Future Directions

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Further investigations into the mechanisms by which the atherosclerotic plaque and its hemostatic milieu undergoes transformation from a stable to a vulnerable configuration will identify new targets for pharmacologic and other manipulations to reduce the ability of a given trigger or combination of triggers to induce plaque rupture and intra-coronary thrombosis. Certain genetic variants may confer particular susceptability to various triggers, allowing more targeted recommendations for primary and secondary prevention. The use of serum markers of inflammation to predict cardiac events may evolve such that risk increases over shorter time periods may be appreciable; i.e., a heightened risk for the next month as opposed to the next 6-12 mo. If this could be accomplished, it might facilitate adjustments of lifestyle and therapy during relatively short periods of significantly increased susceptability to external triggers.

In addition to improving the understanding of plaque biology, clinically applicable methods will need to be developed to detect vulnerable plaques in patients (198). Contrast arteriography, currently the most widely used technique to visualize the coronary arteries, visualizes the degree to which plaques obstruct the arterial lumen and can determine gross features of plaque such as large ulcerations (16). Arteriography has limited ability to identify obstructive plaques that are likely to produce acute coronary

Percent of Mi's that are Triggered

(1,700 patient interviews in the NHLBI Ml Onset Study)

Anger (R.R 2.3) Sexual activity (R.R 2.1)

Heavy physical exertion (R.R. 5.6)

At least 245,000 Mi's per year are triggered.

Fig. 16. Percent of myocardial infarctions that are triggered. Reprinted with permission from ref. 209.

syndromes and cannot identify the minimal nonobstructive lesions that are often the culprits in acute syndromes (16). Intravascular ultrasound, a clinically available imaging modality, has greatly improved the ability to visualize the structure of the coronary artery, albeit with limited resolution (199). Emerging new technologies, such as optical coherence tomography (200,201), magnetic resonance imaging of the coronary arteries (202), thermal detection techniques (203,204), intravascular electrical impedance imaging (205), and various forms of spectroscopy may provide a superior means of imaging vulnerable plaques. Near-infrared spectroscopy (206-208) has the potential to image both the architecture as well as the biochemical composition of atherosclerotic material.

Current data suggest that the well-characterized triggers of infarction account for 15-20% of all infarctions (209) (Fig. 16). It is likely that further epidemiological studies will identify additional triggers, particularly the less well studied issues related to mental stress, and to the onset of events occurring during sleep. It is not possible to free human beings from the circumstances that appear to trigger the onset of acute cardiovascular disease. The goals of future research will be to elucidate further the mechanisms connecting human circumstances to plaque rupture and intracoronary thrombosis and to develop therapy to weaken or sever these links.

• Current data suggest at least 15-20% of acute myocardial infarctions may be triggered.

• All acute cardiovascular events studied have displayed a circadian variation, with a morning (6 am to noon) excess (relative risk almost 1.4) and a nighttime nadir. The risk is further increased with adjustment for time of awakening.

• Besides awakening, other triggers of acute myocardial infarction identified in carefully controlled epidemiologic studies include, heavy physical exertion, sexual intercourse, and outbursts of anger. Exposure to substances such as marijuana, cocaine, and heavy air pollution have also been shown to be triggers.

SUMMARY: KEY POINTS

• Despite the excess of relative risk of infarction (risk increases of 1.5- to 100-fold) imparted by these activities, the low risk of myocardial infarction, on an hourly basis, keeps the absolute risk increase imparted by these activities quite small in most cases.

• The relative risk of physical exertion or sexual activity triggering infarction can be reduced by vigorous exercise several times weekly.

• Most physiologic processes thought to be implicated in the genesis of acute coronary syndromes display a similar circadian pattern. The morning hours are characterized by an increase in blood pressure, heart rate, sympathetic nervous system activity, and by a relatively prothrombotic, hypofibrinolytic state.

• b-Blockers and aspirin have been demonstrated to attenuate the morning increase in infarction incidence.

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