Br Heart J 1988;60:1 17-24 Neuroendocrine activation after acute myocardial infarction H M McALPINE,* JJ MORTON,t BRENDA LECKIE,I A RUMLEY4, G GILLEN,* H J DARGIE* From the Departments of *Cardiology, tBiochemistry, and tMedical Research Council Blood Pressure Unit, Western Infirmary, Glasgow SUMMARY The extent of neuroendocrine activation, its time course, and relation to left ventricular dysfunction and arrhythmias were investigated in 78 consecutive patients with suspected acute myocardial infarction. High concentrations of arginine vasopressin were found within six hours of symptoms, even in the absence of myocardial infarction (n = 18). Plasma catecholamine concentrations also were highest on admission, whereas renin and angiotensin II concentrations rose progressively over the first three days, not only in those with heart failure but also in patients with no clinical complications. Heart failure, ventricular tachycardia, and deaths were associated with extensive myocardial infarction, low left ventricular ejection fraction, and persistently high concentrations of catecholamines, renin, and angiotensin II up to 10 days after admission, whereas in uncomplicated cases concentrations had already returned to normal. The clinical presentation of acute myocardial infarc- tion varies widely. Some patients have only mild constitutional upset, while others suffer intense vasoconstriction, arrhythmias, heart failure, or shock. In common with other major acute illnesses, myocardial infarction is accompanied by many metabQlic and hormonal changes which may be related to the severity of illness and clinical outcome.' Although stimulation of neuroendocrine systems may be an appropriate response to acute myocardial injury, those hormones that promote vasoconstric- tion or tachycardia might also be harmful. Of the vasoconstrictor mechanisms, catecholamine release has been the most extensively studied. Numerous reports have confirmned the initial observations in 1952 by Forssman2 of raised concen- trations of urinary'5 and plasma'4 catecholamines after myocardial infarction. High concentrations of catecholamines are frequently associated with the presence of heart failure, shock, or ventricular arr- hythmias,'78 and the potential for reducing infarct size and arrhythmias by interference with the cate- cholamine response by fi blockers has attracted much interest.'" Requests for reprints to Dr H M McAlpine, Department of Cardiology, Western Infirmary, Dumbarton Road, Glasgow GIl 6NT. Accepted for publication 15 February 1988 Other vasoconstrictor hormones also may be important after myocardial infarction, and compared with catecholamines little is known of the role of the renin-angiotensin system. Preliminary observations indicate that concentrations of plasma renin are raised in some patients after myocardial infarction, particularly in association with heart failure, shock, or ventricular fibrillation.l"" Furthermore, inhibi- tion of angiotensin II formation in those with heart failure may confer haemodynamic benefit.' 16 Nausea, vomiting, and administration of mor- phine'7"8 may stimulate release of another potent vasoconstrictor, arginine vasopressin, but little is known about the activation of arginine vasopressin in this clinical setting. The vasoconstrictor effects of these neuroendocrine systems on the coronary and peripheral circulations may be mutually facilitatory,"4' and they may have the potential to decrease myocardial and peripheral perfusion as well as lowering cardiac output. We studied the extent and time course of the stimulation of the release of renin, angiotensin II, catecholamines, and arginine vasopressin in a large consecutive series of patients admitted to the coron- ary care unit with suspected myocardial infarction. Patients and methods We studied 78 consecutive patients with suspected 117 on January 13, 2021 by guest. Protected by copyright. http://heart.bmj.com/ Br Heart J: first published as 10.1136/hrt.60.2.117 on 1 August 1988. Downloaded from
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Br Heart J 1988;60:1 17-24
Neuroendocrine activation after acute myocardialinfarctionH M McALPINE,* J J MORTON,t BRENDA LECKIE,I A RUMLEY4, G GILLEN,*H J DARGIE*
From the Departments of *Cardiology, tBiochemistry, and tMedical Research Council Blood Pressure Unit,Western Infirmary, Glasgow
SUMMARY The extent ofneuroendocrine activation, its time course, and relation to left ventriculardysfunction and arrhythmias were investigated in 78 consecutive patients with suspected acutemyocardial infarction. High concentrations ofarginine vasopressin were found within six hours ofsymptoms, even in the absence of myocardial infarction (n = 18). Plasma catecholamineconcentrations also were highest on admission, whereas renin and angiotensin II concentrationsrose progressively over the first three days, not only in those with heart failure but also in patientswith no clinical complications. Heart failure, ventricular tachycardia, and deaths were associatedwith extensive myocardial infarction, low left ventricular ejection fraction, and persistently highconcentrations ofcatecholamines, renin, and angiotensin II up to 10 days after admission, whereasin uncomplicated cases concentrations had already returned to normal.
