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(Circulation. 1997;96:3233-3239.)
© 1997 American Heart Association, Inc.

Articles

Mechanisms Precipitating Acute Cardiac Events

Review and Recommendations of an NHLBI Workshop

James E. Muller, MD; Peter G. Kaufmann, PhD; Russell V. Luepker, MD; Myron L. Weisfeldt, MD; Prakash C. Deedwania, MD; James T. Willerson, MD; ; for the Mechanisms Precipitating Acute Cardiac Events Participants¹

From the University of Kentucky Medical Center (J.E.M.); the NHLBI (P.G.K.); the University of Minnesota (R.V.L.); Columbia University College of Physicians and Surgeons (M.L.W.); the University of California, San Francisco, School of Medicine (P.C.D.); and the University of Texas Medical School, Houston (J.T.W.).

Key Words: NHLBI • cardiovascular diseases • coronary disease • epidemiology • prevention

	Introduction

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The National Heart, Lung, and Blood Institute held a workshop on August 28–29, 1995, to survey what is known about mechanisms precipitating acute cardiac events and to assess the potential that advances in this field can lead to new methods of prevention of acute cardiovascular disease. Based on data presented at the workshop and subsequent discussions, this document summarizes some of the factors involved in the onset of cardiac events and describes research opportunities in this rapidly developing, multidisciplinary field.

This field can best be appreciated by viewing its relationship to the traditional fields of research on coronary artery disease, as shown in Fig 1. This figure illustrates some of the factors involved at each of several stages of disease, from the cumulative effects of risk factors to long-term management and rehabilitation. Extensive research has been conducted on long-term risk exposure, short-term treatment, and long-term preventive therapy. The study of precipitating or triggering mechanisms—the events occurring in the hours and minutes before the cardiovascular event—has been limited by the fact that they occur primarily out of hospital and over a brief time period in individuals who cannot be identified prospectively among those at high risk for a coronary heart disease (CHD) event.

View larger version (29K): [in this window] [in a new window]   Figure 1. Position of relatively undeveloped area of research on conversion of chronic to acute disease with respect to traditional areas of research on coronary artery disease. ASA indicates aspirin; AF, autonomic function; CABG, coronary artery bypass graft; EP, electrophysiological; ETT, exercise treadmill testing; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; and SCD, sudden cardiac death. Adapted from Reference 23.

The interval during which chronic disease is converted to an acute event is becoming more accessible to study because of progress in the traditional areas. It is known that onset of most acute coronary disease is caused by disruption of a vulnerable atherosclerotic plaque leading to thrombosis. A well-documented morning increase in all major cardiovascular events—sudden cardiac death, nonfatal myocardial infarction, unstable angina, and stroke—indicates an important role of the patient's physiology, activities, and behavior in their onset.

Although much has been learned, numerous questions remain, and many research opportunities are apparent. Pursuit of these opportunities is likely to clarify the mechanisms of disease onset and facilitate the development of preventive therapies designed to sever the link between a potential trigger and the cardiovascular event.

The importance of pursuing the opportunities in the field of triggering arises from the possibility of improved methods of prevention. Because cardiovascular disease often presents with sudden death, all attempts to improve acute treatment are severely limited in their ability to help the majority of patients destined to have a fatal event. Even before we attain the ultimate goal of eliminating atherosclerosis, a better understanding and prevention of triggering would make it possible to prevent numerous premature cardiovascular deaths.

	Epidemiology

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Although it is a commonly held belief that stressful events cause heart attacks, strokes, and sudden death, epidemiological study of the phenomenon has been developed only recently. In the past, medical scientists, recognizing the complex and chronic underlying pathogenesis of atherosclerosis, were skeptical of the frequency and significance of such triggering of disease onset. Lack of information in fatal cases and recall bias among survivors made systematic investigations difficult. However, better understanding of the pathophysiology of acute cardiovascular disease, new epidemiological methods, and more detailed evaluation of available data have led to an improved understanding of triggering.

In addition to the well-documented morning increase of cardiovascular events associated with awakening, more recent data indicate that other activities such as heavy exertion, anger, and sexual activity all increase the risk of acute myocardial infarction. Although these activities are associated with a significantly increased relative risk of cardiac events, the absolute risk difference produced by any single potential trigger is small because baseline risk is extremely low.

