Varnauskas, - BMJ

British HeartJournal, I975, 37, I022-I036.

Effect of chronic beta-adrenergic receptor blockadein congestive cardiomyopathy

F. Waagstein, A. Hjalmarson, E. Varnauskas, and I. WallentinFrom the Department of Medicine x, Division of Cardiology and Department of Clinical Physiology, Sahlgren'sHospital, University of Goteborg, Sweden

Adrenergic beta-blocking agents were given to 7 patients with advanced congestive cardiomyopathy who hadtachycardia at rest (98 ± I3 beatslmin). The patients were on beta-adrenergic receptor blockade for 2 to 12months (average 5.4 months). One patient was given alprenolol 50 mg twice daily and the other patients were

given practolol 50 to 400 mg twice daily. Virus infection had occurred in 6 of the patients before the onset ofsymptoms of cardiac disease. All patients were in a steady state or were progressively deteriorating at thestart of beta-adrenergic receptor blockade. Conventional treatment with digitalis and diuretics was unalteredor reduced duning treatment with beta-blocking agents. An improvement was seen in their clinical conditionshortly after administration of the drugs. Continued treatment resulted in an increase in physical workingcapacity and a reduction of heart size.

Noninvasive investigations including phonocardiogram, carotid pulse curve, apex cardiogram, and echo-

cardiogram showed improved ventricular function in all cases. The present study indicates that adrenergicbeta-blocking agents can improve heart function in at least some patients with congestive cardiomyopathy.Furthermore, it is suggested that increased catecholamine activity may be an importantfactor for the develop-ment of this disease, as has been shown in animal experiments.

Conventional therapy in congestive cardiomyopathyhas failed to change the final outcome of the disease(Goodwin and Oakley, I972). It was recently stated(Goodwin, I974) that, 'at the present time theprognosis for severe congestive cardiomyopathy isso bleak and treatment so unsatisfactory that cardiactransplantation may be considered in desperatecases'. Despite reduction in heart size with bed rest,which is also seen in normal people who are immob-ilized (Saltin et al., I968), relapse has occurred inmany cases after mobilization. The rate of throm-boembolic complications has been high (McDonald,Burch, and Walsh, I972). Several other disadvan-tages may be expected from prolonged bed rest(Deitrick, Whedon, and Shorr, I948).

In a recent study immediate relief from ischaemicchest pain was reported when the cardioselectivebeta-adrenergic receptor agent practolol was givento patients with acute myocardial infarction. Thedrug was well tolerated though some of thesepatients had signs of latent left-sided heart failure(Waagstein, Hjalmarson and Wasir, I974). In somepatients with acute myocardial infarction, acutecongestive heart failure, and supraventricular tachy-Received ig November I974.

cardia, which did not respond to conventionaltherapy such as digitalis and frusemide, the injec-tion of practolol was followed by disappearance ofthe signs of pulmonary congestion (F. Waagsteinand A. Hjalmarson, unpublished data). It wasthought that the positive effect in these patientswas the result of a decrease in left ventricular ex-ternal work expressed as the product of systolic

CoseNoI F59

2 M59

3 F34

4 M55

5 M55

6 F33

7 F38

Alprenolol 50mqx 2

Proctolol OOmgx 2

Proctolol 200mgx2

Practolol lOOmgx 2

Practolol 50mgx2Proctolol 3 2

68 b9 70 71 72 73 74FIG. i Duration of heart disease in years andtreatment with beta-adrenergic receptor blockingagents in patients with congestive cardiomyopathy.

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Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy 1023

blood pressure and heart rate. On the basis of thesefindings it was considered that patients with con-gestive heart failure from other causes might alsorespond well to a reduction of tachycardia by beta-adrenergic receptor blockade.

In the present study adrenergic beta-blockingagents were, therefore, given to patients with con-gestive cardiomyopathy of unknown origin, withlong-standing signs of cardiac failure and a restingheart rate of about IOO beats/min. The effect of thetreatment with beta-adrenergic blockade on theirclinical condition, physical working capacity, andheart function, as judged from noninvasive tech-niques, forms the basis of this report.

SubjectsSeven patients, 3 men and 4 women, 33 to 59 years ofage (47.5 + II.9) with a history of heart disease rangingfrom 6 months to 6 years (2.6+2.2) were studied (Fig.I). The patients were chosen on the basis of a diagnosisof cardiomyopathy with congestive heart failure and anincreased heart rate at rest. Their heart rates were 85 toII5 (98 ± I3) beats/min. The diagnosis of congestivecardiomyopathy was based on the criteria given byGoodwin and Oakley (1972). Patients with overt cor-onary heart disease, congenital heart disease, acquiredvalvular disease, and hypertensive heart disease wereexcluded. Coronary angiograms were obtained in 2patients (Cases I and 6) and were normal.

All patients were in a steady state or were deteriorat-ing progressively at the start of therapy with the beta-adrenergic receptor blocking agents. None of the patientshad suffered during three months before the start ofbetablockade from any acute episode of disease indic-ating acute myocarditis, acute coronary heart disease, oracute embolism, for example.The patients were on oral treatment with digitalis

(digoxin) and diuretics (frusemide, spironolactone) for

congestive heart failure, except for one (Case 7) whoreceived only digitalis. Two patients (Cases 2 and 6) hadbeen given parenteral injections of ethacrynic acid orfrusemide in addition. The treatment with digitalis anddiuretics was unaltered or reduced during the time thatpractolol was given. The clinical data are given in thecase reports below and in Fig. i and Table I.

