lisinopril lowers cardiac adrenergic drive and increases...

472

Lisinopril Lowers Cardiac Adrenergic Drive andIncreases ,8-Receptor Density in the

Failing Human Heart

Edward M. Gilbert, MD; Anthony Sandoval, MD; Patti Larrabee, BS; Dale G. Renlund, MD;John B. O'Connell, MD; and Michael R. Bristow, MD, PhD

Background. In subjects with heart failure, angiotensin converting enzyme inhibitors exhibit mildsystemic antiadrenergic effects, as deduced from treatment-related lowering of systemic venous norepi-nephrine levels. The effects of angiotensin converting enzyme inhibitors on cardiac adrenergic drive insubjects with heart failure has not previously been investigated.Methods and Resuls.In a placebo-controlled, double-blind crossover study of 14 patients, we measured

cardiac and systemic adrenergic drive, myocardial and lymphocyte 1-adrenergic receptors, and hemody-namic changes at baseline and after 12 weeks of therapy. Relative to placebo, lisinopril therapy was

associated with only minimal, statistically insignificant changes in hemodynamics, a significant increasein myocardial P-receptor density, no significant (P<.05) changes in cardiac or systemic adrenergic drive,and no detectable change in lymphocyte P-receptor density. When subjects were rank ordered into groupswith the highest and lowest coronary sinus norepinephrine levels, those with the highest norepinephrinelevels exhibited significant decreases in central venous norepinephrine, coronary sinus norepinephrine,and an increase in myocardial 1receptor density relative to changes in placebo or relative to baselinevalues. Subjects with lower cardiac adrenergic drive exhibited no significant changes in coronary sinus or

systemic norepinephrine levels or in myocardial 1-receptor density.Conclusions. The angiotensin converting enzyme inhibitor lisinopril lowered cardiac adrenergic drive

and increased 1-receptor density in subjects with increased cardiac adrenergic drive but had no effects onthese parameters in subjects with normal cardiac adrenergic drive. These data suggest that cardiacantiadrenergic properties contribute to the efficacy of angiotensin converting enzyme inhibitor in subjectswith heart failure. (Circulation 1993;88:472-480)KEY WORDs * angiotensin converting enzyme * lisinopril * 13-adrenergic receptors

A ctivation of the adrenergic and renin-angiotensinsystems in heart failure partially compensatesfor reduced intrinsic pump function by stabiliz-

ing central blood pressure and increasing contractilityand heart rate, thereby improving perfusion of organswith autoregulatory control of flow.1-4 Although activa-tion of these systems may initially be helpful, evidencesuggests that their chronic activation may contribute tothe pathophysiology of heart failure.1-6The adrenergic and renin-angiotensin systems are

closely interrelated. For example, renin release is under3,1-adrenergic control, and angiotensin II may modu-

late adrenergic activity by facilitating synaptic release ofnorepinephrine.8-12 Thus, a therapeutic intervention inheart failure that antagonizes one of these systems mayalso inhibit the other.

Vasodilator therapy with a variety of agents mayimprove clinical symptoms and hemodynamic function

Received August 30, 1991; revision accepted March 26, 1993.From the Division of Cardiology, University of Utah School of

Medicine, Salt Lake City, Utah.Presented at the 61st Scientific Sessions of the American Heart

Association, Washington, DC, November 14-17, 1988.Correspondence to Division of Cardiology, University of Colo-

rado Health Sciences Center, 4200 E. Ninth Avenue, B139,Denver, CO 80262 (Dr Bristow).

in heart failure.13-'8 However, each class of vasodilatorsmay have different effects on adrenergic activity. Forexample, administration of the direct-acting vasodilatorhydralazine'5 or the calcium channel antagonist nifedi-pine19 increases central venous norepinephrine concen-trations in subjects with heart failure. In contrast, theacute20 and chronic20,21 administration of angiotensinconverting enzyme (ACE) inhibitors significantly lowersvenous norepinephrine concentration in heart failure,indicating a fall in generalized adrenergic activity.The ACE inhibitor-associated reduction in venous

norepinephrine concentrations may be the result ofimprovements in hemodynamic function or secondaryto mitigation of angiotensin II-facilitated norepineph-rine release. The latter explanation is supported by theobservation that ACE inhibitors decrease angiotensinII-facilitated norepinephrine release in animalmodels.22-25The clinical significance of the antiadrenergic effects

of ACE inhibition is not known, but it is possible thatthis property is an important component of the thera-peutic efficacy of ACE inhibitors in heart failure. Thepurpose of this study was to measure the effects ofACEinhibition on cardiac adrenergic activity and myocardial3-adrenergic receptors in subjects with heart failure.The data indicate that chronic therapy with ACE inhib-

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Gilbert et al Antiadrenergic Effects of Lisinopril 473

itors is associated with a decrease in both systemic andcardiac adrenergic drive and an increase in myocardial3-adrenergic receptor density but only in subjects with

increased baseline adrenergic activity.