Mental stress has been found to be associated with myocardial ischemia even at low heart rates in CHD patients and may be a frequent trigger. Prospective studies have found that measures of hostility predict development of coronary artery disease and mortality 20 to 30 years later. Psychological depression also has been observed to predict coronary events. Several other psychosocial influences (eg, lack of social support) have been associated with increased risk. Acute emotions, such as anger, may confer increased risk directly through neural and neuroendocrine pathways and may lower the threshold at which other triggers become effective. Few intervention studies have been conducted in this area, but their results have been encouraging.

Studies have shown that certain agents may prevent triggering. ß-Blockers appear to decrease the morning peak in events, suggesting that sympathetic stimulation may play a role in a significant number of acute events. Aspirin diminishes the morning peak in nonfatal infarction and the increased risk associated with anger. Because aspirin has significant antithrombotic effects, it is likely that the prothrombotic tendencies associated with awakening and anger contribute to triggering of acute events.

Finally, the well-known sex differences in occurrence of cardiovascular disease may be related in part to differences in vulnerability to specific triggers. There is evidence that platelet reactivity and endothelial dysfunction differ between men and women and that estrogen may result in development of atherosclerotic plaques with characteristics different from those seen in men. The autonomic nervous system regulation of the cardiovascular system may differ by sex, and women may respond differently to emotionally provocative external events.

The epidemiological study of acute precipitants or triggers of cardiovascular events is still in its infancy. Progress may be facilitated by application of new technologies, such as evaluation of autonomic function, extended ECG monitoring, and internal cardioverter-defibrillator devices with telemetry, that can provide new information about the pathophysiology of disease onset.

	Role of the Autonomic Nervous System in Triggering

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Epidemiological evidence strongly implicates activation of the sympathetic component of the autonomic nervous system as a causal link in the onset of cardiovascular disease. For the higher incidence of nonfatal myocardial infarction, sudden cardiac death, and transient myocardial ischemia in the morning hours, the causal nature of the association is supported by the finding that the peak is reduced in subjects receiving ß-adrenergic blockade. Heightened sympathetic activity may contribute to fatal arrhythmias, particularly in the presence of myocardial ischemia.

Although such measures of increased sympathetic activity are associated with a poor outcome, increasing parasympathetic tone through exercise training results in marked increases in heart rate variability and prevents ventricular fibrillation in animal models. Pharmacological alteration of sympathovagal balance has also been attempted. Improvement of sympathovagal balance might be associated with a decrease in risk of triggering.

Specific Recommendations
1. The interrelationships between the autonomic nervous system (and triggers identified by epidemiological studies), local influences on vasomotor tone, the coagulation system, and pathological changes in the coronary vessels should be delineated more completely.

2. Changes in sympathovagal balance should be studied as a potential triggering mechanism for cardiovascular events.

3. Efforts should be made to determine whether changes in the autonomic control of the circulation has a predictable effect on triggered cardiac events.

	Role of Neural Factors and of Ischemia in Precipitating Sudden Cardiac Death

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Sudden cardiac death is widespread and is the most serious of the cardiac diseases, but it is less amenable to study because the victims cannot contribute historical information for epidemiological investigations. Nevertheless, substantial evidence now indicates that its incidence has a peak in the morning and that it is triggered by events that are similar to those that trigger nonfatal myocardial infarction. In addition to the occasional easily recognized triggering of sudden death by physical exertion, both acute and subacute psychological stress may serve as triggers.

It has been reported that anger is the predominant behavioral affect in the majority of patients who experience life-threatening arrhythmias. It has also been shown that in patients with long-QT syndrome, there is an association between episodes of anger and fear and the occurrence of syncopal attacks and torsade de pointes.

In animal models that emulate the states of anger and fear, electrical instability in the form of T-wave alternans and ventricular fibrillation can be induced during both stress and poststress periods. It is conceivable that in many instances, myocardial ischemia provides an important substrate and acts as a trigger for ventricular tachyarrhythmias.

