Correspondence
Inflammation, Aspirin, and the Risk of Cardiovascular Disease
N Engl J Med 1997; 337:422-424August 7, 1997
- Article
To the Editor:
Ridker and colleagues (April 3 issue)1 have provided important new information that will be useful in assessing the risk of cardiovascular events and in optimizing prophylaxis. Both Ridker et al. and Maseri, in his editorial,2 speculate that the antiinflammatory effects of aspirin may be important in reducing the risk of myocardial infarction when the level of C-reactive protein is high.
It seems unlikely that the antiinflammatory effects of aspirin have an important role, since these effects are minuscule and short-lived at the dosage used in the study by Ridker et al. (325 mg every other day). Were these effects of aspirin indeed important, higher doses would be expected to confer a greater cardioprotective effect. I am not aware of any controlled study that has demonstrated a greater effect with higher doses.
An alternative possibility is that an elevated level of C-reactive protein is associated with increased coagulability (local or systemic, or both) and that the cardioprotective effects of aspirin are proportional to the magnitude of this increase in coagulability.
2 ReferencesWilliam M. Murray, M.D.
5020 Ritter Rd., Mechanicsburg, PA 170551
Ridker PM ,Cushman M ,Stampfer MJ ,Tracy RP ,Hennekens CH . Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979
Full Text | Web of Science | Medline2
Maseri A . Inflammation, atherosclerosis, and ischemic events -- exploring the hidden side of the moon. N Engl J Med 1997;336:1014-1016
Full Text | Web of Science | Medline
To the Editor:
The report by Ridker et al. adds further support to the response-to-injury hypothesis proposed 20 years ago by Ross et al.1 However, the conclusion that the benefits of aspirin arise, at least in part, from its antiinflammatory activity is difficult to accept. A dose of one aspirin tablet every other day can hardly be considered an antiinflammatory regimen of the drug. The short (15-minute) biologic half-life of aspirin adds to the doubt. The salicylate resulting from the degradation of aspirin is a very weak contributor to its antiinflammatory effects.
It still seems probable that the unique properties of both aspirin and platelets — namely, aspirin's acetylation of the enzyme cyclooxygenase and a platelet's inability to synthesize the new enzyme — are responsible for all the antithrombotic effects observed.
1 ReferencesJohn J. Bruno, Ph.D.
17 Oyster Landing Rd., Hilton Head Island, SC 299281
Ross R ,Glomset J ,Harker L . Response to injury and atherogenesis. Am J Pathol 1977;86:675-684
Web of Science | Medline
To the Editor:
Ridker and colleagues report that in their study the effect of aspirin on the risk of cardiovascular disease was largely confined to patients with elevated C-reactive protein levels and that an elevated level of C-reactive protein was associated with arterial but not venous thrombosis. The authors hypothesize that the benefits of aspirin in this subgroup reflect antiinflammatory rather than antiplatelet effects of this agent. We suggest an alternative hypothesis.
Platelets are inflammatory cells.1 In evolutionary terms, platelets are derived from hemocytes — single circulatory blood cells with the combined functions of participating in the inflammatory response, oxygen carriage, and hemostasis.2 Activated platelets secrete numerous proinflammatory molecules, including thromboxane A 2, which is blocked by aspirin.
The association of platelet activation with the inflammatory process is well documented in inflammatory bowel disease.3 Platelet activation may contribute to the microvascular thrombosis and infarction reported in association with this condition.
With regard to the link between interleukin-6 and C-reactive protein, to which the authors refer, it should be noted that interleukin-6 has a stimulatory effect on megakaryocytes4 and may thus be linked to alterations of platelet function.
For these reasons, we propose that in further work addressing these intriguing observations, researchers should avoid a spurious dichotomy between the thrombotic and inflammatory effects of platelets.
4 ReferencesMary R. Cahill, M.D.
Royal London Hospital, London E1 1BB, United KingdomIvan J. Perry, M.D., Ph.D.
