Role of Inflammatory Mediators in the Pathogenesis of Plaque Rupture

Inflammation is a central mechanism leading to atherothrombosis. Its complex relationship with platelet function and coagulation strongly influences the development of plaque rupture in acute coronary syndrome (ACS). The discontinuous nature of the progression from insignificant disease to vulnerable plaque rupture correlates with the sudden transition of an asymptomatic patient to acute myocardial infarction (MI). Studies of atherosclerotic plaques that cause fatal thrombosis emphasize the characteristics of the vulnerable high-risk plaque, and most notably, the relationships among leukocytes, platelets, and endothelial cells. Contemporary clinical investigations seek a method of identifying high-risk atherosclerotic lesions before they rupture. Current evidence suggests that more than one high-risk plaque frequently resides in the coronary vasculature prone to plaque rupture.¹ The existence of multiple potential sites of acute vascular occlusion, as well as the worse prognosis in such patients,² is powerful evidence that the inflammatory process leading to these events is systemic with local effects, and not a primarily focal process. 

Chronic inflammation plays an important part in the progression and vulnerability of plaques. The physical disruption of a plaque either by means of a fracture in the fibrous cap or a superficial erosion of the intima is brought about by an imbalance between the mechanical forces that causes disruption of the plaque and the strength of the plaque. Inflammatory cells at vulnerable plaques are activated and then secrete enzymes to destroy the extracellular matrix and weaken the fibrous cap, with subsequent rupture and thrombosis. The lack of smooth muscle cells that produce new collagen is also a feature of fragile atherosclerotic plaques. The lipid-laden core of the plaque contains macrophages that degrade the lipid core, giving it a more friable necrotic characteristic. Moreover, some enzymes secreted by inflammatory cells can produce proinflammatory mediators to maintain and exponentially amplify the local inflammatory reaction. The thin fibrous cap and increased necrotic core places more stress on the shoulder regions of the plaque, a common area of plaque rupture leading to vascular occlusion and ACS.

The significant correlations found among markers of inflammation, platelet function, and hypercoagulability likely represent a pathophysiologic link, and may become a foundation to identify high-risk patients on the basis of a particular biomarker profile. This review evaluates the known mediators of local and systemic inflammation that have been implicated in the atherothrombotic process (Figure 1; Tables 1 and 2), and considers which may be valuable to the clinician now and which have potential to have clinical utility in the future (Table 3).

C-Reactive Protein (CRP)

Composed of five 23-kDa subunits, CRP is a circulating pentraxin that plays a major role in the immune response. Although hsCRP is primarily secreted from the liver as a result of cytokines stimulation from adipocytes in response to inflammation, other cells and tissues (including adipose tissue itself) may exacerbate hsCRP production.³ Thus the hsCRP level can be falsely elevated in obese patients in addition to genetic polymorphisms that could explain the variability observed among different genders and ethnicities.⁴ Controversy remains as to whether CRP is simply a marker of inflammatory risk or has a direct role in the atherothrombotic process. 

Prospective epidemiologic studies have demonstrated that when measured with high-sensitivity (hs) assays, hsCRP strongly and independently predicts risk of MI, stroke, peripheral arterial disease, and sudden cardiac death, even when low-density lipoprotein (LDL) and plasminogen activator inhibitor-1 levels are low.⁵ The multivariable hazard associated with hsCRP is larger than that associated with either hypertension or hypercholesterolemia.⁶ These data apply to both genders across all age levels and have been consistent in diverse populations. Absolute vascular risk is higher in individuals with elevated hsCRP levels and low LDL levels than in those with elevated LDL levels but low levels of hsCRP. The magnitude of this relationship is at least as large as that of hypertension and smoking.⁷ 

In clinical practice, hsCRP is one component of the global risk prediction process. Levels of hsCRP <1, 1-3, and >3 mg/L should be interpreted as lower, moderate, and higher relative vascular risk, respectively, when considered along with traditional markers of risk, a finding recently corroborated with the Framingham Heart Study.⁸ Values of hsCRP >8 mg/L may represent an acute-phase response caused by an underlying inflammatory disease or intercurrent major infection and should be repeated in 2-3 weeks. Consistently high values, however, represent a very high risk of future cardiovascular disease. Furthermore, the increased risk is linear across the full range of hsCRP levels. Additive risk can be estimated using the Reynolds risk scores.⁹ Levels of hsCRP >3 mg/L also predict recurrent coronary events, thrombotic complications after angioplasty, poor outcome in the setting of unstable angina, and vascular complications after bypass surgery. Additionally, hsCRP has prognostic usefulness in acute ischemia, even without troponin level elevation, suggesting that an enhanced inflammatory response at the time of hospital admission can determine subsequent plaque rupture. 

