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Inflammatory profile in unstable angina versus stable angina in patients undergoing percutaneous interventions
Inflammatory profile in unstable angina versus stable angina in patients undergoing percutaneous interventions Shahram Yazdani, MD, Alan D. Simon, MD, Raghuraman Vidhun, MD, Carolyn Gulotta, RN, Allan Schwartz, MD, and LeRoy E. Rabbani, MD New York and Roslyn, N.Y.
Background Inflammatory markers have been shown to be elevated in acute coronary syndromes. Recently, interleukin-6 was demonstrated to be elevated in unstable angina compared with stable angina. However, the effect of percutaneous coronary interventions on the levels of inflammatory markers is less well known.
Methods and Results In this study, we measured the levels of interleukin-6 and interleukin-1 by using enzymelinked immunosorbent assays in patients with angina pectoris undergoing coronary interventions and in healthy control subjects. Interleukin-6 was significantly elevated in patients with unstable angina compared with patients with stable angina (P = .01). There were no significant differences between the levels of interleukin-1 in patients with unstable angina versus patients with stable angina and healthy control subjects. Furthermore, at 1-month follow-up after percutaneous coronary interventions, there were no longer any significant differences between the levels of interleukin-6 in patients with unstable angina versus patients with stable angina and healthy control subjects.
Conclusions These data suggest that interleukin-6 levels may correlate with instability of atheromatous plaques and that the decrease of interleukin-6 levels after percutaneous coronary interventions may represent plaque reendothelialization and stabilization. (Am Heart J 1998;136:357-61.)
Inflammation has been implicated to play a major role in the development and progression of coronary artery disease.1,2 Recent pathologic studies of patients with coronary atherosclerosis have shown plaques to contain macrophages as well as T-lymphocytes.3 Moreover, T-lymphocytes found in the atherosclerotic plaques are memory T cells in a state of chronic activation demonstrated by the expression of surface antigens such as very late activation antigen-1 integrin4 and human leukocyte antigen-DR.5 There is also evidence that inflammation may be a major factor in the development of acute coronary syndromes. C-reactive protein, an acute-phase reactant, has been shown to be elevated in unstable angina as well as in acute myocardial infarction.6,7 Biasucci et al.8 recently detected elevated levels of interleukin-6, a proinflammatory
From the Division of Cardiology, Department of Medicine, Columbia-Presbyterian Medical Center, and Saint Francis Hospital. Supported by National Heart, Lung, and Blood Institute Physician Scientist Award (K11 HL-02578) (L.E.R.) and the Sol and Margaret Berger Foundation (L.E.R.). Submitted July 8, 1998; accepted Feb. 26, 1998. Reprint requests: LeRoy E. Rabbani, MD, Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/90408
cytokine,9 in patients with unstable angina. However, the effect of percutaneous coronary interventions used to treat unstable angina on the degree of inflammation is unknown. We hypothesized that levels of the interleukin-6 and interleukin-1, another proinflammatory cytokine that induces interleukin-6 secretion, are increased in unstable angina compared with stable angina and that percutaneous coronary interventions would attenuate the elevated levels of interleukin-6 and interleukin-1 in unstable angina. We demonstrate in this study that the levels of interleukin-6 are elevated in unstable angina compared with stable angina, whereas there are no significant differences in the levels of interleukin-1 in unstable angina versus stable angina. Furthermore, at 1 month after percutaneous interventions, there was no longer any significant difference in the levels of interleukin-6 between each group.
Methods This study was undertaken after approval by the respective Institutional Review Boards at the participating hospitals. Patient selection was between July 1995 and April 1996; patients referred for percutaneous coronary interventions to
American Heart Journal August 1998
358 Yazdani et al.
the cardiac catheterization laboratories at the participating hospitals were approached for enrollment in the study. Fiftynine patients were enrolled, as were 9 healthy control subjects. Unstable angina was defined as chest pain at rest within 24 hours of intervention accompanied by ST or Twave changes in 2 consecutive leads. Stable angina was defined as exertional chest pain relieved by rest. Informed consent was obtained from each patient before enrollment. Thirty-three patients underwent percutaneous transluminal coronary angioplasty (PTCA) and 26 patients received coronary stents; 22 patients with stable angina had PTCA, and 20 patients received coronary stent placement. Ten patients with unstable angina had PTCA and 7 patients received coronary stents. Seven patients were lost to follow-up and were excluded from the final analysis.
