Background The pathogenesis of unstable angina is poorly understood,and predicting the prognosis is problematic. Evidence suggeststhat there may be active inflammation, possibly in the coronaryarteries, in this syndrome. We therefore studied the prognosticvalue of measurements of the circulating acute-phase reactantsC-reactive protein and serum amyloid A protein, which are sensitiveindicators of inflammation.
Methods We measured C-reactive protein, serum amyloid A protein,creatine kinase, and cardiac troponin T in 32 patients withchronic stable angina, 31 with severe unstable angina, and 29with acute myocardial infarction.
Results At the time of hospital admission, creatine kinase andcardiac troponin T levels were normal in all the patients, butthe levels of C-reactive protein and serum amyloid A proteinwere 0.3 mg per deciliter (exceeding the 90th percentile ofthe normal distribution) in 4 of the patients with stable angina(13 percent), 20 of the patients with unstable angina (65 percent),and 22 of the patients with acute myocardial infarction (76percent). The 20 patients with unstable angina who had levelsof acute-phase reactants 0.3 mg per deciliter had more ischemicepisodes in the hospital than those with levels <0.3 mg perdeciliter (mean [±SD] number of episodes per patient,4.8 ±2.5 vs. 1.8 ±2.4; P = 0.004); 5 patientssubsequently had a myocardial infarction, 2 died, and 12 requiredimmediate coronary revascularization. In contrast, no deathsor myocardial infarction occurred among the 11 patients withlevels of acute-phase reactants <0.3 mg per deciliter, andonly 2 of them required coronary revascularization. Among thepatients admitted with a diagnosis of acute myocardial infarction,unstable angina preceded infarction in 14 of the 22 patients(64 percent) with levels of acute-phase reactants 0.3 mg perdeciliter but in none of the 7 patients with levels <0.3mg per deciliter.
Conclusions Elevation of C-reactive protein and serum amyloidA protein at the time of hospital admission predicts a pooroutcome in patients with unstable angina and may reflect animportant inflammatory component in the pathogenesis of thiscondition. .
In patients with unstable angina, persistent or worsening symptomsand signs of ischemia despite full medical therapy indicatea poor prognosis1,2,3,4,5,6. However, at the time of hospitaladmission, it is not possible to predict whether unstable anginawill remit or progress to myocardial infarction, because thecauses of instability and the mechanisms underlying its evolutionare not known.
A role for inflammation in unstable angina is suggested by histologicstudies of unstable coronary plaques,7,8,9,10 evidence of thesystemic release of thromboxanes and leukotrienes,11,12,13 andthe presence of activated circulating leukocytes14,15. Furthermore,increased concentrations of plasma C-reactive protein, the prototypalacute-phase reactant, have been reported in some patients withunstable angina,16 in patients with coronary artery diseaseand other types of angina,17 and in 20 percent of patients whohave an acute myocardial infarction within six hours after theonset of symptoms, before any elevation of myocardial-enzymelevels in serum18. The acute-phase reactants are very sensitive,although nonspecific, markers of inflammation. However, previousstudies of the acute-phase reactants in unstable angina wereperformed with routine assays for C-reactive protein, whichhave limited sensitivity.
We undertook a prospective study of patients with severe unstableangina, patients with severe coronary artery disease and chronicstable angina, and patients with a myocardial infarction ofless than six hours' duration. We used newly developed, highlysensitive immunoassays for C-reactive protein and serum amyloidA protein, another acute-phase protein19. In addition, we measuredcardiac troponin T, a specific marker of myocardial necrosis20.
Methods
Patients
Group 1 comprised 32 outpatients with stable angina that hadlasted for more than six months, angiographically confirmedcoronary artery disease, and no clinically evident ischemicepisodes during the previous week. The group included 26 menand 6 women, with a mean (±SD) age of 58 ±9.4years. All 32 patients were taking aspirin; in addition, someused oral nitrates, calcium antagonists, and beta-blockers asrequired.
Group 2 comprised 31 of the 82 patients with severe unstableangina who were hospitalized in our coronary care unit betweenMarch 1992 and March 1993. There were 28 men and 3 women, witha mean age of 59.8 ±8.4 years. The criteria for enrollmentin group 2 included angina at rest with at least two episodesin the previous 48 hours or one episode lasting more than 20minutes, ST-segment deviations that were diagnostic of myocardialischemia during anginal attacks, an episode of chest pain withinthe previous 24 hours, and no elevation in the serum creatinekinase or lactate dehydrogenase concentration on admission.The symptoms of unstable angina had started 2 to 15 days (mean,6 ±4) before admission. The criteria for exclusion werean interval of more than 24 hours since the last ischemic episodebefore hospitalization (28 patients), a myocardial infarctionwithin the previous month (10), an elevated creatine kinaseor lactate dehydrogenase level on admission (4), intercurrentinflammatory or neoplastic conditions likely to be associatedwith an acute-phase response (7), valvular heart disease (1),and a left bundle-branch block invalidating the ST-segment analysis(1). All patients underwent Holter monitoring for the first24 hours after admission and received various combinations ofcalcium antagonists, oral nitrates, beta-blockers, and aspirin;intravenous nitrates and heparin were given as required forpersistent ischemia. Coronary angiography was performed withinfive days after admission in 15 patients with refractory anginarequiring urgent revascularization; in 8 patients angiographywas performed five to nine days after admission, and in 4 itwas performed five to seven days after they had had a myocardialinfarction.
Group 3 comprised 29 of the 105 patients admitted during thesame period with a diagnosis of possible acute myocardial infarction.There were 21 men and 8 women, with a mean age of 60 ±10years. The criteria for enrollment were admission within 6 hoursafter the onset of prolonged chest pain, with ST changes typicalof infarction and a normal serum creatine kinase level on admission,rising within 8 to 24 hours to a level that was diagnostic ofinfarction. The criteria for exclusion were admission more than6 hours after the onset of symptoms (41 patients, 34 of whomhad elevated creatine kinase levels on admission), inflammatoryor neoplastic disease (21), a left bundle-branch block or atrialfibrillation (13), and a chronic dissecting aortic aneurysm(1).
Study Protocol
Venous blood samples were obtained during a single outpatientvisit for patients in group 1, and on admission to the hospital,6 hours later, daily for three days, and at discharge for patientsin groups 2 and 3; in group 2 additional blood samples wereobtained every 6 hours for the first 24 hours. Coded plasmasamples were stored at -70 °C and analyzed for C-reactiveprotein, serum amyloid A protein, and cardiac troponin T ina single batch at the end of the study; all decisions regardingthe care of the patients were made independently of these measurements.Total creatine kinase levels were determined routinely whenthe blood samples were obtained. A major coronary event wasdefined as myocardial infarction or cardiac death; a minor eventwas defined as urgent coronary angioplasty or bypass graftingbecause of the failure of medical therapy to control ischemicepisodes and, in group 3, postinfarction angina. All patientsgave informed consent to participate in the study, and the protocolwas approved by the Ethics Committee of the Catholic Universityof Rome.
