Jorge PLUTZKY, MD Cardiovascular Division Brigham and Women's Hospital, Boston, MA, USA

Inflammatory Markers and Coronary Artery Disease

Inflammation is essential to human defense and survival. Indeed, the complex components of the inflammatory process that involve multiple cell types and a dazzling array of proteins protect us against a dangerous world of potentially infectious pathogens. 1 The inflammatory system represents a veritable army of different divisions - T lymphocytes, B lymphocytes, monocytes, macrophages - prepared to recognise an invader, rapidly escalate troop numbers, and launch multiple weapons - cytokines, chemokines, adhesion molecules, enzymes - to fight these outside threats. Failing these responses, a mere splinter or scratch could prove fatal. And yet, despite this protective role, inflammation has recently come under intense scrutiny as a culprit in many common disorders, including atherosclerosis and diabetes mellitus. ^2,3

A dual part for inflammation in physiology and pathology

A dual part for inflammation in both physiology and pathology is not a new concept. Auto-immune diseases like rheumatoid arthritis result from normal inflammatory processes mis-directed against a patient's ownReferences 1.American Heart Association; National Heart, Lung, and Blood Institute; Grundy SM, Cleeman JI, Daniels SR, Donato KA, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev 2005;13:322-27 2.Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III39-43. 3.Hognestad A, Aukrust P, Wergeland R, et al. Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation. Clin Cardiol 2004;4:199-203. 4.Ballantyne CM, Blazing MA, Hunninghake DB, et al. Effect on high-density lipoprotein cholesterol of maximum dose simvastatin and atorvastatin in patients with hypercholesterolemia: results of the Comparative HDL Efficacy and Safety Study (CHESS). Am Heart J 2003:146:862-69. 5.Kamalesh M, Rao R, Sawada S, Friend A, Schellhase E, Evans T. Effect of 80 mg/day simvastatin therapy on cardiovascular outcomes in adults with versus without metabolic syndrome. Am J Cardiol 2006;97:1487-89. antigens - a failure of the army to recognise "self". ⁴

Similar themes arise regarding inflammation in atherosclerosis. ² A key step in atherogenesis is the induction of adhesion molecules on the endothelium, a critical step fostering monocyte entry into the vessel wall. ⁵ Once in the artery, monocytes can differentiate into lipid-laden foam cells. Pro-inflammatory cytokines stimulate medial vascular smooth muscle cells (VSMC) to migrate from the media into the intima where they can also replicate. These VSMC are the source of matrix proteins that make up the fibrous cap separating the circulation from the highly thrombogenic necrotic lipid core of later stage atherosclerotic lesions. Rupture of the fibrous cap underlies most acute myocardial infarctions (MI). ² Plaques vulnerable to rupture are characterised by large necrotic lipid cores, thin fibrous caps, and increased macrophage content. In this context, atherosclerosis can be considered as a healing process, involving inflammation gone awry. Inflammatory cells can be viewed as entering the arterial wall as a response to injury induced by cardiovascular risk factors like cigarette smoke, elevated low-density lipoprotein (LDL) levels, and hyperglycaemia.

Inflammation in atherosclerosis and cardiovascular events

A predictor of cardiovascular outcomes

The science regarding the inflammatory nature of athero-sclerosis is now colliding with clinical medicine through increasing evidence that inflammatory markers can predict future cardiovascular events. This extensive data set has its origins in evidence that Creactive protein (CRP) levels predict outcomes in patients with unstable angina and/or acute myocardial infarction (MI). 6 Importantly, the CRP values used in many of these studies fall within the normal range of an ultra-sensitive CRP assay, consistent with lowgrade inflammation, and not the markedly elevated CRP values seen with severe infection or rheumatoid arthritis. Subsequent studies in many different settings have shown that levels of inflammatory markers like CRP predict future cardiovascular events. 7 For example, increased CRP predicted future cardiovascular events in apparently healthy men and women without a history of prior cardiovascular event. ^8,9

Particularly intriguing are data that CRP levels offer predictive value independently of the total cholesterol:high-density lipoprotein (HDL) ratio. Indeed, a recent work showed that individuals in the Nurses' Health Study who had average LDL levels but higher CRP values still had an increased risk of future cardiovascular events, with risk similar to those with higher LDLs. ¹⁰ This observation frames perhaps the most useful current clinical use of CRP: to identify individuals eligible for risk factor modification who might otherwise have been ignored. This issue is now being prospectively studied in a large randomised study examining placebo versus statin (rosuvastatin) in a cohort of individuals with elevated CRP but whose average LDL levels are low enough to not qualify for statin therapy. ¹¹

Interestingly, CRP has also been found to predict the risk for the future development of diabetes mellitus among an otherwise healthy cohort of women. ¹² Thus, inflammation may be another example of the closely intertwined nature of atherosclerosis and diabetes mellitus.

