treatment of hypertrophic obstructive cardiomyopathy with verapamil · british heartjournal, 1979,...

British Heart Journal, 1979, 42, 35-42

Treatment of hypertrophic obstructivecardiomyopathy with verapamilM. KALTENBACH, R. HOPF, G. KOBER, W.-D. BUSSMANN, M. KELLER,AND Y. PETERSEN

From Zentrum der Inneren Medizin, Abteilung fur Kardiologie Klinikum derJ. W. Goethe- UniversitdtFrankfurt/M, Germany

suMMARY Twenty-two patients with hypertrophic obstructive cardiomyopathy were treated with thecalcium inhibitor, verapamil, which was administered in a mean oral dose of 480 mg per day. After anaverage of 15 months of treatment (4 to 24 months), the QRS amplitude in the electrocardiogram wassignificantly reduced from 4-2 to 3-8 mV. Heart volume calculated from chest x-ray films in the supineposition decreased significantly from 858 to 766 ml per 1-73 M2. In 10 patients, follow-up heart catheter-isation showed a decrease in left ventricular muscle mass in 7 patients and a slight increase in 3 patients.Coronary artery diameter decreased in 7 patients, increased in 1, and was unchanged in 2. The reductionin coronary artery diameter is considered to be a consequence of a reduced heart muscle mass. Fromall available clinical data it is concluded that verapamil treatment is superior to beta-blocker therapy.

Hypertrophic obstructive cardiomyopathy (HOCM),first described in the last century, is now oftendiagnosed. Medical treatment with beta-blockers,especially with propranolol, has been in use formore than 10 years. Long-term follow-up, however,has cast considerable doubt on the effectiveness ofthis therapy. It seems that the progression of thedisease cannot be stopped and that a recurrence ofsymptoms is common (Edwards et al., 1970;Goodwin, 1970; Hubner et al., 1973; Stenson et al.,1973; Morrow et al., 1975; Loogen et al., 1976;Rothlin et al., 1976; Sowton, 1976).

Experimentally, it has been shown that certainforms of cardiomyopathy can be prevented withcalcium inhibitor drugs. This was shown for thehereditary cardiomyopathy of the Syrian hamster(Lossnitzer, 1975). Recently, similar findings werereported in the cardiomyopathy induced by doxo-rubicin (Daniels et al., 1976). Though there aredifferences between experimentally induced cardio-myopathy and that found in humans, the myocardialdamage may be the consequence of a similarmechanism in which the calcium ion plays an im-portant role (Fleckenstein, 1969; Witzke and Kaye,1976; Wrogemann and Pena, 1976).

Patients with HOCM may have a remarkablyhigh left ventricular contractility even in the ad-vanced stages of the disease. Their sensitivity to

Received for publication 30 March 1978

catecholamines and to digitalis is also well known.These features of the disease may be related to anincreased availability of intracellular calcium. Aftera pilot study, a clinical trial with the calcium in-hibitor, verapamil, was initiated (Kaltenbach et al.,1976).

Methods

Twenty-two patients, 18 men and 4 women, aged 19to 44 years, were studied. Informed consent wasobtained from all patients.Symptoms were evaluated by means of a question-

naire. Electrocardiograms were recorded every 3months with special attention to accurate calibra-tion. In addition, phonocardiograms, carotid pulsetracings, and M mode echocardiograms (PickerSystem) were recorded.Heart volume, calculated from chest x-rays films

in the supine position at a tube-film distance of 2 m(Klepzig and Frisch, 1965), was determined every 6months. In addition, conventional chest x-ray filmsin the standing position were taken. Before treat-ment with verapamil, right and left heart catheter-isation was done in all patients, and selective coron-ary arteriograms (Sones technique) and biplanecine left ventriculograms were obtained. Right ven-triculograms were taken only when a systolic pres-sure gradient was recorded within the right ven-tricle.