Plasma Protein Assays
C-reactive protein was assayed by rate nephelometry (BehringNA latex CRP; Behring Institute, Scoppito, l'Aquila, Italy)and, in samples with less than 0.25 mg of C-reactive proteinper deciliter, by an automated monoclonal-antibody, solid-phase,sandwich-type enzyme immunoassay (IMX, Abbott Laboratories,North Chicago), calibrated with the World Health Organization'sInternational Reference Standard for CRP Immunoassay (85/506)21;the range of values detected by the assay is 0.005 to 3.0 mgper deciliter. The median normal value for C-reactive proteinis 0.08 mg per deciliter, with 90 percent of normal values <0.3mg per deciliter and 99 percent <1.0 mg per deciliter22.Serum amyloid A protein was measured by an automated monoclonal-polyclonal-antibody,solid-phase, sandwich-type enzyme immunoassay (Abbott)23. Thenormal mean (±SD) concentration is 0.37 ±0.36mg per deciliter; the median value is 0.30 mg per deciliter(range, 0.07 to 2.64), with 82 percent of normal values <0.5mg per deciliter and 96 percent <1.0 mg per deciliter23.Troponin T was measured by enzyme immunoassay (Boehringer, Mannheim,Germany).
Statistical Analysis
The data on C-reactive protein and serum amyloid A protein,which were not normally distributed, were analyzed with twononparametric tests: the Mann-Whitney rank-sum test and Spearman'srank correlation coefficient24. The chi-square test was usedto compare discrete variables, and unpaired t-tests to compareclinical variables. P values less than 0.05 (two-tailed) wereconsidered to indicate statistical significance.
Results
Patients with Stable Angina
The concentration of C-reactive protein was 0.3 mg per deciliterin only 4 of the 32 patients (13 percent) with stable angina(group 1) (Figure 1); the median concentration of serum amyloidA protein in these 4 patients was 0.3 mg per deciliter (range,0.1 to 1.3). In the other 28 patients with stable angina (88percent), the median concentration of serum amyloid A proteinwas 0.15 mg per deciliter (range, 0.1 to 0.4). There were nodifferences in clinical or angiographic characteristics betweenpatients with levels of C-reactive protein 0.3 mg per deciliterand those with levels <0.3 mg per deciliter. At six months,all four patients in whom C-reactive protein had initially beenelevated were still stable.
Figure 1. Plasma Levels of C-Reactive Protein (Panel A) and Serum Amyloid A Protein (Panel B) in Patients with Stable Angina (Group 1), Patients with Unstable Angina and Levels of C-Reactive Protein <0.3 mg per Deciliter on Admission (Group 2A), and Patients with Unstable Angina and Levels of C-Reactive Protein greater than or equal to 0.3 mg per Deciliter on Admission (Group 2B).
Solid circles denote urgent coronary-artery bypass or angioplasty, and solid squares cardiac death or myocardial infarction. Adm. denotes admission. In one patient, the peak value for serum amyloid A protein, which exceeded the values on the scale, is shown numerically and joined by a dashed line to the corresponding value on admission. The level of C-reactive protein is <0.3 mg per deciliter (dashed horizontal line in Panel A) in 90 percent of normal subjects. The median normal level of serum amyloid A protein is 0.3 mg per deciliter (dashed horizontal line in Panel B); 96 percent of normal subjects have levels of serum amyloid A protein <1.0 mg per deciliter.
Patients with Unstable Angina
Plasma Protein Levels on Admission
The mean (±SD) concentrations of creatine kinase (80±53 IU per liter [range, 20 to 229; reference range,30 to 230]) and troponin T (0.02 ±0.04 µg per liter[range, 0 to 0.14; reference range, 0 to 0.2]) were normal inall 31 patients with unstable angina (group 2). In contrast,the concentration of C-reactive protein was <0.3 mg per deciliterin only 11 of the 31 patients (35 percent) (group 2A). The plasmaC-reactive protein concentration was increased in the other20 patients (65 percent) (group 2B) (P<0.001 for the comparisonwith the stable-angina group) (Figure 1). Serum amyloid A proteinlevels were normal in all but one patient in group 2A and wereraised in all the patients in group 2B (Table 1).
Table 1. Levels of C-Reactive Protein and Serum Amyloid A Protein and Clinical Characteristics in 31 Patients with Unstable Angina.
Clinical Characteristics
There were no differences between groups 2A and 2B with respectto base-line clinical characteristics or treatment (Table 1),and among the 27 patients in whom coronary angiography was performedduring the study, the C-reactive protein level was not correlatedwith the number of diseased vessels, severity or extent of lesions,or number of segments involved25. Age, sex, risk factors, andbase-line therapy were similar in the patients with stable anginaand those with unstable angina, and there were no significantdifferences between the two groups in the number of stenoticvessels or the pattern of coronary disease.
Clinical Course in the Hospital
The patients with levels of C-reactive protein <0.3 mg perdeciliter on admission to the coronary care unit were dischargedsooner (mean, 5.4 ±3 days) than those with elevated levels(mean, 9.8 ±7 days; P = 0.04). Furthermore, among thepatients with normal levels of C-reactive protein on admission,there were only six ischemic episodes, five of which were clinicallysilent, in the first 24 hours of Holter monitoring. There werefew episodes of recurrent angina and no major coronary events(Table 2). Only two patients required coronary-artery bypassgrafting, at day 9 in the first patient and at day 5 in thesecond, and both had an acute-phase response during the firstfour days of monitoring, with the C-reactive protein level increasingfrom 0.25 to 1.9 mg per deciliter in the first patient and from0.27 to 3.2 mg per deciliter in the second, and the serum amyloidA protein level increasing from 0.20 to 1.53 mg per deciliterin the first patient and from 0.28 to 3.0 mg per deciliter inthe second. Despite therapy that included intravenous nitratesand heparin, both patients had recurrent episodes of anginaat rest (the first had five episodes, and the second had three),requiring urgent surgical revascularization. Of the 15 bloodsamples obtained from these two patients during the first fourdays of the study, 5 had levels of C-reactive protein and serumamyloid A protein above the normal range, but none had abnormallevels of creatine kinase or troponin T (Figure 2). The levelsof C-reactive protein and serum amyloid A protein remained normalin the other nine patients until discharge; these patients hadfew episodes of ischemia during hospitalization (mean, 1.4 ±2.3),and they did not require angioplasty or bypass surgery.
Figure 2. Changes in the Median Levels of C-Reactive Protein (Open Circles) and Serum Amyloid A Protein (Solid Circles) and the Mean Level of Cardiac Troponin T (Solid Squares) after Admission in Patients with Unstable Angina and Concentrations of C-Reactive Protein <0.3 mg per Deciliter (Group 2A) Whose Symptoms Were Controlled with Medical Therapy, Two Patients in Group 2A with Increased Values for C-Reactive Protein and Serum Amyloid A Protein and Worsening Symptoms, and Patients with Unstable Angina and Concentrations of C-Reactive Protein greater than or equal to 0.3 mg per Deciliter (Group 2B).
The data at discharge in Group 2B do not include the six cases of cardiac death or myocardial infarction or the seven cases of urgent bypass surgery. Adm. denotes admission, and Dis. discharge.
Among the patients with C-reactive protein levels 0.3 mg perdeciliter on admission, there were 24 ischemic episodes, 11of which were clinically silent, in the first 24 hours of Holtermonitoring. The duration of electrocardiographic signs of ischemiawas significantly longer in these patients, and the number ofepisodes of recurrent angina significantly higher, than in thegroup with normal levels of C-reactive protein on admission(Table 2). Moreover, six of the patients with elevated levelsof C-reactive protein had major coronary events: five had amyocardial infarction within 10 days after admission, and oneof the five, who had a large infarct, died of congestive heartfailure within 1 month; one other patient died after emergencybypass surgery. All six of these patients had increased levelsof C-reactive protein (median, 2.72 mg per deciliter; range,1.09 to 8.25) and serum amyloid A protein (median, 6.53 mg perdeciliter; range, 2.7 to 26.42) on admission. Only two patientswith levels of C-reactive protein >1.0 mg per deciliter andlevels of serum amyloid A protein >2.7 mg per deciliter didnot have major coronary events; however, both required urgentcoronary angioplasty. Indeed, 12 of 20 patients had refractoryunstable angina requiring urgent bypass surgery or angioplasty(Table 2 and Figure 1).
