Br Heart J 1990;63:26-31

Short term haemodynamic effects of convertingenzyme inhibition before and after eating inpatients with moderate heart failure caused bydilated cardiomyopathy: a double blind study

Bo Herrlin, Christer Sylven, Olof Nyquist, Olof Edhag

AbstractThe haemodynamic changes that follow ameal can mimic the response to avasodilator drug. To avoid overestimat-ing the beneficial effects of treatment inuncontrolled studies, measurements ofhaemodynamic function are usuallyperformed with patients in the fastingpostabsorptive state. But such recordingsare not representative of the restingpatient during daily life. In this doubleblind placebo controlled study the shortterm haemodynamic effects of enalaprilwere assessed during 12 hours in 19patients with moderate heart failurecaused by dilated cardiomyopathy. Thepatients ate lunch and dinner and werestudied in the absorptive and postabsorp-tive phases. In the placebo group systemicvascular resistance, mean arterial pres-sure, and the rate-pressure product fellsignificantly (5-16%) after lunch. Fourhours after lunch the haemodynamicfunction had returned to baseline-thatis the postabsorptive state. Enalapril,accentuated the haemodynamic effectsduring the absorptive state producing alarger post-prandial fall in mean arterialblood pressure and rate-pressureproduct and changes in the absorptivephase were maintained into the post-absorptive phase. Pulmonary wedgepressure fell significantly after treatmentwith enalapril. These overall changesduring the study period indicated thatenalapril reduced the preload and after-load on the heart-over and above thereduction produced by eating.These findings suggest that the effects

of enalapril given at rest to patients withmoderate heart failure unload the heartand enhance the reduction of afterloadinduced by meals.

Cardiac Division,Department ofMedicine, HuddingeUniversity Hospital,Huddinge, SwedenB HerrlinC SylvenO NyquistO EdhagCorrespondence toDr Bo Herrlin, Departmentof Medicine, HuddingeHospital, S-141 86Huddinge, Sweden.

Accepted for publication20 July 1989

The haemodynamic effects of drugs are usuallystudied in fasting patients. Such recordings donot represent the effects in resting patients whoare eating normally. Splanchnic vasodilatationin the absorptive phase may change centralhaemodynamic function'` by reducing the sys-temic afterload.

Activation of the renin-angiotensin system,which increases systemic vascular resistance,4is an important compensatory mechanism intreated heart failure. Angiotensin-converting

enzyme inhibitors cause systemic vasodilata-tion and reduce the load on the heart.56 In heartfailure such drugs may enhance the haemo-dynamic effects seen in the absorptive phase.We investigated the complex haemodynamic

effects of enalapril and eating and absorption ina double blind, controlled, randomised study ina homogeneous group of patients with treatedmoderate heart failure caused by dilatedcardiomyopathy. We studied the angiotensin-converting enzyme inhibitor, enalapril,because its bioavailability was reported not tobe influenced by food intake7 and because asingle oral dose gives therapeutic serum con-centrations throughout a 12 hour study period.

Patients and methodsPATIENTSWe studied 19 patients (16 men and threewomen (41-62 years old (mean (SD)) 51 (6)years)), with moderate heart failure caused bydilated cardiomyopathy, which was treatedwith digoxin and frusemide. None of thepatients had oedema and all had been clinicallystable for at least two weeks. Inclusion criteriawere an echocardiographically determined leftventricular end diastolic dimension of >30mm/m2, a left ventricular shortening fraction of< 20%, and an exercise capacity of > stage IIIand < stage IX according to a revised Naugh-ton protocol.8 We excluded patients withprimary valve disease, suspected ischaemicheart disease, or congenital valve disease; thosetaking concomitant vasodilating agents; andthose with right sided heart failure caused bypulmonary disease. The study protocol wasapproved by the local ethics committee. Allpatients gave their informed consent beforeentering the study.

PROTOCOLThe patient was admitted to hospital andserved meals containing a known concentrationof sodium. The daily doses of digoxin andfrusemide remained unchanged. On the firstday the blood volume was determined andechocardiography, a chest x ray, and an exer-cise test were performed. Serum albuminlabelled with iodine-131 was used to measurethe total blood volume.Echocardiography was performed on

patients in the left lateral position (ATL MarkIII, 13 mm and 3 MHz transducer). Thetransducer position and cardiographic gainwere adjusted to obtain optimal recordings of

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Short term haemodynamic effects of enalapril before and after eating

left ventricular dimensions in the short axis.We measured the left ventricular end diastolicdiameter (LVEDD) and left ventricular endsystolic diameter (LVESD).9 The mean valuefor five consecutive beats was calculated. Theleft ventricular shortening fraction was derivedfrom the difference between LVEDD andLVESD divided by LVEDD.