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M. Kaltenbach, R. Hopf, W.-D. Bussmann, M. Keller, and Y. Petersen

In 10 patients, right and left heart catheterisationwas repeated after 14 to 24 months (average 19months) treatment with verapamil. The follow-upstudy also included selective coronary arteriographyand ventriculography. In addition, left ventricularcontractility was studied at rest and during exerciseby means of a Millar double-tip catheter. Thepatients were exercised for 6 minutes on a bicycleergometer in the supine position at a workload of 50to 100 watts. After recovery from the first exercisetest, 10 mg verapamil was injected intravenously anda second exercise test was performed using the sameworkload and the same duration of exercise. Pres-sure and contractility (dP/dt max and dP/dt/P)were recorded through the Millar catheter, with onetransducer in the apex and the other in the outflowtract of the left ventricle. Contractility reserve isdefined as the difference between dP/dt max at restand dP/dt max during exercise.

Coronary artery diameters were measured indifferent sites from the cineangiograms using a TVcamera mounted on a cineprojector for high mag-nification. Left ventricular muscle mass was calcu-lated from left ventricular free wall and left ventricu-lar end-diastolic volume. Left ventricular end-diastolic volume and left ventricular end-systolicvolume were determined from outlines of the leftventricle in two planes (RAO 400 and LAO 50°).For these calculations, Simpson's rule using the

computer system 'Volumat' (Siemens) was applied.X-ray magnification factor was determined (Kalten-bach et al., 1975) and used for calculation ofcoronary diameter, left ventricular volume, and leftventricular muscle mass (see Fig. 5).

Medication

Before the study, most patients had been treated forseveral months or years with beta-blocking agents,such as propranolol (120 to 240 mg per day) orpindolol (7 5 to 15 mg per day). In patients receivinga beta-blocker this treatment was stopped for atleast one week before verapamill was started. Afterone week of treatment with verapamil 80 mg t.d.s.,the dose was increased to 160 mg t.d.s. (480 mg perday). In some patients, the dose was further in-creased after several months to 720 mg per day. Thedrug was always administered orally.

Statistical methods

Student's t test was used to analyse the differences inthe mean values before and after treatment. Thecriterion of significance was P < 0 05. Every patientserved as his own control.

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Treatment of hypertrophic obstructive cardiomyopathy with verapamil

Results

SYMPTOMSSixteen patients were symptomatic. Eleven of thesepatients reported lessening or complete relief ofchest pain or breathlessness on effort. Six patientshad only minor subjective symptoms and noticed noessential change during treatment.

HEART RATE AND BLOOD PRESSUREThe average heart rate decreased from 68 to 65beats/min. Statistically, this difference was notsignificant. Blood pressure fell to normal in onepatient with moderate hypertension during treat-ment with verapamil. No change was observed inthe remaining patients.

ELECTROCARDIOGRAMAfter an average period of treatment of 15 months(4 to 24 months) a significant reduction in QRSamplitude was observed. The average-Sokolow in-dex (sum of maximal S and R deflections in leadsVl to V6) decreased from 42 to 3-8 mV. Twelvepatients showed a decrease in QRS amplitude, in 5patients this was unchanged, and 3 patients showedan increase in amplitude. The reduction of QRSamplitude was accompanied by a tendency for STsegments to return towards normal; Fig. 1 shows atypical example. The changes in QRS amplitudeduring treatment with verapamil were compared

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with the values during previous treatment withbeta-blockers (Fig. 2). During treatment withbeta-blockers most patients had shown an un-changed or even increased QRS amplitude. In con-trast, a distinct decrease was observed during vera-pamil treatment.

PHONOCARDIOGRAM, CAROTID PULSE, ANDECHOCARDIOGRAMThe systolic murmur of HOCM did not disappearduring treatment with verapamil, but in somepatients there was a decrease in intensity of themurmur. Carotid pulse tracings showed no signifi-cant change. No conclusions can be drawn from alimited number of echocardiographic studies.

CHEST X-RAY AND HEART VOLUMEHeart volume was calculated in 21 patients fromchest x-ray films in the supine position. Measure-ments made before and after an average of 14months treatment (2 to 24 months) are shown inFig. 3. On average, heart volume decreased from 858to 766 ml per 1*73 M2; in 16 patients there was adecrease, in 3 patients an increase, and in 2 no changein heart volume. Conventional chest x-ray films inthe standing position showed no essential change, andthere were no signs of pulmonary congestion.