Representative case reportsCase I A 59-year-old woman had septicaemia at theage of 25. No sign of heart disease was seen at that time.In I962 a routine medical examination revealed thirdand fourth heart sounds but electrocardiogram and x-rayof the heart were normal. The patient had no cardiacsymptoms except for infrequent ectopic beats. In AprilI968 heart failure developed rapidly over a period of afew weeks, culminating in pulmonary oedema. No clin-ical evidence of infection was present. Erythrocytesedimentation rate, white blood cells, temperature, andvirus titres taken on two occasions, were normal. Electro-cardiogram showed left ventricular hypertrophy butthe heart volume derived from the x-ray was 8oo ml or410 ml per M2n. The patient improved on digitalis anddiuretics. Left ventricular catheterization revealed aleft ventricular end-diastolic pressure of I9 mmHg(2.5 kPa). Selective coronary angiogram was normal. Thepatient continued to have effort dyspnoea and wasgraded in functional group II until April I972 when hersymptoms grew worse, with increasing dyspnoea andperipheral oedema. From August 1972 the patient shiftedbetween functional groups III and IV. During 6 monthsthe patient was admitted to hospital on 4 occasions fora total of 24 months. Chest x-ray showed a pronouncedincrease in heart size (see Table 4 and Fig. 7), and rightheart catheterization showed an increase in the meanpulmonary arterial pressure. Loud diastolic extrasounds, shortened left ventricular ejection time, andhighly pathological apex cardiogram and echocardiogramwere also recorded (see Tables 5 to 8 and Fig. 2). InJanuary I973, atrial fibrillation occurred which waseasily converted by DC shock. The patient was given

TABLE I Clinical and electrocardiographic findings in 7 cases of congestive cardiomyopathy before start ofbeta-blockade

Case Sex Age Possible virus Chest pain Dyspnoea Peripheral Ascites Rhythm QRS complexNo. (yr) infection on exercise on exercise oedema

I F 59 - + + - Sinus Left ventricularhypertrophy

2 M 59 (+) - + + - Atrial Left bundle-branch blockfibril-lation

3 F 34 + + + + - Sinus ,. , .4 M 55 + - + + _ Sinus Left ventricular

hypertrophy5 M 55 + (+) + + - Sinus Left bundle-branch block6 F 33 + - + + + Nodal Left anterior hemiblock7 F 38 + - + _ - Sinus Left ventricular

hypertrophy



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a b

FIG. 2 Case z. Phonocardiogram and apex cardiogram before beta-blockade (a) and I2 monthsafter (b). Note the total disappearance of a very strong third heart sound and reduced amp-litude of the fourth heart sound. The ejection sound, E, is almost unchanged. In the apexcardiogram, note that the early diastolic rise to a very high rapid filling wave (RFW) haschanged to a normal diastolic filling pattern after I2 months of beta-blockade. From above:ECG lead II; PCG: earlike, 25 Hz, 50 Hz, apex cardiogram, 200 Hz and 400 Hz.

quinidine. Severe dyspnoea at rest persisted and theresting heart rate averaged iii beats/min. The patientthen had 0.25 mg digoxin, 40 to 8o mg frusemide, ando.8 g quinidine sulphate daily and was later given thebeta-blocking agent alprenolol 50 mg twice daily. Theheart rate was reduced to go beats/min and an immediaterelief of orthopnoea was seen within a few days. Duringthe following 2 to 3 months there was clinical improve-ment. Reinvestigation 12 months later confirmed thisimprovement (see Tables 3, 5 to 8 and Fig. 2). At thattime the patient was on digoxin, frusemide, quinidine,and alprenolol.

Case 2 A 5o-year-old carpenter had suffered from re-current throat infections of long duration since 1966.Antibiotics were given but the patient always stayed atwork despite high fever. In February 1969, about onemonth after a throat infection, he suddenly developedexertional dyspnoea and retrosternal pain on deep in-spiration. The pain disappeared after one week but thedyspnoea increased steadily, culminating in pulmonaryoedema. On admission to hospital he had atrial fibrilla-tion, with a ventricular rate of I6o beats/min. Someimprovement was seen after digitalis and diuretics butthe atrial fibrillation persisted with a ventricular rate ofabout i10 beats/min at rest. DC conversion was not doneat this time. The heart size was 690 ml per mi.

Slow deterioration occurred until December 197Iwhen he was in functional group III-IV. From thattime he was admitted to hospital 9 times for a total of2j months until treatment with the beta-blocker wasstarted. During the short periods at home he sufferedfrom severe nocturnal dyspnoea and he had to sleep inthe sitting position. In addition, since I969, the patienthad short attacks of fainting related to exercise of mod-erate intensity. The frequency of the attacks was stillincreasing. Observation with telemetry and tape record-ing of electrocardiogram failed to reveal episodes ofbradyarrhythmia or ventricular tachyarrhythmia. Elec-trocardiogram was normal and no effect was seen aftertherapeutic trials with different anticonvulsants. Theattacks were, therefore, interpreted as being caused byinadequate cardiac output during exercise. In February1973 treatment with practolol was started, resulting inimprovement and disappearance of the nocturnal dys-pnoea within a few days. It was then possible to with-draw spironolactone and the intermittent injections offrusemide. The resting heart rate was reduced (seeTable 2) and an improvement in working performancewas seen (see Table 3). The episodes of fainting werethen infrequent. In March I974 he underwent an opera-tion for a perforated appendix. The postoperative periodwas complicated by wound infection but he was never-theless in good cardiopulmonary condition. Noninvasiveinvestigation including echocardiography, which was



