The role of propranolol in the treatment of acute myocardial infarction

SPECIAL

ARTICLE

The Role of Propranolol of Acute Myocardial Hiltrud

S. Mueller

and Stephen

C

LASSIFICATION of adrenergicreceptorswas first suggestedby Dale,’ who showed that preparations of ergot abolished the motor effects of adrenalineor sympathetic stimulation. Ahlquist2 subsequentlysubclassifiedthe adrenergicreceptors as alpha and beta types. Ahlquist’s classification has been supported by studies in which selective blockade of the alpha and beta receptors could be produced by different drugs. The first compound found to specifically block responsesattributed to beta-adrenergicreceptors was dichloroisoprenaline.3It antagonized the inotropic and chronotropic actions of sympathetic nervous activity and the peripheral vasodilator action of isoprenaline, but did not block responses associatedwith alpha-adrenergicreceptors.4’5 Dichloroisoprenaline, however, possessedintrinsic sympathomimetic activity, increasingthe rate and force of cardiac contraction. Propranolol wassubsequently introduced for clinical evaluation becauseit possessedno intrinsic sympathomimetic activity and wasrelatively free of sideeffects. Both theoretical and experimental considerations support Black’s6 early recommendation for the use of beta-adrenergicblockade in ischemicheart diseaseto oppose the “anoxiating effects” of adrenaline on the heart. Raab et al.’ suggestedin the early 1960sthat myocardial ischemiain coronary artery diseasewas frequently triggered by catecholaminereleaserather than by suddenalteration in coronary perfusion alone. More recent studies,showingcatecholaminereleaseby ischemic myocardium,‘-” and other studies,demonstrating deterioration of ischemicmyocardium with isoproterenol,12-‘5 suggestthat this enhanced neuroadrenergicactivity may be harmful. Propranolol appearsto exert a number of potentially beneficial effects in acute myocardial infarction. It reducesoxygen requirementsby decreasing From the Department of Cardiology and Medicine, St. Louis University, School of Medicine, St. Louis, MO. Reprint requests should be addressed to Hiltrud S. Mueller, M.D., Department of Cardiology and Medicine, St. Louis University, School of Medicine, St. Louis, MO. 63103. 0 19 77 by Grune di Stratton, Inc. Progress

in Cardiovascular

Diseases,

Vol.

XIX,

in the Treatment Infarction

No. 5 (March/April),

M. Ayres

heart rate and myocardial contractility,16”’ improves subendocardialperfusion in ischemic myocardium,‘* reducescatecholamine-inducedlipolysis thus favoring glycolysis,!’ shifts the oxyhemoglobin dissociation curve to the right promoting the unloading of oxygen,20j21 and decreasesthe enhanced platelet aggregation characteristic of stress.22 The use of beta-adrenergicblocking drugsin the managementof arrhythmias after myocardial infarction hasbeen recently reviewed.23This article will emphasize the metabolic and hemodynamic effects of propranolol in the acute state of infarction. EFFECT OF PROPRANOLOL ISCHEMIC MYOCARDIUM

ON

Beta-adrenergicstimulation increasesmyocardial oxygen consumption by increasingheart rate and force and veIocity of myocardial contraction. Shell and Sobel% demonstrated the additive nature of these two effects by showing that isoproterenolproduced tachycardia increased infarct size to a greater degree than similar levels of tachycardia produced by ventricular pacing. An important effect of propranolol would be the expected decreasein beta-adrenergic-mediated changesin myocardial oxygen consumption. We2’ observed that propranolol, administeredintravenously to 208patients in the early hours of acute myocardiaMinfarction, decreasedmyocardial oxygen consu.mption from 9.20 to 7.20 ml/100 g/min (Fig. 1). Similar results were obtained by Haneda et a1.26 who sampledselectively from the ischemic myocardium following experimental coronary occlusion in 10 dogs. Ischemiczone myocardial oxygen consumption decreasedfrom 3.48 to 2.45 ml/min following occlusion and decreasedfurther to 1.73 ml/mm following administration of propranolol. The animal studieshave the advantageof analyzing regional changesin oxygenation immediately after restriction of coronary flow and administration of propranolol. The initial decreasein oxygen consumption was accompaniedby a decreasein coronary venous oxygen tension and shift from myocardial lactate extraction to lactate production. 1977

405

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MUELLER

MVo,

CBF m1/100g/min

ml/l00g/min I3

90

II

7

5

50 Mean

77

64’.