The clinical presentation of acute myocardial infarc-tion varies widely. Some patients have only mildconstitutional upset, while others suffer intensevasoconstriction, arrhythmias, heart failure, orshock. In common with other major acute illnesses,myocardial infarction is accompanied by manymetabQlic and hormonal changes which may berelated to the severity ofillness and clinical outcome.'Although stimulation of neuroendocrine systemsmay be an appropriate response to acute myocardialinjury, those hormones that promote vasoconstric-tion or tachycardia might also be harmful.Ofthe vasoconstrictor mechanisms, catecholamine
release has been the most extensively studied.Numerous reports have confirmned the initialobservations in 1952 by Forssman2 of raised concen-trations of urinary'5 and plasma'4 catecholaminesafter myocardial infarction. High concentrations ofcatecholamines are frequently associated with thepresence of heart failure, shock, or ventricular arr-hythmias,'78 and the potential for reducing infarctsize and arrhythmias by interference with the cate-cholamine response by fi blockers has attracted muchinterest.'"
Requests for reprints to Dr H M McAlpine, Department ofCardiology, Western Infirmary, Dumbarton Road, GlasgowGIl 6NT.Accepted for publication 15 February 1988
Other vasoconstrictor hormones also may beimportant after myocardial infarction, and comparedwith catecholamines little is known of the role of therenin-angiotensin system. Preliminary observationsindicate that concentrations of plasma renin areraised in some patients after myocardial infarction,particularly in association with heart failure, shock,or ventricular fibrillation.l"" Furthermore, inhibi-tion of angiotensin II formation in those with heartfailure may confer haemodynamic benefit.' 16
Nausea, vomiting, and administration of mor-phine'7"8 may stimulate release of another potentvasoconstrictor, arginine vasopressin, but little isknown about the activation of arginine vasopressinin this clinical setting. The vasoconstrictor effectsof these neuroendocrine systems on the coronaryand peripheral circulations may be mutuallyfacilitatory,"4' and they may have the potential todecrease myocardial and peripheral perfusion as wellas lowering cardiac output.We studied the extent and time course of the
stimulation of the release of renin, angiotensin II,catecholamines, and arginine vasopressin in a largeconsecutive series of patients admitted to the coron-ary care unit with suspected myocardial infarction.
Patients and methods
We studied 78 consecutive patients with suspected117
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acute myocardial infarction admitted to our coronary
care unit within six hours of the onset of symptoms.We excluded those patients with a previous history ofcardiac failure and those who were maintained on
long term diuretic treatment, because neuroen-
docrine activation may have been present before theonset of acute myocardial infarction. We alsoexcluded those with atrial fibrillation or frequentextrasystoles on admission because they wereunsuitable for radionuclide ventriculography.
All patients included for study had a gated tech-netium-99m radionuclide scan performed on admis-sion to measure the left ventricular ejection fraction(normal >45%), and venous blood samples were
taken to measure the concentrations of plasma activerenin (normal range 10-50 yU/ml), angiotensin II(normal range 3-12 pmol/l), arginine vasopressin
(normal range 0-3-0-7 pg/ml), adrenaline (normalrange undetectable - 0-2 nmol/1), and noradrenaline(normal range 0-2-3-0 nmol/l). Plasma was separatedwithin 15 minutes and frozen for assay later. Toavoid the discomfort of repeated venepuncture we
inserted an indwelling venous cannula. Venous bloodsampling was repeated during bed rest on days 1, 2,and 3 after admission, and again after 30 minutes'supine rest on day 10. The diagnosis of acutemyocardial infarction was based on standard elec-trocardiographic features on the serial electrocar-diograms and on a significant rise of serum creatinekinase and its MB isoenzyme.