The behaviorally induced changes leading to life-threatening ventricular arrhythmias may result both from direct influences of catecholamines acting on the electrically unstable myocardium and from an indirect influence through impairment of myocardial perfusion. The available experimental evidence from animal models indicates that heightened sympathetic tone, whether induced by direct nerve stimulation, infusion of catecholamines, or imposition of anger-like states, can lead to ventricular fibrillation, especially when the heart has been sensitized by acute myocardial ischemia. It is conceivable that the presence of ischemia and myocardial damage results in regions of sympathetic denervation that can lead to electrical inhomogeneity during periods of heightened sympathetic tone. However, it is not clear how sympathetic stimulation provokes ventricular arrhythmias.

It is known that residual vagal tone can protect the heart against ventricular fibrillation during periods of stress by presynaptic inhibition of norepinephrine release and by opposing formation of the second messenger at the muscarinic receptor level. The interplay between sympathetic activity and vagal tone can be studied by evaluating heart rate variability and baroreceptor sensitivity, two of the most important predictors of long-term outcome in survivors of acute myocardial infarction. It is not clear whether reduced heart rate variability and impaired baroreceptor sensitivity are merely markers of a susceptible substrate or important mechanisms in the genesis of ventricular arrhythmias.

Although the mechanisms leading to sudden cardiac death are influenced by many factors, the majority of cases result from a fatal ventricular arrhythmia, in most cases preceded by myocardial ischemia. Observations in patients concerning precipitants of a fatal arrhythmia not preceded by ischemia have been difficult to obtain, and there is no animal model of the process. Studies in patients with internal cardioverter-defibrillators have shown morning peaks in discharges and may yield valuable information on other triggering activities.

Progress has been made in identifying the myocardial substrate that is vulnerable to a fatal arrhythmia. Noninvasive assessment by measurement of dispersion of refractoriness and T-wave alternans can identify patients at increased risk of events and may prove useful for identifying precipitating mechanisms.

Specific Recommendations
1. Studies should be conducted to identify both physical and mental activities that precede the occurrence of sudden death and thereby identify precipitants. Useful data can be derived from studies of internal cardioverter-defibrillator patients and the general population.

2. Noninvasive markers of myocardial vulnerability to arrhythmia should be sought and tested to identify precipitants as well as to identify and monitor patients at risk.

	Cardiovascular Events During Sleep

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The occurrence of myocardial infarction and sudden cardiac death during sleep raises unique questions about triggering mechanisms. Clearly, sleep is a time when the individual is relatively protected from known precipitating factors; therefore, the frequency of events during sleep is much lower than during waking hours. Nevertheless, 12% to 15% of all cardiac events and almost 36 000 deaths annually occur during sleep, resulting in a substantial health problem and raising the question of mechanism. It may be that these events are influenced by changes in autonomic control as central nervous system activity changes during various sleep stages and that they cluster during periods of rapid eye movement (REM) sleep, when sympathetic stimulation approaches the level reached during daytime triggers. However, the role of autonomic influences during various stages of sleep is poorly understood. Although it is known that sleep is associated with increased vagal activity, major surges in sympathetic activity that accompany periods of REM sleep have the potential of triggering ischemic episodes and ventricular arrhythmias. This may be especially important after myocardial infarction, when the inherent ability to activate the vagus nerve during sleep is impaired. Patients with sleep disturbances may have altered sleep cycles, including altered periods of REM sleep, which can increase potential for adrenergically triggered arrhythmias.

Specific Recommendations
1. Studies are needed on the causes of cardiac events during sleep. Such studies would be facilitated by noninvasive markers of myocardial vulnerability to arrhythmias such as T-wave alternans and electrophysiological indicators of sleep stages.

	Pathophysiology and Detection of Plaque Disruption

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The majority of acute cardiovascular events, whether they occur during sleep or wakefulness, are now known to result from disrupted atherosclerotic plaques. Disruption of coronary artery plaques can lead to occlusive thrombosis, accentuated vasoconstriction, and neointimal proliferation.

There is a new understanding of the relationship between the degree of prior stenosis caused by a plaque and plaque disruption. In contrast to previous theory, it is now known that plaques need not be stenotic to rupture and cause occlusive thrombosis. However, stenotic plaques, although fewer in number in any individual, cause at least one third of thrombotic events. Stenotic plaques also serve as a marker for the number of nonstenotic plaques present. Finally, disruption of nonstenotic plaques that are relatively small may lead to a mural thrombus causing growth of the plaque but no acute symptoms.

