treatment of spontaneous angina pectoris with blocking agents a … · 1236 guazzi, fiorentini,...

British Heart journal, 1975, 37, 1235-1245.

Treatment of spontaneous angina pectoriswith beta blocking agentsA clinical, electrocardiographic, andhaemodynamic appraisal

Maurizio Guazzi, Cesare Fiorentini, Alvise Polese, Fabio Magrini, and Maria T. OlivariFrom Istituto di Clinica Medica II, Istituto Ricerche Cardiovascolari, and Centro Ricerche Cardiovascolari delConsiglio Nazionale delle Ricerche, University of Milan, Milan, Italy

Propranololandpractolol were tested inpatients with repeated daily occurrence ofspontaneous angina. Twenty-one showed ST segment depression (type I) and 15 ST segment elevation (type II) during angina. Theefficacy of the treatment was evaluated in subjective (number of reported episodes ofpain) and cijective terms(number of episodes of electrocardiographic abnormalities documented during periods of continuousrecording): practolol was fully effective in 42 per cent and propranolol in 38 per cent of type I cases; intype II angina 73 per cent of the cases fully responded to propranolol, none of the patients in this groupgiven practolol improved.

The study also showed that: (a) the effects on angina are strictly dose-dependent, and optimal results areachieved at individualized doses; (b) within the same subject the response may be preferential to one beta-blocker as opposed to the other; (c) propranolol is more effective in type II angina; (d) the occurrence of heartfailure is uncommon even with high doses of beta blockers; (e) the relief of angina is due to prevention ofischaemia and not to a placebo or anaesthetic effect; (f) the prevention of ischaemia is not adequately explainedby reduction of the mechanical effort and the oxygen need of the myocardium; (g) the antianginal effect ispossibly dissociated from the beta blockade of the heart.

The hypothesis that beta-blocking agents influence the coronary vasomotion is discussed.

The basis for the treatment of angina pectoris byheta blockers may be viewed in terms of the patho-physiology of angina and its relation to cardiacadrenergic stimulation. Angina pectoris is thoughtto be the result of an imbalance between myocardialoxygen demand and supply (Gorlin, 1965). Betablockade is directed at the prevention of myocardialischaemia and resultant pain by restricting cardiaccontractile effort. This is achieved throughpharmacological blockade of the myocardial beta-adrenergic receptors, thereby attenuating theincrease in myocardial oxygen requirement whichaccompanies adrenergic stimulation, namely, duringemotional stress or physical exercise.

Chest pains coming on at rest, not related todeliberate laboratory stress or any other detectableeliciting factor, accompanied by unequivocalelectrocardiographic alterations are defined as'spontaneous' angina. The electrocardiographicReceived 18 April 1975.

changes in spontaneous angina may present in twodifferent forms: (a) ischaemic ST segment depres-sion in the leads reflecting left ventricular epicardialpotentials (which we call angina type I); (b) STelevation in some leads with reciprocal depressionin the opposite leads, which is characteristic of thevariant form of angina pectoris described byPrinzmetal et al. (1959) (angina type II). Haemo-dynamic monitoring during continuous electro-cardiographic recording has shown that neithertype of electrocardiographic change is preceded byvariations of heart rate, arterial pressure, cardiacoutput, or duration of right and left ventricularcontraction (Guazzi et al., 1971b; 1975). Conse-quently, these episodes of acute myocardial ischae-mia are not attributable to changes in the work ofthe heart and its oxygen needs. Spontaneous angina,therefore, cannot be interpreted on the basis of theclassical pathophysiology. In particular, an in-creased contractile effort consequent on catechol-

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1236 Guazzi, Fiorentini, Polese, Magrini, and Olivari

amine stimulation can be excluded as the triggermechanism of the ischaemia. For these reasons theeffect of beta blockers in spontaneous anginaappeared worthy of investigation.

