Neuroendocrine Activation After Acute Myocardial Infarction Jay N. Cohn, MD

Neuroendocrine response after acute myocardiai infarction (Ml) resuits in activation of the sympathetic nervous system, the renin-angiotensin system, and vasopressin and atriai natriuretic peptide release. The net effect of this response is vasoconstriction, cardiac stimulation and regional flow redistribution that may have a favorable effect in some situations and a deleterious effect in others. The possibie adverse effects of vasoconstriction were studied in a Veterans Administration Cooperative Study that evaluated a 46-hour infusion of sodium nitroprusside in the setting of acute MI. in the presence of miid, probably primarily diistoiii left ventricuiar dysfunction, nitroprusside appeared to have an adverse effect on long-term survival. However, in the presence of more severe, probably predominantly systoiic dysfunction, nitroprusside had a favorable effect on the prognosis. Therefore, the decision of whether to accept or inhibit neuroendocrine activation in acute MI probably depends on the severity of the disease and the timing of the therapeutic intervais. (Am J Cardioi 1966;65:26 I-31 I)

From the Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. This study was supportedin part by the Cooperative Studies Program, Veterans Administration, Minneapolis, Minnesota. Address for reprints: Jay N. Cohn, MD, Box 488, University of Minnesota Medical School,Minneapolis, Minnesota 55455.

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he circulatory disturbance of acute myocardial infarction (MI) usually is accompaniedby neuroendocrine stimulation. Therapy usedin the treatment of acute MI may contribute to the neurohormonal response.The purposeof this study was to examine the physiologic implications of the neurohormonal response and to determine if the net effect of this responseis favorable or unfavorable.

T

EVIDENCE FOR NEUROENDOCRINE STIMULATION

Plasmacatecholaminesincreasein patients with acute MI.le3 Someof the increasein circulating norepinephrine may be the result of a reduction in norepinephrine clearance. It is also likely that increasedlevels of circulating norepinephrine reflect an increasein spillover of norepinephrine from the synaptic cleft into the bloodstream.4 The regional sourceof the norepinephrinein the acute MI syndrome is unknown. Becauseinfarcted myocardium rapidly becomesdepleted of norepinephrine,5it is interesting to speculatea myocardial sourceof the high circulating levelsof norepinephrine. However, the magnitude of the norepinephrine responseindicates that it is from a generalized sympathetic reflex response distributed throughout the sympathetic nervous system. Becausethe magnitude of the sympathetic responsein patients with acute MI appearsto parallel the severity of the hemodynamic derangement,3,6,7 and becausethe elevated plasma levels tend to return to the normal range over the first 24 to 48 hours,8,9it is highly likely that sympathetic activation represents a reflex responseto some hemodynamic deficit, e.g., a decreasein cardiac output, a reduction in tissue perfusion, a decreasein carotid/aortic pressureor pulse pressure,or someother as yet unrecognized reflex stimulation of the sympathetic nervous system. Renin-angiotensin stimulation frequently occurs in patients with acute MI, particularly when left ventricular failure is present.10,11 In the hypotensivepatient, the increasein plasma renin activity may occur through renal sympatheticstimulation induced by baroreceptorunloading. A correlation between plasma norepinephrine and plasma renin activity supportsthis possibility.8The sympathetic responsemay be attenuated in patients who have had chronic heart failure in whom baroreceptorresponse to a decreasein blood pressureoften is inhibited.12Even in the latter instance, however, renal baroreceptorscontrolling renin releasestill appearto be active and this may account for renin stimulation in the absenceof sympathetic stimulation. l 3

TABLE

I Physiologic

Effects

of Sympathetic

Nervous

System

Ill Physiologic

II Physiologic

Effects

of Renin-Angiotensin

Effects

TABLE

of Antidiuretic

Hormone

Release Increased Coronary Systemic Regional

Increased myocardial contractility Tachycardia Atrial and ventricular arrhythmias Coronary vasoconstriction Decreased vascular compliance Increased vascular resistance Decreased venous capacitance Regional blood flow redistribution Myocardial hypertrophy

TABLE

TABLE

(Vasopressin)

Stimulation

IV Physiologic

free water reabsorption vasoconstriction vasoconstriction blood flow redistribution