92

72”’

Fig. 1. Effect of propranolol on myocardial perfusion and metabolism. Control values are shown at the left, results after propranolol at the right of the horizontal axis. Coronary blood flow (CBF) and myocardial oxygen consumption (MVCJ uniformly decreased after propranolol. Myocardial lactate metabolism improved. Production of lactate (-ExL) shifted to extraction (ExLl or the rate of lactate extraction increased. +++p < 0.001.

Propranolol further decreased oxygen consumption but by a different and presumably beneficial mechanism, since coronary venous oxygen tension and lactate metabolism improved. These observations, together with our findings2’ that the propranolol-produced decrease in oxygen consumption was accompanied by decreased myocardial oxygen extraction and improved myocardial lactate metabolism (Fig. l), strongly suggest that the decrease in oxygen consumption following propranolol reflects diminished oxygen requirements. These observed decreases in myocardial oxygen consumption appear to explain much of the beneficial effect of propranolol in acute myocardial infarction. Improved distribution of myocardial blood flow leading to increased oxygen delivery to ischemic zones may also be an important component of propranolol’s action in this situation. The initial concern, that the propranolol-induced decrease in coronary blood flow might be harmful in ischemic heart disease,27’28 could not be confirmed in experimental infarction. Pitt et al.29 and Becker et al.,3o using different methods, showed that propranolol decreased regional perfusion in nonischemic myocardium, while flow remained essentially unchanged in ischemic areas. Furthermore, it became apparent that the effect of

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propranolol on transmural distribution of myocardial blood flow is remarkably different in ischemic compared to nonischemic tissue. Becker et al.ls compared the distribution of radioactive microspheres before and after propranolol administration in experimental infarction. Propranolol decreased radioactivity rather evenly throughout the myocardial wall in the noninfarcted regions; in contrast, it increased radioactivity in the subendocardium of the ischemic regions, suggesting a beneficial redistribution of flow. While a decrease in heart rate, permitting increased diastolic flow, plays an important role in improving subendocardial perfusion, other factors, such as increase of coronary vascular resistance in the nonischemic region 27931-33and decrease of the transmural pressure gradients in the ischemic and nonischemic regions,31 3436 may also be operative. In myocardial infarction in man, propranolol decreased total coronary blood flow from an average of 77 ml/l 00 g/min to 64 ml/l 00 g/min (Fig. l), associated with an increase in coronary vascular resistance in the majority of patients.” Another important effect of propranolol is the change in the pattern of substrate utilization by the ischemic and nonischemic myocardium. Increased adrenergic activity during acute infarction stimulates lipolysis leading to a release of free fatty acids from adipose tissue throughout the body. 37-40 High plasma free fatty acid concentrations have been shown to enhance myocardial free fatty acid uptake and to increase myocardial oxygen consumption,41-44 to produce arrhythmias in experimental myocardial infarction,45-48 and to increase infarct size.49 We examined the importance of high plasma free fatty acid levels in acute ischemic heart disease by sequential measurements of myocardial substrate uptake during the first 72 hr of acute myocardial infarction.” Thirty-six percent of 40 patients exhibited plasma free fatty acid concentrations greater than 800 PM/liter and myocardial free fatty acid extraction ratios greater than 15% of arterial levels. Preferential utilization of free fatty acids was shown by low myocardial respiratory quotients, averaging 0.76. Complications, including hypotension, left ventricular failure, and arrhythmias, were more common in these patients than in those with lower plasma free fatty acid concentrations and higher myocardial respiratory quotients. Studies performed in 20 patients with acute myo-

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cardial infarction 20 min after intravenous administration of propranolol revealed that plasma free fatty acid contents had decreased from an average of 938 to 873 PM/liter (not statistically significant), while the myocardial respiratory quotient had increased from 0.81 to 0.93 (p < O.OOl), indicating enhanced carbohydrate utilization.25 Myocardial glucose extraction increased from 0.4% to 3.0% of arterial concentration. Similar findings were reported by Opie et al.19 They showed, in experimental myocardial infarction, that propranolol reduced the utilization of 14C palmitic acid and increased that of glucose in ischemic myocardium. The net effect of reducing myocardial oxygen requirements, improving subendocardial perfusion, and shifting myocardial substrate utilization is an improvement in myocardial energetics. Kligfeld et al.51 showed that propranolol treatment of the isolated and globally ischemic rat heart produced a 20% increase in tissue creatine phosphate (p < O.OS), a 39% increase in tissue ATP/AMP (p < 0.0.5), and a 40% decrease in tissue lactate content (p < 0.001). Three studies measuring myocardial lactate fluxes after myocardial infarction demonstrated improved metabolism following propranolol. In experimental infarction, Haneda et a1.26 observed ischemic zone lactate metabolism to shift from 16% production to 4% extraction following propranolol. We52 observed a similar shift from 70% lactate production to 4% extraction associated with a decrease of hydrogen ion and l-norepinephrine concentration in the coronary venous blood. We demonstrated similar improvements in lactate metabolism in patients with acute myocardial infarction.25 PROPRANOLOL AND VENTRICULAR PERFORMANCE

