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Quenching the flames of atherosclerosis
Emerging innovative strategies to curb inflammation.
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Cardiovascular specialists derive considerable satisfaction from our increasing ability to address many aspects of the traditional risk factor profile over the last decades.
We have multiple tools for managing high levels of LDL. We possess a multiplicity of increasingly effective agents for controlling BP. Smoking rates have declined in the United States, and pharmacologic and behavioral adjuncts to control this formerly prevalent risk factor have become available. We seem to have plumbed the depths of antiplatelet and anticoagulant strategies. While the antiplatelet agents currently available have some limitations, we can generally target thrombotic pathways until bleeding complications supervene. Thus, we currently possess effective tools for many of our traditional risk factors.
Nonetheless, we face a residual burden of cardiovascular events even in those who have achieved guideline-mandated target levels of therapies directed against these traditional risk factors.
A growing body of evidence suggests that inflammation contributes to the pathophysiology of atherosclerosis and its complications. Indeed, smoldering inflammation may contribute to the residual burden of risk in individuals optimally managed for their traditional cardiovascular risk factors. Once we have our patients on an appropriately tailored contemporary cocktail of lifestyle and pharmacologic interventions that target their traditional panel of risk factors, how can we assess and address inflammation that may remain to incite further cardiovascular mischief?
The use of biomarkers of inflammation to measure this inflammatory burden has garnered considerable interest over the last decade. In particular, CRP, while controversial, has emerged in many studies as an important tool in this regard. Many other biomarkers of inflammation exist and provide a fruitful field for further research. Some of the emerging biomarkers of inflammation that have captured the most interest include myeloperoxidase and lipoprotein-associated phospholipase A2 (Lp-PLA2).
Practical applications
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How can the practitioner approach residual inflammatory burden in patients on optimal traditional medical therapy? First off, we must never forget lifestyle modification to achieve an ideal weight, and incorporation of physical activity into daily life. Much of the inflammatory burden we encounter in today’s practice not engendered by traditional risk factors likely results from excess adiposity, particularly accumulation of visceral fat. While less appealing than a quick pharmaceutical fix, diet and exercise could go a long way towards reducing cardiovascular risk in our contemporary population.
In the pharmacologic arena we have a number of well-established anti-inflammatory agents. Why not use them for cardiovascular indications? The corticosteroids, while effective anti-inflammatory agents, have major undesired metabolic effects that might mitigate any cardiovascular benefit. The corticosteroids lower insulin sensitivity, promote obesity, raise BP, and cause dyslipidemia.
The NSAIDs likewise effectively limit inflammation. However, signals of increased cardiovascular risk both with cyclooxygenase-2 selective and nonselective agents have emerged. These cardiovascular events may result from a net pro-thrombotic action or subtle but important increases in BP due to NSAID therapy. Disease-modifying agents have proven useful in rheumatoid arthritis and other inflammatory diseases. Low-dose methotrexate remains an intriguing possibility as an overall anti-inflammatory treatment for cardiovascular indications but remains untested in this regard. Anti-cytokine therapies such as strategies that neutralize tumor necrosis factor alpha (TNF-) have exhibited untoward effects in patients with congestive HF, limiting enthusiasm for their application in cardiovascular risk reduction.
A number of imaginative anti-inflammatory strategies are currently in development. Early biomarker studies of an inhibitor of Lp-PLA2 (darapladib, GlaxoSmithKline) were recently presented at the European Society of Cardiology Congress 2008. Genetic and experimental data have pointed to a role of the products of the enzyme 5 lipoxygenase, involved in generating pro-inflammatory leukotrienes, in promoting atherosclerosis and cardiovascular events. VIA Pharmaceuticals is developing an inhibitor of this enzyme for cardiovascular indications. Naturally occurring anti-inflammatory agents such as the serine proteinase inhibitor Serp-1 have shown intriguing beneficial effects on experimental atherosclerosis and are currently undergoing clinical evaluation. As Serp-1 appears to inhibit endogenous fibrinolytic enzymes, its anti-inflammatory efficacy must outweigh any interference with our endogenous fibrinolytic mechanisms.
In sum, we have a great deal to learn about how to assess inflammation in our patients with or at risk for CVD, and what to do about inflammation that persists despite optimum current medical therapy. Basic and clinical research in progress may help us over this hurdle in the years to come.
Peter Libby, MD, is Chief of Cardiovascular Medicine at Brigham and Women’s Hospital, Cardiovascular Division. He is also Co-section Editor of the Vascular Medicine/Intervention section of the Cardiology Today Editorial Board.