MethodsStudy Objectives

This study was a prospective, double-blind, placebo-controlled, crossover study of the ACE inhibitor lisino-pril in subjects with heart failure. The primary objectivewas to measure the effects ofACE inhibition on cardiacadrenergic drive and myocardial 3-adrenergic receptordensity in heart failure. Secondary objectives were torelate changes in systemic and cardiac adrenergic activ-ity induced by ACE inhibition to changes in cardiacfunction.

Subject EligibilityPatients .18 years of age were eligible for study entry

if they had symptomatic congestive heart failure and aleft ventricular ejection fraction of <0.45. All patientswere clinically stable and on constant doses of cardiacmedications for at least 2 weeks before study entry.Patients with unstable angina; myocardial infarctionwithin 3 months of study entry; systolic blood pressure<80 mm Hg; valvular stenosis; primary renal, hepatic,or hematologic disorders; and pregnant or nursingwomen were excluded from study entry. Permissibleconcomitant cardiac medications included diuretics,digitalis glycosides, class I antiarrhythmic drugs, ni-trates, and anticoagulants. During the study period,diuretic dose was adjusted when clinically indicated, butdoses of all other concomitant medications were unal-tered. Excluded medications were f-adrenergic block-ers, calcium channel blockers, other antihypertensivemedications, and other vasodilators. All patients signedinformed written consent forms approved by the HumanSubjects Committee of the University of Utah MedicalCenter.

Study DesignThe study consisted of three treatment periods: a

2-week baseline period and two 12-week double-blindperiods. During the baseline period, all patients re-ceived a single-blind oral placebo once daily. Baselinenoninvasive and invasive measurements were madeduring the second week of the baseline period. Aftercompletion of the baseline period, patients were ran-domly assigned to receive lisinopril or placebo. Theinitial oral dose of study medication was 5 mg/d. After 2weeks, the dose was increased to 10 mg/d if the 5-mgdose was well tolerated. After 2 additional weeks, thedose was again increased to 20 mg/d if study medicationwas well tolerated. Subjects continued on the highesttolerated dose of medication for a total of 12 weeks oftherapy, at which time the hemodynamic and adrenergicmeasurements were repeated. Subjects were thencrossed over to receive the alternative therapy. Thealternative medication was begun at the equivalent of 5mg/d and titrated upward as in the first 12-week double-blind treatment period. After 12 weeks of treatment onthe second study medication, hemodynamic and adren-ergic measurements were again repeated.

Clinical and Hemodynamic MeasurementsClinical and hemodynamic measurements were made

during the baseline period and during the last week ofthe two double-blind treatment periods. During thebaseline period, two modified Naughton exercise toler-ance tests26 were performed, with measurement ofmaximal oxygen consumption by expired gas analysiswith mass spectrometry.27 Dyspnea or fatigue was usedas the end point to terminate exercise. All other reasonsfor termination of exercise excluded patients from fur-ther participation in the study. Patients were also ex-cluded if maximal oxygen consumption varied by morethan 20% between tests. The average exercise durationand maximal oxygen consumption were used for thebaseline value. A single exercise tolerance test wasperformed at the end of both of the two double-blindtreatment periods. Radionuclide ventriculography wasperformed at rest and during maximal supine bicycleexercise for measurement of left ventricular ejectionfraction. Chest radiography, electrocardiography, and

TABLE 1. Patient Entry Characteristics

ClinicalAge (years)SexMaleFemale

DiagnosisIDCCAD

NYHA functional classIIIIIIV

Resting LVEFExercise LVEFMaximum exercise duration (min)Maximum oxygen consumption (mL- kg- . min-1)

InvasiveHeart rate (bpm)Mean systemic artery pressure (mm Hg)Mean right atrial pressure (mm Hg)Mean pulmonary artery pressure (mm Hg)Mean pulmonary wedge pressure (mm Hg)Cardiac index (L. min-l m-2)Systemic vascular resistance (Wood units)Pulmonary vascular resistance (Wood units)

