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Plasma catecholamine levels in acute myocardial infarction: Influence of beta-adrenergic blockade and relation to central hemodynamics
Plasma catecholamine levels in acute myocardial infarction: Influence of beta-adrenergic blockade and relation hemodynamics
to central
In a prospective study, 20 patients with acute myocardial infarction were randomly assigned in a double-blind fashion to treatment with intravenous metoprolol followed by oral metoprolol or placebo. All patients underwent hemodynamic monitoring for 24 hours. Plasma adrenaline and noradrenalin levels were estimated at baseline (mean 6.0 f 0.9 hours from onset of symptoms) and at 1 and 24 hours after the start of therapy. Plasma adrenaline and noradrenalin levels were elevated in all but one patient, with a further increase at 1 hour after administration of metoprolol (p < 0.05). At baseline pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = -0.44; p < 0.05) and noradrenalin levels (r = -0.44; p < 0.05). There was also an inverse relationship between stroke volume index and the plasma noradrenalin level (r = -0.44; p < 0.05) but not the plasma adrenaline level. These relationships were lost after the baseline measurements. However, between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both adrenaline (r = -0.48; p < 0.05) and noradrenalin levels (r = -0.66; p < 0.01). Thus, in the early stages of myocardial infarction high plasma catecholamine levels are associated with the hemodynamic markers of severe left ventricular damage. Beta-adrenergic blockade with metoprolol pr0duced.a further increase in catecholamine levels that was associated with an increase in systemic vascular resistance. (AM HEART J 1988; 11538.)
Donal P. Murray, M.D., M.R.C.P., Robert D.S. Watson, M.D., M.R.C.P., Alex V. Zezulka, M.R.C.P., R. Gordon Murray, F.R.C.P., and William A. Littler, M.D., F.R.C.P.Birmingham, England
One would expect that all of the metabolic derangements of acute stress, including a marked increase in catecholamine release,l would accompany the profound physical and psychological stress of acute myocardial infarction. As early as 1943, Raab2 reported an increase in adrenaline and noradrenalin levels in patients with exercise-induced angina pectoris. Subsequent studies reported high urinary and plasma catecholamine levels in patients with acute myocardial infarction. 3-5 Serial determinations of plasma catecholamine levels suggested that the highest levels were found in patients with the most severe left ventricular damagesv7 and were associated with an increased incidence of ventricular arrhythmias in acute myocardial infarction.7-g From the Department ham, East Birmingham Received
for publication
Reprint requests: cine, Cork Regional
38
of Cardiovascular Hospital and Feb. 23, 1987;
Medicine, University Dudley Road Hospital. accepted
Donal Murray, M.D., University Hospital, Cork, Ireland.
July
of Birming-
28, 1987.
Department
of Medi-
In view of the detrimental effects of high catecholamine levels on cardiac function and rhythm, it was postulated that beta-adrenergic blockade might have a beneficial effect in the setting of acute myocardial infarction. However, the effects of betaadrenergic blockade on plasma catecholamine levels of are controversial,10-14 whereas the relationship such changes to central hemodynamics has not been explored. The Metoprolol In Acute Myocardial Infarction (MIAMI) trial afforded the opportunity to study changes in circulating catecholamine levels in acute myocardial infarction and the influence of beta-adrenergic blockade on these changes.15 The aims of this study were: (1) to investigate the effects of intravenous followed by oral administration of the selective beta-1-adrenergic blocker, metoprolol, on catecholamine levels in the early stages of acute myocardial infarction; and (2) to study the relationship between plasma catecholamine levels and central hemodynamics in acute myocardial infarction.
Volume Number
115 1, Part P
METHODS
Twenty consecutive patients who fulfilled the criteria for inclusion in the MIAMI trial were studied.15 Inclusion criteria included onset of symptoms of acute myocardial infarction lessthan 24 hours before admission in patients lessthan 75 years old. Exclusion criteria were: current therapy with a beta blocker or calcium antagonist, cardiac failure, hypotension (systolic blood pressure< 105 mm Hg), and bradycardia (X65 bpm). Nineteen patients were male and onewasfemale. The meandelay from onset of symptoms to initiation of therapy was 6.0 + 0.9 hours. The clinical diagnosis of myocardial infarction was confirmed by the evolution of an infarct pattern on the ECG and an increasein the cardiac enzyme levels of all 20 patients. The site of infarction wasinferior in 12, anterior in six, and posterolateral in two. During the study patients were given analgesics,diuretics, and other drugs as indicated. However, useof beta blockers and calcium channel blockers was avoided. Informed consent was obtained from all patients. Study protocol. A No. 7 French catheter wasplaced in the pulmonary artery of all 20 patients. Patients were then randomly assignedin a double-blind fashion to treatment with metoprolol, 15 mg administered intravenously in divided doses,followed by 50 mg orally every 6 hours or placebo. Hemodynamic measurements were made and blood was drawn from the pulmonary artery line of the thermodilution catheter for determination of plasmacatecholamine levels at baseline and at 1 hour and 24 hours after randomization. Catecholamine measurement. Blood specimens for measurement of catecholamine levels were drawn into cooledsyringes and transferred to heparinized tubes in ice water (the tubes silsocontained 5 nmol/L glutathione as antioxidant for specimen analysis by the catechol-omethyl transferase [COMT] method). Sampleswere centrifuged at 4OC for 7 minutes, and the plasmatransferred to cooled tubes and stored at -20’ C within 30 minutes of sampling. Considerable care and attention was given to the sampling of specimens because of the recognized lability of catecholamines in blood. Samples were not drawn within 20 minutes of venousor arterial cannulation to reduce the effects of anxiety on plasma levels. An interval of 30 minutes between sampling and storage at -20’ C was a maximum. Plasma levels of adrenaline and noradrenalin were measuredin two laboratories by means of two different methods.Assayswere performed in our own laboratory by means of a modification of the method of Peuler and Johnso+ with a partially purified extract of rat liver COMT. Plasma levels of adrenaline and noradrenalin were also measured in the laboratories of Hassle, Goteborg, Sweden, by means of liquid chromatography and electrochemical detection.17Both methods are radioenzymatic, with a high degree of specificity and sensitivity. The results from the two assayswere compared to assess reproducibility. In our laboratory the upper limit of normal for adrenaline is 63 pg/ml and for noradrenalin is Patients.
