Acute Coronary Events

Abstract

In the United States alone, more than 400,000 Americans die annually from coronary artery disease and more than 1,000,000 suffer acute coronary events, i.e., myocardial infarction and sudden cardiac death.¹ Considering the aging of our population and increasing incidence of diabetes and obesity, the morbidity from coronary artery disease, and its associated costs, will place an increasing, substantial burden on our society.² Between 2010 and 2030, total direct medical costs spent in the US for cardiovascular diseases are projected to triple from 273 to 818 billion dollars.² Although effective treatments are available and considerable efforts are ongoing to identify new strategies for the prevention of coronary events, predicting such events in an individual has been challenging.³ In hopes of improving our ability to determine the risk of coronary events, it is prudent to review our knowledge of factors that lead to acute coronary events.

Coronary Atherosclerotic Disease as a Prerequisite for Coronary Events

Coronary atherosclerosis is the underlying condition for coronary events with few exemptions. Events are rarely caused by coronary dissection, arteritis, myocardial bridging, thromboembolism, or coronary vasospasm, without obvious coronary artery disease.⁴ In some of these instances, more sensitive tools for the detection of coronary artery disease revealed its presence after all.⁵ Coronary atherosclerosis is known to develop in childhood and adolescence, as evident from fatty streaks, seen in pathology studies of individuals dying of trauma or other noncardiac causes.⁶ Depending on the constellation of genetic and environmental factors, coronary artery disease progresses throughout adulthood and is found in most middle age individuals in developed nations. Autopsy series in US communities among young adults (mean age 36±14 years), dying from non-natural causes, revealed to have coronary atherosclerosis in more than 80% of the autopsy sample with approximately 8% having obstructive disease.⁷ Thus, most individuals—age 40 or older—in our society have evidence of coronary atherosclerosis. However, the annual incidence of acute coronary events in the US for individuals 40 years and older is 0.2-1 %,¹ which is a relatively small number—considering the wide spread prevalence of coronary artery disease. All of the above observations strongly suggest that factors other than the mere presence of coronary atherosclerosis need to be involved for an acute coronary event to occur.

Plaque Morphology Associated with Acute Coronary Events

Typically, two atherosclerotic plaque morphologies are associated with acute coronary events, plaque rupture, and plaque erosion. A few (2-7%) cases are attributable to a third plaque morphology termed calcified nodule.⁸ In an autopsy series of 241 cases of sudden coronary death, plaque rupture accounted overall for 31% of culprit plaque morphology.⁹ When cases with acute thrombus are considered, plaque rupture is found at the culprit lesion site in 59-75% of patients.^{9, 10} Denudation of the coronary arterial endothelium, also termed “erosions”, is found in 19% of plaques in all patients with sudden coronary death, and in 36-44% of plaques with acute thrombus (Figure 1).⁹ Fresher thrombi are more frequently associated with plaque rupture than erosion, suggesting that the former is more frequently associated with acute presentation.¹¹

Figure 1.

Histopathologic images of partially and complete coronary arterial lumen occlusion, due to thrombosis. Panel A shows an example of plaque erosion with non-occlusive thrombus in a 73-year-old man, without history of coronary artery disease, who died suddenly. The plaque shown—located in the proximal LAD—is the potential culprit lesion. The thrombus is adhering to a proteoglycan-rich intima, as demonstrated in the magnified section. Early organization of the thrombus is evident, near the intima. Panel B shows plaque erosion, with occlusive thrombus, in a 37-year-old man, who suffered an unwitnessed sudden cardiac death. The plaque shown, located in the proximal LAD, is the likely culprit lesion. Although early necrotic core (NC) is present (black arrows), there is no connection between NC and thrombus. Panel C demonstrates a ruptured plaque—with occlusive thrombus (Thr)—in a 47-year-old man with no history of coronary artery disease, who died suddenly. The plaque shown located in the proximal LAD is the likely culprit lesion. The fibrous cap is disrupted (yellow arrow), allowing the exposure of the necrotic core to the blood stream. All specimens were stained using Movat pentachrome.