Figure 1
Exclusion criteria Patients with history of coronary heart failure, recent myocardial infarction within the previous 4 weeks documented by enzymes, malignancies, or known infections were excluded.
Patient stratification Patients were stratified into 2 groups: group 1, patients with at least 1 episode of rest pain lasting <20 minutes were classified as having unstable angina; group 2, patients referred for elective percutaneous coronary interventions with chronic stable exertional chest pain and no episodes of rest pain were classified as having stable angina.
Blood samples Initial blood samples were drawn from the venous sheath at the time of percutaneous coronary interventions before any drugs were administered. The follow-up blood samples as well as the blood samples from healthy control subjects were drawn by venipuncture from the subject’s forearm. Each time, 30 mL of blood was collected and divided into 10 mL tubes containing 1 mL of 3.10% sodium citrate. The plasma was separated by centrifugation at 3000 rpm for 15 minutes and stored at –70° C until it was assayed for interleukin-6.
Cytokine measurements The plasma levels of interleukin-6 and interleukin-1 were measured by commercially available immunoassay kits (Ultrasensitive Cytoscan, BioSource).
Statistics The baseline characteristics of patients were measured with the unpaired Student t test for continuous variables and the chi-square test for discrete variables. The analysis of variance (ANOVA) test with Bonferroni correction was used to compare the plasma interleukin-6 and interleukin-1 levels between each group.
Comparison of initial and follow-up interleukin-6 (IL-6) levels in patients with unstable angina (top) and stable angina (bottom). Values were compared by use of ANOVA test with Bonferroni correction. Results are shown as mean ± SE (*P < .05). Points on left representing initial values are connected by straight lines to follow-up values on right.
Results There were no significant clinical differences in the baseline clinical and demographic characteristics of patients with unstable angina versus stable angina except that patients with unstable angina were more likely to be receiving heparin and nitroglycerin and to have higher cholesterol levels. The values of initial and follow-up levels of plasma interleukin-6 are
American Heart Journal Volume 136, Number 2
Figure 2
Comparison of initial interleukin-1 levels in patients with unstable angina and stable angina and healthy control subjects. Values were compared by ANOVA test. Results are shown as mean ± SE.
shown in Fig. 1. Plasma interleukin-6 levels were significantly higher in patients with unstable angina compared with patients with stable angina (mean ± standard error [SE] of 2.2 ± 0.4 vs 1.07 ± 0.2 pg/mL, respectively, P = .01) as well as healthy control subjects (mean ± SE of 2.2 ± 0.4 vs 0.4 ± 0.7 pg/mL, respectively, P = .01). At 1-month follow-up, there were no longer any significant differences between the plasma levels of interleukin-6 in patients with unstable angina versus patients with stable angina (mean ± SE of 1.1 ± 0.3 vs 0.7 ± 0.1 pg/mL, respectively, P = .1). The values of interleukin-1 are shown in Fig. 2. There were no significant differences in the levels of interleukin-1 in patients with unstable angina versus patients with stable angina (mean ± SE of 0.3 ± 0.1 vs 0.6 ± 0.3 pg/mL, respectively, P = .5) as well as healthy control subjects (mean ± SE of .3 ± .1 vs .5 ± .2 pg/mL, P > .5, respectively).
Discussion In this study, we demonstrate that plasma interleukin-6 levels are elevated in unstable angina and that there is an attenuation of interleukin-6 levels in unstable angina after percutaneous coronary interventions. Moreover, there were no significant differences between the levels of interleukin-1 in patients with unstable angina versus those with stable angina.
