Br Heart J 1991;65:137-42

Influence of angiotensin converting enzymeinhibition on pump function and cardiaccontract'lity in patients with chronic congestive

heart failure

Leo H B Baur, Johan J Schipperheyn, Jan Baan, Arnoud van der Laarse, Beert Buis,Ernst E van der Wall, Volkert Manger Cats, Arjan D van Dijk, Jacobus A K Blokland,Marijke Frolich, Albert V G Bruschke

Department ofCardiology,University HospitalLeiden, TheNetherlandsLH B BaurJ J SchipperheynJ BaanA van der LaarseB BuisE E van der WallV Manger CatsA D van DijkA V G BruschkeDepartment ofNuclear Medicine,University HospitalLeiden, TheNetherlandsJ A K BloklandDepartment ofPathologicalChemistry, UniversityHospital Leiden, TheNetherlandsM Fr6lichCorrespondence toDr Leo H B Baur,Department of Cardiology,University Hospital Leiden,Building 1, C5-P33,Rijnsburgerweg 10,2333 AA Leiden,The Netherlands.Accepted for publication23 October 1990

AbstractEleven patients with coronary arterydisease and chronic heart failure werestudied before and three months afterthe angiotensin converting enzymeinhibitor enalapril was added to theirfrusemide medication. The followingwere measured: left ventricular pressureand volume with transient occlusion ofthe inferior vena cava, radionuclideangiography, and hormone concentra-tions in plasma. As in other reportedstudies, the clinical condition of thepatients improved and their exercisetolerance increased moderately. Addi-tion of enalapril reduced end diastolicand systolic pressure, reduced ven-tricular volume, and concomitantlyincreased the ejection fraction. The endsystolic pressure-volume relation shiftedto the left as it did in a similar animalstudy. In the animal study unloading bya vasodilator did not induce a leftwardshift, so it can be inferred that in thepresent study unloading combined witha decrease in the angiotensin concentra-tion was instrumental in remodelling theheart. Though unloading was expected tohave a beneficial effect on the oxygen sup-ply/demand ratio of the heart, thepatients still showed the same drop inthe ejection fraction during exercise asthey did before treatment with enalapril,and early diastolic filling did notimprove. Normally, regression of car-diac dilatation is only found if pumpfunction improves; the present studyshowed that unloading in combinationwith angiotensin converting enzymeinhibition reshapes the ventricle withoutimproving intrinsic pump function.

The addition of an angiotensin convertingenzyme inhibitor such as enalapril to the con-ventional treatment of rest, salt restriction,and a diuretic has become an establishedapproach in the treatment of patients withsevere congestive cardiac failure. Angiotensinconverting enzyme inhibition producesarterial and venous vasodilatation andimproves cardiac pump function by unloadingthe left ventricle. As a result the clinical con-dition improves and the exercise tolerance`'and life expectancy of the patients increases.4

After myocardial infarction the ventricle

dilates mainly as a result of slippage ofbundles of myocardial cells.5 Unloading of theheart by angiotensin converting enzymeinhibition reduces ventricular volume,' 6 7mainly by lowering the filling pressure, butperhaps also by remodelling, because exten-sive postinfarct dilatation seems to be rever-sible. Moreover, it is clear that the observedimprovement in exercise tolerance is due notonly to better pump function but also to amore efficient distribution of the peripheralcirculation. It is a matter of debate whetherthe pump function improves only because ofthe unloading and remodelling or becausethere is also some improvement in the intrin-sic function of the cardiac muscle.

Intracoronary injection of angiotensin con-verting enzyme inhibitors blocked the directinotropic action of angiotensin II,."o but thelong term effect may be to enhance musclefunction by improving metabolism and allow-ing hypoxic muscle cells to recover their con-tractility.We studied 11 patients with chronic con-

gestive heart failure with dyspnoea class II-IV (New York Heart Association) before andafter three months of treatment with enalapriladded to a regimen of diuretics, salt restric-tion and, in some, digitalis or antiarrhythmicagents. Haemodynamic function was exten-sively measured. We used on line pressure-volume studies with transient occlusion of theinferior vena cava and radionuclide angio-graphy at rest and during exercise to identifythe effects of unloading, of remodelling, and ofa possible improvement of myocardialfunction.