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TABLE 2 Resting blood pressure and heart rate before and during chronic beta-blockade

Case No. Shortly before beta-blockade After 3 to 7 days on beta- After 2 to 12 months on beta-blockade blockade

Systolic Diastolic HR Systolic Diastolic HR Systolic Diastolic HRBP BP BP BP BP BP(mmHg)

I I37 80 III I15 80 90 I37 75 8i2 I26 87 115 125 87 82 I42 82 743 Ino 8o 97 IOI 64 9I 105 69 874 I13 8i I07 I02 64 9I 128 6I 745 145 87 83 140 8o 68 135 78 606 I06 70 86 Ioo 65 53 IIO 8o 387 158 80 85 I48 80 75 I30 68 7IMean+SD I29±2I 8I±6 98±I3 II8±20 74±+0 79±14 I26±I4 73±8 69±+6

Note: Values are means of at least 5 measurements. Conversion factor from Traditional to SI units: I mmHg,o0.I33 kPa.

only performed after chronic beta-blockade, showedsigns of general cardiomyopathy and no sign of outflowobstruction. A clear reduction of heart size was seen(see Table 4). Attempts to withdraw the beta-blockingagent were followed by immediate relapse of noctunmaldyspnoea and more frequent attacks of fainting.

Case 4 A 55-year-old man had recurrent duodenalulcers since I940. In I97I, his stomach was resected foracute stenosis. He had never complained about hisstomach since that time. Heart size at the time of opera-tion was 335 ml per M2. Electrocardiogram and bloodpressure as well as the resting heart rate were normal.

In September 1972 the patient developed a commoncold, and in the subsequent 2 weeks he went into cardiacfailure. Erythrocyte sedimentation rate, leucocytes,temperature, and virus titres were within the normalrange. Electrocardiogram now showed left ventricularhypertrophy. The heart size was still within the normalrange (390 ml per M2) but the apex cardiogram waspathological with an a/H ratio of26 per cent but a normalrapid filling wave. Improvement was seen after digitalisand diuretics and the patient's condition was stable infunctional group II to III until June I973. He thencaught a common cold again, and after that the diseaseprogressed rapidly, with development of nocturnal

TABLE. 3 Physicalchronic beta-blockade

work test before and after

Case Shortly before After 3 to 7 After 2 to 12No. beta-blockade days on beta- months on beta-

(kpmlmin) blockade blockade(kpm/min) (kpm/min)

I FG IV 5002 FG IV - 5003 400 400 5004 300 300 6005 450 600 7506 200 300 4007 300 400 500

Note: Values are means of at least 5 measurements.FG= functional grade.

dyspnoea and pleural effusion. He was taken into hos-pital in January I974 in a bad condition with dyspnoeaand a clinical picture of low cardiac output syndromewith faint radial pulses, coldness of the periphery, andsevere acrocyanosis. He could hardly walk and com-plained of dizziness in the upright position.

TABLE 4 Heart volumes and body weight before and 2 to 12 months after chronic beta-blockade

Case No. Before beta-blockade After beta-blockade

Total heart Heart Body weight Total heart Heart Body weightvolume (ml) volume per m2 BSA (ml) (kg) volume (ml) volume per m2 BSA (ml) (kg)

I 1430 830 58.5 88o 460 63.52 2300 I030 102.5 I790 790 II5.73 1440 800 76.9 1190 68o 73.04 I 60 670 57.2 910 500 66.25 1740 88o 82.0 I590 820 82.06 1370 820 56.9 1380 820 57-37 585 380 53.0 585 390 50.5



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FIG. 3 Case 4. Phonocardiogram and apex cardiogram before (a and c, respectively), andafter 2 months of beta-blockade (b and d, respectively). Note that the initial regurgitationmurmur disappears and the strong third and fourth heart sounds decrease to normal ampli-litudes; the filling pattern of the apex cardiograms also returns to normal after beta-blockade.



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Noninvasive investigation showed signs of increasedfilling pressure of the left ventricle in early diastole(see Table 7 and Fig. 3) and enlarged left ventriculardiameter (see Table 8) and small stroke volume (seeTable 6). This was confirmed by left and right heartcatheterization and increased heart size in x-ray (seeTable 4). After administration of practolol there was noimmediate effect, but after about one month improve-ment was seen which was still in progress three monthslater. Initially the arterial hypotension and dizziness inthe upright position previously seen were somewhataccentuated. After 2 months these symptoms had com-pletely disappeared. The patient is now in a better con-dition than before the start of the disease in SeptemberI972. Reinvestigation showed improvement in all in-vasive parameters' as well as noninvasive parameters,except for an unchanged left ventricular diameter (seeTables 3-8 and Fig. 3).

MethodsResting blood pressures and heart rates were calculated asthe mean of at least 5 observations with the patient lyingin bed in the morning.

Exercise tests were performed on an electrically brakedbicycle-ergometer (Elema-Schonander EM 369/I). Themaximum attainable work loads were expressed inkpm/min (i kpm/min=o.i6 W). The patients werekept for 4 minutes on each work load. The work loadswere increased stepwise in the same manner beforeand after beta-blockade.

Heart volumes were measured from a chest x-ray takenin the standing position, according to Jonsell (I939) andexpressed in ml per m2 body surface area.

