Pregnancy-Associated Plasma Protein A as a Marker of Acute Coronary Syndromes
Antoni Bayes-Genis, M.D., Cheryl A. Conover, Ph.D., Michael T. Overgaard, Ph.D., Kent R. Bailey, Ph.D., Michael Christiansen, M.D., David R. Holmes, Jr., M.D., Renu Virmani, M.D., Claus Oxvig, Ph.D., and Robert S. Schwartz, M.D.
Background Circulating markers indicating the instability ofatherosclerotic plaques could have diagnostic value in unstableangina or acute myocardial infarction. We evaluated pregnancy-associatedplasma protein A (PAPP-A), a potentially proatheroscleroticmetalloproteinase, as a marker of acute coronary syndromes.
Methods We examined the level of expression of PAPP-A in eightculprit unstable coronary plaques and four stable plaques fromeight patients who had died suddenly of cardiac causes. We alsomeasured circulating levels of PAPP-A, C-reactive protein, andinsulin-like growth factor I (IGF-I) in 17 patients with acutemyocardial infarction, 20 with unstable angina, 19 with stableangina, and 13 controls without atherosclerosis.
Results PAPP-A was abundantly expressed in plaque cells andextracellular matrix of ruptured and eroded unstable plaques,but not in stable plaques. Circulating PAPP-A levels were significantlyhigher in patients with unstable angina or acute myocardialinfarction than in patients with stable angina and controls(P<0.001). A PAPP-A threshold value of 10 mIU per liter identifiedpatients who had acute coronary syndromes with a sensitivityof 89.2 percent and a specificity of 81.3 percent. PAPP-A levelscorrelated with levels of C-reactive protein and free IGF-I,but not with markers of myocardial injury (troponin I and theMB isoform of creatine kinase).
Conclusions PAPP-A is present in unstable plaques, and circulatinglevels are elevated in acute coronary syndromes; these increasedlevels may reflect the instability of atherosclerotic plaques.PAPP-A is a new candidate marker of unstable angina and acutemyocardial infarction.
Patients with acute coronary syndromes are at considerable riskfor serious complications and death. Clinical outcomes mightbe improved by rapid and accurate diagnosis, followed by appropriatetherapy. Diagnostic tests for myocardial injury include technetium-99msestamibi scanning to identify defects in myocardial perfusion,1echocardiography to identify abnormalities in left ventricularwall motion,2 and measurements of circulating levels of theMB isoform of creatine kinase,3 myoglobin,4 troponin I,5 andtroponin T6 to identify myocardial necrosis. Each test reflectsdifferent steps of the pathway from coronary occlusion to myocardialischemia: impairment of coronary-artery flow, ischemic myocardialdysfunction, and eventually, myocardial-tissue necrosis. Theavailability of a sensitive and specific early marker of theinstability of plaques, whose levels become elevated beforeor in the absence of an elevation of other markers of myocardial-cellinjury, might improve diagnostic and therapeutic decision makingand, possibly, the value of traditional tests.7
We hypothesized that pregnancy-associated plasma protein A (PAPP-A),which is found in both men and women, might be such a markerand could identify patients with unstable atherosclerotic plaques.PAPP-A is a high-molecular-weight, zinc-binding metalloproteinase.8,9It is thus a potentially proatherosclerotic molecule and hasrecently been shown to be a specific activator of insulin-likegrowth factor I (IGF-I),9 a mediator of atherosclerosis.10,11PAPP-A antigen is typically measured during pregnancy (levelsincrease to about 100 IU per liter at term) with the use ofroutine assays with limited sensitivity.12,13,14
We examined the level of expression of PAPP-A in unstable plaquesfrom patients who died suddenly of cardiac causes. We also assessedcirculating PAPP-A levels in patients with acute coronary syndromes(unstable angina and acute myocardial infarction), using a highlysensitive immunoassay.