Cardiac volume was measured radiologicallyby Jonsell's method.'0 Patients performed theexercise test sitting on an electrically brakedergometer. The load was increased every twominutes according to a modified Naughtonprotocol':Stage I II III IV V VI VII VIII IXW 10 20 30 50 70 90 110 130 150The patients exercised until limiting symp-

toms developed-that is dyspnoea or fatigue orboth.On the third day at 5.30 am the patient was

given a light breakfast and his or her daily doseof digoxin and frusemide. The right ventriclewas catheterised at 8 am. A triple lumenballoon tipped thermodilution catheter(Edwards Laboratory, USA) was introducedvia an antecubital or femoral vein underfluoroscopic guidance and was used to measurethe right atrial, pulmonary arterial, andpulmonary capillary wedge pressures. A poly-ethylene arterial catheter was introduced intothe brachial or femoral artery to measuresystemic pressure. The patient was placed inbed and transported to the coronary care unitfor haemodynamic monitoring for 12 hoursafter two hours of rest. We used Hewlett-Packard transducers (HP 1290) and a Hewlett-Packard patient monitoring system (Model HP78342A). All haemodynamic measurementswere done by the same physician (BH). Themeasurements ofhaemodynamic function weremade with the zero reference level at themidaxillary line with the patient supine and thebed in a horizontal position. Before eachhaemodynamic measurement we checked thatthe zero transducer pressure was the sameas atmospheric pressure; calibration scaleswere displayed electronically. Cardiac outputwas measured by a bedside cardiac outputcomputer (Cardiac Computer, EdwardsLaboratories, model 9520) with the use of an

iced injectate. Heart rate was derived from a

continuously recorded electrocardiogram. Thepatients were randomised double blindly toenalapril 10 mg or placebo, and drugs were

given at 0 hours. Recordings were made at 0, 1,2, 3, 4, 5, 6, 8, and 12 hours. The patients ateportions of meals of their own choice after oneand five hours. Snacks and coffee or tea were

not allowed but water was available.Serum concentrations of enalaprilat were

measured by radioimmunoassay."

ANALYSES

Mean right atrial pressure (RAP), mean

pulmonary artery pressure (MPAP), mean pul-monary capillary wedge pressure (PCWP),systolic systemic arterial pressure (SAP), andmean systemic arterial pressure (MAP) weremeasured by electronic integration. The mean

of at least six determinations was calculated;each was the average for 12 seconds. Cardiacoutput (CO) was determined in triplicate.Heart rate (HR) was determined for one min-ute. Derived haemodynamic variables werecalculated as follows:

Cardiac index (CI) (1/min/m2) = CO/body surface area

Stroke volume index (SVI) (ml/beat/m2) =CI/HR

Systemic vascular resistance (SVR)(dyn.s.cmn5)

= 80 x (MAP-RAP)/COPulmonary vascular resistance (PVR)

(dyn.s.cm5) = 80 x (MPAP-PCWP)/CORate-pressure product (RPP) (beats.mm Hg

min) = HR x SAP

STATISTICAL ANALYSISValues are given as means (SD). Unpaired ttests were used to evaluate differences betweentwo groups. Multiple comparisons of repeatedmeasurements were tested by analysis ofvariance and Fisher's protected least squaresignificance test. A p value of <0 05 wasregarded as significant.

ResultsTen patients were randomly allocated toenalapril and nine to placebo. One patientbecame symptomatically hypotensive six hoursafter administration of enalapril and was suc-cessfully treated with an infusion of saline.This patient was excluded from further study.The remaining 18 patients completed the studywithout complications.Table 1 shows the clinical characteristics and

non-invasive findings. The mean heart volumeand the daily dose of frusemide were signifi-cantly larger in the group receiving enalaprilthan in the placebo group (p < 0-05). Othercharacteristics were similar in the two groups.All patients had concentrations of serumsodium within the normal range.There were no significant differences in

haemodynamic variables between the twogroups at baseline (0 hour, table 2).

Table 1 Clinical characteristics, non-invasivefindings,blood volume, and serum sodium

Placebo group Enalapril group(n= 9) (n= 9) pvalue

Age (yr) 53 (3) 50 (7) NSSex (F/M) 2/7 1/8 NSDuration of symptoms

(mnth) 21 (12) 41 (30) NSFrusemide dosage

(mg/day) 98 (45) 158 (65) <0 05ECG (AF/SR) 2/7 3/6 NSExercise duration (s) 701 (93) 692 (173) NSChest x ray, heartvolume (ml/m') 712 (144) 872 (168) <0-05

Echocardiography:LVEDD (mm/m') 37 (5) 39 (3) NSFS (%) 11 (4) 11 (3) NS

Bloodvolume(1) 5-8 (1-4) 6-3 (1 3) NSSerum sodium (mmol/l) 140 (2) 142 (2) NS

AF, atrial fibrillation; FS, left ventricular fractional shortening;LVEDD, left ventricular end diastolic diameter; SR, sinusrhythm.