This is an expansion of earlier work on Prinz-metal's (type II) angina (Guazzi et al., 1971a); italso presents our experience with a large popula-tion of patients suffering from type I angina. Theresults of the study are reported both for theirpractical importance, especially if confirmed byothers, and for their theoretical interest in relationto the pathogenesis of spontaneous angina, themechanism of the antianginal action of betareceptors' antagonists, and their effects on thecirculatory function of patients suffering fromspontaneous angina. To assess the relative im-portance of local anaesthetic effect and beta-adrenergic antagonism in the treatment of thesepatients, propranolol, which has cell membraneactivity, was tested as well as practolol, which hasnot (Fitzgerald, 1969).

Subjects and Methods

SubjectsPatients were selected for the study who on admissionhad a daily occurrence of at least three episodes of chestpain at rest, of typical quality and location. The historyof angina in these patients varied from four months tothree years. Cases in which there was a sudden increasein severity and frequency of angina were excluded.Patients with a history or evidence of heart failure,arterial hypertension, or valvular or pulmonary diseaseswere also excluded from the study. The purpose andthe nature of the investigative programme, the possibleclinical benefits, and the scientific aspects of the studywere explained in detail to each patient; without induce-ment all willingly consented to participation in thestudy. Twenty-one patients with type I angina wereinvestigated. The basal electrocardiogram was normalin 10 cases, in 7 it showed old myocardial infarcLton,and in 8 it showed flat or negative T waves in the lateralpraecordial leads. In each case angina was accompaniedby T wave inversion and ST segment depression in theleads reflecting left ventricular epicardial potentials.Fifteen patients with type II angina entered the study.The baseline electrocardiogram was normal in 7, itshowed old infarction in 5, and negative T waves in theinferior leads in 3. Seven of these patients during anginashowed ST segment elevation in the anterior and 8 inthe inferior leads, with reciprocal depression in theopposite leads.

Plan of investigationIt was felt that more convincing evidence of the efficacyof the treatment could be provided through the evalua-tion not simply of the subjective response (number ofepisodes of pain reported) but also of the objectiveeffects (number of episodes of electrocardiographic

changes of ischaemia documented during continuousrecording). Accordingly the investigation was designed asfollows: (a) daily charting in a diary throughout the run-in and trial of the number, time, and circumstances ofthe anginal attacks in the 24 hours. (b) Administrationduring the run-in (first week of hospitalization) ofplacebo tablets identical in colour, shape, and taste tothe active drug to be given, with allowance of nitro-glycerin consumption. (c) Continuous electrocardio-graphic recording during 7 to 8 hours after the run-inperiod (the hours during which this was carried outwere selected as indicated below). (d) Haemodynamicevaluation the day after the continuous recording of theelectrocardiogram. (e) Oral administration ofpropranololor practolol continued for several days, the choice ofthe drug to start with being made randomly. (f) Repeatof the electrocardiographic monitoring after a fullsubjective effect was obtained (full effect was consideredto be achieved only after the patients had remained freeof pain for at least one week), or after the discontinuanceof the drug was decided (the criteria for discontinuanceare noted below). (g) Replacement of the discontinueddrug with the other. (h) Repeat of the electrocardio-gram continuous recording after a full subjectiveresponse to the new drug was obtained or after themaximal arbitrary dosage was reached. (i) Replacement,in the responding subjects, of the active drug by placebotablets in equal number. (j) Re-establishment of theactive treatment, and discharge on the same doses ofthe drug which had induced optimal therapeutic effect.The haemodynamic evaluations were repeated duringthe periods f and h.

Daily charting of the anginal episodes was valuableboth for estimating the subjective response to treatmentand for indicating during which hours of the day anginaoccurred most often for each patient in the pretreatmentstate. The electrocardiographic tests were repeatedduring these same hours during the periods c, f, and h,and consisted of a 7 to 8 hour recording of the fourleads which presented the most evident alterations ofischaemia. In every case these alterations were so clearthat they could be consistently detected even at a record-ing speed as low as 0 5 mm/s.

Propranolol was distributed in four equal doses inthe 24 hours, the dosage starting at 80 mg da:ly which,according to the patient's response, was subsequentlyincreased by 80 mg every other day, with an arbitraryupper limit of 800 mg daily. The increment wasinterrupted at any lower dosage which induced a fullantianginal effect. The drug was discontinued whenhalf the maximal dose had been reached without anytendency of angina to decrease being observed, or atany amount which induced adverse side effects (primarily,excessive bradycardia or clinical signs of cardiacinsufficiency). Practolol was started at 200 mg daily,and increased by 200 mg every other day in accordancewith the same criteria as for propranolol; the arbitraryupper limit was 500 mg four times a day.

