Definition Of Acute Coronary Syndrome Biology Essay

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The acute coronary syndrome is a term used to describe unstable angina and ST elevation myocardial infarction and non ST elevation myocardial infarction (NSTEMI) (Qing, 2007).

These entities comprise a spectrum of disease that encompasses ischemia with no myocardial damage, ischemia with minimal myocardial damage; partial thickness and full thickness myocardial infarcts. It may present as a new phenomenon or on a background of chronic stable angina.

Their definition depends on the specific clinical presentation of each element of the clinical triad (history of coronary artery disease), ECG changes and the changes in the levels of cardiac markers. However, an ACS may occasionally occur in the absence of ECG changes or elevation in the cardiac biomarkers (Davidson, 2008).


This syndrome is a serious health care problem as it is responsible for 20% of all medical emergency department (ED) admissions with the highest risk for adverse events and death (Bayes-Genis et al, 2000). Recent statistics show that approximately 8 out of a total of 95 admissions to the ED are of patients with chest pain or other symptoms suggestive of ACS. Each year around 7.8 million people suffer an AMI while another 6.8 million develop unstable angina. There are also a significant number of people who die of ACS before or shortly after presentation to the ED (Wu, 2007). On the other hand, there are reports showing that 2.1% to 3.8% of patients with MI are missed in the emergency department owing to lack of sensitivity of currently available diagnostic tools(Pope et al., 2000), (Lee et al.,1987) and 7.1% to 15.7% of patients with ACS suffer reinfarction or death within 30 days of presentation (White,1999). Despite the use of sensitive biomarkers of myocardial necrosis, a number of patients presenting to the ED with chest pain are discharged and return with a full blown picture of AMI within 48 hours (Puelo et al., 1994). The primary objective of their management therefore is the early and accurate diagnosis of ACS so that prompt and appropriate treatment can be initiated.

In Pakistan limited available data shows that ACS comprises 43% of all admissions to the ER of the National Centre for Cardiovascular Diseases in Karachi (Kazim, 2009).


2.3.1 Unstable angina

UA is a clinical syndrome characterized by rapidly worsening angina, angina on minimal exertion or angina at rest. From an aetiological perspective, unstable angina may be classified as follows (Braunwald, 1999):

Type 1: thrombosis

A non occlusive thrombus at the site of a ruptured or fissured plaque. Type 2: severe progressive arterial obstruction

Accelerated thrombosis is an important underlying cause of unstable angina. The cause of this acceleration is not yet clear; the occurrence of subclinical, frequent minor thrombi has been suggested as a possible mechanism. Type 3: coronary vasospasm/vasoconstriction

Dynamic constriction of the coronary arteries may affect the large conductance vessels as In Prinze metal angina or small coronary resistance arteries as in Microvascular angina. Type 4: inflammation

There is growing evidence that unstable angina may be caused by inflammation of the atherosclerotic plaque. Increased activity of macrophages in plaques can cause the release of proteinases such as collagenase and stromelysin, which can break down the extracellular matrix and lead to plaque rupture. The inflammatory response is reflected in raised serum concentrations of markers such as C reactive protein (CRP) and serum amyloid A.

Type 5: increased myocardial oxygen consumption

When myocardial oxygen supply is compromised by a flow limiting atherosclerotic plaque, an increase in myocardial oxygen demand may be sufficient to trigger unstable angina. Patients with chronic stable angina may develop unstable angina with thyrotoxicosis, infection, fever, or tachyarrhythmias, all of which increase myocardial oxygen demand.

Myocardial infarction

AMI may be classified as follows (Thygesen et al., 2007) Type 1

Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection.

Type 2

Myocardial infarction secondary to ischemia due to either increased oxygen demand or decreased supply, e.g coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension or hypotension. Type 3

Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by presumably new ECG change or evidence on angiography. Type 4a

MI associated with PCI. Type 4b

MI associated with stent thrombosis as documented by angiography or at autopsy.

Type 5

MI associated with CABG.


Inflammation and dysfunctional endothelium are two pivotal components in the initiation and progression of atherosclerosis. It evolves over decades through a complex interplay of humoral and molecular factors and eventually results in the formation of an atherosclerotic plaque.