Yazdani et al. 359
Recent clinical and pathologic studies point to inflammation as a major factor in development of acute coronary syndromes. It has long been known that monocytes penetrate the coronary plaques, engulf oxidized low-density lipoproteins, and secrete matrix metalloproteinases, which contribute to plaque destabilization.10 T cells are also present in the plaques and are in an activated state.4,5 Further evidence comes from studies showing systemic levels of acute phase reactants such as serum amyloid, C-reactive protein, and fibrinogen to be elevated in unstable angina and acute myocardial infarction.5,11 Interleukin-6 is a cytokine that is induced in a variety of inflammatory conditions. It has been shown to be elevated in viral12 and bacterial infections13 as well as in certain neoplasms.14 In turn, interleukin-6 has been shown to induce hepatic acute-phase proteins.15 It is also involved in activation of T cells16 as well as induction of B-cell differentiation.17 In addition, interleukin-6 has been demonstrated to have procoagulant properties.18 Recently, interleukin-6 has been investigated in acute coronary syndromes. Newman et al.19 showed interleukin-6 levels to be elevated in acute myocardial infarction. A study by Biasucci et al.8 showed interleukin-6 levels to be elevated in unstable angina. Furthermore, there was a positive correlation between interleukin-6 levels in most patients and C-reactive protein as well as prognosis. In our study, plasma levels of interleukin-6 were elevated as much as 2-fold in patients with unstable angina compared with patients with stable angina. This is consistent with the previous studies and further demonstrates that acute coronary syndromes may be viewed not only as prothrombotic states but also as inflammatory conditions. The mean level of interleukin-6 in unstable angina in our study (2.17 pg/mL) was lower than that reported by Biasucci et al. (5.25 pg/mL). This could be caused by differences in the timing of the blood drawing. In the study by Biasucci et al., the mean time from the last ischemic episode and blood sampling was 12 ± 8 hours, whereas in our study the time from·last episode of ischemia and arrival at the catheterization laboratory where blood samples were taken was longer (in most cases 24 to 36 hours). The higher plasma levels of interleukin-6 could also represent a sicker patient population in the study by Biasucci et al. Interleukin-6 is also a procoagulant factor. Elevated interleukin-6 levels correlate with the degree of proco-
American Heart Journal August 1998
360 Yazdani et al.
agulation seen in septic shock.20 Furthermore, injection of interleukin-6 has been shown to induce a procoagulant state in baboons21 as well as in human beings.22 Interleukin-6 may influence the coagulation pathway through its induction of C-reactive protein, which in turn causes peripheral blood monocytes to synthesize tissue factor.23 This procoagulant activity of interleukin-6 might contribute to the instability of plaques at the site of rupture in unstable angina. Interleukin-1, another proinflammatory cytokine produced by monocytes, was not significantly different in unstable angina versus stable angina in this study. Interleukin-1 has been implicated in many inflammatory conditions including bacterial as well as viral infections.24 It is cytotoxic to certain neoplasms.25 Moreover, it has been shown to induce monocytes to secrete interleukin-6.26 Like interleukin6, interleukin-1 also induces hepatic production of certain acute-phase reactants.27 However, there are certain differences in the biologic activities of interleukin-1 and interleukin-6. The secretion of some hepatic proteins such as fibrinogen is only induced by interleukin-6 and not interleukin-1.27 One reason for the lack of elevation of interleukin-1 in unstable angina in our study might be that their peak levels were missed. Because interleukin-1 induces interleukin-6, it is possible that interleukin-1 levels were elevated earlier in the course of disease and that by the time of blood drawing their levels had subsided. Also, a good portion of interleukin-1 in the plasma travels bound to large proteins such as interleukin1RA, complements, and β-2-microglobulin.28 As such, this portion might have not been detected by our assay. Another reason could be that certain inflammatory factors are induced selectively whereas others are inhibited in unstable angina. This could point to a complex relation between different inflammatory cells and factors in unstable angina and deserves further investigation. This study also demonstrated that at 1-month followup after percutaneous coronary intervention, there was no longer any significant difference in the levels of interleukin-6 between the 2 groups. Because ruptured plaques become stable after coronary intervention, it is reasonable to postulate that prothrombotic and proinflammatory conditions subside. It has been shown that endothelial integrity returns 4 weeks after PTCA29 as well as after stent placement.30 Therefore attenuation of interleukin-6 levels in unstable angina at 1 month after intervention might reflect plaque stabilization.
