Pregnancy-Associated Plasma Protein-A Elevation in Patients With Acute Coronary Syndrome and Subsequent Atorvastatin Therapy

doi:10.1016/j.amjcard.2007.07.045

The American Journal of Cardiology

Volume 101, Issue 1, 1 January 2008, Pages 35-39

https://doi.org/10.1016/j.amjcard.2007.07.045 Get rights and content

Pregnancy-associated plasma protein-A (PAPP-A) was associated with atherosclerotic plaque vulnerability, whereas statin therapy was associated with increased plaque stability. Eighty-six patients presenting with clinical indications (non–ST-elevation myocardial infarction, unstable angina, and stable angina) for invasive coronary angiography and subsequent verified coronary artery disease (CAD) were randomly assigned in a double-blind manner to atorvastatin 10 or 80 mg/day. PAPP-A, high-sensitivity C-reactive protein (hs-CRP), and lipids were measured at baseline (before statin therapy) and at 1 and 6 months. PAPP-A was significantly increased in 35 patients with acute coronary syndrome (ACS) compared with 51 patients with stable CAD (p <0.001). Patients randomly assigned to atorvastatin 10 mg did not show a significant decrease in PAPP-A from baseline at 1 or 6 months. Patients treated with atorvastatin 80 mg showed a significant decrease at 1 month compared with baseline, but not at 6 months. hs-CRP was not significantly different between the ACS and stable CAD groups. Patients receiving atorvastatin 10 mg showed no hs-CRP decrease at 1 or 6 months, whereas it significantly decreased in the 80-mg group at 6 months, but not at 1 month. In conclusion, PAPP-A significantly increased in patients with ACS compared with those with stable coronary disease. High-dose atorvastatin significantly decreased PAPP-A at 1 month and hs-CRP at 6 months in patients with verified CAD. Low-dose atorvastatin did not produce this effect.

Section snippets

Methods

Patients were identified for this study at the time they were scheduled for invasive coronary arteriography. Angiography was performed for clinical indications in a study approved by the institutional review board of Abbott Northwestern Hospital (Minneapolis, Minnesota). The patients surveyed included both inpatient and outpatient populations. Patients underwent medication review to determine whether they were using a statin at the time of presentation. Inclusion criteria were 18 years old, no

Results

Ninety-five patients gave consent to participate in the study, 9 of whom were found to have no CAD using coronary angiography. Of the 86 remaining patients, 35 had a diagnosis of ACS and 51 had a diagnosis of stable coronary disease. Figure 1 shows that PAPP-A in the ACS group was more than double that of patients with stable CAD at 2.05 (interquartile range 1.02 to 4.45) versus 0.75 mIU/L (interquartile range 0.42 to 1.47, p <0.001). hs-CRP was higher in the ACS group (Figure 1), but not

Discussion

This study found that PAPP-A increased in patients with ACS compared with patients with stable CAD. This finding was consistent with previous PAPP-A studies that showed increased levels in patients with unstable coronary artery lesions⁴ and a recent study that showed PAPP-A increased in patients with ST-elevation myocardial infarction.¹² Previous studies suggested that infarction of the myocardium by itself did not lead to increased PAPP-A.⁴ Rather, it was likely that plaque instability in this

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Cited by (26)