Noninvasive investigations were performed in all patients,including phonocardiogram from 5 standard areas, apexcardiogram, pulse tracings from the carotid artery,jugular vein, and liver, and echocardiogram. Alltracings with the exception of the echocardiograms weremade with an 8-channel ink-recorder (Mingograph 8i,Elema-Schonander) at a paper speed of I00 mm/s. Thephonocardiograms were recorded with an accelerationmicrophone (type Elema-Schonander EMT 25C) fixedto the thoracic wall with adhesive tape. The apex cardio-gram and the pulse tracings were all done with a specialhandheld funnel-shaped pickup (Wikstrand, Wallentin,and Nilsson, to be published) with an internal dia-meter of 2.3 cm connected to a crystal transducer(Elema-Schonander EMT 5Io C) with a 35 cm latextube. This combined system has a frequency response ofo.o9-6o Hz (-3db) and a time constant of i.8-4.6 S(depending on the amplification). The left ventricularejection time was measured from the carotid pulse andcorrected for the heart rate according to Meiners(Meiners, 1958; Hartman, I964; Willems and Kesteloot,x967). This correction expresses left ventricular ejectiontime as a percentage of the normal for the heart rateconcerned. The apex cardiogram was recorded with

1 These data will be published in a future communication.

the patient in the left lateral position. The a wave wasexpressed as a percentage of the total amplitude of thepulse curve (H). Analogous to this conventional a/Hratio, the rapid filling wave (RFW) was also expressedas the RFW/H ratio, since most changes were seen inthe early diastolic part of the apex cardiogram becauseof the very disturbed left ventricular function of thepatients in this study. All measurements were calculatedas the mean of at least 3 cardiac cycles.

Echocardiography: a commercially available ultrasono-scope (Ekoline 20, Mark II, Smith-Kline) was employed,using a 2.25 MHz transducer, with I0 cm focus and witha repetition rate of Iooo impulses/s. Polaroid photo-graphs of the time-motion echo display were taken froma slave storage oscilloscope (Tektronix 603). The stan-dard technique (Feigenbaum, 1972) of examining themitral and aortic valves and the size of the left atriumand left ventricle was followed. Much care and time weretaken to get the anteroposterior diameter of the leftventricle just below the aortic root and through or veryclose to both the anterior and posterior mitral leaflets.In order to standardize the measurement of the leftatrium the beam had to go through and visualize theaortic leaflets as well. The stroke volume was calculatedfrom the end-diastolic and end-systolic volumes derivedby the cube method (Pombo, Troy, and Russell, I97I)and the ejection fraction from the stroke volume andend-diastolic volume. The mean rate of circumferentialfibre shortening (mean VcF) was calculated accordingto Cooper and co-workers (I972), with the exception thatleft ventricular ejection time in the formula was derivedfrom the carotid pulse curve.

ResultsAdrenergic beta-receptor blocking agents weregiven for 2 to I2 months (Fig. i) to the 7 patients(Table i). One patient was given alprenolol in adose of 50 mg twice daily and the other 6 patientswere given practolol in a dose of 50 to 400 mg twicedaily. Before the treatment with beta-blockingagents these patients had severe manifestations ofcongestive cardiomyopathy as described in the casereports above. Four patients experienced an immed-iate reduction of dyspnoea and retrosternal oppres-sion. The 3 remaining patients reported a gradualimprovement starting after one month of treatment.Two patients with peripheral oedema and ascites,which had been resistant to large doses of diuretics,had a diuresis after the beta-blockade and weremaintained free of oedema with lower doses ofdiuretics or none at all (see Table 9). In 3 patients(Cases I, 2, and 4) the improvement was consider-able and a clear improvement was seen in Cases 5to 7, whereas the changes were less in Case 3, buteven this patient reported improved exercise per-formance. The patients generally complained ofmuscle tiredness at the beginning of beta-blockade,even at a low degree of physical exercise, and



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TABLE 5 Amplitudes of the heart sounds as judgedfrom phonocardiograms before and 2 to 12 monthsafter chronic beta-blockade

Case Pulmonary 3rd heart sound 4th heart soundNo. component of 2nd

heart sound

Before After Before After Before After

I 4 N (2) 5 0 4 22 - N (I-2) o *3 3-4 3-4 0 0 3 24 4 N (2) 4 I 5 I

5 4 N (2-3) 3 2 4 26 4 N (2-3) 4 37 3-4 N (2) 5 0 4 I

* Atrial fibrillation.t Nodal rhythm.Note: Amplitude of sounds are judged on subjective s-degree

scale. o= no detectable component; i = very weak heartsound; 2 = weak heart sound; 3= moderate heart sound;4=strong heart sound; 5=very strong heart sound; N=normal heart sound. See text for further explanation.

dizziness when standing. After I to 2 months oftreatment these symptoms had almost completelydisappeared.

Resting heart rate and blood pressure

The heart rate and the systolic blood pressuredecreased shortly after the start of beta-blockade(Table 2). A further reduction in heart rate wasseen at the time of reinvestigation, whereas theresting systolic blood pressure tended to return tothe same level as before beta-blockade. The dias-tolic blood pressure fell somewhat just after thestart of beta-blockade and then remained at thislower level.

TABLE 6 Relative left ventric-ular ejection time before and afterchronic beta-blockade in congest-ive cardiomyopathy

Case Before(%) After(%)No.

I 85 922 8o3 85 924 74 875 92 956 64 8o7 87 go

Note: Left ventricular ejection timeis rate-corrected according toMeiners (1958) and expressed as a

percentage of normal.

