Clinical Investigator

Clin Investig (1992) 70 : S 73-S 78

© Springer-Verlag 1992

Pathophysiology and triggers of acute myocardial infarction: clinical implications S.N. Willich, A.H. Jimenez, G.H. Toiler, R.A. DeSilva, and J.E. Muller Institute for Preventionof CardiovascularDisease,DeaconessHospital, Harvard MedicalSchool,Boston Klinikum Steglitz, FreeUniversityof Berlin

Summary. A new approach to identification of the triggering mechanisms of acute myocardial infarction has been provided by the observation that the disease occurs more frequently during the morning hours compared to other times of day. This circadian variation results primarily from an increased relative risk during the initial 2-3 h after awakening and arising. The precise relationship between the onset of myocardial infarction and external factors such as activity and meal patterns needs to be determined in controlled epidemiologic studies. The possible underlying pathophysiologic mechanisms responsible for the circadian pattern of myocardial infarction include acute variations of blood pressure, heart rate, platelet aggregability and fibrinolytic activity, leading to an increased risk of plaque rupture and intracoronary thrombosis. Clinical implications of these findings include the need to design preventive regimens to provide maximum protection at the time of peak risk of myocardial infarction.

Key words: Myocardial infarction - Triggers Pathophysiology - Circadian variation

Cardiovascular diseases account for approximately 50% of the mortality in industrialized societies; about half of those deaths are due to myocardial infarction or sudden cardiac death. The majority of these fatalities occur within a few hours after the onset of symptoms prior to hospital admission [12]. Since for this group of patients the means of treatment are very limited, the most effective way of reducing mortality includes trying to improve prevention. However, although knowledge of the long-term risk factors and of the chronic evolution of coronary atherosclerosis has been

markedly advanced during the last decades, very little is known about the acute pathophysiologic events leading to the onset of myocardial infarction. A new approach to identification of the underlying mechanisms of the transition of chronic to acute coronary artery disease has been suggested by the observation that myocardial infarction occurs more frequently during the morning hours compared to other times of the day [19, 32]. A similar pattern has been reported for other cardiovascular diseases, including sudden cardiac death [20, 31], myocardial ischemia [18, 26], and stroke [16]. This circadian pattern indicates the presence of triggering factors that occur or are effective more often during or just before the time of day of an increased clinical event rate. Furthermore, these findings challenge the conventionally held point of view that the onset of myocardial infarction is not related to external factors such as physical activities. In the present article, recent studies will be reviewed that are pertinent to possible triggering factors of myocardial infarction and the underlying pathophysiologic mechanisms that may lead to the onset of the event. These findings have generated interesting hypotheses as to a triggering cascade of myocardial infarction. Although firm clinical recommendations cannot be derived yet, the studies in this research area may have important implications for improving preventive strategies of the disease, e.g., by revising dosage and timing of cardiac medication.

Triggering factors Numerous anecdotal reports indicate a temporal association between external events and the onset of acute myocardial infarction. In an early descrip-

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tion of myocardial infarction in the beginning of this century, unusual events such as emotional upset were already being mentioned as having precipitated the disease in some cases [22]. However, only a few studies have addressed this problem systematically with conflicting results. Based on observational data on 2600 patients, Master concluded that "coronary occlusion takes place irrespective of the physical activity being performed or the type of rest taken" [17]. A retrospective analysis of questionnaires obtained in the MILLS Study demonstrated that possible triggering factors of the disease may be identified in about 50% of cases [29]. In case control studies, strenuous physical activity was shown to be associated with a small excess risk of sudden cardiac death [27]. The recent observations of a circadian variation in the onset of myocardial infarction have contributed new aspects. It has been consistently documented that the risk of myocardial infarction demonstrates a primary peak during the morning and in some studies an additional secondary peak in the evening [19, 32]. This pattern was observed in different subgroups of patients categorized according to gender, age, regional distribution, and past medical history. Therefore, these findings ap-

pear to indicate the presence of factors that are more likely to occur during certain times of day compared to others. Some subgroups of patients showed a more even circadian distribution of myocardial infarction, including those with non-Q-wave myocardial infarction [13], diabetes (ISIS-2 results), and those on fi-adrenergic blocking agents or on aspirin prior to the event [19, 25, 32]. Although these results were partially obtained in retrospective analyses and need prospective confirmation, the altered circadian pattern may indicate specific pathophysiologic characteristics or protective mechanisms pertinent to these groups of patients. Currently, large-scale epidemiologic studies are being conducted to determine the relationship between the onset of myocardial infarction and external factors such as wake-sleep rhythm, activity pattern, meal pattern, unusual life events, and medication. Preliminary results [l 5, 33] demonstrated that the circadian variation of myocardial infarction results primarily from an increased risk during the initial 2-3 h after the subjects awaken and arise (Fig. 1). This narrowing of the time interval of increased risk of the disease may further aid in identification of the mechanisms involved and in improving preventive measures.