The rupture of an unstable plaque is a central feature of the initiation of the ACS and is characterized by sudden total or near-total occlusion of a coronary artery (Chang, 2010). The incidence of vulnerable plaques evolving into clinical events ranges from 4% to 13% per year in patients with single vessel disease (Moreno, 2010).

2.4.1 Initiation of atherosclerosis; the role of endothelium

Because endothelial cells are involved in hemostasis, a dysfunctional endothelium produces a prothrombotic environment leading to the development of atherosclerotic lesions (Corti, 2003).

Some of the classic cardiovascular risk factors such as hypertension, diabetes, and

Fig-2.1: Evolution of ACS: Link between cardiovascular (CV) risk factors, endothelial dysfunction, inflammation, and acute coronary syndromes.

hypercholesterolemia have been recognized to induce endothelial dysfunction by reducing the bioavailability of nitric oxide (NO), increasing tissue endothelin 1 (ET-1) content (Ruschitzka et al., 2000) and activating pro-inflammatory signaling pathways such as nuclear factor kappa B (Kinlay, 2001), which is involved in the expression of many cytokines, enzymes, and adhesion molecules (Barnes et al., 1997).

2.4.2 Atherosclerotic plaque formation

Endothelial dysfunction and expression of adhesion molecules is followed by the migration of monocytes into the sub endothelium, where they transform into macrophages. This differentiation process includes the upregulation of various receptors , including CD36 and the scavenger receptor A that are responsible for the internalization of oxidized low density lipoprotein (LDL), and formation of foam cells. Eventually fatty streaks are produced which is the first cellular hall mark of atherosclerosis.

These activated macrophages release mitogens and chemo-attractants that perpetuate the process by recruiting additional macrophages and vascular SMC formation by digesting the extracellular matrix from the media into the injured media. This may eventually compromise the vascular lumen. The recruited SMC and macrophages significantly contribute to plaque growth, not only by increasing their number but also by synthesizing extracellular matrix components. Macrophages are able to elaborate MMPs which contribute to plaque disruption and thrombus formation by degradation of the extracellular matrix (Corti, 2003).

2.4.3 Progression of plaque:

There are two main parts of the vulnerable atherosclerotic plaque, also called a thin fibrous cap atheroma: the lipid-rich core, and the meshwork of extracellular-matrix proteins that forms the fibrous cap. This plaque is prone to rupture, resulting in the liberation of thrombogenic material thrombus formation.

The atherosclerotic plaque passes through a slow progressive phase which is mediated by endothelial dysfunction. Macrophages involved in the formation of foam cells eventually

undergo apoptosis to initiate the release of MMP'S leads to the shedding of membrane microparticles, causing exposure of phosphatidylserine on the cell surface and conferring a potent procoagulant activity. This initiates the phase of rapid plaque growth. Rapid plaque growth is thrombus-mediated. Evidence suggests that plaque rupture, subsequent thrombosis, and fibrous thrombus organization are also important in the progression of atherosclerosis in both asymptomatic patients and those with stable angina. Plaque disruption with subsequent change in plaque geometry and thrombosis results in a complicated lesion. Such a rapid change in atherosclerotic plaque geometry may result in acute occlusion or subocclusion with clinical manifestations of unstable angina or other ACS (Burke et al., 1997).

Fig-2.2: Initiation, progression, and complication of human coronary atherosclerotic plaque.

1, Normal artery. 2, accumulation of leucocytes. 3, Evolution to fibrofatty stage. 4,expression of tissue factor and matrix-degrading proteinases that weaken fibrous cap of plaque. 5,fibrous cap ruptures causing acute coronary syndromes 6, healing response 7, superficial erosion of endothelial



Effective management of ACS relies on accurate and timely diagnosis. A second goal is to define the risk of myocardial ischemia and recurrent cardiac events (Rogers, 2000). Aside from patient's history, signs and symptoms, current diagnostic tools consist of ECG, and cardiac enzymes which include CK, CKMB and Troponins.

However, their diagnostic accuracy varies. In a study of 775 consecutive patients with chest pain who were admitted to a cardiac care unit, acute myocardial infarction was diagnosed in 10 percent of patients with normal ECG findings (11 of 107 patients) in the emergency department (Slater et al., 1987). CK has low specificity for cardiac damage, whereas CKMB is more cardiac specific. Troponins are the preferred markers for the diagnosis of myocardial injury; however, both CKMB and Troponins take four to six hours to rise to detectable levels in the serum. Moreover, these markers are able to single out only a portion of patients who are at a high risk of developing ACS. The introduction of high sensitive cardiac troponin assays with lower limits of detection has aided the earlier diagnosis of AMI (Bartunek, 2010).