TABLE 7 Apex cardiogram before andafter chronic beta-blockade in congestivecardiomyopathy

Case RFW/H(%) a/H(%)No.

Before After Before After

I 38 2 9 92 8 - *3 I7 22 i6 I94 I7 5 II 75 II 0-I 3I 356 50 I2 -t -t7 22 5 27 5

* Atrial fibrillation, no a wave.t Nodal rhythm, no a wave.RFW=rapid filling wave; H= total amplitudeof pulse curve; a = height of a wave.

Exercise test

A slight improvement was recorded I to 3 daysafter commencement of the treatment with beta-blocking agents. Later there was a further rise inphysical working capacity (Table 3) and the systolicblood pressure increased to a higher level duringexercise as compared to the pretreatment level.During beta-blockade treatment the exercise testwas interrupted because of muscle fatigue or generalexhaustion rather than because of dyspnoea, palpita-tion, or retrosternal oppression, as was the case inthe pretreatment exercise test.

X-ray of the heartA significant reduction of heart size as judged fromchest x-ray was seen in 3 (Cases I, 2, and 4) out ofthe 6 cases with enlarged hearts (Table 4). Somereduction occurred in Case 3. In 2 cases the heartsize was unaltered.

PhonocardiogramThe amplitude of the pulmonary component of thesecond heart sound and of the diastolic extra soundswas judged according to a subjective 5-degree scale(Table 5). A fourth heart sound and pulmonarycomponent of degree 4 to 5 were considered patho-logical. Since clear-cut third heart sounds are alwayspathological in this age group, even degree 3 wasconsidered abnormal. Because of poor clinicalcondition, Case 2 was not investigated before thestart of beta-blockade. Case 3 had an enormouslydilated left ventricle and weak and diffuse heartsounds. The other 5 patients had moderate to strongthird heart sounds, which in Cases i, 4, and 7 dis-appeared after beta-blockade (Fig. 2-4). A decreasein amplitude occurred in the other 2 cases. Of 5



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FIG. 4 Case 7. Phonocardiogram and apex cardiogram before (a and c, respectively), andafter 2 months of beta-blockade (b and d, respectively). After beta-blockade there was a returnto normnal of the third andfourth heart sounds and of the diastolic part of the apex cardiogram(as in Cases i and 4).



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TABLE 8 Echocardiography of left atrium and left ventricle before and afterchronic beta-blockade in congestive cardiomyopathy

Case Left ventricular Left atrial Mean VcF* Ejection fractionNo. end-diastolic diameter (cm) (circumferencels)

diameter (cm)

Before After Before After Before After Before After

I 6-7 5.2 5.0 3.0 0.77 0.482 6.8 5.3 -t 0.353 8.4 8.5 3.9 4.2 0.52 0.47 - -*4 6.2 6.o 4.5 3 9 0.5I o.66 0.21 0.585 6.9 7.I 4.8 4.8 o.6o 0.72 -t -t6 5.2 4.8 3.9 3.9 0.59 o.69 (o.3I)t (047)t7 5.3 4.9 2.9 2.9 0.94 I.33 0.54 0.72

* Mean velocity of circumferential fibre shortening.t Difficult to calculate mean VCF because of atrial fibrillation.t Difficult to calculate ejection fraction because of pathological movement of interventricularseptum.

patients in sinus rhythm, 4 had strong or very strongfourth heart sounds. These sounds decreased tonormal amplitudes after beta-blockade. A similarreturn to normal of the pulmonary componentwas seen in all cases except Case 3. Three patients(Cases 3, 4, and 5) had a typical murmur of mitralregurgitation. Since the echocardiograms gave no

suspicion of rheumatic changes of the mitral valve,this regurgitation was considered secondary to adilatation of the left ventricle (see Table 8). Themurmur disappeared in Case 4 (Fig. 3), diminishedin Case 5, but was unchanged in Case 3.

Left ventricular ejection timeWhen expressing left ventricular ejection time as apercentage of the normal (relative left ventricularejection time) according to Meiners (I958), valuesbelow go per cent are abnormal. Of the 6 patients, 5had a relative ejection time below go per cent (Table6), and in 2 of these it was extremely low (Cases 4and 6). After chronic beta-blockade the left ven-tricular ejection time was considerably longer inCases 4 and 6, with lesser increases in the others;no patient showed shortening of the ejection time.

TABLE 9 Daily dosage of digitalis and diuretics just before starttherapy and after 2 to 12 months of treatment

of beta-blocker

Case ,-blockade Digoxin Frusemide Ethacrynic acid Spironolactone Frusemide orNo. (orally) (orally) (orally) (orally) (orally) ethacrynic acid

(mg) (mg) (mg) (mg) (intravenously)

I - 0.25 8o - -+ 0.25 80 - -

2 - 0.5 I60 200 Ethacrynicacid 50 mg*

+ 0.5 80 -3 - 0.25 40 -

+ 0.25 404 - 0.25 80

+ 0.25 405 - 0.25 40

+ 0.25 406 _ 0.25 500 80 200 Frusemide 8o mg

+ 0.I25 200 2007 - 0.25

+ 0.25 -

* Occasionally during this period.



