American Heart Journal
Volume 141, Issue 6 , Pages 881-883, June 2001

PRINCE’s prospects: Statins, inflammation, and coronary risk☆☆☆

Beirut, Lebanon, and San Francisco, Calif

From the aDivision of Cardiology, Hotel-Dieu de France Hospital and the French School of Medicine of the St-Joseph University, Beirut, Lebanon, and the bSan Francisco General Hospital and the University of California, San Francisco, Calif

Received 5 February 2001; accepted 20 February 2001.

Article Outline

 

See related article on page 893 .

Over the past decade lipid-lowering therapy with statins has emerged as a cornerstone therapy in the treatment of patients with coronary artery disease. The efficacy of these drugs was proved in both primary and secondary prevention trials where mortality and myocardial infarction rates were significantly reduced compared with placebo.1, 2 What remains uncertain, however, is whether the benefit of these drugs is solely due to their cholesterol-lowering properties or if it extends beyond that and involves other pathways, such as the coagulation and inflammation systems. Experimental studies suggest that lipid lowering with statins improves endothelial function, decreases platelet aggregation and platelet interaction with the coagulation system, and inhibits inflammation.3, 4, 5 Vasodilators and antiplatelet and antithrombotic drugs have been studied extensively, particularly in acute coronary syndromes, and are clearly effective. In contrast, inflammation has not been a direct target of therapy.

Perhaps it should be. In a nested case-control analysis from the Physicians’ Health Study,6 higher C-reactive protein (CRP) levels predicted future cardiovascular events in healthy, middle-aged men, and aspirin reduced events more in those with higher rather than lower levels of this inflammatory marker. The benefit of aspirin could have been due to its anti-inflammatory properties. Yet an equally plausible explanation is that aspirin is acting as an antiplatelet agent in the hypercoagulable milieu of heightened inflammation.

CRP and other markers of inflammation are strong predictors of outcome in unstable angina.7, 8 Suppressing inflammation might reasonably be expected to improve outcome. Yet, in a recent randomized clinical trial during the acute phase of unstable angina, SoluMedrol reduced the levels of CRP but not the event rate.9 This dissociation between CRP levels and events could be interpreted as evidence that CRP is a marker more than a causal factor for recurrent coronary events. Clearly, much more needs to be learned about the role of inflammation in all phases of coronary disease. The Pravastatin Inflammation CRP Evaluation (PRINCE) trial, the rationale and design of which are outlined in this issue of the Journal, will investigate the interaction between statins and the inflammatory system in patients with and without hyperlipidemia. PRINCE will hopefully improve our understanding of the mechanism of coronary atherosclerosis and the benefit of lipid-lowering therapy.

Back to Article Outline

Inflammation in unstable coronary syndromes 

Slightly more than half of patients with unstable angina have elevated CRP levels, and these levels are a marker of increased mortality and morbidity during the short- and long-term follow-up.7, 8 Inflammation appears to be a cause and not just a consequence of acute coronary syndromes.10 On a cellular level, leukocytes are activated in unstable angina, both in the systemic circulation and inside the culprit lesion. Neutrophils in patients with acute coronary syndromes spontaneously clump, show increased pseudopodes, and exhibit multiple cytoplasmic vacuoles and evidence of granular extrusion.11 The expression of the CD11b/CD18 receptor on their membrane, a marker of activation, is upgraded. Increased expression of CD11b/CD18 receptors does not occur in other cardiac and noncardiac conditions but appears to be specific to acute coronary syndromes.12 The site of granulocyte and monocyte activation has been localized to the coronary artery, probably at the level of the culprit lesion. Secretion of enzymes and inflammatory mediators by leukocytes is also increased during acute coronary syndromes. Some of these enzymes, such as the metalloproteinases, can directly undermine the integrity of the fibrous cap resulting in plaque fissuring or rupture.13 Metalloproteinases also damage endothelium and basal membranes, leading to endothelial dysfunction.

Back to Article Outline

Inflammation in healthy patients at risk for coronary artery disease 

Recent epidemiologic studies have shown that a heightened inflammatory tone is present in patients at risk for coronary disease years before the onset of the cardiac event. These findings support the concept that inflammation may be a trigger for instability rather than its consequence. In the Physicians’ Health Study, which randomized healthy patients without a history of coronary artery disease to aspirin and beta-carotene, the CRP level at baseline was an independent predictor of an atherothrombotic event during follow-up.6 Similar findings were observed in 28,263 healthy postmenopausal women who were followed up for a mean of 3 years.14 Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than were models based on lipid levels alone. The levels of high sensitivity CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with low-density lipoprotein (LDL) cholesterol levels below 130 mg/dL.