In 8 of 20 patients the values for C-reactive protein and serumamyloid A protein doubled between 24 and 72 hours after admission,in the absence of elevated levels of cardiac troponin T or anyother evidence of myocardial necrosis. Three of these eightpatients had major coronary events, and another five requiredurgent angioplasty (in three patients) or bypass surgery (intwo) to control symptoms in spite of therapy with intravenousheparin and, in one patient, thrombolytic treatment.
There were no increases in creatine kinase or cardiac troponinT levels in any of the blood samples obtained during the observationperiod except those obtained after the development of electrocardiographicallyconfirmed myocardial infarction in five patients with raisedlevels of C-reactive protein on admission. Therefore, the raisedlevels of C-reactive protein and serum amyloid A protein inour patients cannot be attributed to the presence of myocardialnecrosis.
The sensitivity of a C-reactive protein level 0.3 mg per deciliteron admission as a marker for subsequent cardiac events (myocardialinfarction or death), urgent angioplasty, or bypass graftingwas 90 percent, the specificity was 82 percent, and the positivepredictive value was 90 percent. The sensitivity, specificity,and positive predictive value changed only slightly when thelevel of serum amyloid A protein was used as a prognostic markeron admission (90, 73, and 86 percent, respectively). When anyincrease in the level of C-reactive protein or serum amyloidA protein was considered at any time during the study, the sensitivityrose to 100 percent with a specificity of 82 percent and a positivepredictive value of 90 percent.
Patients with Myocardial Infarction
Plasma Protein Levels on Admission
Troponin T was undetectable and creatine kinase values werenormal (mean, 136.2 ±77; range, 21 to 228; referencerange, 30 to 230) in all 29 patients with myocardial infarction(group 3). In contrast, the levels of C-reactive protein andserum amyloid A protein at admission were <0.3 mg per deciliterin only seven of the patients (24 percent) (group 3A) (Table 3).None of these 7 had had unstable angina before admission,as compared with 14 of the 22 patients (64 percent) with elevatedlevels of C-reactive protein on admission (P = 0.01) (Table 3).Two patients with normal values for C-reactive protein onadmission had had chronic stable angina, but in the other five,the myocardial infarction was unheralded. In the group of 22patients with elevated C-reactive protein levels on admission(group 3B), 1 had a history of chronic stable angina, and 7presented with unheralded myocardial infarction (Table 3); theother 14 patients had all had their last episode of unstableangina within 48 hours before the myocardial infarction. Inthe group as a whole, there was no correlation between the timefrom the onset of symptoms of myocardial infarction (mean, 3.3±1.6 hours) and the C-reactive protein or serum amyloidA protein level on admission.
Table 3. Levels of C-Reactive Protein and Serum Amyloid A Protein and Clinical Characteristics in 29 Patients with Myocardial Infarction.
Follow-up in Hospital
The values for the acute-phase proteins on admission were alsorelated to the subsequent course of disease. Angina after myocardialinfarction occurred in only one of seven patients with normallevels of C-reactive protein on admission, and none of thesepatients had recurrent infarction in the hospital or requiredrevascularization. In contrast, 14 of the 22 patients (64 percent)admitted with elevated C-reactive protein levels had postinfarctionangina, 6 of whom required coronary revascularization, and 3patients had recurrent infarction while in the hospital, althoughnone died (Table 4 and Figure 3).
Figure 3. Concentrations of C-Reactive Protein (Panel A) and Serum Amyloid A Protein (Panel B) in Patients Admitted with Myocardial Infarction, with (Open Squares) or without (Open Circles) a History of Unstable Angina.
Group 3A had levels of C-reactive protein or serum amyloid A protein <0.3 mg per deciliter on admission; group 3B had levels 0.3 mg per deciliter. Solid triangles denote recurrent angina, solid circles urgent coronary revascularization, and solid squares reinfarction. Adm. denotes admission. Peak values that exceeded those on the scale are shown numerically and joined by a dashed line to the corresponding values on admission. The level of C-reactive protein is <0.3 mg per deciliter (dashed horizontal line in Panel A) in 90 percent of normal subjects. The median normal level of serum amyloid A protein is 0.3 mg per deciliter (dashed horizontal line in Panel B); 96 percent of normal subjects have levels of serum amyloid A protein <1.0 mg per deciliter. The levels of creatine kinase and cardiac troponin T were normal on admission in all patients.
The patients with a history of unstable angina before myocardialinfarction generally had higher values for acute-phase proteins(median level of C-reactive protein, 0.84 mg per deciliter;range, 0.39 to 6.98; median level of serum amyloid A protein,1.74 mg per deciliter; range, 0.32 to 28.24) than those in whomthe infarction was unheralded or preceded by stable angina (medianlevel of C-reactive protein, 0.31 mg per deciliter; range, 0.24to 0.89; P<0.001; median level of serum amyloid A protein,0.34 mg per deciliter; range, 0.07 to 0.79; P<0.001). Allpatients with a value for either C-reactive protein (four patients)or serum amyloid A protein (nine patients) >1.0 mg per deciliteron admission had had unstable angina before the myocardial infarction.
The typical acute-phase response of C-reactive protein and serumamyloid A protein after infarction was observed. The medianpeak value for C-reactive protein was 5.04 mg per deciliter(range, 0.67 to 15.8) at a mean of 45.7 ±20.2 hours,and the median peak value for serum amyloid A protein was 20.3mg per deciliter (range, 0.66 to 114.0) at a mean of 43.3 ±24hours. Creatine kinase levels rose to 1628 IU per liter (range,316 to 5044). There was no correlation between the peak creatinekinase value and the admission or peak value for C-reactiveprotein or serum amyloid A protein. Peak values for C-reactiveprotein in the patients with confirmed infarction (Figure 3)overlapped those in the patients with unstable angina and C-reactiveprotein values 0.3 mg per deciliter on admission (group 2B),but the latter patients had no increase in creatine kinase ortroponin T levels and no signs of myocardial infarction (Figure 1).
When all three groups of patients (those with stable angina,those with unstable angina, and those with myocardial infarction)were combined, there was, as expected, a close correlation betweenthe concentrations of C-reactive protein and serum amyloid Aprotein (Figure 4).
Figure 4. Correlation between the Concentrations of C-Reactive Protein and Serum Amyloid A Protein in the Combined Groups with Unstable Angina and Myocardial Infarction.
Ci denotes confidence interval.
Discussion
Previous studies have reported elevated values for acute-phaseproteins in patients with unstable angina16,26,27 and in thosewho have had a myocardial infarction,26,27,28,29,30,31 but thesestudies did not investigate the prognostic importance of theelevated values, nor did they exclude the possibility that myocardial-celldamage causes the acute-phase response. The results of our studyconfirm the observation that the plasma concentration of C-reactiveprotein is elevated in the majority of patients with unstableangina, and we also found that C-reactive protein is elevatedat the time of hospital admission in all patients with myocardialinfarction and a history of unstable angina. Creatine kinaseand troponin T levels were within normal limits in all thesepatients, indicating that the C-reactive protein response isnot induced by myocardial necrosis, which is known to be a potentstimulus of acute-phase reactants.