Patients and methodsPATIENTSEleven men (aged 48-66 (mean 59)) withchronic congestive heart failure caused bycoronary artery disease and myocardial infarc-tion completed the study within a period of 18months. The patients gave their informedconsent and the protocol of the study wasapproved by the hospital ethics committee.Eighteen patients entered the study but sevendid not complete it. Three died suddenlyduring follow up, one underwent a coronarybypass operation, and three stopped the treat-ment with enalapril because of side effects.

Inclusion criteria were cardiac failure classII-IV (New York Heart Association) and a left

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Baur, Schipperheyn, Baan, van der Laarse, Buis, van der Wall, Manger Cats, van Dijk, Blokland, Frolich, Bruschke

ventricular ejection fraction <45% at rest, asmeasured by radionuclide angiography. Stableexercise dependent angina was not a reason forexclusion and patients with mild mitral regur-gitation secondary to ventricular dilatation orpapillary muscle dysfunction were also notexcluded. Exclusion criteria were severe hyper-tension, myocardial infarction less than fourmonths before, albuminuria, serum creatinineconcentrations > 150 umol/l, and valvar orcongenital heart disease.

STUDY PROTOCOLPatients were admitted to the cardiology wardonce before treatment and again after threemonths of treatment. During each admissionan exercise test was performed with radio-nuclide imaging of the left ventricle, followedafter one or two days by a right and leftheart catheterisation with pressure-volumemeasurements and balloon occlusion of theinferior vena cava to determine the pressure-volume relations of the left ventricle. Bloodsamples were taken with appropriate precau-tions to measure plasma renin and angiotensinconverting enzyme activity and concentrationsof angiotensin II and atrial natriuretic peptidein the resting state. All prior medication wascontinued throughout the study and treatmentwith enalapril was started (< 20 mg/day). Thefirst dose was given after the haemodynamictests were completed and the effects werecarefully monitored. After three months allvariables were measured again.

BIOCHEMICAL MEASUREMENTSTo exclude the effect of physical activity bloodsamples were taken at 6.00 am before thepatients rose. Blood samples for themeasurement ofangiotensin II and angiotensinconverting enzyme activity were collectedseparately and a combination of EDTA andphenanthroline or ofheparin and aprotinin wasadded, respectively. The samples were kept onice, centrifuged in a precooled centrifuge, andstored at - 70°C. Angiotensin convertingenzyme activity was measured spectro-photometrically with a test kit (Paesel, Frank-furt, Germany) that had 15 U/I as its lowerlimit of reference range. Plasma renin activitywas measured by radioimmunoassay of theangiotensin I generated from the a2 precursorunder standard conditions (Baxter, Cam-bridge, Massachusetts, USA). Enalapril wastested for possible interference in the assay andconcentrations of the drug up to 50 ig/ml didnot show such effect. The reference range forangiotensin II in normotensive individuals is0-25 pmol/l plasma (median 18 pmol/l). Nor-mal values ofplasma renin activity in ambulantindividuals (with unrestricted salt intake) are1 67 (0-83) ug/l per hour. After extraction onSeppac C18 column (Waters, Bedford, Massa-chusetts, USA) angiotensin II was measuredby a radioimmunoassay with antibodies gen-erated in rabbits. Atrial natriuretic peptide wasmeasured by a radioimmunoassay (ImmunoNuclear, Amsterdam, The Netherlands). Theupper limit ofthe reference range was 68 pg/mlin plasma.