Plasma
catecholamines
in AMI
39
Table I. Baseline clinical and hemodynamic characteristics of metoprolol- and placebo-treated patients Baseline clinical and hemodynamic data Infarct site Anterior Inferior Hemodynamics HR @pm) SBP (mm Hg) PCWP (mm Hg) CI (L/min/mz) SVI (ml/m’) SVR (dynes/se&m-‘)
Metoprolol (n = 10)
Placebo (n = 10)
4
5
6
5
82 f 5
3.4 + 0.4 42.1 k 7.4
80 138 14.5 3.3 41.2
1216 k 178
1336 -+ 221
134 f 8 14.5 r 2.6
1-t i zk s
4 9 2.7 0.5 7.2
HR = Heart rate; SBP = systolic blood pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; SVI = stroke volume index; SVR = systemic vascular resistance.
400 pg/ml. The coefficient of variation is consistently less than 10%. Statistics. Differences between meanswere assessed by meansof paired and unpaired Student’s t tests as appropriate, Differences in mean plasma catecholamine levels between the metoprold and placebogroups were assessed at each stage. Also, changes in plasma catecholamine levels between baseline and 1 hour and 24 hours in the metoprolol group were compared in the two treatment groups. Correlation coefficients were performed by means of linear regressionanalysis.p Values < 0.05 were considered significant. Results are expressedas mean * standard deviation. RESULTS
Ten of our study patients were randomly assigned with metoprolol and 10 to placebo. The patient groups were matched with regard to infarct site and baseline hemodynamics (Table I). At baseline all but one of our study patients had elevated concentrations of either adrenaline or noradrenalin. The mean adrenaline level at baseline was 203 pg/ml (range 57 to 491) and the mean noradrenalin level was 640 pg/ml (range 220 to 1412). A strong correlation was observed between results of assays of both adrenaline and noradrenalin by the two different techniques: r = 0.82 and 0.84, respectively 03 < 0.01). For comparison with the hemodynamic data the results from our own laboratory were used. Relationship to central hemodynamics. At baseline, pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = 0.44, p < 0.05; Fig. 1) and noradrenalin (r = 0.44, p < 0.05; Fig. 1) levels. An inverse relationship was to treatment
40
Murray
et al.
American
January T988 Heart Journal
25
20
20
PCWP
PCUP 15
I5
tmnHg) IO Y = 8.1+0,022x
.
Y = 8.4+,005X
5
r - 0.44
r - 0.44 D < 0.05
D < 0,05
I 100
I 200
, 300
Plasm0
I lroo
r 500
0 3do
6k Plasma
ADR (Wml)
12bO NAUR (Dw'ml)
Fig. 1. Relationship between baselinepulmonary capillary wedgepressure(PC WP) and plasmaadrenaline (ADR) and noradrenalin (NADR) levels.
e 20 Y - .15x-51
r - .04 P < 0.05
10
0
100
200
300
400
300
!m
600
Plmnq(LDR
ADR rR9mt
900
1200
1500
CW/n%l~
2. Relationship betweenstroke volume index (SVI) and plasmaadrenaline (ADR) and noradrenalin (NADR) levels.
Fig.
Table
II. Hemodynamic changesfrom baselineto 1 hour Hemodynamics
HR (bpm) MAP (mmHg) PCWP(mmHg) CI (L/min/m2) SVI (ml/ml) SVR (dynes/se&m-‘) HR = heart rate; MAP = mean nary capillary wedge pressure; index; SVR = systemic vascular
Metoprolol (n = 10) -15 -14
+ 2 * 2
+2.2 -6.8
k 1.0 f 0.4 + 1.2
+378
+ 94
-0.9
Placebo (n = 10) -1 -4 -3.4 -0.1 -1.0 +88
& 3 f 2 z!T 1.1 * 0.1 + 0.5 & 76
observed
between
stroke volume index and the level (P = -0.44; p < 0.05) but not between stroke volume index and the plasma adrenaline level (F = -0.30; Fig. 2). These relationships were lost after the baseline measurements. The correlations were similar when results from tbe second laboratory were used. During the first hour of double-blind treatment, metoprolol produced a reduction in heart rate 0, < O.Ol), cardiac index (p < O.Ol), and stroke vofume index 0, < 0.01) and an increase in pulmonary capillary wedge pressure (p < 0.05) and systemic
plasma noradrenalin p Value
arterial blood pressure; PCWP = ptioCI = cardiac index; SVI = stroke volume resistance.
Volume Number
115 1, Part 1
D <0.05 .u ,I *.
Plasma catecholamines
A SVR UOO Y!!ic%E
.
200 .
.
l
:
.
.
0
p.
44
I/.
= -17X-66 r- 048
Y
600
in AM
s
I
’
1
* .