Propranolol would be used extensively in acute myocardial infarction if it did not exert a negative inotropic effect. This negative inotropism is largely due to beta-adrenergicblockade, since the membrane-stabilizing“quinidine-like” effect does not seemto be relevant with therapeutic dosesof the drug.53-56 The importance of the betaadrenergicresponseto stresswas demonstratedby Sonnenblick et al.57Theseinvestigators,evaluating myocardial force-velocity relationships in intact and unsedatednormal man, observed that propranolo1 did not significantly influence restingcardiac

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function in the supine position but prevented the increase in myocardial contractility and the dlecreasein left ventricular dimensionassociatedwith exercise. Ludbrook et aL5’ studied the effect of propranolol in the resting heart using a kymographic technique for evaluation of wall motion. They observedthat the drug decreasedthe amplitude and velocity of left ventricular wall motion; slight increasesin heart size and decreasesin systolic time intervals were not statistically significant. Beta-adrenergicsupport, however, plays a particularly important role in the diseasedheart. Chidsey et a1.59evaluated the significance of this mechanismby administeringpropranolol to calves that had developed severeright ventricular failure 10 wk after ligation of the right pulmonary artery. Propranolol had little effect when administered.to the animalsprior to the development of heart failure. Striking deterioration of right ventricular function, however, wasobservedwhen propranolol was given to animalswith advancedright ventricular failure; cardiac output fell, and right ventricular end-diastolicpressurerose from 30 to 41 mm Hg. Significant depressionof ventricular function by propranolol probably occurs mainly in patients with moderate to severe heart disease.60-62 Stephen62 observedheart failure in 14 of 2000 patients who received propranolol. Eight of them had congestive failure prior to propranolol administration. All patients except one recovered with withdrawal of medication. The decreaseof ventricular function by propranolo1 doesnot appear to be of clinical importance in patients with acute myocardial infarction who are in functional (Killip) classesI or II. In OUTpatients, studied within the first 12 hr of acute myocardial infarction, heart rate decreasedfrom an averageof 80 to 73 beats/min.25All indicesof arterial pressuredecreased;mean arterial pressuredecreasedfrom 92 to 72 mm Hg, systolic pressure from 130 to 107 mm Hg, and diastolic pressure from 72 to 62 mm Hg. Cardiac index fell from 2.7 to 2.3 liter/min/sq M (Fig. 2) due in part LOa decreasein stroke volume and in part to a decreasein heart rate. Systemic vascular resistanceincreased from 1416 to 1600 dynes set cmV5.Other studies of propranolol in acute myocardial infarction have demonstrated directionally similar changes, although reduction in heart rate has usually ‘been more profound. 63-65Differences in the heart rate

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PAW mmHg

Cl L/min /M2 3.25

20

2.75

15

2.25

IO

1.75

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5

2.7

2.3”’

14

14

Fig. 2. Effect of propranolol on hemodynamics. Control values are shown at the left, results after propranolol at the right of the horizontal axis. Cardiac index (Cl) decreased in all but one patient. Pulmonary artery wedge pressure (PAW) decreased in six patients with the highest pressures prior to propranolol and increased in the remaining patients. +++p < 0.001.

response to propranolol may relate to the doseof

propranolol and to the time of administration, relative to the onset of infarction. Our studieswere performed earlier (within the first 12 hr) than those of others and may include persistance of vagal effects on sinusnode activity. Our studiesand those of others63-65showedthat propranolol decreasedpulmonary wedge pressure in certain patients with acute myocardial infarction, suggestingimproved function of ischemic areas.We administeredpropranolol to 20 patients with varying pulmonary wedgepressures.In six patients, wedge pressurewas greater than 1Smm Hg; propranolol produced substantial reductions in all of them (Fig. 2). Alderman et al.66 demonstrated in patients with coronary artery diseasewithout acute infarction that propranolol increased diastolic compliance and diastolic volume of the diseasedleft ventricle, but not of the ventricle with normal function. A number of recent observations suggestthat the elevation in left ventricular filling pressure noted with acute ischemiais due to increasedventricular stiffness rather than to significant increasein end-diastolic volume. Pepine and