The use of statin therapy to reduce vascular risk in individuals with elevated hsCRP, even when LDL levels are low, is a fundamental concept of atherosclerosis prevention. In the JUPITER trial, healthy men and women with LDL <130 mg/dL at increased risk with hsCRP >2 mg/L treated with rosuvastatin experienced a significant reduction in major adverse cardiac events.¹⁰ All prespecified subgroups within JUPITER significantly benefited from statin therapy, including those considered to be at low risk, such as women, non-smokers, those without metabolic syndrome, and those with a Framingham score <10%. From a public policy perspective, the 5-year number needed to treat within JUPITER was only 25, a value smaller than the comparable 5-year number needed to treat associated with the treatment of hyperlipidemia or hypertension in primary prevention. 

Within the JUPITER cohort, an 80% risk reduction was observed among those who not only reduced LDL to <70 mg/dL, but who also reduced hsCRP to below 1 mg/L. This observation confirms prior work in high-risk secondary prevention, demonstrating the importance of achieving dual goals for LDL and hsCRP. In the PROVE IT-TIMI 22 trial, in patients with ACS treated with statin therapy, achieving levels of hsCRP <2 mg/L was as important for long-term event-free survival as achieving LDL <70 mg/dL; the best long-term outcomes were found in those who achieved both these goals.¹¹ The concept of dual goals for statin therapy has been corroborated in the A-to-Z clinical trial.¹²

Levels of hsCRP do not simply reflect the presence of subclinical disease but indicate an increased propensity for plaque disruption and/or thrombosis. hsCRP levels correlate only modestly with underlying atherosclerotic disease, as measured by carotid intimal medial thickness or by coronary calcification.¹³ Elevated hsCRP levels occur more often in patients with frankly ruptured plaques than in those with erosive disease or those who died of non-vascular causes. Some studies suggest that hsCRP has only a marginal predictive effect, based on the observation that the addition of hsCRP to risk prediction models only minimally increases predictive value.¹⁴ Once age and smoking are accounted for, neither the blood pressure nor LDL nor HDL increase the C-statistic.¹⁵ 

hsCRP may directly contribute to the progression of plaque and/or atherosclerotic plaque instability. hsCRP exerts an effect on arterial endothelial cells through interaction with complement, increasing the expression of complement inhibitory factors on the endothelial cells. hsCRP-mediated complement activation regulates the inflammatory reaction by promoting the removal of debris from tissues and the deleterious effects of complement activation. However, some of these reported effects may be artifact, due to contamination of the hsCRP preparations.¹⁶ Regardless, whether hsCRP is a biomarker of risk rather than a causal risk factor, hsCRP evaluation should be a routine part of coronary risk prediction, certainly in patients with estimated Framingham risks of 5% or more.

Matrix Metalloproteinases (MMP)

The matrix metalloproteinases are a family of zinc metalloendopeptidases that are mainly secreted by monocyte-derived macrophages and smooth muscle cells. They are expressed in atherosclerotic plaques, and induce degradation of extracellular matrix proteins, including collagens and elastins.¹⁷

MMPs have been identified in the vascular remodeling process and play important roles in the pathogenesis and progression of atherosclerosis, especially plaque formation and rupture. MMP-1 is able to initiate breakdown of the interstitial collagens and its level was found to be greater in ACS patients than in stable angina patients or controls.¹⁸  MMP-2 causes sustained intracoronary platelet activation and its release in the coronary circulation of ACS patients derives in part from these activated platelets.¹⁹ MMP-2 has also been found to be an independent predictor of all-cause mortality post ACS.²⁰ Elevated MMP-8 level may have value for predicting ACS. There is a significant increase in MMP-8 and decrease in TIMP-2 during acute MI, suggesting that they are markers of plaque vulnerability.²¹ MMP-9 has the potency for collagen cleaving and disintegrating extracellular plaque matrix causing collagen containing plaque instability and rupture.²² It is expressed in atherosclerotic plaques at multiple sites within the vascular tree and circulating concentrations may reflect vessel wall expression. Therefore, it can serve as a circulating biomarker reflecting proinflammatory state and causing a local effect on plaque destabilization and progression.²³ A study by Kobayashi et al showed that MMP-9 levels were elevated earlier than hsTnT and had a higher diagnostic value for early ACS, but not for late ACS, reflecting that markers of plaque rupture or vulnerability precedes that of myocardial damage²⁴ and this might allow earlier diagnosis of ACS, unlike currently where acute MI is diagnosed based on markers of myocardial damage.

