Correspondence
C-Reactive Protein and Serum Amyloid a Protein in Unstable Angina
N Engl J Med 1995; 332:398-400February 9, 1995
- Article
To the Editor:
In associating the acute-phase reactants C-reactive protein and amyloid A protein with clinical outcome in unstable angina, Liuzzo et al. (Aug. 18 issue)1 provide further evidence that coronary atherosclerosis is an inflammatory disease. However, the importance of their data depends substantially on the acceptance of the view that these reactants are circulating markers of the activity of atherosclerosis and not just indicators of recent myocardial ischemia.
Moreover, whereas the authors find prognostic value in the levels of C-reactive and amyloid A proteins over periods of days to weeks, the plasma concentration of another acute-phase reactant, fibrinogen, has been found to be correlated with the risk of heart disease independently of traditional risk factors over many years.2,3 Do Liuzzo and colleagues suspect that these various acute-phase reactants have one or several associations with atherosclerotic vascular disease? Also, are fibrinogen, C-reactive protein, and amyloid A protein passive indicators of “atheroscleritis,” or might these proteins participate in the disease itself (i.e., through prothrombotic actions)?
3 ReferencesMatthew F. Muldoon, M.D.
University of Pittsburgh, Pittsburgh, PA 152611
Liuzzo G ,Biasucci LM ,Gallimore JR , et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994;331:417-424
Full Text | Web of Science | Medline2
Kannel WB ,Wolf PA ,Castelli WP ,D'Agostino RB . Fibrinogen and risk of cardiovascular disease. JAMA 1987;258:1183-1186
CrossRef | Web of Science | Medline3
Heinrich J ,Balleisen L ,Schulte H ,Assmann G ,van de Loo J . Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994;14:54-59
CrossRef | Medline
To the Editor:
The report by Liuzzo et al. on the prognostic value of C-reactive protein and amyloid A protein in patients with severe unstable angina refers to troponin T as a serum marker assessed for its usefulness as a prognostic indicator in such patients. The results of this study conflict with current data on the use of troponin T in both patients with unstable angina and those with acute myocardial infarction.
The patients considered in the study had Braunwald's class III1 unstable angina (angina at rest during the preceding 48 hours). Liuzzo et al. state that none of them had troponin T concentrations greater than 0.2 μg per liter on admission and that there were no elevations of creatine kinase or troponin T during hospitalization, except in 5 of 31 patients who had elevated levels of troponin T, creatine kinase, or both after the development of electrocardiographic changes consistent with acute myocardial infarction. This finding contrasts with the results of two recent studies showing that 39 percent of patients with class III angina had troponin T levels greater than 0.2 μg per liter2 and that 56 percent of patients with unstable angina of classes I through III had troponin T levels greater than 0.5 μg per liter.3 The latter study also found that elevated levels of troponin T preceded the development of either changes in the serum levels of the MB isoenzyme of creatine kinase or electrocardiographic changes by approximately 12 hours in patients who did not initially have evidence of an acute myocardial infarction on admission but in whom myocardial infarction developed during hospitalization.3
Liuzzo and colleagues also state that none of the 29 patients with documented acute myocardial infarctions were found to have elevated troponin T concentrations at the time of study enrollment. Once again, this contradicts recent data indicating that serum troponin T concentrations greater than 0.5 μg per liter were detected within three hours of the onset of chest pain in 50 percent of patients with acute myocardial infarctions3 and another study that showed that 51 percent of patients presenting within four hours of the onset of symptoms of myocardial infarction had detectable troponin T concentrations greater than 0.1 μg per liter.4
Perhaps these discrepancies could be explained by the exclusion of a large number of patients (51 of 82) from the study sample or by the procedure used to process the serum assays. The samples analyzed for troponin T were stored at -70°C until the completion of the study (a one-year period) and were analyzed in a single batch. The manufacturer's product insert5 recommends storing these samples at -20°C for up to three months to ensure stability. Also, calibration techniques for the troponin T analyzer were not mentioned in the article.
5 ReferencesJames Ryan, M.D.
Mary Frances Ward, R.N.
Andrew E. Sama, M.D.
North Shore University Hospital, Manhasset, NY 110301
Braunwald E . Unstable angina: a classification. Circulation 1989;80:410-414
CrossRef | Web of Science | Medline2
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
Full Text | Web of Science | Medline3
Katus HA ,Remppis A ,Neumann FJ , et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation 1991;83:902-912
Web of Science | Medline4
Bakker AJ ,Koelemay MJ ,Gorgels JP , et al. Troponin T and myoglobin at admission: value of early diagnosis of acute myocardial infarction. Eur Heart J 1994;15:45-53
Web of Science | Medline5
Cardiac T ELISA troponin T assay. Indianapolis: Boehringer–Mannheim Corporation, 1994 (package insert).
To the Editor:
Liuzzo et al. showed that plasma concentrations of C-reactive protein were elevated at the time of hospital admission in 65 percent of patients with unstable angina and that such elevation predicts a poor outcome during hospitalization.
