American Heart Journal
Volume 147, Issue 6 , Pages 945-947, June 2004

Inflammation and restenosis: is there a link?

  • Deepak L Bhatt, MD

      Affiliations

    • Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
    • Corresponding Author InformationReprint requests: Deepak L. Bhatt MD, FACC, FSCAI, FESC, Director, Interventional Cardiovascular Fellowship, Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Desk F25, 9500 Euclid Ave, Cleveland, OH 44195, USA.

Article Outline

 

See related article on page 1071.

The deleterious role of arterial inflammation as a pathological mechanism in atherothrombotic disease is now incontrovertible.1 Measurement of plasma markers of inflammation has been established to enhance risk prognostication above that obtained using clinical variables alone. In particular, high sensitivity C-reactive protein (hs-CRP) has been validated as a reliable, reproducible, and inexpensive marker of inflammation.2 The ability of hs-CRP to delineate risk in patients undergoing percutaneous coronary intervention (PCI) is beyond that afforded by clinical or angiographic factors.3 The value of inflammatory markers has been most striking in unstable patients, but has also been demonstrated in stable ischemic syndromes.4, 5 Interestingly, the most robust association of outcomes and inflammatory markers, including hs-CRP, has been with mortality and, to a lesser extent, myocardial infarction.6 The relationship with target vessel revascularization, however, has been much less lucid.

The paper by Gomma et al in this issue of the Journal highlights that the data regarding the ability of hs-CRP to predict restenosis have been mixed. In this well-done study, 133 patients underwent elective stenting and subsequent 6-month quantitative coronary angiography. There was no correlation between CRP (or interleukin-6 or serum amyloid A) and restenosis. This finding is in contrast to several reports that have found a relationship between inflammatory markers and restenosis, with some analyses finding that preprocedural CRP is a strong predictor.7, 8 More contemporary studies of both stable and unstable coronary artery disease patients undergoing PCI have not demonstrated a consistent link between preprocedural measurements of inflammatory markers and restenosis.9, 10 Perhaps this is due in part to the greater prevalence of statin use in patients undergoing PCI currently. Statins have been shown to reduce levels of inflammatory markers, most notably hs-CRP. In patients being treated with statins, the predictive capabilities of hs-CRP are somewhat diminished.11, 12 The fact that such a high percentage of patients in the study by Gomma et al utilized statins is a testament to the fact that cardiologists in general, and interventionalists in particular, have acknowledged the importance of statins and their complementarity to revascularization—quite a marked departure from the abysmal rates of statin utilization observed in PCI studies in the 1990s.13 Another potential confounder in reported associations between inflammation and restenosis is that patients with unstable coronary syndromes are more likely to have elevated markers of inflammation; unstable angina and acute myocardial infarction are known clinical risk factors for restenosis. There are data supporting the role of CRP in predicting restenosis even in stable coronary artery disease, but the relationship is less robust.

Another critical factor in evaluating the literature about inflammation and restenosis has to do with the timing of measurement. Postprocedural CRP, in particular 48 to 72 hours after PCI, has been shown to correlate more closely with restenosis than preprocedural CRP. In fact, CRP levels at 48 hours have been associated with restenosis after carotid stenting as well.14 Furthermore, other inflammatory mediators, such as monocyte chemoattractant protein-1 also appear to predict restenosis when measured after, but not necessarily before, PCI.15 However, it is often impractical to obtain any blood test on stable patients 2 to 3 days after PCI, as they would have been discharged after an uncomplicated PCI in most parts of the world. However, when such a delayed postprocedural level is obtained, it may be particularly relevant to patient management. The Immunosuppressive Therapy for the Prevention of Restenosis after Coronary Artery Stent Implantation (IMPRESS) trial randomized patients with elevated levels of CRP (>5mg/L) measured 72 hours after PCI to receive either oral prednisone or placebo and found a significant reduction in restenosis rates and late loss in those who received steroid therapy.16

The relationship between inflammation and restenosis is complex. For example, the presence of CRP in plaque does appear to be associated with restenosis, and CRP is more likely found in patients with unstable versus stable coronary syndromes.17 Further adding to the confusion, it appears that an increased serum level of CRP is associated with progression of disease at areas remote from the initial stented lesion, though not necessarily to in-stent restenosis per se.18 Thus, studies that examine a relationship between inflammatory markers and need for any repeat revascularization (as opposed to target lesion revascularization specifically) may overestimate the relationship between inflammatory markers and restenosis. In the future, the strength of any connection between inflammatory markers and restenosis may be dwarfed once evaluations of single nucleotide polymorphisms and haplotypes of genes controlling inflammatory processes becomes commonplace.19