In conclusion, interleukin-6, a proinflammatory and prothrombotic cytokine, was significantly elevated in unstable angina compared with stable angina and healthy control subjects. This elevation was no longer present 1 month after percutaneous coronary interventions. This phenomenon may represent attenuation of the inflammatory condition as plaques become stable and quiescent.
References 1. Yarnell JWG, Baker IA, Sweetnam A, Bainton D, O’Brien JR, Whitehead PJ, et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. Circulation 1991;88:836-44. 2. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;90:36-44. 3. Hansson GK, Jonasson L, Seifert PS, Stemme S. Immune mechanisms in atherosclerosis. Atherosclerosis 1989;9:567-78. 4. Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb 1992;12:206-11. 5. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989;135:169-75. 6. Liuzzo G, Biasucci LM, Gallimore R, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994;331:417-24. 7. de Beer FC, Hind CR, Fox KM, Allan RN, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial infarction. Br Heart J 1982;47:239-43. 8. Biasucci LN, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, et al. Elevated levels of interleukin-6 in unstable angina. Circulation 1996;95:874-7. 9. Le J, Vilcek J. Interleukin 6: a multifactorial cytokine regulating immune reactions and the acute phase protein response. Lab Invest 1989;61:588-602. 10. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995;77:863-8. 11. Kruskal JB, Commerford PJ, Franks JJ, Kirsh RE. Fibrin and fibrinogen related antigens in patients with stable and unstable coronary artery disease. N Engl J Med 1987;317:1361-5. 12. Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol 1989;19:689-94. 13. Van der Meer J, Helle M, Aarden L. Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection. Eur J Immunol 1989;19:413-6. 14. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988;332:83-4. 15. Gauldie J, Richards C, Hamish D, Lansdorp P, Baumann H. Interferon beta2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the
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20.
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22.
major acute phase protein response in liver cells. Proc Natl Acad Sci U S A 1987;84:7251-5. Lotz M, Jirik F, Kabouridis P, Tsoukas C, Hirano T, Kishimoto T, et al. B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med 1988;167:1253-8. Beagley KW, Eldrige JH, Lee F, Kiyono H, Everson MP, Koopman WJ, et al. Interleukins and Ig A synthesis: human and murine interleukin 6 induce high rate Ig A secretion in IgA-committed B cells. J Exp Med 1989;169:2133-48. van der Poll T, Levi M, Hack CE, ten Cate U, van Deventer SJH, Eerenberg AJM, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994;179:1253-9. Newman FJ, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995;92:748-55. Massignon D, Lepape A, Bienvenu J, Barbier Y, Boileau C, Coeur P. Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state. Haemostasis. 1994;24:36-48. Mestries JC, Kruihof EK, Gascon MD, Herodin F, Agay D, Ythier A. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994;5:275-81. Stouthard J, Levi M, Hack E, Veenhof C, Romijn H, Sauerwein H, et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996;76:738-42.
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23. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. Creactive protein induces human peripheral monocytes to synthesize tissue factor. Blood 1993;82:513-20. 24. Le J, Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest 1987;56:234-48. 25. Lachman LB, Dinarello CA, Llansa ND, Fidler IJ. Natural and recombinant human interleukin 1-a is cytotoxic for human melanoma cells. J Immunol 1986;136:3098-102. 26. Tosado G, Seamon KB, Goldman ND, Sehgal PB, May LT, Washington GC, et al. Monocyte-derived human B-cell growth factor identified as interferon-beta2 (BSF-2, IL-6). Science 1988;239: 502-4. 27. Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med 1990;7:147-59. 28. Dinarello CA, Biological bases for interleukin-1 in disease. Blood 1996;87:2095-147. 29. Steele P, Chesebro JH, Stanson AW, Holmes DR, Dewanjee MK, Badimon L, et al. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res 1985;57:105-12. 30. Van Belle E, Tio FO, Couffindal T, Maillard L, Passeri J, Isner JM. Stent endothelialization: time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation 1997;95:438-48.