HEART CATHETERISATIONCatheterisation data obtained in 10 patients at thesecond study were compared with those obtained atthe first catheterisation (Table). In 4 patients, thishad been performed more than one year before thebeginning of treatment with verapamil.

In 5 patients the systolic pressure gradient inthe left ventricle was smaller, in 2 it was un-changed, and in 1 it was greater. In 1 of the 10patients, no gradient was present, and in 1 the

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Table Haemodynamic and other measurements before and after verapamil treatment

Case no. Beginning of Duration of Dates of LVEDV EF LV muscle massverapamil treatment catheterisation (ml per 1 73 mi) (%)treatment (mth) (ml per 1 73 mi)

1 6.1975 14 b 10.11.1972 105 63 148a 31.8.1976 142 63 101

2 4.1975 15 b 7.3.1974 85 78 122a 14.9.1976 89 76 110

3 9.1974 24 b 11.12.1974 72 75 151a 7.9.1976 95 85 104

4 9.1974 24 b 19.8.1974 149 88 154a 7.9.1976 146 93 112

5 3.1974 23 b 25.6.1973 86 89 126a 27.9.1976 90 88 138

6 7.1975 16 b 26.3.1975 201 80 417a 21.9.1976 109 71 318

7 4.1975 19 b 9.3.1972 109 85 349a 23.11.1976 131 86 296

8 6.1975 17 b 29.5.1972 80 89 91a 9.11.1976 120 90 134

9 5.1975 18 b 29.7.1971 117 90 232a 9.11.1976 179 91 301

10 6.1975 15 b 11.12.1974 98 90 250a 14.9.1976 114 90 213

Average b 110 82 204a 121 83 182

measurement could not be repeated. As shown inFig. 4, the gradient at rest and after provocationdid not always change in the same manner.

Left ventricular muscle mass decreased in 7patients and increased in 3 (Fig. 5). In the 3 patientswith increased left ventricular muscle mass the firstcatheterisation had been performed 2 to 3 yearsbefore the beginning of verapamil treatment. Afurther increase of left ventricular muscle mass mayhave occurred before treatment with verapamil.Because of a pronounced reduction in wall thick-

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Fig. 4 Systolic pressure gradients within the leftventricle as measured at the times of the first and secondcatheterisation. Before verapamil, * = rest, * =provocation, 0 = post-extrasystolic. After verapamil,gradients shown by arrow ( t or ).

ness, muscle mass even decreased in some patientswith increased left ventricular end-diastolic volume.Left ventricular end-diastolic pressure and ejectionfraction were not affected by the treatment.

SELECTIVE CORONARY ARTERIOGRAPHYTwo independent investigators measured the coron-ary artery diameters at 5 different sites (Fig. 7). Theinvestigators were not aware whether they wereanalysing the first or the second coronary arterio-gram of a given patient. Correction was made fordifferences in x-ray magnification. Premedicationwas identical in all patients. Seven patients showeda decrease, 1 an increase, and 2 no change in coron-ary artery diameters (Fig. 7). On the average, bothright and left coronary arteries were significantlyreduced in diameter (8 and 9% respectively) and incross-sectional area (15 and 17%). A typicalexample is shown in Fig. 8.The results are summarised in the Table. In

general there are parallel reductions in interven-tricular gradient, left ventricular muscle mass, QRSamplitude, heart volume, and coronary arterydiameter, during oral verapamil treatment.