With the dawn of the drug-eluting stent era, the value of all clinical or serum parameters that had previously been associated with restenosis will need to be reevaluated.20 While an economically attractive idea, preprocedural CRP-based allocation of patients to receive a drug-eluting stent would be inappropriate. Although postprocedural CRP levels drawn 48 to 72 hours afterwards may be useful to predict restenosis, the information would be unavailable at the actual time of potential drug-eluting stent implantation. However, if oral compounds are validated in randomized clinical trials as a means to lower restenosis to levels seen with drug-eluting stents, perhaps such therapies could be initiated at the time of stent implantation and discontinued in those with low 72-hour CRP levels; this strategy could greatly enhance the cost-effectiveness of oral antirestenosis compounds that are currently being evaluated.21 Of course, this type of strategy would need to be tested prospectively before being implemented.

Importantly, revascularization itself appears to raise levels of inflammatory markers, as noted in the study by Gomma et al.22, 23, 24 Thus, performance of PCI is somewhat analogous to de novo plaque rupture inasmuch as both induce a proinflammatory state (Figure 1). However, this comparison should not be misinterpreted to mean that PCI is contraindicated in states of heightened inflammation, such as acute coronary syndromes. In contradistinction, the greatest benefit of PCI is likely in those patients with elevated levels of inflammatory markers.6, 25 However, results of PCI may be further improved with concomitant use of already indicated agents that also have anti-inflammatory properties. For example, glycoprotein IIb/IIIa inhibitors such as abciximab have been found to blunt the rise of CRP that otherwise occurs in association with PCI.24 Agents such as clopidogrel and peroxisome proliferator-activated receptor-γ agonists also appear to have anti-inflammatory activity which might be particularly relevant to patients undergoing PCI.1, 26, 27 In the future, drugs designed to have specific anti-inflammatory action may be useful adjuncts to PCI, by suppressing the inflammatory cascade PCI initiates.28, 29, 30

  • View full-size image.
  • Figure 1. 

    Cycle of arterial inflammation. Plaques, particularly unstable ones, produce inflammatory mediators, especially upon rupture. Such rupture may be clinically silent or overt, or may be induced by PCI in a similar fashion. The subsequent release of inflammatory mediators may promote adverse clinical events. Medical and device-based strategies may be useful to help suppress this inflammatory response and thereby break the cycle of inflammation that leads to further plaque activity. PCI, percutaneous coronary intervention; EPD, emboli protection devices; GP IIb/IIIa, glycoprotein IIb/IIIa inhibitors; DES, drug-eluting stents; −, Decreases.

Additionally, the occurrence of embolization, in particular in thrombus-laden lesions such as during PCI of acute myocardial infarction, probably contributes to the cycle of inflammation and inflammatory marker release.31 Interestingly, increased levels of baseline inflammatory markers appear to predict the occurrence of embolization in the setting of percutaneous intervention.32 Emboli protection devices will likely be beneficial in this regard, certainly in high-risk lesions, but perhaps eventually in routine intervention, and may substantially decrease the proinflammatory nature of PCI.

Importantly, the most critical role of inflammatory markers lies in their ability to predict recurrent ischemic events and particularly mortality, rather than restenosis.33 As in other clinical scenarios, hs-CRP has been shown to predict death during follow-up after percutaneous coronary intervention.11 Hence, measurement of hs-CRP is useful in risk stratification of PCI patients, and hs-CRP will likely soon be complemented by an array of inflammatory markers, enabling point of care testing and enhanced risk stratification, serving as a prelude to measurements of individual patient genomic profiles and personalized medicine.

Thus, while the link between inflammation and restenosis may be debatable, the more important link lies with inflammation and atherothrombotic disease progression, myocardial infarction, and death. Therefore, a strategy of long-term secondary preventive measures, including lifestyle modification and pharmacotherapy to target ongoing arterial inflammation, is quite complementary to an interventional approach, incorporating strategies such as drug-eluting stents and emboli protection devices, to treat arterial disease.34 Such a multipronged attack will be necessary to break the tight link between arterial inflammation and adverse clinical events.

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References 

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PII: S0002-8703(04)00022-5

doi:10.1016/j.ahj.2003.12.027

American Heart Journal
Volume 147, Issue 6 , Pages 945-947, June 2004

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