University College, Cork, Ireland1
Page CP . Platelets as inflammatory cells. Immunopharmacology 1989;17:51-59
CrossRef | Web of Science | Medline2
Iwanaga S . Primitive coagulation systems and their message to modern biology. Thromb Haemost 1993;70:48-55
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Collins CE ,Cahill MR ,Newland AC ,Rampton DS . Platelets circulate in an activated state in inflammatory bowel disease. Gastroenterology 1994;106:840-845
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Wong GG ,Witek-Giannotti JS ,Temple PA , et al. Stimulation of murine hemopoietic colony formation by human IL-6. J Immunol 1988;140:3040-3044
Web of Science | Medline
To the Editor:
The study reported by Ridker et al. shows that C-reactive protein, as an acute-phase reactant, predicts the risk of myocardial infarction and stroke. However, this study was mostly concerned with the serum level of C-reactive protein as an inflammatory marker, and there is no mention of its presence in the normal and atherosclerotic arterial wall in humans.1,2 We have previously measured the level of C-reactive protein eluted from the human arterial wall with different degrees of atherosclerosis.1 Fatty streaks and uncomplicated fibrous plaques contained the highest levels of C-reactive protein. Lower levels were found in areas of intimal thickening, and only a few normal areas contained the protein.1,2
The accumulation of C-reactive protein in the atherosclerotic wall suggests a local inflammatory event. It is difficult to establish whether the protein is produced locally or derived from the circulation, but both mechanisms are involved in the accumulation of most of the proteins present in the arterial wall. We found that C-reactive protein was localized around the foam cells of fatty streaks, suggesting its local synthesis.3 For such a strongly responsive and potent acute-phase reactant as C-reactive protein, the small but constant and clinically significant increase in its plasma levels, as Ridker et al. observed in their study, may suggest its slow release from the arterial wall with atherosclerotic lesions.
It is also important to mention that not only C-reactive protein but also other acute-phase reactants, such as complement proteins C3, C4, and C9, as well as important inflammatory cytokines, such as interleukin-6 and interleukin-8, are accumulated in the atherosclerotic wall.1,3,4 The complement system, which is an important immune effector, is present in the arterial wall in its activated form, and this is an important observation, since C-reactive protein is one of its known potent activators.3
Thus, C-reactive protein seems to be directly involved in promoting local inflammation by activating other mediators. Its increased concentration in plasma and clinically predictive role should be correlated and indeed reflect, as shown by Ridker et al., events occurring at the level of the arterial wall, where inflammation is responsible for the progression of the atherosclerotic lesion.
4 ReferencesHorea Rus, M.D., Ph.D.
Florin I. Niculescu, M.D., Ph.D.
University of Maryland School of Medicine, Baltimore, MD 212011
Vlaicu R ,Rus HG ,Niculescu F ,Cristea A . Immunoglobulins and complement components in human aortic atherosclerotic intima. Atherosclerosis 1985;55:35-50
CrossRef | Web of Science | Medline2
Reynolds GD ,Vance RP . C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med 1987;111:265-269
Web of Science | Medline3
Niculescu F ,Rus HG ,Vlaicu R . Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterial tissues with atherosclerosis. Atherosclerosis 1987;65:1-11
CrossRef | Web of Science | Medline4
Rus HG ,Vlaicu R ,Niculescu F . Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996;127:263-271
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Murray raises the intriguing possibility that our observations are attributable to an association between C-reactive protein and hypercoagulability. This hypothesis, however, is not supported by our finding that there was no association between C-reactive protein and venous thrombosis, a disease more closely linked to hypercoagulability than to atherothrombosis.
Dr. Bruno suggests that the antithrombotic effects of aspirin may explain our results and that the apparent increase in the efficacy of aspirin across quartiles of C-reactive protein simply reflects a greater benefit among those at greater risk. In prior reports on aspirin from the Physicians' Health Study, we observed no greater benefits in higher-risk subgroups.1,2
We concur with Drs. Murray and Bruno that the short half-life of aspirin renders a conventional antiinflammatory contribution from this agent less likely. Our data do raise the question of whether this contribution is adequate for microinflammatory inhibition. In this regard, the points made by Drs. Cahill and Perry, that platelets themselves can be considered inflammatory cells and that they secrete proinflammatory molecules, are of considerable interest.