-200
-240
-160
-80
0
80
A ADR kW/ml)
0
200
kO0 A NADR
600 (~ahiil)
800
Fig. 3. Relationship between changein systemic vascular resistance(SVR) from 0 to 1 hour and changes in adrenaline (ADR) and noradrenalin (NADR) levels.
vascular resistance (p < 0.05; Table II). Subsequent-
ly, there was an attenuation of this effect, so that at 24 hours the only significant hemodynamic difference between the groups was a greater reduction in heart rate among metoprolol-treated compared to placebo-treated patients. Between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both noradrenalin (r = 0.66; p < 0.01) and adrenaline (I = 0.48; p < 0.05) levels (Fig. 3). No correlation was observed between the changes in catecholamine levels and changes in the other hemodynamic parameters. Effects of beta blockade. In the placebo-treated group the mean adrenaline level decreased gradually from 246 +- 164 pg/ml to 196 + 124 pg/ml at 1 hour and 130 f 96 pg/ml at 24 hours, whereas noradrenalin remained elevated throughout the 24 hours (Fig. 4). In the metoprolol-treated group adrenaline levels increased from 160 f 136 pg/ml at baseline to 193 + 201 pg/ml at 1 hour and 212 +- 387 pg/ml at 24 hours. Noradrenalin levels also increased in the metoprolol-treated group from 586 & 245 pg/ml at baseline to 757 f 333 pg/ml at 1 hour and 767 f 739 pg/ml at 24 hours. Thus, at both 1 and 24 hours after initiation of treatment, both plasma adrenaline and noradrenalin levels increased in the metoprololtreated compared to the placebo-treated patients. These increases were statistically significant (p < 0.05). DlSCUSSlON
Previous investigators have demonstrated a relationship between plasma catecholamine levels and
indices of left ventricular damage in acute myocardial infarction. Videbaek et a1.6 demonstrated a relationship between plasma catecholamine concentrations and clinical status, whereas Nadeau and de Champlain”7 noted a correlation between peak catecholamine levels and peak enzyme release in 26 patients observed for 48 hours after onset of symptoms of acute myocardial infarction. This is the first study in which catecholamine concentrations have been related to central hemodynamics in acute myocardial infarction. A high pulmonary capillary wedge pressure and low stroke volume index are important markers of impaired left ventricular function in acute myocardial infarction.1gr20 It is to be expected, therefore, that there should be a direct relationship between pulmonary capillary wedge pressure and an inverse relationship between stroke volume index and plasma adrenaline and noradrenalin concentrations at baseline. Plasma catecholamine levels are also elevated in chronic heart failure and have been correlated with hemodynamic indices of left ventricular dysfunction. Thomas and MarkszO demonstrated a direct relationship between the plasma noradrenalin concentration and the degree of left ventricular dysfunction as assessed by systolic time intervals, whereas Francis et al.” observed a linear relationship between the plasma noradrenalin concentration and pulmonary wedge pressure and an inverse relationship between the plasma noradrenalin concentration and stroke volume index. In a stiJdy of 106 patients, Cohn et a1.22found the plasma noradrenalin concentration to be a better indication of prognosis in chronic heart failure than hemodynamic in-
42
Murray
et al.
X
A NADR
1
1 h.
Oh. PLACEBO
-
24 h.
MEfOPRoLOL
- - -
- -
x - P < 0.05
Fig. 4. Changesin plasmaadrenaline (ADR) and noradrenalin (NADR) from 0 to 24 hours. Significance values represent differences in changesfrom baselinevalues, comparing metoprolol with placebo.
dices of myocardial dysfunction. Our patient population was too small to examine whether plasma catecholamine levels are of prognostic significance in acute myocardial infarction. However, the relationship observed between hemodynamics and catecholamine concentrations suggest that this may be the case. High plasma adrenaline or noradrenalin levels were found in all but one of our patients studied within 6 hours (range 4 to 12) of onset of symptoms of acute myocardial infarction. A further increase in both plasma adrenaline and noradrenalin concentrations was found after intravenous administration of 15 mg of the selective beta-l antagonist, metopro101,followed by 50 mg orally, compared to a placebo-
treated group. These differences were still apparent at 24 hours. Adrenaline levels gradually decreased in the placebo-treated group, whereas noradrenalin levels remained elevated over the 24-hour study period. There are a number of theoretic grounds for the use of beta blockade in the setting of acute myocardial infarction. High catecholamine levels increase myocardial contractility and myocardial oxygen consumption. Beta-adrenergic blockers are thought to exert an antiischemic effect by reducing myocardial contractility. In addition, high catecholamine levels can induce hypokalemia, which is known to be arrhythmogenic.24 Both propanolol and atenolol have been shown to abolish the decrease in potassi-
Volume Number
115 1, Part 1
urn that results from adrenaline infusion15 and occurs in acute myocardial infarction.24,26 However, the effects of beta blockade on plasma catecholamine levels are controversial. A number of studies have demonstrated an increase in the noradrenalin level in response to propranolol in a variety of clinical situations, particularly after acute administration. Irving et al.l” and Hansen et al.ll demonstrated an increase in noradrenalin levels in beta-blocked patients with ischemic heart disease both at rest and during exercise, whereas Christensen2 demonstrated high catecholamine levels in hypertensive patients receiving propranolol compared to a control group. A similar increase in adrenaline and noradrenalin levels in dogs with coronary artery occlusion was demonstrated by McGrath et al. after intravenous metoprolol. In contrast, Mueller et a1.14demonstrated a decrease in both adrenaline and noradrenaline levels after intravenous administration of propranolol to patients with a mean delay of 10 hours from onset of symptoms of acute myocardial infarction. They suggested that the decrease in catecholamine levels in response to propranolol might be related to blockade of the central beta