Pathophysiology The demonstration of a lesion of an atherosclerotic plaque in association with an intraluminal thrombus led 20 years ago to the hypothesis that an acute plaque rupture with subsequent exposure of collagen may be a mechanism of coronary thrombosis [5]. Initially, it was unclear whether this rupture occurs primarily from the plaque into the lumen (with participation of vasa vasorum) or vice versa from the lumen into the plaque [3]. Further developing this concept, Davis and Thomas found in almost all cases of acute myocardial infarction a rupture of the cap of the atherosclerotic plaque with an adjacent intraluminal occlusive thrombus and often an additional intramural thrombus [8]. Further investigations of the atherosclerotic plaque demonstrated multiple possible combinations in regard to the degree of stenosis, shape of plaque, and biochemical and cellular composition that presumably determine the relative vulnerability of a cap of the lesion [7, 24]. After an acute plaque rupture, complete thrombotic occlusion may occur; however, there are multiple subsequent formations of stenosis possible, ranging from complete recovery without residual stenosis to total occlusion [27].

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Fig. 2. [21] Hypothetical model of a cascade of external events and pathophysiologic mechanisms in triggering acute myocardial infarction. Physical or mental stress triggers the rupture of a vulnerable plaque. A major plaque rupture may lead to an occlusive thrombus. In the case of a minor plaque rupture, circadian coagulability or coronary tone changes may then lead from a nonocclusive to an occlusive thrombus with subsequent myocardial infarction or sudden cardiac death

In many cases of acute myocardial infarction, the underlying atherosclerotic lesion appears to be of only minor degree [14]. Therefore, many researchers have focused their attention on the possible role of the hemostatic systems and of the endothelium in triggering acute intracoronary thrombosis [10, 30]. The complex systems of procoagulating and antithrombotic factors are usually in a state of balance, which may be disturbed by numerous factors, including endothelial lesions or absence or functional defects of coagulation factors. The activity of the thrombotic systems may be a marker for long-term risks but appears also to be associated with short-term risk of acute coronary artery disease [10]. It has been demonstrated that the exposure of collagen, ]ipids, and smooth muscle cells after plaque rupture leads to the activation of platelets and the coagulation cascade system [10]. In addition, release of phase-active substances, an increased coronary tone or increases in plasma catecholamine levels may contribute to the risk of subsequent myocardial ischemia. It has been estimated that in only one-fourth of patients coronary thrombosis results from superficial intimal injury or blood stasis [7, 10]. Other contributing factors of the development of coronary thrombosis include increased platelet aggregability, decreased endogenous fibrinolytic activity, and increased coronary tone. Several studies

examined the possible role of circadian variations of physiological parameters for the triggering of acute coronary artery disease. During the morning, several changes occur that may contribute to an increased likelihood of intracoronary thrombosis. Platelet aggregability increases after assumption of an upright posture [4, 28], endogenous fibrinolytic activity is at its trough during the same time [1], and coronary tone is apparently increased [23]. Furthermore, blood viscosity has been shown to increase during the morning thereby further enhancing the risk of thrombosis [9]. Although the temporal relationship of increased risk of clinical events and change of pathophysiologic parameters does not prove a causal relationship, a hypothesis of the triggering phase of myocardial infarction has been proposed [21] (Fig. 2). It is conceivable that physical or mental stress acutely produces hemodynamic changes, increasing the risk of plaque rupture. A major plaque rupture leads to a thrombotic coronary occlusion with myocardial infarction or sudden cardiac death. In the case of a minor plaque rupture, acute circadian coagulability changes may then further increase the growth of a nonocclusive thrombus, leading to myocardial infarction or sudden cardiac death. Although the precise relationship between these events is not clear and needs to be investigated