Pharmacological testsThe fact that in several cases in both groups the anginaimproved better on one rather than the other of the

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Treatment of spontaneous angina pectoris 1237

two beta blockers could have been attributable to adifferent degree of cardiac beta blockade induced byone drug as compared with the other in that particularpatient. A quantification of the beta-adrenergic blockadeof the heart seemed likely to prove or disprove thisinterpretation. Consequently changes induced in theresting heart rate by scalar doses (0 5, 1, 2, 5 Fg/ inover 5 minutes) of isoprenaline administered intra-venously through a continuous infusion pump weretested before treatment and at each increasing amountsof the two drugs. We considered that an increase in rateof 30 beats/min or an absolute tachycardia of 110 beats/min in the control phase was a satisfactory and safeend-point for the test. Such response was generallyelicited by an isoprenaline dose of 5 l±g/min. Beat-to-beat variations of pulse rate were detected through acardiotachograph. The isoprenaline effect was tested 6hours after the previous dose of the beta-receptorantagonist.

Haemodynamic methodsThe cardiovascular function of these patients wasassessed by the following measurements: heart rate(HR); arterial pressure (AP); mean right atrial pressure(MRAP); cardiac index (CI); tension-time index perminute (TTI); left ventricular work (LVW); leftventricular mean rate of systolic ejection (MSEJR); leftventricular mean isometric contraction (dP/dt). In type Iangina group measurements were performed in thecontrol state in nine subjects; five of them were re-investigated while on propranolol and seven while onpractolol; in three cases the study was repeated duringboth periods of treatment. Twelve type II anginalpatients were investigated in the untreated state andwhile on propranolol; in three ofthese the haemodynamicevaluation was also repeated during practolol.

Studies were carried out three hours after the lastdose of beta blocker in the steady state, without pre-medication, in the supine position. Steady state wasconsidered to be achieved when heart rate and arterialpressure had stabilized. In any case, the measurementswere not begun until at least 30 minutes after completingthe catheter introductions. For the measurement ofright atrial pressure a polyethylene catheter was insertedinto an antecubital vein and positioned in the rightatrium. An 18-gauge Teflon catheter needle, introducedinto the brachial artery, was used to sample indocyaninegreen for cardiac output and to monitor arterial pressure.Dye dilution analyses of cardiac output were performedafter injection of indocyanine green (5 mg) into theright atrium and withdrawal from the brachial artery.

Cardiac index, stroke index, and mean systolic ejectionrate were calculated in the standard fashion. Measure-ments of the pre-ejection period and left ventricularejection time were obtained from the simultaneousrecording, at a paper speed of 100 mm/s, of the electro-cardiogram, carotid sphygmogram and phonocardio-gram, according to the method reported by Weissler,Harris, and Schoenfeld (1968). The left ventricular meandP/dt was derived by dividing the diastolic arterialpressure by the simultaneous values of the pre-ejectionperiod. Tension-time index per minute was obtained as

the product of mean systolic arterial pressure, leftventricular ejection time, and heart rate; left ventricularminute work was calculated from the following formula:

LVW(kg.mperm2bsa) -MSAP x SI x HR x 0-136

1000

where MSAP = mean systolic arterial pressure inmmHg; SI = stroke index in ml per m2 bsa; HR =heart rate.

Results

Clinical and electrocardiographic effectsIn patients of both groups no antianginal effect wasobserved while on placebo during the run-in period.

