parisi AF, BraunwaldE: Effect of captopril on progressive ventricular dilatationafter anterior myocardial infarction. N Engl J Med 1988;319:80-86

7. Riegger GAJ, Liebau G, Holzschuh M, Witkowski D, SteilnerH, Kochsiek K: Role of the renin-angiotensin system in thedevelopment of congestive heart failure in the dog assessed bychronic converting-enzyme blockade. Am J Cardiol 1984;53:614-618

8. Pfeffer JM, Pfeffer MA: Angiotensin converting enzyme inhi-bition and ventricular remodeling in heart failure. Am J Med1988;84(suppl 3A):37-44

9. Pfeffer MA, Pfeffer JM, Steinberg C, Finn P: Survival after anexperimental myocardial infarction: Beneficial effects of long-term therapy with captopril. Circulation 1985;72:406-412

10. Hussain MN, Benedict CR: Radioenzymatic microassay forsimultaneous estimations of dopamine, norepinephrine andepinephrine in plasma, urine and tissues. Clin Chem 1985;31:1861-1864

11. Sealey J, Laragh JH: How to do a plasma renin assay, inLaragh JH (ed): Topics in Hypertension. New York, YorkeMedical Books, 1980, pp 244-256

12. Bodola F, Benedict CR: Rapid simplified radioimmunoassayof arginine vasopressin and atrial natriuretic peptide inplasma. Clin Chem 1988;34:970-973

13. Armstrong PW, Stopps TP, Ford SE, de Bold AJ: Rapidventricular pacing in the dog: Pathophysiologic studies ofheart failure. Circulation 1986;74:1075-1084

14. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, LevineTB, Cohn JN: Acute vasoconstrictor response to intravenousfurosemide in patients with chronic congestive heart failure.Ann Intem Med 1985;103:1-6

15. Kubo SH, Clark M, Laragh JH, Borer JS, Cody RJ: Identifi-cation of normal neuroendocrine activity in mild congestiveheart failure: A stimulating effect of upright posture anddiuretics. Am J Cardiol 1987;60:1322-1328

16. Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-WilsonP: Untreated heart failure: Clinical and neuroendocrineeffects of introducing diuretics. Br Heart J 1987;57:17-22

KEY WORDS * congestive heart failure * neuroendocrinehormones * left ventricular dysfunction * clinical trials

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Rudin-Toretsky and S YusufG S Francis, C Benedict, D E Johnstone, P C Kirlin, J Nicklas, C S Liang, S H Kubo, E

Dysfunction (SOLVD).with and without congestive heart failure. A substudy of the Studies of Left Ventricular Comparison of neuroendocrine activation in patients with left ventricular dysfunction

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1990 American Heart Association, Inc. All rights reserved.

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