50±3

104

113

2102

0.23±0.020.22±0.029.3±0.919.2±1.5

86±483±35±122±314±22.1±0.120±12.2±0.5

AdrenergicRight atrial norepinephrine (pg/mL) 449±109Arterial norepinephrine (pg/mL) 307±78Coronary sinus norepinephrine (pg/mL) 597±154Myocardial Bm. (fmol/mg protein) 33±5Myocardial Kd (pmol/L) 14±4Lymphocyte Bmax (fmol/mg protein) 63±10Lymphocyte Kd (pmol/L) 26±6

IDC, idiopathic dilated cardiomyopathy; CAD, coronary arterydisease; NYHA, New York Heart Association; LVEF, left ventric-ular ejection fraction; bpm, beats per minute. Values aremean±SEM.


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474 Circulation Vol 88, No 2 August 1993

clinical laboratory tests, including a complete bloodcount with differential, platelet count, urinalysis, andmultichannel chemistry profile, were also performed.

Cardiac catheterization was performed on the lastday of each treatment period. Patients fasted overnightbefore catheterization. Diuretics were not administeredon the day of the catheterization, but study medicationwas given 2 hours before catheterization. Patients re-

ceived preoperative sedation with diazepam (10 mg

PO). A 9F sheath was inserted percutaneously into theright internal jugular vein, and a 20-gauge catheter wasinserted into the right femoral artery under local anes-thesia. When technically possible, a 7F multipurposecatheter (MA-2, Argon Medical, Athens, Tex) wasinserted into the coronary sinus via the right internaljugular sheath, and the catheter position was confirmedby contrast dye injection and blood gas measurement ofthe coronary sinus sample. Simultaneous coronary sinusand arterial blood samples followed by a right atrialblood sample were obtained for measurement of cate-cholamine concentration and placed into iced tubescontaining ethyleneglycol-bis-(13-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Right ventricularendomyocardial biopsy specimens were obtained bypreviously described methods.28 Briefly, a 50-cm rightventricular bioptome was inserted through the rightinternal jugular sheath and was positioned against theright intraventricular septum under fluoroscopic guid-ance, and specimens were obtained. Four to six speci-mens (20 to 40 mg) were obtained for -3-adrenergic

receptor analysis. A pulmonary artery catheter was theninserted, and systemic and pulmonic pressures were

measured. Cardiac output was measured by the Fickmethod. Heart rate was determined by electrocardio-graphic telemetry. Derived hemodynamic measureswere calculated according to standard formulas.

Adrenergic MeasurementsWe have previously described in detail the technique

of f8-adrenergic receptor density measurement in endo-myocardial biopsy specimens.29 Briefly, biopsy speci-mens were immediately placed in ice-cold 10-mmol/LTris buffer, 1-1tmol/L EGTA buffer, pH 8.0, and grosslyvisible fibrous tissue was dissected free. The remainingsample was blotted dry and weighed. Crude membranepreparations were then made by homogenization, ex-

traction of contractile proteins in 0.5-mol/L KCl, andmultiple washes of a pellet from centrifugation at50 000g. The radioligand [125Ijiodocyanopindolol(ICYP) was used for identifying /3-adrenergic receptors.Duplicate tubes containing seven increasing concentra-tions of ICYP with and without 10-6 mol/L (-)-pro-pranolol were prepared. The assay was begun with theaddition of membrane preparation for 120 minutes.ICYP bound to membranes was then trapped by vac-

uum filtration, with specific binding defined as totalbinding minus propranolol-displaceable binding. Maxi-mum bound ICYP (B..) and the ICYP dissociationconstant (Kd) were determined by a nonlinear least-squares regression analysis of one form of the Michael-

TABLE 2. Overall Response to Lisinopril or Placebo Therapy

Lisinopril (n= 14)

Pre Post

Placebo (n= 14)Pre Post

NoninvasiveRest LVEFExercise LVEFMaximum exercise duration (min)Max Vo2 (mL. kg.* min1)

InvasiveHeart rate (bpm)Mean SAP (mm Hg)Mean RAP (mm Hg)Mean PAP (mm Hg)Mean PAWP (mm Hg)CI (L. min1 m-2)SVR (Wood units)PVR (Wood units)

AdrenergicMyocardial Bm.. (fmol/mg protein)Myocardial Kd (pmol/L)Lymphocyte Bma, (fmol/mg protein)Lymphocyte Kd (pmol/L)RA norepinephrine (pg/mL)ART norepinephrine (pg/mL)CS norepinephrine (pg/mL)