Abbreviations: LAD: left anterior descending coronary artery; NC: necrotic core; thr: Thrombus.

The “Vulnerable” Atherosclerotic Plaque

Plaque rupture is most commonly associated with acute coronary events and identification of coronary atherosclerotic plaques which are prone to rupture, termed vulnerable plaques, is currently being intensely investigated. Pathology and clinical studies revealed that the atherosclerotic plaque type at the greatest risk of rupture is a thin-cap fibroatheroma, characterized by a large necrotic core covered by a thin layer of fibrous cap (Figure 2).^{8, 12-14} Early in the atherosclerotic process, only minimal fatty infiltration is evident in the arterial wall. The necrotic core increases in volume secondary to several mechanisms, particularly macrophage infiltration and their demise, and intraplaque hemorrhage with free cholesterol derived from erythrocyte membranes.^{15, 16} The necrotic core is separated from the flowing blood by an ultrathin (mean thickness 23 μm) layer of fibrous tissue that is depleted of smooth muscle cells, and then infiltrated by macrophages as well as T-lymphocytes at the site of disruption. Plaque growth, ongoing inflammation within the fibrous cap, external sheer stress, and other factors, may particularly affect the “thinnest region” of the fibroatheroma, which may tear exposing the highly thrombogenic material to the blood stream (Figure 2).^{8, 12} Pathology, as well as clinical studies using coronary angioscopy, consistently documented thrombus formation at sites of plaque rupture, and also, frequently at sites of plaque erosions.^{8, 11, 17, 18}

Figure 2.

Histopathologic images of thin cap fibroatheromas at various stages. Panel A shows an example of an intact thin cap fibroatheroma, with large necrotic core (NC), in a 47-year-old man who died suddenly. The plaque shown — located in the proximal RCA— resulted in 70% cross-sectional lumen narrowing. Panel B shows a plaque rupture with non-occlusive thrombus (Thr), in the LCx, of a 44-year-old woman, without history of coronary artery disease, who died suddenly. The yellow arrow marks the site of the disrupted fibrous cap. Panel C demonstrates a coronary arterial cross-section, with evidence of several healed plaque ruptures, in a 55-year-old man, who died suddenly—prior to scheduled cardiac catheterization. Autopsy revealed severe three-vessel coronary artery disease. Shown is a plaque in the proximal LCx causing 80% lumen narrowing. The magnified section and black arrows highlight multiple necrotic cores (NC), which ruptured at different points in time leading to the multi-layered appearance. All specimens were stained using Movat pentachrome.

Abbreviations: NC: necrotic core; RCA: right coronary artery; LCx: left circumflex coronary artery; Thr: thrombus.

It is important to note that contrary to common perception, there is compelling evidence that plaque rupture and thrombus formation most often do not lead to coronary events.^{19, 20} Rather, both plaque rupture and thrombus formation are fairly frequent events, which are instrumental in plaque progression and development of lumen stenoses.^{19, 21} Postmortem studies in non-selected patients without history of heart disease, who died from non-cardiac causes, reveal evidence of coronary arterial plaque rupture in 8-11%.^22-24 In patients who died from non-cardiac causes, but had risk factors for coronary artery disease, 16% reveal coronary plaque ruptures¹⁹ and 31% of a similar patient population show plaque ruptures in one study that used extensive coronary arterial sectioning.²⁵ Pathology and clinical studies show that plaque rupture and thrombus formation are frequently present in the absence of symptoms.^{17-19, 24} In another autopsy study, investigators found evidence of prior plaque rupture and thrombus formation in the vast majority of coronary arterial stenoses, 50% or greater, despite absence of symptoms in many.²⁶ A different group of investigators confirmed these findings, and revealed that multiple healed plaque ruptures are typically necessary for a high grade coronary arterial stenosis to develop (Figure 2).^{27, 28} Indeed, only 11% of plaque ruptures are virgin in nature, i.e., they were not preceded by prior ruptures of the same plaque in these studies.²⁸ Lastly, clinical studies using angioscopy or intravascular ultrasound found evidence of thrombus and plaque rupture remote from culprit sites in patients with unstable and stable symptoms, further confirming its frequent presence—despite the lack of events originating from their sites.^{18, 29}

