Precipitating Factors in Acute Cardiovascular Disease
James J. Stec, BS*Research Assistant
Institute for Prevention of Cardiovascular Disease
Geoffrey H. Tofler, MBBS*
Associate Professor of Medicine
Harvard Medical School
Co-Director, Institute for Prevention of Cardiovascular Disease
*Deaconess Hospital
Boston, MA
Quick Overview
The importance of acute risk, which until recently was recognized only for anecdotal cases, lies in its potential to fill several gaps in cardiovascular risk assessment that remain despite knowledge of chronic risk factors gained from studies such as the Framingham Heart Study. (6) The primary data supporting the role of acute risk factors are epidemiologic findings that acute cardiovascular disease onset is more likely during the morning hours after arising. (1-4,7-10) Recently, studies have identified potential triggering activities that could precipitate onset of disease. (4,11-13 ) In the Determinants of Onset of Myocardial Infarction Study (ONSET), (13) an ongoing study sponsored by the National Institutes of Health in which more than 1,800 patients have been interviewed to identify possible triggers of their infarction and to obtain the needed control data, heavy exertion (exertion estimated to be >6 METS) produced a 5.9-fold increase in risk of infarction in the subsequent hour. The relative risk ranged from 107 in sedentary individuals who engaged in physical exertion less than once per week to only 2.4 among patients who performed heavy physical exertion more than five times per week. The relative risk of infarction in the 2 hours following an episode of anger was 2.3. (14) These data support the anecdotal impression that episodes of exertion and anger are capable of triggering AMI.
Triggering may occur when stressors produce hemodynamic, vasoconstrictive, and prothrombotic forces-acute risk factors-that, in the presence of a vulnerable atherosclerotic plaque, cause plaque disruption and thrombosis. The arterial pressure surge (15) and heart-rate increase induced by stressors could lead to plaque rupture. Vasoconstriction could increase shear stress at the plaque site and worsen the flow reduction produced by a fixed stenosis. An increase in platelet reactivity (16) and blood viscosity (17) could create a prothrombotic state, increasing the likelihood of thrombus formation and infarction. While there is normally an increase in circulating tissue-type plasminogen activator activity following adrenergic stimuli, this increase may be attenuated in the presence of atherosclerosis and elevated levels of plasminogen activator inhibitor (PAI-1). (18,19) A state of decreased fibrinolytic potential may increase the risk of thrombus formation. Catecholamines also exhibit a prominent surge after stressors that may contribute to disease onset.
Although autopsy studies generally reveal severe atherosclerotic stenosis at the base of a fatal coronary thrombus, (20) there is angiographic evidence that in many patients surviving a myocardial infarction, the degree of stenosis is relatively mild and that obstructive thrombus accounts for the majority of the obstruction to blood flow. (21) These findings are consistent with the hypothesis that stresses external to the plaque may trigger rupture in a previously nonobstructive plaque, and may explain the absence of prior symptoms in many patients presenting with AMI.
Appreciation of the role of thrombosis in the onset of myocardial infarction has led to the investigation of hemostatic predictors of disease onset. Fibrinogen, factor VII, von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and platelet reactivity have all been linked to disease onset and provide promising markers for future use in risk stratification. Fibrinogen, the best studied of these factors, modifies blood coagulation, blood viscosity, and platelet aggregation. (22) In addition to being an independent predictor of myocardial infarction onset, (23) fibrinogen is associated with traditional risk factors such as age, smoking, elevated cholesterol, and diabetes mellitus. (24-27) The Northwick Park Heart Study found that elevated levels of fibrinogen and factor VII coagulant activity were associated with increased risk for ischemic heart disease. (28)
The available data permit formulation of a general hypothesis regarding the manner in which daily activities may trigger coronary thrombosis. (5) This hypothesis is depicted in Figure 1.
Figure 1
Plaque Vulnerability and Coronary Thrombosis
It is proposed that the initial step in the process leading to coronary thrombosis is the development, with advancing age, of a vulnerable plaque. Plaque vulnerability is defined functionally as the susceptibility of a plaque to rupture. Development of such vulnerability is a poorly understood process but is presumably a dynamic, potentially reversible disorder caused by changes in the constituents of the plaque, its blood supply through vasa vasorum, or the functional integrity of the overlying endothelium.
