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J Am Coll Cardiol, 2007; 49:279-289, doi:10.1016/j.jacc.2006.08.051 (Published online 3 January 2007).
© 2007 by the American College of Cardiology Foundation
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CARDIOVASCULAR GENOMIC MEDICINE

Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine

Saif Anwaruddin, MD*, Arman T. Askari, MD, FACC* and Eric J. Topol, MD, FACC{dagger},1,*

* Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio
{dagger} Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, California.

Manuscript received March 15, 2006; revised manuscript received July 6, 2006, accepted August 28, 2006.

* Reprint requests and correspondence: Dr. Eric J. Topol, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. (Email: etopol{at}scripps.edu).


   Abstract
Top
 Abstract
Endothelium
 Platelets
 Leukocytes
 Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
 References
 
Acute coronary syndromes represent a complex phenotype involving the interplay of many elements. The risk of developing an acute coronary syndrome and related complications has been defined by variables such as age, diabetes, smoking history, serum creatine phosphokinase, or electrocardiographic findings. However, in the past 5 years the wide-scale acceptance of a protein—troponin—has changed the diagnostic profile. With advances in molecular medicine, this protein is a segue to a panel of molecular assays that will improve screening and tailored intervention. We expound upon some of these factors and the potential they may carry in changing clinical medicine.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CAD = coronary artery disease
  CRP = C-reactive protein
  EPC = endothelial progenitor cells
  GP = glycoprotein
  FLAP = 5-lipoxygenase activating protein pathway
  LDL = low-density lipoprotein
  MI = myocardial infarction

Coronary artery disease (CAD) is increasing in prevalence and is predicted to become the dominant cause of mortality worldwide by 2020. A burgeoning body of literature exists that implicates inflammation as being central to atherogenesis and, ultimately, atherothrombosis (1). In fact, the inflammatory process appears to be more extensive than previously thought and may involve multiple vulnerable plaques within the coronary bed and, in many patients, other arterial trees simultaneously (2). That an integral link among inflammation, atherogenesis, and atherothrombosis exists is fundamental to understanding acute coronary syndromes (ACS). Translating this understanding and the emerging concept of differential genetic heritability between myocardial infarction (MI) and atherosclerosis (3) into the development of quantifiable molecular risk factors in otherwise healthy, asymptomatic individuals is a major goal for prevention.

As the mechanisms and pathways involved in the processes of plaque rupture, thrombosis, and response to injury are defined, a logical evolution would be to use this opportunity to better define risk of future events and complications. Use of molecular markers of inflammation after ACS to predict the likelihood of recurrence or even appropriate response to therapy may facilitate targeted therapeutic strategies based on a comprehensive molecular risk profile (4) rather than on demographic and clinical characteristics.

The goal of this review is to provide insight into the complex interactions between the inflammatory and cellular mechanisms involved in the pathogenesis of ACS and the response to injury. The prognostic value of some of these novel markers and relevant data on proposed therapeutic interventions will be addressed so that in time we can use these markers to prevent ACS events or, at least improve, clinical outcomes.


   Endothelium
Top
 Abstract
 Endothelium
Platelets
 Leukocytes
 Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
 References
 
Compromise of endothelial integrity is felt to be fundamental, not only to the initiation and progression of atherosclerotic disease, but also to the onset of ACS. Leukocytes are believed to contribute to direct endothelial damage in this setting. Irrespective of the underlying contributor, endothelial damage and dysfunction remain integral to atherogenesis and the development of an ACS.

Circulating endothelial cells as a marker of panvascular injury.   Circulating endothelial cells are a marker of arterial injury in vascular disease. Notably, significantly elevated levels of circulating endothelial cells have been observed in patients with ACS compared with those with stable angina (5). More recently, it was discovered that elevated levels of circulating endothelial cells measured in patients within 48 h of an ACS independently predict subsequent short- and long-term outcomes (6).

Role of the subendothelial matrix von Willebrand factor (vWF) in ACS.   Through the actions of a key component, vWF, on factor VIII activity, the matrix contributes to modulation of the coagulation cascade and to the pathogenesis of ACS. Beyond its role in facilitating coagulation protein interaction, vWF binds to subendothelial collagen via its A3 domain and initiates platelet adhesion via the glycoprotein (GP) 1b receptor (7). Experimental evidence suggests that both vWF and high shear stress may be responsible for platelet aggregation in acute MI. Conversely, inhibition of the GP1b receptor from serum of patients with an acute MI or unstable angina by a vWF antibody results in reduced shear-induced platelet aggregation (8). Ultimately, increased levels of vWF have been associated with suboptimal angiographic results and increased adverse events across the spectrum of ACS (9,10).