Although the hypothesis has not been proved in a prospective study, it is considered highly likely that plaques with a lipid pool and a thin, weakened fibrous cap infiltrated by macrophages are the most vulnerable to disruption. The structural integrity of the plaque cap is dependent on many factors, particularly the equilibrium between synthesis and degradation of collagen and elastin molecules. Recent advances in understanding the role of cytokines and proteases involved in this balance offer promise of new therapeutic methods to stabilize plaques. The marked reduction in cardiac events observed in recent lipid-lowering studies may result from plaque stabilization and remodeling.

There is much interest in the role of inflammation within or surrounding the plaque as a precursor of plaque rupture. Unstable lesions may be particularly prone to infection with cytomegalovirus, chlamydia, or helicobacter that results in an inflammatory response and plaque instability. Alternatively, hemodynamic stress leads to rupture of the plaque, which may also incite an inflammatory and healing response. Evidence supporting the role of inflammation includes the visible presence of inflammatory cells in and around the unstable lesion, activation of metalloproteinases at the location of plaque fissuring and the measurement of a wide variety of inflammatory mediators in and around the unstable lesion itself. Supporting this entire concept is recent work identifying C-reactive protein level in the plasma as a long-term predictor of myocardial infarction risk. The study also shows that aspirin is associated with reduced C-reactive protein levels and reduced infarcts, perhaps by an anti-inflammatory mechanism.

At present, there are no validated invasive or noninvasive methods to identify plaques that are vulnerable to disruption in patients. Efforts to identify such plaques would be greatly aided by availability of an animal model of plaque disruption and thrombus. It may then be possible to develop new imaging techniques that identify characteristics of vulnerable plaques that are different from those of stable plaques. Locally released markers may also allow one to identify such plaques. The clinical goal would be to develop a noninvasive means to identify vulnerable plaques and administer prophylactic treatment. Such treatment may involve systemic or local drug delivery in the catheterization laboratory. With regard to systemic measures, there is little direct information on the role of risk factor modification (control of hypertension, hypercholesterolemia, smoking, sedentary behavior, and estrogen deficiency) in differential plaque composition and complexity at different stages of plaque development.

Development of methods to image denuded endothelium is an important goal. Endothelial damage is the earliest marker of the atherosclerotic process and results in impaired myocardial perfusion through changes in coronary vasodilator function. Endothelium-dependent vasomotion may be improved by cholesterol-lowering interventions, reducing the incidence of acute cardiac events triggered by physical and mental stressors. Thus, early detection of endothelial dysfunction would not only facilitate study of the earliest stages of plaque formation but also open the possibility that early treatment is initiated or that vasoactive substances such as prostacyclin and nitric oxide synthase could be restored at these sites.

Specific Recommendations
1. Efforts should be increased to identify the features of atherosclerotic plaques that predispose them to disruption and to clarify the role of endothelial vasodilator dysfunction in acute cardiac events.

2. Experimental animal models of atherosclerosis in which plaque disruption can be triggered under controlled conditions are needed. Genetically manipulated animal models may be useful in this regard.

3. Methods are needed to identify plaques considered vulnerable to disruption. Patients with such plaques should then be followed to determine whether such sites have a higher incidence of disruption leading to infarction and death.

4. The process of plaque disruption, endothelial dysfunction, and thrombosis in the carotid arteries, which are more amenable to study than the coronary arteries, should be clarified, thereby elucidating the causes of stroke and possibly providing information about the relationship of plaque characteristics and instability in vessels at other locations.

5. Intervention trials of therapies for vulnerable plaques and to restore endothelial function eventually should be conducted.