23±2

23±2

9.1±1.018.7±1.4

83±5

82±3

5±124±4

16±2

2.1±0.1

20±1

2.4±0.5

31±5

11±3

57±10

24±6

695±300

282±80

864±354

26±2

25±3

9.1±1.3

19.5±2.0

75±3*

86±2

5±122±3

13±2

2.2±0.1

20±2

2.4±0.7

49±7*t

14±4

62±9

16±3tj287±72*§

309±50

534±107

25±2

25±3

9.6±1.1

20.2±1.9

79±4

81±3

4±1

22±3

12±2

2.2±0.1

20±2

2.6±0.6

48±6

12±3

72± 11

20±4

269±64

244±42

383±66

24±2

23±4

9.2±1.1

19.5± 1.8

76±3

85±3

5±124±3

14±2

2.2±0.1

21±2

3.0±0.7

46±5

17±4

70±12

50±13t

759±352*

310±100

730±332

LVEF, left ventricular ejection fraction; max Vo2, maximal oxygen consumption; bpm, beats per minute; SAP,systemic arterial pressure; RAP, right atrial pressure; PAP, pulmonary artery pressure; PAWP, pulmonary arterywedge pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance, RA, rightatrial; ART, arterial; CS, coronary sinus. Values are mean±SEM.

*P<.10 vs pre, paired t; tP<.05 vs placebo change from pre; *P<.05 vs pre, paired t; §P<.10 vs placebo change from pre.


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is-Menton equation. Protein measurements were madeby Peterson's modification30 of the method of Lowry etal.31A 50-mL heparinized mixed venous blood sample

was obtained for measurement of lymphocyte f3-adren-ergic receptor density by a modification of a previouslydescribed technique.32 Briefly, a Ficoll gradient wasused for harvesting lymphocytes. Crude membranepreparations were then prepared by homogenizationand multiple washes of a 50 000g pellet. The radioligandICYP was used for identifying P-adrenergic receptors.Duplicate tubes containing eight increasing concentra-tions of ICYP with and without 10-6 mol/L (-)-pro-pranolol were prepared. The assay was begun with theaddition of the membrane preparation and incubatedfor 90 minutes, followed by vacuum filtration. Bindingparameters and protein measurements were deter-mined as for myocardial membranes.

Plasma catecholamine concentrations of blood sam-ples from right atrium, systemic artery, and coronarysinus were analyzed by a radioenzymatic method (CAT-a-Kit, Amersham, Chicago, Il1).33

Statistical AnalysisThe values for noninvasive, invasive, and adrenergic

variables before and after lisinopril and placebo treat-ment were compared with their respective baselinevalues with the paired Student's t test. Since the trialwas a crossover design, the baseline values for the

second study period (weeks 13 to 24) were the end-of-study values for period 1 (weeks 1 to 12). Because valuesfor norepinephrine concentration were not normallydistributed, the log transformation of norepinephrineconcentration was used for paired analysis of thesevariables. To evaluate the effect of baseline adrenergicactivity on the response of adrenergic indexes to lisino-pril and placebo therapy, all subjects were divided byrank order into two subsets determined by coronarysinus norepinephrine concentration. Differences be-tween coronary sinus norepinephrine subsets were eval-uated with the unpaired Student's t test. Additionally,changes from baseline with lisinopril treatment werecompared with changes from baseline with placebotreatment by Student's t test. All values are expressed asmean±SEM. Differences were considered significantwhen P<.05.

ResultsPatient Characteristics

Although 20 subjects were enrolled into the study,serial coronary sinus sampling was technically possiblein only 14 subjects. This report is based on the data fromthese 14 subjects. Entry characteristics are given inTable 1. Subjects received a mean lisinopril dose of16.4±1.3 mg/d (range, 5 to 20 mg/d) and a meanplacebo dose of 17.5±1.4 mg/d (range, 5 to 20 mg/d).One patient required hospitalization for heart failureafter his condition deteriorated when he was crossed

TABLE 3. Response to Lisinopril of "High" (Group A) and "Low" (Group B) Coronary SinusNorepinephrine Subsets