   Platelets
Top
 Abstract
 Endothelium
 Platelets
Leukocytes
 Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
 References
 
The importance of platelets in thrombosis and ACS is well established. Through release of various constituents, expression of various receptors, and interactions with leukocytes and the endothelium, platelets function as inflammatory mediators in patients with ACS (Fig. 1). Platelets provide a pivotal link between inflammation and thrombosis in ACS.


Figure 1
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  		Figure 1 Platelets: Key Mediators of Inflammation

CD40R = CD40 receptor; GP-1b = glycoprotein 1b receptor; IL-8 = interleukin 8; MCP-1 = monocyte chemoattractant protein-1; PSGL = P-selectin glycoprotein ligand; sCD40 = soluble CD40; vWF = von Willebrand factor.

 
CD40 and CD40L.   CD40 and CD40L have been found on platelets and several other cell types in functional-bound and soluble (sCD40L) forms. Although many platelet-derived factors have been identified, recent evidence suggests that CD40L is actively involved in the pathogenesis of ACS. Through direct platelet-to-cell stimulation, most notably the interaction between CD40L on activated platelets and the CD40 receptor on endothelial cells, CD40L, drives the inflammatory response. Such interactions facilitate increased expression of adhesion molecules on the surface of endothelial cells and release of various stimulatory chemokines. These events, in turn, facilitate activation of circulating monocytes as a trigger of atherosclerosis (11).

Both CD40L and sCD40L contain separate domains allowing for direct binding to the {alpha}IIbB3-receptor on platelets. It has been suggested that this CD40L-platelet {alpha}IIbB3 receptor interaction is important for stability of platelet-based thrombus (12). Stimulation of the {alpha}IIbB3 receptor is known to release sCD40L from within platelets (13) in addition to activating other platelets.

Beyond known proinflammatory and thrombotic properties of CD40L, experimental evidence suggests that CD40L-induced platelet activation leads to the production of reactive oxygen and nitrogen species, which are able to prevent endothelial cell migration and angiogenesis (14). As a consequence of inhibiting endothelial cell recovery, the risk of subsequent coronary events may be greater.

Clinical studies have supported the involvement of CD40L in ACS and the prognostic value in ACS populations. Levels of sCD40L have been shown to be an independent predictor of adverse cardiovascular events after ACS (15) with increased levels portending a worse prognosis (16,17). Importantly, specific therapeutic strategies have shown to be beneficial in reducing risk associated with sCD40L (Table 1) (16–22). The interaction of sCD40L and glycoprotein IIb/IIIa receptor is important in thrombosis and thrombus stability. Glycoprotein IIb/IIIa inhibitors such as abciximab may provide benefit in this high-risk population (17), with the caveat being the increased levels of sCD40L and potential worsening of the proinflammatory state and increased mortality seen with GP IIb/IIIa inhibitor underdosing (23,24).


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  		Table 1. Effect of Medical Therapy on CD40L
 
These observations support the premise that platelet activity is central to the proinflammatory and prothrombotic states in ACS. CD40L and sCD40L seem to link these processes and underscore the need to identify those at higher risk, who may benefit from more aggressive or even more selective therapy.

Platelet-leukocyte interaction.   The platelet serves as an intermediary between various cell types, most notably, the leukocytes. P-selectin, expressed on the surfaces of both endothelium and activated platelets, and platelet-leukocyte interactions that occur via P-selectin and its natural ligand P-selectin glycoprotein ligand-1 (PSGL-1) both appear to be important in thrombus generation.

Increased levels of soluble P-selectin have been shown to predict future cardiovascular events in apparently healthy women (25), to predict those patients with an ACS at high risk, and to potentially differentiate those patients with ACS versus stable angina (26). Despite these data, the utility of P-selectin as a marker of platelet activation in ACS remains uncertain. A more sensitive marker of thrombosis in patients with unstable coronary syndromes may be platelet-leukocyte aggregate levels (27).


   Leukocytes
Top
 Abstract
 Endothelium
 Platelets
 Leukocytes
Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
 References
 
The inflammatory responses leading to the disruption of plaque and subsequent events in ACS is characterized by a varied cellular presence. The relationship between monocyte-derived macrophages and the pathogenesis of atherosclerotic coronary artery disease (CAD) has been well studied. In addition to macrophages, the importance of other leukocytes in these processes has become apparent.

Studies have suggested a relationship between leukocytosis and adverse cardiac events after acute MI (28) and ACS (29) has been demonstrated. The mechanisms by which leukocytosis may lead to worse outcomes may include proteolytic damage, leukocyte aggregation, microvascular obstruction, infarct expansion, electrical instability, and impaired revascularization among others (30).