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Herrlin, Sylven, Nyquist, Edhag

Table 2 Haemodynamic measurements (mean (SD)) in the placebo and enalapril groups

Placebo group

Baseline Absorptive phase Postabsorptive phase

Oh 2h 3h Sh

HR 82 (14) 81 (11) 82 (8) 83 (12)RAP 4 (3) 5 (3) 5 (4) 5 (4)*MPAP 20 (8) 19 (6) 19 (5) 21 (8)PCWP 1 1 (8) 10 (7) 10 (6) 12 (8)MAP 85 (9) 81 (9)* 80 (12)* 84 (10)CI 2 5 (0-5) 2-8 (0.5)** 2-7 (0 6)* 2-5 (0 6)SVI 31 (8) 35 (8)*** 33 (9) 30 (9)SVR 1402 (308) 1176 (245)*** 1194 (230)*** 1371 (268)PVR 159 (37) 144 (38) 136 (46)** 158 (53)RPP 9422 (1729) 8914 (1567)* 8915 (1605)* 9227 (1621)

Statistical differences within groups compared with baseline are indicated as *p < 0 05, **p < 0-01, ***p < 0-001.Statistical differences in changes from baseline between groups are indicated as tp < 0-05, ttp < 0-01.HR, heart rate (beats/min); RAP, right atrial pressure (mm Hg); MPAP, mean pulmonary artery pressure (mm Hg); PCWP, pulmonary capillarywedge pressure (mm Hg); MAP, mean arterial pressure (mm Hg); CI, cardiac index (1/min/m2); SVI, stroke volume index (ml/m2); SVR, systemicvascular resistance (dyn.s.cm'); PVR, pulmonary vascular resistance (dyn.s.cmnf); RPP, rate-pressure product (beats. mm Hg/min).

HAEMODYNAMIC FUNCTION BEFORE AND AFTERMEALS IN THE PLACEBO GROUPAfter the first meal (lunch), haemodynamicchanges were greatest two and three hours afterthe start of the study (one and two hours afterthe meal) (table 2). Two hours after the start ofthe study (one hour after the meal, fig 1) meanarterial pressure (- 5 (4)%, p < 0 05), systemicvascular resistance (- 16 (9)%, p < 0-001), andthe rate-pressure product (-5 (6)%, p < 0 05)were lower while the cardiac and stroke volumeindices were higher (12 (8)%, p < 0-01 and 13(7)%, p < 0-001, respectively). Heart rate,right atrial pressure, mean pulmonary arterypressure, and pulmonary capillary wedge pres-sure were unchanged. These values returned tobaseline five hours after the start of the study(four hours after the first meal); this indicatedthe start of the postabsorptive phase (fig 2).The changes after the second meal (dinner)were similar to those after the first one.

Fluctuations in haemodynamic variablesnot associated with eating were assessed bycomparing estimates from postabsorptivedeterminations-that is at baseline and afterfive and 12 hours (fig 3). Compared withbaseline values, right atrial pressure wasincreased after five hours while, in addition,after 12 hours heart rate, mean pulmonaryartery and pulmonary capillary wedge pres-sures, cardiac index, and rate pressure productwere also increased.

HAEMODYNAMIC FUNCTION IN THE ENALAPRILGROUPSerum concentrations of enalaprilat rose afteronly two hours (20'4 (9'8) ng/ml) (fig 4).

Although the concentration was highest afterfour hours (27-9 (8-2) ng/ml), the differencebetween two and five hours was not statisticallysignificant. After five hours the serum concen-trations fell, reaching 1 1 7 (7 0) ng/ml after 12hours. In the absorptive phase, after two andthree hours, the changes in haemodynamicfunction resembled those in the placebo group.Compared with baseline values the meanarterial pressure, systemic vascular resistance,and rate-pressure product decreased (- 15(6)%, p < 0-0001; -23 (9)%, p < 0 001; and- 12 (13)%, p < 0-01, respectively). Thecardiac index and stroke volume indexincreased (+ 14 (9)%, p < 0 05; and 17 (15)%,p < 0-01, respectively). However, comparedwith placebo, the mean arterial pressuredecreased more (p < 0-01) with enalapril, andafter three hours the stroke volume index wasincreased (p < 005) and the rate-pressureproduct had fallen (p < 0O01). In contrast withthe findings in the placebo group, pulmonarycapillary wedge pressure decreased (- 24(25)%, p < 0-01) and after three hours the heartrate (-6 (7)%, p < 0-05) was slower. Thechanges seen during the absorptive phase weremaintained into the postabsorptive phase (thatis five hours after the start ofthe study). Exceptfor a further decrease in heart rate, no changeswere found between two, three, and five hours.