Methods
Collection and Analysis of Tissue
Atherosclerotic arteries were obtained at autopsy from eightpatients within 24 hours after sudden death from cardiac causes,as defined previously.15 The characteristics of acute ruptureof plaques, erosion of plaques, and stable plaques were alsodefined previously.15 Immunohistochemical staining was performedon 5-µm-thick paraffin sections with use of a peroxidase-labeledstreptavidin–biotin method.16 Monoclonal human antibodyagainst PAPP-A (234–5)13 was used at a concentration of20 µg per milliliter. Sections were also stained withantibodies against macrophage CD68 (clone KP-1, Dako, Carpinteria,Calif.) at a dilution of 1:200 and with antibodies against smooth-muscle-actin (clone 1A4, IgG2a, Dako) at a dilution of 1:500. Thetotal area of plaque and the percentage of the area that stainedfor PAPP-A were evaluated. Quantitative immunohistochemicalanalysis was performed with use of a quantitative color-imageanalysis system (Diagnostic Instruments, Sterling Heights, Mich.).
Patient Population
The study groups consisted of 17 patients with acute myocardialinfarction, 20 with unstable angina, 19 with stable angina,and 13 age-matched control patients without clinical or angiographicevidence of coronary atherosclerosis. All subjects were consecutivelyidentified and approached for consent as they were scheduledto undergo coronary arteriography in the Mayo Clinic cardiaccatheterization laboratory.
Acute myocardial infarction was defined as prolonged chest painaccompanied by ST-segment elevation or depression evolving intopathologic Q-wave or T-wave inversion and confirmed by a findingthat the creatine kinase MB fraction was more than twice theupper limit of the normal range and by a troponin I level ofmore than 0.5 ng per milliliter. Unstable angina was definedas chest discomfort at rest with either ST-segment depressionof at least 0.1 mV or T-wave inversion in two or more contiguouselectrocardiographic leads, a creatine kinase MB fraction thatwas within normal limits, and angiographically confirmed coronaryartery disease. Chronic, stable, effort-induced angina was diagnosedas chest pain of at least six months' duration accompanied byevidence of severe coronary artery disease on coronary angiographyand by the absence of clinically evident ischemic episodes duringthe week preceding arteriography.
Exclusion criteria were advanced kidney or liver failure, overtheart failure, and a history of major surgery or trauma withinthe previous month. Patients with known or suspected systemicthrombotic disorders (other than those of coronary origin) orinflammatory diseases were excluded, as were those who werepregnant. Angiographically severe coronary artery disease wasdefined by the presence of one or more stenoses of at least70 percent in any major coronary artery. To identify a possibleassociation between PAPP-A levels and the extent and severityof coronary artery disease discovered at angiography, the Jenkinsscore was calculated for every patient.17 Scores can range from0 to 32, with higher scores indicating more severe disease.
Blood samples were obtained at the time of coronary angiography,placed on ice, and centrifuged within 30 minutes at 1600xg for5 minutes. All samples were analyzed by personnel who had noknowledge of the subjects' clinical data. The mean (±SD)time from the last ischemic episode to blood sampling was 8.4±3.0hours in the group with myocardial infarction and 9.4±3.9hours in the group with unstable angina.
The study was approved by the institutional review board ofthe Mayo Clinic and Foundation, and all patients gave oral informedconsent.
Plasma Protein Assays
PAPP-A levels were determined by means of a biotin–tyramide–amplifiedenzyme immunoassay with a limit of detection of 0.03 mIU perliter and intraassay and interassay coefficients of variationof 10 percent and 15 percent, respectively. PAPP-A polyclonalantibodies were used for capture18 and a combination of monoclonalantibodies was used for detection.13 The assay was calibratedagainst the World Health Organization's international referencestandard 78/610, which is the standard for pregnancy-associatedproteins.
A highly sensitive latex-particle–enhanced immunoturbidimetricassay (Kamiya Biomedical, Seattle) was used to quantitate thelevel of C-reactive protein. Total IGF-I and free IGF-I weremeasured by commercially available immunoradiometric assays(Diagnostic Systems Laboratories, Webster, Tex.). We hypothesizedthat increased PAPP-A levels would lead to increased levelsof free IGF-I as a result of proteolysis by IGF-binding protein4.9 Creatine kinase MB and cardiac troponin I were measuredwith an immunochemiluminometric assay (Chiron, Emeryville, Calif.)in a standard fashion at the Mayo Clinic clinical laboratory.