All of the above observations strongly suggest that an acute coronary event is not a necessary consequence of coronary plaque rupture, rather, it is an unusual correspondence of a plaque rupture or erosion (Figure 3). Most commonly, plaque ruptures or erosions occur without symptoms and lead to progression of plaque volume. These observations suggest that identifying plaques that are prone to rupture, i.e., “vulnerable” plaques, may not be as significant as commonly perceived. This concept was recently confirmed in the PROSPECT study, which followed 697 patients after Virtual Histology® intravascular ultrasound, for 3 years, for the occurrence of adverse cardiac events.¹⁴ While 595 thin cap fibroatheromas were identified by intravascular ultrasound in 313 of 623 patients, only 26 of these plaques were sites of subsequent events at 3 years – almost all (if not exclusively) events were related to rehospitalization for unstable or progressive angina. Indeed, of more than 3,000 non-culprit lesions identified by intravascular ultrasound at baseline in 673 patients with acute coronary syndrome, only 6 were subsequently related to myocardial infarction and death after 3 years.¹⁴ The PROSPECT study confirmed smaller clinical investigations using optical coherence tomography,³⁰ suggesting that the identification of a potentially “vulnerable” plaque may confer some increase in coronary event risk—but it is far less than generally assumed. Importantly, since PROSPECT employed IVUS for predicting events based on plaque characteristics confined to a lesion but not patient level analysis, it remains unclear if individual plaque characteristics confer incremental predictive value over established risk factors, e.g., total plaque burden assessment etc, for subsequent acute events in patients.

Figure 3.

The progression of coronary artery disease. In panel A, a cross-section of a normal artery is shown. Atherosclerotic plaque has accumulated in the next drawing (B) leading to external vascular remodeling, to minimize lumen encroachment. Panel C illustrates the event of plaque rupture and plaque hemorrhage leading to intramural thrombus. In the vast majority of cases, such plaque rupture will lead to plaque healing and growth (Panel D). In some cases, thrombus material is embolized distally, which may cause symptoms of coronary arterial insufficiency or asymptomatic microinfarctions (Panel E). In case plaque rupture coincides with a thrombosis conducive state at the site of plaque rupture or erosion, arterial thrombosis and occlusion may occur which may trigger a coronary event (Panel F).

In addition to the aforementioned observations, there is intriguing evidence on the temporal instability of plaque morphology, which may further reduce the significance of identifying plaque characteristics at a given point in time. In a clinical study, using intravascular ultrasound, the majority of thin-cap fibroatheromas changed into thick-cap fibroatheromas—after only one year follow up.³¹ Conversely, some thick-cap fibroatheromas as well as some mild plaques, described as intimal thickening at baseline, changed into thin-cap fibroatheromas over 12 months. If confirmed, these data suggest that a plaque that appears vulnerable at a given time may be less vulnerable just months later, while another plaque, initially not vulnerable, may have developed vulnerable characteristics within the same time frame. More serial imaging data are needed to conclusively establish the temporal stability of plaque morphology, but the preliminary data available corroborate observations from pathology studies for coronary artery disease to be an active process, which likely is constantly changing.

The Significance of Vascular Thrombosis

Pathology studies of sudden coronary death reveal the presence of an acute thrombus in 52% of cases, which acutely or subacutely lead to partial or complete arterial occlusion (Figure 1).⁹ However, this incidence increases to 74% if one included chronic total occlusions. Similarly, angiographic studies in patients suffering from acute coronary events show evidence of coronary artery disease and arterial thrombosis in most cases.^{32, 33} In the absence of an arrhythmia, resulting from acute ischemia, the degree and location of coronary arterial thrombosis and the resulting lumen obstruction determines the severity of the event, i.e., the development and extent of myocardial infarction. A pathology series found coronary intraluminal thrombus in 76% of patients dying suddenly of myocardial ischemia.³⁴ Healed myocardial infarctions were found in approximately half of those cases without obvious vascular thrombosis, suggesting that a coronary event in the past eventually lead to myocardial scar formation and lethal arrhythmia. Thus, the vast majority (>80-90%) of sudden coronary deaths are either the immediate result or a sequela of acute coronary arterial thrombosis.