EXERCISE TESTSThe exercise test was performed in combina-tion with radionuclide imaging on a normalupright bicycle ergometer. The workload wasincreased stepwise from 10 W by 10 W everyminute until exhaustion. A Toshiba 40Agamma camera was used to make two radio-nuclide scintigrams, the former in the 10minutes immediately before exercise and thelatter during the last three minutes of exercise.Red blood cells were labelled in vivo by inject-ing 750 MBq (20 mCi) technetium-99m. Gatedradionuclide angiograms were made in the 400left anterior oblique position with a 30°caudocranial tilt to obtain optimal separation ofthe right and left ventricles. The volume of theleft ventricle was calculated from the number ofventricular counts and the activity of a bloodsample measured simultaneously. Data werecollected in a matrix of 64 x 64 pixels.

HAEMODYNAMIC MEASUREMENTSA 7 F thermodilution Swan-Ganz flow directedcatheter was introduced into a femoral vein andits tip was floated into a branch of a pulmonaryartery. It was used to measure pressures andcardiac output (by thermodilution and the Fickmethod). An 8 F Cordis pigtail catheter with atip manometer was introduced percutaneouslyinto the femoral artery and advanced into theleft ventricle. It was used for left ventricularangiography and simultaneous pressuremeasurements. Left ventricular angiogramswere filmed in two directions-the 300 rightanterior oblique and the 600 left anterioroblique positions. Later the angiograms weredigitised and left ventricular end diastolic andend systolic volumes were estimated by aPhilips Analytical Processing Unit system.The time constant for the exponential decay

of pressure (X) was calculated according to themethod described by Weiss et al." Sub-sequently a second 8 F custom made pigtailcatheter, with ten electrodes (Webster Labs,Baldwin Park, Califomia, USA),'2 13 wasintroduced into the left ventricle to measurevolume. Its tip was carefully positioned in theapex and a 0 03 mA root mean square 20 kHzalternating current was passed between themost apical electrode and the one close to theaortic valve. Left ventricular volume was cal-culated on line from the voltages betweenadjacent pairs of electrodes between thecurrent electrodes'314 by an analogue signalconditioner processor (Sigma-5, Leycom, Oes-tgeest, The Netherlands). Combined with thepressure signal from the tip manometer pres-sure-volume loops were displayed contin-uously on an X-Y oscilloscope.To obtain pressure-volume loops under

changing loading conditions a balloon catheter(Meditech, Watertown, Massachusetts, USA)was introduced percutaneously into thefemoral vein and the balloon was positioned inthe inferior vena cava. When the balloon wasinflated with carbon dioxide the venous returnto the heart was reduced sufficiently to allow theend systolic pressure-volume relation""7 andthe relation between dP/dt,. and end diastolicvolume'8 to be determined.

138

Cardiac contractility after ACE inhibition

Absolute values of end diastolic and endsystolic volumes measured by conductancecatheter were calibrated afterwards against theradionuclide data in eight patients, or, if thesedata were not available, the volumes were

estimated from the ventriculograms.We used Student's paired t test to compare

data obtained before and after treatment.

ResultsCLINICAL RESPONSE TO TREATMENT

Before treatment two patients were in heartfailure class II, eight in class III, and one inclass IV. On average they had been in heartfailure for 20 months (range 1-96 months).Two patients had moderate angina and two hadsevere angina. Five patients were treated withdigoxin, 10 with frusemide, and three with longacting nitrates. In addition, one patient tookflecainide and another amiodarone. All patientswere given anticoagulant treatment withcoumadin. The cardiac medication was contin-ued without change throughout the study.

Seven patients tolerated a dosage of 20 mgenalapril a day and four were given a daily doseof 10 mg. Eight patients improved clinicallybut in three the clinical condition remainedunchanged. Two of the four patients withangina reported a reduction in episodes ofpain.

BIOCHEMICAL RESPONSES

Treatment reduced converting enzyme activityin the plasma from an average of 14-06 U/1 to

2A45 U/I (p < 0-0001). Plasma renin activitybefore treatment was high (mean 6-33 ug/l perhour) and it increased to 24-8 ug/l per hour

after treatment (p < 0005). Plasma concentra-

tions of angiotensin II were raised beforetreatment (30-0 pmol/l) and dropped to 10-1

pmol/l after treatment (p < 0 05). Initially theplasma concentration of atrial natriuretic factorwas considerably raised (189 pg/ml). Afterthree months of treatment it had dropped to

103 pg/ml (p < 005). Baseline aldosteroneconcentration was also raised (0-8 umol/l)before treatment and it fell (but not signific-antly) to 0-4 umol/l during treatment.

