Surrogate markers for cardiovascular disease: functional markers.

Endothelial Dysfunction The endothelium constitutes the largest organ system in the body. “Endothelial function” refers to a multitude of physiological functions of the vascular endothelium that are achieved via secretion of diverse bioactive substances. This renders the endothelium an active participant in healthy homeostasis of the vascular wall that includes normal vasomotion, inhibition of platelet aggregation and thrombus generation, and maintenance of relative impermeability. Cardiovascular risk factors activate a number of pro-oxidative genes in the vascular wall resulting in generation of reactive oxygen species that ultimately promote endothelial release of transcriptional and growth factors, proinflammatory cytokines, chemoattractant substances, and adhesion molecules.1–3 This complex cascade of events underlies the transition from normal endothelial function to endothelial dysfunction. One of the earliest manifestations of increased vascular oxidant stress is the reduced bioavailability of nitric oxide (NO) as a result of inhibition and uncoupling of endothelial NO synthase, the enzyme responsible for generation of NO, and from rapid catabolism of available NO by reactive oxygen species to peroxynitrite and hydrogen peroxide that can further amplify vascular oxidative stress. The resulting functional consequences include abnormal vasomotor activity, development of a procoagulant endothelial surface, inflammation, and, ultimately, plaque formation. Clinical measurements of endothelium-dependent vasodilation (NO-mediated process) by a variety of different techniques provide a marker of endothelial integrity. Almost all conventional risk factors for atherosclerosis are associated with endothelial dysfunction. These include sedentary lifestyle and obesity, hypercholesterolemia, hypertension, diabetes, insulin resistance, smoking, and aging. The extent of endothelial dysfunction appears to correlate with the traditional risk factor “burden,” thus implying that combined or repeated injury to the vascular endothelium results in greater dysfunction. Nevertheless, there is considerable heterogeneity in the magnitude of dysfunction observed in individuals with similar risk factor profiles.4,5 Novel risk factors such as infections, hyperhomocystinemia, genetic heterogeneity, and the variable duration of exposure to individual risk factors presumably account for some of this observed variability. Moreover, evidence now suggests that endothelial function may be modulated not only by factors causing vascular injury but also by repair mechanisms, potentially mediated via circulating endothelial progenitor cells.6 Thus, the concept has been put forth that endothelial vasodilator function is a reflection of overall vascular health, or a barometer of the injury/repair inflicted by multiple environmental and genetic factors, and, therefore, could potentially serve as a useful diagnostic and prognostic tool in individual patients. It is important to realize that the presence of a similar risk factor profile does not necessarily imply the presence of an equivalent degree of endothelial dysfunction. Thus, the observation that assessment of endothelial function can provide an independent prediction of future cardiovascular risk demonstrates not only the crucial pathophysiologic role of this entity to existing vascular disease but also how the disease is likely to progress with time.