Editorial: Fire extinguishers. Are there new strategies for controlling the inflammation that ignites atherosclerosis?

Gratifying advances over the last decades have furnished cardiovascular specialists with multiple tools to address many aspects of the traditional risk factor profile. We now have at our disposal effective methods for managing high levels of LDL, controlling blood pressure, and even curbing smoking, which has finally declined in the United States.

Nonetheless, even those who reach guideline-mandated targets for therapies directed against these traditional risk factors face a lingering threat of cardiovascular events. Growing evidence suggests that inflammation contributes to the pathophysiology of atherosclerosis and its complications. Indeed, smoldering inflammation may play a role in this residual risk that affects individuals despite aggressive management of their traditional cardiovascular risk factors. Once we have our patients on a customized 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 trouble?

The use of biomarkers of inflammation to evaluate this inflammatory burden has garnered considerable interest over the last decade. In particular, C-reactive protein (CRP), while controversial in some quarters, has emerged in many studies as an important tool in this regard. Many other biomarkers of inflammation 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).

The use of CRP to analyze inflammatory status in clinical trials of statins has generated intriguing data that suggest that direct anti-inflammatory effects of this class of drugs, beyond their effective LDL-lowering, contribute to their improvement of cardiovascular outcomes. Evidence is accumulating in support of “dual targets” for statin therapy. First, the agent and dose of statin should aim to attain the currently mandated and risk-level appropriate LDL target level. Second, titration of the statin dose to achieve a CRP of less than 2 mg/l may provide further clinical benefit, although current guidelines do not advise this practice.

Practical applications
How can the practitioner approach residual inflammatory burden in patients on optimal traditional medical therapy? First off, we must always incorporate lifestyle modification to achieve an ideal weight and make physical activity part of daily life. Much of the inflammatory burden we encounter in today’s practice not caused by traditional risk factors likely results from excess adiposity, particularly accumulation of intra-abdominal (visceral) fat. While less appealing than a quick pharmaceutical fix, diet and exercise could go a long way toward reducing cardiovascular risk in our contemporary population.

In the pharmacologic arena, we have a number of established anti-inflammatory agents. Why not use them for cardiovascular indications? The corticosteroids, while effective anti-inflammatory agents, also can cause insulin resistance, promote obesity, raise blood pressure, and heighten hypertriglyceridemia, all unfavourable changes that can counterbalance any cardiovascular benefit.

The non-steroidal anti-inflammatory agents (NSAIDs) likewise effectively limit inflammation, but emerging evidence indicates increased cardiovascular risk both with cyclooxygenase-2 selective and nonselective agents. These cardiovascular events may result from a net pro-thrombotic action or subtle but important increases in blood pressure. Low-dose methotrexate, an intriguing possibility as an overall anti-inflammatory treatment for cardiovascular indications, remains untested in this regard. Anti-cytokine therapies, such as strategies that neutralize tumor necrosis factor-α (TNF-α), have exhibited potential adverse effects in patients with congestive heart failure, limiting enthusiasm for their application in cardiovascular risk reduction. Peroxisome proliferation activating receptor (PPAR) agonists display numerous anti-inflammatory actions in pre-clinical work and as revealed by biomarker studies in humans. Yet, PPAR-α agonists have shown mixed cardiovascular benefits in clinical trials, and the results of some studies of PPAR-γ agonists have shown adverse cardiovascular signals.

Strategies in the pipeline
A number of imaginative anti-inflammatory strategies are currently in development. Many programs in development target cytokines or chemokines beyond TNF-α. Some such strategies will undoubtedly undergo clinical evaluation for cardiovascular indications. Endocannabinoid receptor CB1 antagonism reduces inflammation in patients. In contrast, endocannabinoid receptor CB2 stimulation can exert anti-inflammatory actions in mice. The enzyme Lp-PLA2 can generate pro-inflammatory lipids in atherosclerotic plaques. Inhibitors of this enzyme have entered clinical development. Genetic and experimental data have suggested a role for the products of the enzyme 5-lipoxygenase, involved in generating pro-inflammatory leukotrienes, in promoting atherosclerosis and cardiovascular events. Inhibitors of this enzyme and its activating protein (FLAP) likewise have received consideration for cardiovascular indications.

In sum, we have a great deal to learn about assessing inflammation in our patients with or at risk for cardiovascular disease and dealing with inflammation that persists despite optimum current medical therapy. Basic and clinical research in progress may help us extinguish these inflammatory flames in the years to come.