HAEMODYNAMIC RESPONSES TO ENALAPRIL

Table 1 shows the haemodynamic data. Rightatrial pressure, mean pulmonary artery pres-

sure, pulmonary capillary pressure, and leftventricular end diastolic pressure all declinedafter treatment. Mean aortic pressure also fell.Cardiac index remained practically unchanged.Systemic vascular resistance fell significantly,while the pulmonary vascular resistance alsodeclined but not significantly.Table 2 shows the volume data obtained by

radionuclide angiography. The end diastolicand end systolic volume indices of the leftventricle fell significantly. In nine patients inwhom pressure-volume loops could be re-

corded both before and after treatment, thediastolic pressure-volume relation shifted to

the left (fig 1). The ejection fraction at rest

increased slightly from 0-24 (0-09) to 0 30(0-1 1) (p < 0 05).

REMODELLING OF THE VENTRICLE

Pressure-volume loops could be recorded innine patients. In two (patients 2 and 5) it wasnot possible to position the conductance cath-eter in the correct position. Figure 1 shows theshift of the two families of pressure-volumeloops, obtained by obstructing the inferior venacava before and after treatment in patient 4.The diastolic pressure-volume relation was

shifted towards the left, which indicates that

Table I Haemodynamic function before treatment and three months after treatment with enalapril

PVR SVRCase HR MPRA MPAP MPCP LVEDP MAOP CI (N.s. m5) (N.s. m') LVEF dP/dt,, Tno (beats/min) (mm Hg) (mm Hg) (mm Hg) (mm Hg) (mm Hg) (I/min) (x 105) (x 105) (%) (mm Hg/s) (ms)

Before treatment1 59 15 35 25 20 72 1-5 287 1630 38 659 632 111 9 43 30 26 71 2-4 246 1139 30 970 753 70 5 21 12 10 101 3-6 92 1152 34 1553 314 61 4 16 10 12 84 2-2 130 1752 42 897 665 90 7 22 16 15 84 2-8 79 1059 21 - -

6 48 4 13 1 1 12 94 2-7 72 1352 38 541 617 10 36 35 26 22 81 18 205 1648 23 1316 588 105 8 20 18 25 70 1.1 77 2384 12 665 719 83 14 33 - 20 95 2 3 260 1268 28 1200 6010 100 5 43 28 25 87 23 320 1680 28 1047 621 1 85 5 31 - 25 86 2.8 87 1212 15 1018 40

Mean 83 7.5 28.5 19-6 19.3 84.0 2.3 169 1480 28 987 59(SD) 21 37 1021 714 57 98 06 92 371 15 300 13

After three months' treatment with enalapril1 65 13 29 25 25 72 1-7 112 1532 33 697 782 100 5 36 25 25 60 239 164 846 35 668 353 77 6 17 9 10 105 3-4 88 1100 31 1716 384 69 3 17 9 12 92 2-5 153 1575 42 844 595 88 7 15 13 13 74 2.1 35 1155 29 - -

6 61 3 14 7 8 82 368 70 803 41 674 357 72 5 25 13 14 67 1-6 300 1569 35 938 578 92 3 25 18 18 68 2-0 139 1372 19 711 459 65 11 28 14 11 58 2-6 282 852 23 1218 5510 107 3 16 11 14 70 3.0 75 1011 29 1370 2711 79 2 27 11 25 73 2-3 81 1187 23 1141 55

Mean 80 5.5 225 141 159 74.5 25 136 1182 309 998 48(SD) 15 3.4 6.8 5.9 6-1 13.2 0-7 82 280 7-0 337 15

p 0-001 005 005 005 005 0.05 005

CI, cardiac index per m' body surface area; HR, heart rate; LVEDP, left ventricular end diastolic pressure; LVEF, left ventricular ejection fraction; MAOP, meanaortic pressure; MPAP, mean pulmonary artery pressure; MPCP, mean pulmonary capillary pressure; MPRA, mean right atrial pressure; PVR, pulmonaryvascular resistance; SVR, systemic vascular resistance.