Factors and Conditions Associated with Increased Acute Coronary Event Risk

Since most plaque ruptures and erosions do not lead to symptomatic arterial thrombosis, other factors must be present for acute coronary events to occur. Numerous conditions are associated with an increased risk of acute coronary events (Table).³⁵ For many, it remains unclear if they are associated with the development/progression of coronary atherosclerosis, with the frequency of plaque alterations, with conditions conducive to thrombotic vascular occlusion, or with a combination of these. Factors and conditions associated with increased acute coronary event risk may be further categorized into those that are related to coronary atherosclerotic plaque characteristics, coronary flow dynamics, intrinsic hemostatic/fibrinolytic dysfunction, neurohormonal dysregulation, and environmental factors and triggers (Table). Some of the most intriguing concepts will be discussed here. Studies using both IVUS and CT suggest that plaques with large volume (and presumably large lipid core) are of greater risk triggering acute coronary events compared to plaques with smaller volumes, possibly due to larger mass of thrombogenic material exposed to the blood stream.^{14, 36} Furthermore, the location of such plaques is of importance. Autopsy and clinical studies revealed that culprit lesions occur predominantly in proximal coronary arteries near branch points where there is turbulent flow.^{8, 37} Certain shear stress and blood flow characteristics may promote “high-risk” plaques and thrombosis favorable blood flow dynamics.^{38, 39} There has been a particular interest in the intuitive notion that the larger the baseline lumen obstruction, the greater the risk of an occlusive thrombus in the setting of plaque rupture or erosion. This concept, however, has remained unproven. While patients enrolled in the CASS registry with >50% LAD stenosis were of greater risk of subsequent anterior wall myocardial infarction compared to those with less severe lesions, the possibility that other lesions within the same vessel caused the event could not be excluded.⁴⁰ Both the PROSPECT and VIVA study suggested that smaller luminal area at plaque site is associated with increased event rates, but because rehospitalization or revascularization were the vast majority of these endpoints, an association with acute myocardial infarctions or sudden death was not evident.^{13, 14} Angiographic studies established that patients with 50% or greater stenosis have a much higher event rate compared to patients with non-obstructive disease.^{41, 42} However, at least two confounders may explain this phenomenon: 1) Patients with 50% or greater stenosis are likely to have a greater total atherosclerotic plaque burden than patients with non-obstructive disease, which may explain the higher event rate rather than the actual 50% stenosis itself. 2) Patients with 50% or greater stenosis may be distinct from patients with mild disease by more active, progressive coronary artery disease, i.e., they have a higher frequency of plaque ruptures/erosions, hence formed more advanced stenoses, and with that, their likelihood increases of coinciding with an unfortunate constellation of thrombosis promoting factors. On the other hand, several angiographic studies suggest that the majority of myocardial infarctions arise from plaques with only mild-moderate lumen narrowing.^43-45 Pathology studies reported variable results for diameter stenosis (values were transformed from the original reported area stenoses) at the site of acute thrombus. Some studies found most such lesions to be less than 50% stenotic⁴⁶ but others reported the majority with >50% lumen narrowing.²⁴ Pathology studies are known to overestimate coronary artery stenoses by 25-30% compared to angiographic techniques because no lumen reference is used.⁴⁷ At present, therefore, we do not have good evidence supporting the notion that greater baseline lumen stenosis is an important factor for occlusive thrombus after plaque alteration. On the other hand, above referenced studies are in agreement, that most acute events arise from plaques that are at least 25-50% lumen obstructive, suggesting a certain plaque volume is necessary to trigger clinically significant thrombosis.