Table 1 shows the incidence of pain in the 24hours for the type I angina group, and the numberof episodes of electrocardiographic alterationdocumented during continuous electrocardiographicrecordings, in the untreated state, after propranololand after practolol. The maximal dosage adminis-tered and the sequence in which the two drugswere given are also indicated. In Cases 2, 6, and 18episodes of ST segment depression were recordedwhich were unaccompanied by pain; the figures inparentheses indicate these episodes. Twelve patients(Cases 1 to 12) received propranolol first, whichinduced a full antianginal effect in four (Cases 1 to4); in Cases 5 to 10 the drug was discontinued atdoses noted in the Table, and replaced withpractolol. The reasons were: excessive bradycardia(Cases 6 and 8); some degree of noctumal dyspnoea(Cases 5 and 9); no tendency of angina to decreasedespite progressive increase of dosage (Cases 7 and10). In each of these cases practolol induced fullrelief of angina without any noticeable adverse sideeffect. Case 12 died from cardiac arrest duringangina while treated with a daily amount of 160 mgpropranolol, which was ineffective in reducing thenumber of pain reports. It is noteworthy that inmany of the patients an antianginal response wasobtained at doses of practolol relatively equal to orlower than those doses of propranolol which hadbeen ineffective.Nine patients received practolol first, which was

fully effective in three cases (13, 14, 15); in six(Cases 16 to 21) angina did not show any tendencyto decrease. Propranolol was then administered,and doses could be reached which were fullyeffective in Cases 16, 17, and 18 and partiallyeffective in Cases 19 and 20. In Case 19 bradycardiaprevented the administration of the upper arbitrarydose. In Cases 16 and 21 propranolol abolishedangina at doses proportionally lower than those ofpractolol, which had been ineffective.

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TABLE 1 Nunber of reports ofpain in the 24 hours, and nunber of episodes of electrocardiographic alterationsof ischaemia in the untreated state, after propranolol and after practolol in the group of patients sufferingfrom type I angina pectoris.

Control Propranolol Practolol

Case Reports of pain ECG Dose Reports of pain ECG Dose Reports of pain ECGNo. 24 hr study mg/day 24 hr study mg/day 24 hr study

1 6-8 2 240 None None2 9-10 4 (4) 480 None None -

3 2-4 1 160 None None -

4 4-5 2 160 None None - -5 3-4 2 240 2-4 2 600 None None6 3-5 2 (2) 160 3-5 2 (1) 800 None None7 8-10 3 400 8-15 2 600 None None8 3-4 1 240 2-3 1 600 None None9 3-4 1 160 3-4 None 400 None None10 4-5 1 400 4-5 2 600 None None11 10-13 4 320 1-2 1 - -12 6-7 3 160 - - - -

Control Practolol Propranolol

13 4-5 1 2000 None None -

14 2-3 1 800 None None15 1-4 1 600 None None16 3-4 1 1000 4-5 2 240 None None17 3-5 2 1000 4-5 1 480 None None18 15-22 6 (3) 1000 16-20 7 (2) 400 None None19 4-6 2 1000 3-6 2 480 1-3 120 6-8 2 1200 5-8 3 800 1-3 121 4-5 3 1000 5-6 2 320 None None

Figures in parentheses are additional and indicate the episodes of ischaemia recorded in the absence of pain.

TABLE 2 Number of reports of pain in the 24 hours, and nunber of episodes of electrocardiographic abnor-malities of ischaemia in the group of patients suffering from type II angina pectoris.

Control Propranolol Practolol

Case Reports of pain ECG Dose Reports of pain ECG Dose Reports of pain ECGNo. 24 hr study mg/day 24 hr study mg/day 24 hr study

1 8-12 6 (7) 240 None None2 5-6 8 (7) 480 None None3 2-3 3 (3) 160 None None - -4 10-12 3 (4) 240 None None5 4-7 3 400 None None - -

6 4-5 2 240 None None - -

7 8-12 3 (1) 160 1-2 None - -

8 8-10 6 800 None None -

9 0 0 (10) 800 0 None -

Control Practolol Propranolol

10 4-10 2 1000 8-10 2 240 None None11 3-5 2 1200 3-4 1 320 None None12 10-15 6 (4) 1600 10-12 6 (3) 640 None None13 4-6 1 1000 3-5 1 400 1-2 None14 8-10 4 1000 8-10 5 600 6-9 215 3-4 2 1200 3-5 3 640 3-5 2

Figures in parentheses are additional and indicate the episodes of ischaemnia recorded in the absence of pain.