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Baur, Schipperheyn, Baan, van der Laarse, Buis, van der Wall, Manger Cats, van Dijk, Blokland, Frolich, Bruschke

Table 2 Responses measured during technetium-99m exercise testing

HRPPCase MWL HR rest HR load LVEF rest LVEF load DEF EDVI rest ESVI rest SVI rest (mm Hg/min)no (W) (beats/min) (beats/min) (%) (%) (%) (ml) (ml) (ml) ( x 103)

Before treatment1 40 50 90 18 14 -4 104 85 19 9-902 50 100 145 20 19 - 1 123 98 25 18-853 110 65 105 32 32 0 142 109 33 9 954 70 60 100 19 24 5 125 101 24 15-555 100 88 135 21 13 -8 189 149 40 24 306 110 66 100 38 31 -7 116 72 44 15-557 90 100 150 24 15 -9 103 78 25 24-008 80 112 142 12 12 0 121 107 14 18-469 80 82 120 42 37 - 5 121 87 34 22-8010 60 90 108 19 19 0 153 124 29 14-5811 120 95 120 21 18 -3 135 107 28 20-40Mean 83 83 120 24 21 -3 130 102 29 18-58(SD) 25 19 20 9 8 4 25 22 9 4-41

After three months' treatment with enalapril1 60 70 100 18 - - 94 77 17 13-502 100 90 125 27 23 -4 145 106 39 15-003 130 63 100 30 30 0 101 71 30 19-504 75 68 110 20 16 -4 64 51 13 21-455 110 90 125 23 19 -4 197 152 45 20-006 90 64 90 49 36 -13 73 37 36 15-757 90 80 135 30 18 -12 92 74 18 21-608 125 90 160 22 16 -6 101 79 22 18-409 70 75 120 53 47 -6 96 74 22 19-2010 60 77 130 27 19 -8 101 74 27 19-5011 130 74 150 27 21 -6 126 92 34 26-25Mean 90 77 122 30 22 -6 108 81 28 19-10(SD) 28 10 21 11 12 4 37 22 10 3-52p 0 05 0-05 0 05 0-01

DEF, reduction of ejection fraction at rest; EDVI, end diastolic volume per m' body surface area; ESVI, end systolic volume per m' body surface area; HR rest,heart rate at rest; HR load, heart rate during maximal exercise; HRPP, heart rate x pressure product; LVEF rest, left ventricular ejection fraction at rest; LVEFload, left ventricular ejection fraction during maximal exercise; MWL, maximal workload; SVI, stroke volume per m' body surface area.

the passive diastolic properties of the ventriclehad changed. This was consistently seen in allpatients in whom a pressure-volume loop couldbe recorded. Figure 2 shows the shifts of theend diastolic volumes of the whole group.

Figure 1 Plots ofrepresentative pressure-volume loops duringpreload reduction byocclusion of the inferiorvena cava before (A), andafter three months'treatment with enalapril(B). The pressure-volumeloops shifted to the leftwithout a change in theslope of the end systolicpressure-volume reaction.

Figure 2 Shift in the enddiastolic pressure-volumerelation before occlusion ofthe inferior vena cava innine patients before (A)and after (B) threemonths of treatment withenalapril.

Left ventricular volume (ml)

A

B

o 8o 160 120OLeft ventricular end diastolic volume inc

EXERCISE TOLERANCEIn seven patients the maximum workloadincreased, in two it remained unchanged, andin two it decreased after treatment (table 2). Onaverage the maximum exercise capacityincreased slightly but not significantly. Heartrate at maximal workload remained practicallythe same, as did the rate-pressure product.Though eight patients felt that their exercisetolerance had improved, only four increasedtheir maximum rate-pressure product. Threeof them did so at the expense of a considerabledrop of the ejection fraction during exercise,more than observed before treatment; in thefourth patient the ejection fraction was notmeasured after treatment.