Effects

of Atrial

Natriuretic

Peptide

Release

System

Regional vasodilation and vasoconstriction Inhibition of sympathetic, renin-angiotensin stimulation Inhibition of renal sodium reabsorption

and vasopressin

Stimulation Presynaptic stimulation of norepinephrine Decreased arterial compliance Increased arterial resistance Renal sodium retention Renal potassium loss Thirst Regional blood flow redistribution Myocardial hypertrophy

release

Intrarenal mechanismsmay contribute to renin stimulation, e.g.,through macula densaresponseto reduction in sodium load. Furthermore, furosemide has a striking stimulatory effect on renin release,presumably through an intrarenal mechanism.Furosemideadministeredearly in the course of acute MI may accentuatethe neurohormonal responseto the disease.14 An increasein plasma arginine vasopressinlevelsalso is noted in patients with acute M1.8J5The mechanismof this apparently nonosmotic stimulus to vasopressinreleaseis not fully understood,although morphine administration may play a role in some patients. Atria1 natriuretic peptide (ANP) levelsalso probably increasein responseto an increasein left atria1pressurein the patient with acute MI. l6 Although it would be expected that ANP levels would decreaseas the elevated left ventricular filling pressure normalizes after the acute event,studiesof this phenomenonhavenot beenreported. EFFECTS OF NEUROHORMONAL STIMULATION

Reflex stimulation of the sympathetic nervoussystem (Table I) and renin-angiotensin system(Table II) results in vascular and cardiac effects aimed teleologically at supporting arterial pressure.Increasesin arteriolar resistance and reductions in arterial compliancesupport mean arterial and systolic pressuresin the face of a decreasing stroke volume. Support of arterial pressuremay be particularly important in maintaining myocardial perfusion through a proximal stenosisin a coronary artery.17 A reflex increasein heart rate helpsto maintain cardiac output, and an increase in myocardial contractility may augment stroke volume. Venoconstriction induced by neurohormonal stimulation shifts blood from the venous reservoir to the heart to augment cardiac filling and

TABLE Stimulation

V Potential of Acute

Deleterious Myocardial

Effects of Neurohormonal Infarction

Ventricular arrhythmias Tachycardia Reduced perfusion to ischemic myocardium Increased ventricular filling pressure Increased aotic impedance Increased myocardial oxygen consumption Reduced sodium and water excretion

support cardiac contraction by a Frank-Starling mechanism. Volume effects may be accentuatedby renal vasoconstriction and by angiotensin-induced aldosteronesecretion. Finally, both norepinephrine and angiotensin may contribute to early myocardial protein synthesisthat leads to myocardial hypertrophy. Releaseof vasopressinand ANP has lesswell-established cardiovasculareffects.The effect of vasopressinon free water excretion and on regional vascular tone are well known (Table III), but it is not clear if the blood levels achievedduring acute MI are adequateto induce these physiologic effects.l8 Atria1 peptide has direct effectson the kidney and as a vasodilator and vasoconstrictor, but it also may interfere with the responseof the sympathetic nervous system, the renin-angiotensin system and arginine vasopressinrelease (Table IV).19 Although theseneurohormonal responsesmay be appropriate and well-tolerated when the heart is normal, these physiologic effects may becomedeleterious in the setting of acute myocardial damage (Table V). The increasein vascular resistanceand decreasein compliance raise the impedanceto left ventricular ejection and may adversely affect left ventricular output. The increase in heart rate and contractility augment myocardial oxygen consumption and may aggravate ischemia. The increase in preload mediated by vasoconstriction and sodium retention may not producean appropriate increasein stroke volume becausethe damagedventricle is operating on a flat Frank-Starling curve. Furthermore, the increased preload may impedesubendocardialperfusion and aggravate ischemia-inducedpump dysfunction (Fig. 1). Finally, neurohormonal stimulation may contribute directly to

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A SYMPOSIUM:

THE RENIN-ANGIOTENSIN

SYSTEM -TISSUE

SPECIFIC ISSUES

Early Treatment

. PLACEBO 0 Nitroprurrida

Late Treatment FlGURE 1. Vii cyds of acute myacardial infarction evenhmtinginapumpfaiiorsanhkndeathinpartrelatedto feehack loops involving both systolic and diastok dysfuwtlOll.TbftdVWSl?l?ffCXtOfVacrocomtrletion induced by neurohmnonai sttmulation is particularly related to systolic dysfmctlon that can be mo&rated by vasodilatar therapy. Biastolii dysfmctbn in acute myocardial infarction is mars transient and daes not appear to respond favorably to vasodilatar therapy. LVED = lefl ventricular end-diastotii presswe.