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RIGHT VENTRICLE 32cmRIGHT VENTRICLE 1.6cm*-SEPTUM

ECG ECG LVIDdLVIDd LEFT VENTRICLE 4.8cm

LEFT VENTRICLE 5.2cm - P OPOSTERWOR

A. Febr -74 B June -74FIG. S Case 6. A) February 1974: the right ventricle is dilated and the septum moves towardsthe anterior wall in systole because of volume load secondary to tricuspid regurgitation. B)J7une 1974: after 4 months of beta-blockade the anteroposterior dimension of the right ventriclehas decreased from 3.2 to i.6 cm, but the septum still moves anteriorly during systole. A slightdecrease of the left ventricular internal diastolic diameter (LVIDd) is also seen.

Apex cardiogramAll patients in whom measurement could be madehad extremely abnormal apex cardiograms, withhigh rapid filling waves and/or high a waves(Table 7, Fig. 2-4). Both rapid filling waves andthe a waves were expressed as a percentage of thetotal amplitude of the curve (H). After treatmentthere was a decrease in the rapid filling wave/Hratio in all patients except Case 3 and a decrease ofthe a waves in 2 of them. Fig. 2-4 show the apexcardiograms of Cases I, 4, and 7 with completereturn to normal after beta-blockade. No changeswere seen in Case 3.

EchocardiographyThe left ventricular end-diastolic diameter was verylarge (6.2 to 8.4 cm) in 4 cases and slightly enlargedin Cases 6 and 7 (Table 8 and Fig. 5). It was notmeasured initially in Case 2. Only a range could begiven in Case i before beta-blockade because ofpoordefinition of the endocardium. After beta-blockertreatment this dimension decreased in Cases i, 6,and 7. There was no change in the other 3 cases.The anteroposterior dimension of the left atrium

was enlarged in 3 cases, close to the upper normallimit in 2 cases, and normal in Case 7. After beta-blockade the left atrium decreased in Cases i and 4(cf. the changes of the apex cardiogram of thesecases, Fig. 2 and 3), probably increased slightly inCase 3, and was unchanged in the others. Sincethere were abnormal septal movements and there-fore asymmetrical contractions of the left ventriclecaused by conduction disturbances (Table i) orgross tricuspid regurgitation (Case 6), the ejectionfraction could only be calculated in 2 cases beforetreatment, and it increased after beta-blockade inboth of them.The mean rate of circumferential shortening

(mean VCF) was calculated in 5 cases before treat-ment. This rate increased in all except Case 3.Note that all cases, except Case 7, even after beta-blockade, had depressed left ventricular function asjudged from the mean VCF and the ejection fraction.Case 2, who was only investigated after beta-blockade, had highly abnormal dimensions and avery low ejection fraction. The dominant clinicaldisturbance in Case 6 was tricuspid regurgitation,which decreased clinically after beta-blockadeThe dimension of the right ventricle decreased



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A. Oct. -72 B. Jan.-74FIG. 6 Case i. Frank leads. Note the decrease ofthe QRS loops in all projections after 12 monthsof beta-blockade. The horizontal maximum beforeis in October 1972 2.0 mV (A), in January 19741.3 mV (B). The calibration signal in H is i mV.

from 3.2 to i.6 cm. Probably the left ventricle de-creased somewhat and contracted better (Fig. 5).The jugular and hepatic pulse tracings showed lessevidence of tricuspid regurgitation.

VectorcardiogramVectorcardiographic signs of left ventricular hyper-trophy were seen in Cases I, 4, and 7. In the other4 patients there were conduction disturbances whichmade this diagnosis impossible (Table i). In Cases4 and 7 new vectorcardiograms were recorded afterabout 3 months on beta-blockade and showed nosignificant changes in Case 7 and a small but signi-ficant decrease in horizontal maximum vector from2.8 mV to 2.3 mV in Case 4. In Case i, however,there was a much longer observation period, withI2 months on beta-blockade. This patient showed aremarkable change of the vector loops, with adecrease of the horizontal maximum vector from2.0 to I.3 mV (Fig. 6).

DiscussionChronic treatment with beta-adrenergic receptorblocking agents in 7 patients with congestive cardio-myopathy over periods ranging from 2 to I2 months

a b

FIG. 7 Case I. Frontal chest x-ray before (a) and after (b) 12 months of treatment with beta-blockers showing obvious decrease in heart size.



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resulted in an improved clinical condition with lessexertional dyspnoea and retrosternal oppression,allowing the patients increased physical activity.This was reflected in higher physical workingcapacities at the exercise test. The findings fromthe noninvasive investigations indicate that heartfunction was improved during chronic beta-blockade. In some patients a pronounced reductionin heart size was found during this treatment. In all7 cases in this study, the relative left ventricularejection time increased, indicating an increasedstroke volume. The AV02-difference was studiedduring exercise in 2 cases and no change was seenin one patient and a reduction from a very highvalue was seen in the other patient. The improvedworking capacity in these patients therefore couldnot have resulted from an increased AV02-differ-ence; it was reached with a lower maximum heartrate and is likely, therefore, to have been attainedby higher stroke volumes. This was confirmed in onepatient (Case 4) in whom the stroke volume was in-vestigated during maximal exercise using an in-vasive technique (to be published).The diagnosis of congestive cardiomyopathy was