Elevated levels of circulating cardiac troponin, are found in about one-third of the

patients with ACS and are associated with an increased short-term risk of death and nonfatal myocardial infarction (Antman et al., 1996), (Hamm et al., 1992), (Hamm., 1997), (Ohman et al., 1996). Although the absolute short-term risk in troponin-negative patients is significantly lower as compared with troponin-positive patients, the large number of patients without troponin elevation remains clinically challenging with respect to risk assessment and therapeutic management. Specifically, the six-month risk of death or nonfatal myocardial infarction in troponin-negative patients was 8.4% in the c7E3 Anti Platelet Therapy in Unstable Refractory angina (CAPTURE) trial (Hamm et al., 1999).

Substantial research efforts have been directed towards the detection of vulnerable plaques responsible for ACS including sophisticated imaging techniques, these methods however, are invasive and expensive therefore their use in daily practice is limited. Therefore the measurement of a sensitive and specific early biomarker of plaque instability, whose levels are increased before myocardial necrosis, should allow for earlier diagnosis and improve therapeutic decision-making.


Risk stratification in ACS is based upon clinical features, ECG and cardiac enzymes especially Troponins. However, a clinical diagnosis of 'suspected ACS' has low diagnostic accuracy when based only on the ECG and clinical symptoms (Goodacre, 2002), (Bertrand et al., 2002). ST elevation has high specificity but low sensitivity for infarction, and three-quarters of those with acute coronary symptoms do not have ST elevation on presentation (Carruthers et al., 2005). Risk stratification cannot therefore rely simply on the presence of ST elevation, and more accurate risk prediction tools are required. Risk stratification in emergency departments can reduce hospital admissions, and the introduction of troponin assays has aided this process (Fox et al., 2004; Scirica, 2004). However, the negative predictive value of troponin on arrival is poor, because of the time required for efflux of this marker from cardiomyocytes (Fox, 2004). Thus, a more integrated approach to risk prediction is required. Research has put forward a number of candidate biomarkers such as hs CRP, MPO and PAPP-A.


The NIH Definition Working Group defines 'biomarker' as follows:

"A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention" (NIH Definition Working Group, 2001).

Biomarkers play a pivotal role in the diagnosis and management of patients with ACS. For a cardiac biomarker to be clinically useful it must meet certain diagnostic, therapeutic and prognostic requirements. Although some biomarkers have been incorporated into contemporary clinical care, the inability of the currently available gold standard i.e Troponins to satisfy the requirements of an ideal biomarker has stimulated active investigation and research has produced a growing list of candidate biomarkers. However the search for an ideal cardiac biomarker has become increasingly challenging as none of the proposed biomarkers have been able to meet all the requirements and have thus not been incorporated into routine clinical use.

Amongst the plethora of emerging cardiac biomarkers, Myeloperoxidase (MPO) and Pregnancy Associated Plasma Protein A (PAPP-A) have been proposed to have a role superior to that of others.


Myeloperoxidase is an enzyme of the innate immune defense system found predominantly in the azurophilic granules of neutrophils, monocytes and some subtypes of tissue macrophages. It has emerged as a potential participant in the initiation and propagation of CAD and ACS, because of which it has been proposed as risk marker and a diagnostic tool for patients admitted to the emergency room with chest pain with suspected ACS.

2.8.1 Mechanism of action

MPO catalyzes the conversion of chloride and hydrogen peroxide to hypochlorite and is secreted during inflammatory conditions. When released into the neutrophils, one of the initial products generated is Hypochlorous acid, a compound with potent antibacterial capabilities; however, when released into the circulation, it can also damage surrounding tissues and contribute to various disease processes including atherosclerosis (Klebanoff, 2005).

2.8.2 Potential mechanisms for MPO's contribution to CAD

Inflammatory events have been implicated at all stages in the evolution of atherosclerotic plaque, from the early development of endothelial dysfunction, to formation of the mature atheroma and its subsequent rupture (Ross, 1999), thereby incriminating MPO in its pathogenesis as it is released by neutrophils gathered at the site of inflammation.