EFFECT OF INTRAVENOUS VERAPAMIL ON LEFTVENTRICULAR CONTRACTILITYAs verapamil can be shown to reduce contractility,11 patients with HOCM were studied using aMillar double-tip catheter. Eight of these patientshad been treated with oral verapamil before this in-vestigation; 3 had not been treated. Haemodynamicmeasurements were made at rest and on exercise.After recovery, 10 mg verapamil were given intra-

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Coronary artery diameter Gradient (mmHg) Sokolow index Heart volume

hange) (mm) (% change) Rest Provocation (mV) (% change) (ml) (% change)

5 9 -17 20 65 53 -ll 817 -184-9 4 6 4-7 66949 -14 28 52 3 -34 763 - 94-2 -40 0 2-3 6943-8 56 89 6-0 8203-6 9 24 4-0 7313-9 15 43 4-2 7113-9 0 32 43 4-2 0 657 - 84-2 0 0 2-9 8533@1 ~~~-26 =°31 + 7 80 - 53 1 0 =0 3-1 810

6-0 0 60 > 5 10455-8 32 60 = 5 856 -183-4 0 40 3-2 6453 4 0 0 = 4 225 - 22 872 +265-0 -10 0 35 5-5 901 -24.5 0 = 1 5-2 8802 9 + 15 75 20 3 6 +273+415 3 t+4293 -9604-1 -12 0 56 1-7 + 4 633 - 83-6 0 =4 2-1 +4 581

venously and a second exercise test was performed10 minutes later. Left ventricular systolic and end-diastolic pressures fell from 147 to 132, and 20 to16 mmHg, respectively. The intraventricular pres-sure gradient remained unchanged. The heart rateon exercise was significantly higher after verapamil.Contractility was unchanged after verapamil and thiswas so at rest as well as during exercise.

In contrast, beta-blocking drugs cause a distinctreduction in contractility at rest and a completeabolition of contractility reserve, as measured byidentical methods.

SIDE EFFECTSOne patient had a first degree atrioventricular blockwith a PR interval of 03 s during administration ofverapamil in a dose of 480 mg per day. After reduc-tion of the daily dose to 240 mg, the PR intervalbecame normal. In the remaining patients therewas no change in PR interval. Five patients com-plained of dizziness, nausea, headache, or chestpain during the first weeks of treatment. Thesesymptoms disappeared while treatment continued.

Discussion

It is our clinical impression from this study thatverapamil offers a better therapeutic approach toHOCM than the treatment with beta-blockers.Since most of the patients had been on conventionalbeta-blocker therapy before starting treatment withverapamil, the improvement in subjective and ob-jective indices on verapamil could be compared withresults of this preceding treatment. Because patients

and investigators regarded beta-blockers as effectivetreatment, a placebo effect of verapamil seems un-likely. Subjective symptoms disappeared or lessenedconsiderably in two-thirds of the patients who hadbeen symptomatic on beta-blocker treatment.Usually, it took several weeks of treatment withverapamil before subjective improvement wasnoticed. The disappearance or lessening of leftventricular hypertrophy on the electrocardiogramwas very impressive in some patients. In others, onlyslight changes were noted; this was particularly truefor patients whose electrocardiograms did not show atypical left ventricular hypertrophy pattern. The im-provement in the electrocardiogram was remarkablewhen compared with the finding of unchanged orincreasing QRS amplitudes during treatment withbeta-blockers.

Using chest x-ray films in the supine position, asignificant decrease in heart size was noted, whereasconventional chest x-ray films showed no change insize or configuration of the heart. Radiographicsigns of left ventricular failure were not observedduring verapamil treatment. Since acute drugadministration can influence heart size, all heartvolume determinations were made 2 days afterwithdrawal of verapamil. The same procedure wasadopted for heart volume determination during thepreceding period of beta-blocker therapy. Thediminished heart volume must therefore be attribu-ted to a sustained reduction in heart size and not toan acute effect of verapamil. Since beta-blockadeincreases heart size, one could argue that the re-duction in heart size might be attributed to a with-drawal of beta-blockers. However, the beta-blocker

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19 6 74

-VEDv: 149ml per 1 73m2EF: 88%.

