Plasma catecholamines in acute myocardial infarction

Clinical

communications

Plasma catecholamines infarction

in acute

myocardial

Reginald A. Nadeau, M.D., F.R.C.P.(C)’ Jacques de Champlain, M.D., Ph.D.** Montreal,

Quebec, Canada

Reports of plasma catecholamine measurements in acute myocardial infraction have been relatively few. Early studies’-” were carried out with a limited number of samples. More recently, Videbaeck and associates7measured total catecholamines at 2-hour intervals, the first sample being obtained within 12 hours of the onset of myocardial infarction. A consistant elevation of catecholamines was found and values remained stable over a 48-hour study period. Strange and coworkers’ measured total catecholamines within 1 to 10 hours of onset of acute chest pain and found a stable elevation over a 40-hour period. Vetter and colleagues” reported catecholamine elevation within 1 hour of acute chest pain onset and measurements at hourly intervals for 5 hours showed no pattern of change. The recent development of an accurate and sensitive method,“’ requiring small volumes of blood, has permitted sufficient serial sampling to describe with greater precision the changes in circulating catecholamine levels occurring within the first 48 hours after the onset of acute chest pain. This study was carried out in patients admitted to the coronary care unit with acute chest pain within the preceeding 24 hours and in whom a definite diagnosis of acute myocardial infarction was established. Materials

and

methods

Twenty-three men and three women with an average age of 57 + 2 years (ranging from 41 to 78 From the Service de Cardiologie, Hdpital du Sacr&Coeur, Quebec, and the Department of Physiology, Faeult6 Universit6 de Montreal, Montreal, Quebec, Canada. Received

for publication

Feb.

16, 1979.

Accepted

for publication

July

31, 1979.

Reprint HApital Canada. *Associate, “*J.

548

de

Montreal, MQdecine,

requests: Reginald A. Nadeau, M.D., Service de Cardiologie. du Saw&Coeur, 5400 ouest, Boul. Gouin, Montreal, Quebec, Medical

C. Edwards

Research Professor

November,

Council of Cardiovascular

of Canada. Research.

1979, Vol. 98, No. 5

TIME

0

! , 1

I 6

OF ENTRY

I 12

I 18

I 24

HOURS Fig.

1.

according

Cumulative curve of entry of patients into the study to the time lapse since onset of acute chest pain.

years) were studied. There were eight cases of anterior or anterolateral infarction and 18 cases of inferior or posteroinferior infarction. Zero time was determined by the onset of acute prolonged chest pain (Fig. 1) and not by the appearance of ECG changes or the elevation of serum enzymes. Except for two patients, whose onset was actually witnessed during monitoring, this timing is necessarily subjective and may have a large factor of error. The first blood sample from an antecubital vein was drawn upon admission to the coronary care unit. Total CPK activity was measured on blood drawn for the catecholamine determinations. Blood pressure and heart rate values were recorded at the time of each blood sampling. The ECG was monitored continuously on magnetic tape for the first 16 hours after admission and intermittently thereafter at hourly intervals. SGOT levels were determined upon admission and twice more within the following 48 hours. Patients initially received oral diazepam for sedation and demerol intramuscularly for pain. IntraOW-8703/79/110548

+ 07$00.70/O

~1 1979

The

C. V.

MO&y

co.

Plasma

catecholamines

in acute MI

CATECHOLAMINES

0

1

I

1

I

I

I

1

1

4

8

12

16

20

24

I

32

I

I

40

48

hours

2. Mean

Fig.

levels

&SE.

of plasma

catecholamines

in 26 patients

related

to time

of onset

of acute

chest

pain.

venous lidocaine was administered when ventricular arrhythmias were detected. Patients treated only with intravenous lidoCaine, oral diazepam, or demerol administered intramuscularly were included. Patients receiving other medication were not part of this study. Patients with clinical manifestations of heart failure or cardiogenic shock were excluded. No dietary control was carried out. Acute myocardial infarction was subsequently proven in all patients both electrocardiographically and by elevated CPK and SGOT elevation 100% or more above control values. Serum catecholamine levels were determined using the radiometric enzymatic microtechnique of Coyle and Henry” as modified by de Champlain and associates” for serum determinations. Blood samples collected without anticoagulant at 0” C. were centrifuged without delay, and determinations were carried out in duplicate on the serum. Normal values for plasma catecholamines obtained in 15 normotensive subjects averaged 0.218 ng./ml. These values were reported elsewhere’” and it was pointed out that age or sex did not appear to change catecholamine values. Results