The involvement of MPO was first suggested by the observation that Myeloperoxidase is enriched within the human atheroma (Daugherty et al., 1994). Since then, numerous studies have been conducted to investigate its role and have shown that it acts in the following manner:

Formation of atherogenic LDL:

Numerous oxidizing agents produced by the activity of MPO, such as HOCl, dityrosine, chlorotyrosine and nitrotyrosine are present in the human atheroma. In addition, LDL isolated from human atheroma contains greater amounts of these products than circulating LDL from healthy controls (Hazen, 1997) (Leeuwenburgh et al., 1997), suggesting the role of MPO in the formation of atherogenic or oxidized LDL. MPO derived products convert LDL into a form which is readily taken by monocytes and macrophages while simultaneously promoting its oxidation. Its oxidized form, which is cytotoxic (Hessler et al., 1983) is readily taken up by the scavenger receptor CD36 (Podrez et al., 2000), a major participant in the evolution of fatty streak which is the first cellular hallmark of atherosclerosis.

Generation of dysfunctional HDL particles:

Recent evidence shows that HDL is the target for site specific modifications by MPO and its derived oxidants impairing the ability of HDL to remove cholesterol from cells. HDL isolated from human atheroma contains not only MPO, but also its derived oxidants. Promotion of endothelial dysfunction:

Endothelial dysfunction, one of the first steps of atherogenesis, is promoted by MPO via limitation of the availability of nitric oxide (NO). MPO-generated oxidants have been reported capable of inhibiting the activity of Nitric Oxide Synthase. Reactive nitrogen species such as those generated by MPO have also been shown to uncouple NOS. NO synthesis is further inhibited by HDL modified by a MPO-generated chlorinating system, which results in delocalization of endothelial NOS from its normal plasma membrane location. Further, MPO and HOCl both reduce the availability of NADPH, an essential NOS cofactor (Nicholls, 2005).

Fig-2.3: Scheme illustrating multiple processes throughout the evolution of

atherosclerosis in which MPO is implicated.

2.8.4 MPO and development of the unstable plaque:

Since MPO levels have been found to be elevated in culprit atherosclerotic lesions prone to rupture (Sugiyama, 2001) and the ability of systemic MPO levels to predict the likelihood of clinical events suggests that MPO may be involved in the transition of a mature atherosclerotic plaque to vulnerable one. Studies conducted by Baldus et al and Brennan et al have shown that serum MPO levels are predictive of adverse cardiac events including MI and death, at the time of presentation and afterwards upto six months (Brennan et al., 2003) (Baldus et al., 2003).

2.8.5 MPO levels in ACS

One of the earlier studies conducted by Brennan et al showed that the plasma levels of myeloperoxidase in patients presenting with chest pain of ACS ranged from 0 to 4666 pM, with a median of 198 pM and an interquartile range of 119 to 394 pmol/L. These levels were significantly higher than those observed in the 115 control subjects (median, 120 pmol/L; interquartile range, 97 to 146 pmol/L; P<0.001) (Brennan et al., 2003). These results were supported by a study conducted later on by Mocatta et al. (Mocatta et al, 2007). A recent study reported the same results and found that the levels of MPO in CAD increased progressively from SCAD to NSTEMI to STEMI. MPO level was 422 (327-591·8) pmol/L in patients with stable CAD, 684 (428-1068) pmol/L in patients with non-ST-segment elevation acute coronary syndromes and 893.1 (497-1489.6) pmol/L in patients with acute myocardial infarction (P < 0·001) (Ndrepepa et al., 2008). These results were however contradicted by Kubala, who showed that there was no difference in the levels of MPO in patients with and without SCAD [421 pM (321 pM, 533 pM) vs. 412 pM (326 pM, 500 pM) in CAD vs controls, respectively p<0.05] (Kubala, 2008). A more recent study showed that mean myeloperoxidase levels in ST segment elevation myocardial infarction patients were 631 pmol/L, non-ST-segment elevation myocardial infarction patients 624 pmol/L and unstable angina patients 589.5 pmol//L and were significantly higher than non-cardiac chest pain patients 223 pmol/L and also healthy volunteers 199 pmol/L (p<.001) (Gururajan et al.,2009).

