Atherosclerosis is a complex process and a major contributor to morbidity and mortality in much of the world. Endothelial cells play a critical role in blood vessel homeostasis by modulating the release of vasoactive substances, and disruption or dysfunction of this monolayer of cells initiates abnormal vascular function and accelerates the atherosclerotic process. Endothelial dysfunction may be evident in healthy subjects with cardiovascular risk factors and is also present in patients with advanced atherosclerosis. Emerging data suggest that the presence of endothelial dysfunction in the coronary or peripheral vasculature portends a worse prognosis, even in patients without overt atherosclerosis.1 Although injury to the endothelium is a key development in the atherosclerotic process, the cycle may be abated or potentially reversed by lifestyle or pharmacologic methods. Endogenous endothelial progenitor cells may also play a role in repairing damaged endothelium.

Physiologic and anatomic tests for subclinical atherosclerosis are available, but these techniques have largely been used in research arenas.2 Coronary artery endothelial function testing is an invasive tool that focuses on the vascular bed of most clinical importance and interest. The arterial response after administration of acetylcholine is monitored by changes in vessel size, blood flow, and vascular resistance. Endothelial dysfunction is defined as a relative lack of vasodilation or, in some cases, paradoxical vasoconstriction. Damage to the endothelium occurs throughout the vascular tree; thus, the peripheral circulation is often adequate for testing vascular function and allows for the evaluation of large populations, often with a noninvasive tool. The commonly used technique of brachial artery ultrasound uses sonographic visualization of the brachial artery before and during reactive hyperemia to determine flow-mediated dilation (FMD). Although fairly simple to perform, this technique has quality-control and reproducibility issues, which limit its universal applicability. Newer methods for the bedside evaluation of endothelial function are presently being developed.3 Clinical testing of endothelial function allows one to determine the impact of cardiovascular risk and disease and, in the future, might be a tool used to more clearly monitor and deliver treatment.

Subclinical atherosclerosis may also be detected noninvasively by measuring the intima media thickness (IMT) of the carotid artery. Intima media thickness detected by ultrasonography is independently associated with an increased risk of cardiovascular disease, and this technique is increasingly being used as a surrogate end point in interventional trials lasting at least 1 year.4 It remains unclear, however, how much additional information beyond that afforded by traditional risk factors is gained by adding IMT to risk assessment. The determination of atherosclerotic plaque of the carotid artery is related to total plaque burden and is a different measurement from IMT. There is debate as to which marker in the carotid artery is best to focus on.

The institution of lifestyle alterations and medications that are linked to improved cardiovascular outcomes are often of the same things that impact on the development of atherosclerosis. For example, cholesterol-altering therapies have, for the most part, been shown to be effective in improving FMD and IMT and have also proven to be beneficial in large clinical end-point trials.5 Lifestyle changes are often more difficult to quantify, but may lead to equally dramatic and rapid changes in surrogate markers and outcomes. Eating a single high-fat meal or smoking a cigarette has been shown to have immediate effects on vascular function,6 and large-scale studies support the cardioprotective behaviors of a heart-healthy diet and smoking cessation. Although surrogate markers such as FMD and IMT are useful windows into the pathogenesis of atherosclerosis, vascular structure and function are dynamic and complicated processes; thus, short-term benefits to the endothelium do not always equate to long-term improvements in outcomes.

Exercise training has been associated with improvements in cardiovascular morbidity and mortality and is an essential component of primary and secondary prevention of cardiac events. The positive effects of exercise training may be directly linked to improved endothelium-dependent vasodilation of conduit coronary arteries, likely by increased expression of endothelial nitric oxide synthase.7 Exercise training has been shown to improve coronary endothelium-dependent vasodilation in patients with coronary artery disease. Endothelial function correlates with exercise capacity, and improvements in endothelial function are associated with improved exercise tolerance. Our group has demonstrated that peripheral vascular endothelial function correlates with exercise time, even in the absence of coronary artery ischemia.8 Interestingly, some of the same therapies that target an improvement in endothelial function also have beneficial effects on exercise capacity. One such intervention is statin therapy, as evidenced by a recent study showing that high-dose atorvastatin improved exercise walk time in patients with peripheral vascular disease, thus serving as an example of the interaction between vascular endothelial function and exercise capacity.9

In this issue, Chan and colleagues10 examine the role of diet and exercise training in improving endothelial function and atherosclerosis in the setting of present-day advanced pharmacotherapeutics. The authors incorporated noninvasive methods, notably physiologic testing with brachial artery ultrasound for FMD, of assessing the vasculature, anatomic measurements of carotid IMT, and plaque burden, as well as various biochemical assays known to relate to cardiovascular risk. The study followed 156 middle-aged patients with coronary artery disease enrolled into an intense program, including lifestyle and pharmacotherapeutic attention, for 2 years. As expected, there was a progressive, significant improvement in lipid levels over the study period. There was a substantial increase in the use of statin therapy to help achieve the goal lipid levels, whereas use of other medications remained relatively stable during the study. The number of metabolic equivalents during stress testing improved as well. Interestingly, however, although the patients enjoyed a decrease in body weight, waist circumference, and energy counts within the first year, some of the improvement had been lost by the second year, suggesting difficulty in maintaining good lifestyle habits. There was a nonsignificant worsening in FMD and IMT during the 2-year follow-up, and substantial increases in plaque size and area were noted. Logistic regression analysis indicated that increases in dietary fiber, decreases in homocysteine levels, and body fat/weight equated to improved markers of endothelial function and carotid plaque. Thus, the authors suggest that the association between a higher-energy diet and better FMD was related to higher fiber intake and more exercise.

This manuscript highlights the complex interplay among diet, lifestyle, and pharmacotherapy in patients with atherosclerosis. It also exposes variations in the surrogate markers commonly used in the evaluation of cardiovascular risk. Although the overall trends of endothelial function and IMT worsened over time, specific items, such as fiber, homocysteine levels, and body weight, positively influenced these indices. It is also interesting to note that although intensive medical and lifestyle therapies were used in the study population, carotid plaque increased, thereby suggesting progression of disease despite seemingly appropriate therapy. The study does not have a control group; thus, it is unclear whether the intervention attenuated the progression of atherosclerosis at all. It is also difficult to tease out the different effects that lifestyle compared with pharmacologic interventions have on specific markers of atherosclerosis. The impact of inflammation was also not evaluated in this study.

The tenets of cardiovascular prevention are to slow down progression and potentially regress or reverse atherosclerosis. However, despite advanced cardiovascular pharmacotherapeutics and targeted adjustments in lifestyle, such as weight control, exercise, and smoking cessation, coronary and peripheral arterial diseases remain significant public health concerns. As demonstrated in Chan and colleagues' study, intense focus on lifestyle and medications does not necessarily point toward beneficial changes in subclinical atherosclerosis. Rather, data such as these are helpful in teasing out possible mechanisms or in defining individual factors that might have a role in altering the management of patients with this burdensome disease. Thus, despite recent substantial improvements in morbidity and mortality associated with heart and vascular disease, present-day lifestyle alterations and pharmacotherapy are certainly "worth it" but are by no means a solution toward the goal of eliminating atherosclerosis.

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