Dichotomizing cell types involved in atherogenesis compared with the development of ACS is difficult. However, the neutrophil, a hallmark of acute inflammation, has been thought to be vital to acute plaque rupture with autopsy specimens of culprit lesions from acute MI patients demonstrating higher concentrations of activated neutrophils that in those without ACS (31). At the other end of the spectrum, infiltration of the atherosclerotic plaque with monocytes and eventual uptake of oxidized low-density lipoprotein (LDL) particles is thought to be central to formation of atherosclerotic plaque. Activated macrophages are believed to facilitate ongoing inflammation present within the plaque, and thus may be important in the initiation of ACS (Fig. 2).


Figure 2
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  		Figure 2 Leukocyte Secretory Products

HGF = hepatocyte growth factor; IFN-{gamma} = interferon gamma; IL-18 = interleukin-18; LDL = low-density lipoprotein; MCP-1 = monocyte chemoattractant protein-1; MMPs = matrix metalloproteinases; MPO = myeloperoxidase; NO = nitric oxide; VCAMs = vascular cell adhesion molecule.

 
Leukocyte secretory products and ACS.   Several leukocyte secretory products, including myeloperoxidase, monocyte chemoattractant protein-1, various interleukins, matrix metalloproteinases, pregnancy-associated plasma protein A, leukotriene B4, hepatocyte growth factor, and interferon gamma, have been associated with atherogenesis, atherothrombosis, ACS, and outcomes after ACS (Table 2) (32–51). For example, myeloperoxidase, a powerful oxidant released from both neutrophils and monocytes, has been demonstrated in patients with coronary artery disease (52), has been implicated in having a role in plaque destabilization (50), and has been associated with a worse prognosis in patients presenting with an ACS (51). Although the majority of these leukocyte secretory products link inflammation and atherothrombosis, their clinical applicability has not been adequately defined. Nevertheless, there exists encouraging data that emphasize the potential future utility of some, if not all of these products.


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  		Table 2. Selected Leukocyte Secretory Products and Possible Involvement in ACS
 

   Progenitor Cells
Top
 Abstract
 Endothelium
 Platelets
 Leukocytes
 Progenitor Cells
Adipocytes
 Genetic Risk, Molecular Risk...
 References
 
Derived from bone marrow sources and peripheral mononuclear cells, circulating endothelial progenitor cells (EPCs) have been shown to possess several characteristics that may facilitate the use of these cells as novel markers of endothelial dysfunction as well as of ongoing tissue repair and/or regeneration. Characteristics such as their pluriopotency, ability to regenerate damaged endothelium, and the ability to "home" to damaged or ischemic tissue and contribute to neovascularization have elevated interest in these cells with novel prognostic and therapeutic goals in mind.

Endothelial progenitor cells represent a promising biomarker of endothelial dysfunction, one of the earliest stages of atherogenesis. In a study of patients with risk factors for CAD, reduced levels of EPCs correlated with higher degrees of endothelial dysfunction. Conversely, augmenting EPC volume through mechanisms, including transplantation, facilitates neovascularization and re-endothelialization and attenuates myocardial ischemia, supporting a role for EPCs in maintaining the homeostasis of the endothelial wall. Assessing for EPC levels may be more useful, given their correlation with established risk factors for CAD (53), their correlation with the presence of atherosclerosis (54), and with their prognostic ability in patients with established CAD (55). However, levels of circulating EPCs did not predict acute MI, suggesting a role for EPCs in atherosclerosis progression, but not in acute plaque rupture.

Although a natural, EPC-mediated repair mechanism that exists after myocardial injury has been demonstrated (56), this process occurs at a rate that precludes any meaningful functional recovery after MI. Experimental evidence has suggested that delivery of cytokine-expanded CD34+ EPCs via direct injection into the infarct border zone (57) may be able to augment the natural repair mechanisms and facilitate improvement in myocardial function. These observations highlight that a homing mechanism exists following myocardial injury, which, if harnessed, can contribute to myocardial repair facilitated, in part, by EPCs.

Although EPCs represent a promising biomarker of endothelial dysfunction, they also maintain an ability to participate in the repair process. In a healthy state, there is a role for progenitor cells in preservation of the endothelial wall. In states of endothelial dysfunction, reduced levels and functionality of EPCs and other circulating progenitor cells may impair these abilities and predispose to further injury. Manipulation of these progenitor cells may provide a therapeutic strategy for treating early stages of endothelial injury or preventing adverse remodeling after MI.