receptors, the beta-adrenergic receptors. It is possible, therefore, that different central effects of propranolol and metoprolol might explain the difference in results between the study of Mueller et a1.14and ours. Alternatively, the differences might be methodologic: our catecholamine results were consistent when measured in two separate laboratories by two well-recognized and reproducible techniques with a high degree of specificity and sensitivity. In contrast, Mueller et a1.14 used a nonfluorometric method that is less reliable. We have previously described an increase in systemic vascular resistance in a larger population of patients with acute myocardial infarction treated with metoprolol.25 The relationship observed in the present study between the changes in plasma catecholamine levels and changes in systemic vascular resistance during the first hour after drug administration provides evidence that the hemodynamic response was the result of the effects of the unopposed action of catecholamines on the alpha receptors in the arterioles. This may have reflected a reflex increase in sympathetic tone after a metoprolol-induced decrease in arterial pressure and cardiac output; alternatively, a drug-induced decrease in systemic clearance of catecholamines from the circulation could have been responsible.27 The increased catecholamine levels and increased systemic vascular resistance would be expected to increase myocardial oxygen consumption and thus counteract the
Plasma
catecholamines
in AM
43
oxygen-sparing effects that were suggested by the decrease in heart rate and stroke work index. The possible disadvantages of increased systemic vascular resistance on myocardial oxygen consumption may explain, in part, the limited impact of acutephase beta blockade on myocardial infarct size in the recently reported multicenter studies.15,27 Conclusions. We have studied the effects of acute myocardial infarction on circulating catecholamine concentrations and the influence of the selective beta-1-adrenergic blocker, metoprolol, on these levels. We found elevated levels of both adrenaline and noradrenalin in all but one patient. The high catecholamine levels were related to impaired left ventricular function as indicated by high pulmonary capillary wedge pressure and low stroke volume index. The increase in catecholamine levels in response to metoprolol was associated with an increase in systemic vascular resistance. The resulting increase in myocardial oxygen consumption may have counteracted some of the other beneficial hemodynamic effects of beta blockade and thus explain the rather limited effect of beta blockade in limiting myocardial infarct size in humans.
REFERENCES
1. Levi L. Neuroendocrinology in anxiety. Br J Psycho1 1969; 3:40-6. 2. Raab W. The pathogenic significance of adrenaline and related substances in the heart muscle. Exp Med Surg 1943; 1:188-225. 3. Gazes PC, Richardson JA, Woods EF. Plasma catecholamine concentrations in myocardial infarction and angina pectoris. Circulation 1959;19:657-61. 4. Valori C, Thomas M, Shillingford J. Free noradrenalin and adrenaline excretion in relation to clinical syndromes following myocardial infarction. Am J Cardiol 1967;20:605-10. 5. Havashi KD. Moss AV. Yu PN. Urinarv catecholamine excretion in acute myocardial infarction. Circulation 1969; 40:473-81. 6. Videbaek JN, Christensen NJ, Sterndorff B. Serial determination of plasma catecholamines in myocardial infarction. Circulation 1972;46:846-55. 7. Siggers DC, Salter C, Fluck DC. Serial plasma adrenaline and noradrenalin levels in myocardial infarction using a new double isotope technique. Br Heart J 1971;33:878-83. 8. McDonnald L, Baker C, Bray C, et al. Plasma catecholamines after myocardial infarction. Lancet 1969;2:1021-4. 9. Jewitt DE, Mercer CJ, Reid D. Free noradrenalin and adrenaline excretion in relation to the development of arrhythmias and heart failure in patients with acute myocardial infarction. Lancet 1969;1:635-41. 10. Irving MH, Britton BJ, Wood WG. Effects of beta adrenergic blockade on plasma catecholamines in exercise. Nature 1974; 248:531-3. 11. Hansen JF, Hesse B, Christensen NJ. Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease. Eur J Clin Invest 1978;8:31-6. 12. Christensen NJ. Plasma catecholamines and arterial hypertension. Acta Med Stand 1976;602 (suppl):57. 13. McGrath BP, Lim SP, Leversha A. Myocardial and peripheral catecholamine response to acute coronary artery constric-
44
14.
15.
1s.
17. 18.
19.
Murray
et al.
tion before and after propranoIo1 treatment in the anesthetized dog. Cardiovasc Res 1983;15:28-34. Mueller HS, Rao PS, Fletcher J. Propranalol during the evolution and subsequent 10 days of myocardial infarction in man: hemodynamic, initial cardiac energetic and neurohormonal responses. Clin Cardiol 1979;2:393-9. The Miami Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebocontrolled international trial. Eur Heart J 1985;6:199-226. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 1977;21:625-36. Nadeau RA, de Champlain J. Plasma catecholamines in acute myocardial infarction. AM HEART J 1979;98:548-54. Verdouw PD, Hagemeijer F, van Dorp WG, van der Vorm A, Hugenholtz P. Short-term survival after acute myocardial infarction predicted by hemodynamic parameters. Circulation 1975;52:413-19. Forrester JS, Diamond GA, Swan HJC. Correlative classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977;39:137-45.
BOUND
VOLUMES
20. 21
22. 23. 24. 25. 26.
Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233-43. Francis GA, Goldsmith SR, Cohn JN. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. AM HEART J 1982;104:725-31. Cohn JA, Levine BT, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23. Struthers AD, Whitesmith R, Reid JL. Metabolic and haemodynamic effects of increased circulating adrenaline in man. Br Heart J 1983;50:277-81. Nordrehaug JE, Johannsen ISA, Lippe G, et al. Effect of timolol on changes in serum potassium concentration during acute myocardial infarction. Br Heart J 1985;53:388-93. Murray DP, Murray RG, Rafiqi E, Littler WA. Early beta blockade in acute myocardial infarction. Eur Heart J 1985;6 (suppl 1):124. ISIS-1 Collaborative Study Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-l. Lancet 1986;2:57-66.