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in the future, it appears possible that the sympathetic nervous system represents an underlying key variable. Physical or mental stress may lead via increase of sympathetic tone to hemodynamic changes, to coagulability increases, and thereby increase acutely the clinical event rate. Clinical implications The epidemiologic and pathophysiologic findings are complemented by clinical observations. Two of the most powerful drugs in reducing mortality of myocardial infarction are aspirin and/7-adrenergic blocking agents. The efficacy of aspirin in unstable angina, acute myocardial infarction, and primary and secondary prevention of cardiovascular disease is likely to be associated with the reduction of platelet activity [2, 11]. It is of interest that aspirin appears to be particularly effective in reducing myocardial infarction during the morning, that is, during the time period of increased platelet aggregability [25]. The protective mechanisms of/7-blockers are not completely understood. Several possible factors include antiarrhythmic properties of the drug, anti-ischemic effects, infarct reduction, increased vascularization, possible antiplatelet mechanisms,

and interference with lipid metabolism. Since /~blockers also appear to exert a time differential benefit, i.e., reduce the risk of myocardial infarction during the morning relatively more than during other times of day [19, 32], it is attractive to speculate that these drugs interfere with mechanisms exhibiting a circadian variability. An important benficial mechanism of/7-blockers may be the attenutation of the blood pressure surge that occurs after awakening and arising [6]. Preliminary results of a study with carvedilol, a new/7-blocker with additional e-blocking properties, demonstrated an effective blood pressure reduction in a group of ten normal subjects during 24 h. Furthermore, platelet aggregability and endogenous fibrinolytic activity during the morning appeared not to be adversely affected by carvedilol (Fig. 3), which is of importance in the light of prior studies indicating a possible prothrombotic effect of/7-blockers [34]. Although further studies are needed to investigate the triggering phase of myocardial infarction, preliminary clinical conclusions may be drawn. Since the time interval after awakening and to rising is associated with an increased risk of myocardial infarction, currently available pharmacotherapy should be designed to provide maximum thera-

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py at the time of peak risk. A particular timing of aspirin appears not to be crucial since the effect on platelet activity lasts much longer than 24 h. For /3-blockers, it appears prudent to design the regimen so that optimal plasma levels are present when the patient awakens and arises. Whether this can be achieved (and whether this will improve prevention of myocardial infarction) by administration of long-acting fl-blockers or by/3-blockers taken late at night needs to be determined in future investigations. References 1. Andreotti F, Davies G J, Hackett DR, Khan MI, DeBart ACW, Aber VR, Maseri A, Kluft C (1988) Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onst of myocardial infarction, sudden cardiac death, and stroke. Am J Cardiol 62:635-637 2. Anti-platelet Trialist Collaboration (1988) Secondary prevention of vascular disease by prolonged anti-platelet treatment. Brit Med J 296:320 3. Barger AC, Beeuwkes R I I I , Lainey LL, Silverman KJ (1984) Hypothesis: Vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 310:175 177 4. Brezinski DA, Toiler GH, Muller JE, Pohjola-Sintonen S, Willich SN, Schafer AI, Czeisler CA, Williams GH (1988) Morning increase in platelet aggregability: Association with assumption of the upright posture. Circulation 78:35-40 5. Constantinides P (1966) Plaque fissures in human coronary thrombosis. J Artheroscler Res 1 : 1-17 6. Conway J, Boon N, Davies C, Jones JV, Sleight P (1984) Neural and humoral mechanisms involved in blood pressure variability. J Hypertension 2:203-208 7. Davies MJ (1990) A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation [Suppl II] 82:II-38-II-46 8. Davies M J, Thomas AC (1985) PIaque fissuring - the cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br Heart J 53 : 363-373 9. Ehrly AM, Jung G (1973) Circadian rhythm of human blood viscosity. Biorheology 10: 57%583 10. Fuster V, Stein B, Ambrose JA, Badimon L, Badimon SY, Chesebro JM (1990) Atherosclerotic plaque rupture and thrombosis : Evaluating concepts. Circulation [Suppl] 82: II47-II-59 11. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, Le Winter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: Results of a Veterans Administration Cooperative Study. N Engl J Med 309: 396-403 12. L6wel H, Lewis M, Keil V, K6nig W, H6rmann A, Bolte HD, Gostomzyk J (1988) Zur Herzinfarksituation in einer sfiddeutschen Bev61kerung: Ergebnisse des Augsburger Herzinfarktregisters 1985. Z Kardiol 77:451-489 13. Klieman N, Goodman D, Schechtman K, Roberts R, Diltiazem Reinfarction Study (1988) Lack of diurnal variation in the occurrence of non-Q-wave myocardial infarction: Results of a prospective study. J Am Coll Cardiol 1988; 11 : 27A (Abstract) 14. Little WL, Constantinescu M, Applegate RJ, Kutcher MA,