A value for C-reactive protein 0.3 mg per deciliter on admissionhad a sensitivity of 90 percent and a specificity of 82 percentfor predicting subsequent cardiac events (cardiac death, myocardialinfarction, or the urgent need for coronary revascularization).The sensitivity increased to 100 percent in the patients witha value for C-reactive protein >1.0 mg per deciliter on admissionand in those who had any rise in the C-reactive protein levelduring the study. These findings are consistent with the increasedvalues for C-reactive protein in the patients with myocardialinfarction preceded by unstable angina.
The results were similar with measurements of serum amyloidA protein, another extremely sensitive acute-phase reactant.Indeed, serum amyloid A protein may be more useful in routinepractice than C-reactive protein, because it has an even widerdynamic range and because none of the commercially availableautomated assays for C-reactive protein are sufficiently precisein the low range, as compared with the assay for serum amyloidA protein used in this study. Measurement of both serum amyloidA protein and C-reactive protein slightly increased the prognosticprecision, but for clinical purposes the information providedby each alone is the same. However, it is essential to recognizethe requirement for assays of C-reactive protein and serum amyloidA protein with a suitably high sensitivity, encompassing thenormal range of values.
The acute-phase response of C-reactive protein and serum amyloidA protein is a nonspecific phenomenon reflecting cytokine-mediatedhepatic production triggered by most forms of inflammation,infection, and tissue injury. Our patients were carefully selectedto eliminate intercurrent disorders likely to be associatedwith an acute-phase response, and similar attention to intercurrentprocesses will be essential for the practical application ofour findings.
An association has been reported between prognosis and the persistenceof pain at rest or episodes of silent ischemia during Holtermonitoring1,2,3,4,5,6. We also found that the number and lengthof recurrent ischemic episodes in patients with favorable outcomesdiffered significantly from the number and length of episodesin patients with unfavorable outcomes, which confirms the resultsof previous studies,1,2,3,4,5,6 but the sensitivity and specificityassociated with the use of recurrent ischemia as a prognosticmarker were lower than those associated with the use of C-reactiveprotein measurements. A recent study reported elevated levelsof cardiac troponin T in 39 percent of patients with anginaat rest, which were significantly related to prognosis, butthe report contained no information on the number or durationof ischemic episodes20. The absence of elevated values of cardiactroponin T in our patients may reflect the absence of long-lastingischemic episodes in our study group.
Our results, together with the evidence of an inflammatory componentdocumented in previous studies,7,8,9,10,11,13,14,15,16,17 haveimportant pathophysiologic implications, and the predictivecorrelation between the level of C-reactive protein and theclinical outcome links the acute-phase response with pathogeneticevents. However, it is not known whether the elevated levelsof acute-phase proteins are related to the type of inflammatorystimuli or to the intensity of the individual response32. Itis also not known whether the stimuli triggering the productionof acute-phase proteins arise from the heart15 or other partsof the body14. Ischemia-induced endothelial damage, oxidizedlow-density lipoprotein,33 immune complexes, and reactivationof dormant cytomegalovirus or chlamydia infection34,35 are allpotential causes of vascular injury and an acute-phase response.In addition to their practical clinical importance, the presentobservations point to new avenues of investigation into thecauses of unstable angina and myocardial infarction.
Supported by a grant from the Centro Ricerche Coronariche.
We are indebted to Professors A. Menini and G. Satta for helpwith laboratory investigations, to Dr. G. Caligiuri and thenurses of the coronary care unit at Policlinico Gemelli fortheir assistance, and to Ms. B. Sontrop for assistance in thepreparation of the manuscript.
Source Information
From the Istituto di Cardiologia (G.L., L.M.B., A.G.R., A.M.) and Istituto di Microbiologia (R.L.G.), Universita Cattolica del Sacro Cuore, Rome; and the Immunological Medicine Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London (J.R.G., M.B.P.).
Address reprint requests to Dr. Liuzzo at the Istituto di Cardiologia, Universita Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy.
References
Mulcahy R, Daly L, Graham I, et al. Unstable angina: natural history and determinants of prognosis. Am J Cardiol 1981;48:525-528. [CrossRef][Medline]
Mulcahy R, Al Awadhi AH, de Buitleor M, Tobin G, Johnson H, Contoy R. Natural history and prognosis of unstable angina. Am Heart J 1985;109:753-758. [CrossRef][Medline]
Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 1986;314:1214-1219. [Abstract]
Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina. J Am Coll Cardiol 1987;10:756-760. [Abstract]
Nademanee K, Intarachot V, Josephson MA, Rieders D, Mody FV, Singh BN. Prognostic significance of silent myocardial ischemia in patients with unstable angina. J Am Coll Cardiol 1987;10:1-9. [Abstract]
Langer A, Freeman MR, Armstrong PW. ST segment shift in unstable angina: pathophysiology and association with coronary anatomy and hospital outcome. J Am Coll Cardiol 1989;13:1495-1502. [Abstract]
Kohchi K, Takebayashi S, Hiroki T, Nobuyoshi M. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results at autopsy. Circulation 1985;71:709-716. [Free Full Text]
Sato T, Takebayashi S, Kohchi K. Increased subendothelial infiltration of the coronary arteries with monocytes/macrophages in patients with unstable angina: histological data on 14 autopsied patients. Atherosclerosis 1987;68:191-197. [CrossRef][Medline]
Baroldi G, Silver MD, Mariani F, Giuliano G. Correlation of morphological variables in the coronary atherosclerotic plaque with clinical patterns of ischemic heart disease. Am J Cardiovasc Pathol 1988;2:159-172. [Medline]
Wallsh E, Weinstein GS, Franzone A, Clavel A, Rossi PA, Kreps E. Inflammation of the coronary arteries in patients with unstable angina. Tex Heart Inst J 1986;13:105-108. [Medline]
Vejar M, Fragasso G, Hackett D, et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990;63:163-168. [Medline]
Ciabattoni G, Ujang S, Sritara P, et al. Aspirin, but not heparin, suppresses the transient increase in thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty. J Am Coll Cardiol 1993;21:1377-1381. [Abstract]
Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia: in vivo evidence for 5-lipoxygenase activation. Circulation 1992;85:230-236. [Free Full Text]
Serneri GG, Abbate R, Gori AM, et al. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation 1992;86:790-797. [Free Full Text]
Mazzone A, De Servi S, Ricevuti G, et al. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation 1993;88:358-363. [Free Full Text]
Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease. Am J Cardiol 1990;65:168-172. [CrossRef][Medline]
Juhan-Vague I, Alessi MC, Joly P, et al. Plasma plasminogen activator inhibitor-1 in angina pectoris: influence of plasma insulin and acute-phase response. Arteriosclerosis 1989;9:362-367. [Free Full Text]
Andreotti F, Roncaglioni MC, Hackett DR, et al. Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction. J Am Coll Cardiol 1990;16:1553-1560. [Abstract]
Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 1983;34:141-212. [Medline]
Hamm CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327:146-150. [Abstract]
WHO Expert Committee on Biological Standardization. Thirty-seventh report. World Health Organ Tech Rep Ser 1987;760:21-22.
Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for human C-reactive protein. Clin Chim Acta 1981;117:13-23. [CrossRef][Medline]
Wilkins J, Gallimore JR, Tennent GA, et al. Rapid automated enzyme immunoassay of serum amyloid. Clin Chem 1994;40:1284-1290. [Free Full Text]
Glantz SA. Primer of biostatistics. 2nd ed. New York: McGraw-Hill, 1987:287-330.
Bogaty P, Brecker SJ, White SE, et al. Comparison of coronary angiographic findings in acute and chronic first presentation of ischemic heart disease. Circulation 1993;87:1938-1946. [Free Full Text]
de Beer FC, Hind CRK, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982;47:239-243. [Free Full Text]
Kushner I, Broder ML, Karp D. Control of the acute phase response: serum C-reactive protein kinetics after acute myocardial infarction. J Clin Invest 1978;61:235-242.
Marhaug G, Harklau L, Olsen B, Husby G, Husebekk A, Wang H. Serum amyloid A protein in acute myocardial infarction. Acta Med Scand 1986;220:303-306. [Medline]
Maury CPJ, Totterman KJ, Gref C-G, Ehnholm C. Serum amyloid A protein, apolipoprotein A-I, and apolipoprotein B during the course of acute myocardial infarction. J Clin Pathol 1988;41:1263-1268. [Free Full Text]
Shainkin-Kestenbaum R, Winikoff Y, Cristal N. Serum amyloid A concentrations during the course of acute ischaemic heart disease. J Clin Pathol 1986;39:635-637. [Free Full Text]
Bausserman LL, Sadaniantz A, Saritelli AL, et al. Time course of serum amyloid A response in myocardial infarction. Clin Chim Acta 1989;184:297-305. [CrossRef][Medline]
Yoshimoto T, Nakanishi K, Hirose S, et al. High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor. J Immunol 1992;148:3596-3603. [Abstract]
Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A 1987;84:2995-2998. [Free Full Text]
Hendrix MGR, Daemen M, Bruggeman CA. Cytomegalovirus nucleic acid distribution within the human vascular tree. Am J Pathol 1991;138:563-567. [Abstract]
Linnanmaki E, Leinonen M, Mattila K, Nieminen MS, Valtonen V, Saikku P. Chlamydia pneumoniae-specific circulating immune complexes in patients with chronic coronary heart disease. Circulation 1993;87:1130-1134. [Free Full Text]
Pundziute, G., Schuijf, J. D., Jukema, J. W., Decramer, I., Sarno, G., Vanhoenacker, P. K., Boersma, E., Reiber, J. H.C., Schalij, M. J., Wijns, W., Bax, J. J.
(2008). Evaluation of plaque characteristics in acute coronary syndromes: non-invasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J
29: 2373-2381
[Abstract][Full Text]
El Kebir, D., Jozsef, L., Filep, J. G.
(2008). Opposing regulation of neutrophil apoptosis through the formyl peptide receptor-like 1/lipoxin A4 receptor: implications for resolution of inflammation. J. Leukoc. Biol.
84: 600-606
[Abstract][Full Text]
Ferrante, G., Cosentino, N., Barlis, P., Niccoli, G.
(2008). Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study. Eur Heart J
29: 1922-1923
[Full Text]
Biasucci, L. M., Leo, M., De Maria, G. L.
(2008). Local and Systemic Mechanisms of Plaque Rupture. ANGIOLOGY
59: 73S-76S
[Abstract]
Han, H., Hansen, T. R., Berg, B., Hess, B. W., Ford, S. P.
(2008). Maternal undernutrition induces differential cardiac gene expression in pulmonary hypertensive steers at high elevation. Am. J. Physiol. Heart Circ. Physiol.
295: H382-H389
[Abstract][Full Text]
Tousoulis, D, Charakida, M, Stefanadis, C
(2008). Endothelial function and inflammation in coronary artery disease. Postgrad. Med. J.
84: 368-371
[Abstract][Full Text]
Bogaty, P., Boyer, L., Simard, S., Dauwe, F., Dupuis, R., Verret, B., Huynh, T., Bertrand, F., Dagenais, G. R., Brophy, J. M.
(2008). Clinical utility of C-reactive protein measured at admission, hospital discharge, and 1 month later to predict outcome in patients with acute coronary disease. The RISCA (recurrence and inflammation in the acute coronary syndromes) study.. J Am Coll Cardiol
51: 2339-2346
[Abstract][Full Text]
Foglieni, C., Maisano, F., Dreas, L., Giazzon, A., Ruotolo, G., Ferrero, E., Li Volsi, L., Coli, S., Sinagra, G., Zingone, B., Alfieri, O., Becker, A. E., Maseri, A.
(2008). Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes. Am. J. Physiol. Heart Circ. Physiol.
294: H2831-H2837
[Abstract][Full Text]
Ortolani, P., Marzocchi, A., Marrozzini, C., Palmerini, T., Saia, F., Taglieri, N., Baldazzi, F., Silenzi, S., Bacchi-Reggiani, M. L., Guastaroba, P., Grilli, R., Branzi, A.
(2008). Predictive value of high sensitivity C-reactive protein in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention. Eur Heart J
29: 1241-1249
[Abstract][Full Text]
Caymaz, H. O., Yuksel, G.
(2008). Fate of Incidental, Asymptomatic Lesions Discovered During Percutaneous Coronary Intervention. ANGIOLOGY
59: 193-197
[Abstract]
Ulucay, A., Demirbag, R., Yilmaz, R., Unlu, D., Gur, M., Selek, S., Celik, H.
(2008). The Relationship Between Plasma C-Reactive Protein Levels and Presence and Severity of Coronary Stenosis in Patients With Stable Angina. ANGIOLOGY
58: 657-662
[Abstract]
Issac, T. T., Dokainish, H., Lakkis, N. M.
(2007). Role of Inflammation in Initiation and Perpetuation of Atrial Fibrillation: A Systematic Review of the Published Data. J Am Coll Cardiol
50: 2021-2028
[Abstract][Full Text]
Grootendorst, D. C., de Jager, D. J., Brandenburg, V. M., Boeschoten, E. W., Krediet, R. T., Dekker, F. W., The NECOSAD Study Group,
(2007). Excellent agreement between C-reactive protein measurement methods in end-stage renal disease patients no additional power for mortality prediction with high-sensitivity CRP. Nephrol Dial Transplant
22: 3277-3284
[Abstract][Full Text]
Spagnoli, L. G., Bonanno, E., Sangiorgi, G., Mauriello, A.
(2007). Role of Inflammation in Atherosclerosis. JNM
48: 1800-1815
[Abstract][Full Text]
Chen, W. Q., Zhang, L., Liu, Y. F., Chen, L., Ji, X. P., Zhang, M., Zhao, Y. X., Yao, G. H., Zhang, C., Wang, X. L., Zhang, Y.
(2007). Prediction of atherosclerotic plaque ruptures with high-frequency ultrasound imaging and serum inflammatory markers. Am. J. Physiol. Heart Circ. Physiol.
293: H2836-H2844
[Abstract][Full Text]
Scirica, B. M., Morrow, D. A., Cannon, C. P., de Lemos, J. A., Murphy, S., Sabatine, M. S., Wiviott, S. D., Rifai, N., McCabe, C. H., Braunwald, E., for the Thrombolysis in Myocardial Infarction (TIM,
(2007). Clinical Application of C-Reactive Protein Across the Spectrum of Acute Coronary Syndromes. Clin. Chem.