catecholamine

values. Mean plasma values were related to time of

American

Journal

Mean

catecholamine

Heart

onset of acute chest pain which preceded admission. As shown in Fig. 2, circulating catecholamine levels remained elevated during the first day but these levels gradually decreased during the second 24 hours. Enzyme levels. The corresponding values for serum CPK are given in Fig. 3. The rise in enzyme levels occurred later than that for catecholamines and reached a plateau after 16 hours. Because maximum catecholamine and CPK values did not occur simultaneously in individual patients, there was no correlation between catecholamines and CPK values from the same blood sample. The relationships, however, between peak CPK, as well as peak SGOT values and peak catecholamine levels, were significant. This is shown in Fig. 4. Heart rate and blood pressure. Average heart rate and blood pressure values were initially elevated and gradually declined thereafter. A significant correlation between heart rate and circulating catecholamine levels could be found, as shown in Fig. 5. The correlation between diastolic and systolic blood pressures and catecholamine levels was not significant. Blood pressure levels and catecholamine values were found to be significantly higher when patients presented a heart rate above 100 (Fig. 6). Patients with sinus bradycardia (HR < 60/minute) tended to have 549

Nadeau and de Champlain CPK

b/ml

0

I 4

I 8

3. Mean

levels

, 1

I 12

I 16

I 20

I 24

I 32

1 40

1 48

hours Fig.

lower catecholamine sure values.

*SE.

of plasma

levels and lower

CPK

in 26 patients

blood pres-

Site of infarction. Results obtained according to site of infarction are compared in Table I. During the first 24-hour period, average catecholamine values were lower, but not significantly so, in casesof inferior or posterior infarction. During the second 24-hour period, average catecholamine levels remained elevated in anterior and/or lateral infarction cases but decreased significantly (p < 0.001) in patients with inferior and/or posterior necrosis. Average CPK levels, as well as systolic and diastolic blood pressure values, were not significantly different between bot.h groups of patients. Heart rate values were consistently and significantly lower (p < 0.01) however, in inferior-posterior infarction for both 24-hour periods. Ventricular arrhythmias. The relative incidence of ventricular premature beats and of ventricular tachycardia is illustrated in Fig. 7. Fifty-five per cent of patients observed within 1 hour of onset of acute chest pain presented ventricular ectopic beats (> 60/hour) and/or short bouts of ventricular tachycardia (three consecutive ventricular premature contractions). Sixty per cent of the patients observed within the first 6 hours after the onset of acute chest pain presented ventricular ectopic activity, with a frequency of more than one ectopic beat/minute. The per cent of patients with this frequency of

550

related

to time

of onset

of acute

chest

pain.

premature beats declined thereafter. Runs of ventricular tachycardia were not observed in patients observed more than 12 hours after onset of chest pain. No other major arrhythmias were recorded. Catecholamine levels were found to be significantly higher when determined while patients were presenting ectopic ventricular activity. This was true both during the first and the second 24-hour periods after onset of acute infarct (Fig. 8). No difference was observed as to site of infarction. Discussion

The present observations confirm the early increase in sympathetic tone following acute myocardial infarction. Previous studies on circulating catecholamine levels used less sensitive techniques and therefore the number of determinations were limited. Videbaeck and associates,’ with serial measurements every 2 hours, reported higher but stable catecholamine values over the first 48 hours. Griffiths and Leung,’ however, observed a gradual fall in catecholamine values within the first 24 hours. Our own results confirm, as well as the more recent observations of Vetter and colleagues,” that circulating catecholamines are elevated very early after chest pain and remain initially at quite high levels without appreciable fluctuation. The initial sympathetic responsemay be part of the general body response

Plusma

catecholamines

CATECHOLAMINES

I.U./ml.

VS

HEART

in acute MI

RATE ( 48 hours)

bts/min

500 -

175

400 -

is

300 -

if

200 -

F5

l

150

.

r=0.52 1

n=26

p
loo-

-..

*

50-

*I

*. I

,

,

1460

E 0

1060

g

r=.424 n=137

r=0.49 660

p
n=26 pso.05

260

Y

0.5

10

20

ng/m1

.30

9

max CATECHOLAMINES Fig. 4. Relation between peak catecholamine levels and peak SGOT levels and peak CPK levels in 23 patients during 48 hours following onset of acute chest pain.

to pain, anxiety, and distress. Catecholamine liberation has been shown to occur from the ischemic myocardium.” This may be a result of the effect of hypoxia on nerve endings, compounded by lactate accumulation and a lowered pH. Reflex sympathetic activation from the ischemic myocardium is also a distinct possibility. Staszewska-Barczak’,’ demonstrated a reflex outpouring of catecholamines from the adrenal medulla in the early stages of myocardial infarction. Relation

to

blood

pressure

and

heart

rate.