Table. Factors and Conditions Associated with Increased Risk for Acute Coronary Events.

This table lists some of the established factors and conditions that are associated with increased acute coronary event risk. Note that there may be other, less well established factors, and unknown conditions which are not included.

Coronary Plaque Characteristics	Coronary Blood Flow Dynamics	Intrinsic Hemostasis Factors	Metabolic & Inflammatory Conditions	Neuro- Hormonal Imbalance	Environmental Factors & Drugs
Plaque burden Lumen encroachment Lesion location Plaque composition Plaque Biology Plaque configuration and remodeling Endothelial Dysfunction	Blood viscosity Shear stress Reduced blood flow/low cardiac output Vascular tone and reactivity Arterial hypertension	Platelet function/volume Circadian variation Factor V Leiden deficiency Von Willebrand factor deficiency Antiphospholipid syndrome	Diabetes Obesity Dyslipidemia Connective tissue diseases Infections Renal disease	Stress Catecholamine Surges Depression Exertion Autonomic dysfunction Endocrine imbalance	Smoking Pollution Climate Legal drugs Illegal drugs Diet Sedentary life style

Of potentially pivotal importance are internal hemostasis function, platelet aggregation, and fibrinolysis at the time of plaque rupture/erosion. Patients with systemic alterations of their coagulation system, e.g., antiphospholipid syndrome, von Willebrand factor, or factor V Leiden deficiency, are at increased risk for acute coronary events compared to normal controls.^48-51 Importantly, this association remains intact even after adjusting for inflammatory markers and other established risk factors.⁵⁰ Elevated platelet volume and high platelet reactivity also were found to be associated with increased acute coronary event risk.^{52, 53} For other disorders, such as protein C & S deficiency, the data are less conclusive at present.⁴⁸ Several hemostatic proteins have been associated with increased risk of acute coronary events. Fibrinogen levels are independently predictive of myocardial infarction, even when accounting for inflammatory markers, e.g., C-reactive protein.⁵⁴ Other factors, such as D-dimer and tissue plasminogen activator, also have been shown to be predictive of acute events.⁵⁵ Even in patients without obvious hemostatic deficiency, hemostasis functions, platelet reactivity and fibrinolysis are influenced by numerous factors— which may reduce or enhance their function throughout a given day. There is strong evidence for circadian variation of hemostasis and platelet function leading to relative hypercoaguability in the morning.⁵⁶ Several large clinical studies found a peak of myocardial infarction and sudden cardiac death in the early morning hours, suggesting a possible association with a thrombosis conducive state during that time.⁵⁷ However, a causal relationship – while intuitive – is not proven and other factors, e.g., rising catecholamine and cortisol levels, must also be considered. In addition to circadian variation, the ability of the coagulation system to prevent thrombosis, in response to a stimulus, varies throughout the day based on diet, stress, co-morbidity, exposure to toxins (e.g., smoking, pollution), drug intake (legal and illegal), and local metabolic conditions.^58-64 Thus, because of the almost minute-to-minute variability of hemostasis function, it is exceedingly difficult to predict its performance at a given point in time, i.e., at the time of plaque rupture/erosion.

A strong body of evidence supports a key role for inflammation in the development and progression of atherosclerosis.¹⁵ Numerous cytokines, mediators, and proteins have been identified which influence cholesterol uptake into the arterial wall and the generation/accumulation of atherosclerotic plaque.¹⁵ In addition, inflammation is involved in destabilizing the plaque and in promoting thrombosis.⁶⁵ Conditions that are associated with enhanced inflammation, e.g., obesity, infections, are generally associated with increased coronary event risk.⁶⁶ It is interesting to note that similar to the variability of hemostasis functions, inflammatory processes show a circadian variability, which may contribute to states of temporary hypecoaguability.⁶⁷