Intrinsic plaque characteristics and extrinsic factors that predispose to and initiate plaque disruption remain areas of intense investigation. Richardson and coworkers have reported that in 63% of the cases, rupture of the plaque occurred at the junction of a lipid pool with normal tissue. (29) The presence of a lipid core, a thin fibrous cap, and increased macrophage activity seem to be important factors that predispose an atherosclerotic plaque to rupture. Disease onset may begin when a physical or mental stress produces a hemodynamic change sufficient to rupture a vulnerable plaque. The rupture of the plaque may be major or minor, depending on factors such as the amount and type of collagen exposed. (30) A major plaque rupture may produce a thrombogenic focus sufficiently intense to induce an occlusive coronary thrombosis, leading to myocardial infarction or sudden cardiac death. On the other hand, a minor rupture may result in a mural thrombus that either fails to produce symptoms or leads to unstable angina or non-Q-wave myocardial infarction. The site of rupture may then gradually stabilize or, alternatively, further trigger activity, causing an increase in coagulability or vasoconstriction, which may lead to complete occlusion of the artery.
An inverse relation probably exists between the degree of plaque vulnerability and the intensity of triggering stimulus required to produce plaque rupture. For instance, an elderly person with a severe fixed stenosis and an extremely vulnerable plaque may require only a minimal amount of stress (climbing stairs or mild anger) to induce plaque rupture and development of thrombosis. On the other hand, a young individual with a minor lumen irregularity but without a particularly vulnerable plaque may require a major stress (such as heavy lifting) to trigger plaque rupture and thrombus formation. Combinations of triggering mechanisms may also lead to thrombosis. For example, physical exertion (producing a minor plaque rupture) together with cigarette smoking (producing coronary artery vasoconstriction and a relatively hypercoagulable state) may result in acute disease onset in a particular individual, whereas either stressor alone may be of little consequence in that individual.
Further studies, from the epidemiologic to the clinical and molecular level, are needed to determine the role of stressors and plaque vulnerability in disease onset. Insight into triggering offers a new approach to prevention through the identification and treatment of plaques vulnerable to disruption and through the development of pharmacologic and nonpharmacologic means to sever the linkage between a potential trigger and its pathologic consequence. By focusing on the immediate period of transition from chronic stable coronary disease to the acute unstable manifestations of coronary disease, this research also has the potential to lead to improved recognition of warning signs and symptoms for AMI.
References
1. Muller JE, Stone PH, Turi ZG, et al. Circadian variations in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315-1322.
2. Willich SN, Linderer T, Wegscheider K, and others. Increased morning incidence of myocardial infarction in the ISAM study: absence with prior beta-adrenergic blockade. ISAM Study Group. Circulation. 1989;80:853-858.
3. Hjalmarson A, Gilpin EA, Nicod P, et al. Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction. Circulation. 1989;80:267-275.
4. Tofler GH, Muller JE, Stone PH, et al. Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombolysis in Myocardial Infarction study (TIMI) population. J Am Coll Cardiol. 1992;20:1045-1055.
5. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733-743.
6. Levy D, Kannel WB. Cardiovascular risks: new insights from Framingham. Am Heart J. 1988;116:266-272.
7. Pell S, D'Alonzo CA. Acute myocardial infarction in a large industrial population: report of a 6-year study of 1,356 cases. JAMA. 1963;185:831-838.
8. Willich SN, Levy D, Rocco MB, et al. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol. 1987;60:801-806.
9. Marler JR, Price TR, Clark GL, et al. Morning increase in acute onset of ischemic stroke. Stroke. 1989;20:473-476.
10. Mulcahy D, Keegan J, Cunningham D, et al. Circadian variation of total ischemic burden and its alteration with anti-anginal agents. Lancet. 1988;2:755-759.
11. Sumiyoshi T, Haze K, Saito M, et al. Evaluation of clinical factors involved in onset of myocardial infarction. Jpn Circ J. 1986;50:164-173.
12. Tofler GH, Stone PH, Maclure M, et al. Analysis of possible triggers of acute myocardial infarction (MILIS Study). Am J Cardiol. 1990;66:22-27.
13. Mittleman MA, Maclure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion: protection of regular exertion. N Engl J Med. 1993;329:1677-1683.
14. Mittleman MA, Maclure M, Sherwood JB, et al. Triggering of acute myocardial infarction onset by episodes of anger. Circulation. 1995;92:1720-1725.
15. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood pressure. Lancet. 1978;1:795-797.
16. Tofler GH, Brezinski DA, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518.
17. Ehrly AM, Jung G. Circadian rhythm of human blood viscosity. Biorheology. 1973;10:577- 583.
18. Rosing DR, Brakman P, Redwood DR, et al. Blood fibrinolytic activity in man: diurnal variation and the response to varying intensities of exercise. Circ Res. 1970;27:171-184.
19. Andreotti F, Davies GJ, Hackett DR, et al. Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol. 1988;62:635-637.
20. Falk E. Plaque rupture with severe preexisting stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J. 1983;50:127-134.
21. Brown BG, Gallery CA, Badger RS, et al. Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intra-coronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations. Circulation. 1986;73:653-661.
22. Ernst E. Fibrinogen: its emerging role as a cardiovascular risk factor. Angiology. 1994;45:87-93.
23. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501-505.
24. Krobot K, Hense H, Cremer P, et al. Determinants of plasma fibrinogen: relation to body weight, waist-to-hip ratio, smoking, alcohol, age and sex: results from the Second MONICA Augsbury Survey, 1989-1990. Athero Throm. 1992;12:780-788.
25. Balleisen L, Bailey J, Epping PH, et al. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Throm Haemost. 1985;54:475-479.
26. Barasch E, Benderly M, Graff E, et al. Plasma fibrinogen levels and their correlates in 6,457 coronary heart disease patients: the Bezafibrate Infarction Prevention (BIP) Study. J Clin Epidemiol. 1995;48:757-765.
27. Kannel W, Wolf P, Castelli W, et al. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA. 1987;9:1183-1186.
28. Meade TW, Brozovic M, Chakrabarti RR, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Heart Study. Lancet. 1986;6:533-537.
29. Richardson PD, Davis MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941-944.
30. Badimon L, Badimon JJ, Galvez A, et al. Influence of arterial damage and wall shear rate on platelet deposition: ex vivo study in a swine model. Arteriosclerosis. 1986;6:312-320.
Return to Index of Articles for Clinician;
Volume 14.4
- Faculty Listing 3
- Introduction: Community Message in Acute Myocardial Ischemia 4
- Concept of Community Chest Pain Centers in Emergency Departments 5
- Reawakening Awareness of the Importance of Prodromal Symptoms in the Shifting Paradigm to Early Heart Attack Care (EHAC) 7
- The Role of Emergency Medicine in the Future of American Medical Care: A Summary of the Josiah Macy, Jr, Foundation Conference 12
- From ACC/AHA Guidelines to Best Practice: Can "Acute MI Report Cards" Save Lives?Measuring Quality of Care for Patients With Cardiovascular Disease 16
- Improving Lay Responses to Cardiovascular Emergencies and the Potential of Shifting the Paradigm to Early Heart Attack Care 18
- National Survey of Chest Pain Centers Rationale and Potential Results 21
- Outpatient Rule-Out Myocardial Infarction in Observation Units 22
- Reducing Time to Thrombolytic Treatment 24
- Intervention Programs to Reduce Patient Delays in Acute Myocardial Infarction 29
- Public Education Using the Early Heart Attack Care Program Shawnee Mission Medical Center 31
- School Component: Early Heart Attack Care Program Development and Evaluation 33
- Educational Strategies to Prevent Prehospital Delay in Patients at High Risk for Acute Myocardial Infarction 36
- Precipitating Factors in Acute Cardiovascular Disease 41
- Use of Myocardial Perfusion Imaging in the Emergency Department for Risk Stratification 44
- The Evolution of Chest Pain Centers: The Impact of Technological Advances on the Evaluation of Patients With Possible Acute Ischemic Coronary Syndrome 47
- Critical Pathways for Triage and Treatment of Chest Pain Patients in the Emergency Department 53
- Chest Pain Centers: An Emerging Model for the Emergency Evaluation of Chest Pain and Treatment of Acute Myocardial Infarction 56
- The Key to Success in the Chest Pain Emergency Department: The Observational Role of theNurse 59
- Triage in Moderate Risk Patients With Chest Pain: The Emerging Role of Real-Time Continuous ECG Monitoring 61
- Diffusion of Innovations: The Introduction and Impact of the Chest Pain Emergency
- Department and its Comparison to the Coronary Care Unit Development 64
- Economics of Chest Pain Centers: What Really Matters? 68
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