53: 1800-1807
[Abstract][Full Text]
Patel, D. N., King, C. A., Bailey, S. R., Holt, J. W., Venkatachalam, K., Agrawal, A., Valente, A. J., Chandrasekar, B.
(2007). Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-{kappa}B and C/EBPbeta Activation. J. Biol. Chem.
282: 27229-27238
[Abstract][Full Text]
Authors/Task Force Members, , Bassand, J.-P., Hamm, C. W., Ardissino, D., Boersma, E., Budaj, A., Fernandez-Aviles, F., Fox, K. A.A., Hasdai, D., Ohman, E. M., Wallentin, L., Wijns, W., ESC Committee for Practice Guidelines (CPG), , Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K., Filippatos, G., Kristensen, S. D., Widimsky, P., McGregor, K., Sechtem, U., Tendera, M., Hellemans, I., Gomez, J. L. Z., Silber, S., Funck-Brentano, C., Document Reviewers, , Kristensen, S. D., Andreotti, F., Benzer, W., Bertrand, M., Betriu, A., De Caterina, R., DeSutter, J., Falk, V., Ortiz, A. F., Gitt, A., Hasin, Y., Huber, K., Kornowski, R., Lopez-Sendon, J., Morais, J., Nordrehaug, J. E., Silber, S., Steg, P. G., Thygesen, K., Tubaro, M., Turpie, A. G.G., Verheugt, F., Windecker, S.
(2007). Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J
28: 1598-1660
[Full Text]
El Kebir, D., Jozsef, L., Khreiss, T., Pan, W., Petasis, N. A., Serhan, C. N., Filep, J. G.
(2007). Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation. J. Immunol.
179: 616-622
[Abstract][Full Text]
Zhao, Y., Zhou, S., Heng, C.-K.
(2007). Impact of Serum Amyloid A on Tissue Factor and Tissue Factor Pathway Inhibitor Expression and Activity in Endothelial Cells. Arterioscler. Thromb. Vasc. Bio.
27: 1645-1650
[Abstract][Full Text]
Ridker, P. M.
(2007). C-Reactive Protein and the Prediction of Cardiovascular Events Among Those at Intermediate Risk: Moving an Inflammatory Hypothesis Toward Consensus. J Am Coll Cardiol
49: 2129-2138
[Abstract][Full Text]
Altwegg, L. A., Neidhart, M., Hersberger, M., Muller, S., Eberli, F. R., Corti, R., Roffi, M., Sutsch, G., Gay, S., von Eckardstein, A., Wischnewsky, M. B., Luscher, T. F., Maier, W.
(2007). Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes. Eur Heart J
0: ehm078v3-8
[Abstract][Full Text]
NACB WRITING GROUP MEMBERS, , Morrow, D. A., Cannon, C. P., Jesse, R. L., Newby, L. K., Ravkilde, J., Storrow, A. B., Wu, A. H.B., Christenson, R. H.
(2007). National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes. Circulation
115: e356-e375
[Full Text]
Palmerini, T., Marzocchi, A., Marrozzini, C., Reggiani, L. B., Savini, C., Marinelli, G., Di Bartolomeo, R., Branzi, A.
(2007). Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis. Eur. J. Cardiothorac. Surg.
31: 685-690
[Abstract][Full Text]
Oren, H., Erbay, A. R., Balci, M., Cehreli, S.
(2007). Role of Novel Biomarkers of Inflammation in Patients With Stable Coronary Heart Disease. ANGIOLOGY
58: 148-155
[Abstract]
Blanco-Colio, L. M., Martin-Ventura, J. L., Munoz-Garcia, B., Orbe, J., Paramo, J. A., Michel, J.-B., Ortiz, A., Meilhac, O., Egido, J.
(2007). Identification of Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (sTWEAK) as a Possible Biomarker of Subclinical Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
27: 916-922
[Abstract][Full Text]
NACB WRITING GROUP MEMBERS, , Morrow, D. A., Cannon, C. P., Jesse, R. L., Newby, L. K., Ravkilde, J., Storrow, A. B., Wu, A. H.B., Christenson, R. H., NACB COMMITTEE MEMBERS, , Christenson, R. H., Apple, F. S., Cannon, C. P., Francis, G., Jesse, R. L., Morrow, D. A., Newby, L. K., Ravkilde, J., Storrow, A. B., Tang, W., Wu, A. H.B.
(2007). National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes. Clin. Chem.
53: 552-574
[Full Text]
Sabatine, M. S., Morrow, D. A., Jablonski, K. A., Rice, M. M., Warnica, J. W., Domanski, M. J., Hsia, J., Gersh, B. J., Rifai, N., Ridker, P. M, Pfeffer, M. A., Braunwald, E., for the PEACE Investigators,
(2007). Prognostic Significance of the Centers for Disease Control/American Heart Association High-Sensitivity C-Reactive Protein Cut Points for Cardiovascular and Other Outcomes in Patients With Stable Coronary Artery Disease. Circulation
115: 1528-1536
[Abstract][Full Text]
Scott Baker, K., Ness, K. K., Steinberger, J., Carter, A., Francisco, L., Burns, L. J., Sklar, C., Forman, S., Weisdorf, D., Gurney, J. G., Bhatia, S.
(2007). Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood
109: 1765-1772
[Abstract][Full Text]
Cai, H., Song, C., Endoh, I., Goyette, J., Jessup, W., Freedman, S. B., McNeil, H. P., Geczy, C. L.
(2007). Serum Amyloid A Induces Monocyte Tissue Factor. J. Immunol.
178: 1852-1860
[Abstract][Full Text]
Houslay, E. S, Sarma, J., Uren, N. G
(2007). The effect of intensive lipid lowering on coronary atheroma and clinical outcome. Heart
93: 149-151
[Abstract][Full Text]
Antoniucci, D.
(2007). Differences among GP IIb/IIIa inhibitors: different clinical benefits in non-ST-segment elevation acute coronary syndrome percutaneous coronary intervention patients. Eur Heart J Suppl
9: A32-A36
[Abstract][Full Text]
Liuzzo, G., Santamaria, M., Biasucci, L. M., Narducci, M., Colafrancesco, V., Porto, A., Brugaletta, S., Pinnelli, M., Rizzello, V., Maseri, A., Crea, F.
(2007). Persistent Activation of Nuclear Factor Kappa-B Signaling Pathway in Patients With Unstable Angina and Elevated Levels of C-Reactive Protein: Evidence for a Direct Proinflammatory Effect of Azide and Lipopolysaccharide-Free C-Reactive Protein on Human Monocytes Via Nuclear Factor Kappa-B Activation. J Am Coll Cardiol
49: 185-194
[Abstract][Full Text]
Lupia, E., Bosco, O., Bergerone, S., Dondi, A. E., Goffi, A., Oliaro, E., Cordero, M., Del Sorbo, L., Trevi, G., Montrucchio, G.
(2006). Thrombopoietin Contributes to Enhanced Platelet Activation in Patients With Unstable Angina. J Am Coll Cardiol
48: 2195-2203
[Abstract][Full Text]
McMahon, M, Grossman, J, Chen, W, Hahn, B H
(2006). Inflammation and the pathogenesis of atherosclerosis in systemic lupus erythematosus. Lupus
15: 59-69
[Abstract]
Daneshtalab, N., Lewanczuk, R. Z., Russell, A. S., Jamali, F.