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In summary, 80 per cent of the patients in type Igroup had total abolition of the anginal symptomsby beta blockers; in 38 per cent of the cases theoptimal effect was obtained with propranolol, in42 per cent with practolol.

In the responder subjects it was found that:treatment did not significantly influence the baselineelectrocardiogram; the antianginal effect was dose-dependent; and the phasic electrocardiographicchanges of myocardial ischaemia were abolished inparallel with the relief of the subjective symptoms.In this connexion the disappearance also of the STsegment changes which were not accompanied bypain was of particular interest.

After replacement of the active drug by placeboeach of these patients complained again of anginawithin 2 to 3 days.

Table 2 summarizes the findings in the type IIangina group. Propranolol was given in nine cases(1 to 9): angina was completely relieved in eight ofthem and reduced in one (Case 7). In Cases 10 to 15practolol was unsuccessful; in the same casespropranolol gave the following results: no effect intwo (Cases 14 and 15), partial relief of angina in one(Case 13), and complete relief in three (Cases 10to 12). In these last patients propranolol waseffective at doses proportionally lower than those ofpractolol, which had been ineffective. As for type Iangina it was found in the responder patients that:treatment did not change the baseline electro-cardiogram; the antianginal response was dose-related; improvement was subjective and objective;and treatment was effective on both the painfuland painless electrocardiographic changes caused byischaemia. The success of propranolol is remarkablein Case 9, in whom none of the recorded episodesof ST segment elevation was accompanied by pain.

In summary, in type II angina administration ofbeta blockers was fully effective in 73 per cent ofthe cases; none of the patients in this group whowere given practolol improved; propranolol suc-ceeded in 66 per cent of the cases in which practololhad failed. In each of the responder subjects anginareappeared after replacement of the active drugwith placebo.

Isoproterenol infusionThe average increments of the resting pulse rateinduced by isoprenaline in the untreated state wereas follows: 9 per cent at 0 5 ,ug/min, 17 per cent at1 jig/min, 33 per cent at 2 jg/min, and 37 per centat 5 pLg/min. While propranolol and practololshowed (Tables 1 and 2) great differences in thesame patient as far as the effect on angina is con-cerned, equivalent doses of the two drugs showed

comparable blocking properties on the isoprenaline-induced tachycardia. In each case the response rateprogressively fell in parallel with the increasingamount of the beta blocker, and it fully disappearedat the average daily doses of 192 mg propranololand 533 mg practolol. These figures were bothsignificantly lower (P < 0-01) than those requiredto achieve a complete antianginal effect, theaverage effective antianginal doses of propranololand practolol being, respectively, 368 and 688 mga day. In Fig. 1 (Case 11 in Table 2) a graphicpresentation is given of the relation betweenincreasing amounts of practolol and propranolol,blockade of the isoprenaline-induced tachycardia,and antianginal effect. Though practolol andpropranolol had shown similar degrees of blockadeof the response to isoprenaline, only propranololrelieved the anginal symptoms.

In no case in this study did isoprenaline infusionprecipitate angina.

Haemodynamic effectsOur previous studies (Guazzi et al., 1971a, b; 1975)showed that in both types of angina the electro-cardiographic abnormalities of ischaemia are notpreceded, and consequently not attributable to,variations from the baseline of the circulatoryfunctions which determine the haemodynamic loadof the heart and its oxygen needs. The favourableeffects of the beta blockers, therefore, are not to beinterpreted as a prevention or a restriction of asudden increase in the mechanical effort of theheart, which indeed is not responsible for elicitingspontaneous attacks of angina. In the present studythe hypothesis was considered that variations inthe baseline haemodynamic load on the leftventricle after treatment might be somehow relatedto the improvement of the anginal symptoms. InFig. 2 (type I angina) and Fig. 3 (type II angina)changes from the control state (C) induced bypractolol (Pc) and propranolol (Pr) on the basalvalues of left ventricular work (LVW) and tension-time index (TTI) are related to the antianginalresponse. The values corresponding to full relief ofangina are indicated by open squares. It is evidentthat in both types of angina no consistent relationexists between variations of LVW and TTI fromthe control state and relief of angina; actually, thisoccurred at levels of LVW and TTI either higheror lower than in the untreated condition. It is alsoremarkable that one of the two beta blockers wassuccessful in some cases in which the other hadfailed, though the levels of left ventricular loadwere higher after the former and lower after thelatter drug as compared to the pretreatment state.