Statistical Analysis
Results of analyses of histopathological data are presentedas means ±SD. We used Student's t-test to compare erodedand ruptured plaques with stable plaques. We used analysis ofvariance or two-way cross-tabulation with the chi-square test,when appropriate, to compare differences between groups in demographicand angiographic characteristics. Data on PAPP-A, free IGF-I,total IGF-I, and C-reactive protein, which were not distributednormally, were summarized by medians and ranges and were comparedamong the groups with use of the Kruskal–Wallis test.When the results indicated that there were significant differencesbetween groups, we made pairwise group comparisons using theWilcoxon rank-sum statistic. Associations among circulatinglevels of these proteins were assessed by Spearman's rank-correlationcoefficient. Associations of PAPP-A with risk factors and comparisonsof PAPP-A levels in each group after adjustment for these riskfactors were assessed with use of multiple linear regression,with the logarithm of PAPP-A as the dependent variable.
We used receiver-operating-characteristic (ROC) analysis onthe levels of PAPP-A and C-reactive protein for myocardial infarctionand unstable angina. The ROC curve is a common test to quantitatethe diagnostic accuracy of medical tests. This strategy plotsthe true positive fraction, or sensitivity, against the falsepositive fraction (1 – specificity) by varying the thresholdvalue for the test. The threshold is varied with increasinglystringent criteria for positivity. The ROC curve thus indicatesthe probability of a true positive result as a function of theprobability of a false positive result for all possible thresholdvalues. The area under the ROC curve assesses the relative accuracyof two diagnostic tests. An area of 0.5 indicates that the testresults are no better than those obtained by chance, whereasan area of 1.0 indicates a perfectly sensitive and specifictest. The areas under the curve for PAPP-A and C-reactive proteinlevels were compared according to the method of DeLong et al.19P values less than 0.05 were considered to indicate statisticalsignificance. All P values are two-sided.
Results
Expression of PAPP-A in Unstable Plaques
Four ruptured plaques and four eroded plaques were identifiedas culprit unstable lesions in the arteries obtained at autopsyfrom eight patients. Four stable plaques were also identified.There were no significant differences in the total area of theplaques among the ruptured plaques (mean, 7.1±1.4 mm2),eroded plaques (mean, 8.0±3.7 mm2), and stable plaques(mean, 5.7±2.1 mm2). In plaques with large lipid coresand cap rupture, staining for PAPP-A occurred mostly in theinflammatory shoulder region (Figure 1A), in areas surroundingthe lipid core, and localized with CD68-positive cells (notshown). In fibrous plaques with superficial erosion, PAPP-Awas identified within spindle-shaped smooth-muscle cells containing-actin (not shown), in the extracellular matrix (Figure 1B),and in noneroded endothelial cells (Figure 1C). Quantitativeimage analysis showed that the level of expression of PAPP-Ain fibrous eroded plaques exceeded that in ruptured plaques(28.3±16.8 percent vs. 18.5±8.0 percent), butthe difference was not statistically significant (P=0.34). PAPP-Awas absent or only minimally expressed in stable plaques (Figure 1D).Quantitative image analysis showed that the level of expressionof PAPP-A was significantly lower in stable plaques (3.2±1.9percent) than in ruptured plaques (P=0.01) or eroded plaques(P=0.02).
Figure 1. Expression of Pregnancy-Associated Plasma Protein A (PAPP-A) in Unstable and Stable Coronary Atherosclerotic Plaques.
The expression of PAPP-A was determined immunohistochemically by staining with antihuman PAPP-A monoclonal antibodies (reddish-brown areas). Panel A shows PAPP-A in an inflammatory shoulder area densely infiltrated by macrophages. The inflammatory infiltrate is present between the cholesterol core (arrowhead) and the luminal thrombus (asterisk). In Panel B there is intense staining for PAPP-A within spindle-shaped smooth-muscle cells and in the extracellular matrix of an eroded plaque. In Panel C PAPP-A is present in noneroded endothelial cells of an eroded plaque. In Panel D PAPP-A is absent in a stable plaque. The bar equals 50 µm.
Circulating Marker Proteins in Acute Coronary Syndromes
To determine whether the abundant expression of PAPP-A in unstableplaques might translate into elevated circulating levels, wemeasured PAPP-A levels in patients with acute coronary syndromes(myocardial infarction and unstable angina) and in those instable condition (patients with stable angina and controls withoutatherosclerosis). Table 1 shows the age, sex, risk factors,base-line therapy, and angiographic results in the four groups.Patients with stable angina had three-vessel disease significantlymore frequently than did patients with myocardial infarction(P=0.004), but no significant differences were observed amongthe groups with stable angina, unstable angina, and myocardialinfarction regarding the coronary atherosclerotic burden, asevaluated by the Jenkins score (P=0.88). The control subjectshad lower levels of risk factors than the three other groups,but the levels were similar among these three groups.