2.8.6 MPO and early detection of AMI:

Brennan et al in 2003, reported that while Troponins take 4-6 hours to rise to detectable levels in the serum, MPO levels were elevated as early as within 2 hours after the onset of symptoms in patients of AMI who were initially negative for troponin (Brennan et al, 2003). Thus suggesting that measurement of MPO may be useful In the ED for the early diagnosis of AMI, and may also help in the identification of patients with unstable angina preceding myocardial necrosis.

2.8.7 Diagnostic accuracy of MPO:

Limited studies have been carried out on the diagnostic accuracy of MPO. Baldus et al divided their study population into six groups based on the levels of MPO and troponin T, and reported diagnostic threshold of MPO for ACS of 1531 and 2413 pmol/L(Baldus et al, 2003). The ROC analysis conducted by Brennan et al yielded a cutoff value of 198 pmol/L and showed a higher sensitivity, specificity, negative predictive value and positive predictive value of MPO (65.7%, 60.7%, 53.3% and 72.2%) when compared with troponin, CK-MB and CRP (Baldus et al., 2003). AUC of MPO was also the highest for the cohort that was consistently negative for Troponin T as compared to the rest of the markers studied (p<0.001), whereas the study by Ndrepepa showed that elevated MPO levels were associated with the presence of ACS with an area under the ROC curve of .731 (95% CI 0.692-0.771; p<.001) (Ndrepepa et al., 2008). A more recent study evaluating the diagnostic accuracy of MPO in ACS showed that from the receiver operator characteristic (ROC) curve analysis, the optimum value above which myeloperoxidase can be considered positive was found to be 331 pmol/L. The area under the curve was found to be 0.956 with 95% CI (0.934 to 0.973) (p<0.0001) and multivariate analysis revealed myeloperoxidase to be an independent diagnostic marker for early diagnosis of ACS (Gururajan et al., 2009).

2.8.8 MPO and risk stratification in ACS

MPO appears to be a marker of risk stratification in ACS. Zhang and colleagues reported an odds ratio of 11.9 (95% CI: 5.5-25.5) (Zhang et al., 2001). In a multivariate analysis, Baldus and colleagues showed that MPO, cTroponinT, sCD40 ligand, vascular endothelial growth factors and CRP were independent predictors of the outcome. In the study conducted by Mocatta et al Cox proportional hazards analysis indicated that older age, pre-existing type 2 diabetes, below-median LVEF, and above-median levels of plasma NT-proBNP and plasma MPO were significantly predictive of mortality in a cohort of AMI patients. Median MPO levels of 379 pmol/L contributed to mortality independently of the other factors (p = 0.03, risk ratio = 1.8, 95% confidence interval: 1.1 to 3.1) (Mocatta et al., 2007).

The role of Myeloperoxidase across the spectrum of CAD therefore needs further investigation as research has so far put forward contradictory results.


Pregnancy associated plasma protein-A (PAPP-A) is an emerging biomarker in the category of markers of inflammation and plaque instability produced by the syncytiotrophoblasts of the placenta. PAPP-A was originally discovered as a glycoprotein found in the serum of pregnant women (Lin et al., 1974). Although the function of this complex in pregnancy remains unknown, it is being used for the screening of Down's syndrome in first trimester of pregnancy.

2.9.1 Structure

It circulates in the form of an approximately 500 kDa heterotetramer (Bonno et al., 1994) which consists of two PAPP-A peptides complexed with two pro-eosinophilic major basic protein peptides via a number of disulfide bonds.

2.9.2 Mechanism of action:

PAPP-A was identified by Lawrence et al (Lawrence et al., 1999) as the metalloproteinase which cleaves insulin-like growth factor binding protein-4 (IGFBP-4), resulting in the inhibition of insulin-like growth factor-I (IGF-I). The proform of eosinophil major basic protein (pro-MBP) inhibits the enzymatic activity of PAPP-A. The insulin-like growth factors are important physiologic regulatory proteins which control cell proliferation and metabolism and are implicated in the promotion of atherogenesis and restenosis (Bayes-Genis b, 2000). IGFBP-4 is released from IGF-I by the activity of PAPP-A, thus promoting IGF-I signaling.