made according to the criteria of Goodwin andOakley (I972) who defined the disease as a diffuseprimary myocardial disease of unknown origin witha depressed systolic function of the ventricles.Hypertrophic cardiomyopathy has been excluded, asechocardiograms and phonocardiograms showed nosigns of outflow tract obstruction or of interven-tricular septal hypertrophy (Feigenbaum, 1972;Abbasi et al., I972). Suspected metabolic disorderswere excluded by normal levels of urine catechol-amines and normal thyroid function tests. A collagendisease was not likely in these patients since theerythrocyte sedimentation rate and the titre of theantinuclear factor were within normal limits.Biopsies from buccal or rectal mucosa showednormal histology. Coronary heart disease was com-pletely excluded only in two patients (Cases iand 6), two woman with no history of chest painand with normal coronary angiograms. Coronaryarterial disease cannot be absolutely excluded in theother cases, but all presented the clinical andhaemodynamic features of left ventricular failureas in congestive cardiomyopathy. In 2 (Cases 3 and5) retrosternal oppression on exercise was present,which disappeared after beta-blockade; angina-likechest pain has been reported in io per cent of caseswith congestive cardiomyopathy despite normalcoronary angiograms (Gau et al., 1970). Theseauthors noticed that a QS pattern could also beseen in patients with congestive cardiomyopathyand normal coronary angiograms. In one patient(Case 6) pressure tracings from both ventricles (to

be published) and the form of the apex cardiogramsuggested constriction. This was thought to be ofmyocardial origin. The heart was greatly dilatedand additional pericardial constriction was ex-cluded by angiocardiography.The genesis of congestive cardiomyopathy is

generally accepted to be of multifactorial origin butthe causes operative in individual cases are rarelyidentifiable. In 6 of our cases the onset of symptomsoccurred shortly after what might have been a virusinfection. It is important to stress that none hadany signs of infection during the last 3 monthsbefore the start of treatment with beta-blockade.Furthermore, the onset of symptoms occurred 6months to 6 years (average 2.6 years) before thestart of beta-blockade. One patient (Case 6), whoalready had some clinical findings indicating heartdisease (enlargement of the heart but no subjectivesigns), suffered serious progression of her heartdisease during the third trimester of pregnancy,shortly after a severe common cold. Intermittentinfection may unmask a latent disease or aggravatea pre-existing one.The management of congestive cardiomyopathy

has not changed much during the past decadeexcept for the use of pacemakers in bradyarrhyth-mias, lignocaine and DC shock in ventriculartachyarrhythmias, and frusemide and spironolac-tone in the treatment of oedema. The progressionof the disease has, however, never been reportedto be changed by this therapy, and death oftenresults from a final ventricular arrhythmia. Theregimen of prolonged bed rest advocated byMcDonald and co-workers (I972) is difficultto administer when permanent improvementcannot be guaranteed. However, a reduction ofsympathetic activity during prolonged bed restcomparable to the beta-blockade in this study couldpossibly explain a reduction in heart size seen in thestudy of McDonald and co-workers (I972). Touse beta-receptor blocking agents in congestivecardiomyopathy seems paradoxical since the heartmight be dependent upon raised sympatheticactivity. However, reduction of a high heart ratemight reduce the energy demand of the myocardium(Braunwald, I97I) and allow better diastolic fillingand thus increase the stroke volume, therebyimproving the efficiency of the heart and possiblyallowing more energy to be used for the contractilework.

In the present study only patients with a steadyprogression of the disease have been included. Thepatients had been given conventional treatment withdigitalis and diuretics for several weeks in hospitalwithout significant benefit before the start of treat-ment with beta-blockers. The digitalis and diuretics



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were somewhat reduced after a time on beta-blockersand in some cases even stopped (Table 9). Inter-ruption of beta-blockade in the early stages of treat-ment was followed by prompt return of symptoms.It, therefore, seems unlikely that the improvementin cardiac function and relief of symptoms observedin this study could have occurred by chance or beena part of the natural history of the disease.The clinical impression of improvement in the

present cases was confirmed by changes in bothinvasive and noninvasive parameters of left ven-tricular function. An early effect of depressed leftventricular function is hypertrophy of the leftatrium, associated with the increase in end-diastolicpressure and the volume of the ventricle (Romhiltand Scott, I972; Hammermeister and Warbasse,I974). The corresponding noninvasive findings areloud fourth heart sounds and high a waves in theapex cardiograms, and it seems well accepted that ana/H ratio more than 15 per cent indicates a patho-logical end-diastolic pressure (Rios and Massumi,I965; Epstein et al., I968; Voigt and Friesinger,I970; Gibson et al., I974). When this atrial com-pensation becomes inadequate the filling pressurehas to increase earlier in diastole leading to a rise ofthe pressure in the pulmonary circulation; thisresults in pathological third heart sounds, pro-nounced rapid filling waves in the apex curves, loudpulmonary components of the second heart sound,and sometimes mitral regurgitation if there isdilatation of the left ventricle. In these cases highend-diastolic pressures can be seen with a/H ratiosbelow I5 per cent, probably because of insufficientatrial contraction to give enough additional pres-sure rise. Left ventricular ejection time decreases,mostly because stroke volume is a major factordetermining this period (Braunwald, Sarnoff, andStainsby, I958; Weissler, Peeler, and Roehil, I96I;Fabian et al., 1972). All patients in this study hadseveral noninvasive findings typical of the lastgroup. If the pump function of the left ventricleimproves, these changes can be expected to bereversed. This was seen after beta-blockade, themost pronounced changes being a normalizationof the pulmonary components and of the rapid fillingwaves, and disappearance of the pathological thirdheart sounds. The changes of the apex curves anddiastolic extra sounds shown in Fig. 2 to 4 areremarkable. Such a dramatic return to normaltracings has not been seen in non-surgical cases inspite of experience of more than 5000 non-invasiveinvestigations in our laboratory (Wallentin, un-published observations).