ventricular arrhythmias that can precipitate ventricular fibrillation. Becauseneurohormonally mediated vasoconstriction could have either favorable or unfavorable effectson the acutely infarcted ventricle, in 1975 we initiated a multicenter trial of short-term infusion of sodium nitroprusside in patients within 24 hours of acute MI.*O Although therapy was not aimed at inhibiting the neurohormonal response,its goal wasto counteract the vasoconstrictionand thus lower impedanceto left ventricular output. Because our preliminary studies indicated that nitroprusside infusion improved left ventricular global function without increasing heart rate,*’ this intervention appearedto be an appropriate probe to test whether vasoconstrictionwas good or bad in the setting of acute MI. The multicenter trial was performed in 11 Veterans Administration Hospitals under sponsorshipof the Veterans Administration Cooperative Studies Program. A total of 8 12 men with presumedacute MI were randomized after Swan-Ganz catheterization had confirmed the presence of an elevated pulmonary capillary wedge pressure >12 mm Hg. They received,in double-blind fashion, an infusion of sodium nitroprusside or placebo titrated to reduce the pulmonary wedgepressureto 60%of the control value or until systolic blood pressuredecreasedbelow a prescribed limit or a maximal dosehad been reached. The infusion was continued for 48 hours with dosage adjustment if necessaryto maintain the goal pressure. The mortality in these2 treatment groups appearedto be significantly influenced by the timing of the institution of the infusion in relation to the course of the myocardial infarction. In patients in whom treatment was begun within 9 hours after the clinical onset of acute MI, nitroprusside had a statistically significant adverseeffect on 13-weekmortality (Fig. 2). In contrast, patients randomized and begun on infusion more than 9 hours from the onset of their infarct exhibited a statistically significant beneficial effect on mortality of nitroprusside infusion. This difference in survival between these 2 randomized groups persistedthrough 1 year of follow-up (Table VI). 30

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5 2

80 * cl9 hours

Infarction

No.

Deaths

%

No.

Deaths

%

377 126 251

91 36 55

24.1 28.6 21.9

368 112 256

93 23 70

25.3 20.5 27.3

filling pressuresremained elevated more than 9 hours after the onsetof MI probably had more severeglobal left ventricular systolic dysfunction in which the favorable effects of nitroprusside outweighed any possibleadverse effectson coronary perfusion. In this group, persistentleft ventricular diastolic hypertension in the placebo-treated patients may have contributed to persistent subendocardial ischemia that resulted in worsening of ventricular function and a higher mortality rate. In support of the suggestionthat the patients who were randomized early were less sick than the patients randomized later is the observedmortality rate in the placebogroups. Mortality at 13 weeks was 50% higher in the group randomized more than 9 hours after onsetof the infarct, and mortality at 1 year remained 33% higher in the group randomized late. Although this study with sodium nitroprusside addressedonly the systemic vasoconstrictor responseas a manifestation of neurohormonal stimulation in acute MI, the data allowed us to propose a more rational understanding of the role of reflex vasoconstriction in the setting of acute MI. In milder forms of acute MI, when diastolic dysfunction is more prominent than systolic dysfunction, vasoconstriction supports coronary perfusion pressure but does not adversely affect left ventricular function. Inhibition of vasoconstriction in this setting is not beneficial. In more severeinfarcts when systolic function is adverselyaffected,vasoconstrictionaggravatesleft ventricular dysfunction and may contribute to progressive subendocardial ischemia and a worsening clinical state. In this latter situation, vasodilator therapy has a beneficial effect. Furthermore, when systolic dysfunction persistsafter MI, the clinical syndrome of chronic heart failure is accompanied by neurohormonal stimulation and vasoconstriction.23We now know that vasodilator therapy to counteract this vasoconstriction has a favorable effect on both left ventricular function and the course of the clinical syndrome.24 CONCLUSIONS

Thus, we can view neurohormonal responsesin acute MI asboth potentially beneficial and potentially harmful. Selection of the appropriate patient for the appropriate therapy is a challenge that can be met only by collection of appropriate physiologic data. REFERENCES 1. Gazes PC, Richardson JA, Woods EF. Plasma catecholamine concentrations in myocardial infarction and angina pectoris. Circulation 1959;19:657-661.