Group A (n=7) Group B (n=7)Pre Post Pre Post

NoninvasiveRest LVEF 22+2 24±3 23±3 28±5Exercise LVEF 22±3 25±3 23±4 26±5Maximal exercise duration (min) 9.8±1.5 9.6±2.1 8.5±1.3 8.5±1.6Maximal Vo2 (mL. kg`. min-1) 18.5±1.8 19.7±2.9 18.9±9.2 19.4±2.9

InvasiveHeart rate (bpm) 91±7 79±5 76±6 71±5Mean SAP (mm Hg) 88±5 88±6 83±6 85±7Mean RAP (mm Hg) 8±2 6±2 3±1 4±1Mean PAP (mm Hg) 31±5 24±5 17±4 19±4Mean PAWP (mm Hg) 20±4 15±4 12±3 11±2CI (L. min1 Mr2) 1.9±0.2 2.2±0.2 2.3±0.2 2.3±0.2SVR (Wood units) 21±2 20±2 18±2 21±2PVR (Wood units) 3.0±0.8 2.7±1.2 1.7±0.4 1.9±0.8

AdrenergicMyocardial Bm.. (fmol/mg protein) 32±9 52±8*t 30±6 39±11Myocardial Kd (pmol/L) 15±7 12±3 8+2 17±9Lymphocyte B.,. (fmol/mg protein) 75±17 68±14 40±7 55±12Lymphocyte Kd (pmol/L) 34±10 21±6 15±4 9±1RA NE (pg/mL) 1199±552 330±117*t 192±25 226±63ART NE (pg/mL) 412±147 340±74 152±24 265±62CS NE (pg/mL) 1547±619 398±148*t 181±41 442±160

LVEF, left ventricular ejection fraction; maximal Vo2, maximal oxygen consumption; bpm, beats per minute; SAP,systemic arterial pressure; RAP, right atrial pressure; PAP, pulmonary artery pressure; PAWP, pulmonary arterywedge pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; RA, rightatrial; NE, norepinephrine; ART, arterial; CS, coronary sinus. Values are mean±SEM.

*P<.05 vs pre, paired t; tP<.05 vs placebo change from pre.


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over from lisinopril to placebo (determined after com-pletion of the study). However, his condition improvedwith bed rest and intravenous diuretic therapy, blindedstudy medication was continued, and he completed thestudy. No other significant adverse events occurredduring the study, and no significant changes were ob-served in any clinical laboratory tests.

Right ventricular endomyocardial biopsy was nottechnically possible in one subject because of a septalscar from an old inferior wall myocardial infarction. Allother measurements were completed in all 14 subjects.

Response to TherapyThe responses of invasive, noninvasive, and adrener-

gic variables to therapy with lisinopril and placebo aregiven in Table 2. With lisinopril treatment, systemicvenous norepinephrine concentration tended to de-crease, but this was not statistically significant. Therewas also a small but statistically significant decrease inlymphocyte Kd with lisinopril therapy. All other vari-ables did not change with lisinopril therapy. Placebotherapy was associated with an increase in lymphocyteKd. No other variable changed with placebo therapy,although a trend toward an increase in venous norepi-nephrine concentration was observed. By between-group analysis, the changes in lymphocyte Kd werestatistically significant, but this is of uncertain relevance.There were no other significant differences in changesfrom baseline between lisinopril and placebo treatment.To examine whether an "order effect" caused by the

crossover nature of the trial design might have beenpresent, we analyzed the response to lisinopril or pla-cebo in the first and second periods of the study. Withthe exception of heart rate, baseline data for the secondperiod (13 to 24 weeks) of the study did not differ fromthe first period (1 to 12 weeks). Heart rate decreasedfrom 85.8±4.2 beats per minute to 75.3 beats perminute (P=.04) between the two baseline periods. Thisreduction in heart rate did not appear to be related to achange in the adrenergic drive or hemodynamic status,since coronary sinus norepinephrine (597±154 pg/mL,first baseline; 671±336 pg/mL, second baseline) andpulmonary wedge pressure (14.4±2.1 mm Hg, firstbaseline; 14.3±2.3 mm Hg, second baseline) did notchange between the two baseline periods. Myocardialbiopsy 8-receptor density tended to be higher (P=.08)on the second baseline (47.3 vs 32.6 fmol/mg). Thesechanges (heart rate) or tendencies (biopsy receptordensity) were observed in subjects randomized to eitherlisinopril or placebo in study period 1.