Clinical examination and chest x rays were perfor-med on admission and at frequent intervals thereafterto detect the presence of heart failure. For thepurposes of this study we defined clinical left ven-
tricular failure as the presence ofeither basal crepita-tions or a third heart sound together with radiologicalpulmonary venous congestion sufficient to warranttreatment with frusemide. We made a note ofthe useof frusemide, which was the only diuretic used, andother drugs that might influence neuroendocrineactivation during the period of study. Sustainedventricular tachycardia, symptomatic non-sustainedventricular tachycardia, and ventricular fibrillationwere noted during routine monitoring in the coro-
nary care unit over the first 48 hours.
Results
CLINICAL COURSE
Acute myocardial infarction was confirmed in 60patients (mean (SEM) age 52-9 (1-2) years). Thosepatients in whom myocardial infarction was sub-sequently excluded acted as a control group for thisstudy (n = 18, age 53-6 (1-9) years). Most of thesepatients were discharged from the coronary care uniton their second day; so for the control group there are
McAlpine, Morton, Leckie, Rumley, Gillen, Dargie
no data for day three. Thirteen patients (age 56-6(1-9) years) with myocardial infarction developedclinical evidence of left ventricular failure during thestudy period, including two with cardiogenic shock.Four patients died during their hospital admission-one within 24 hours in cardiogenic shock, two withintractable left ventricular failure on days seven and11, and one, who had previously had uncomplicatedinfarction, from late ventricular fibrillation onday 14.Four patients had one or more episodes of ven-
tricular fibrillation within 24 hours of admission.One of these patients died in cardiogenic shock,whereas the others subsequently had an uneventfulclinical course. Two patients, one of whom was inheart failure, developed complete heart block on dayfour that required temporary cardiac pacing. In bothcases, sinus rhythm had returned within 72 hours.Three patients who had no other clinical complica-tions had atrial flutter or fibrillation in the first twodays. Because these episodes lasted < 1 hour, notreatment was given. Late ventricular tachycardiaoccurred in two patients, both ofwhom had sustainedextensive myocardial damage with evidence of heartfailure.
Satisfactory radionuclide scans were available for69 of the 78 patients studied. In those with acutemyocardial infarction left ventricular ejection frac-tion correlated inversely with the cumulative releaseof creatine kinase isoenzyme MB over the first threedays (r = -0-62; p < 0-001). Mean (SEM) peakrelease of creatine kinase MB was higher (316-6(42-1) U/1) in patients with left ventricular failure andejection fractions were lower (23-3 (3-9)%) than inthose without heart failure (192-5 (20-5) U/I and 33.5(1-6)% respectively; both p < 0-01). In the controlgroup themean ejection fraction was 49-6 (2-8)%. Onadmission there were no significant differences inblood pressure between those with acute myocardialinfarction and the control group. Although all groupsshowed a fall in blood pressure, those with leftventricular failure had significantly lower systolicpressures at day 2 than the control group (108 (4)mm Hg v 127 (3-4) mm Hg respectively; p = 0-002)and these differences were maintained at day 10.Three patients who developed heart failure had
been on f blockers that were stopped at admission.None of the patients with uncomplicated myocardialinfarction was on ,B blockers at admission, andtreatment with f blockers or diuretics was not startedduring the study period. Twenty patients withoutheart failure were given intravenous nitrates for aperiod of 24-48 hours because of persisting orrecurrent cardiac pain without evidence of reinfarc-tion. For those with clinical evidence of left ven-tricular failure during their admission the mean
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Neuroendocrine activation after acute myocardial infarction
p.cO.0O1 9-
8-
7AL LVF
Fig 1 Changes (mean (SEM)) in arginine vasopressinconcentration over 10 days in patients with heart failure(L VF), those without heart failure (no L VF), and thosewithout myocardial infarction (no MI). Shaded area isnormal range.
frusemide dosage at day 3 was 95 (22 7) mg. Figures1-4 show the pattern of neuroendocrine activationfor the control group and for those with myocardialinfarction in the presence and absence of heartfailure. Significance values were derived fromStudent's paired and unpaired t tests, and r valuesfrom Pearson's correlation coefficients.