	Role of Hemodynamic Forces in Onset of Arterial Thrombosis

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Since arterial thrombosis has been shown to result from plaque disruption and often occurs within minutes after activities known to elevate systemic arterial pressure, it has been postulated that surging hemodynamic forces precipitate plaque rupture. Despite the logical appeal of this scenario and the parallels in the circadian cycles of blood pressure and acute ischemic events, no direct supporting evidence is yet available because of the difficulty of directly studying hemodynamic forces and plaque disruption in patients, as well as the lack of animal models of the process. On the contrary, disrupted plaques unaccompanied by occlusive arterial thrombosis are often encountered as incidental findings at autopsy, suggesting that, in some cases, disease onset results from acute increases in thrombotic and/or vasoconstrictive forces at the site of a previously disrupted plaque. Regardless of the role of hemodynamic forces in the onset of acute events, it is clear that both shear stress and intraluminal pressure are important factors in chronic plaque development and in modulating the action of the endothelium.

Specific Recommendations
1. The role of hemodynamic forces in causing plaque disruption (fissuring, ulceration, rupture) should be investigated. The research should build on advances in engineering and the physical sciences pertinent to plaque disruption.

2. Advances in the basic areas should be applied to in situ and in vivo situations. The catheterization laboratory provides an excellent setting to study this issue in humans with atherosclerosis.

3. The long-term interaction between physical forces and development of atherosclerosis requires study in greater detail.

	Role of Prothrombotic Forces in Onset of Arterial Thrombosis

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Although the atherosclerotic plaque, perhaps disrupted acutely by hemodynamic forces, is the underlying cause of arterial thrombosis, both systemic and local thrombogenic factors are likely to play important roles in the acute process. On the systemic level, activities known to trigger disease onset, such as mental and physical stress, are associated with increases in platelet activity. Locally, disruption of a plaque may expose tissue factor, a component of plaques that is a potent stimulus for thrombosis. Atherosclerotic endothelium may lack its normal antithrombotic activity. Thus, a combination of prothrombotic forces may lead to acute disease onset.

Elevated levels of fibrinogen increase risk of CHD, and low levels of fibrinogen reduce incidence of new events in patients with angina and hypercholesterolemia.

Specific Recommendations
1. Identify methods to inhibit the multiple mediators of acute thrombosis. This could include inhibitors of tissue factor, antagonists to platelet glycoproteins IIb, IIIa, or Ib, and other agents with greater antithrombotic effect than aspirin.

2. Develop the means to restore antithrombotic substances at local injury sites. This could include use of forms of tissue plasminogen activator resistant to its inhibitor, methods to stimulate local prostacyclin production, nitric oxide synthase activity, or inhibition of local LDL oxidation.

3. Characterize the thrombotic tendencies produced by activities that lead to triggering.

	Relationship Between Intensity of the Trigger and Vulnerability of the Substrate

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
It is likely that acute onset of disease occurs when the intensity of a trigger exceeds the threshold of vulnerability of the substrate. A mild trigger may be sufficient with a highly vulnerable substrate, whereas a less vulnerable substrate would require a more intense trigger. In the presence of a very fragile plaque, it is likely that an activity that is ordinarily a weak trigger could lead to an event. For the occurrence of an arrhythmia unrelated to thrombosis, a weak trigger superimposed on a highly vulnerable myocardial substrate would be sufficient.

These trigger/substrate relationships are of importance for the design of preventive measures. Since it is impossible to control the intensity of most triggering activities of patients, it appears logical to attempt to reduce substrate vulnerability. For the vulnerable plaque, this could perhaps be done by administration of a collagenase inhibitor or genetic modification of the inflammatory process. For the electrically vulnerable myocardium, drugs that show a more targeted mechanism of action might be developed to suppress the trigger or reduce the vulnerability of the substrate, with less proarrhythmic potential or adverse effects.

	Role of Genetic Factors in Acute Disease Onset

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The role of certain genetic factors, such as familial hypercholesterolemia, in causing a long-term increase in the risk of cardiovascular disease is well established. However, much less is known about the manner in which genetic factors influence the risk that a certain activity may trigger disease onset. For instance, it is not known whether the risk factors leading to plaque formation are identical to those predisposing to acute events. For example, such alleles are known to exist for tumor necrosis factor- and have been shown to correlate with severity of myocardial infarction.

The identification of such genes through epidemiological studies and their manipulation in animals offers great promise for research advances. Gene therapy to decrease risk is currently limited by available vectors and limitations of devices that allow delivery of the agent to the location of the plaque.

Specific Recommendations
1. Epidemiological studies should include evaluation of associations between candidate genotypes, anonymous markers, and acute disease onset.