Background Inflammatory markers have been shown to be elevated in acute coronary syndromes. Recently, interleukin-6 was demonstrated to be elevated in unstable angina compared with stable angina. However, the effect of percutaneous coronary interventions on the levels of inflammatory markers is less well known.
Methods and Results In this study, we measured the levels of interleukin-6 and interleukin-1 by using enzymelinked immunosorbent assays in patients with angina pectoris undergoing coronary interventions and in healthy control subjects. Interleukin-6 was significantly elevated in patients with unstable angina compared with patients with stable angina (P = .01). There were no significant differences between the levels of interleukin-1 in patients with unstable angina versus patients with stable angina and healthy control subjects. Furthermore, at 1-month follow-up after percutaneous coronary interventions, there were no longer any significant differences between the levels of interleukin-6 in patients with unstable angina versus patients with stable angina and healthy control subjects.
Conclusions These data suggest that interleukin-6 levels may correlate with instability of atheromatous plaques and that the decrease of interleukin-6 levels after percutaneous coronary interventions may represent plaque reendothelialization and stabilization. (Am Heart J 1998;136:357-61.)
Inflammation has been implicated to play a major role in the development and progression of coronary artery disease.1,2 Recent pathologic studies of patients with coronary atherosclerosis have shown plaques to contain macrophages as well as T-lymphocytes.3 Moreover, T-lymphocytes found in the atherosclerotic plaques are memory T cells in a state of chronic activation demonstrated by the expression of surface antigens such as very late activation antigen-1 integrin4 and human leukocyte antigen-DR.5 There is also evidence that inflammation may be a major factor in the development of acute coronary syndromes. C-reactive protein, an acute-phase reactant, has been shown to be elevated in unstable angina as well as in acute myocardial infarction.6,7 Biasucci et al.8 recently detected elevated levels of interleukin-6, a proinflammatory
From the Division of Cardiology, Department of Medicine, Columbia-Presbyterian Medical Center, and Saint Francis Hospital. Supported by National Heart, Lung, and Blood Institute Physician Scientist Award (K11 HL-02578) (L.E.R.) and the Sol and Margaret Berger Foundation (L.E.R.). Submitted July 8, 1998; accepted Feb. 26, 1998. Reprint requests: LeRoy E. Rabbani, MD, Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/90408
cytokine,9 in patients with unstable angina. However, the effect of percutaneous coronary interventions used to treat unstable angina on the degree of inflammation is unknown. We hypothesized that levels of the interleukin-6 and interleukin-1, another proinflammatory cytokine that induces interleukin-6 secretion, are increased in unstable angina compared with stable angina and that percutaneous coronary interventions would attenuate the elevated levels of interleukin-6 and interleukin-1 in unstable angina. We demonstrate in this study that the levels of interleukin-6 are elevated in unstable angina compared with stable angina, whereas there are no significant differences in the levels of interleukin-1 in unstable angina versus stable angina. Furthermore, at 1 month after percutaneous interventions, there was no longer any significant difference in the levels of interleukin-6 between each group.
Methods This study was undertaken after approval by the respective Institutional Review Boards at the participating hospitals. Patient selection was between July 1995 and April 1996; patients referred for percutaneous coronary interventions to
American Heart Journal August 1998
358 Yazdani et al.
the cardiac catheterization laboratories at the participating hospitals were approached for enrollment in the study. Fiftynine patients were enrolled, as were 9 healthy control subjects. Unstable angina was defined as chest pain at rest within 24 hours of intervention accompanied by ST or Twave changes in 2 consecutive leads. Stable angina was defined as exertional chest pain relieved by rest. Informed consent was obtained from each patient before enrollment. Thirty-three patients underwent percutaneous transluminal coronary angioplasty (PTCA) and 26 patients received coronary stents; 22 patients with stable angina had PTCA, and 20 patients received coronary stent placement. Ten patients with unstable angina had PTCA and 7 patients received coronary stents. Seven patients were lost to follow-up and were excluded from the final analysis.
Figure 1
Exclusion criteria Patients with history of coronary heart failure, recent myocardial infarction within the previous 4 weeks documented by enzymes, malignancies, or known infections were excluded.