ARGININE VASOPRESSINConcentrations of arginine vasopressin were highestat admission and declined rapidly over the next 48hours (fig 1). In those with proven myocardialinfarction, arginine vasopressin concentrations were
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Fig 2 Changes (mean (SEM)) in adrenaline
concentration over 10 days in patients with heart failure
(LVF), those without heart failure (no LVF), and those
without myocardial infarction (no MI). Shaded area is
normal range.
119
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On.. Doiyl Dty2' Doy3 Do;ylOFig 3 Changes (mean (SEM)) in noradrenalineconcentration over 10 days in patients with heart failure(L VF), those without heart failure (no L VF), and thosewithout myocardial infarction (no MI). Shaded area isnormal range.
higher in 50 patilents who were given narcotic anal-gesics before admission to the coronary care unit(range 0.15-39.98 pg/mi, median 7.19 pg/mi) than in10 patients whose pain had spontaneously settled(range 017-292 pg/m, median 1.31 pg/mi; p =
0007). Arginine vasopressin concentrations alsotended to be higher in the seven controls on narcoticanalgesics (range 022-19n9 pg/mi, median 4n2 pg/mi)than in the eleven controls who did not requireanalgesia (range0102-16 pg/mi; median1941 pglmi).This difference was not statistically significant. Tenpatients required one or more further doses ofdiamorphine in the 12 hours before blood samplingon day 1, and although arginine vasopressin concen-tration had fallen significantly the median concentra-
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sP.C ,O<-O FO1 p0-050-001V.rp O05
On Day Doy 2 Day 3 Day loadmisson
Fig 4 Changes (mean (SEM)) in renin concentration over10 days in patients with heartfailure (LVF), those withoutheartfailure (no LVF), and those without myocardialinfarction (no MI). Shaded area is normal range.
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r Heart J: first published as 10.1136/hrt.60.2.117 on 1 A
tion (3-63 pg/ml, range 0.3-9-9 pg/mi) was higherthan in those (n = 40) who had analgesia only at orbefore admission (median 2-84, range 0. 12-20-02 pg/ml; NS). In those with acute myocardial infarction,arginine vasopressin concentrations correlated withadrenaline concentrations on admission (r = 0.57, p< 0.001), but were only poorly correlated with thecumulative release of creatine kinase isoenzyme MBover the first three days (r = 0-37, p < 0.01). By day10 mean concentrations of arginine vasopressin hadreturned almost to normal in all three groups ofpatients.
CATECHOLAMINESOn admission the mean plasma adrenaline concen-tration was raised in all three groups of patients.Plasma adrenaline concentration was significantlyhigher in those with heart failure (mean 3-54 (1-3)nmol/l, range 0.03-15.9) than in those without (0-96(0 25) nmol/l, range undetectable -74 nmol/l) andalso in those in whom myocardial infarction wasexcluded (0.35 (0.05) nmol/l, range undetectable- 0-61 nmol/l). During the course of the admissionall three groups showed a progressive decline in meanadrenaline concentrations towards normal (fig 2).Plasma noradrenaline concentrations also fell sig-nificantly during the course of the hospital stay inpatients without heart failure and in the controlgroup; in those without heart failure mean concentra-tions were just above the upper limit of normal onadmission (3.12 (0.43) nmol/l (range 0.05-11.93nmol/1), but they were within the normal range in thecontrols (2-34 (0-31) nmol/l) range 0-7-46 nmol/l).On admission mean plasma noradrenaline concentra-tions were at twice the upper limit of normal inpatients with heart failure (mean 6-2 (2.3) nmol/lrange 0.16-29.9 nmol/l), and high concentrationspersisted over the next three days (fig 3). Correlationsbetween heart rate and catecholamine release onadmission were poor (adrenaline r = 0 3, noradren-aline r = 0.4), mainly because of the variability inheart rate in patients with inferior myocardial infarc-tion. Catecholamine concentrations on admission,however, correlated with the cumulative release ofcreatine kinase MB (adrenaline r = 0.46, p < 0.001;noradrenaline r = 0 39, p < 0-01) and they alsocorrelated inversely with ejection fraction (adren-aline r =- 042, p <0-02; noradrenaline r = - 0.53,p < 0-002).