The data on PAPP-A levels are shown in Table 2. The Kruskal–Wallistest indicated that the differences among the groups were asfollows. The median PAPP-A levels in control subjects (7.4 mIUper liter; range, 3.8 to 10.4) were not significantly differentfrom those in patients with stable angina (8.4 mIU per liter;range, 4.4 to 22.5; P=0.07). In the group of patients with unstableangina, the median PAPP-A levels (14.9 mIU per liter; range,6.3 to 63.4) were significantly higher than those in the controlgroup (P<0.001) or the group with stable angina (P<0.001).In the group of patients with myocardial infarction, the medianPAPP-A levels (20.6 mIU per liter; range, 9.2 to 46.6) werealso significantly higher than those in the control group (P<0.001)or the group with stable angina (P<0.001). The PAPP-A levelsdid not differ significantly between the group with unstableangina and the group with myocardial infarction (P=0.75).
Table 2. Median Levels of Pregnancy-Associated Plasma Protein A, C-Reactive Protein, and Free and Total Insulin-like Growth Factor I.
Multiple-regression models showed that the PAPP-A level wasnot associated with age, sex, risk factors, or medications.Among the three groups with atherosclerosis, the PAPP-A levelwas significantly and inversely associated with the extent ofatherosclerosis, expressed as the number of vessels with clinicallysignificant luminal stenosis (one, two, or three vessels) (P=0.04),but it was not associated with the Jenkins score (P=0.27). Thisresult probably reflects the coexistence of quiescent atheroscleroticplaques with active, vulnerable, or fissured plaques in thecoronary tree.
Circulating Levels of C-Reactive Protein, IGF-I, and Markers of Myocardial Injury
The Kruskal–Wallis analysis of C-reactive protein levelsindicated that there were significant differences among thegroups. Levels of C-reactive protein were significantly higherin the patients who had had a myocardial infarction than inthe patients with unstable and stable angina (P=0.02 and P=0.001,respectively), and the levels were slightly but significantlyhigher in the patients with unstable angina than in those withstable angina (P=0.045). In the control group the levels ofC-reactive protein were significantly lower than those in themyocardial-infarction group (P=0.006). The level of C-reactiveprotein was significantly associated with the PAPP-A level inpatients with acute coronary syndromes (Spearman's rho=0.61,P<0.001) (Figure 2). The levels of C-reactive protein werenot associated with age, sex, risk factors, medications, orthe extent of coronary atherosclerosis.
Figure 2. Correlation between Levels of Pregnancy-Associated Plasma Protein A (PAPP-A) and Levels of C-Reactive Protein and Free Insulin-like Growth Factor I (IGF-I) in 17 Patients with Myocardial Infarction and 20 Patients with Unstable Angina.
A significant association was found between the levels of PAPP-A and C-reactive protein (Spearman's rho=0.61, P<0.001) and the levels of PAPP-A and free IGF-I (Spearman's rho=0.39, P=0.02).
No significant differences in free IGF-I levels were found amongthe groups; however, a weak but significant correlation wasobserved between free IGF-I levels and PAPP-A levels in patientswith acute coronary syndromes (Spearman's rho=0.39, P=0.02)(Figure 2). No significant differences were found in total IGF-Ilevels between patients with acute coronary syndromes and patientsin stable condition (Table 2), and no correlation with PAPP-Alevels was observed.
Creatine kinase MB levels were not elevated in blood samplesfrom patients with unstable angina, and only 3 of 20 patientswith unstable angina had troponin I levels above normal (mean,1.6±0.7 ng per milliliter). In the group of patientswith myocardial infarction, the peak levels of troponin I andcreatine kinase MB were 60.9 ng per milliliter (range, 1.3 to368) and 76.3 ng per milliliter (range, 4.4 to 341), respectively.In this group, there were no significant correlations betweenthe level of PAPP-A and the level of either troponin I (Spearman'srho=0.33, P=0.18) or creatine kinase MB (Spearman's rho=0.23,P=0.36) (Figure 3). Even when the patients with unstable anginaand the patients with myocardial infarction were combined, therewas no significant association between the level of PAPP-A andthe level of either troponin I (Spearman's rho=0.07, P=0.69)or creatine kinase MB (Spearman's rho=0.10, P=0.57). Therefore,the elevated PAPP-A levels in these patients cannot be attributedto myocardial necrosis.