Burrows MT, KahI FR, Santamore WP (1988) Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild to moderate coronary artery disease? Circulation 78:1157 1166 15. Maclure M, Sherwood JB, Andrade S, Goldberg RJ, Toiler GH, Muller JE (1990) Increased risk of myocardial infarction onset within the 2 hours after awakening. Circulation [Suppl III] 82:III-281 (Abstract) 16. Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP, Hier DB, Wolf PA, Caplan LR, Foulkes MA (1989) Morning increase of stroke onset. Stroke 20:473 476 17. Master AM (1960) The role of effort and occupation (including physicians) in coronary occlusion. JAMA 100:475480 18. Mulcahy D, Keegan J, Cunningham D, Quyyumi A, Crean P, Park A, Wright C, Fox K (1988) Circadian variation of total ischemic burden and its alteration with anti-anginal agents. Lancet II : 755-759 19. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler C, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel BE, Willerson JT, Braunwald E, MILIS Study Group (1985) Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 313:1315 1322 20. Muller JE, Ludmer PL, Willich SN, Toiler GH, Aylmer G, Klangos I, Stone PH (1987) Circadian variation in the frequency of sudden cardiac death. Circulation 75:131 138 21. Muller JE, Toiler GH, Stone PH (1989) Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 79:733-743 22. Obraztov VP, Strazhesko ND (1910) The symptomatology and diagnosis of coronary thrombosis. In: Vorobeva VA, Konchalovski MP (eds) Works of the First Congress of Russian Therapists 26-43 23. Quyyumi AA, Panza JA, Lakatos E, Epstein SE (1988) Circadian variation in ischemic events: Causal role of variation in ischemic threshold due to changes in vascular resistance (abstract). Circulation [Suppl II] 78 :II-331 24. Richardson PD, Davies MJ, Born GV (1989) Influence of plaque configuration and stress distribution on fissuring of coronary aterosclerotic plaques. Lancet II : 941-944 25. Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH 0990) Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 82:897-902 26. Rocco MB, Barry J, Campbell S, Nabel E, Cook EF, Goldman L, Selwyn AP (1987) Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation 75 : 395-400 27. Siscovick DS, Weiss NS, Fletcher RH, Lasky T (1984) The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med 311:874-877 28. Toiler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE (1987) Morning increase in platelet response to ADP and epinephrine. Association with the time of increased risk of myocardial infarction and sudden cardiac death. N Engl Med 316:1514-1518 29. Toiler GH, Stone PH, Maclure M, Edelman E, Davis VG, Robertson T, Antmann EM, Muller JE, MILIS Study Group (1990) Analysis of possible triggers of acute myocardial infarction (The MILIS Study). Am J Cardiol 66:22-27 30. Willerson JT, Campbell WB, Winniford MD, Schmitz J, Apprill P, Firth BG, Ashton J, Smitherman T, Bush L, Buja LM (1984) Conversion from chronic to acute coronary artery disease: Speculation regarding mechanisms. Am J Cardiol 54:1349-1354

$78 31. Willich SN, Levy D, Rocco MB, Toiler GH, Stone PH, Muller JE (1987) Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol 60:801-806 32. Willich SN, Linderer T, Wegscheider K, Leizorovicz A, Alamercery I, Schr6der R, ISAM Study Group (1989) Increased morning incidence of myocardial infarction in the ISAM Study: Absence with prior beta-adrenergic blockade. Circulation 80:853 858 33. Willich SN, L6wel H, Lewis M, Arntz R, Baur R, Winther K, Keil U, Schr6der R, TRIMM Study Group (1991) Association of wake time and the onset of myocardial infarction - Friggers and Mechanisms of Myocardial infarction

(TRIMM) Pilot Study. Circulation [Suppl VI] 84:VI-62VI-67 34. Winther K, Hansen K, Klysner RI, Geisler A, Knudsen B, Glazer S, Gormsen J (1985) Platelet aggregation and beta-blockers. Lancet 1 : 224-225

Dr. S.N. Willich Department of Medicine Klinikum Steglitz Free University of Berlin Hindenburgdamm 30 W-1000 Berlin 45, FRG