AVAILABLE
TO SUBSCRIBERS
Bound volumes of the AMERICAN HEART JOURNAL are available to subscribers (only) for the 1988 issues from the Publisher at a cost of $47.00 ($60.00 international) for Vol. 115 (January-June) and Vol. 116 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (800) 325-4177, ext. 361. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
to central
In a prospective study, 20 patients with acute myocardial infarction were randomly assigned in a double-blind fashion to treatment with intravenous metoprolol followed by oral metoprolol or placebo. All patients underwent hemodynamic monitoring for 24 hours. Plasma adrenaline and noradrenalin levels were estimated at baseline (mean 6.0 f 0.9 hours from onset of symptoms) and at 1 and 24 hours after the start of therapy. Plasma adrenaline and noradrenalin levels were elevated in all but one patient, with a further increase at 1 hour after administration of metoprolol (p < 0.05). At baseline pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = -0.44; p < 0.05) and noradrenalin levels (r = -0.44; p < 0.05). There was also an inverse relationship between stroke volume index and the plasma noradrenalin level (r = -0.44; p < 0.05) but not the plasma adrenaline level. These relationships were lost after the baseline measurements. However, between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both adrenaline (r = -0.48; p < 0.05) and noradrenalin levels (r = -0.66; p < 0.01). Thus, in the early stages of myocardial infarction high plasma catecholamine levels are associated with the hemodynamic markers of severe left ventricular damage. Beta-adrenergic blockade with metoprolol pr0duced.a further increase in catecholamine levels that was associated with an increase in systemic vascular resistance. (AM HEART J 1988; 11538.)
Donal P. Murray, M.D., M.R.C.P., Robert D.S. Watson, M.D., M.R.C.P., Alex V. Zezulka, M.R.C.P., R. Gordon Murray, F.R.C.P., and William A. Littler, M.D., F.R.C.P.Birmingham, England
One would expect that all of the metabolic derangements of acute stress, including a marked increase in catecholamine release,l would accompany the profound physical and psychological stress of acute myocardial infarction. As early as 1943, Raab2 reported an increase in adrenaline and noradrenalin levels in patients with exercise-induced angina pectoris. Subsequent studies reported high urinary and plasma catecholamine levels in patients with acute myocardial infarction. 3-5 Serial determinations of plasma catecholamine levels suggested that the highest levels were found in patients with the most severe left ventricular damagesv7 and were associated with an increased incidence of ventricular arrhythmias in acute myocardial infarction.7-g From the Department ham, East Birmingham Received
for publication
Reprint requests: cine, Cork Regional
38
of Cardiovascular Hospital and Feb. 23, 1987;
Medicine, University Dudley Road Hospital. accepted
Donal Murray, M.D., University Hospital, Cork, Ireland.
July
of Birming-
28, 1987.
Department
of Medi-
In view of the detrimental effects of high catecholamine levels on cardiac function and rhythm, it was postulated that beta-adrenergic blockade might have a beneficial effect in the setting of acute myocardial infarction. However, the effects of betaadrenergic blockade on plasma catecholamine levels of are controversial,10-14 whereas the relationship such changes to central hemodynamics has not been explored. The Metoprolol In Acute Myocardial Infarction (MIAMI) trial afforded the opportunity to study changes in circulating catecholamine levels in acute myocardial infarction and the influence of beta-adrenergic blockade on these changes.15 The aims of this study were: (1) to investigate the effects of intravenous followed by oral administration of the selective beta-1-adrenergic blocker, metoprolol, on catecholamine levels in the early stages of acute myocardial infarction; and (2) to study the relationship between plasma catecholamine levels and central hemodynamics in acute myocardial infarction.
Volume Number
115 1, Part P
METHODS
Twenty consecutive patients who fulfilled the criteria for inclusion in the MIAMI trial were studied.15 Inclusion criteria included onset of symptoms of acute myocardial infarction lessthan 24 hours before admission in patients lessthan 75 years old. Exclusion criteria were: current therapy with a beta blocker or calcium antagonist, cardiac failure, hypotension (systolic blood pressure< 105 mm Hg), and bradycardia (X65 bpm). Nineteen patients were male and onewasfemale. The meandelay from onset of symptoms to initiation of therapy was 6.0 + 0.9 hours. The clinical diagnosis of myocardial infarction was confirmed by the evolution of an infarct pattern on the ECG and an increasein the cardiac enzyme levels of all 20 patients. The site of infarction wasinferior in 12, anterior in six, and posterolateral in two. During the study patients were given analgesics,diuretics, and other drugs as indicated. However, useof beta blockers and calcium channel blockers was avoided. Informed consent was obtained from all patients. Study protocol. A No. 7 French catheter wasplaced in the pulmonary artery of all 20 patients. Patients were then randomly assignedin a double-blind fashion to treatment with metoprolol, 15 mg administered intravenously in divided doses,followed by 50 mg orally every 6 hours or placebo. Hemodynamic measurements were made and blood was drawn from the pulmonary artery line of the thermodilution catheter for determination of plasmacatecholamine levels at baseline and at 1 hour and 24 hours after randomization. Catecholamine measurement. Blood specimens for measurement of catecholamine levels were drawn into cooledsyringes and transferred to heparinized tubes in ice water (the tubes silsocontained 5 nmol/L glutathione as antioxidant for specimen analysis by the catechol-omethyl transferase [COMT] method). Sampleswere centrifuged at 4OC for 7 minutes, and the plasmatransferred to cooled tubes and stored at -20’ C within 30 minutes of sampling. Considerable care and attention was given to the sampling of specimens because of the recognized lability of catecholamines in blood. Samples were not drawn within 20 minutes of venousor arterial cannulation to reduce the effects of anxiety on plasma levels. An interval of 30 minutes between sampling and storage at -20’ C was a maximum. Plasma levels of adrenaline and noradrenalin were measuredin two laboratories by means of two different methods.Assayswere performed in our own laboratory by means of a modification of the method of Peuler and Johnso+ with a partially purified extract of rat liver COMT. Plasma levels of adrenaline and noradrenalin were also measured in the laboratories of Hassle, Goteborg, Sweden, by means of liquid chromatography and electrochemical detection.17Both methods are radioenzymatic, with a high degree of specificity and sensitivity. The results from the two assayswere compared to assess reproducibility. In our laboratory the upper limit of normal for adrenaline is 63 pg/ml and for noradrenalin is Patients.