Figure 3. Correlation between Pregnancy-Associated Plasma Protein A (PAPP-A) Levels and the Levels of the Cardiac Necrosis Markers Troponin I and Creatine Kinase MB in 17 Patients with Acute Myocardial Infarction.
No significant association was found between the levels of PAPP-A and the levels of troponin I (Spearman's rho=0.33, P=0.18) or creatine kinase MB (Spearman's rho=0.23, P=0.36).
PAPP-A as a Diagnostic Marker of Acute Coronary Syndromes
The mean (±SE) area under the ROC curve for PAPP-A was0.94±0.03 among the patients with acute myocardial infarctionand 0.88±0.05 among the patients with unstable angina,with control patients and patients with stable angina servingas the ROC control group. In a parallel analysis, C-reactiveprotein had a mean area under the curve of 0.81±0.07among the patients with myocardial infarction and 0.67±0.08among the patients with unstable angina. These differences betweenthe two markers were significant both for the group with myocardialinfarction (P=0.03) and for the group with unstable angina (P=0.01)(Figure 4). These data suggest that PAPP-A is a valuable marker— better than C-reactive protein — for the identificationof patients with acute coronary syndromes.
Figure 4. Receiver-Operating-Characteristic (ROC) Curves for the Levels of Pregnancy-Associated Plasma Protein A (PAPP-A) and C-Reactive Protein (CRP) in 17 Patients with Acute Myocardial Infarction and 20 Patients with Unstable Angina.
The mean (±SE) area under the curve for PAPP-A was 0.94±0.03 among the patients with acute myocardial infarction and 0.88±0.05 among the patients with unstable angina. The mean areas under the curve for C-reactive protein were 0.81±0.07 and 0.67±0.08, respectively. There were significant differences between the areas under the curve for the two markers in the group of patients with acute myocardial infarction (P=0.03) and in the group of patients with unstable angina (P=0.01), with control patients and patients with stable angina serving as the ROC control group.
A threshold level of 10 mIU of PAPP-A per liter had the highestcombined sensitivity and specificity for the identificationof acute coronary syndromes. The sensitivity and specificityof PAPP-A levels above 10 mIU per liter were 89.2 percent and81.3 percent, respectively. The sensitivity of PAPP-A levelsabove 10 mIU per liter was 94.1 percent in the case of myocardialinfarction and 85.0 percent in the case of unstable angina.In the case of the groups without atherosclerosis, only 1 of13 control subjects (8 percent) and 5 of 19 patients with stableangina (26 percent) had PAPP-A levels of more than 10 mIU perliter.
Discussion
We found a relation between unstable coronary disease and thelevels of PAPP-A. PAPP-A is a member of the metzincin superfamilyof metalloproteinases9 originally identified in the serum ofpregnant women.20 Circulating PAPP-A levels are used in thefetal diagnosis of Down's syndrome.14 Only recently has PAPP-Abeen identified outside pregnancy in nonplacental tissue.9,21
Histologic evidence of an association between PAPP-A and acutecoronary syndromes comes from the evaluation of unstable plaquesin patients who have died suddenly of cardiac causes. Usingspecific monoclonal antibodies, we found that PAPP-A was abundantlyexpressed in both eroded and ruptured plaques but was only minimallyexpressed in stable plaques. Our findings suggest that PAPP-Amay be produced by activated cells in unstable plaques and releasedinto the extracellular matrix. Whether PAPP-A can degrade extracellularmatrix remains unclear. Other metalloproteinases have been associatedwith macrophage-rich shoulder regions of atherosclerotic lesions22and circumstantially implicated in plaque rupture.23
The finding of a high level of expression of PAPP-A in unstableatherosclerotic plaques prompted us to assess circulating PAPP-Alevels in patients with acute coronary syndromes. Circulatinglevels of PAPP-A were significantly elevated in patients withunstable angina and patients with myocardial infarction. Wedetermined that a PAPP-A threshold of 10 mIU per liter accuratelyidentified patients with acute coronary syndromes.