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0 5 10 15 0 5 10 15

Percent increase of heart rate0 0 0 7 0 000 XPlocebo0 0 0 16 10 0 0 P t0 0 0 20 14 0 0 XPractolol6 0 0 31 22 0 0 ::¢ Propronolol

.................... .. ......-2~~~*..... ........ ... 240:e: . ,e, *.,160......'t} .'t,'.......'

5 10 15

FIG. 1 Relation between increasing amounts of practolol and propranolol; blockade of theisoprenaline-induced tachycardia and antianginal response in a patient suffering from type IIangina pectoris. The number of episodes of chest pains in the 24 hours is indicated by verticalbars. Though equivalent doses of the two drugs induce comparable degree of blockade of the rateresponse to isoprenaline, only propranolol is effective on angina.

CPc PrC P Pr

3000-

2 500-EE

1=E-

I-

2000-

1500C Pc Pr

FIG. 2 Relation between changes of left ventricular work (LVW)and tension-time index per minute (TTI) from the control state (C),and antianginal effects of practolol (Pc) and propranolol (Pr) inpatients with type I angina pectoris. Values corresponding to fullrelief of angina are indicated by open squares.

D 05-

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5 2 012 10 220 16 1433 28 18

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CosesQ._a

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FIG. 3 Relation between changes of left ventricular work (LVW)and tension-time index per minute (TTI) from the control state (C),and antianginal effects of practolol (Pc) and propranolol (Pr) inpatients with type II angina pectoris. Values corresponding to fullrelief of angina are indicated by open squares.

The possible deleterious effect on the functionof the heart is one of the major limitations in theuse of beta-blocking agents. Concern about the riskof inducing heart failure can sometimes influencethe management of patients with angina pectoris so

as to prevent administration of these drugs ineffective antianginal doses. It is felt that in thecurrent study the number of patients and thedoses of the beta-receptors antagonists were largeenough to provide useful information on this topic.

In subjects of both groups (see under Methods)the circulatory function was evaluated in the un-

treated state and during treatment with betablockers at the doses indicated in Tables 1 and 2.In Fig. 4 (type I angina) and Fig. 5 (type II angina)the haemodynamic values before therapy are

compared with those detected in the same subjectsafter propranolol (blocked circles) or practolol(open circles). In type I angina propranolol signi-ficantly reduced the heart rate and cardiac index.The circulatory changes caused by practolol,though statistically not significant, indicate that thedrug does not reduce, and possibly improves, thefunction of the heart. In type II angina the results

were in some respects different. Propranolol againreduced the heart rate, but it significantly aug-mented the left ventricular dP/dt, mean rate ofsystolic ejection, and cardiac index. Changesinduced by practolol were not significant.

Discussion

Previous favourable experience (Guazzi et al.,1971a) with beta blockers in spontaneous angina isconfirmed in the present investigation: beta-adrenergic antagonists fully abolished the symptomsin 80 per cent of the cases in type I and 73 per centin type II angina.

Since placebo therapy itself can be successful ina high proportion of patients suffering from anginapectoris (Beecher, 1955), the assessment of treat-ment in this disease must be done with the utmostcaution. In the current trial a placebo effect can beexcluded because: (a) placebo administration inthe run-in period was ineffective in each case; (b)in those patients who responded to the treatmentsubstitution of placebo for the active drug causedprompt reappearance of the anginal symptoms;

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1242 Guazzi, Fiorentim, Polese, Magrini, and Olivari

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* Propronolol- Dr-rulu

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FIG. 4 Averages (+ SE) of haemodynamic functions in the control (C) state and aftertreatment (T) with propranolol (blocked circles) and practolol (open circles) in patientssuffering from type I angina pectoris. HR, heart rate; MAP, mean arterial pressure;MRAP, mean right atrial pressure; CI, cardiac index; dP/dt, left ventricular dP/dt;MSEJR, left ventricular mean rate of systolic ejection (index).