The Perfect Storm Scenario Leading to an Acute Coronary Event

While there are numerous factors and conditions which play a role in the pathophysiology of acute coronary events, it is very clear that their respective contributions in isolation are insufficient to adequately predict events. Available data for individual plaque characteristics, fibrinogen levels, C-reactive protein (as a marker for inflammation), cholesterol levels, diabetes, and numerous other factors and conditions, indicate only small relative increases of acute coronary event risk for a given individual compared to controls.^{14, 36, 54, 68} Largest hazard ratios have been found in patients with high coronary atherosclerotic plaque burden as estimated by coronary calcium scoring.⁶⁹ In conjunction with traditional risk factors, e.g., diabetes, hypertension, hyperlipidemia etc., the area under the receiver operating characteristic curve for calcium scoring increased to 0.83 for predicting myocardial infarction or cardiac death, which indicates good diagnostic accuracy—yet still insufficient for accurate prediction.⁶⁹ Given the frequency of “vulnerable” plaque features and the very large number of subjects with evidence of plaque ruptures without apparent symptoms, it is apparent that either we have not identified a very important mechanism for triggering acute coronary events or acute events are not caused by a single or few factors, but rather by the unfortunate constellation of numerous conditions. Given the complexity of factors involved, the latter situation is more likely, i.e., a ‘perfect storm’ scenario is necessary for an event to occur. The discussed variability of key processes, such as hemostasis and inflammation, further support the hypothesis that an unfortunate constellation of occlusive thrombosis promoting factors must coincide at the time of plaque rupture or erosion to cause an acute coronary event. Thus, the probability of the timing of an acute event appears to be influenced by the formation of multiple factors - which are poorly understood at this time - and likely also by chance. While this hypothesis is difficult to prove, it most satisfactorily explains the apparent variability in the occurrence of acute coronary events and our difficulties in predicting events in individuals.⁷⁰

Therefore, coronary events likely occur with the unfortunate convergence of (1) a nidus for thrombosis in a coronary artery (plaque rupture, erosion, or calcified nodule) in combination with (2) an inability of the patient to prevent clinically significant thrombus formation at a given point in time. The balance between these two factors may vary with time. The coronary arterial nidus, for example, may be relatively confined and limited, but may coincide temporally with enhanced thrombogenesis. This is a combination that might be seen in a subject (with an acute coronary event) who has mild, focal coronary arterial disease and no recurrent events. In contrast, the stimulus for thrombosis may be strong such as that which occurs with extensive plaque rupture, but the propensity for clinically significant thrombosis may be low such as seen in many patients with severe coronary artery disease who never experience myocardial infarction or sudden cardiac death. Furthermore, there is ample evidence that the balance between thrombosis promoting and antagonizing factors is frequently fragile for days after a plaque alteration, since any thrombus formation is conducive for more extensive thrombosis.^{71, 72} The severity of ischemia—caused by an acute coronary event—depends on the location of vascular blood flow restriction and its supplied myocardial territory, as well as collateral blood flow, current metabolic demands, and other factors. Finally, chance may also play a role in determining the severity of myocardial arrhythmia as myocardial ischemia may coincide with membrane properties conducive to arrhythmia, e.g., at a vulnerable point, within the cardiac cycle, possibly paired with electrolyte imbalances.

Implications for Preventative Measures

The concepts presented in this review detail important implications for preventative strategies. Overall, the occurrence of an acute coronary event appears to result from an unfortunate coincidence of a coronary arterial stimulus for clinically significant thrombosis and a thrombosis conducive state, at the site of the plaque rupture or erosion (Figure 4). The probability of an event is influenced by the frequency and strength of thrombogenic stimuli within the coronary arteries, and by the frequency and extent of the thrombosis favorable condition. In general, the greater the plaque burden and the activity of the coronary artery disease, the more plaque ruptures/erosions will occur, which increases the chance that a stimulus will coincide with a state that may permit the development of a vascular occlusive thrombus. This concept is supported by strong evidence of increased coronary event risk in patients with progressive coronary atherosclerotic plaque burden and accelerated plaque progression.^{73, 74}

Figure 4.