2. Nadeau RA, de Champlain J. Plasma catecholamines in acute myocardial infarction. Am Heart J 1979;98:548-554. 3. Karlsbcrg RP, Cryer PE, Roberts R. Serial plasma catecholamine response early in the course of clinical acute myocardial infarction: relationship to infarct extent and mortality. Am Heart J 1981;102:24&29. 4. Esler M. Assessment of sympathetic nervous function in humans from noradrenaline plasma kinetics. C/in Sci 1982,62:247-254. 5. Russell RA, Crafoard J, Harris AS. Change in myocardial composition after coronary ejection. Am J Physiology 1961;200:995-998. 6. Valori C, Thomas M, Shillingford J. Free noradrenaline and adrenaline excretion in relation to clinical syndromes following myocardial infarction. Am J Cardiol 1967:20:605-617. 7. McDonald L, Baker C, Bary C, McDonald A, Restreaux N. Plasma catecholamines after cardiac infarction. Lancet 1969;2;1021-1023. 6. McAlpine HM, Morton JJ, Leckie B, Rumely A, Gillen G, Dargie HJ. Neuroendccrine activation after acute mywardial infarction. Br Heart J 1988; 60:117-124. 9. Francis GS, Cohn JN. Catccholamines in cardiovascular disease. Upjohn Co., Kalamazoo, Ml, 1987:20-32. 10. Michorowski B, Ceremuzynski L. The renin-angiotensin-aldosterone system and the clinical cause of acute mvocardial infarction. Eur Heart J 1983;4:259264. 11. Vaney C, Waeber B, Turini G, Margalith D, Brunner HR, Perret C. Renin and the complications of acute myocardial infarction. Chest 1984;86:4043. 12. Olivari MT, Levine TB, Cohn JN. Abnormal neurohormonal response to nitroprusside infusion in congestive heart failure. JACC 1983;2:4/ l-41 7. 13. Levine TB, Olivari MT, Cohn JN. Dissociation of the responses of the reninangiotensin system and sympathetic nervous system to a vasodilator stimulus in congestive heart failure. Int J Cardiol 1986;8:973-977. 14. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. A?n Intern Med 1985:103:1-6. 15. Schaller MD, Nussberger J, Feihl F, Waeber B, Brunner HR, Perret C, Nicod P. Clinical and hemcdynamic correlates of elevated plasma arginine vasooressin after acute mvwardial infarction. Am J Cardiol /98750:11781lSi. 16. Hamosh P, Cohn JN. Left venricular function in acute myocardial infarction. J Clin Itwest 1971;50:523-533. 17. Schwartz JS, Carlyle PF, Cohn JN. Effect of coronary arterial pressure on coronary stenosis resistance. Circulation 1980,61:70-76. 16. Goldsmith SR, Francis GS, Cowley AW, Goldenberg IF, Cohn JN. Hemodynamic effects of infused arginine vasopressin in congestive heart failure. JACC 1986;8:779-783. 19. Carson P, Carlyle PF, Cohn JN. Hemodynamic, neurohumoral, and renal response to atrial natriuretic peptide infusion in the conscious dog. In: Brenner BM, ed. Biologically Active Atrial Peptides. New York: Raven Press, /987:322325. 20. Cohn JN, Franc&a JA, Francis GS, Archibald D, Tristani F, Fletcher R, Montero A, Cintron G, Clarke J, Hager D, Saunders R, Cobb F, Smith R, Loch H, Settle H. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure. N Engl J h4ed 1982;306:1129-1135. 21. Franciosa JA, Guiha NH, Limas CJ, Rodriguera E, Cohn JN. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lmzcet 1972;1:650-654. 22. Franciosa JA, Guiha NH, Limas CJ, Paz S, Cohn JN. Arterial pressure as a determinant of left ventricular tilling pressure after acute myocardial infarction. Am J Cardiol 1974;34:506-512. 23. Cohn JN, Mashiro I, Levine TB, Mehta J. Role of vasoconstrictor mechanisms in the control of left ventricular performance of the normal and damaged heart. Am J Cardiol 1979;44:1019-1022. 24. Cohn JN, Archibald DG, .&ache S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (V-HEFT). N Engl J Med 1986; 314:1147-1152.

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Neuroendocrine activation after acute myocardial infarction.

Neuroendocrine response after acute myocardial infarction (MI) results in activation of the sympathetic nervous system, the renin-angiotensin system, ...
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