Despite the lack of overall change in baseline databetween study periods 1 and 2, there were differences inthe response to lisinopril in the first vs the second studyperiod. In the first study period, subjects treated withlisinopril exhibited an increased 8-receptor density(from 22±2 to 51±9 fmol/mg; P=.02), a decreasedsystemic venous norepinephrine (from 564±177 to250±103 pg/mL; P=.02), and a trend toward a reducedcoronary sinus norepinephrine (from 864±353 to533±107 pg/mL; P=.08). In the second study period,there were no significant differences in the above pa-rameters, but trends in the same direction as in studyperiod 1 translated into no significant differences in theend-of-study value minus baseline values in the twoperiods. There were no significant differences in the

placebo group change from baseline values in eitherstudy period. The reason for the difference in behaviorof lisinopril-treated patients in study period 1 vs 2 wasthat, by chance, five of the seven subjects in study period1 were in the high coronary sinus norepinephrine subset(see below), whereas in period 2, only two lisinopril-treated patients were in this category. As would beexpected from the crossover design, this preponderanceof subjects in the high coronary sinus norepinephrinesubset appeared in the placebo group in the secondstudy period (five in the second, two in the first period).However, since placebo had no effect on any adrenergicparameter, the changes in the placebo group did notdiffer between periods 1 and 2.

Response to Therapy of Subjects With "High" and"Low" Cardiac Adrenergic Activity

Subjects were divided by rank order into two groupsof equal number determined by coronary sinus norepi-nephrine. For lisinopril treatment, coronary sinus nor-epinephrine concentration ranged from 404 to 4964pg/mL in the "high" subset (group A) and 71 to 339pg/mL in the "low" subset (group B). Table 3 presentsnoninvasive and invasive measurements before and af-ter lisinopril treatment for groups A and B. Subjects ingroup A tended to have a higher resting heart rate,higher right heart pressures, and lower cardiac index

CL

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0.

CL

t

acU

2500 -

2000-

1500-

1000-

500-

0-

p - 0.018

High Low

80

o p. 0.022

000T00.0

E 40CD

20

20

0%High Low

FIG 1. Bar graphs showing coronary sinus norepinephrineconcentrations (top panel) and myocardial /3-adrenergic re-ceptor density (bottom panel) before (solid bars) and after(hatched bars) 12 weeks oflisinopril therapyforpatients in the"high" (group A, n= 7) and "low" (group B, n= 7) coronarysinus norepinephrine subsets. Coronary sinus norepinephrineconcentration significantly (P<.05) decreased and myocar-dial 8-adrenergic receptor density significantly increased withlisinopril therapy in the "high" subset. These changes were notobserved in the "low" coronary sinus norepinephrine subset.

101.


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than group B subjects, but these differences were notsignificant. With lisinopril treatment, there were trendstoward hemodynamic improvement in group A and an

improvement in left ventricular ejection fraction ingroup B, but these changes were not significant. Figure1 presents the changes in coronary sinus norepineph-rine concentration and myocardial 13-receptor densityfor groups A and B. In group A subjects, treatment withlisinopril was associated with a significant fall in coro-

nary sinus norepinephrine concentration and a signifi-cant increase in myocardial 3-receptor density. Nochanges occurred in group B. Lymphocyte (-receptordensity did not change in either group.For placebo treatment, coronary sinus norepineph-

rine concentration ranged from 282 to 853 pg/mL ingroup A and 145 to 234 pg/mL in group B. Table 4presents noninvasive and invasive measurements beforeand after placebo treatment for groups A and B.Subjects in group A tended to have higher right heartpressures than group B subjects. There were no changesin noninvasive, invasive, or adrenergic variables in ei-ther subset. However, as shown in Table 4 Fig 2,systemic venous and coronary sinus norepinephrineconcentrations tended to increase with placebo therapyin group A. Lymphocyte (3-receptor density did notchange in either group.

In group A, there were significant differences in thepercent change from baseline for lisinopril vs placebotherapy for myocardial Bma.,, right atrial norepinephrine

concentration, and coronary sinus norepinephrine con-centration. In group B, there were no significant differ-ences in change from baseline for lisinopril vs placebotherapy.