CD40 / CD40 Ligand

CD40 is a type I transmembrane protein receptor and a member of the tumor necrosis factor superfamily; its gene is located in chromosome 20 (q12-q13.2). CD40 and CD40 ligand (CD40L) are expressed by fibroblasts, endothelial cells, smooth muscle cells, and platelets. Platelets express CD40L after stimulation with a wide range of platelet activators, such as thrombin and thrombin receptor agonists, like collagen. More than 95% of circulating soluble CD40L (sCD40L) comes from activated platelets. 

CD40/CD40L expression is upregulated in atheroma-associated cells, but the exact mechanism remains unknown. It is postulated that it activates smooth muscle cells and fibroblasts, and increases plaque vulnerability by enhanced neovascularization. There are significantly higher levels in patients with ACS compared with healthy patients.²⁵ Higher levels of sCD40L in patients with CAD have been seen in a variety of scenarios, but there is a wide variation among studies with genetic polymorphism providing a possible explanation for this occurrence.²⁵ Intracoronary sCD40L levels are higher in the culprit coronary artery than in the peripheral circulation, reflecting a potent local inflammatory process.²⁶

Three large trials explored the role of sCD40L in CAD: the Woman’s Health Study, CAPTURE, and MIRACL. In these studies, an elevated sCD40L level correlates with higher risk for cardiovascular events and three-fold increase in death or MI, and is an independent risk factor for recurrent cardiovascular events. However, other studies found no correlation with CAD or ACS.²⁷ sCD40L levels are altered by some medications, most notably clopidogrel, which decreases the levels in short and long term, although platelet surface receptor CD40L expression increases after 1 year of dual-antiplatelet therapy with aspirin.

In contradistinction, platelet surface receptor CD40L expression increases after a year of dual-antiplatelet therapy with aspirin.²⁸ Despite being a promising biomarker and strong surrogate of platelet activation in ACS, sCD40L lacks a standardized measuring protocol. There also are conflicting clinical studies showing associations with ACS, restenosis after PCI, and recurrent cardiovascular events, but no predictive value in CAD or ACS.

Interleukins

Interleukins are cytokines that mediate communications between leukocytes and control the interactions and functions of leukocytes in inflammation. With respect to CAD, there are several interleukins that have been the focus of investigation.

The IL-1 group of cytokines consists of 11 subtypes, of which IL-1α and IL-1β play conspicuous roles. These agents are secreted by inflammatory cells, especially monocytes and macrophages after phagocytosis of cholesterol crystals. The response to inflammation in ischemia is mediated by IL-1 receptor (IL-1R). IL-1R antagonist (IL-1Ra) is an acute-phase reactant secreted by the liver in vast quantities as a control mechanism when the IL-1 system is activated. This has been found to be a reliable marker of both IL-1 system activation and severity of inflammation. Elevated IL-1Ra levels have been observed in patients with CAD and ACS. IL-1 blockade has demonstrated favorable effects on coronary flow and endothelial function in patients with rheumatoid arthritis.²⁹ Antagonizing the effects of IL-1β is of potential interest given their proven efficacy in other chronic inflammatory diseases.

IL-6 is a cytokine and an intercellular mediator that is produced by a variety of cells. It plays a prominent role in the atherosclerotic process due to it proinflammatory (activation of adhesion molecule, elevation of TNF and CRP) and prothrombotic (platelet aggregation, vascular smooth muscle cell proliferation, and activation of coagulation pathway) properties. IL-6 levels are increased in stable CAD and ACS, even when other factors that independently raise IL-6 are comparable.³⁰ Levels of both IL-6 and hsCRP correlate well in patients with stable and unstable CAD, which may suggest the role of a common inflammatory pathway. Combination of IL-6, CRP, and high MCSF or low Tumor Growth Factor-β1 predicted adverse outcomes in patients with CAD independent of traditional risk factors. Statins have been found to decrease the levels of IL-6; however, levels are still higher compared to other inflammatory markers in post-MI patients on maximal therapy enabling this to be used as a marker of disease process. However in the ARIC study, CRP, IL-6, and other novel biomarkers did not provide any additional prognostic information in a model that included traditional risk factors.³¹

