ACEs occurs in both a circulating and a tissue form (ie, endothelial tissue ACE). Interestingly, ACEs affect both sides of the endothelial balance by stimulating the production of angiotensin II (a vasoconstrictor) and reducing bradykinin (a vasodilator) by converting it to an inactive substance. Thus, ACEs have a significant impact on the vasculature, summarized in Table 2.18 In a state of endothelial dysfunction, an imbalance of vasoactive regulators results in higher levels of ACEs (which promote vasoconstriction, vascular remodeling, coagulation, and inflammation) and inhibits bradykinin and the release of NO (which promotes vasodilation, inhibits vascular remodeling, stimulates the release of tPA, and reduces inflammation).
Establishing the Significance of the Causal Pathway. This biochemical picture produces a nice snapshot that may have clinical relevance, but the central question for the family physician is still: So what? All of the basic scientific research and the DOEs that produce the evidence in this section offer little consolation to the clinician. Theory is nice; outcomes are critical.
Evidence of clinical relevance may be found in the fact that several factors are associated with endothelial dysfunction, which establishes an important link between endothelial function and disease. These factors include atherosclerosis, heart failure, hypertension, hypercholesterolemia, cigarette smoking, insulin resistance/diabetes mellitus, withdrawal of estrogen, and homocysteine. Thus, many major cardiovascular risk factors are associated with endothelial dysfunction (Figure 3).18 Because the endothelium regulates vasodilation, inhibition of vascular smooth muscle growth, inflammation, and antithrombotic factors, endothelial dysfunction is associated with vasoconstriction, vascular smooth muscle growth, inflammation, and thrombosis.
Fortunately, there are a large number of studies supporting this research.30 Several recent clinical studies support the model represented in Figure 3.18 Some of these are POEMs, but the majority are DOEs.
CLINICAL REVIEWS DOEs
Associations are important observations, but they do not demonstrate causation. Further evidence supporting the endothelial-cardiovascular link is found in DOEs. For example, diet and lifestyle changes, such as physical exercise and smoking cessation, have been shown to improve endothelial function. The administration of antioxidants, lipid-lowering agents, estrogens (in women), calcium antagonists, and ACE inhibitors have also been shown to improve endothelial function. ACE inhibitors are especially interesting, because they offer a pharmacologic approach that can be used in conjunction with lifestyle changes.
A large number of DOEs are underway or have recently been completed that evaluate the clinical implications of the described biochemistry. For example, the Trial on Reversing Endothelial Dysfunction17 evaluated the response of endothelium-dependent vasodilation to the ACE inhibitor quinapril. This study confirmed the hypothesis that ACE inhibitors improve endothelial function in patients with documented endothelial dysfunction. Other studies, soon be completed, will add to the body of disease-oriented knowledge supporting the central role of the endothelium in cardiovascular disease.
POEMs
Only one major POEM-based study has been conducted in this field. The investigators of the Quinapril Ischemic Events Trial evaluated approximately 1700 patients with a recent percutaneous transluminal coronary angioplasty. Unpublished results indicate that cardiac ischemic end points (cardiovascular death, nonfatal MI, need for revascularization, unstable angina) were improved with the use of an ACE inhibitor. It is interesting to note that the primary outcome for all of these studies is either death or cardiovascular morbidity. Work on other POEM-relevant outcomes, such as other morbidities, side effects, and patient preferences, has not been completed. In addition, studies in other patient groups that are more relevant to primary care, such as those focused on primary or secondary prevention, are needed.
Discussion
Limitations of Causal Pathways
Because of a lack of POEMs—notably POEM evidence of effectiveness—physicians may feel uncertain about proper treatment and fear being misguided. Causal pathways offer important assistance because they provide the logic to help physicians fill in the gaps while waiting for the POEMs to arrive. Finding evidence for each link in the causal pathway provides the support physicians need. However, causal pathways can deceive. As an example, there was an excellent (but wrong) causal pathway that suggested internal mammary artery ligation would benefit coronary artery disease patients.31 The proposed mechanism was that ligation of the artery would force more blood to the myocardium. Clinical experience supported the procedure, since many patients noted fewer symptoms.31 However, a randomized controlled trial including a sham surgery clarified the misunderstanding and eliminated the pathway.32 More recently, oncologists are evaluating causal pathways suggesting that early diagnosis of breast cancer in those younger than 50 years32,33 or of prostate cancer35 is beneficial. However, early detection of lung cancer and ovarian cancer offers little benefit.35-37 Causal pathways must be based on hard evidence, but still carefully evaluated using common sense and experience.