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Wiener67 and Barry et a1.‘j8observedend-diastolic pressureto rise without significant changein enddiastolic volume in angina produced by pacing. These investigators estimated stiffness by plotting the logarithm of early and *end-diastolicpressures againstearly and end-diastolicleft ventricular volumes; the curves were shifted in the direction of increasedstiffness in all patients. Similar findings were recorded by Gaaschet a1.6gwho madeobservations of left ventricuiar pressure-volumerelationshipsduring spontaneousanginapectoris. McLaurin et al.” found a decreasein peak negative dP/dt together with an increasein end-diastolic pressure and a decreasein end-diastolic volume in 15 patients during pacing-inducedanginapectoris. They postulated impaired diastolic relaxation as an explanation for apparent decreases in left ventricular diastolic complianceduring acute ischemia. While increasedventricular stiffness is probably an important causeof elevated left ventricular enddiastolic pressurein acute ischemia,impaired myocardial contractility with increasedventricular volume also occurs. Sharma et al.,‘i for example, observedparallel increasesin volume and pressure in exercise-inducedanginapectoris, and Palacioset a1.72reported similar findings in global ischemia produced by reducing coronary inflow in a right heart bypass preparation, controlled by atrial pacing and pharmacologically denervated by betaadrenergicreceptor and ganglionicblockade. The effect of propranolol on ventricular performance appearsto depend upon whether the myocardium is chronically diseasedor acutely ischemic. This difference is best understood by considering the distribution of regions of varying function. Certain regions are composed of necrotic or fibrotic tissueand are unresponsiveto greater adrenergenic blockade or stimulation. Other regionsare ischemic, poorly contractile, stiff, and exposed to locally released1-norepinephrine. Propranolol improves oxygenation and promotesultimate survival in these areas.Other regionsof myocardium may be normal or chronically diseased.The effect of propranolol on theseregions is related to their dependence upon adrenergic activity for support of contractile function. The more ventricular function is determined by the mechanicaland contractile properties of ischemic areas,the more likely propranolol will improve ventricular function. Most studies suggestthat such is the casein patients with acute myocardial infarction who are in functional classI and early classII.

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CLINICAL EXPERIENCE WITH PROPRANOLOL IN ACUTE MYOCARDIAL INFARCTION

In 1965, Snown’74 first reported a substantial reduction of mortality in patients who had received propranolol. He treated 52 patients with 60 mg propranolol daily for 21 days and compared them to 55 control subjects. The mortality was 16% in the treated and 29% in the untreated group. The study, however, was performed without a placebo control and without randomization. Several randomized double-blind studieswere then initiated, which did not confirm the encouraging results of Snow. Balcon et a1.75randomized 114 patients with acute myocardial infarction, using 80 mg propranolol or placebo for 28 days. They found no difference in mortality, occurrence of shock, arrhythmias, and chest pain between the two groups. Heart failure, hypotension, and bradycardia, however, occurred more frequently in the propranolol-treated patients. Similar results were obtained in a multicenter randomized trial in 195 patients with acute myocardial infarction.76 Clausen et al.,” evaluating smaller dosagesof propranolol (40 mg daily) in 110 patients with acute myocardial infarction, observed no differencebetween the treated and untreated groups. After these results, propranolol wasnot further used in the treatment of acute myocardial infarction until the beginning of this decade.The recognition that development of irreversibleleft ventricular pump failure is related to the volume of damagedmyocardium emphasizedthe importance of preservation of ischemicmyocardium. Our early observationsin man that beta-adrenergicstimulation produced metabolic deterioration of jeopardized myocardium in different stagesof ischemic heart disease,i4’i5 together with the findings of Maroko et a.l.‘s that propranolol reduced infarct size in experimental infarction, revived interest in propranolol in the treatment of acute myocardial infarction. In a pilot study performed in 20 patients with acute myocardial infarction, 0.1 mg/kg intravenous propranolol was tolerated we11.25 Chest pain, unresponsiveto conventional therapy, disappeared.None of the patients developed left ventricular failure. Cardiac work and oxygen consumption decreased,and myocardial metabolism improved. In 24 patients, receiving intravenously 0.05-0.10 mg/kg propranolol within 24 hr after acute infarction, decreasein heart rate was the