Pregnancy-associated plasma protein-A in atherosclerosis: Molecular marker, mechanistic insight, and therapeutic target
2018, Atherosclerosis
Citation Excerpt :
Statins, also known as 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have been widely used to reduce the risk of cardiovascular events in both primary and secondary prevention. Treatment with high-dose atorvastatin (80 mg/d) for one month was shown to decrease serum PAPP-A levels in ACS patients, suggesting that blocking PAPP-A might be also involved in the beneficial effects of atorvastatin on cardiovascular system [122]. Conversely, circulating PAPP-A levels are unchangeable in ACS patients receiving low-dose atorvastatin (10 mg/d) or fluvastatin (80 mg/d) therapy [122,123].
Pregnancy-associated plasma protein-A (PAPP-A), a member of the metzincin metalloproteinase superfamily, can enhance local insulin-like growth factor (IGF) bioavailability through proteolytic cleavage of three IGF binding proteins. In patients with coronary atherosclerosis disease (CAD), elevated PAPP-A levels are significantly associated with a higher risk of cardiovascular events. Accumulating evidence indicates that this protease exerts a proatherogenic effect by altering a variety of pathological processes involved in atherosclerosis, including lipid accumulation, vascular inflammation, endothelial dysfunction, vascular smooth muscle cell proliferation and migration, plaque stability, and thrombus formation. Moreover, blockade of its proteolytic activity by stanniocalcin or microRNAs is protective against atherosclerosis development. In this review, we summarized the latest advances regarding the roles of PAPP-A in the pathogenesis of atherosclerosis with an emphasis on its diagnostic and prognostic values in CAD.
PAPP-A in cardiac and non-cardiac conditions
2013, Clinica Chimica Acta
Citation Excerpt :
Statins have been widely used in cardiovascular diseases for their versatile function such as regulation of lipid level, anti-inflammation and endothelium repair. However, it remains unknown whether stains have established an effect in reducing PAPP-A. Miedema et al. [58] reported that high-dose atorvastatin (80 mg/d) could decrease the serum PAPP-A in ACS patients after one month treatment. However, these results could not be confirmed in ACS patients under the low-dose atorvastatin (10 mg/d or 20 mg/d) or fluvasatin (80 mg/d) [59].
Pregnancy-associated plasma protein-A (PAPP-A), a newly discovered member of insulin like growth factors (IGFs) axis, has been reported to be a biomarker in both cardiac and non-cardiac conditions. PAPP-A mainly acts as a protease cleaving IGF inhibitors — IGF binding proteins (IGFBPs), thereby setting free IGFs. In cardiac conditions, PAPP-A plays an important role in progressive atherosclerosis. As a biomarker, PAPP-A is not only sensitive, specific and early for diagnosis of acute coronary syndrome, but also an independent risk factor for all-cause mortality or combined cardiovascular events. In non-cardiac conditions, PAPP-A is a new anti-aging target. PAPP-A knock out (KO) mice have a prolonged lifespan than the wild type. In addition, PAPP-A is also a biomarker associated with malignant cancer and end stage renal disease.
The expression of IGFs and IGF binding proteins in human carotid atherosclerosis, and the possible role of IGF binding protein-1 in the regulation of smooth muscle cell proliferation
2012, Atherosclerosis
Citation Excerpt :
The different gene association profiles between IGFBP-1 and other five IGFBPs indicated the gene expression of these binding proteins might be regulated differently. Recently, IGFBP-4 activity has been of focus since pregnancy-associated plasma protein-A (PAPP-A), an IGFBP-4 protease, has been shown to be increased in patients with acute coronary syndrome, and double knockout mice lacking ApoE and PAPP-A showed decreased lesion development [22,23]. These studies suggest that the bioavailability of IGF-1 in atherosclerotic lesions, regulated by its affinity for IGFBP-4, may influence plaque progression.
Proliferation of smooth muscle cells (SMCs) in the fibrous cap of atherosclerotic lesions has been proposed to be important for plaque stability. Since the insulin-like growth factor (IGF) system has been implicated to play a role in atherosclerosis and plaque stability, we investigated the expression of members of the IGF system in carotid plaques, in particular IGFBP-1 and its role in the regulation of SMC proliferation.
Gene expression profiles of the IGF system in 164 human carotid plaques obtained from our Biobank of Karolinska Endarterectomies (BiKE) were analyzed. Expression of IGFBP-1 mRNA was significantly increased in carotid plaques compared with normal iliac arteries in contrast to IGF-1, IGF-2, and IGFBP-3 to IGFBP-6. The expression of IGFBP-1 mRNA correlated positively to that of CD163, CD68, IL-1β, IL-6, TNFα, IGFBP-4 and IGFBP-5. Immunohistochemistry demonstrated co-localization of IGFBP-1 with SMCs and macrophages. In vitro studies showed that IL-1β, IL-6 and TNFα stimulated IGFBP-1 mRNA expression in SMCs. IGFBP-1 stimulated SMC proliferation through ERK1/2 activation but independently of the IGF-1 receptor. In addition, IGFBP-1 modulated the effect of IGF-1 on SMC proliferation and ERK1/2 activation.
Our results demonstrate that IGFBP-1 mRNA and protein is detected at increased levels in human carotid plaques, possibly as a consequence of plaque inflammation. IGFBP-1 affects SMC proliferation and may be involved in the regulation of plaque stability.
Studies on the effects of heparin products on pregnancy-associated plasma protein A
2011, Clinica Chimica Acta