Since PAPP-A is a member of the metzincin metalloproteinase superfamily, is synthesis by the various cell types involved in atherogenesis, and plays a role in regulation of IGF, suggest that it is involved in atherosclerotic plaque progression and instability.

2.9.3 Histological evidence:

Ample histological evidence supports the role of PAPP-A in plaque instability. Brugger-Andersen recently demonstrated that PAPP-A was strongly expressed in the ECM of atherothrombotic plaques collected by aspiration thrombectomy during Percutaneous intervention (Pci) of patients with STEMI (Brugger-Andersen et al., 2010).

2.9.4 PAPP-A and plaque instability

The theories implicating PAPP-A in plaque instability are paradoxical. Since it possesses proteolytic activity and high PAPP-A concentrations have been associated with unstable plaques and impaired clinical outcome, PAPP-A is thought to have a role in matrix degradation of plaques. However, aside from the degradation of IGF-1 binding proteins, no other proteolytic role has been found for PAPP-A (Crea, 2005). A pro-atherogenic action of IGF-1 has been suggested for IGF because in vitro studies have shown that IGF may induce macrophage activation, chemotaxis, LDL-cholesterol uptake by macrophages and stimulates the release of pro-inflammatory cytokines (Renier et al., 1996), (Bayes-Genis, 2000). However, more recent evidences suggest that IGF-1 may protect against atherosclerosis by preserving endothelial function, promoting plaque stability and exerting anti-inflammatory and anti-oxidant effects (Conti et al., 2004), (Conti et al., 2005). If IGF is "cardioprotective", then it may be hypothesized that elevated PAPP-A levels are also cardioprotective (Crea, 2005).

2.9.5 PAPP-A and the Acute Coronary Syndrome

Aside from its role in the pathogenesis of ACS, PAPP-A has also been investigated for its clinical utility and has been found to have important diagnostic and prognostic value. It has also been found to be of value in the risk stratification of patients. Diagnostic value

Bayes-Genis et al. (Bayes-Genis et al., 2001) observed that PAPP-A levels were higher in patients with ACS as compared to those with SCAD. They reported a sensitivity for PAPP-A of 89.2% and a specificity of 81.3% in discriminating ACS from CSA and control (healthy) subjects at a cut off value of 10 mIU/L. Similar findings were also reported by Khosravi et al (Khosravi et al., 2002). These authors, like Bayes-Genis previously, also found significantly higher concentrations of PAPP-A in patients with ACS compared to control subjects. Contrary to the findings of these investigations, a small study by Dominguez-Rodriguez et al. in patients with STEMI did not found any difference in PAPP-A concentrations in patients compared to controls in samples taken (mean± S.D.) 6.3±2.8 h after the onset of symptoms (Dominguez-Rodriguez et al., 2005). A more recent study conducted by Iversen et al, carried out serial sampling in patients with STEMI, and found significantly higher mean PAPP-A values at admission in patients with STEMI than in those with non-ST elevation myocardial infarctions or unstable angina pectoris (27.6 vs 12.2 mIU/L, p < 0.01). In samples drawn < 2 hours after admission, the sensitivity of PAPP-A was superior (93%) to that of CKMB (60%) and troponin T (61%). They thus concluded that in the early stages of STEMI, PAPP-A seems to be a more sensitive marker of myocardial infarction than CKMB and troponin T. The peak concentrations of circulating PAPP-A were found 5.77 hours (95% CI 4.95 to 6.58) after the onset of symptoms. This was significantly earlier (p=0.001 for all values) than for troponin T and CKMB, for which the corresponding times were 21.88 hours (95% CI 18.92 to 24.83) for troponin T and 14.41 hours (95% CI 13.03 to 15.78) for CK-MB (Iversen et al., 2008).

In patients presenting to the emergency department with symptoms suggestive of ACS, Elesber et al. reported that PAPP-A levels were predictive of a final diagnosis of ACS in a multivariable model (p = 0.039) (Elesber et al., 2007). Serum PAPP-A levels were significantly higher (p=0.001) in patients with a final diagnosis of acute coronary syndrome (median, 2.0 mIU/L; 25th quartile, 1.2; 75th quartile, 4.9) compared to patients with a final diagnosis of non-cardiac chest pain (median IQR,1.2 mIU/L; 0.7-1.6).