Overall changes from baseline values duringthe 12 hour study period were computed asareas under the curve (fig 2). Compared withplacebo, enalapril reduced heart rate (p < 0 05),pulmonary capillary wedge pressure (p < 0 05),mean arterial pressure (p < 0-01), and rate-pressure product (p < 0 01).

Figure I Mean (SD)and individual changes(mean at baseline and attwo hours (one hour afterthe first meal)) in theplacebo group. See table 2for abbreviations.

100-

_ 90

I S.80-

4 70-

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2Time (h)

400I Ip<0.050 2

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Short term haemodynamic effects of enalapril before and after eating

Enalapril group

Baseline Absorptive phase Postabsorptive phase

Oh 2h 3h 5h

87 (20) 85 (18) 81 (19)* 80 (15)**5 (3) 4 (2) 5 (2) 4 (2)tt

25 (7) 22 (5) 22 (5) 22 (5)t15 (7) 1 1 (4)** 12 (4)* 12 (6)*tt83 (7) 71 (8)***tt 69 (8)***t 70 (6)***tt2-3 (0-4) 2-6 (0-3)* 2-5 (0-3) 2-4 (0-7)

28 (9) 32 (9)** 33 (9)**t 31 (10)*t1416 (288) 1067 (192)*** 1035 (212)*** 1150 (223)**174 (63) 187 (44) 187 (48) 168 (39)

9833 (2077) 8522 (1779)** 7774 (1440)***tt 7687 (978)***tt

DiscussionThis is the first placebo controlled, randomiseddouble blind study showing the short termhaemodynamic effects of an angiotensin-con-verting enzyme inhibitor in heart failure andthe extent to which these effects are affected byeating, absorption, and postabsorption. In agroup of patients with treated moderate heartfailure caused by dilated cardiomyopathy,enalapril reduced left ventricular preload andafterload during both the absorptive and post-absorptive phases and hence throughout the 12hour study period. Heart rate and the leftventricular metabolic cost, estimated as therate-pressure product, decreased.The principal features of central haemody-

namic function during the absorptive phase(one hour after ingestion) were similar incontrols and patients with varying degrees of

heart failure."2"6 Systemic vascular resistancedecreased with or without decreases in meanarterial blood pressure and heart rate while thecardiac index increased. These systemic effectsreflect absorptive splanchnic hyperaemia andare the result of a locally mediated vascularresponse to digested nutrients in the lumen17and their composition.8 19 The hyperaemiaseems to be limited to tissues that are active indigestion and was maximal after 30-90 minuteswhen the local blood flow increased 30-150%."32O2 In healthy individuals splanchnichyperaemia was paralleled by an increase inrenal blood flow, but this haemodynamic re-sponse to food seemed to be specific to protein-rich meals.22 Information on blood flowdistribution to other vascular beds during theabsorptive phase is scarce. Studies in animalssuggest that blood flow to the brain and heart

0 2 4 6 8 10 12

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4 I

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Figure 2 Absolute changes in haemodynamic measurements compared with baseline (mean (SEM)) after enalapril(a) and placebo ( x ). Arrows indicate meals. p values indicate differences between the two groups in the respectiveareas under the curve calculatedfrom zero. See table 2for abbreviations.

200-100-~

EU 0

c -100--200-

x -300-l -400-

-500-'

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*

-_ _E~

E

.4

-2-Sh 12h

L ** 8-

3- - 62--1-~ -2

051 L 2"

.4

0- 0.

-1 -2-5h 12h

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-1200Sh 12h 5h 12h

Figure 3 Spontaneous haemodynamic changes compared with baseline (mean (SD)) in the placebogroup during postabsorptive phases atfive and12 hours. Significant differencesfrom baseline as tested by analysis of variance are indicated as *p < 005 and **p < 0-01. See table 2forabbreviations.

is unaltered and that to skeletal muscle isunaltered or reduced.2' Although the centralhaemodynamic changes during the absorptivephase are similar in individuals with or withoutvarying degrees of heart failure, the distribu-tion of blood flow to other organs may differwith the cardiac capacity.