INDICES OF CONTRACTILITYOn average the values of dP/dt. were belownormal before (987 (300) mm Hg/s) andremained unchanged after treatment (988 (337)

-,-- mm Hg/s). The inferior vena cava could be300 obstructed effectively in only four patients; in

the other five patients in whom pressure-volume loops were recorded the inflation of theballoon did not reduce diastolic pressure andvolume either before or after treatment. Figure3 shows the typical almost parallel shift to theleft of the end systolic pressure-volume rela-tion, which indicated almost unchanged endsystolic pressure-volume relation. The meanvolume intercept shifted from 128 (65) to 55(24) ml and the slope remained practically thesame (0 34 (0.22) mm Hg/ml before and 0-28(0- 10) mm Hg/ml after treatment). The slope ofthe relation between dP/dt,,,, and end diastolicvolume also remained practically unchanged-

140 160 mean 1-64 (2-31) mm Hg.s7'.ml-' before anddex (ml) 1-23 (0 48) mm Hg.s-'.ml7P after treatment.

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140

Cardiac contractility after ACE inhibition

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Figure 3 (Left) End systolic pressure-volume relattreatment with enalapril in four patients with successthe inferior vena cava. (Right) Relation between dPbefore and after three months of treatment with enalksuccessful preload reduction by occlusion of the inferio

METABOLIC COND:Normally the lefincreases during 4absence of a rise aas a sign of highcor hypoxic suppiby a limited coroithe mean ejectidecreased from 0at maximum worremained unchafrom 0-19 to 0 2ejection fractionnine patients, rewas measured oraverage, the eje(dropped from 0 3maximum worklin the ejection fr.

50r / more pronounced, and in three ofthese patientsthe maximal rate-pressure product increased.The only patient whose ejection fractionincreased during exercise and who attained arate-pressure product of 15 5 ( x 10') mm Hg/min, exercised to a rate-pressure product of21-4 (x 10') mm Hg/min after treatment buthis ejection fraction fell.

Because relaxation in early diastole is an,,,, , active, energy dependent process, the negative

0 300 peak dP/dt and the time constant T of the!50- / / exponential decay of pressure immediatelyafter a negative peak dP/dt are both regarded asindices of the metabolic condition of the heartmuscle. There was little change in the peaknegative dP/dt (903 (190) mm Hg/s, and 891(229) mm Hg/s) (NS). The value of T also didnot change significantly after treatment (table

0 3~~~~~~0 .

5 30 DiscussionEarlier studies showed that addition of anangiotensin converting enzyme inhibitor to thefrusemide treatment of patients with severecardiac failure improved their clinical condi-tion, exercise tolerance, and prognosis.41920After three months of treatment the left ven-tricle was smaller and the heart produced thesame cardiac output at a lower filling pressureagainst a lower aortic pressure."5The present

0 300 study confirms these results. Biochemical dataso- / show that the inhibition of the angiotensin

converting enzyme was effective in all patientsand that the angiotensin II and atrial

-9er° natriuretic concentrations were reduced. Mosty-, patients felt better and their maximum work-

load increased. As a result of the treatment thepressure-volume loops shifted to the left andthe recordings showed that the support struc-ture of the ventricle had changed. Figure 1shows that the reduction of diastolic ven-0 300 tricular volume achieved by lowering end dia-End diastolic volume (ml) stolic pressure was much more important than

tion before and after three months the slight changes induced by an acute reduc-sful preload reduction by occlusion of tion of pressure of the same magnitude. This'/dt. and end diastolic volue shows that the collagen support structure oftheapril in the samefour patients with heart has indeed been reshaped.,or vena cava.