The main function of IL-8 is the recruitment and activation of monocytes and neutrophils at sites of inflammation. Preliminary studies suggest IL-8 receptors CXCR1 and CXCR2 may serve as markers of CAD and may be useful in monitoring disease progression: lower levels are found in patients responding to therapy.^32,33

IL-10 is secreted by activated monocytes, macrophages, and lymphocytes, and promotes the differentiation of CD4+T cells to Th2-type immune response. This in turn downregulates numerous inflammatory pathways, including MMPs, adhesion molecules, smooth muscle cell differentiation, and migration.³⁴ In chronic low-grade inflammatory state, elevated IL-10 has improved nitrous oxide bioavailability with increased vasodilator response and experimental studies have demonstrated increased superoxide generation within the vascular wall. IL-10 apparently negates the effect of elevated CRP and is capable of predicting the clinical outcomes independent of other risk factors in patients with ACS. 

IL-17 is produced mostly by activated T cells and has multiple proinflammatory actions like promoting the production of other cytokines, chemokines, adhesion molecules and proinflammatory mediators from cells like endothelial cells, smooth muscle cells, and macrophages. Elevated levels of IL-17 correlated with high levels of IL-6, IL-8, and hsCRP, and are present in patients with unstable angina and acute MI. IL-18 is expressed in a variety of cells including macrophages and vascular endothelial cells in the heart. It induces IFN-γ production from T-lymphocytes and natural killer cells. Elevated levels of IL-18 are predictive of cardiovascular outcomes in the short- and long-term periods.

The main problem with utilizing interleukins as markers of CAD is that they are involved in almost all the inflammatory responses in the body and are not specific for coronary atherosclerosis activity, particularly in patients with concomitant chronic inflammatory diseases. 

Adhesion Molecules

Cellular adhesion molecules are transmembrane glycoproteins that mediate cell-cell and cell-extracellular matrix interactions. The adhesion molecules, intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), are involved in transmigration of leukocytes to areas of inflammation. E-selectin and P-selectin are stimulated by inflammatory cytokines; these molecules  are active in the early development of atherosclerosis by promoting margination of the leukocytes in the blood stream. 

Leukocytes, fibroblasts, epithelial cells, and endothelial cells secrete ICAM-1. VCAM-1 is found in macrophages, smooth muscle cells, and endothelial cells. Higher concentrations of ICAM-1 have been associated with the development of coronary atherosclerosis compared to VCAM-1. Some studies have shown a relationship between ICAM-1 and disease severity,³⁵ while others have not.³⁶ 

P-selectin appears to be stored in the alpha granules of activated platelets and Weibel-Palade bodies of endothelial cells. Although P-selectin is elevated in patients with CAD, it does not consistently distinguish cardiac from non-cardiac causes of chest pain as it is also elevated in other conditions like diabetes and thrombotic consumptive platelet disorder. A higher than normal baseline level has been correlated with delayed and unsuccessful coronary thrombolysis among acute MI patients, as well as predicting the risk of future cardiovascular events.³⁷ Conversely, E-selectin is expressed on activated endothelial cells. Levels correlate with the extent of atherosclerosis in the coronary and carotid vasculatures. Studies have shown variable serum levels of E-selectin in ACS, suggesting a more central role in stable plaque rather than unstable ones.^38,39

Tumor Necrosis Factor-Alpha (TNF-α)

TNF-α is produced mainly by activated macrophages and stimulates acute phase reaction as a part of a group of cytokines. It regulates the inflammatory cascade by promoting the release of other cytokines and chemokines, activating endothelial cells to express adhesion molecules and producing reactive oxygen species that recruit activated leukocytes to areas of inflammation. TNF-α was found to be a significant predictor of CAD among men independent of CRP levels. While age and tobacco affect TNF-α levels, TNF-α affects adipocytes to influence lipid metabolism.⁴⁰ Osteoprotegerin is a member of the TNF receptor family that is an independent risk factor for cardiovascular events and correlates CAD severity, including number of coronary plaques.⁴¹

Interferon-Gamma (IFN-γ)

