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Journal of the American College of Cardiology Vol. 44, No. 1, 2004© 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00Published by Elsevier Inc. doi:10.1016/j.jacc.2004.04.002

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DITORIAL COMMENT

he Yin and Yangf Arterial Inflammation*oger Mills, MD, FACC,eepak L. Bhatt, MD, FACCleveland, Ohio

he recent wave of enthusiasm for including inflammations one of the primary pathophysiologic processes in cardio-ascular disease has substantial merit (1). Arterial inflam-ation is central to plaque progression and plaque rupture.mong clinical markers of inflammation, C-reactive protein

CRP), a complex pentameric protein largely of hepaticrigin, is the current gold standard (2,3). In a variety oflinical situations, the elevation of CRP predicts adverseutcomes, including mortality (4,5). Beyond its “biomarker”ole, CRP probably actively participates in atherothrombo-is. For example, CRP opsonization of low-density lipoproteinLDL) cholesterol mediates LDL uptake by macrophages.

See page 44

Although CRP has caught our attention, many otherro-inflammatory factors also indicate patient risk andarticipate in the atherosclerotic process, including interleu-in (IL)-6, tumor necrosis factor (TNF)-alpha, interferonamma, monocyte chemoattractant protein-1, cell adhesionolecules, nuclear factor kappa B, CD 40, lipoprotein-

ssociated phospholipase A2, myeloperoxidase, nitroty-osine, and matrix metalloproteinase-9 (6). The list offfenders grows larger almost weekly.Although inflammation plays an important part in the

athogenesis of atherothrombotic syndromes, not all in-ammatory mediators are evil. Analogous to the thromboticascade, inflammatory pathways have counterbalancing fac-ors to keep the system in check. The inflammatory cascadeaintains a delicate balance of pro- and anti-inflammatoryolecules that regulate homeostatic functioning. Control of

eart rate with a balance of sympathetic and parasympa-hetic tone and regulation of intravascular volume by aalance of salt-retaining and -wasting mechanisms providether examples of a basic biological principal: physiologicalegulation involves a balance of stimulating and repressingorces. Our concepts of arterial inflammation should nowxpand to both sides of the equation. Although the focus ofhis editorial comment is coronary atherosclerosis, the sameatterns of pro- and anti-inflammatory cytokine balance

*Editorials published in the Journal of the American College of Cardiology reflect theiews of the authors and do not necessarily represent the views of JACC or themerican College of Cardiology.From the Department of Cardiovascular Medicine, Cleveland Clinic Foundation,

Bleveland, Ohio.

ccur in congestive heart failure, peripheral arterial disease,nd stroke (7).

Genetic determinants affect levels of high-sensitivityRP as well as other inflammatory moieties (8). Beyond

enetics, environmental factors may influence CRP levels asell as levels of other inflammatory markers and mediators

9). Obesity, in particular abdominal adiposity, is a powerfulodulator of CRP levels. Adipocytes produce IL-6 in

bundance and lead to CRP production by the liver;ubcutaneous fat contains messenger ribonucleic acidmRNA) for CRP as well (10). Exercise and weight lossesult in lower CRP levels (11). Smoking and hormoneeplacement therapy raise CRP levels, whereas light-to-oderate alcohol intake is associated with lower CRP levels.otentially, in patients with periodontitis, antimicrobialeriodontal treatment may lower levels of inflammatoryarkers, including CRP. Statins, niacin, peroxisome

roliferator-activated receptor gamma and alpha agonists,nd antiplatelet therapy are just some of the medicationshat have been shown to lower CRP and diminish itsro-inflammatory effects (12). In the “big picture,” factorshat lower CRP are generally associated with cardiovascularenefit and factors that raise CRP are largely detrimental.long with other potential inflammatory mediators, the

nterplay of these pro- and anti-inflammatory factors mayetermine the state of vascular health (Fig. 1).In this issue of the Journal, Fichtlscherer et al. (13) have

rovided evidence to link pro- and anti-inflammatory mod-lators directly to endothelial function. Using plethysmog-aphy to assess forearm blood flow in patients with coronaryrtery disease, they demonstrated an association betweenmpaired endothelial function and elevated CRP. In addi-ion, their data suggest that higher IL-10 levels preservedndothelial vasodilation in response to acetylcholine, even inhe setting of elevated CRP levels. These findings buildpon a substantial body of prior work suggesting thatlevated IL-10 levels are beneficial in patients with acuteoronary syndromes, particularly in those with elevatedRP levels (6,14,15).Interleukin-1, IL-6, IL-12, and IL-18 are all pro-inflam-atory cytokines, whereas IL-10 is an anti-inflammatory

ytokine (16). Interleukin-10 has several anti-inflammatoryroperties, including the ability to inhibit production ofNF-alpha, IL-8, tissue factor, and matrix metallo-roteinase-9 (17). Low levels of IL-10 are associated with theetabolic syndrome in obese women, although obesity itself

s associated with elevation in CRP, IL-6, and also IL-10.urthermore, various interactions between interleukins andRP may occur. For example, human coronary artery smoothuscle cells are capable of producing CRP and can be

timulated to do so by IL-1-beta, IL-6, and TNF-alpha.articularly relevant to the study by Fichtlscherer et al. (13),uman recombinant CRP induces expression of IL-18 byndothelial cells, an effect inhibited by treatment with IL-10.