most striking response,while stroke volume fell only moderately. Pulmonary wedge pressuresincreased2-3 mm Hg, and propranolol waswell toterated (Am sterdam et al., personal communication). Eleven of 12 patients treated with 0.1 mg/kg propranolol intravenously becauseof persistentor recurrent chest pain within 6 hr after acute infarction, experienced amelioration of pain and showed an immediate sharp drop in ST-segment elevations4g (Gold et al., personal communication). These investigators confirmed our observations that propranolol decreasedpulmonary wedgepressure in certain patients with high pressuresprior to treatment. Propranolol, administeredan averageof 7.6 hr after acute infarction to 20 patients, appeared to delay the evolution of infarction.65 Using serial serum creatine phosphokinase (CPK) measurements,all events of the CPK curve (rise, peak, and decay) occurred significantly later compared to those of the untreated group. Heart rate, stroke volume, and arterial pressurefell, while pulmonary wedge pressuretransiently increased an average of 3 mm Hg. All patients tolerated propranolol well except one, who electively received digitalis becauseof a remaining increasein pukmonary wedge pressure.Scheidt et al. (personalcommunication) evaluated in detail the effect of intravenous propranolol in 20 patients early after acute myocardial infarction. The hemodynamic results were very similar to those already reported. These investigators alsousedpropranolol in patients with recurrent ischemic pain early after acute infarction. Chest pain was relieved in most circumstances, left ventricular failure, electrocardiographic conduction delays, or other complications were not observed.Propranolol, 0.1 mg/kg ad.ministered intravenously to 20 patients within 24 hr after acute myocardial infarction, was tolerated well and showed no adverseclinical or hemodynamic effects (Pitt et al., personal communication). Ten patients received propranolol intravenously (3-8 mg) within 24 hr after acute infarction@ (Forrester et al., personalcommunication). Pulmonary wedgepressuredecreasedin certain patients, the averageincreasedfrom 12 to 14 mm Hg. No adverseeffects were observed. The potentially protecting properties of propranolol in acute myocardial ischemiawithout infarction were reported by severalgroups.In ,arandomized study of 68 patients with unstableangina, the propranolol-treated patients experienced less coronary events than the placebo group.80A.brupt

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cessation of oral propranolol (80-400 mg/day) in 11 patients with frequent and severe angina pectoris was followed by 13 acute coronary events, 4 of them myocardial infarctions (2 deathsJ81 In a double-blind crossover efficacy trial of 20 patients, sudden withdrawal of large doses of propranolol (160-320 mg/day) evoked symptoms in 10 patients; 6 had serious withdrawal complications, such as intermediate syndrome, fatal myocardial infarction, sudden death, and ventricular tachycardia.” Patients admitted to a coronary care unit because of prolonged ischemic chest pain developed a myocardial infarction less frequently when under long-term beta-adrenergic blockade.83 Thirty of 90 treated patients experienced infarction in contrast to 62 of 90 untreated subjects. The results of experimental and clinical research

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suggest that propranolol can play an important role in the treatment of acute myocardial infarction. It decreases cardiac work and improves perfusion and metabolism of ischemic myocardium. Much of the effectiveness of propranolol depends upon the functional state of the heart. The more left ventricular function is determined by the mechanical and contractile properties of ischemic areas, the more likely propranolol will improve oxygenation of jeopardized myocardium. However, the more ventricular performance is determined by chronically diseasedmyocardium, the more likely propranolol can be harmful. With careful evaluation of benefits and potential hazards and careful selection of patients, propranolol ap-

pears to be a promising drug to protect ischemic myocardium

in acute infarction.