Patient stratification Patients were stratified into 2 groups: group 1, patients with at least 1 episode of rest pain lasting <20 minutes were classified as having unstable angina; group 2, patients referred for elective percutaneous coronary interventions with chronic stable exertional chest pain and no episodes of rest pain were classified as having stable angina.
Blood samples Initial blood samples were drawn from the venous sheath at the time of percutaneous coronary interventions before any drugs were administered. The follow-up blood samples as well as the blood samples from healthy control subjects were drawn by venipuncture from the subject’s forearm. Each time, 30 mL of blood was collected and divided into 10 mL tubes containing 1 mL of 3.10% sodium citrate. The plasma was separated by centrifugation at 3000 rpm for 15 minutes and stored at –70° C until it was assayed for interleukin-6.
Cytokine measurements The plasma levels of interleukin-6 and interleukin-1 were measured by commercially available immunoassay kits (Ultrasensitive Cytoscan, BioSource).
Statistics The baseline characteristics of patients were measured with the unpaired Student t test for continuous variables and the chi-square test for discrete variables. The analysis of variance (ANOVA) test with Bonferroni correction was used to compare the plasma interleukin-6 and interleukin-1 levels between each group.
Comparison of initial and follow-up interleukin-6 (IL-6) levels in patients with unstable angina (top) and stable angina (bottom). Values were compared by use of ANOVA test with Bonferroni correction. Results are shown as mean ± SE (*P < .05). Points on left representing initial values are connected by straight lines to follow-up values on right.
Results There were no significant clinical differences in the baseline clinical and demographic characteristics of patients with unstable angina versus stable angina except that patients with unstable angina were more likely to be receiving heparin and nitroglycerin and to have higher cholesterol levels. The values of initial and follow-up levels of plasma interleukin-6 are
American Heart Journal Volume 136, Number 2
Figure 2
Comparison of initial interleukin-1 levels in patients with unstable angina and stable angina and healthy control subjects. Values were compared by ANOVA test. Results are shown as mean ± SE.
shown in Fig. 1. Plasma interleukin-6 levels were significantly higher in patients with unstable angina compared with patients with stable angina (mean ± standard error [SE] of 2.2 ± 0.4 vs 1.07 ± 0.2 pg/mL, respectively, P = .01) as well as healthy control subjects (mean ± SE of 2.2 ± 0.4 vs 0.4 ± 0.7 pg/mL, respectively, P = .01). At 1-month follow-up, there were no longer any significant differences between the plasma levels of interleukin-6 in patients with unstable angina versus patients with stable angina (mean ± SE of 1.1 ± 0.3 vs 0.7 ± 0.1 pg/mL, respectively, P = .1). The values of interleukin-1 are shown in Fig. 2. There were no significant differences in the levels of interleukin-1 in patients with unstable angina versus patients with stable angina (mean ± SE of 0.3 ± 0.1 vs 0.6 ± 0.3 pg/mL, respectively, P = .5) as well as healthy control subjects (mean ± SE of .3 ± .1 vs .5 ± .2 pg/mL, P > .5, respectively).
Discussion In this study, we demonstrate that plasma interleukin-6 levels are elevated in unstable angina and that there is an attenuation of interleukin-6 levels in unstable angina after percutaneous coronary interventions. Moreover, there were no significant differences between the levels of interleukin-1 in patients with unstable angina versus those with stable angina.
