Abstracts & Commentaries
Sources: Dechend R, et al. Circulation. 2003;108:261-265; Sano T, et al. Circulation. 2003;108:282-285.
In the Dechend study, German investigators examined the role of Chlamydia pneumoniae (CP) in the atherosclerotic inflammatory process, based on previous studies indicating that this organism can be cultured from coronary atheromata. This group had previously demonstrated that CP-infected vascular smooth muscle cells (VSMC) can activate various nuclear transcription factors in target genes, leading to enhanced thrombogenicity and cytokine production. They have also shown that statins favorably modify this process. In the present study, they demonstrate that human macrophages infected with CP are able to transmit the infection to VSMC and that processes modulated by the HMG CoA reductase enzyme induce CP-stimulated cellular interactions and activation. Statins were shown to reduce the risk of CP infection of VSMC; reduce the production of IL-6 and PAI-1 expression; and reduce activation of membrane-bound compounds, such as RAC1 and RhoA, all of which could be reversed by mevalonate. Furthermore, NF-kb activation was observed following CP infection and was reduced by statins in a dose-dependent fashion; this was also blocked by mevalonate. Other cellular phenomena, involving RANTES and MCP-1, were activated in infected macrophages and VSMC; this was also decreased by statins. Induction of IL-6 and IL-8 similarly was favorably modulated by statins. Reactive oxygen species were diminished by statins and in infected VSMC, RHO, and RAC prenylation were inhibited by statins.
Dechend and associates believe that monocytes and macrophages may harbor CP in a persistent state not amenable to antibiotic treatment. The infection can be spread through involvement of VSMC, confirming immunomodulatory cross talk between the infected and noninfected cells. They state that "statins may decrease not only the chain of events leading to inflammation and activation in infected VSMC but also their propensity to become infected." Proliferation and secretion of IL-2 and other cytokines within the atherosclerotic plaque was stimulated by CP infection. The atherosclerotic lesion contains inflammatory CD-4 T cells and macrophages; T cells are activated and secrete cytokines. Only human cells were used in this study and the CP strain used was isolated from a human plaque; thus, it would appear that the results are germane to humans. Statins appear to interrupt the vicious cycle stimulated by CP infection and the subsequent activation of inflammatory cytokines and NF-kB.
Comment by Jonathan Abrams, MD
These in vitro data, while somewhat difficult for the uninitiated to follow the intracellular molecular pathways, clearly suggest that CP infection may potentiate activation of atherosclerotic plaques and demonstrate that statins can reduce macrophage-mediated CP signaling and transmission. This presumably represents a nonlipid or pleiotropic benefit of the HMG CoA reductase inhibitors. The study further supports the hypothesis that chronic CP infection can potentiate adverse vascular events by immunomodulation of a variety of phenomena within the plaque. Inflammatory cells, reactive oxygen species, cytokines, and chymokines are all involved in these processes. Thus, CP may not only contribute to inflammation leading to atherothrombosis but may also make the plaque more vulnerable to rupture. Statins in this model were impressively effective in blocking a variety of adverse intracellular pathways. The fact that mevalonate can, in turn, block the effects of statins indicates that products of HMG CoA reductase inhibition other than decreasing cholesterol production occur with statins and are important nonlipid moieties, confirming pleiotropic effects of this drug.
Plaque Rupture
A separate study by Sano and colleagues focusing on plaque rupture using intravascular ultrasound (IVUS) comes from Japan and suggests that C-reactive protein (CRP) activation may contribute to the identification of plaques at high risk for rupture in patients with acute myocardial infarction (AMI). Sano et al performed coronary angiography on 90 consecutive ST elevation AMI within 6 hours of symptoms. Subjects were divided into a normal and elevated CRP group (> 3 mg/dL). There were no clinical features differentiating the 2 groups, which consisted of 43 and 47 patients, respectively. Serum markers and angiographic findings were identical. However, the high CRP group was associated with a higher rate of plaque rupture, with fissuring and dissection in 56% of the entire group; this phenonoma was more frequent in the elevated CRP cohort (58% vs 34%; P = .03). After multivariate logistic regression adjustment, "the presence of ruptured plaque alone correlated with elevated serum CRP." Sano et al point out that CRP may be synthesized following the acute stimulus of myocardial necrosis. The elevated CRP in such patients is speculated to reflect the status of the coronary lesion just before rupture as opposed to reflecting myocardial necrosis. Furthermore, Sano et al suggest that high CRP reflects the activity of activated macrophages, which are capable of degradation of extracellular matrix and secretion of proteolytic enzymes predisposing to plaque rupture. CRP has been associated with "active" angina, and it has been suggested that high CRP may predict the future risk of AMI. Recent data suggest that CRP may be a player, not just a marker, in promoting vascular inflammation and plaque destruction. In normal CRP patients, 44% had nonrupture lesions, and many were due to plaque erosion; such lesions may have a less robust inflammatory response. Sano et al conclude that these data should be taken into account when performing percutaneous coronary interventions (PCI), as prior studies have indicated that CRP is a marker for adverse outcomes in this setting, possibly associated with the no reflow phenomenon or acute occlusion after angioplasty. Sano et al have described a lipid pool-like image on IVUS that is common in the plaque rupture group, which may be a marker for less-than-optimal PCI results.
Comment by Jonathan Abrams, MD
The use of CRP measurements in acute coronary syndromes (ACS) or acute ST elevation AMI (STEMI) has not reached the clinical arena as yet, nor should it. Nevertheless, there are increasing data that this inflammatory marker, if elevated, is a predictor of adverse outcomes and, as this study suggests, may have some correlation with plaque rupture. There was a 70% incidence of rupture in the 43 high CRP individuals compared to 34% in the normal CRP individuals. As Sano et al point out, there may be some false negatives through the use of IVUS, but, nevertheless, the data are intriguing, particularly the increased presence of the lipid pool-like image on IVUS that occurred in half of the high CRP patients and only 30% of the normal CRP group. It must be kept in mind that these patients all had ST elevation MI, and the data may not be predictive of elevated CRP in individuals with ACS or a non-STEMI. It is likely that CRP levels will become part of the routine AMI and ACS lab package in the near future, although at the present time there are no definite interventions that can be recommended over and above the present pharmacological cocktails for these patients. The interested reader is referred to an editorial in the same issue of Circulation titled, "The Future of Biomarkers In Acute Coronary Syndromes. Moving Towards a Multi-Marker Strategy," by Morrow and Braunwald, which impressively lays out the case that future practice is likely to include routine measurements of a number of biomarkers, including creatinine clearance, BNP or NT-proBNP, high sensitivity CRP, CD40, ligand, and troponin.1 It seems that a "heart attack" is no longer a simple event!
Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.
Reference
1. Marrow DA, Braunwald E. Circulation. 2003;108:250-252.
In the Dechend study, German investigators examined the role of Chlamydia pneumoniae in the atherosclerotic inflammatory process, based on previous studies indicating that this organism can be cultured from coronary atheromata.
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