Packer et al' and Siemienczuk et al16reported a decrease in pulmonary capillarywedge pressure during the absorptive phase inpatients with heart failure, but we found nochange. This difference might be because ourpatients had a lower filling pressure. Differ-ences in the selection of patients, study design,and spontaneous haemodynamic changes maybe relevant.We did not standardise the amount and

composition of the meals eaten by our patients,who ate as much as they wanted and probablythe same as they normally did.

In the placebo group we saw increases inheart rate, pressures, and cardiac index after 12hours and in the postabsorptive phase. Theseresults are at variance with those reported byPacker et al, who found a gradual decrease inpulmonary capillary wedge pressure during 24hours after right heart catheterisation. 5 Massieet al reported similar results.23 In contrast, wefound increases in right atrial and pulmonarycapillary wedge pressures after 12 hours and inthe postabsorptive state, but we did not stopdiuretics on the day of investigation. Diuresisduring the morning could have added to lowerfilling pressures at baseline. Such differencesin basal haemodynamic conditions underscorethe importance of well defined basal conditionsin order to avoid bias introduced by the designof a clinical trial.Two hours after the oral administration of

Figure 4 Concentrationcurve of serum enalaprilat(mean (SD)).

10 mg of enalapril the serum concentration ofenalaprilat was 20-4 (9-8) ng/ml. After 12 hoursit was 117 (7 0) ng/ml. The serum concentra-tion curve resembled that found in controls6and the time to peak concentration was notdelayed, as has been reported in severe heartfailure.24 Angiotensin-converting enzymeinhibition in the 90% range was reported atonly 10 ng/ml.25 Therefore, angiotensin-converting enzyme inhibition was likely to beeffective from the second to the twelfth hour ofthis study.During the absorptive phase the reduction of

afterload was more pronounced with enalaprilthan with placebo. Though the reduction ofafterload during the absorptive phase in theplacebo group was transient, it was maintainedinto the postabsorptive phase after enalapril. Inaddition, enalapril reduced heart rate andpreload as expressed by a decreased pulmonarycapillary wedge pressure while no change wasseen in the placebo group. These enalaprilinduced changes increased from recordingsduring the absorptive phase to those of thepostabsorptive phase, in keeping with shortterm pharmacodynamic studies on heart failurein which maximal haemodynamic effects,including heart rate and afterload reduction,were seen 4-8 hours after administration of asingle oral dose.6 So we would not expect themaximal afterload reduction in the enalaprilgroup to occur as early as two and three hoursafter administration. Indices measured aftertwo and three hours, however, resembled thosemeasured five hours after administration. Thisindicates that after two and three hours, duringthe absorptive phase, the total reduction ofafterload is a summation of enalapril-inducedand meal-induced vasodilatation.The patients were given diuretics on the day

of investigation and this may have potentiatedthe haemodynamic changes produced byenalapril owing to complex interactionsbetween diuretics and converting enzymeinhibitors.26 Notwithstanding this fact, theaim of the study was to describe the shortterm haemodynamic effects of enalapril in anexperimental situation that resembled, as far aspossible, the daily routine of the patient at rest.In addition to meals, this routine also includes acontinuation of long term medication.

In short term studies of congestive heartfailure, inhibition of angiotensin-convertingenzyme activity reduced systemic arterial pres-sure and systemic peripheral resistance and

161L4-

- 12E 10-a 8Z 6-

4 2-0

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Short term haemodynamic effects of enalapril before and after eating

increased the cardiac index. In most vascularbeds (limbs, 27-29 brain,30 liver,29 and coron-aries27 31) tissue flow is maintained throughhomoeostatic vasodilatation. Information on

splanchnic blood flow was ambiguous. Theincrease in the cardiac index was directedmainly to the kidneys where the regional bloodflow was increased.2729 During the absorptivephase splanchnic vasodilatation induced byenalapril was supplemented by physiologicalsplanchnic vasodilatation, which was probablycaused by regionally active vasodilating agents.

CONCLUSIONS(a) The principal haemodynamic effects ofeating and absorption seemed to be similar incontrols and patients with varying degrees ofheart failure. After a meal there was a transientreduction of afterload and an increase incardiac index. (b) When meals were beingeaten regularly angiotensin-converting enzymeinhibition by enalapril in patients withmoderate heart failure caused by dilatedcardiomyopathy produced signs of a balancedreduction in preload and afterload with a

decreased rate-pressure product. The afterloadreduction was additional to that induced bymeals. (c) To avoid bias in clinical trials thestudy design should be double blind with wellcontrolled basal conditions.

This study was supported by funds from the KarolinskaInstitute and the Swedish Heart and Lung Foundation.

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