Back to Article Outline

Why is inflammation deleterious? 

A growing body of evidence suggests that inflammation plays a crucial role in the onset and progression of atherosclerosis. Oxidation of LDL cholesterol in the vessel wall represents the first step in a sequence of events leading to monocyte adhesion to endothelial cells with ensuing infiltration of the intima, secretion of proinflammatory cytokines, proliferation of smooth muscle cells, loss of endothelial function, and activation of the clotting system.15 The pathologic features of the atherosclerotic plaque are typical of chronic inflammation.

During an acute coronary event, conversion of the culprit coronary lesion from inactive to active is accompanied by an acute inflammatory response that enhances all the physiopathologic processes that lead to instability: plaque rupture, platelet aggregation, thrombosis, and vasospasm. Inside the culprit lesion, activated macrophages synthesize and secrete different metalloproteinases, which weaken the fibrous cap, leading to its rupture. In patients dying soon after the onset of myocardial infarction, the culprit plaque exhibits a rich inflammatory infiltrate, located predominantly at the site of rupture.16 Macrophages present at that site are highly activated. In contrast, plaques that did not rupture were composed mainly of smooth muscle cells, with a few macrophages showing no signs of activation.

Back to Article Outline

Statins in patients with coronary artery disease 

The mechanism by which statins reduce events has been a subject of debate. When the treatment groups of both primary and secondary prevention trials are compared, the reduction in events is proportional to the reduction in LDL cholesterol levels, across the range of LDL cholesterol levels that have been studied to date. This relationship also holds for trials where cholesterol levels were reduced by other means. Thus LDL cholesterol reduction by itself appears to be a sufficient explanation for the benefits seen in these trials.

On the other hand, statins have been reported to induce a broad range of potentially beneficial effects through widely different mechanisms.17, 18 These “pleiotrophic” effects are carefully defined by some authors to exclude beneficial consequences of LDL cholesterol lowering, such as improvements in endothelial function, for example. Others use the term indiscriminately. Most of the true pleiotrophic effects of statins have only been demonstrated in tissue culture or at high drug concentrations, where the applicability to clinical atherosclerosis is uncertain. In experiments where patients are given statins, it is difficult to disentangle pleiotrophic effects from the consequences of LDL cholesterol lowering.

Back to Article Outline

Do statins have a direct anti-inflammatory effect? 

This debate is relevant to the topic of inflammation because whether the anti-inflammatory effects of statins are mediated through LDL cholesterol lowering or are an independent pleiotrophic effect is controversial and potentially important. The available data are helpful but hardly conclusive. In a subgroup analysis of the Cholesterol and Recurrent Events (CARE) trial, CRP levels were measured on stored serum samples from baseline and at 5 years in 472 patients who did not have an event during the study.5 Among patients receiving placebo, the CRP level increased over 5 years by approximately 20%, whereas these levels decreased in pravastatin-treated patients, also by about 20%. In a preliminary report covering 87% of the 6605 patients in the Air Force/Texas Coronary Prevention Study (AF/TexCAPS) CRP levels predicted coronary events and lovastatin reduced CRP levels by 14.8% in the first year of treatment. In a preliminary report of a randomized crossover design study comprising 19 patients, simvastatin, pravastatin, and atorvastatin in equipotent doses each reduced CRP levels after just 6 weeks of treatment.20

In these studies the reduction in CRP levels did not correlate with the reduction in LDL cholesterol levels. This lack of correlation may constitute evidence that statins have a direct pleiotrophic effect on inflammation. However, it is also possible that a relationship may exist but be obscured by noise. Atherosclerosis and its inflammatory component are driven by many factors (genetic predisposition, risk factors, stage of disease, medications, undiscovered risk modulators) interacting in complex ways, and CRP levels are only a rough measure of inflammatory activity. In any case, it now seems clear that CRP reductions are not seen only with pravastatin, but that this is a class effect of statins.

Some experiments have shed light on the complex relationships among statins, cholesterol levels, favorable effects, and the possible mechanisms involved. For example, lovastatin reduces the surface expression of CD11b on monocytes and thus reduces their adhesiveness to vascular endothelium.21 Coincubation with mevalonate, but not with LDL cholesterol, reverses this effect, suggesting that isoprenoid intermediates but not cholesterol itself are crucial for expression of CD11b. This response is more pronounced when the tests were performed on monocytes isolated from the blood of patients with hypercholesterolemia treated with statins ex vivo.