(2006). Drug-disease interactions: losartan effect is not downregulated by rheumatoid arthritis.. J Clin Pharmacol
46: 1344-1355
[Abstract][Full Text]
Weiss, T W, Kvakan, H, Kaun, C, Prager, M, Speidl, W S, Zorn, G, Pfaffenberger, S, Huk, I, Maurer, G, Huber, K, Wojta, J
(2006). No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis. J. Clin. Pathol.
59: 1186-1190
[Abstract][Full Text]
Libby, P., Ridker, P. M.
(2006). Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice. J Am Coll Cardiol
48: A33-A46
[Abstract][Full Text]
Rahmani, M., Cruz, R. P., Granville, D. J., McManus, B. M.
(2006). Allograft Vasculopathy Versus Atherosclerosis. Circ. Res.
99: 801-815
[Abstract][Full Text]
James, S. K., Lindback, J., Tilly, J., Siegbahn, A., Venge, P., Armstrong, P., Califf, R., Simoons, M. L., Wallentin, L., Lindahl, B.
(2006). Troponin-T and N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality Benefit From Coronary Revascularization in Acute Coronary Syndromes: A GUSTO-IV Substudy. J Am Coll Cardiol
48: 1146-1154
[Abstract][Full Text]
Maki-Petaja, K. M., Hall, F. C., Booth, A. D., Wallace, S. M.L., Yasmin, , Bearcroft, P. W.P., Harish, S., Furlong, A., McEniery, C. M., Brown, J., Wilkinson, I. B.
(2006). Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti-Tumor Necrosis Factor-{alpha} Therapy. Circulation
114: 1185-1192
[Abstract][Full Text]
Kontush, A., Chapman, M. J.
(2006). Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis. Pharmacol. Rev.
58: 342-374
[Abstract][Full Text]
Suzuki, M., Saito, M., Nagai, T., Saeki, H., Kazatani, Y.
(2006). Systemic Versus Coronary Levels of Inflammation in Acute Coronary Syndromes. ANGIOLOGY
57: 459-463
[Abstract]
Biasucci, L. M., Rizzello, V.
(2006). Pregnancy-associated plasma protein-a: do specific markers of vascular or plaque activation exist, and do we really need them?. Clin. Chem.
52: 913-914
[Full Text]
Oroszlan, M., Herczenik, E., Rugonfalvi-Kiss, S., Roos, A., Nauta, A. J, Daha, M. R, Gombos, I., Karadi, I., Romics, L., Prohaszka, Z., Fust, G., Cervenak, L.
(2006). Proinflammatory changes in human umbilical cord vein endothelial cells can be induced neither by native nor by modified CRP. Int Immunol
18: 871-878
[Abstract][Full Text]
Scirica, B. M., Morrow, D. A., Verma, S., Devaraj, S., Jialal, I., Scirica, B. M., Morrow, D. A., Verma, S., Devaraj, S., Jialal, I.
(2006). The Verdict Is Still Out. Circulation
113: 2128-2151
[Full Text]
Guven, A., Cetinkaya, A., Aral, M., Sokmen, G., Buyukbese, M. A., Guven, A., Koksal, N.
(2006). High-Sensitivity C-Reactive Protein in Patients with Metabolic Syndrome. ANGIOLOGY
57: 295-302
[Abstract]
Tsimikas, S., Willerson, J. T., Ridker, P. M.
(2006). C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients.. J Am Coll Cardiol
47: C19-C31
[Abstract][Full Text]
Hermann, M., Ruschitzka, F.
(2006). Novel anti-inflammatory drugs in hypertension. Nephrol Dial Transplant
21: 859-864
[Full Text]
Tedgui, A., Mallat, Z.
(2006). Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. Physiol. Rev.
86: 515-581
[Abstract][Full Text]
Tousoulis, D, Charakida, M, Stefanadis, C
(2006). Endothelial function and inflammation in coronary artery disease. Heart
92: 441-444
[Abstract][Full Text]
Suleiman, M., Khatib, R., Agmon, Y., Mahamid, R., Boulos, M., Kapeliovich, M., Levy, Y., Beyar, R., Markiewicz, W., Hammerman, H., Aronson, D.
(2006). Early Inflammation and Risk of Long-Term Development of Heart Failure and Mortality in Survivors of Acute Myocardial Infarction: Predictive Role of C-Reactive Protein. J Am Coll Cardiol
47: 962-968
[Abstract][Full Text]
McCaffery, J. M., Frasure-Smith, N., Dube, M.-P., Theroux, P., Rouleau, G. A., Duan, Q., Lesperance, F.
(2006). Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin.. Psychosom. Med.
68: 187-200
[Abstract][Full Text]
Engstrom, G., Hedblad, B., Rosvall, M., Janzon, L., Lindgarde, F.
(2006). Occupation, Marital Status, and Low-Grade Inflammation: Mutual Confounding or Independent Cardiovascular Risk Factors?. Arterioscler. Thromb. Vasc. Bio.
26: 643-648
[Abstract][Full Text]
Armstrong, E. J., Morrow, D. A., Sabatine, M. S.
(2006). Inflammatory Biomarkers in Acute Coronary Syndromes: Part II: Acute-Phase Reactants and Biomarkers of Endothelial Cell Activation. Circulation
113: e152-e155
[Full Text]
Lee, K. W.J., Hill, J. S., Walley, K. R., Frohlich, J. J.
(2006). Relative value of multiple plasma biomarkers as risk factors for coronary artery disease and death in an angiography cohort.. CMAJ
174: 461-466
[Abstract][Full Text]
Meuwissen, M, van der Wal, A C, Niessen, H W M, Koch, K T, de Winter, R J, van der Loos, C M, Rittersma, S Z H, Chamuleau, S A J, Tijssen, J G P, Becker, A E, Piek, J J
(2006). Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction. J. Clin. Pathol.
59: 196-201
[Abstract][Full Text]
Lenderink, T., Heeschen, C., Fichtlscherer, S., Dimmeler, S., Hamm, C. W., Zeiher, A. M., Simoons, M. L., Boersma, E., for the CAPTURE Investigators,
(2006). Elevated Placental Growth Factor Levels Are Associated With Adverse Outcomes at Four-Year Follow-Up in Patients With Acute Coronary Syndromes. J Am Coll Cardiol
47: 307-311
[Abstract][Full Text]
Bursi, F., Rocca, W. A., Killian, J. M., Weston, S. A., Knopman, D. S., Jacobsen, S. J., Roger, V. L.
(2006). Heart Disease and Dementia: A Population-based Study. Am J Epidemiol
163: 135-141
[Abstract][Full Text]
Pepys, M. B., Hawkins, P. N., Kahan, M. C., Tennent, G. A., Gallimore, J. R., Graham, D., Sabin, C. A., Zychlinsky, A., de Diego, J.
(2005). Proinflammatory Effects of Bacterial Recombinant Human C-Reactive Protein Are Caused by Contamination With Bacterial Products, Not by C-Reactive Protein Itself. Circ. Res.
97: e97-e103
[Abstract][Full Text]
De Servi, S., Mariani, M., Mariani, G., Mazzone, A.
(2005). C-Reactive Protein Increase in Unstable Coronary Disease: Cause or Effect?. J Am Coll Cardiol
46: 1496-1502
[Abstract][Full Text]
Palmerini, T., Marzocchi, A., Marrozzini, C., Ortolani, P., Saia, F., Bacchi-Reggiani, L., Virzi, S., Gianstefani, S., Branzi, A.