RENIN-ANGIOTENSIN SYSTEMOn admission mean plasma renin and angiotensin IIconcentrations were normal in the patients withmyocardial infarction, but they rose by the third dayto more than three times the upper limit of thenormal range (203 (69) p U/ml and 43.5 (8-6) pmo/ll
McAlpine, Morton, Leckie, Rumley, Gillen, Dargie
1 8O p COO40\
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On Day l Day 2 D3ay- Day 0
Fig 5 Changes (mean (SEM)) in angiotensin IIconcentration over 10 days in patients with heart failure(LVF), those without heartfailure (no LVF), and thosewithout myocardial infarction (no MI). Shaded area isnormal range.
respectively). In the control group, mean concentra-tions of renin and angiotensin II remained normalthroughout the study period, apart from a transientrise in angiotensin II on day 1 to 13.2 (3.5) pmol/l(range 1.9-48 pmol/l). Left ventricular failure wasclinically present on admission in nine patients, andoccurred later in four patients. Three patients hadbeen treated with frusemide before blood sampling atadmission (range 40-80 mg dose); plasma concentra-tions of angiotensin II were raised in only one. Twopatients with cardiogenic shock and four patientswith acute heart failure had not received diuretics;angiotensin II concentrations were raised in five ofthem. By day 3 the group treated for heart failure hadhigh mean renin and angiotensin II concentrations(559 (303) pU/1 (range 95-3855 pU/ml) and 102 (33)pmol/l (range 16-400 pmol/l) respectively). Reninand angiotensin II, however, also rose significantly inpatients without heart failure in whom the meanconcentrations were more than twice the upper limitof normal (104 (14) pU/1 (range 4-455 pU/ml) and26.8 (3.3) pmol/l (range 1-90 pmol/l) respectively) atthe third day. This included high angiotensin IIconcentrations in 16 of 27 patients who had receivedno drug treatment other than analgesia on admissionto hospital. By day 10, renin and angiotensin IIconcentrations had returned to normal in patientswithout heart failure, but high concentrations con-tinued in most of those treated for persistent heartfailure (figs 4 and 5). The table shows the angiotensinII concentrations in all 13 patients with heart failureand their respective diuretic dosages. Renin andangiotensin II concentrations correlated well onadmission (r = 0 56), at day 3 (r = 0.83), and at day
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Neuroendocrine activation after acute myocardial infarction
Table Individual angiotensin II concentrations (pmol/l) andfrusemide dosage (mg) over the previous 24 hours in patients withheartfailure. Shading indicates presence of clinical heartfailure
CaseNo OA F Day I F Day 2 F Day 3 F Day 10 F Outcome
10 (r = 0 80) (p < 0001). Renin on admissioncorrelated with catecholamines (adrenaline, r = 0 59,p < 0 001; noradrenaline, r = 0 37, p < 0 01) andalso with peak creatine kinase MB (r = 0 43, p <0-001). We found no significant correlations betweenconcentrations of arginine vasopressin or ejectionfraction and activation of the renin-angiotensin sys-tem.
RELATIONS WITH ARRHYTHMIAS AND DEATHVentricular fibrillation occurred in four patientswithin the first 24 hours. Three had normalnoradrenaline concentrations and only mildly raisedadrenaline concentrations on admission. Thisincluded one patient in whom ventricular fibrillationdeveloped during blood sampling (adrenaline 0-21nmol/l, noradrenaline 3-01 nmol/l). They sub-sequently had an uneventful recovery. The fourthpatient was in cardiogenic shock and died within 24hours. Angiotensin II concentration on admissionwas markedly raised in this patient (34.4 pmol/l), aswere adrenaline (4-4 nmol/l) and noradrenaline (3-4nmol/l).Three other patients died in hospital. Two had
progressive intractable heart failure with highangiotensin II and noradrenaline concentrations atday 3. The clinical condition of the third patient hadbeen uncomplicated despite a low ejection fraction(13%) and he died on day 14 from late ventricularfibrillation. At day 10 he had raised catecholamineconcentrations (adrenaline 0A45 nmol/l, noradren-aline 7-7 nmol/l) and also high angiotensin II (17pmol/l).Two patients with symptomatic episodes of ven-
tricular tachycardia had very high catecholamineconcentrations on admission (adrenaline 1-25 and7.44 nmol/l, noradrenaline 6-43 and 6-15 nmol/l) andraised angiotensin II concentrations (15-2 and 25pmol/l). Furthermore, both of these patients had low
left ventricular ejection fractions (7% and 22%),although only one had clinical signs of heart failure.Atrial flutter and fibrillation were seen in twopatients with inferior myocardial infarction, andthese were not associated with raised catecholamineconcentrations. Late ventricular tachycardia occur-red in a further two patients, both ofwhom had beentreated for heart failure and had persistently highcatecholamine and angiotensin II concentrations atday 3.Thus in this small group of patients with arrhyth-
mias, primary ventricular fibrillation was not closelyrelated to the magnitude of neuroendocrine activa-tion, although episodes of ventricular tachycardia onadmission were accompanied by very high cate-cholamine concentrations. Late life threatening ven-tricular arrhythmias and deaths occurred only inthose with major left ventricular dysfunction, whichwas also associated with persistently high cate-cholamine and angiotensin II concentrations.