Plasma
catecholamines
in AMI
39
Table I. Baseline clinical and hemodynamic characteristics of metoprolol- and placebo-treated patients Baseline clinical and hemodynamic data Infarct site Anterior Inferior Hemodynamics HR @pm) SBP (mm Hg) PCWP (mm Hg) CI (L/min/mz) SVI (ml/m’) SVR (dynes/se&m-‘)
Metoprolol (n = 10)
Placebo (n = 10)
4
5
6
5
82 f 5
3.4 + 0.4 42.1 k 7.4
80 138 14.5 3.3 41.2
1216 k 178
1336 -+ 221
134 f 8 14.5 r 2.6
1-t i zk s
4 9 2.7 0.5 7.2
HR = Heart rate; SBP = systolic blood pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; SVI = stroke volume index; SVR = systemic vascular resistance.
400 pg/ml. The coefficient of variation is consistently less than 10%. Statistics. Differences between meanswere assessed by meansof paired and unpaired Student’s t tests as appropriate, Differences in mean plasma catecholamine levels between the metoprold and placebogroups were assessed at each stage. Also, changes in plasma catecholamine levels between baseline and 1 hour and 24 hours in the metoprolol group were compared in the two treatment groups. Correlation coefficients were performed by means of linear regressionanalysis.p Values < 0.05 were considered significant. Results are expressedas mean * standard deviation. RESULTS
Ten of our study patients were randomly assigned with metoprolol and 10 to placebo. The patient groups were matched with regard to infarct site and baseline hemodynamics (Table I). At baseline all but one of our study patients had elevated concentrations of either adrenaline or noradrenalin. The mean adrenaline level at baseline was 203 pg/ml (range 57 to 491) and the mean noradrenalin level was 640 pg/ml (range 220 to 1412). A strong correlation was observed between results of assays of both adrenaline and noradrenalin by the two different techniques: r = 0.82 and 0.84, respectively 03 < 0.01). For comparison with the hemodynamic data the results from our own laboratory were used. Relationship to central hemodynamics. At baseline, pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = 0.44, p < 0.05; Fig. 1) and noradrenalin (r = 0.44, p < 0.05; Fig. 1) levels. An inverse relationship was to treatment
40
Murray
et al.
American
January T988 Heart Journal
25
20
20
PCWP
PCUP 15
I5
tmnHg) IO Y = 8.1+0,022x
.
Y = 8.4+,005X
5
r - 0.44
r - 0.44 D < 0.05
D < 0,05
I 100
I 200
, 300
Plasm0
I lroo
r 500
0 3do
6k Plasma
ADR (Wml)
12bO NAUR (Dw'ml)
Fig. 1. Relationship between baselinepulmonary capillary wedgepressure(PC WP) and plasmaadrenaline (ADR) and noradrenalin (NADR) levels.
e 20 Y - .15x-51
r - .04 P < 0.05
10
0
100
200
300
400
300
!m
600
Plmnq(LDR
ADR rR9mt
900
1200
1500
CW/n%l~
2. Relationship betweenstroke volume index (SVI) and plasmaadrenaline (ADR) and noradrenalin (NADR) levels.
Fig.
Table
II. Hemodynamic changesfrom baselineto 1 hour Hemodynamics
HR (bpm) MAP (mmHg) PCWP(mmHg) CI (L/min/m2) SVI (ml/ml) SVR (dynes/se&m-‘) HR = heart rate; MAP = mean nary capillary wedge pressure; index; SVR = systemic vascular
Metoprolol (n = 10) -15 -14
+ 2 * 2
+2.2 -6.8
k 1.0 f 0.4 + 1.2
+378
+ 94
-0.9
Placebo (n = 10) -1 -4 -3.4 -0.1 -1.0 +88
& 3 f 2 z!T 1.1 * 0.1 + 0.5 & 76
observed
between
stroke volume index and the level (P = -0.44; p < 0.05) but not between stroke volume index and the plasma adrenaline level (F = -0.30; Fig. 2). These relationships were lost after the baseline measurements. The correlations were similar when results from tbe second laboratory were used. During the first hour of double-blind treatment, metoprolol produced a reduction in heart rate 0, < O.Ol), cardiac index (p < O.Ol), and stroke vofume index 0, < 0.01) and an increase in pulmonary capillary wedge pressure (p < 0.05) and systemic
plasma noradrenalin p Value
arterial blood pressure; PCWP = ptioCI = cardiac index; SVI = stroke volume resistance.
Volume Number
115 1, Part 1
D <0.05 .u ,I *.
Plasma catecholamines
A SVR UOO Y!!ic%E
.
200 .
.
l
:
.
.
0
p.
44
I/.
= -17X-66 r- 048
Y
600
in AM
s
I
’
1
* .
