Carrying the cholesterol example further, many clinicians have long believed that screening for hypercholesterolemia is justified. This is because they trusted the previously described causal pathway. Only recently has the clinical trial evidence provided us with POEMs that support cholesterol screening. Initially, POEM evidence confirmed that lowering cholesterol had beneficial effects on cardiovascular disease in those with a history of myocardial infarction.8-9 Later data supported cholesterol lowering in those patients without a previous history of myocardial infarction.10-11 The final link (confirming that screening the entire population is justified) is not complete, but the bulk of POEM evidence in conjunction with the causal pathway supports this hypothesis.
When faced with a lack of POEM evidence in this example, physicians had the choice of waiting for POEMs or acting on the causal pathway that was supported by logic, an understanding of pathophysiology, and DOEs. Most groups, such as the National Cholesterol Educational Program (NCEP) adopted the latter approach, the results of which have since been validated. Other causal pathways, such as those supporting mammography before age 50 years and prostate-specific antigen screening for prostate cancer, are awaiting more DOEs and POEMs to validate the proposed causal pathway links. Until then, subjects of this type are open to intense controversy.
Rationale for mechanisms
Although POEMs are helpful for developing patient care strategies, it is still necessary to understand underlying pathophysiologic and treatment mechanisms. Knowing that a low-fat diet reduces heart disease is important but not as important as knowing how it reduces heart disease. This knowledge is useful in several ways. First, understanding the mechanism facilitates the learning of new concepts. For example, understanding the Frank-Starling principle helps the clinician understand a wide range of physiologic phenomena, from the response of some murmurs to physical examination maneuvers, to predicting a response to a variety of pharmacotherapies. Second, understanding the mechanism allows researchers to develop new treatments (eg, lipid-lowering medications) and helps physicians assess which other treatments are most likely to work. To take an extreme example, we may recognize that diets high in fruits and vegetables are heart-healthy but also know that our patient population prefers fried fast food. Without realizing that one mechanism by which fruits and vegetables improve cardiovascular health is by decreasing fat intake, we may mistakenly urge our patients to consume deep-fried vegetables. Clearly, for both the researcher and the clinician, an understanding of mechanisms is helpful.
Endothelium dysfunction
A Prospective Example. Recent evidence, both POEMs and DOEs, supports the use of ACE inhibitors for the treatment of a variety of cardiovascular diseases.12-17 Why do angiotensin-converting enzyme (ACE) inhibitors work? Is there a common pathway? Would an understanding of the mechanisms change physicians’ understanding of the causal pathway for cardiovascular disease? If so, will that affect treatment? To best address these questions it is important to review endothelial physiology.
Endothelial Physiology and Pathophysiology. The endothelium was once considered a relatively inert barrier that allowed diffusion between the blood and the vascular smooth muscle.18 It is now recognized that the endothelium is the largest internal organ. With more than a trillion cells, it has a mass greater than the liver. In a 70-kg man, the total vascular surface area is equivalent to 6 tennis courts.18,19 More important, the endothelium is recognized as an active organ responsible for a large number of critical functions, some of which are summarized in Table 1.18 The endothelium has numerous endocrine and paracrine functions. For example, it senses hemodynamic forces and hormonal changes around the vasculature and responds by synthesizing and releasing biologically active substances (Figure 2).18 Release of these substances controls or moderates vascular tone, vascular remodeling, hemostasis and thrombosis, and inflammation. (Vascular tone is reviewed in this report. Details of the other actions are reviewed elsewhere.20-23) Recent evidence supports the belief that the endothelium is central to the causal pathway depicted in Figure 3.18 This figure demonstrates how a variety of risk factors other than hypercholesterolemia may interact and how the entire cardiovascular disease spectrum is interrelated.
Perhaps the most critical of the endothelium’s functions is the maintenance of vascular tone. Vascular relaxation and contraction are accomplished through the production of several factors that have an impact on the underlying vascular smooth muscle. Nitric oxide (NO) is an important and potent vasodilator24,25 and an inhibitor of platelet aggregation. It also plays a role in cardiac contractility, endothelial permeability, endothelial-leukocyte interactions, and thrombosis.26 Bradykinin is another vasodilator that works both directly on the smooth muscle and indirectly by stimulating the release of NO.27-29 Because it is also a potent stimulator of tissue plasminogen activator (tPA) secretion, bradykinin has beneficial antithrombotic effects. 25 Several substances stimulate endothelial-dependent vascular contractions. For example, acetylcholine, nicotine, and hypoxia stimulate contraction through the endothelium. The endothelium also regulates the release of the vasoconstricting agents thromboxane A2 and angiotensin II.19,28