IFN-γ is a prototypic cytokine produced by CD4Th1 lymphocytes, CD8 cytolytic T cells, macrophages, and B- lymphocytes. IFN-γ is expressed in arterial plaques and it is responsible for inducing the production of numerous chemokines including adhesion molecules, MCP-1. It helps in the differentiation of infiltrating monocytes to macrophages and inhibits collagen production by inhibiting smooth muscle cells to weaken the fibrous cap, leading to a fragile plaque that is prone to rupture. It is difficult to detect secondary to its limited systemic secretion as well as difficulty in determining if the increased plasma levels of IFN-γ in patients undergoing cardiac catheterization are derived from their coronary atherosclerotic disease or subclinical extracardiac inflammation. However, activation of the IFN axis in patients with coronary atherosclerosis is associated with worse clinical outcomes after 1 year.⁴²

Pregnancy-Associated Plasma Protein-A (PAPP-A)

PAPP-A is a metalloproteinase that was originally detected in the serum of pregnant women and found to be produced in the placenta. It was later found in fibroblasts, vascular smooth muscle cells, and ruptured atherosclerotic plaques in both men and women. It is believed to contribute to the inflammatory process by degrading insulin-like growth factor (IGF) binding protein, thus releasing IGF-1 into the circulation, which apparently has a cardio-protective effect in low levels. PAPP-A is released during plaque destabilization, but is not expressed in stable plaques. Levels of PAPP-A and CRP are highly correlated, but there is no association between PAPP-A and CK-MB or troponin I, indicating that the level goes up prior to any cardiac damage.⁴³ PAPP-A was also a strong independent predictor of non-fatal MI or death in ACS. PAPP-A identifies patients at risk, and may be a marker for the presence and extent of coronary atherosclerosis.

Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

Lp-PLA2 is a platelet activating factor acetylhydrolase that belongs to the A2 phospholipase superfamily, and is produced by macrophages and lymphocytes, which are detected in human atherosclerotic lesions. It is specific for inflammation associated with atherosclerosis that occurs within the arterial wall.⁴⁴ It promotes inflammation by hydrolyzing oxidized phospholipids in modified LDL leading to its proinflammatory effects. As a result, the necrotic core increases in the plaque, the fibrous cap becomes thinner, and inflammatory mediators increase within the plaque leading to vulnerable plaque morphology. Moreover, levels of Lp-PLA2 are decreased in early plaques compared to more advanced plaques with higher necrotic core burden. 

Elevated Lp-PLA2 and hsCRP levels were highly significant predictors of ACS in patients with stable CAD in the PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) trial. Lp-PLA2 was found to be an independent predictor of risk for CAD and stroke. A near two-fold increased risk for future cardiovascular events has been reported in patients with elevated Lp-PLA2 after adjustment for markers of inflammation, renal dysfunction and hemodynamic stress.⁴⁵ In the IBIS-2 study, Lp-PLA2 inhibition by darapladib was shown to prevent necrotic core expansion.⁴⁶ The dal-PLAQUE study showed evidence of delayed progression of plaque burden with use of dalcetrapib, an Lp-PLA2 inhibitor, as measured by total vessel area using MRI.⁴⁷ However, a larger trial with clinical endpoints of varespladib was stopped early due to lack of efficacy. Lp-PLA2 levels have been highly correlated with LDL cholesterol levels, which may in part explain these disparate results. Currently, the STABILITY and SOLID-TIMI 52 trials are evaluating the clinical benefit of darapladib in chronic CAD and MI, respectively.

Monocyte Chemoattractant Protein-1 (MCP-1)

Monocytes are involved in atherogenesis, potentiating inflammatory responses during early plaque development and initiating breakdown and rupture of the fibrous cap of atherosclerotic lesions. Monocytes are attracted to sites of inflammation by a small chemokine termed MCP-1. MCP-1 has been detected in endothelial cells, vascular smooth muscle cells in atherosclerotic arteries, as well as atherosclerotic lesions. It has been suggested that MCP-1 directly stimulates the proliferation and migration of vascular smooth muscle cells. The deletion of CCR2 genes that express the receptor for MCP-1 has been shown to suppress the development of atherosclerotic lesions by inhibiting monocyte recruitment in animal models. No significant difference was noticed in the levels of MCP-1 irrespective of the extent of stable atherosclerotic disease. This suggests that the activation and attraction of circulating monocytes are initiated at sites of plaque instability.⁴⁸ Increased levels were found in ACS, suggesting an inflammatory etiology. The OPUS-TIMI study showed a positive correlation between MCP-1 concentrations and increased risk of death and MI.⁴⁹ The Dallas Heart study and ARIC study showed that plasma MCP-1 concentrations among CHD patients were not significantly different from age-matched control subjects.