A shift of the diastolic pressure-volumerelation of the human left ventricle under theinfluence of enalapril has not been reported

ITION OF THE HEART before, but similar results have been obtainedt ventricular ejection fraction experimentally by treating rats with chronicexercise and a drop or even the large myocardial infarctions with captopril.2"at maximum workload is taken Unloading the heart with a predominantlyer overt myocardial ischaemia arterial vasodilator, hydralazine, did notression of contractility caused produce such an effect.' From this it can benary reserve. Before treatment inferred that the ventricle is reshaped onlyion fraction for the group because unloading is combined with a reduc--24 (0-09) at rest to 0-21 (0-08) tion of the angiotensin concentration. Thiskload; it fell in seven patients, conditional role of a reduction of angiotensin isnged in three, and increased supported by the results of experimental4 in one. After treatment the studies that point to a crucial role of suchdecreased during exercise in reduction in changing the collagen structure ofmained constant in one, and the heart. A comparison ofthe effects ofdifferentnly at rest in one patient. On types of hypertension and of angiotensin con-ction fraction after treatment verting enzyme inhibition on rat hearts showed30 (0-11) at rest to 0-22 (0- 12) at that renovascular hypertension induced car-oad. In seven patients the fall diac hypertrophy with a higher collagen con-action during exercise became tent than low renin hypertension caused by

141

Baur, Schipperheyn, Baan, van der Laarse, Buis, van der Wall, Manger Cats, van Dijk, Blokland, Frolich, Bruschke

infrarenal banding.23 Regression of hyper-trophy with angiotensin converting enzymeinhibition is accompanied not only by a reduc-tion of collagen content but also by a consider-able change in the ratio of type I and type IIIcollagen.24 25

Because the support structures in the heartwere reshaped, the collagen tethers betweenbundles of cardiac fibres must first have beendissolved and later reformed.26 Acute un-loading shifts the diastolic pressure-volumerelation only slightly to the left,'5 but in com-bination with the reconstruction of collagentethers such a shift to a lower volume can berepeated until an appreciably lower volume isreached. This implies that remodelling of theheart will occur only if the heart is unloadedwhile the plasma concentrations of angiotensinII are simultaneously reduced. In an experi-mental study, treatment with a vasodilator thatunloads the heart but activates the renin-angiotensin-aldosterone system did not reduceheart size.'

In the acute experiment a leftward shift ofthe end systolic pressure-volume relation isusually interpreted as a sign of improved con-tractility.52728 The same is true for the relationbetween dP/dt,., and end diastolic volume,'827but is such interpretation still correct in a longterm study in which the ventricle is consider-ably remodelled and reduced in size? We foundno additional evidence of an improvement ofintrinsic contractile function in this study. Adirect positive effect of enalapril would havebeen unlikely, because angiotensin II wasweakly inotropic in isolated cardiac muscle"'0and angiotensin converting enzyme inhibitorshad a weakly negative inotropic action.29 Con-tractile function might have improved, how-ever, by improvement in the heart's meta-bolism. Coronary reserve is usually reduced incardiac failure and regional hypoxia of themuscle may add to the problem of cardiacfailure caused by previous infarctions. Theunloading of the heart may have a beneficialeffect on its metabolism by reducing oxygenconsumption, but lowering coronary perfusionpressure may have an opposite effect. Thepresent data on reduction of ejection fractionduring exercise suggest that the net effect of theunloading treatment on the oxygen balance wasnegligible or in some patients even slightlynegative. Nor did the data on ventricularrelaxation indicate an improvement in cardiacmetabolism. So there seems little reason tosuppose that treatment with an angiotensinconverting enzyme inhibitor in this group ofpatients improved intrinsic muscle function,despite the leftward shift of end systolic pres-sure-volume relation and the relation betweendP/dt. and end diastolic volume. Theimprovement of pump function seems to besolely the result of the remodelling of the heart,without recruitment of hitherto hypoxic fibres.

We thank Dr B van Meurs and Mr A van Benthum of PhilipsMedical Systems for their help with the calculations ofventricular volumes on the Philips APU-system.This study was supported by a grant from Merck, Sharp and

Dohme.

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