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4.11 43. Crass MF III, Shipp JC, Pieper GM: Effects of catecholamines on myocardial endogenous substrates and contractility. Am J Physiol228:618, 1975 44. Opie LH: Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Am J Cardiol36:938,1975 45. Mailing FM, Moran NC: Ventricular arrhythmias induced by sympathomimetic amine in unanesthetized dsogs following coronary artery occlusion. Circ Res 5:409,1957 46. Ceremuzynski L, Straszewska-Barczak J, Herbaczynska-Cedro K: Cardiac rhythm disturbances and the release of catecholamines after acute coronary occlusion in dogs. Cardiovasc Res 3:190, 1969 47. Jewitt DE, Mercer CJ, Reid D, et al: Free noradrenaline and adrenaline excretion in relation to the development of cardiac arrhythmias and heart failure in patients with acute myocardial infarction. Lancet 1:635, 1969 48. Nelson PC: Effect of heparin on serum free fatty acids, plasma catecholamines and the incidence of arrhythmias following acute myocardial infarction. Br Med J 3:735,1970 49. Kjekshus JK, Mjgs OD: Effect of inhibition of lipolysis on infarct size after experimental coronary artery occlusion. J Clin Invest 52:1770, 1973 50. Mueller HS, Ayres SM: Prognostic implications of varying myocardial fatty acid and carbohydrate metabolism in acute myocardial infarction in man. Circulation 46(Suppl II):195, 1972 51. Kligfleld P, Horner H, Smithen C, et al: Metabolic effect of propranolol on ischemic myocardium. Circulation Sl(Suppl II):26, 1975 52. Religa A, Mueller ,HS, Evans R, et al: Metabolic effect of propranolol on ischemic tissue in human and experimental myocardial infarction. Clin Res 21:954, 1974 53. Coltart DJ, Meldrum S: The effect of racemic propranolol, dextro-propranolol and racemic practolol on the human and canine cardiac transmembrane action potential. Arch Int Pharmacodyn Ther 192:188,1971 54. Coltart DJ, Gibson DG, Shand DG: Plasma propranolol levels associated with suppression of ventricular ectopic beats. Br Med J 1:490, 1971 55. Nies AS, Shand DG: Clinical pharmacology of propranolol. Circulation 52:6, 1975 56. Wilson AG, Brooke OG, Lloyd HJ, et al: Mechanism of action of beta-adrenergic receptor blocking agents in angina pectoris; comparison of action of propranolol with dexpropranolol and practolol. Br Med J 4:399,1969 57. Sonnenblick E, Braunwald E, Williams J Jr, et al: Effects of exercise on myocardial force-velocity relations in intact unanesthetized man; relative roles of changes in heart rate, sympathetic activity, and ventricular dimensions. J Clin Invest 44: 12, 1965 58. Ludbrook P, Karliner .I, Kostuk W, et al: Effects of intravenously administered propranolol on wall motion abnormalities. Am J Cardiol 31:712, 1973 59. Chidsey C, Vogel J: Adrenergic mechanisms in heart failure, in Kattus A, Ross G, Hall V (eds): Cardiovascular Beta Adrenergic Responses. Berkeley, Univlersity of California Press, 1970, p 81 60. Vogel JHK, Blount SG Jr: Modification of cardiovascular responses by propranolol. BI Heart J 29:310, 1967

412 61. Epstein SE, Braunwald E: Clinical and hemodynamic appraisal of beta adrenergic blocking drugs. Ann NY Acad Sci 139:952,1967 62. Stephen SH: Unwanted effects of propranolol. Am J Cardiol 18:463, 1966 63. Amsterdam EA, Hilliard G, Williams DO, et al: Hemodynamic effects of propranolol in acute myocardial infarction. Circulation 48(Suppl IV):138, 1973 64. Forrester J, Chatterjee K, Parmley WW, et al: Hemodynamic profiles in acute myocardial infarction and their therapeutic implications. Circulation 48(Suppl IV):59, 1973 65. Cairns JS, Klassen G: Modification of acute myocardial infarction (AMI) by iv propranolol (p). Circulation 52(SupplII):107, 1975 66. Alderman EL, Coltart DJ, Robinson SC, et al: Effects of propranolol on left ventricular function and diastolic compliance in man. Circulation 48(Suppl IV):87, 1973 67. Pepine CJ, Wiener L: Relationship of angina1 symptoms to lung mechanics during myocardial ischemia. Circulation 46:863, 1972 68. Barry WH, Brooker JZ, Alderman EL, et al: Changes in diastolic stiffness and tone of the left ventricle during angina pectoris. Circulation 49:255,1974 69. Gaasch WH, Adyanthaya AV, Wang VH, et al: Prinzmetal’s variant angina: Hemodynamic and angiog raphic observations during pain. Am J Cardiol 35:683, 1975 70. McLaurin LP, Rolett EL, Grossman W: Impaired left ventricular relaxation during pacing-induced ischemia. Am J Cardiol 32:751, 1973 71. Sharma B, Raphael MJ, Thadani U: Left ventricular pressure-volume changes during exercise-induced pain in patients with angina pectoris. Br Heart J 36:1038, 1974 72. Palacios I, Johnson RA, Newell JB, et al: Left ven-

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