Yazdani et al. 359
Recent clinical and pathologic studies point to inflammation as a major factor in development of acute coronary syndromes. It has long been known that monocytes penetrate the coronary plaques, engulf oxidized low-density lipoproteins, and secrete matrix metalloproteinases, which contribute to plaque destabilization.10 T cells are also present in the plaques and are in an activated state.4,5 Further evidence comes from studies showing systemic levels of acute phase reactants such as serum amyloid, C-reactive protein, and fibrinogen to be elevated in unstable angina and acute myocardial infarction.5,11 Interleukin-6 is a cytokine that is induced in a variety of inflammatory conditions. It has been shown to be elevated in viral12 and bacterial infections13 as well as in certain neoplasms.14 In turn, interleukin-6 has been shown to induce hepatic acute-phase proteins.15 It is also involved in activation of T cells16 as well as induction of B-cell differentiation.17 In addition, interleukin-6 has been demonstrated to have procoagulant properties.18 Recently, interleukin-6 has been investigated in acute coronary syndromes. Newman et al.19 showed interleukin-6 levels to be elevated in acute myocardial infarction. A study by Biasucci et al.8 showed interleukin-6 levels to be elevated in unstable angina. Furthermore, there was a positive correlation between interleukin-6 levels in most patients and C-reactive protein as well as prognosis. In our study, plasma levels of interleukin-6 were elevated as much as 2-fold in patients with unstable angina compared with patients with stable angina. This is consistent with the previous studies and further demonstrates that acute coronary syndromes may be viewed not only as prothrombotic states but also as inflammatory conditions. The mean level of interleukin-6 in unstable angina in our study (2.17 pg/mL) was lower than that reported by Biasucci et al. (5.25 pg/mL). This could be caused by differences in the timing of the blood drawing. In the study by Biasucci et al., the mean time from the last ischemic episode and blood sampling was 12 ± 8 hours, whereas in our study the time from·last episode of ischemia and arrival at the catheterization laboratory where blood samples were taken was longer (in most cases 24 to 36 hours). The higher plasma levels of interleukin-6 could also represent a sicker patient population in the study by Biasucci et al. Interleukin-6 is also a procoagulant factor. Elevated interleukin-6 levels correlate with the degree of proco-
American Heart Journal August 1998
360 Yazdani et al.
agulation seen in septic shock.20 Furthermore, injection of interleukin-6 has been shown to induce a procoagulant state in baboons21 as well as in human beings.22 Interleukin-6 may influence the coagulation pathway through its induction of C-reactive protein, which in turn causes peripheral blood monocytes to synthesize tissue factor.23 This procoagulant activity of interleukin-6 might contribute to the instability of plaques at the site of rupture in unstable angina. Interleukin-1, another proinflammatory cytokine produced by monocytes, was not significantly different in unstable angina versus stable angina in this study. Interleukin-1 has been implicated in many inflammatory conditions including bacterial as well as viral infections.24 It is cytotoxic to certain neoplasms.25 Moreover, it has been shown to induce monocytes to secrete interleukin-6.26 Like interleukin6, interleukin-1 also induces hepatic production of certain acute-phase reactants.27 However, there are certain differences in the biologic activities of interleukin-1 and interleukin-6. The secretion of some hepatic proteins such as fibrinogen is only induced by interleukin-6 and not interleukin-1.27 One reason for the lack of elevation of interleukin-1 in unstable angina in our study might be that their peak levels were missed. Because interleukin-1 induces interleukin-6, it is possible that interleukin-1 levels were elevated earlier in the course of disease and that by the time of blood drawing their levels had subsided. Also, a good portion of interleukin-1 in the plasma travels bound to large proteins such as interleukin1RA, complements, and β-2-microglobulin.28 As such, this portion might have not been detected by our assay. Another reason could be that certain inflammatory factors are induced selectively whereas others are inhibited in unstable angina. This could point to a complex relation between different inflammatory cells and factors in unstable angina and deserves further investigation. This study also demonstrated that at 1-month followup after percutaneous coronary intervention, there was no longer any significant difference in the levels of interleukin-6 between the 2 groups. Because ruptured plaques become stable after coronary intervention, it is reasonable to postulate that prothrombotic and proinflammatory conditions subside. It has been shown that endothelial integrity returns 4 weeks after PTCA29 as well as after stent placement.30 Therefore attenuation of interleukin-6 levels in unstable angina at 1 month after intervention might reflect plaque stabilization.
In conclusion, interleukin-6, a proinflammatory and prothrombotic cytokine, was significantly elevated in unstable angina compared with stable angina and healthy control subjects. This elevation was no longer present 1 month after percutaneous coronary interventions. This phenomenon may represent attenuation of the inflammatory condition as plaques become stable and quiescent.
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