The complex interplay of factors contributing to acute coronary event risk. The purpose of this illustration is to convey the complexity of factors influencing event risk, but not to provide a complete list of factors and associations involved. Both coronary thrombogenicity, i.e., a stimulus for clinically significant arterial thrombosis, and a thrombosis favorable condition need to be present for a coronary event to occur.

Conversely, absence of coronary atherosclerotic plaque, as confirmed on IVUS or CT, essentially excludes the possibility of acute coronary events in the short and midterm.^{41, 75, 76} On the other hand, the more conducive the conditions are to thrombosis, the greater the event risk will be—even with mild coronary artery disease in the setting of plaque rupture or erosion, which is suggested by the increased event risk, in patients with hypercoagulable states.⁷⁷

The available data suggests coronary event probability to be fundamentally a function of the amount of potentially vulnerable substrate: while a single, potentially vulnerable plaque is rather unlikely to cause an acute event, the more coronary atherosclerotic plaques are present, the greater the likelihood that recurrent vulnerable features will develop, and rupture or erosion of any of these plaques will trigger an event in the setting of a vascular thrombosis favorable state.

The requirement of plaque rupture or erosion coinciding with an occlusive, clinically significant thrombus promoting condition hinders our ability to predict such event to happen, as both occur with great variability. Similar to the “perfect storm” analogy, one may establish certain probabilities for both plaque rupture/erosion and occlusive thrombus favorable conditions to coincide, but a substantial residual component of uncertainty will remain. It appears intuitive that the more variables and factors can be considered, the more accurate the estimate will be for the probability of an acute event to occur. Importantly, since coronary atherosclerosis essentially is a “conditio sine qua non” assessing its extent, severity, and location must be considered fundamental for risk estimates. Furthermore, plaque characteristics, extent of lumen obstruction, and the activity of coronary artery disease (rate of progression) appears to be promising for estimating coronary event risk. Factors influencing coagulation, e.g., inflammatory states, co-morbidity, disposition, environmental factors, etc., must be considered in conjunction with “coronary” risk factors to maximize our ability to predict events. The concepts described here underscore the need to recognize and address atherosclerosis as a systemic disease.^{78, 79} Intervening exclusively on single, potentially vulnerable plaques is unlikely to reduce the incidence of acute coronary events.^{14, 80} On the other hand, slowing or halting the activity of coronary atherosclerotic disease, e.g., lipid lowering therapy and risk factor modification,⁸¹ decreasing the risk of coronary arterial thrombosis, e.g., antiplatelet therapy,⁸² and mitigating the effect on resulting ischemia e.g., cellular membrane stabilization,^{83, 84} are prudent measures for reducing the risk of acute coronary events and their consequences. Unfortunately, despite contemporary preventative measures, studies, e.g., PROVE-IT and PROSPECT, demonstrate that events still occur with significant frequencies.^{14, 85} More discriminate risk models may help us to direct advanced therapeutic measures, e.g., anticoagulation or even ICD placement, to individuals at the highest risk, which would be prohibitive in less well defined populations. Conversely, patients at lower risk may be saved unnecessary medication and interventions. Ultimately, however, preventing the development of significant coronary atherosclerosis must be the most critical goal, which may be achieved by implementing policies for life style/diet modifications and genetic profiling.^{86, 87}