Sinus tachycardia and elevated blood pressure are regarded as good indicators of sympathetic overactivity. The importance of autonomic disturbances at the initial period of acute infarction in determining early mortality has been stressed.’ I Fox and co-workers’; studied the prognostic significance of an initially high syst,olic blood pressure in acute myocardial infarction. Mortality rate, the incidence of major arrhythmias, and the incidence of heart failure were all greater in patients with initial systolic hypertension. These patients also had higher SGOT levels suggesting more extensive infarction. A poorer prognosis has also been associated with initial sinus tachycardia.“’ In our study, patients with sinus tachycardia had significantly

American

Heart

~Journul

.60

.90

1.20

1.50

CATECHOLAMINES

3.0

Fig. 5. Heart rate at time in relation to catecholamine acute chest pain.

1.80

2.10

2.40

2.70

3.0

(rig/ml)

of plasma catecholamine sampling levels determined after onset of

higher catecholamine levels. Sinus tachycardia is usually related to incipient heart failure, and reflects the increased sympathetic drive in response to falling cardiac output or to atria1 distension. Patients with clinical or radiological evidence of left heart failure were deliberately excluded from our series. Relation to serum enzyme levels. Previous studies’;. IX carried out with measurements of urinary catecholamines suggested a relationship between catecholamine excretion and elevation of LDH, SGOT levels, and of white blood cell count, considered indicators of the extent of myocardial damage. The correlation reported here between peak catecholamine levels and peak CPK and SGOT values suggest some relation between these variables. Catecholamines may themselves affect enzyme liberation from the heart.“’ Although the amount of enzyme liberated may reflect the extent of structural damage induced by ischemia, both catecholamine and anoxia accelerate substrate utilization and therefore may act synergistically to alter cellular function. Relation to infarct size. The lower levels observed in inferior-posterior infarction patients may indicate a lessmarked sympathetic response. Parasympathetic effects predominate in this type of infarction. This is corroborated by the slower

551

Nadeau

and

de Champlain

HEART C

RATE

boa

bO-

1000 >100-

l.OO0 I 5

.bO-

d 3 I+

.bO-

3

CATECHOLAMINES Fig. 6. Catecholamine levels, rates below 60 beats/minute, **p < 0.01.

Table

SYSTOLIC BLOOD PRESSURE

DIASTOLIC BLOOD PRESSURE

mean systolic blood pressure, and mean diastolic pressure in patients between 60 and 100 beats/minute, and above 100 beats/minute.

with heart *p < 0.05;

I Mean catecholamines

Anterior

and lateral

Inferior

and posterior

infarctions infarctions

First 24-hours Second 24-hours First 24-hours Second 24-hours

1.73 1.81 1.05 0.45

-c -c 2 +

.49 .19 .lO .07***

Mean heart rate 108 122 76 72

f f i f

Mean systolic BP 8 6 3** 8**

1391 125 2 121 f 114 k

Mean diastolic BP 6 3 6 4

86 82 77.3 73.3

Mean CPK

k” t5 t 2 * 3

403 635 635 436

I f -c t

120 148 97 72

**p < 0.01. ***p < 0.001

heart rates observed. The relation between catecholamine levels and infarct site may also reflect a lesser degree of left ventricular dysfunction in posteroinferior infarcts. A recent study suggested that site of infarction is important in determining outcome of sudden death,“’ and that beta-blocking agents reduce mortality in anterior or anterolateral infarction significantly, probably by prevention of lifethreatening arrhythmias. It is intriguing to speculate whether the higher catecholamine values observed in anterior infarction during both first and second 24-hour periods can be related to the beneficial effect of beta-adrenergic blockage reported in the Multicenter Study. Relation to ventricular arrhythmias. The increased adrenergic response in myocardiai infarction has always been suspected of contributing to the occurrence of the arrhythmias of the

552

early phase.” Because exogenous catecholamines can, experimentally, cause ventricular extrasystoles or tachycardia after coronary occlusion,” they are easily incriminated and invoked as causes of rhythm disturbances. An increased incidence of arrhythmias has usually been observed in patients with greater urinary catecholamine excretion rates? ?’ or with higher plasma catecholamine concentrations. McDonald and coworkers’ found plasma catecholamine levels to be higher in patients with atria1 dysrythmias and early ventricular dysrhythmias. Siggers and colleagues5 found a relationship between plasma adrenaline levels and ventricular arrhythmias. Experimentally, Richardson and associates” were unable to establish a correlation between plasma catecholamine concentrations and the incidence and severity of ventricular arrhythmias in dogs after coronary artery ligation. However,

November,

1979,

Vol.