2. Candidate genes should be tested in genetically manipulated animals (knockouts and transgenics) to sort out the complex factors that possibly cause increased genetic susceptibility to acute disease.

3. Methods to decrease the amount of virus needed as a genetic vector and to restrict transfection to specific tissue such as vascular smooth muscle cells or endothelial cells should be developed.

4. Methods for delivering site-specific intra-arterial therapy are needed.

	Clinical Implications

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The knowledge currently available about precipitants of cardiovascular disease onset should, in most instances, be used to reassure both healthy individuals and cardiac patients about the relative safety of most activities that are thought to be potential triggers. Although activities such as heavy exertion, anger, and sexual activity may double the risk of an acute event, the increase in absolute risk is negligible because the baseline risk of infarction occurring in any given hour is very small. For a healthy 50-year-old man, it is only one in a million.

However, there are two instances in which counseling to avoid a potential trigger is appropriate. The risk that sudden heavy exertion will cause an infarction in a sedentary patient with cardiac disease approaches one in one thousand, and such activities should be discouraged. Likewise, patients who are habitually angry can increase annual risk substantially and should be advised to seek appropriate counseling.

The primary clinical importance of triggering is apparent from analysis of the percentage of cases of acute cardiovascular disease that result from triggers. The four triggers of infarction that have been well characterized (awakening, anger, physical exertion, and sexual activity) account for 17% of the events in those interviewed in the Determinants of Myocardial Infarction Onset Study, or more than 200 000 infarctions annually. It is speculated that additional studies might identify triggers in approximately one third of cases. An additional one third of cases may involve subtle triggers that are never identified, and in a final third, the onset of the disease is likely to result from processes within the plaque entirely unrelated to the activities of the patient.

	Summary

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
The following specific recommendations were highlighted.

Monitoring trends. It is clear that population patterns of cardiovascular diseases are changing. The majority of mortal cardiovascular events occur out of hospital. Better methods are needed to monitor events and classify the circumstances under which they occur. In addition, population studies that include tracking of the widespread use of medications such as aspirin, ß-blockers, and other therapies can provide an estimate of their effects.

Retrospective patient studies. It is likely that new factors that may be triggers of acute events will be discovered from systematic retrospective studies of patients. Both short-term (hours) and long-term (days to weeks) influences may be involved. There may be differences between triggers of first and subsequent events.

Autopsy studies. Detailed postmortem examinations of coronary pathology provide important data that cannot be obtained otherwise. When linked with detailed behavioral data, it can also lead to better understanding of the relationship between triggers and plaque morphology.

Prospective patient studies. A variety of factors that are potential precipitants could be studied either in retrospective cohort studies or nested case-control studies or in prospective studies of survivors of a CHD event. Factors such as acute-phase reactants, autonomic status, sleep apnea, depression, and fatigue are among the many factors whose role requires further investigation.

Transient ischemia. The availability of methods to measure transient myocardial ischemia, which is often not associated with pain, provides a unique opportunity to study precipitating events. Monitoring of patients under various sources of stress, with systematic study of the occurrence of ischemia, has considerable potential.

Treatment strategies. As more information accumulates on precipitating factors or triggers, clinical trials may be indicated, particularly among identified high-risk individuals. These trials could include behavioral, pharmacological, or other treatment approaches. End points should include hard events and may include intermediate markers such as transient ischemia.

Sex differences. Relatively little is known about specific factors that precipitate events in women, and more population information is needed. Differences may involve the biology of the pathophysiological mechanisms leading to ischemia, such as platelet reactivity, endothelial dysfunction, or autonomic nervous system function. They could also result from different external influences, such as psychophysiological differences in response to stress or anger. Observational studies indicating sex differences in the triggers of ischemia may lead to insight into different mechanisms of disease in men and women.

Psychosocial factors. Although the importance of mental stress and negative emotions such as depression and hostility have been described, their specific importance as precipitants of cardiac events requires clarification. Little is known about triggers of sudden cardiac death and even less about triggers of stroke. These are of interest in their own right and may provide additional insights into myocardial infarction and transient ischemic events.