CRP: simple marker or specific mediator?

The mechanism underlying the association between CRP and cardiovascular events remains obscure. It is tantalising to speculate that CRP is reflecting the cellular inflammatory responses at work in the vessel wall promoting atherosclerosis and plaque rupture. This remains to be proven. Certainly LDL itself is pro-inflammatory, suggesting elevated CRP levels may simply be a consequence of this. More recent studies have considered whether CRP is simply a marker or may play a direct role as a mediator promoting atherosclerosis. ¹³ CRP has been reported to promote leukocyte adhesion, increase LDL uptake and oxidation, and change nitric oxide release, to name a few examples.

Despite these early data for CRP as a specific mediator, many inflammatory markers may predict cardiovascular events. They include serum amyloid A, interleukin 6, tumour necrosis factor-alpha (TNF-a), and circulating levels of adhesion molecules shed from the endothelial surface. ¹⁴ The usefulness of any of these proteins for predicting risk in populations is determined by a number of variables other than just the science, including the ease, reproducibility, cost, and access to the assay for that given predictor. In this regard, CRP also stands out with a straightforward, reproducible, and relatively inexpensive high-sensitivity assay.

Inflammation as a therapeutic target?

Taken together, this burgeoning story for inflammation in atherosclerosis has framed a more direct and clinically relevant question: is inflammation a therapeutic target? In this regard, what treatments lower CRP? Although it remains unclear whether lowering CRP changes cardiovascular outcomes, the extent of the data cited above has increased the interest in testing the impact of various therapies on inflammatory markers. The assumption has been that lowering CRP would be consistent with overall cardiovascular benefit, even if exact mechanisms remain to be defined. Not surprisingly, the largest amount of evidence for CRP reduction exists for the HMG-coA reductase inhibitors (statins). ¹⁵ In several large clinical trials, statin therapy correlated with significant CRP reductions. Moreover, a post-hoc analysis has suggested that patients who lowered their CRP levels with statin therapy were also the ones most likely to enjoy cardiovascular risk reduction. ¹

Fibrate therapy

Other therapies may also modulate inflammation and specifically CRP. One such intervention is fibrate therapy. The VA-HIT (Veteran Affairs HDL Intervention Trial) was a landmark clinical study that demonstrated a fibrate could decrease cardiovascular events in patients with fairly average baseline LDL. 16 fibrates have also been reported to lower CRP. ^17,18 The mechanism of this CRP response is unclear given that fibrates (like gemfibrozil and fenofibrate) also improve key lipid parameters such as HDL and triglycerides. Alternatively, fibrates also have a unique mechanism of action as ligands for the nuclear receptor/transcription factor peroxisome proliferator activated receptoralpha (PPAR-a). ^19,20 Like other steroid hormone nuclear receptors, e.g. thyroid hormone receptor, estrogen receptor, in response to its partner ligand, in this case fibrates, PPARa becomes a transcription factor controlling target gene expression. For example, the expression of apoA1, a key element of HDL, is induced by PPAR-a activation. ²¹ Presumably, this is one way in which fibrates increase HDL levels. ²²

Recently, PPAR expression in vascular and inflammatory cells has been established, with mounting evidence that PPAR-a activation can limit inflammation and atherosclerosis, at least in vitro and in animal models. ²³ The number of PPAR-a regulated target genes with relevance to inflammation and atherosclerosis is continuously expanding, and already includes key genes in endothelial cells (decreased adhesion molecules), macrophages (decreased tissue factor, increased cholesterol transporters), and lymphocytes (decreased cytokines). ²⁰

The clinical implications of PPAR-a activation remain unproven but a scientific basis certainly exists for the clinical benefits of fibrates in the regulation of these target genes involved in inflammation and atherosclerosis. Interestingly, recent data suggests that CRP itself may be repressed by PPAR-a activation. ²⁴

Atherosclerosis seen through a new window: inflammation

Converging lines of evidence from the basic sciences, epidemiology, and even clinical trials have provided a new window into atherosclerosis. Through this window, a new perspective emerges regarding the inflammatory nature of this disease process. From this vista, we can see off in the distance the prospect that markers of inflammation may not only be useful in determining risk, but also in directing therapy. The existing and emerging evidence for drugs like statins and fibrates may help move this prospect of inflammation as a therapeutic target closer to our daily efforts in clinical practice geared towards reducing the overwhelming burden of atherosclerosis. The data are eagerly awaited.

References

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