The possibility that aspirin has different effects in different thrombotic settings, such as those associated with plaque rupture as compared with endothelial erosion,3 is supported by the observations of Drs. Rus and Niculescu regarding the presence of C-reactive protein within the atherosclerotic arterial wall.4 Whether this accumulation is more or less apparent in lesions associated with plaque rupture is also an important question to be investigated.
4 ReferencesPaul M. Ridker, M.D.
Charles H. Hennekens, M.D.
Brigham and Women's Hospital, Boston, MA 02215-12041
Steering Committee of the Physicians' Health Study Research Group
Full Text | Web of Science | Medline2
Stampfer MJ ,Sacks FM ,Salvini S ,Willett WC ,Hennekens CH . A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373-381
Full Text | Web of Science | Medline3
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;89:36-44
Web of Science | Medline4
Vlaicu R ,Rus HG ,Niculescu F ,Cristea A . Immunoglobulins and complement components in human aortic atherosclerotic intima. Atherosclerosis 1985;55:35-50
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Murray's timely letter offers me the opportunity to comment further on the progressive reduction of the risk of myocardial infarction with increasing levels of C-reactive protein in patients taking 325 mg of aspirin on alternate days.1 I agree with Dr. Murray that the available evidence is against the hypothesis that aspirin acts as an antiinflammatory drug because of its short plasma half-life and because inflammatory cells can resynthesize cyclooxygenase.
Unpublished data from our group indicate that both in patients with stable angina and in those with unstable angina, the increase in serum C-reactive protein levels in response to diverse inflammatory stimuli is proportional to the base-line levels of C-reactive protein. Thus, the base-line values may be markers of a variable individual propensity for an enhanced acute-phase response. The hyperresponsiveness of acute-phase reactants can result in enhanced production and an enhanced effect of prothrombotic inflammatory cytokines, which under some conditions may contribute to the development of unstable angina, myocardial infarction, and stroke. This hypothesis may link the long-term prognostic value of C-reactive protein levels within the normal range (as observed in the Physicians' Health Study1) and the prognostic value of mildly elevated levels in patients with stable ischemic heart disease2 or unstable angina at the time of hospital discharge3 with the short-term in-hospital prognostic value of markedly elevated levels of C-reactive protein in patients with unstable angina.4 Moreover, my colleagues and I failed to observe significant differences in cytomegalovirus and Helicobacter pylori serum antibody titers between patients with chronic ischemic syndromes and those with acute ischemic syndromes.5 Therefore, the greater effect of aspirin in persons in the higher quartiles of the normal range of C-reactive protein in the Physicians' Health Study1 is not easily explainable. Since the confidence limits for the risk reduction in the four groups may overlap, the differences may simply be due to the fact that the reduction in risk was more easily detectable in the higher-risk group than in the lower-risk group. However, this intriguing finding should be confirmed by other studies before there is extensive discussion about its possible interpretation.
5 ReferencesAttilio Maseri, M.D.
Catholic University of the Sacred Heart, 00168 Rome, Italy1
Ridker PM ,Cushman M ,Stampfer MJ ,Tracy RP ,Hennekens CH . Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979
Full Text | Web of Science | Medline2
Thompson SG ,Kienast J ,Pyke SDM ,Haverkate F ,van de Loo JCW . Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:635-641
Full Text | Web of Science | Medline3
Liuzzo G ,Biasucci LM ,Buffon A , et al. Elevated C-reactive protein at discharge and at three months after waning of symptoms in unstable angina is associated with recurrence of instability during 12 months follow-up. J Am Coll Cardiol1995;250A-251A abstract.
CrossRef4
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 | Medline5
Liuzzo G ,Caligiuri G ,Grillo RL , et al. Helicobacter pylori and cytomegalovirus infections are strongly associated with atherosclerosis, but are not responsible for the instability of angina. J Am Coll Cardiol 1997;29:Suppl A:217A-217A abstract.
CrossRef
- Citing Articles (1)
Citing Articles
1
Henriette Brinks, Amrit Das, Walter J Koch. (2011) A role for GRK2 in myocardial ischemic injury: indicators of a potential future therapy and diagnostic. Future Cardiology 7:4, 547-556
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