Several studies have assessed other serum markers in patientswith unstable angina. Hamm and colleagues found that the diagnosticsensitivity of cardiac-specific troponins in unstable anginais low, since only 22 percent of patients had positive troponinT tests and 36 percent had positive troponin I tests.24 C-reactiveprotein is also a suboptimal diagnostic marker of unstable angina.Liuzzo et al. found that only 20 of 31 patients with unstableangina (65 percent) had elevated levels of C-reactive proteinon admission.25 Both markers are nonetheless associated withunfavorable outcomes when they are elevated.6,25 In our study,troponin I levels were elevated in 3 patients with unstableangina (15 percent) and C-reactive protein levels were elevatedin 10 (50 percent) of these patients. By comparison, PAPP-Alevels of more than 10 mIU per liter were present in 17 of 20patients with unstable angina (85 percent), and in 16 of 17patients with myocardial infarction (94 percent). Thus, PAPP-Alevels appear to be valuable for detecting unstable coronarydisease even when the levels of troponins and C-reactive proteinare not elevated, thus potentially identifying high-risk patientswhose disease might otherwise remain undiagnosed.
In our study, the levels of troponin I and creatine kinase MBwere not associated with PAPP-A levels in patients with acutecoronary syndromes. This finding indicates that PAPP-A is notproduced in response to myocardial necrosis, a potent stimulusfor the synthesis of inflammatory cytokines and acute-phasereactants. The magnitude of injury may reflect the size of theinfarction, which may not be related to the size or magnitudeof the inflammatory response associated with an active plaquein the infarcted artery.
The significant association between PAPP-A levels and C-reactiveprotein levels in patients with acute coronary syndromes isconsistent with growing evidence suggesting that inflammationhas a pivotal role in these syndromes.26,27 The accumulationof macrophages in unstable atherosclerotic lesions stimulatesthe production of metalloproteinases28 and may be associatedwith increases in the plasma levels of C-reactive protein.29We excluded patients with nonatherosclerotic inflammatory disordersin order to avoid potentially confounding results with respectto PAPP-A.
We also found an association between PAPP-A levels and freeIGF-I levels. The recent identification of PAPP-A as the enzymecleaving IGF-binding protein 4, an inhibitor of the action ofIGF, suggests that PAPP-A increases the availability of IGF-I,9thus contributing to the progression of both coronary atherosclerosisand restenosis.30 The free fraction of circulating and locallysynthesized IGF-I induces the migration of vascular smooth-musclecells31 and is important for monocyte chemotaxis and the activationand release of cytokines within the atherosclerotic lesion.32
Our study cannot answer questions such as whether PAPP-A isa primary or secondary component of acute coronary syndromes.Further studies are required to characterize the importanceof PAPP-A within unstable coronary plaques and to elucidatethe diagnostic and prognostic significance of elevated PAPP-Alevels in patients with acute coronary syndromes. Our studywas limited in terms of the number of patients examined, andit is important to confirm the findings with studies of morepatients.
In conclusion, PAPP-A is a new candidate marker for the earlydiagnosis of acute coronary syndromes. Our results demonstratethat circulating PAPP-A levels can identify patients early inthe process of plaque instability, when it might still be possibleto avert myocardial injury. In addition to their practical clinicalimportance, our observations point out new avenues of investigationinto the causes of unstable angina and myocardial infarction.
Supported in part by a grant from La Caixa Foundation (to Dr.Bayes-Genis).
Dr. Conover is a member of the scientific advisory board ofDiagnostic Systems Laboratories, which provided the kit to measureIGF-I.
Source Information
From the Division of Cardiovascular Diseases (A.B.-G., D.R.H., R.S.S.), Endocrine Research Unit (C.A.C.), and Statistics Department (K.R.B.), Mayo Clinic and Foundation, Rochester, Minn.; the Department of Molecular and Structural Biology, University of Aarhus, Aarhus, Denmark (M.T.O., C.O.); the Department of Clinical Biochemistry, Statens Serum Institute, Copenhagen, Denmark (M.C.); and the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C. (R.V.).
Address reprint requests to Dr. Schwartz at the Division of Cardiovascular Diseases, Mayo Clinic, 200 First St., SW, Rochester, MN 55905.
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3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling. Circ Res 1999;85:1040-1045. 
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