DiscussionLisinopril, the lysine analogue of enalaprilat, is a

long-acting ACE inhibitor.34 Oral administration oflisinopril inhibits the pressor response to exogenousangiotensin I, increases plasma renin activity, decreasesplasma ACE activity, and decreases both plasma angio-tensin II and aldosterone concentrations.34,35 In subjectswith heart failure, oral administration of lisinopril re-sults in increases in cardiac output and stroke volume,decreases in systemic vascular resistance and pulmonarywedge pressure,35 and improvement in heart failuresymptoms and exercise tolerance.36 Significant hemody-namic effects have been observed with doses of 10 mg/dor less, and the effects of a single dose may last 24hours.35-37

In this study, we did not observe any significanthemodynamic or exercise tolerance improvements withlisinopril therapy. Subjects with evidence for increasedcardiac adrenergic activity (the "high" coronary sinusnorepinephrine subset) tended to show hemodynamicimprovement, but these changes were small and notstatistically significant. However, other studies with lis-inopril in heart failure using large sample sizes have

TABLE 4. Response to Placebo of "High" (Group A) and "Low" (Group B) Coronary SinusNorepinephrine Subsets

Group A (n=7)

Pre Post

Group B (n=7)

Pre Post

NoninvasiveRest LVEFExercise LVEFETT time (min)Max Vo2 (mL. kg`. mini1)

InvasiveHeart rate (bpm)SAP (mm Hg)RAP (mm Hg)PAP (mm Hg)PAWP (mm Hg)CI (L. min-' m-')SVR (Wood units)PVR (Wood units)

AdrenergicMyocardial Bmax (fmol/mg protein)Myocardial Kd (pmol/L)Lymphocyte Bma. (fmol/mg protein)Lymphocyte Kd (pmol/L)RA NE (pg/mL)ART NE (pg/mL)CS NE (pg/mL)

23+324±49.5+1.819.1+2.7

77±484+87±227±515±22.2±0.220±33.5±1.3

53±611±372±1423±5341+109312+73564+88

24±426+79.6±2.119.5±3.3

84±888±46±230±518±42.3±0.421±43.4±1.1

51±616±4103± 1936±10

1484±68*407±1971164±642

25±524±4

10.8± 1.221.3±2.0

79±389±43±117±211±22.3±0.120±11.6±0.2

45±1014±672±1717±7

286±57177±27202±13

22±423±3

10.0±1.321.1±2.1

77±683±44±123±513±32.2±0.219±22.5±0.6

41±916±742±619±7

208±38213±34295±61

LVEF, left ventricular ejection fraction; ETT, exercise tolerance test; max Vo2, maximal oxygen consumption; bpm,beats per minute; SAP, systemic artery pressure; RAP, right atrial pressure; PAP, pulmonary artery pressure; PAWP,pulmonary artery wedge pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascularresistance; RA, right atrial; NE, norepinephrine; ART, arterial; CS, coronary sinus. Values are mean±SEM.

*P<.10 vs lisinopril change from pre.


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shown improvement in hemodynamics35 and exerciseperformance.36

In contrast to the minor hemodynamic effects oflisinopril in our study, subjects with increased cardiacadrenergic activity (group A) exhibited significant de-creases in coronary sinus and systemic venous norepi-nephrine concentrations in response to lisinopril ther-apy but not in response to placebo. Additionally, thesignificant increase in myocardial /3-adrenergic receptordensity in the high adrenergic drive subset was associ-ated with the fall in coronary sinus and systemic venousnorepinephrine concentrations in subjects treated withlisinopril. These changes were observed only in subjectswith evidence for an increase in adrenergic drive atbaseline and were not observed in subjects with normalbaseline coronary sinus norepinephrine concentrations.The data in this trial were analyzed by the degree of

baseline adrenergic activation, since effects of ACEinhibition on adrenergic neurotransmission would beexpected to be manifest only when adrenergic activity isincreased. One possible explanation for the findings inthis study is that the observed changes in norepineph-rine concentration were an artifact of the division ofsubjects into subsets, resulting in a "regression towardthe mean." If group A norepinephrine values wereelevated because of the random scatter of baseline dataand not because of an actual increase in baselineadrenergic activity, then it would be expected that thesevalues would return toward the mean of the group onrepeat measurement. However, it is unlikely that thisexplains our findings, since norepinephrine concentra-tions decreased in group A with lisinopril therapy butnot with placebo therapy, during which norepinephrineconcentration tended to increase. Thus, the observedchanges in group A (the "high" norepinephrine subset)are likely to be an actual response to pharmacologicalintervention with lisinopril.