Another study conducted recently by Iversen et al, found that In the patients with high-risk NSTE-ACS, PAPP-A was related to the risk of nonfatal myocardial infarction (p = 0.02) and death (p = 0.03). This result was consistent on multivariate analysis of the combination of mortality or nonfatal myocardial infarction (Odds Ratio 2.65, 95% confidence interval 1.40 to 5.03) but not for mortality alone (p = NS). In patients with STEMI, PAPP-A was related to the risk of death (p = 0.01) but not the composite outcome of myocardial infarction and death. This was also true after adjustment for other univariate predictors of death (odds ratio 2.19, 95% CI 1.16 to 4.16) (Iversen et al., 2009). Release patterns of PAPP-A:

Limited data is available on the release patterns of PAPP-A. Qing et al, reported that increases in levels of PAPP-A in patients with ACS are variable occurring either early at 2 hours or late at 30 hours (Qin et al., 2002) whereas Lund et al, demonstrated that the release patterns of PAPP-A were associated with the occurrence and timing of reperfusion. They observed that patients who presented early for treatment had elevated levels whereas as those who presented late did not (Lund et al., 2006). Role of PAPP-A in the risk stratification of patients of ACS:

The ability of PAPP-A to stratify the risk for these patients has been documented in a number of studies carried out on both troponin positive and negative patients, but contradictory results have been obtained. Lund et al, in 2003 tested PAPP-A levels in troponin I negative patients of ACS and found them to be predictive of the combined primary end point of death, AMI, or revascularization. Median [25th, 75th percentiles] admission PAPP-A in the 136 cTnI-negative patients was 2.3 mIU/L [1.6- 3.0]. a cut off of 2.9 mIU/L was associated with the combined primary end point at 6 months (RR, 3.7; 95% CI, 1.6 to 8.9; P=0.0028) and was associated with a 4.6-fold higher adjusted risk of adverse outcome (Lund et al., 2003). In a small cohort of patients with ST-segment elevation acute MI (n = 62), Lund et al. found that PAPP-A >10mIU/L (the highest tertile) was strongly associated with 12-month risk of cardiovascular death or non-fatal MI (p=0.049) (Lund et al., 2006). They did not observe any correlation between PAPP-A and CRP or Troponins.

Heeschen et al, compared the levels of PAPP-A in patients with angiographically validated ACS and in an emergency room population of patients with chest pain, with markers of systemic inflammation and necrosis. Pregnancy-associated plasma protein A levels were significantly higher in patients with ACS (mean 20.9 mIU/l; median 4.9 mIU/l [range 0.1 to 362.5 mIU/l]) as compared with patients with stable angina (mean 8.7 mIU/l; median 1.9 mIU/l [range 0.1 to 113.9 mIU/l]; p = 0.007) and patients without evidence for coronary heart disease (mean 5.2 mIU/l; median 1.4 mIU/l [range 0.1 to 54.1 mIU/l]; p = 0.001 vs. patients with ACS; p =0.044 vs. patients with stable angina), respectively. Mean PAPP-A levels in patients with non-ST-segment elevation myocardial infarction did not significantly differ from mean PAPP-A levels in patients with unstable angina (non-ST-segment elevation myocardial infarction: mean 27.4 mIU/l; median 4.0 mIU/l [range 0.1 to 362.5 mIU/l]; unstable angina: mean 18.1 IU/l; median 5.3 mIU/l [range 0.1 to 221.1 mIU/l]; p =0.50). They observed a positive correlation between PAPP-A levels and Hs-CRP, however no correlation was seen between PAPP-A and troponin T levels. They also showed that higher values of PAPP-A were associated with increased short term cardiovascular risk (OR: 2.44, 95% CI: 2.54-5.89) ( Heeschen et al., 2005).

Recently Lund et al, measured both the free and the total form of PAPP-A in patients of non ST elevation ACS and found that free PAPP-A >1.74 mIU/L; the form released specifically in ACS was strongly with the risk of adverse events over a period of 1 year (risk ratio=2.0; 95% CI 1.0-4.1, P=0.053) (Lund et al, 2010).