LV muscle mass: 154ml per 173m27 97'

LVEDV: 146 ml per 1-73m2EF: 930/0

LV muscle mass: 112 ml per 1-73m2

Fig. 5 End-diastolic and end-systolic contours (RAOand LAO views) of the left ventricle in a patient (case 4)before and after treatment. The wall thickness is shownoutside the end-diastolic contour. Left ventricular musclemass was calculated from end-diastolic volume and leftventricular wall thickness in the RAO (anterior wall) andLAO (posterior wall). After treatment, a decrease in leftventricular muscle mass is observed while there is littlechange in end-diastolic volume. Volume calculations weremade applying Simpson's rule by means of a computersystem. The x-ray magnification was determined byobserving the movement of the catheter tip located in theleft ventricle when the x-ray table was moved a distanceof 7 cm (19.6.74) or 6 cm (7.9.76).

was discontinued before the heart volume deter-mination and the reduction in heart size occurredalso in patients who were not on a beta-blockerbefore treatment with verapamil.The left ventricular pressure gradients recorded

at left heart catheterisation before and after vera-pamil treatment did not show the same consistentimprovement as did the subjective symptoms, elec-trocardiogram, and heart volume, but pressuregradients often do not reflect the severity of thedisorder. However, in several patients the firstcatheterisation had been done 1 to 3 years beforeverapamil treatment, and further deterioration mayhave occurred during this time.When coronary artery diameters are measured all

factors which can influence the dimensions ofcoronary arteries have to be taken into considera-

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Fig. 6 Relation of coronary artery cross-section areaand left ventricular muscle mass in different groups ofpatients (Kober et al., 1973). MS, mitral stenosis; MR,mitral regurgitation; MV, mitral valve disease; AS,aortic stenosis; AR, aortic regurgitation; AV, aorticvalve disease; CM, cardiomyopathy; N, normal.

tion. Vasodilators, such as glyceryl trinitrate, in-crease coronary diameter (Gensini, 1975). A quanti-tative assessment of coronary artery dimensions is,therefore, only possible when the influence of anyacutely administered drug can be ruled out. Inaddition, variations in x-ray magnification have tobe taken into account. There was a genuine reduc-tion in coronary artery cross-sectional area of about16 per cent during treatment with verapamil, whenmeasurements were made carefully observing all theabove-mentioned precautions. In an earlier study(Kober et al., 1973), a direct relation between leftventricular muscle mass and coronary artery cross-sectional area was shown (Fig. 6). It could, there-fore, be assumed that the observed reduction incoronary artery dimension was the consequence of adecrease in ventricular muscle mass. This decreasein left ventricular muscle mass was confirmed bymeasurements computed from the left ventricularangiograms. The observation of a reduction ofcoronary artery diameter provides evidence of a re-duction in left ventricular hypertrophy by a methodwhich is completely independent of all othermeasurements such as QRS voltage, heart volume, orleft ventricular muscle mass determined angio-cardiographically.Whenever new drugs are administered, a drug-

free interval is desirable to assess the efficacy of thenew medication. In the present investigation, how-ever, we chose not to interrupt the treatment; thesubjective and objective changes following thechange of treatment have to be interpreted in thelight of the changes resulting from previous treat-

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DiameterLCA 440 - 4 03mm2RCA 2-72 - 2 50mm2

Cross- sectionarea

LCA 1519 - 12-58mm2RCA 5-81 -Px4991mm2

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treated with verapamil and another matched groupwith beta-blockers, and which will probably givefurther information within the next two years.

References

Daniels, J. R., Billingham, M. E., Gelhart, A., and Bristow,M. R. (1976). Effect of verapamil and propranolol onadriamycin-induced cardiomyopathy in rabbits (abstract).Circulation, 53 and 54, 20.

Edwards, R. H. T., Kristinsson, A., Warrell, D. A., andGoodwin, J. F. (1970). Effects of propranolol on responseto exercise in hypertrophic obstructive cardiomyopathy.British Heart Journal, 32, 219-225.

Fleckenstein, A. (1969). Myokardstoffwechsel und Nekrose. InHerzinfarkt und Schock, pp. 94-109, ed L. Heilmeyerand H. J. Holtmeier. Thieme, Stuttgart.

Gensini, G. G. (1975). Coronary Arteriography. Futura,Mount Kisco, New York.

Goodwin, J. F. (1970). Congestive and hypertrophic cardio-myopathies. A decade of study. Lancet, 1, 731-739.