80-

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FIG. 5 Averages (± SE) of haemodynamic values in the control (C) state and aftertreatment (T) with propranolol (blocked circles) and practolol (open circles) in patientssuffering from type II angina pectoris. Abbreviations as in Fig. 4.

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(c) the improvement was obviously dose-depend-ent; (d) in several cases the response was preferentialto one of the two beta blockers; (d) after adequatedoses the phasic electrocardiographic abnormalitiesdisappeared in parallel with the relief of thesubjective symptoms.So far as we know no systematic study has been

reported on the treatment of spontaneous anginapectoris by beta blockers. Unsatisfactory resultshave been reported in single cases (Whiting et al.,1970; MacAlpin, Kattus, and Alvaro, 1973; Kinget al., 1973; Bodenheimer et al., 1974; Hernandez-Casas, Dear, and Leachman, 1974). It is note-worthy that in the present investigation beta-blocking agents were not given in uniform, pre-determined doses, but the dosage was increaseduntil the optimal effect was achieved. This fre-quently occurred at relatively high doses of thedrugs. We feel that patients with spontaneousangina might have been considered non-respondersto beta blockers simply because they were treatedwith insufficient doses.Three major sites of drug action may be involved

in the improvement of angina: (a) the nervouspathways of transmission of anginal pain might beblocked, or the central awareness of pain altered;(b) the contractile effort and, consequently, themetabolic needs ofthe myocardium may be reduced;(c) the coronary blood supply or its regionaldistribution can be affected by relief of spasm inlarge vessels or by dilatation of arterioles andcollaterals. The first of these hypotheses wasadvanced by Zeft, Patterson, and Orgain (1969) as anexplanation of antianginal action ofthe beta blockers.On this basis questions were raised about theindication for propranolol in the treatment of thisdisorder, since the drug would remove the desirablewarning signal of angina (Aronow, 1973). Findingsin the present study disprove this assumption.Continuous electrocardiographic recordings, in fact,showed that beta blockers not only relieved painbut also abolished the electrocardiographic changesof ischaemia, even those changes that occurred inthe absence of pain. This clearly demonstrates thatthese drugs prevent myocardial ischaemia and notsimply the sensation of pain.

Restriction of the contractile effort and of theoxygen needs of the myocardium is the mechanismthrough which the effects of beta blockers in anginaof effort are commonly explained. This interpreta-tion, however, seems inadequate in spontaneousangina for the following reasons: (a) episodes ofspontaneous angina occur during rest, whenmyocardial need for oxygen is low; (b) they arenot preceded by changes in factors such as heartrate, blood pressure, cardiac output, or duration of

right and left ventricular contraction whichdetermine the myocardial oxygen consumption;(c) in no case did isoprenaline infusion, whichnecessarily increases the mechanical effort of theheart, precipitate angina.A temporarily increased tonus of a large athero-

sclerotic coronary artery with a narrow lumen wassuggested by Prinzmetal et al. (1959) as the causeof spontaneous angina with ST segment elevation.Subsequently several cases have been reported,some with normal coronary arteriograms, in whichcoronary spasm was detected during attacks ofacute ischaemia (Ross and Gorlin, 1968; Dhurand-har et al., 1972; King et al., 1973; McAlpin et al.,1973; MacAlpin, 1973; Oliva, Potts, and Pluss,1973; Linhart, 1974). Severe coronary spasm inassociation with anginal attacks has been found insome patients with classical angina pectoris(Gensini et al., 1962; Demany, Tambe, andZimmerman, 1968). A possible role for coronaryvasoconstriction has been suggested in this form ofangina (MacAlpin, 1973). If changes in the vaso-motor tone were really responsible for spontaneousangina, one could postulate a direct or mediatedinfluence of the beta-blocking agents on thecoronary vasomotor system.No factor could be isolated by clinical and