lood pressure, in part a reflection of the state of the endo-

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51JACC Vol. 44, No. 1, 2004 Mills and BhattJuly 7, 2004:50–2 Editorial Comment

helium, may also modulate the production of inflammatoryolecules and vice versa. Inflammatory mediators may con-

ribute to blood pressure elevation, but blood pressure elevationlso leads to production of cytokines and cell adhesion mole-ules. In fact, CRP, at clinically relevant concentrations, haseen found to potentiate the effects of angiotensin II byp-regulating the expression of angiotensin receptors on vas-ular smooth muscles. C-reactive protein also has been showno reduce endothelial nitric oxide (NO) synthase expressionnd prostacyclin release in cultured human cells. In particular,RP inhibits basal and stimulated NO release by endothelial

ells, apparently through a posttranscriptional effect on endo-helial NO mRNA stability. The incubation of human saphe-ous vein endothelial cells with CRP decreased endothelialelease of NO and increased endothelin-1 production. BecauseO and prostacyclin are both potent vasodilators and

ndothelin-1 is a powerful vasoconstrictor, their modulation byRP could alter vascular tone. Furthermore, CRP, at least in

he setting of acute coronary syndromes, has been shown toensitize endothelial cells to destruction by cytotoxic CD4� Tells. In addition to these effects on the endothelium, CRPirects the recruitment of monocytes into the intima. Inummary, the connection between inflammation and endothe-ial dysfunction suggested by Fichtlscherer et al. (18) has aogent biological basis.

In the study by Fichtlscherer et al. (13), a large percent-ge of patients were receiving aspirin, beta-blockers,ngiotensin-converting enzyme inhibitors, and statins.

hether the relationship they described between CRP and

igure 1. The balance of pro- and anti-inflammatory mediators mayetermine vascular health or illness. The list of inflammatory molecules, inarticular those that are pro-inflammatory, are rapidly expanding. Some ofhe more prominent ones are listed. ACE-I � angiotensin-convertingnzyme inhibitor; ARB � angiotensin receptor blocker; CRP � C-reactiverotein; IL � interleukin; MCP � monocyte chemoattractant protein;MP � matrix metalloproteinase; NF � nuclear factor; PPAR �

eroxisome proliferator-activated receptor; TNF � tumor necrosis factor.

L-10 would be greater or lesser in a population not a

eceiving such therapy is unknown. Aspirin pretreatmentlunts the effects of inflammation on endothelial dysfunc-ion, and statin therapy may reverse endothelial dysfunctionhrough both lipid-lowering and anti-inflammatory path-ays. Good medical therapy in general has been shown to

ower CRP with a corresponding improvement in endothe-ial function as measured by brachial flow-mediated dila-ion.

Endothelial dysfunction is not irreversible; therapies thatower CRP and presumably decrease vascular inflammationave already been demonstrated to restore endothelialealth. Nevertheless, even with current state of the artedical therapy, there are still patients who display an

ngoing elevation of inflammatory markers and all that ismplied by such markers, including endothelial dysfunction.

The work by Fichtlscherer et al. (13) adds further supporto a strategy of multi-marker testing. On a population level,igh-sensitivity CRP (or any surrogate or pathogenicarker) is useful, but for any given individual the incremen-

al risk conferred by CRP elevation is relatively modest. Theichtlscherer et al. (13) findings may help to explain whyome patients with elevated CRP do not experience adverselinical events; perhaps these individuals have elevatedL-10 or other counterbalancing factors. Adiponectin, aytokine produced by adipose tissue, may be anotherounter-regulatory moiety; adiponectin levels tend to moven a direction opposite to CRP (10). Low levels of adiponec-in also correlate with higher levels of IL-6 and phospho-ipase A2. In the future, point-of-care testing of a panel ofnflammatory markers may help to stratify risk more pre-isely in both inpatient and outpatient settings. However,ubstantial further investigation will be required to sort outhe patterns of inflammatory marker expression that haverue predictive value. Parallel developments in single nucle-tide polymorphism and haplotype analysis are likely toomplement these advances. Sophisticated noninvasive im-ging, such as high-resolution magnetic resonance imaging,ill probably further refine our ability to detect risk and

llow correlation between abnormal levels of markers andrterial pathology. Already, higher levels of soluble CD40igand have been correlated with intra-plaque lipid accumu-ation in carotid atheroma as assessed by high-resolution

agnetic resonance imaging (19). Future studies will un-over additional associations between inflammatory markerevels and in vivo plaque characterization.

Although current efforts have been directed at suppress-ng inflammation and lowering CRP in particular, raisingL-10 might provide logical complementary or perhapsven superior therapy (1), although unopposed anti-nflammatory activity, such as the blockade of TNF-alpha,as not proven beneficial in patients with heart disease (20).erhaps Mother Nature has outwitted us once again, withounter-regulatory factors that negate any benefit of oppos-ng just one particular cytokine. Similarly, human recombi-ant IL-10 has not been particularly effective in rheumatoid

rthritis and has even been shown to produce some pro-

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52 Mills and Bhatt JACC Vol. 44, No. 1, 2004Editorial Comment July 7, 2004:50–2

nflammatory effects resulting from the up-regulation of Fcamma receptor expression on macrophages (21). Ournitial simplistic attempts to alter just one particular elementf the inflammatory cascade are unlikely to have the desiredffect. As our understanding of the regulation of physiologicrocesses deepens, the beauty and complexity of counter-egulatory pathways recalls the ancient Chinese concept ofhe natural balance of Yin and Yang, light and dark, positivend negative, male and female. Ultimately, only a betternderstanding of the Yin and Yang of arterial inflammationill enhance our ability to prognosticate risk and effectivelyesign therapy directed to an individual’s specific riskrofile.

eprint requests and correspondence: Dr. Roger Mills, Cleve-and Clinic Foundation, Department of Cardiovascular Medicine,500 Euclid Avenue, Desk F15, Cleveland, Ohio 44195. E-mail:illsr@ccf.org.

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4. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive proteinand other markers of inflammation in the prediction of cardiovasculardisease in women. N Engl J Med 2000;342:836–43.

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