-200
-240
-160
-80
0
80
A ADR kW/ml)
0
200
kO0 A NADR
600 (~ahiil)
800
Fig. 3. Relationship between changein systemic vascular resistance(SVR) from 0 to 1 hour and changes in adrenaline (ADR) and noradrenalin (NADR) levels.
vascular resistance (p < 0.05; Table II). Subsequent-
ly, there was an attenuation of this effect, so that at 24 hours the only significant hemodynamic difference between the groups was a greater reduction in heart rate among metoprolol-treated compared to placebo-treated patients. Between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both noradrenalin (r = 0.66; p < 0.01) and adrenaline (I = 0.48; p < 0.05) levels (Fig. 3). No correlation was observed between the changes in catecholamine levels and changes in the other hemodynamic parameters. Effects of beta blockade. In the placebo-treated group the mean adrenaline level decreased gradually from 246 +- 164 pg/ml to 196 + 124 pg/ml at 1 hour and 130 f 96 pg/ml at 24 hours, whereas noradrenalin remained elevated throughout the 24 hours (Fig. 4). In the metoprolol-treated group adrenaline levels increased from 160 f 136 pg/ml at baseline to 193 + 201 pg/ml at 1 hour and 212 +- 387 pg/ml at 24 hours. Noradrenalin levels also increased in the metoprolol-treated group from 586 & 245 pg/ml at baseline to 757 f 333 pg/ml at 1 hour and 767 f 739 pg/ml at 24 hours. Thus, at both 1 and 24 hours after initiation of treatment, both plasma adrenaline and noradrenalin levels increased in the metoprololtreated compared to the placebo-treated patients. These increases were statistically significant (p < 0.05). DlSCUSSlON
Previous investigators have demonstrated a relationship between plasma catecholamine levels and
indices of left ventricular damage in acute myocardial infarction. Videbaek et a1.6 demonstrated a relationship between plasma catecholamine concentrations and clinical status, whereas Nadeau and de Champlain”7 noted a correlation between peak catecholamine levels and peak enzyme release in 26 patients observed for 48 hours after onset of symptoms of acute myocardial infarction. This is the first study in which catecholamine concentrations have been related to central hemodynamics in acute myocardial infarction. A high pulmonary capillary wedge pressure and low stroke volume index are important markers of impaired left ventricular function in acute myocardial infarction.1gr20 It is to be expected, therefore, that there should be a direct relationship between pulmonary capillary wedge pressure and an inverse relationship between stroke volume index and plasma adrenaline and noradrenalin concentrations at baseline. Plasma catecholamine levels are also elevated in chronic heart failure and have been correlated with hemodynamic indices of left ventricular dysfunction. Thomas and MarkszO demonstrated a direct relationship between the plasma noradrenalin concentration and the degree of left ventricular dysfunction as assessed by systolic time intervals, whereas Francis et al.” observed a linear relationship between the plasma noradrenalin concentration and pulmonary wedge pressure and an inverse relationship between the plasma noradrenalin concentration and stroke volume index. In a stiJdy of 106 patients, Cohn et a1.22found the plasma noradrenalin concentration to be a better indication of prognosis in chronic heart failure than hemodynamic in-
42
Murray
et al.
X
A NADR
1
1 h.
Oh. PLACEBO
-
24 h.
MEfOPRoLOL
- - -
- -
x - P < 0.05
Fig. 4. Changesin plasmaadrenaline (ADR) and noradrenalin (NADR) from 0 to 24 hours. Significance values represent differences in changesfrom baselinevalues, comparing metoprolol with placebo.
dices of myocardial dysfunction. Our patient population was too small to examine whether plasma catecholamine levels are of prognostic significance in acute myocardial infarction. However, the relationship observed between hemodynamics and catecholamine concentrations suggest that this may be the case. High plasma adrenaline or noradrenalin levels were found in all but one of our patients studied within 6 hours (range 4 to 12) of onset of symptoms of acute myocardial infarction. A further increase in both plasma adrenaline and noradrenalin concentrations was found after intravenous administration of 15 mg of the selective beta-l antagonist, metopro101,followed by 50 mg orally, compared to a placebo-
treated group. These differences were still apparent at 24 hours. Adrenaline levels gradually decreased in the placebo-treated group, whereas noradrenalin levels remained elevated over the 24-hour study period. There are a number of theoretic grounds for the use of beta blockade in the setting of acute myocardial infarction. High catecholamine levels increase myocardial contractility and myocardial oxygen consumption. Beta-adrenergic blockers are thought to exert an antiischemic effect by reducing myocardial contractility. In addition, high catecholamine levels can induce hypokalemia, which is known to be arrhythmogenic.24 Both propanolol and atenolol have been shown to abolish the decrease in potassi-
Volume Number
115 1, Part 1
urn that results from adrenaline infusion15 and occurs in acute myocardial infarction.24,26 However, the effects of beta blockade on plasma catecholamine levels are controversial. A number of studies have demonstrated an increase in the noradrenalin level in response to propranolol in a variety of clinical situations, particularly after acute administration. Irving et al.l” and Hansen et al.ll demonstrated an increase in noradrenalin levels in beta-blocked patients with ischemic heart disease both at rest and during exercise, whereas Christensen2 demonstrated high catecholamine levels in hypertensive patients receiving propranolol compared to a control group. A similar increase in adrenaline and noradrenalin levels in dogs with coronary artery occlusion was demonstrated by McGrath et al. after intravenous metoprolol. In contrast, Mueller et a1.14demonstrated a decrease in both adrenaline and noradrenaline levels after intravenous administration of propranolol to patients with a mean delay of 10 hours from onset of symptoms of acute myocardial infarction. They suggested that the decrease in catecholamine levels in response to propranolol might be related to blockade of the central beta receptors, the beta-adrenergic receptors. It is