haemodynamic criteria to account for a favourableresponse to beta blockers in one patient as opposedto no benefit in another, or for a favourable effect ofone beta blocker as opposed to no benefit fromthe other. Changes of the baseline left ventricularload were unrelated to the improvement of theanginal symptoms. Angiographic studies of thecoronary vessels were not carried out systematically;data available, however, do not indicate a relationbetween benefit from beta blockade and presenceor severity of coronary lesions. Therefore theseanalyses did not help to shed light on the mechan-isms of action of beta blockers in spontaneousangina pectoris.Doses required for complete abolition of the

anginal attacks were generally high and possibly inexcess of those necessary for cardiac beta blockadein man. It is reasonable to wonder whether betablockade of the heart and anginal blockade are twoseparate phenomena, each induced by differentdoses of beta blocker. Such dissociation could beestablished through a precise definition andcomparison of the amounts which induce fullcardiac beta blockade and of those which r_lieveangina. Though the doses which inhibited the heartrate response to isoprenaline were greatly andsignificantly lower than those effective on angina,the question cannot be considered definitelyanswered, since in terms of antagonism of iso-

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prenaline the concept of complete beta-receptorblockade is not meaningful. None the less, theisoprenaline tests have provided evidence thatequivalent amounts of propranolol and practololcan have comparable influences on the isoprenaline-induced tachycardia and greatly different effects onthe anginal symptoms. In other words, the degreeof beta-receptor antagonism does not correlatewith the improvement in angina, which supportsthe possibility that cardiac beta blockade andblockade of spontaneous angina are not directlyrelated to each other.

In conclusion, our findings exclude a mere localanaesthetic cell membrane effect; show that betablockers really prevent myocardial ischaemia;indicate that prevention of ischaemia of spontaneousangina is not attributable, or at least entirelyattributable, to a decrease of the mechanical effortof the heart and its oxygen demand; suggest theexistence of an additional still undefined effect,possibly dissociated from the beta blockade of theheart as well as from the membrane activity of thesedrugs.

Congestive heart failure, the most seriousuntoward effect of the beta-receptor antagonists,follows from the negative inotropic action of theseagents (Epstein et al., 1965; Sonnenblick et al.,1965; Bloomfield and Sowton, 1967), but hasactually been an uncommon clinical occurrence(Wolfson et al., 1966; Gillam and Prichard, 1966;Conway, Seymour, and Gelson, 1968). Amsterdam,Gorlin, and Wolfson (1969) have reported thatpropranolol was tolerated in a large number ofpatients suffering from angina with evidence ofcongestive heart failure before treatment. In thepresent study practolol did not significantly alterthe circulatory function of the patients in bothgroups. As compared to propranolol, in type Iangina it induced a minor degree of bradycardiaand less depressive effect on the cardiac inotropicstate. It is also noteworthy that practolol cleared thesymptoms and restored the circulatory function intwo patients in this group who developed cardiacinsufficiency following propranolol. These findingsare in good agreement with the haemodynamicreports of other authors (Sowton et al., 1968;Jewitt, Burgess, and Shillingford, 1970; Leon et al.,1972). The circulatory effects of propranolol were,under some aspects, opposite in type II as com-

pared to type I angina. In the former group ofpatients changes in cardiac index, dP/dt, andmean systolic ejection rate confirm our previousobservations (Guazzi et al., 1971a) and providestatistical evidence of the favourable effects ofpropranolol on the left ventricular function ofpatients suffering from type II angina. The inter-

pretation of these findings, which contrast withthose of many authors (Epstein et al., 1965; Hamerand Sowton, 1965; Sonnenblick et al., 1965), isnot immediately apparent. Since propranololproved to be effective in this type of angina, itmight be postulated that the improvement ofcardiac function after propranolol influenced insome way the relief of angina, or, what seems moreconvincing, that cardiac function improved becausethe coronary circulation was ameliorated and anginaabolished.From a practical point of view the study suggests

that: in spontaneous angina beta blockers areworthy of trial; the dosage must be individualizedand, in the absence of untoward side effects,increased until the optimal response is achieved;the occurrence of heart failure is uncommon evenat high doses of beta-blocking agents; one drug mayproduce beneficial effects where another has failed;the use of propranolol is preferable in cases ofangina showing ST segment elevation.

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