These results suggest that the two pathways of cholesterol and proinflammatory cytokines biosynthesis are linked. Inhibition of cholesterol biosynthesis is therefore important not only for reducing intracellular cholesterol accumulation but also for inhibiting the formation of cytokines.

Back to Article Outline

What will we learn from PRINCE? 

The primary outcome of PRINCE is the change in CRP after 24 weeks of pravastatin treatment. Because pravastatin significantly reduced CRP levels in 19 patients after 6 weeks of therapy,20 the sample size of up to 4000 individuals in PRINCE seems excessive for this end point. Other features of the trial suggest that it has been influenced by marketing considerations in addition to its scientific rationale. Nevertheless, the information to be gained from PRINCE will broaden our knowledge in a clinically important area.

By one count, 47 clinical trials of statins are completed, underway, or about to begin. These trials are being done for research and marketing reasons and will cost hundreds of millions of dollars. Encouraging their sponsors to incorporate as many important scientific questions into the designs of these studies as possible is a worthy objective. As PRINCE sets off to mingle among the other fancifully named statin trials, we can note with a sense of poetic symmetry that PRINCESS is out there too.

Back to Article Outline

References 

  1. Vaughn CJ, Gotto AM, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol. 2000;35:1–10
  2. Cholesterol and Recurrent Events Trial Investigators . The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009
  3. Treasure CB, Klein L, Weintraub WS, et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487
  4. Lacoste L, Lam JYT, Hung J, et al.  Hyperlipidemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction. Circulation. 1995;92:3172–3177
  5. Ridker PM, Rifai N, Pfeffer MA, et al.  Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999;100:230–235
  6. Ridker PM, Cushman M, Stampfer MJ, et al.  Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979
  7. 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
  8. Biasucci LM, Liuzzo G, Grillo RL, et al.  Elevated levels of C-reactive protein at discharge in patients with unstable angina predicts recurrent instability. Circulation. 1999;99:855–860
  9. Azar RR, Rinfret S, Theroux P, et al.  A randomized placebocontrolled trial to assess the efficacy of anti-inflammatory therapy with methylprednisolone in unstable angina. Eur Heart J. 2000;21:2026–2032
  10. Maseri A. Inflammation, atherosclerosis, and ischemic events—exploring the hidden side of the moon. N Engl J Med. 1997;336:1014–1016
  11. Mehta J, Dinerman J, Mehta P, et al.  Neutrophil function in ischemic heart disease. Circulation. 1989;79:549–556
  12. Mazzone A, DeServi S, Ricevuti G, et al.  Increased expression of neutrophil and moncyte adhesion molecules in unstable coronary artery disease. Circulation. 1993;88:358–363
  13. Kai H, Ikeda H, Yasukawa H, et al.  Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol. 1998;32:368–372
  14. Ridker PM, Hennekens CH, Buring JE, et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843
  15. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126
  16. Van der Wal AC, Becker AE, van der Loos CM, et al.  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
  17. Rosenson RS, Tangney CC. Antiatherosclerotic properties of statins. JAMA. 1998;279:1643–1650
  18. Davignon J, Laaksonen R. Low-density lipoprotein-independent effects of statins. Curr Opin Lipidol. 1999;10:543–559
  19. Ridker PM, Rifai N, Miles JS, et al.  Lovastatin 20-40 mg/day lowers high-sensitivity C-reactive protein levels in AFCAPS/TexCAPS. [abstract] Circulation. 2000;102(2 Suppl):II833
  20. Jialal I, Stein D, Balis D, et al.  Effect of HMG-CoA reductase inhibitors on C-reactive protein levels. [abstract] Circulation. 2000;102(2 Suppl):II833
  21. Weber C, Erl W, Weber KSC, et al.  HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997;30:1212–1217

☆ Reprint requests: Rabih R. Azar, MD, MSc, FACC, Division of Cardiology, Hotel-Dieu de France Hospital, PO Box 16-6830, Achrafieh, Beirut, Lebanon. E-mail: razarmd@hotmail.com

☆☆ Am Heart J 2001;141:881-3.

PII: S0002-8703(01)91750-8

doi:10.1067/mhj.2001.115298

Refers to article:

  • The Pravastatin Inflammation CRP Evaluation (PRINCE): Rationale and design

    Michelle A. Albert, Joan Staggers, Paul Chew, Paul M. Ridker, on behalf of the PRINCE Investigators
    American Heart Journal June 2001 (Vol. 141, Issue 6, Pages 893-898)

American Heart Journal
Volume 141, Issue 6 , Pages 881-883, June 2001

Article Tools