possible, therefore, that different central effects of propranolol and metoprolol might explain the difference in results between the study of Mueller et a1.14and ours. Alternatively, the differences might be methodologic: our catecholamine results were consistent when measured in two separate laboratories by two well-recognized and reproducible techniques with a high degree of specificity and sensitivity. In contrast, Mueller et a1.14 used a nonfluorometric method that is less reliable. We have previously described an increase in systemic vascular resistance in a larger population of patients with acute myocardial infarction treated with metoprolol.25 The relationship observed in the present study between the changes in plasma catecholamine levels and changes in systemic vascular resistance during the first hour after drug administration provides evidence that the hemodynamic response was the result of the effects of the unopposed action of catecholamines on the alpha receptors in the arterioles. This may have reflected a reflex increase in sympathetic tone after a metoprolol-induced decrease in arterial pressure and cardiac output; alternatively, a drug-induced decrease in systemic clearance of catecholamines from the circulation could have been responsible.27 The increased catecholamine levels and increased systemic vascular resistance would be expected to increase myocardial oxygen consumption and thus counteract the
Plasma
catecholamines
in AM
43
oxygen-sparing effects that were suggested by the decrease in heart rate and stroke work index. The possible disadvantages of increased systemic vascular resistance on myocardial oxygen consumption may explain, in part, the limited impact of acutephase beta blockade on myocardial infarct size in the recently reported multicenter studies.15,27 Conclusions. We have studied the effects of acute myocardial infarction on circulating catecholamine concentrations and the influence of the selective beta-1-adrenergic blocker, metoprolol, on these levels. We found elevated levels of both adrenaline and noradrenalin in all but one patient. The high catecholamine levels were related to impaired left ventricular function as indicated by high pulmonary capillary wedge pressure and low stroke volume index. The increase in catecholamine levels in response to metoprolol was associated with an increase in systemic vascular resistance. The resulting increase in myocardial oxygen consumption may have counteracted some of the other beneficial hemodynamic effects of beta blockade and thus explain the rather limited effect of beta blockade in limiting myocardial infarct size in humans.
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1. Levi L. Neuroendocrinology in anxiety. Br J Psycho1 1969; 3:40-6. 2. Raab W. The pathogenic significance of adrenaline and related substances in the heart muscle. Exp Med Surg 1943; 1:188-225. 3. Gazes PC, Richardson JA, Woods EF. Plasma catecholamine concentrations in myocardial infarction and angina pectoris. Circulation 1959;19:657-61. 4. Valori C, Thomas M, Shillingford J. Free noradrenalin and adrenaline excretion in relation to clinical syndromes following myocardial infarction. Am J Cardiol 1967;20:605-10. 5. Havashi KD. Moss AV. Yu PN. Urinarv catecholamine excretion in acute myocardial infarction. Circulation 1969; 40:473-81. 6. Videbaek JN, Christensen NJ, Sterndorff B. Serial determination of plasma catecholamines in myocardial infarction. Circulation 1972;46:846-55. 7. Siggers DC, Salter C, Fluck DC. Serial plasma adrenaline and noradrenalin levels in myocardial infarction using a new double isotope technique. Br Heart J 1971;33:878-83. 8. McDonnald L, Baker C, Bray C, et al. Plasma catecholamines after myocardial infarction. Lancet 1969;2:1021-4. 9. Jewitt DE, Mercer CJ, Reid D. Free noradrenalin and adrenaline excretion in relation to the development of arrhythmias and heart failure in patients with acute myocardial infarction. Lancet 1969;1:635-41. 10. Irving MH, Britton BJ, Wood WG. Effects of beta adrenergic blockade on plasma catecholamines in exercise. Nature 1974; 248:531-3. 11. Hansen JF, Hesse B, Christensen NJ. Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease. Eur J Clin Invest 1978;8:31-6. 12. Christensen NJ. Plasma catecholamines and arterial hypertension. Acta Med Stand 1976;602 (suppl):57. 13. McGrath BP, Lim SP, Leversha A. Myocardial and peripheral catecholamine response to acute coronary artery constric-
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tion before and after propranoIo1 treatment in the anesthetized dog. Cardiovasc Res 1983;15:28-34. Mueller HS, Rao PS, Fletcher J. Propranalol during the evolution and subsequent 10 days of myocardial infarction in man: hemodynamic, initial cardiac energetic and neurohormonal responses. Clin Cardiol 1979;2:393-9. The Miami Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebocontrolled international trial. Eur Heart J 1985;6:199-226. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 1977;21:625-36. Nadeau RA, de Champlain J. Plasma catecholamines in acute myocardial infarction. AM HEART J 1979;98:548-54. Verdouw PD, Hagemeijer F, van Dorp WG, van der Vorm A, Hugenholtz P. Short-term survival after acute myocardial infarction predicted by hemodynamic parameters. Circulation 1975;52:413-19. Forrester JS, Diamond GA, Swan HJC. Correlative classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977;39:137-45.
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Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233-43. Francis GA, Goldsmith SR, Cohn JN. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. AM HEART J 1982;104:725-31. Cohn JA, Levine BT, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23. Struthers AD, Whitesmith R, Reid JL. Metabolic and haemodynamic effects of increased circulating adrenaline in man. Br Heart J 1983;50:277-81. Nordrehaug JE, Johannsen ISA, Lippe G, et al. Effect of timolol on changes in serum potassium concentration during acute myocardial infarction. Br Heart J 1985;53:388-93. Murray DP, Murray RG, Rafiqi E, Littler WA. Early beta blockade in acute myocardial infarction. Eur Heart J 1985;6 (suppl 1):124. ISIS-1 Collaborative Study Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-l. Lancet 1986;2:57-66.
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