Echocardiography has been shown to give muchbetter estimation of the left atrial size compared tochest x-ray when angiography was used as a stan-

dard (Hirata et al., I969). In a study at this hospitalit has been found that the echocardiographic antero-posterior dimension of the left atrium is larger inmany cases of myocardial infarction and hyper-tension than in normal individuals of the same age(Wikstrand and Wallentin, to be published). It is,also our experience that echocardiography demon-strates that the left atrium is enlarged in cases ofsevere aortic valvular disease, especially in relationto left ventricular failure, and in many of these casesthis dimension decreases again after surgery. Twoofour cases with very obvious clinical improvement(Cases I and 4, Fig. 2 and 3) also showed a cleardecrease of left atrial size echocardiographically.

Since the lower limit of mean VCF is aboutI circf/s (Paraskos et al., I97I; Cooper et al., I972)4 out of 5 cases had unusually low values, depressedto 50 to 6o per cent of this lower limit. In spite ofan increase in left ventricular ejection time afterbeta-blockade, which per se decreases mean VCF,an increase in mean VCF was seen in all patientsexcept one (Case 3) who was unchanged in allnoninvasive parameters except the left ventricularejection time.

Reduction of vectorcardiographic signs of leftventricular hypertrophy in Cases i and 4 suggestreversal of the process of hypertrophy during treat-ment with beta-blocking agents. At least in Case 4,with unchanged left ventricular end-diastolic dia-meter, the vectorcardiographic findings could notbe influenced by reduction of the heart volume.

It is suggested that the hypertrophy in congestivecardiomyopathy is not just a secondary compen-satory change in a failing heart. Animal experimentshave shown that administration of catecholamineswill increase the rate of heart protein synthesis andthus induce hypertrophy without preceding de-compensation (Kallfelt, Hjalmarson and Isaksson,to be published). Great efforts have been made inan attempt to develop experimental models ofcardiomyopathy. Bajusz and co-workers (I969) haveshown that the natural course of the disease inSyrian hamsters with hereditary cardiomyopathycould be accelerated by digitalis and catecholamineswhen given early in life in a vulnerable phase, andthat treatment with beta-blocking agents could in-hibit the effect ofcatecholamines. Jasmin and Bajusz(I973) have shown that verapamil, which has cal-cium antagonistic properties in the heart cell, couldprevent the development of pathological changes inthe myocardium of these Syrian hamsters. It might,therefore, be questioned whether high sympathetictone in humans with cardiomyopathy also willinduce an increased rate of protein synthesis, hyper-trophy, necrosis, and deterioration ofheart fimction,as found in the animal experiments.



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In the present study one patient with severe con-gestive heart failure (Case I) was treated with thebeta-i- and beta-2-receptor blocking agent alpren-olol for I2 months, with very good results. The other6 patients were given the cardioselective beta-i-receptor blocking agent practolol for 2 to I2 months,with the same beneficial effect. Both these beta-blockers have intrinsic sympathetic stimulatingactivity. Cardioselectivity does not seem to be aprerequisite for the favourable effects of beta-block-ade in congestive cardiomyopathy. The intrinsicstimulatory activity of the beta-blockers might beof importance but this does not seem likely i

view of clinical and experimental data indicatingthat chronic high levels of catecholamines couldinduce cardiomyopathy. This study suggests thatthe blockade of the adrenergic beta-i-receptors ofthe myocardium is essential for favourable treat-ment in congestive cardiomyopathy.A common feature of all the patients in this study

with congestive cardiomyopathy was a high restingheart rate. This is the result of case selection, sincethe primary idea was to study the effect of beta-blockade in such patients with tachycardia. It hasbeen suggested that a high heart rate in advancedcongestive cardiomyopathy is a compensatory mech-anism for depressed systolic function with low strokevolumes. However, in two patients (Cases 4 and 7) ahigh resting heart rate was seen before any cardiacenlargement had developed.

It is possible that patients with cardiomyopathyof various types might be more susceptible tosympathetic stimulation, which might then haveunfavourable effects on the myocardium, as hasbeen seen in an models. All patients withcardiomyopathy do not show tachycardia, whichdoes not favour the suggestion that a high heart rateper se would induce the pathological changes in themyocardium in these patients. However, a normalor low heart rate does not exclude a high degree ofsympathetic influence on the heart cells. It is notknown whether chronic beta-blockade is also ofvalue in patients with congestive cardiomyopathywithout tachycardia. From this study it is notknown whether different types of congestive cardio-myopathy will respond similarly to chronic adren-ergic beta-receptor blockade. It is obvious from thisstudy that at least some patients with congestivecardiomyopathy will react very favourably to suchtreatment. Studies are in progress to evaluate theeffect of chronic beta-blockade in various types ofcongestive cardiomyopathy. It is hoped thatthis will increase our understanding of the patho-physiology of this disease and strengthen the thesisthat treatment with adrenergic beta-receptorblocking agents can influence the progression of

congestive cardiomyopathy and prolong life in thesepatients.

The present study was supported by grants from theSwedish National Association against Heart and ChestDiseases, the Swedish Medical Research Council(B73-03X-2529-o4), ICI-Pharma and Hassle AB.

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Braunwald, E. (I97I). Control of myocardial oxygen con-sumption. Physiologic and clinical considerations. Ameri-can Journal of Cardiology, 27, 4I6.

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