Inflammation in Systemic Vascular Disease: What Can We Learn?

Abundant research over the past decade has implicated inflammation in several facets of systemic vascular disease. Initially, these data focused on early atherogenesis as well as the conversion of stable to unstable vascular lesions (ie, atherosclerotic plaque rupture). It is now clear that inflammation plays a major role in the risk of myocardial infarction and stroke. It also plays a role in the prognosis of patients with heart failure. The clinical expression of these observations has been the adoption of high sensitivity C-reactive protein (hsCRP) as a clinical marker for the risk of cardiovascular disease.12

CRP is a circulating pentraxin important in innate immunity and can be measured in the plasma as a marker of inflammation. CRP is made in the liver as an acute phase response protein but is also made in diseased vascular smooth muscle cells, particularly in atherosclerotic vessels. Thus, CRP may not only serve as a marker for cardiovascular disease risk but also suggests the important role of inflammation in vascular disease. This relationship between inflammation and vascular disease also helps to explain why patients with divergent diseases including systemic inflammatory diseases (ie, systemic lupus erythematosus), arthritis, and periodontal disease have higher risk of cardiovascular disease. This also highlights that inflammation from a variety of causes may lead to vascular disease. 12

HsCRP levels < 1, 1 to 3, and > 3 mg/L have repeatedly been shown to add independent prognostic information on the risk of myocardial infarction, stroke, and cardiovascular death. At all levels of low-density lipoprotein cholesterol (LDL-C), increased hsCRP levels are associated with increased risk. Similar results are present in patients with the metabolic syndrome. The addition of hsCRP to global risk prediction algorithms for cardiovascular disease such as the Framingham Risk Score also assists in identifying patients with highest risk. While these levels are grouped into low, moderate, and high risk based on the above levels, indeed the highest levels confer the highest risk.23

From a population perspective, the proportion of vascular disease attributable to inflammation appears to be as large as that attributable to elevated cholesterol. This observation has had importance for drug development and many novel anti-inflammatory compounds are now being evaluated as potential methods to inhibit atherosclerotic progression.1–3

These inflammatory processes, however, extend beyond the coronary and cerebral circulations and appear to have an impact on all portions of the systemic vasculature. With regard to peripheral arterial disease, for example, elevated levels of several cytokines and hsCRP appear to be of similar importance as smoking for disease development and progression. Recent data have also implicated inflammation as a crucial process in vascular hypertension, and certain antihypertensive agents appear to preferentially impact upon this process.12

To date, the greatest clinical impact of the inflammatory hypothesis of atherosclerosis has been an improved understanding and utilization of statin therapy. Statins lower CRP levels in addition to lowering LDL-C, and data from both primary and secondary prevention trials indicate that the benefit of statin therapy is greater among those with high CRP levels. Further, in the setting of acute ischemia, achieving very low levels of LDL-C (< 70 mg/dL) and low levels of hsCRP (< 2 mg/L) has proven to be important for clinical outcomes. Thus, data now support the concept of “dual targeting,” such that monitoring inflammation as well as cholesterol is recognized as an important method to improve long-term patient outcomes. Currently, trials are under way that target persons with LDL less than 130 but CRP greater than 2, subjects who would not ordinarily qualify for statin therapy, in a primary cardiovascular disease prevention strategy.34

Preliminary reports suggest that CRP is elevated in patients with pulmonary hypertension and a large prospective study is currently under way to define this relationship further. Several lines of evidence suggest the importance of inflammation in the pathogenesis of pulmonary arterial hypertension and improved understanding of inflammation is likely to be of importance in understanding the pathogenesis of pulmonary hypertension, especially since many disorders associated with pulmonary hypertension are associated with several inflammatory pathways.5–7