98. No.

5

Plasma

catecholamines

in acute MI

VENTRICULAR ARRHYTHMIAS

1

Fig.

7.

various

6

12

18

Heart

36

Relative incidence of premature ventricular contractions time intervals after onset of acute chest pain.

Staszewska-Barczak,‘,l using a bioassay technique, related the appearance of arrhythmias to the secretion of adrenaline into the adrenal vein. The present method of catecholamine determination did not allow the separate estimation of noradrenaline and adrenaline levels. Considerable evidence points to the importance of high circulating adrenaline in acute myocardial infarction. The effects of adrenal secretion may be quite different either on metabolic effects, blood pressure, heart rate, or the occurrence of arrhythmias. The arrhythmias observed in most patients with acute myocardial infarction are more frequent in the more severely ill patients. Hypoxemia, acidosis, and the myocardial distension which accompanies heart failure are arrhythmogenie per se and are accompanied by adrenergic stimulation. Arrhythmias themselves can possibly provoke catecholamine secretion by reducing cardiac output. The relative low incidence of ventricular ectopic activity in our series probably reflects the selection of a population of patients without obvious complications. The catecholamine values measured coincidentally while the patients presented arrhythmias were higher than when no arrhythmias were present. It is not possible to establish, however, at this point a causal relationship between the degree of catecholamine elevation and the occurrence of ventricular arrhythmia. While the present manuscript was being prepared for submission for publication, Strange and co-workers’; published a study quite similar in design to our own. In contrast to our observation, they were unable to find any relation between increased catecholam-

American

24

Journal

48

(PVC) and of ventricular

VENTRICULAR

hours

tachycardia

ARRHYTHMIAS 0 m

w/ml

2.0

1

FIRST 24HOURS

(n44)

SECOND

(n=52)

(VT) at

(n=13)

Without PVC With PVC 24 HOURS

(n=6)

8. Catecholamine levels when premature beats, or ventricular tachycardia, were present at time of sampling during either the first or the second 24-hour period after onset of acute chest pain. *p < 0.05; “*p < 0.01.

Fig.

ine concentrations and the incidence of ventricular arrhythmias. Summary

Plasma catecholamine levels were determined in 26 cases of uncomplicated myocardial infarction within 24 hours of onset of acute chest pain. Blood samples were collected at time of entry and at 4-hour intervals during the 48 hours following admission. Average values of plasma catecholamines within 1 hour of onset of pain were 0.87 ng./ml. * 0.21 and remained elevated during the first 24 hours period. A gradual fall in catecholamine values was observed during the second 24-hour period. Catecholamines were higher in patients with sinus tachycardia and lower in patients with sinus bradycardia, and were higher

553

Nadeau

and

de Champlain

in patients with anterior or anterolateral infarction. Catecholamine values were significantly higher when determined while patients presented ventricular ectopic beats or ventricular tachycardia. Sinus tachycardia, ventricular arrhythmias, and elevated plasma catecholamine values may be considered indicators of pain, anxiety, and/or left ventricular dysfunction without necessarily being causally related between themselves. Our thanks to Ms. L. Bouchard and Ms. L. Farley for their technical assistance and to Ms. G. Dub& and the coronary care unit nursing staff for their cooperation.

13.

14.

15.

16.

17.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11. 12.