It has been demonstrated previously that the admin-istration of ACE inhibitors in heart failure reducessystemic venous norepinephrine concentration.19-21 Incontrast, other vasodilators used for the treatment ofheart failure increase systemic venous norepinephrineconcentration.11-18 In this study, lisinopril therapy alsotended to result in a generalized reduction in systemicvenous norepinephrine concentration caused entirely bya lowering of adrenergic drive in the high norepineph-rine subset. In addition, elevated coronary sinus norepi-nephrine concentrations in group A subjects were re-duced by lisinopril therapy but not by placebo. Thesefindings suggest that ACE inhibitors are capable ofexerting a powerful antiadrenergic effect in subjectswith elevated cardiac adrenergic activity. Such an effect,including upregulation of 3-adrenergic receptors, hasrecently been reported in an animal model.38 In humanswith heart failure, the antiadrenergic effect is substan-tial when judged by lisinopril's effects on either coro-nary sinus norepinephrine levels or myocardial /3-recep-tor density. In fact, the observed upregulation ofmyocardial f8-adrenergic receptors was only slightly lessthan the upregulation observed in heart failure patientstreated with chronic ,B-adrenergic blockade.39Although myocardial /3-adrenergic receptors in-

creased with lisinopril therapy in group A, lymphocyte,B-adrenergic receptors did not change. We have previ-ously reported that in subjects with heart failure, the

behavior of lymphocyte f32-adrenergic receptor densitydoes not correlate with myocardial 813-adrenergic recep-tor density.40 The findings in this study are furtherevidence that lymphocyte /3-receptor density cannot beused to evaluate the changes in the cardiac adrenergicpathway.The design of the study does not permit determina-

tion of the mechanism by which lisinopril lowers cardiacadrenergic drive. One possible explanation for ourobservations is that drug therapy improved hemody-namic function, which resulted in a secondary reductionin reflexes responsible for increasing adrenergic drive.However, there were no significant changes in hemody-namic function in our patients with lisinopril therapy,even though large changes were observed in adrenergicindexes. Another possible explanation is that lisinopril-associated reduction in angiotensin II levels eliminatedthe facilitory action of angiotensin II on adrenergicneurotransmission. Such a hypothesis is consistent withour observation that the adrenergic effect was observedonly in subjects with elevated adrenergic activity.Against this explanation is the observation that infu-sions of angiotensin-II into human subjects without41 orwith42 heart failure does not increase systemic adrener-gic drive.41 However, the pressor effects of systemicallyinfused angiotensin-II may activate arterial barore-flexes, causing systemic adrenergic activity to behave ina manner different from cardiac adrenergic neurotrans-

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FIG 2. Bar graphs showing coronary sinus norepinephrineconcentrations (top panel) and myocardial /3-adrenergicreceptor density (bottom panel) before (solid bars) and after(hatched bars) 12 weeks ofplacebo therapy for patients inthe "high" (group A, n=7) and "low" (group B, n=7)coronary sinus norepinephrine subsets. No significantchanges occurred with placebo therapy, although coronarysinus norepinephrine concentration tended to increase in the"high" subset.


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mission. Further studies will be necessary to elucidatethe mechanism by which ACE inhibition lowers cardiacadrenergic drive in heart failure.What is the clinical significance of the reduction in

adrenergic drive with ACE inhibitors? Potentially, theantiadrenergic properties of ACE inhibitors are powerfulenough to contribute to some of the beneficial effects ofthese agents in heart failure. For example, the improvedexercise performance that has been observed with ACEinhibition in heart failure could be related to partialrestoration of the myocardial 13-adrenergic receptorpathway through an increase in 3-adrenergic receptordensity, just as has been reported with ,3-blocker thera-py.39 In addition, reducing resting adrenergic drive mighthave a cardioprotective effect3; this could be one of thereasons why ACE inhibitors are associated with im-proved survival in heart failure.43 This hypothesis issupported by findings of the CONSENSUS trial, in whichimprovement in survival was observed only in patientswith increased indexes of neurohumoral activation.44

In summary, ACE inhibition in subjects with heartfailure and elevated cardiac adrenergic drive is associ-ated with a decrease in coronary sinus and systemicvenous plasma norepinephrine concentrations and anincrease in myocardial P-adrenergic receptor density.These changes are not observed with ACE inhibition insubjects without elevated cardiac adrenergic activity orwith placebo therapy.

AcknowledgmentsSupported in part by a grant from Merck Sharp & Dohme

and by Public Health Services research grant MO1-RR00064from the National Center for Research Resources. E.M.G.was supported in part by a Merck Fellowship Award.

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E M Gilbert, A Sandoval, P Larrabee, D G Renlund, J B O'Connell and M R Bristowhuman heart.

Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing

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