Hubner, P. J. B., Ziady, G. M., Lane, G. K., Hardarson, T.,Scales, B., Oakley, C. M., and Goodwin, J. F. (1973).Double-blind trial of propranolol and practolol in hyper-trophic cardiomyopathy. British Heart J'ournal, 35, 1116-1123.

Kaltenbach, M. (1977). Medikamentose Therapie der koron-aren Herzkrankheit. Arzneimittel-Forschung, 27, 703-707.

Kaltenbach, M., Hopf, R., and Keller, M. (1976). Calcium-antagonistische Therapie bei hypertrophobstruktiverKardiomyopathie. Deutsche medizinische Wochenschrift,101, 1284-1287.

Kaltenbach, M., and Schulz, W. (1975). KineangiographischeBestimmung von Ventrikelvolumina mit Rechnerhilfe.Deutsche medizinische Wochenschrift, 100, 590-593.

Klepzig, H., and Frisc'., P. (1965). Rontgenologische Herz-volumenbestimmung in Klinik und Praxis. Thieme, Stuttgart.

Kober, G., Spahn, G., Becker, H.-J., and Kaltenbach, M(1973). Weite und Querschnittsflache der gr6ssen, epikar-dialen Koronararterien bei Herzmuskelhypertrophie.Zeitschrift fur Kardiologie, 63, 297.

Loogen, F., Krelhaus, W., and Kuhn, H. (1976). Verlaufs-beobachtungen der hypertrophischen obstruktiven Kardio-myopathie (HOCM). Zeitschrift fur Kardiologie, 65, 511-521.

Lossnitzer, K. (1975). Genetic induction of cardiomyopathy.In Heart and Circulation, p. 309, ed J. Schmier and 0. Eich-ler. Handbuch der experimentellen Pharmakolcgie, vol.16 no. 3. Springer, Berlin, Heidelberg, and New York.

Morrow, A. G., Reitz, B. A., Epstein, S. E., Henry, W. L.,Conkle, D. M., Itscoitz, S. B., and Redwood, D. R. (1975).Operative treatment in hypertrophic subaortic stenosistechniques and the results of pre- and postoperative assess-ments in 83 patients. Circulation, 52, 88-102.

Rothlin, M., Arbenz, U., Krayenbiihl, H. P., Turina, J., andSenning, A. (1976). Spatresultate nach Operationen beimuskularer subvalvularer Aortenstenose. Zeitschrift fuirKardiologie, 65, 501-510.

Sowton, E. (1976). Beta-Rezeptorenblocker bei hypertropherCardiomyopathie. In Die Beta-Blocker Gegenwart undZukunft, p. 239, ed W. Schweizer. Huber, Bern.

Stenson, R. E., Flamm, M. D., jun, Harrison, D. C., andHancock, E. W. (1973). Hypertrophic subaortic stenosis.Clinical and hemodynamic effects of long-term propranololtherapy. American Journal of Cardiology, 31, 763-773.

Witzke, D. J., and Kaye, M. P. (1976). Hypertrophic cardio-myopathy induced by administration of nerve growthfactor (abstract). Circulation, 53 and 54, 88.

Wrogemann, K., and Pena, S. D. J. (1976). Mitochondrialcalcium overload. A general mechanism for cell necrosis inmuscle diseases. Lancet, 1, 672-674.

Requests for reprints to Professor Martin Kalten-bach, Abteilung fiir Kardiologie, Zentrum derInneren Medizin, Klinikum der J. W. Goethe-Universitait, Theodor-Stern-Kai 7, 6000 Frankfurt/M 70, West Germany.

Addendum

Since the submission of this paper for publication,the number of patients treated with verapamil hasincreased from 22 to 39, and duration of follow-upnow ranges from 1 to 100 months (mean 26-4months). Experience with additional patients andlonger follow-up confirms the reported favourableresults. In 4 patients, treatment was discontinuedbecause of non-cardiac illnesses: in these patientsdeterioration ensued. Recently serum verapamillevels have been measured (B. G. Woodcock);there appears to be a correlation between verapamillevel and clinical improvement.

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