   Adipocytes
Top
 Abstract
 Endothelium
 Platelets
 Leukocytes
 Progenitor Cells
 Adipocytes
Genetic Risk, Molecular Risk...
 References
 
Obesity has been identified as a risk factor for the development of the metabolic syndrome and subsequent cardiovascular disease. Specifically, visceral adipose tissue has been cited as the principal reservoir of adipocytes. Adipose tissue is a metabolically active organ that contains blood vessels and various active cell types. Acting through various endocrine and paracrine mechanisms, the relevance of adipose tissue to cardiovascular disease stems from its proinflammatory effects. Obesity, especially that which is associated with increased waist-to-hip ratio or increased visceral fat, leads to the up-regulation of various intercellular adhesion molecules, P-selectin, C-reactive protein (CRP), interleukin-6, tumor necrosis factor-{alpha}, interleukin-18, tumor necrosis factor receptors, and plasminogen activator inhibitor-1, among others, are thought to result in a proinflammatory state that contributes to atherogenesis. Suppression of adiponectin, a protective adipokine, also appears to result from obesity.

Although adipocytes produce and secrete a variety of other factors, much is being learned about many of these factors and any relationship to coronary artery disease and ACS. Other examples include the transcription factor GATA2, resistin, CRP, serum amyloid A3, and leptin. Although these represent novel markers and may provide valuable insight with regard to atherosclerotic disease related to obesity, only CRP has been extensively studied in the context of coronary artery disease (Table 3) (58–80).


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  		Table 3. Adipocyte-Related Secretory Products: Relationship to Cardiovascular Disease
 
CRP.   C-reactive protein is an acute phase reactant produced primarily by the liver in response to cytokines such as interleukin-6. It has gained attention not only as a marker of inflammation and cardiovascular risk but as an active participant in the process (81). C-reactive protein adds value beyond traditional cardiovascular risk factors such as LDL in predicting the risk of MI, stroke, need for revascularization, or death from cardiovascular causes (82). The significance of CRP is that it highlights the relationship between ongoing inflammation and future cardiac events. In those with unstable angina, discharge CRP levels predicted long-term risk of recurrent events (83).

Beyond prognostic value, evidence supports the direct involvement of CRP in the development of atherosclerotic plaque. C-reactive protein, identified in atherosclerotic plaque, has been shown to facilitate macrophage uptake of LDL particles (84) and to regulate both macrophage recruitment (85) and vascular adhesion molecule expression (86).

C-reactive protein has become an attractive target for medical therapy in coronary atherosclerosis (Table 4) (87–94). Therapeutic strategies in ACS have focused on modifiable risk factors, but none have focused on inflammation per se. It still remains to be seen what effect specifically targeting CRP will have upon hard clinical end points. A recent study in mice with experimental MI showed that CRP inhibition could markedly reduce infarct size (95). Although statin therapy has been touted for its ability to reduce levels of CRP (87–89,91) only now are studies under way examining the effects of various therapeutic modalities upon CRP levels as a marker of clinical cardiovascular risk (93,94).


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  		Table 4. Effect of Medical Therapy on CRP
 
It is apparent that inflammatory status is a variable that needs to be strongly considered. Whether currently available therapy will reduce inflammation and improve clinical end points has yet to be determined. Nevertheless, CRP provides valuable insight regarding the link between inflammation, CAD, and ACS.


   Genetic Risk, Molecular Risk Factors, and Clinical Medicine
Top
 Abstract
 Endothelium
 Platelets
 Leukocytes
 Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
References
 
Genetic predisposition toward the development of MI is a concept that is only bluntly defined by traditional risk factors such as hypertension or hyperlipidemia. This common complex trait with extensive gene-environment and gene-gene interactions is in the early phase of being genomically unraveled. Complexity of the process is reflected in the number of single nucleotide polymorphisms. For example, the inhibition of the recently identified 5-lipoxygenase activating pathway with a 5-lipoxygenase activating protein pathway (FLAP) blocker in patients with a gain-of-function FLAP or leukotriene A4 haplotype has been shown to reduce the degree of inflammation as measured by various proinflammatory biomarkers, including CRP and leukotriene B4. Similarly, specific variants of PCSK-9 and USF-1, which affect lipoprotein handling, have been shown to provide marked protection from ACS events (96–99). This is a promising example of how such specific genomic information could facilitate individualized prevention.