The workshop participants support three primary recommendations: First, psychological factors are likely to play a major role in acute disease onset and deserve increased study. Second, efforts should be accelerated to identify vulnerable plaques before they cause disease onset. Plaques that are vulnerable to rupture and cause thrombosis, vasoconstriction, and rapid proliferation represent a major health threat to the population. Current technology identifies stenotic plaques but cannot identify nonstenotic, vulnerable plaques or early signs of endothelial disease. Once vulnerable regions can be identified prospectively, intervention studies can be conducted to determine the feasibility of altering fatal and nonfatal cardiac events by use of systemically or locally delivered therapies. Third, opportunities for interdisciplinary dialogue, such as provided by this workshop, should be encouraged in order to provide the necessary communication between researchers studying the numerous aspects of this new research area.

It was the conclusion of workshop participants that pursuit of the above goals and the specific recommendations listed in each section would lead to considerable advances in treatment and prevention of cardiovascular disease.

View larger version (27K): [in this window] [in a new window]   Figure 2. Interactions between chronic and acute risk factors influence pathophysiological processes to modulate the likelihood that a patient with CHD will experience an acute event. Therapeutic influences act at several levels to modify the underlying risk. AAD indicates antiarrhythmic drug; ACEI, ACE inhibitors; and SCD, sudden cardiac death. Figure developed by P. Deedwania, MD.

	Footnotes

 
Reprint requests to Peter G. Kaufmann, PhD, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Bldg 2, MSC 7936, Bethesda, MD 20892-7936.

Guest editor for this article was Salim Yusuf, MBBS, DPhil, Hamilton General Hospital, Ontario, Canada.

¹ Participants are listed in the "Appendix."

	Appendix 1

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
Participants in the Workshop on Mechanisms Precipitating Acute Cardiac Events
Cochairs: Myron L. Weisfeldt, MD, Columbia University College of Physicians and Surgeons; Russell V. Luepker, MD, University of Minnesota.

NHLBI Liaison and Planning Committee: Peter G. Kaufmann, PhD, and Jeffrey Cutler, MD, Division of Epidemiology and Clinical Applications; Alan Berson, PhD, John Fakunding, PhD, Momtaz Wassef, PhD, and Constance Weinstein, PhD, Division of Heart and Vascular Diseases; Clarice Reid, MD, and Pankaj Ganguly, PhD, Division of Blood Diseases and Resources.

Moderators: Prakash Deedwania, MD, University of California, San Francisco, School of Medicine; James E. Muller, MD, University of Kentucky Medical Center; James T. Willerson, MD, University of Texas Medical School at Houston.

Participants: Jeffrey Cutler, MD, National Heart, Lung, and Blood Institute; Peter F. Davies, PhD, University of Chicago; Gaetano M. De Ferrari, MD, Università di Milano, Italy; Toren Finkel, MD, PhD, NHLBI; Margaret Forney-Prescott, PhD, Novartis Corp; Lawrence Friedman, MD, NHLBI; Valentin Fuster, MD, PhD, Mount Sinai Medical Center; Seymour Glagov, MD, University of Chicago; Millicent Higgins, MD, NHLBI; Richard Kirkeeide, PhD, University of Texas at Houston; David S. Krantz, PhD, Uniformed Services University of the Health Sciences; Lewis Kuller, MD, DrPH, Graduate School of Public Health; Matthew N. Levy, MD, Mount Sinai Medical Center; Peter Libby, MD, Brigham and Women's Hospital; Pamela Ouyang, MD, Johns Hopkins University; Nathaniel Reichek, MD, Allegheny General Hospital; Richard Verrier, PhD, Harvard Medical School, Deaconess Hospital; and Douglas P. Zipes, MD, Krannert Institute of Cardiology.

The following references are not intended to be comprehensive or to reflect all of the important and wide-ranging studies relevant to the field of research on precipitating mechanisms.

Received April 14, 1997; revision received July 30, 1997; accepted August 10, 1997.

	References

Top Introduction Epidemiology Role of the Autonomic... Role of Neural Factors... Cardiovascular Events During... Pathophysiology and Detection of... Role of Hemodynamic Forces... Role of Prothrombotic Forces... Relationship Between Intensity... Role of Genetic Factors... Clinical Implications Summary Appendix 1 References

 
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