On the other hand the study by Laterza et al. showed that PAPP-A measured at the time of presentation to the ED was shown to be a modest predictor of adverse events at 30 days. They included 346 patients presenting to the ED with chest pain or other symptoms suggestive of ACS, and found that at a cut-off of 0.22 mIU/L, PAPP-A had a sensitivity of 66.7% (95% CI: 48.2 to 82.0) and a poor specificity of 51.1% (95% CI: 45.4 to 56.8) (Laterza et al., 2004). These findings highlight the need for further investigation of the role of PAPP-A for risk stratification in ACS.

Fig-2.4: Temporal difference in the release of PAPP-A and cardiac troponin in ACS.

A depicts pathophysiological processes encountered in unstable angina, while

B depicts pathophysiological processes encountered in myocardial infarction.

2.10 hs CRP:

High sensitive C-reactive protein (hs-CRP) is an acute phase b globulin with a molecular mass of approximately 118000 daltons that is produced predominantly by hepatocytes under the influence of cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (Schultz and Arnold, 1990). T-cell cytokines cause the production of large amounts of molecules downstream in the cytokine cascade Inflammation is a major mechanism in the process of atherogenesis and in triggering of clinical CAD events by precipitating acute plaque rupture. Some experts propose that CRP, a nonspecific marker of inflammation, is a new tool that improves CAD risk estimation and that it should be used as a routine clinical risk assessment test (Rider et al., 2004).

CRP has been found in atherosclerotic lesions. It binds to low density lipoprotein (LDL), allowing LDL to be taken up by macrophages without the need for modification (Zwaka et al., 2001). CRP induces adhesion molecule expression and the production of interleukin-6 and monocyte chemo attractant protein-1 (MCP-1) in human endothelial cells; these effects might enhance a local inflammatory response within the atherosclerotic plaque by the recruitment of monocytes and lymphocytes (Pasceri et al., 2001; Pasceri et al., 2000). Administration of CRP promotes inflammation in humans and atherosclerosis in an animal model (Bisoendial et al., 2005; Schwedler et al., 2005)and has thus been found to be associated with adverse outcomes in ACS.

2.10.1 hs CRP in ACS:

The serum or plasma concentration of hs CRP is increased in patients with ACS than compared to individuals without established CAD as well as in patients with SCAD (Berk, 1990). The plasma concentration of CRP predicts the long-term risk of a first myocardial infarction, ischemic stroke, or peripheral vascular disease (Ridker et al., 1997; Ridker et al., 2004). In addition, serum CRP is two-fold higher in men with documented CAD and four-fold higher in those with a myocardial infarction compared to control subjects (Anderson et al., 1998). The mechanisms responsible for the association between hs- CRP and CAD are not clear. Similar results were also reported by Yip et al in their study. They reported that the serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 _ 2.3 mg/L vs 1.4 _ 0.7 mg/L, p < 0.0001 [mean _ SD]) and in healthy subjects (2.7 _ 2.3 mg/L vs 1.0 _ 0.6 mg/L, p < 0.0001) (Yip et al., 2004). Levels of hs CRP were also significantly elevated in patients of ACS as compared to SCAD in the study by Espliguero. Mean levels were 2.3 mg/L vs 4.2 mg/L (p<.004). Scirica et al also found that its concentration was higher in patients of STEMI (17.8 vs 10.6 in NSTEMI vs 5.8 mg/l in UA) (Scirica et al., 2007). These findings were again reported by Nyandak who found that patients with ACS had the highest mean hs CRP levels of 5.6 mg/l, followed by SCAD patients 3.54 mg/l and the control group 2.28 mg/l (Nyandak, 2007). These results were supported by Irfan G and Ahmad M in Pakistan who studied 100 patients with ACS and found that the levels of hs CRP were 3.12+ 1.62 mg/dl in UA, 4.38+1.51 mg/dl in NSTEMI and the highest levels of 5.77+2.15 mg/dl were in patients of STEMI (Irfan, 2008).

Over two dozen prospective studies have demonstrated that baseline hs-CRP levels independently predict future myocardial infarction, stroke, cardiovascular death, and incident peripheral arterial disease in apparently healthy individuals (Ridker, 2003). Whether it predicts risk in patients of ACS as well however needs to be investigated as limited studies have been conducted on its ability to stratify risk in these patients.


Fig-2.5: Release of CRP under the influence of cytokines.