Discussion
This study describes for the first time in a largeconsecutive series the extent, time course, andinterrelations of neuroendocrine activation afteracute myocardial infarction. Although raised urinaryaldosterone had been noted as early as 1956,22 the roleof the renin-angiotensin system after myocardialinfarction has been neglected until recently.Preliminary studies measuring renin show a verywide range of individual responses. Vaney et aldescribed raised renin and catecholamine concentra-tions on admission in 19 patients with acute myocar-dial infarction; concentrations were highest in fourof eight patients who subsequently developed car-diogenic shock or ventricular fibrillation.'2 Wentinget al, however, found normal renin concentrations infour patients with heart failure within 12 hours of
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122acute myocardial infarction in the absence of diuretictreatment, although high renin concentrations wereseen at 48-72 hours in two other patients whoreceived inotropes and vasodilators.'5 A much largerstudy by Michorowski and Ceremuzynski of 95patients showed raised renin concentrations in 20 of22 patients within six hours of chest pain in thepresence of heart failure, arrhythmias or shock, butno significant increase in patients without clinicalcomplications.'4These findings are extended and confirmed in our
study, in which most patients had normal concentra-tions of renin and angiotensin II within six hours ofsymptoms, with the exception of those with severeheart failure or shock. Sequential measurements inpatients without clinical complications, however,showed a significant increase in renin and angiotep-sin II by day 3, in the absence of treatment withvasodilators or diuretics. Those treated for heartfailure had very much higher angiotensin II concen-trations at day 3, which persisted at ten days andpresumably for longer.
Stimulation of renin secretion during the firstthree days after myocardial infarction is likely to bedependent on several interacting variables. Theinitially very high arginine vasopressin concentrationmay have suppressed renin release,2324 whereas acutereduction in renal blood flow, together withincreased renal nerve activity may stimulate therenin-angiotensin system.25 26 There seems littledoubt that contraction of blood volume associatedwith diuretic treatment contributed to the extremelyhigh concentrations of renin and angiotensin II inthose with heart failure, but concentrations of thesehormones were raised on admission in nearly half ofthis group before diuretic treatment. We confirmedprevious observations of a relation between cate-cholamines and initial renin concentration,'4 whichsuggests that this may be one of the more importantinitial stimuli to renin secretion in this clinicalsetting.As shown previously,47I8 catecholamine release was
also related to the extent of left ventricular damage asassessed by cardiac release, ejection fraction, and thepresence of heart failure. Whether catecholamineshave any direct influence on infarct size remainsuncertain, but raised urinary and plasma cate-cholamine concentrations have been reported to berelated to the frequency of early ventricular arrhyth-mias.45 In our study only six out of 60 patients hadventricular fibrillation or haemodynamically impor-tant ventricular tachycardia in the first 24 hours, andshort salvos of ventricular extrasystoles were notdocumented. I Blockade at an early stage whencatecholamine concentrations are highest seems alogical tactic both to reduce arrhythmias and limit the
McAlpine, Morton, Leckie, Rumley, Gillen, Dargieextent of infarct damage, and this has been the focusof several studies."' In our study, however, cate-cholamine concentrations were highest in a group inwhom f blockers are generally contraindicated-thatis those patients in whom heart failure is developing.