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Gazes, P. C., Richardson, J. A., and Woods, E. F.: Plasma catecholamine concentrations in myocardial infarction and angina pectoris, Circulation 19:657, 1959. McDonald, L., Baker, C., Bray, C., McDonald, A., and Restieaux, N.: Plasma catecholamines after cardiac infarction, Lancet 2:1021, 1969. Januszewicz, W., Sznajderman, M., Ciswicka-Sznajderman, M., Wocial, B., and Rymaszewski, Z.: Plasma free fatty acid and catecholamine levels in patients with acute myocardial infarction, Br. Heart J. 33:716, 1971. Griffiths. J., and Leung, F.: The sequential estimation of plasma catecholamines and whole blood histamine in myocardial infarction, AM. HEART J. 82:171, 1971. Siggers, D. C., Salter, C., and Fluck, D. C.: Serial plasma adrenaline and noradrenaline levels in myocardial infarction using a new double isotope technique, Br. Heart J. 33:878, 1971. Lukomsky, P. E., and Oganov, R. G.: Blood plasma catecholamines and their urinary excretion in patients with acute myocardial infarction, AM. HEART .J. 83:182, 1972. Videbaeck, J., Christensen, N. J., and Sterndorff, B.: Serial determination of plasma catecholamines in myocardial infarction, Circulation 46:846, 1972. Strange. R. C.. Vetter. N.. Rowe, M. J.. and Oliver, M. F.: Plasma ‘cyclic AMP ‘a&l catecholamines during acute myocardial infarction in man, Eur. J. Clin. Invest. 4:115, 1974. Vetter, N. J., Strange, R. C., Adams, W., and Oliver, M. F.: Initial metabolic and hormonal response to acute myocardial infarction, Lancet 1:284, 1974. de Champlain, J., Farley, L., Cousineau, D., and van Ameringen, M. R.: Circulating catecholamine levels in human and experimental hypertension, Circ. Res. 38: 109, 1976. Coyle, J. T., and Henry, D.: Catecholamines in fetal and newborn rat brains, J. Neurochem. 21:61, 1973. Shahab, L., Wollenberger, A., Haase, M., and Schiller,

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U.: Noradrenalinabgabe aus dem Hundeherzen nach voriibergehender Okklusion einer Koronararterie, Acta Biol. Med. Germ. 22:135, 1969. Staszewska-Barczak, J.: The reflex stimulation of catecholamine secretion during the acute stage of myocardial infarction in the dog, Clin. Sci. 41:419, 1971. Webb, S. W., Adgey, A. A. J., and Pantridge. J. F.: Autonomic disturbance at onset of acute myocardial infarction, Br. Med. J. 3:89. 1972. Fox, K. M., Tomlinson, I. W., Portal, R. W.. and Aber. C. P.: Prognostic significance of acute systolic hypertension after myocardial infarction, Br. Med. J. 3:128, 1975. Norris, R. M.. Mercer. C. J.. and Yeates. S. E.: Sinus rate in acute myocardial’ infarction, Br. Heart .J. 34:901, 1972. Valori, C., Thomas, M., and Shillingford, J.: Free noradrenaline and adrenaline excretion in relation to clinical syndromes following myocardial infarction, Am. J. Cardiol. 20:605, 1967. Jequier, E., and Perret, C.: Urinary excretion of catecholamines and their main metabolites after myocardial infarction: relationship to the clinical syndrome, Eur. J. Clin. Invest. 1:77, 1970. Herbaczynska-Cedro, K.: The influence of adrenaline secretion on the enzymes in heart muscle after acute coronary occlusion in dogs, Cardiovasc. Res. 4:168, 1970. Multicenter International Study: Improvement in prognosis of myocardial infarction by long term beta-adrenoreceptor blockage using Practolol, Br. Med. J. 2:735, 1975. Harris, A. S., and Bisteni, A.: Effects of sympathetic blockade drugs on ventricular tachycardia resulting from myocardial infarction, Am. J. Physiol. 181:559, 1955. Richardson, J. A., Woods, E. F., and Bagwell, E. E.: Circulating epinephrine and norepinephrine in coronary occlusion, Am. J. Cardiol. 6:613, 1960. Jewitt, D. E., Mercer, C. J., Reid, D., Valori, C., Thomas, M.. and Shillingford, J. P.: 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. Rbmillard, G., Leduc, J., and Nadeau, R.: Excretion urinaire des cat&holamines au tours de la phase aigu de l’infarctus du myocarde, Union Med. Can. 99:1801, 1970. Wallace, A. G., and Klein, R. F.: Role of catecholamines in acute myocardial infarction, Am. J. Med. Sci. 268:139, 1969. Opie, L. H.: Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction, Am. J. Cardiol. 36:938, 1975. Strange. R. C.. Rowe. M. J.. and Oliver. M. F.: Lack of relation between venous plasma total catecholamine concentrations and ventricular arrhythmias after acute myocardial infarction, Br. Med. J. 2:921, 1978.

Nwemher.

1979, Vol. 98, No. 5