We have prospectively measured C-reactive protein in 108 consecutive patients hospitalized in our institution with angina at rest of recent onset (within 24 hours) accompanied by ischemic electrocardiographic changes. Blood samples were collected at admission, which was 6.6±5.3 hours after the most recent episode of angina. Patients with elevated creatine kinase MB fractions, conditions known to be associated with an acute-phase response, or recent myocardial infarctions were excluded. C-reactive protein was assayed by rate nephelometry (Beckman CRP, Beckman Instruments, Galway, Ireland). The upper limit of the normal range of C-reactive protein was calculated by determining the 90th percentile of the distribution in a control group of 25 healthy persons matched with the patients for age and sex and was set at 1.0 mg per deciliter.
Levels of C-reactive protein were found to be higher than 1.0 mg per deciliter in 32 patients (30 percent). During hospitalization none of the patients died, 6 patients (6 percent) had myocardial infarctions, and 20 patients (18 percent) had refractory angina requiring emergency revascularization. Table 1Table 1
In-Hospital Outcomes in Patients with Unstable Angina, According to the Level of C-Reactive Protein. shows the distribution of in-hospital outcomes according to whether levels of C-reactive protein were normal or abnormal. Holter monitoring was performed for 72 hours after hospital admission in 92 patients, 29 of whom (32 percent) had at least one ischemic episode. Ischemia was documented by Holter monitoring in 33 percent of patients with abnormal C-reactive protein levels and 31 percent of those with normal protein levels (P not significant).Our results show that in a large population of patients with acute unstable angina, the prevalence of abnormal levels of C-reactive protein was lower than that reported by Liuzzo et al. and did not predict early in-hospital outcomes. Despite similarity in the selection of patients, the differing incidence of cardiac events during hospitalization (24 percent in our population vs. 64 percent in the study by Liuzzo et al.) may account for the differing prognostic value of C-reactive protein in the two studies.
Luigi Oltrona, M.D.
Piera Angelica Merlini, M.D.
Antonio Pezzano, M.D.
Ospedale Niguarda, 20162 Milan, ItalyAuthor/Editor Response
The authors reply:
To the Editor: In response to Dr. Muldoon: only 13 percent of the patients with severe coronary artery disease and stable angina had levels of C-reactive protein above 0.3 mg per deciliter, and among patients with unstable angina, elevated levels of C-reactive protein were not related to the severity of coronary atherosclerosis. Thus, the acute-phase response of C-reactive protein and serum amyloid A is not evidence that atheroma itself is inflammatory; instead, it reflects another, unknown process active in most patients with severe unstable angina. The acute-phase response we observed is not caused by myocardial ischemia in itself, because the level of C-reactive protein was not elevated in patients with variant angina and more prolonged ischemia.1 Serum amyloid A and C-reactive protein have properties that could contribute to atherogenesis and thrombosis, but it is still unknown whether they participate in the progression of unstable angina or are just markers of other processes responsible for this progression.
In reply to Dr. Ryan et al.: patients with episodes of unstable angina lasting more than 30 minutes were excluded from our study in order to avoid a necrosis-induced acute-phase response, whereas in those with infarction the modal time of sampling after the onset of pain was 2 hours in those with previous unstable angina and 3 hours in those without. This may explain the absence of elevated troponin T values in these patients as compared with those studied by Katus et al., who took blood samples from “patients with AMI [acute myocardial infarction] from 3.5 hours . . . after onset of pain.”2 The suggestion of Ryan and colleagues about sample storage is unlikely to be relevant, because all known serum proteins are considerably more stable during storage at -70°C than they are at -20°C. Assay calibration and performance conformed to the manufacturer's specifications.
The C-reactive protein assay used by Oltrona et al. is insufficiently precise and sensitive in the range of concentrations below about 2.0 mg per deciliter to yield any reliable information about C-reactive protein values below 1.0 to 2.0 mg per deciliter. Our article specifically noted the importance of using sensitive assays to measure C-reactive protein and serum amyloid A at levels close to the normal range. Unfortunately, such methods are not yet commercially available with automated instruments, but they can easily be implemented in a competent immunochemistry laboratory. Meanwhile, we would be happy to assay the samples of Dr. Oltrona and colleagues in blinded fashion to address this issue. In addition, their patients were more stable than ours. According to Bayesian theory, the predictive value of any test is lower in low-risk groups. Meanwhile, our original findings have been confirmed in a subsequent multicenter study.3
3 ReferencesGiovanna Liuzzo, M.D
Università Cattolica del Sacro Cuore, 00168 Rome, ItalyMark B. Pepys, M.D.
Royal Postgraduate Medical School, London W12 ONN, United KingdomAttilio Maseri, M.D.
Università Cattolica del Sacro Cuore, 00168 Rome, Italy1
Liuzzo G ,Biasucci LM ,Lanza GA , et al. C-reactive protein is increased in unstable angina but not in active variant angina: is inflammation in acute coronary syndromes related to ischemia? Circulation 1994;90:I-664 abstract.2
Katus HA ,Remppis A ,Neumann FJ , et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation 1991;83:902-912
Web of Science | Medline3
Rebuzzi AG ,Liuzzo G ,Menini E , et al. Powerful prognostic value of troponin T and C-reactive protein in patients with unstable angina. J Am Coll Cardiol1994;77A-77A abstract.
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