The Potential Role of Non-Invasive Imaging for Preventing Acute Coronary Events

Our review highlights the importance of the presence, distribution, extent, and severity of coronary atherosclerotic disease for the probability of acute coronary events to occur. Until recently, these features were only assessable using cardiac catheterization and invasive coronary imaging. Through technologic advancements, particularly in the fields of magnetic resonance imaging and computed tomography, comprehensive coronary plaque assessment is now possible using non-invasive imaging.⁸⁸ Promising prognostic data, particularly for CT coronary angiography, are available, which, importantly, have utilized only a fraction of the available information provided by these technologies.^{41, 89, 90} For example, Ostrom et al. followed 2,538 individuals for a mean of 6.5 years and found an area under the curve of 0.89, predicting total (not cardiac!) mortality, based on simple cardiac CT categories of normal arteries, non-obstructive, and obstructive coronary artery disease— combined with a calcium score and traditional risk factors.⁷⁶ It is conceivable that other characteristics, such as individual plaque burden and composition, total atherosclerotic plaque burden etc., further improve predictive power. In addition, molecular imaging, using advanced biomedical engineering, allows targeting specific metabolic processes, e.g., local inflammation, which may permit monitoring the activity, or even treating, atherosclerotic disease.¹² It appears, therefore, that non-invasive vascular imaging has the potential to substantially impact our ability to identify and manage patients at risk from acute coronary events.^{78, 91, 92}

For the reasons discussed, however, many individuals even with advanced coronary atherosclerotic disease will never experience acute coronary events. The challenge exists in balancing costs and adverse affects of detecting and treating coronary artery disease, with a reduction of coronary events and improved patient outcome.³ This is particularly critical for using imaging for screening purposes among asymptomatic individuals where improved patient outcome must be weighed against risks from imaging and intervention.⁹³ Thus, a staged approach is likely necessary with the least costly and most benign techniques applied to patients of seemingly low risk for screening purposes and advanced imaging reserved for those deemed at higher risk. For example, ultrasound imaging of carotid artery wall thickness provides prognostic information on acute coronary event risk incremental to traditional risk factors.⁹⁴ Many clinical investigations, some ongoing,⁹⁵ will be necessary to define the appropriate role of imaging for the prevention of acute coronary events in patients.

The Potential Role of Biomarkers for Preventing Acute Coronary Events

Numerous biomarkers, reflecting inflammatory and metabolic processes, are associated with increased acute coronary event risk.⁹⁶ Nevertheless, despite intriguing data regarding their involvement in the atherosclerotic process, their respective contribution to hazard for acute coronary events is small.⁹⁷ A prime example is C-reactive protein. The role of inflammation for the development, progression, and “vulnerability” of coronary atherosclerosis has been well established but C-reactive protein is only modestly predictive of acute coronary events, and its effect can be largely attributed to associations with known risk factors for coronary artery disease.^{54, 96, 98} It is possible that the inflammatory processes in the small coronary arteries are insufficient to be detected among other inflammatory activity in the body. However, even biomarkers more specifically involved in the atherothrombotic process, such as neopterin, have not shown to yield large hazard ratios for hard events - further supporting the hypothesis of a multifactorial mechanism for acute events to occur.^{99, 100} A promising target for biomarkers is to evaluate the metabolic activity of coronary atherosclerotic disease, but data to support such application for clinical purposes are currently sparse and only modestly promising.^{96, 101} Another potential goal is to identify a predisposing coagulation system.⁷⁷ However, the varying function of human hemostasis makes it exceedingly difficult to predict a weakness that may be triggered by internal, e.g., circadian variations, postprandial hyperlipidemia, etc., or external factors, e.g., stress, smoking, etc.¹⁰² At this time, the role of biomarkers for evaluating individuals for their coronary event risk appears to be supportive rather than leading.⁹⁶

Conclusions

An acute coronary event is the result of a complex interplay of numerous factors which seems to include a component of chance, hindering our ability to assess the risk of such events to occur. Erosion or rupture of the coronary atherosclerotic plaque is typically required for an event to happen, but it appears to do so only when coinciding with a thrombosis conducive state at the site of plaque rupture or erosion. In the majority of cases, plaque ruptures or erosions take place in the absence of symptoms and commonly lead to healing and progression of coronary arterial narrowing. The coronary atherosclerotic plaque burden and its metabolic activity, as well as conditions promoting vascular thrombosis, have the strongest evidence in support of their association with acute coronary events. Integrating coronary artery characteristics and thrombosis promoting factors into a comprehensive model appears most promising for acute coronary event risk assessment in patients.