With high-throughput genotyping of >500,000 key marker single nucleotide polymorphisms, the ability to identify the susceptibility factors for ACS such as FLAP or leukotriene A4 is greatly enhanced. High-throughput sequencing tools and microarrays will allow for examination and comparison of thousands of genes at once. The potential exists for developing profiles of risk based on genetic information. Ginsburg et al. (100) discuss the value of personalized cardiovascular medicine using not only large-scale genetic profiles but also gene products in revolutionizing the scope of clinical practice. Improved diagnostic sensitivity and refined prognostic value in combination with a tailored therapeutic approach would be the proposed outcome.

More and more genes and gene products are being considered as being valuable in providing information about patients at risk for ACS. As more candidates are introduced through proteomics and metabolomics, their pragmatic utility must be questioned in dedicated clinical trials. A standardized panel of markers used to assess inflammation, plaque vulnerability, and other features may become part of clinical practice, but the selection of which markers to use remains undecided, especially as the selection pool grows in size and complexity. Most of the markers that have been discussed have not yet been examined concurrently in large-scale clinical epidemiologic studies. Transitioning these markers directly into clinical practice without sufficient data stands only to create confusion. Furthermore, of the markers that hold promise in clinical medicine, there is still much to be learned about specific assays, measurement characteristics, and more precise pathophysiologic definitions. sCD40L is an excellent example of this as sample processing and temperature were found to affect measurements (101)—despite our current knowledge, our understanding still remains limited.

Although the discovery of such markers and subsequent studies proving association with ACS will likely continue to take place at an accelerated pace, the rate-limiting step should involve a rigorous process of systematically evaluating these markers prior to transitioning into clinical practice. This would include reproducibility in large populations, a scrutiny of assay methods, cost effectiveness appraisals, an assessment of practicality, and determination of whether value is added beyond current methods of risk stratification.

Conclusions.   It is apparent that a myriad of cellular and molecular mediators involved in the proinflammatory and prothrombotic phases of atherosclerosis and ACS exist. What determines any individual’s clinical manifestations may reflect the interplay of inflammatory components, environmental factors, and genetic susceptibility. Although our understanding of the inflammatory processes is only now expanding, we are just scratching the surface with regard to genetic susceptibility in acute coronary syndromes.

What remains wholly apparent, however, is the complexity of this disease process. It is no wonder, then, that many elements have been individually identified, characterized, and studied in the clinical setting in an effort to understand at least one potential pathway. Although no one entity has ever been found to be the holy grail of the ACS, the understanding of the complex interplay between these components seems to be most important.

In time, risk assessment may take the form of an evaluation of multiple molecular factors using a comprehensive pan-arterial analysis of carefully selected candidate genes and molecules that reflect the variety of cellular and molecular components actively involved in the pathogenesis of clinically apparent disease (Fig. 3).


Figure 3
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  		Figure 3 A Model of Risk Stratification Based on a Representative Panel of Molecular and Genetic Factors

ACS = acute coronary syndrome; CRP = C-reactive protein; EPC = endothelial progenitor cell; FLAP = 5-lipoxygenase activating protein pathway; fn = platelet function; IL = interleukin; LTA4 = leukotriene A4 pathway; MMPs = matrix metalloproteinases; MPO = myeloperoxidase; PAI-1 = plasminogen activator inhibitor; PAPP-A = pregnancy-associated plasma protein A; sCD40L = soluble CD40 ligand; TNF-{alpha} = tumor necrosis factor alpha; VEGF = vascular endothelial growth factor; vWF = Von Willebrand factor.

 
Although using such a panel for disease risk stratification remains an objective, monitoring disease activity and pursuing individualized disease prevention are possible outgrowths of this work. In those with known disease, monitoring for evidence of ongoing inflammation, endothelial dysfunction, or platelet activation may help to identify those at higher risk requiring more intensive or more specific therapy to avert future events. Ultimately, real promise may turn out for primary prevention whereby the use of a panel of molecular markers and candidate genes may identify a particular segment of the population at risk for clinically significant CAD, otherwise undetectable. Screening for early evidence of endothelial dysfunction, up-regulation of inflammation, thrombosis, or genetic susceptibility will likely provide a new more precise assessment of risk for future cardiovascular disease beyond traditional clinical risk factors.


   Footnotes
 
Cardiovascular Genomic Medicine Series edited by Geoffrey S. Ginsburg, MD, PhD.

1 Dr. Topol is supported by National Institutes of Health grant P50 HL077107. Back


   References
Top
 Abstract
 Endothelium
 Platelets
 Leukocytes
 Progenitor Cells
 Adipocytes
 Genetic Risk, Molecular Risk...
 References
 

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R. P. Giugliano and E. Braunwald
The Year in Non ST-Segment Elevation Acute Coronary Syndrome
J. Am. Coll. Cardiol., October 2, 2007; 50(14): 1386 - 1395.
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