Arginine vasopressin release during acute myocar-dial infarction has received little attention. We foundmarkedly raised arginine vasopressin concentrationsat admission, not only in those with myocardialnecrosis but also in some patients in whom myocar-dial infarction had been excluded. Furthermore, thecorrelation between arginine vasopressin concentra-tions and creatine kinase release was poor, suggestingthat factors other than myocardial necrosis are res-ponsible for arginine vasopressin release. Adminis-tration of morphine was strongly associated with theconsiderable increase in arginine vasopressin in boththose with myocardial infarction and in the controlgroup. In contrast, in patients with myocardialinfarction who were not given morphine argininevasopressin was only slightly raised, and this is alsotrue of the control patients who did not receivemorphine. Thus after myocardial infarction argininevasopressin is more likely to be high as a result oftreatment than as a primary response to acutemyocardial infarction. The explanation for thecorrelation between initial concentrations of adren-aline and arginine vasopressin might also be thatthose under greater stress because of pain or nauseaand vomiting had received higher doses ofmorphine.The antidiuretic effect of arginine vasopressin is
well recognised and probably contributes to the lowurine volumes in the first 24 hours after myocardialinfarction. It has been estimated that approximately760 ml water is gained then.27 Although infusion ofarginine vasopressin does not raise blood pressure,except in very high concentration (100 ng/1),28 it is anextremely potent arterial vasoconstrictor. Argininevasopressin has been given as a provocative test forangina and coronary artery spasm,29 and in othersituations in which there is an excess of argininevasopressin, myocardial infarction, arrhythmias,and sudden death have been reported."'32 We donot know whether the concentrations of argininevasopressin seen after myocardial infarction in thisstudy had important haemodynamic effects, but thevasoconstrictor properties of arginine vasopressinmay be enhanced by noradrenaline, and both of thesehormones were at their highest in the first 24 hoursafter admission.The interaction of raised plasma concentrations of
angiotensin II, arginine vasopressin, and cate-cholamines could be harmful in several ways. Argi-nine vasopressin, noradrenaline, and angiotensin IIare potent arterial vasoconstrictors that couldincrease left ventricular afterload and lower coronary
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Neuroendocrine activation after acute myocardial infarction 123perfusion. Similarly tachycardia and arrhythmiasinduced by catecholamine excess could be disadvan-tageous. Furthermore, the combination of vasocon-striction mediated by these hormones and volumeexpansion through the sodium retaining effects ofincreased renal sympathetic nerve activity, stimula-tion of aldosterone secretion, and antidiuresis in thepresence ofraised arginine vasopressin concentrationprovides the setting for the development of acuteheart failure. Treatment with angiotensin convertingenzyme produced short term and long termhaemodynamic improvements in patients withchronic heart failure."35 Inhibition of angiotensin IIproduction in chronic heart failure has also beenassociated with reduction of arrhythmias,'6 a sig-nificant rise in body potassium,7 and a reduction inplasma catecholamine concentrations.' 3 Morerecently beneficial haemodynamic changes havebeen shown with angiotensin converting enzymeinhibitors in heart failure complicating myocardialinfarction.'516 These findings suggest that clinicaltrials of early intervention with angiotensin convert-ing enzyme inhibitors in patients with extensivemyocardial infarction and heart failure should beconsidered.
In addition to these more obvious adversehaemodynamic consequences, neuroendocrineactivation could have other subtle effects on myo-cardial structure and function. Experimentally, highconcentrations of catecholamines and angiotensinII cause diffuse microscopic myocardial cellularnecrosis in rabbits, and in man can cause similarlesions even in the absence of coronary disease.'Recent studies show that infarct expansion andprogressive ventricular dilatation occur in somepatients after myocardial infarction.4 In animalmodels angiotensin converting enzyme inhibitorsmay reduce infarct size,4"'3 increase collateral bloodflow to the infarct zone,43 reduce the incidence ofreperfusion arrhythmias,4 and through improvedventricular remodelling in rats47 can lead to anincrease in survival.'9Thus persisting high concentrations ofangiotensin
II after myocardial infarction could have importantimplications not only for the development of acuteheart failure, but also for long term cardiac structureand function. The observations reported hereprovide a logical basis for the cautious exploration ofthe effects of angiotensin converting enzyme inhibi-tion given early in acute myocardial infarction onventricular structure and function.
References
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