(2005). Preprocedural Levels of C-Reactive Protein and Leukocyte Counts Predict 9-Month Mortality After Coronary Angioplasty for the Treatment of Unprotected Left Main Coronary Artery Stenosis. Circulation
112: 2332-2338
[Abstract][Full Text]
Mallat, Z., Steg, Ph. G., Benessiano, J., Tanguy, M.-L., Fox, K. A., Collet, J.-P., Dabbous, O. H., Henry, P., Carruthers, K. F., Dauphin, A., Arguelles, C. S., Masliah, J., Hugel, B., Montalescot, G., Freyssinet, J.-M., Asselain, B., Tedgui, A.
(2005). Circulating Secretory Phospholipase A2 Activity Predicts Recurrent Events in Patients With Severe Acute Coronary Syndromes. J Am Coll Cardiol
46: 1249-1257
[Abstract][Full Text]
Tam, S. P., Ancsin, J. B., Tan, R., Kisilevsky, R.
(2005). Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE-/- mice. J. Lipid Res.
46: 2091-2101
[Abstract][Full Text]
Cirillo, P., Golino, P., Calabro, P., Cali, G., Ragni, M., De Rosa, S., Cimmino, G., Pacileo, M., De Palma, R., Forte, L., Gargiulo, A., Corigliano, F. G., Angri, V., Spagnuolo, R., Nitsch, L., Chiariello, M.
(2005). C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res
68: 47-55
[Abstract][Full Text]
Liuzzo, G, Giubilato, G, Pinnelli, M
(2005). T cells and cytokines in atherogenesis. Lupus
14: 732-735
[Abstract]
Biasucci, L M, Giubilato, G, Graziani, F, Piro, M
(2005). CRP is or is not a reliable marker of ischaemic heart disease?. Lupus
14: 752-755
[Abstract]
Li, J.-J., Fang, C.-H.
(2005). Effects of 4 Weeks of Atorvastatin Administration on the Antiinflammatory Cytokine Interleukin-10 in Patients with Unstable Angina. Clin. Chem.
51: 1735-1738
[Full Text]
Best, L. G., Zhang, Y., Lee, E. T., Yeh, J.-L., Cowan, L., Palmieri, V., Roman, M., Devereux, R. B., Fabsitz, R. R., Tracy, R. P., Robbins, D., Davidson, M., Ahmed, A., Howard, B. V.
(2005). C-Reactive Protein as a Predictor of Cardiovascular Risk in a Population With a High Prevalence of Diabetes: The Strong Heart Study. Circulation
112: 1289-1295
[Abstract][Full Text]
Huang, P.-H., Chen, L.-C., Leu, H.-B., Ding, P. Y.-A., Chen, J.-W., Wu, T.-C., Lin, S.-J.
(2005). Enhanced Coronary Calcification Determined by Electron Beam CT Is Strongly Related to Endothelial Dysfunction in Patients With Suspected Coronary Artery Disease. Chest
128: 810-815
[Abstract][Full Text]
Thanyasiri, P., Celermajer, D. S., Adams, M. R.
(2005). Endothelial dysfunction occurs in peripheral circulation patients with acute and stable coronary artery disease. Am. J. Physiol. Heart Circ. Physiol.
289: H513-H517
[Abstract][Full Text]
Caligiuri, G., Groyer, E., Khallou-Laschet, J., Zen, A. A. H., Sainz, J., Urbain, D., Gaston, A.-T., Lemitre, M., Nicoletti, A., Lafont, A.
(2005). Reduced Immunoregulatory CD31+ T Cells in the Blood of Atherosclerotic Mice With Plaque Thrombosis. Arterioscler. Thromb. Vasc. Bio.
25: 1659-1664
[Abstract][Full Text]
Kohsaka, S., Menon, V., Lowe, A. M., Lange, M., Dzavik, V., Sleeper, L. A., Hochman, J. S., for the SHOCK Investigators,
(2005). Systemic Inflammatory Response Syndrome After Acute Myocardial Infarction Complicated by Cardiogenic Shock. Arch Intern Med
165: 1643-1650
[Abstract][Full Text]
Hirschfield, G. M., Gallimore, J. R., Kahan, M. C., Hutchinson, W. L., Sabin, C. A., Benson, G. M., Dhillon, A. P., Tennent, G. A., Pepys, M. B.
(2005). Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc. Natl. Acad. Sci. USA
102: 8309-8314
[Abstract][Full Text]
Pepys, M. B.
(2005). CRP or not CRP? That Is the Question. Arterioscler. Thromb. Vasc. Bio.
25: 1091-1094
[Full Text]
Mauriello, A., Sangiorgi, G., Fratoni, S., Palmieri, G., Bonanno, E., Anemona, L., Schwartz, R. S., Spagnoli, L. G.
(2005). Diffuse and Active Inflammation Occurs in Both Vulnerable and Stable Plaques of the Entire Coronary Tree: A Histopathologic Study of Patients Dying of Acute Myocardial Infarction. J Am Coll Cardiol
45: 1585-1593
[Abstract][Full Text]
Tanaka, A., Shimada, K., Sano, T., Namba, M., Sakamoto, T., Nishida, Y., Kawarabayashi, T., Fukuda, D., Yoshikawa, J.
(2005). Multiple Plaque Rupture and C-Reactive Protein in Acute Myocardial Infarction. J Am Coll Cardiol
45: 1594-1599
[Abstract][Full Text]
Hansson, G. K.
(2005). Inflammation, Atherosclerosis, and Coronary Artery Disease. NEJM
352: 1685-1695
[Full Text]
Bisoendial, R. J., Kastelein, J. J.P., Levels, J. H.M., Zwaginga, J. J., van den Bogaard, B., Reitsma, P. H., Meijers, J. C.M., Hartman, D., Levi, M., Stroes, E. S.G.
(2005). Activation of Inflammation and Coagulation After Infusion of C-Reactive Protein in Humans. Circ. Res.
96: 714-716
[Abstract][Full Text]
van Eeden, S. F., Yeung, A., Quinlam, K., Hogg, J. C.
(2005). Systemic Response to Ambient Particulate Matter: Relevance to Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc
2: 61-67
[Abstract][Full Text]
Clapp, B. R., Hirschfield, G. M., Storry, C., Gallimore, J. R., Stidwill, R. P., Singer, M., Deanfield, J. E., MacAllister, R. J., Pepys, M. B., Vallance, P., Hingorani, A. D.
(2005). Inflammation and Endothelial Function: Direct Vascular Effects of Human C-Reactive Protein on Nitric Oxide Bioavailability. Circulation
111: 1530-1536
[Abstract][Full Text]
Maier, W., Altwegg, L. A., Corti, R., Gay, S., Hersberger, M., Maly, F. E., Sutsch, G., Roffi, M., Neidhart, M., Eberli, F. R., Tanner, F. C., Gobbi, S., von Eckardstein, A., Luscher, T. F.
(2005). Inflammatory Markers at the Site of Ruptured Plaque in Acute Myocardial Infarction: Locally Increased Interleukin-6 and Serum Amyloid A but Decreased C-Reactive Protein. Circulation
111: 1355-1361
[Abstract][Full Text]
0.3 mg per deciliter (exceeding the 90th percentile of the normal distribution) in 4 of the patients with stable angina (13 percent), 20 of the patients with unstable angina (65 percent), and 22 of the patients with acute myocardial infarction (76 percent). The 20 patients with unstable angina who had levels of acute-phase reactants 