Citation Excerpt :
Pregnancy-associated plasma protein A (PAPP-A) has been studied as a novel cardiac risk marker in acute coronary syndromes (ACS). Elevated circulating concentrations have been detected in ACS patients and the concentration has been found to be associated with increased risk of major adverse cardiac events such as a new myocardial infarction or death [1–12]. However, recent findings have shown that intravenous medication with heparin products elicits a rapid elevation in the circulating PAPP-A levels.
Intravenous low molecular weight (LMWH) and unfractionated heparin (UFH) increase the circulating concentrations of pregnancy-associated plasma protein A (PAPP-A), a novel cardiac risk marker, in haemodialysis and coronary angiography patients.
To further investigate the mechanisms of heparin effects, free PAPP-A was analysed in serial serum samples collected during haemodialysis (intravenous LMWH), carotid endarterectomy or abdominal aortic aneurysm surgery (intravenous UFH), treatment at intensive care unit (subcutaneous LMWH), and coronary angiography (intravenous bivalirudin). PAPP-A was extracted from plaque tissue samples of endarterectomy and aneurysm patients. The interaction between heparin products and free PAPP-A was studied with gel filtration.
After intravenous UFH and LMWH free PAPP-A increased significantly but bivalirudin had no effect. After LMWH bolus in haemodialysis patients 85% of free PAPP-A was cleared with a half-life of 13.1 min and the rest with a half-life of 96.6 min. Subcutaneous LMWH led to lower and slower free PAPP-A elevation. PAPP-A extracted from plaque tissues was in free form and extraction was strongly enhanced by LMWH. Heparin products increased the molecular size of free PAPP-A.
The heparin-induced PAPP-A elevation is seen in various patients and should be taken into account when PAPP-A is studied as a biomarker.
Is Serum Pregnancy-Associated Plasma Protein A Really a Potential Marker of Atherosclerotic Carotid Plaque Stability?
2010, European Journal of Vascular and Endovascular Surgery
Citation Excerpt :
High uncomplexed amounts of circulating PAPP-A could be a marker of oxidative stress. Stulc and Miedema described that serum PAPP-A levels were significantly higher in patients with severe hypercholesterolemia than in healthy normolipidaemic control subjects, despite the absence of clinically manifest atherosclerosis.20,23 This suggests that an increase in PAPP-A may reflect earlier stages of atherosclerotic lesions, even in the absence of clinical signs of atherosclerosis.
The search for markers predicting risk of plaque rupture in carotid atherosclerosis is still ongoing. Previous findings showed that pregnancy-associated plasma protein-A (PAPP-A) levels correlate with an adverse plaque morphology. However, the role of PAPP-A in plaque destabilisation is still uncertain.
Patients with carotid artery stenosis involved in the study were asymptomatic (n = 29) and symptomatic (n = 37). Carotid plaques were characterised by histology (n = 33). Immunohistochemistry (n = 17) was used to determine expression of PAPP-A and CD68 within the plaques. Serum levels of PAPP-A were measured by the enzyme-linked immunosorbent assay (ELISA).
Circulating PAPP-A levels were significantly higher in patients with unstable versus stable plaques (0.10 ± 0.06 vs. 0.07 ± 0.04 μg ml⁻¹, p = 0.047) and interestingly, in asymptomatic versus symptomatic patients (0.11 ± 0.05 vs. 0.069 ± 0.09 μg ml⁻¹, p = 0.025). These differences remained statistically significant after adjustment for age, gender and degree of stenosis (p = 0.050). PAPP-A expression in plaques correlated significantly with CD68 positive macrophages, cap-thickness and its serological values (r = +0.291, p < 0.001, r = −0.639, p < 0.001 and r = 0.618, p < 0.008, respectively). Furthermore, PAPP-A serum values demonstrated a significant positive predictive value of 68.8% for unstable plaques.
Our present data confirmed the close relationship between expression of PAPP-A and plaque instability and furthermore correlated significantly with cap thickness. However, the question whether PAPP-A is a useful predictive marker of plaque instability remains unresolved.
Identification of myocardial injury in the emergency setting
2010, Clinical Biochemistry
Within the past decade, the use of biomarkers to detect myocardial injury in the emergency department (ED) has been given increasing prominence as evident by the numerous studies and guidelines documenting their use. This review details the scope of the clinical problem, the history of changes in the definition of myocardial infarction (MI) and the new approaches, as well as suggestions for using laboratory biomarkers in the early detection of MI in the ED.

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: This work was supported by grants from the J. Holden DeHaan Foundation, Naples, Florida, and the Pfizer Pharmaceutical Company, New York, New York.

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Coronary artery diseasePregnancy-Associated Plasma Protein-A Elevation in Patients With Acute Coronary Syndrome and Subsequent Atorvastatin Therapy

Section snippets

Methods

Results

Discussion

Am J Obstet Gynecol

Am Heart J

J Am Coll Cardiol

Clin Biochem

J Am Coll Cardiol

J Am Coll Cardiol

J Biol Chem

Elevated pregnancy-associated plasma protein-A in sera from type 2 diabetic patients with hypercholesterolemia: associations with carotid atherosclerosis and toe-brachial index

J Clin Endocrinol Metab

Coronary artery disease
Pregnancy-Associated Plasma Protein-A Elevation in Patients With Acute Coronary Syndrome and Subsequent Atorvastatin Therapy