Myeloperoxidase (MPO)

MPO is an enzyme secreted by a variety of inflammatory cells including activated neutrophils, monocytes, and certain tissue macrophages such as those found in atherosclerotic plaques. It has both prooxidative and proinflammatory properties. It has been implicated in the oxidation of LDL cholesterol, rendering it atherogenic and converting it into a high-uptake form for macrophages, leading to foam cell formation. It plays an important role in the degradation of the fibrous cap and destabilization of atherosclerotic plaques. It is also responsible for decreased cholesterol efflux from plaques and decreased endothelial-derived nitrous oxide bioavailability, leading to endothelial dysfunction. MPO level is associated with the future risk of CAD in healthy individuals and the development of ACS in those with known CAD. The blood and leukocyte MPO activity is found to be higher in patients with CAD than angiographically confirmed normal individuals, and these levels were significant predictors of risk for CAD even after adjustment for white blood cell count and Framingham risk score.⁵⁰ However, the relationship with ACS is stronger, indicating that MPO level is a more potent marker of plaque instability than of atherosclerotic burden.

Adiponectin

Adiponectin is produced by adipocytes and cardiomyocytes. Its role has been identified in the inflammatory pathway via its effect on controlling endothelial activation, adhesion molecule expression, monocyte adhesion and migration into the intima, macrophage activation and foam cell transformation, TNF-α inhibition, smooth muscle cell proliferation and migration into the intima, and platelet aggregation. Hypoadiponectinemia has also been associated with an increase in the necrotic core ratio in both culprit and non-culprit lesions in patients with acute coronary syndrome as demonstrated by virtual histology-intravascular ultrasound (VH-IVUS). Based on this, it appears that adiponectin is more involved in the stability of atherosclerotic plaque rather than the atherosclerotic burden by controlling the inflammatory response. Adiponectin levels are inversely proportional to the body mass index and visceral adiposity. Patients with ACS or complex coronary lesions have lower levels of adiponectin than those with stable CAD or simple coronary lesions.⁵¹ The decreased levels of adiponectin found in patients with elevated CRP point to the potential role of adiponectin in the inflammatory pathway for atherosclerosis.⁵² Patients with hypoadiponectinemia have a 2-fold increase in the prevalence of angiographically determined CAD and higher risk of CAD over a 10-year period independent of traditional risk factors.⁵³ Adiponectin levels can be increased via indirect methods such as lifestyle modification and pharmacologically by means of angiotensin converting enzyme inhibitors, aldosterone receptor antagonists, fish oil, and thiazolidinediones. 

Hepatocyte Growth Factor (HGF)

HGF is an angiogenic growth factor that is secreted by mesenchymal cells of various organs. It is an inflammatory protein that promotes angiogenesis and helps in the healing process. It is believed that low levels may reflect a low-grade stable atherosclerotic disease, while a higher level may indicate unstable disease with ongoing angiogenesis associated with the process of inflammation. HGF level tends to peak around 7 days after acute MI, at which time it has a high correlation with CRP levels, indicating HGF production may be related to the inflammatory nature of acute MI. Elevated HGF may be related to poor outcomes after ACS secondary to extensive inflammation. HGF is associated with collateralization and improved outcomes in patients, but this association that was noticed in clinical studies may be secondary to heparin administration, which stimulates HGF production. There was no relationship between HGF and thrombus.⁵⁴ This marker is not useful for CAD monitoring, as it is not specific and could indicate neovascularization in any organ. However, HGF monitoring has shown promise in animal models for assessing angiogenesis with gene therapy.

Conclusion

The complex interplay of inflammatory mediators leads to an imbalance in the characteristic of an atherosclerotic plaque, resulting in a vulnerable and fragile fibrous cap and eventual vascular occlusion and thrombosis in the coronary vasculature. The search for an accurate biomarker of plaque rupture remains a high scientific priority. Despite the emergence of multiple candidate markers for the detection of ischemia and/or diagnosis of ACS, as yet none of these has sufficient evidence to recommend widespread adoption into clinical practice. 

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From ¹Advocate Illinois Masonic Medical Center, Chicago, Illinois; and ²Gottlieb Memorial Hospital, Melrose Park, Illinois.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 20, 2013, provisional acceptance given December 12, 2013, final version accepted January 22, 2014.

Address for correspondence: Lloyd W. Klein, MD, Gottlieb Memorial Hospital, Professional Office Building, 675 West North Avenue, Suite #314, Melrose Park, IL 60160. Email: lloydklein@comcast.net