Focus: Lipids and the endothelium Content Points: One of the newest and most exciting areas of cardiology research continues to focus on the earliest manifestations of coronary artery disease...endothelial dysfunction. Through its role as a regulator of vascular tone and structure, the endothelium is considerably influenced by cardiovascular risk factors, not the least of which is lipids.

Content outline Content Points: This slide program will review in detail the following points:   - Role of lipids in endothelial health.   - The links between coronary heart disease, cholesterol, and diabetes.   - The benefits of lipid lowering...a review of recent clinical trials.   - Guidelines for cholesterol lowering in clinical practice.   - Therapeutic implications. At the end of this program, three case histories are suggested. They were selected based on patient profiles commonly seen in clinical practice:   - A 73-year-old white female with carotid disease.   - A 48-year-old white male with angina.   - A 38-year-old white male with a family history of coronary artery disease. The purpose of including these cases is to enable speakers to turn the science of medicine into practical clinical medicine. Cases are described, followed by suggestions for opening up the discussion on how to approach those patients to reduce cardiovascular risk.

Endothelial health: A balancing act Content Points: Normal endothelial function is dependent on achieving a balance between nitric oxide activity and angiotensin II, and on normal oxidative metabolism in the arterial wall. At risk of oversimplification, it is helpful to examine some of the basic scientific background which provides the foundation for how lipids can disrupt normal oxidative metabolism. Dr. Victor Dzau’s group from Stanford (and more recently from Harvard Medical School) have hypothesized that medial smooth muscle cells and plaque lipid-laden macrophages express ACE. ACE expression in macrophages is induced by oxidatively modified LDL-C. Their hypothesis is that ACE is involved in modulation of plaque inflammation, and thus becomes a very important oxidant.1

Oxidative stress Content Points: The key point is that endothelial dysfunction promotes an imbalance among vasoactive substances. The vasoconstrictive substances (angiotensin II and tissue ACE) are increased, while the vasorelaxant or growth-inhibiting substances (Nitric Oxide) are decreased.2 The result is a condition of oxidative stress.

Oxidative stress hypothesis: A common pathogenic feature of CV risk factors Content Points: Risk factors that increase oxidative stress are the same as those for coronary artery disease, and include hypertension, diabetes, increased LDL-C, smoking, hyperhomocysteinemia and estrogen withdrawal. In the context of this lecture guide, LDL-C can be a critical risk factor. Endothelial dysfunction occurs in hypercholesterolemic patients, whether or not other coronary risk factors are present, and precedes the onset of coronary atherosclerosis.3,4

Effects of oxidative stress Content Points: Among the effects of oxidative stress, is the altered regulation of vascular tone. In addition, oxidative stress promotes a proinflammatory state, and imposes injury resulting in endothelial cell death.5,6,7

When LDL-C is oxidized... Content Points: These are some of the effects oxidized LDL-C can have on the vessel wall. There is increased production of oxygen free radicals and increased expression of endothelial-derived adhesion molecules. There is also increased migration of monocytes with enhanced entry into subendothelial space. A prothrombotic state occurs due to increased PAI-1 and decreased levels of tissue-plasminogin activator. There is also increased platelet aggregation due to decreases in nitric oxide (NO) and PGI2.5,6,7

Oxidized LDL-C: A common initiating factor for cardiac events Content Points: Effects of oxidized LDL-C seem to result in a destabilized vessel wall from an increasingly fragile plaque prone to rupture, decrease in flow-mediated dilatation, abnormal constriction, and a procoagulant vascular surface. These effects can lead to transient ischemia, unstable syndromes, myocardial infarction, and cardiac death.

Effects of cholesterol lowering on myocardial ischemia Content Points: Evidence for beneficial effects of lipid lowering on myocardial ischemia has been provided from groups working at the Brigham and Women’s Hospital and Harvard Medical School. They used the measurements of ST-segment depression on ambulatory ECG in patients with CAD. They enrolled 40 patients with proven CAD, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Patients were randomized to either an AHA Step 2 diet plus placebo, or to the same diet plus treatment with lovastatin. This slide shows the patient-by-patient effect of cholesterol lowering over six months on the number of episodes of ischemic ST-segment depression. Two of 20 in the placebo group vs 13 of 20 in the treatment group show resolution of ischemia.8

Effects of lipid lowering on endothelial function in hypercholesterolemic patients Content Points: The Harvard results were preceded by a study from Anderson et al which explored the extent to which a year of cholesterol-lowering and antioxidant therapy could restore endothelium-dependent coronary vasodilation in patients with elevated cholesterol and LDL-C levels.9 Endothelium-dependent coronary vasomotion response to acetycholine was assessed at baseline and following one year of therapy in three groups of patients: 1) those randomly assigned to the AHA Step 1 diet, 2) lovastatin and cholestyramine, or 3) those assigned to therapy with lovastatin and probucol. Treatment resulted in significant reductions in LDL-C levels in the groups treated pharmacologically to lower LDL-C. Likewise, the two pharmacologically treated groups experienced improvements in coronary artery diameters following acetylcholine administration vs the diet group. Both treatment groups showed improved endothelium-dependent vasomotion with cholesterol lowering; this may help to explain the reduced incidence of adverse coronary events resulting from cholesterol-lowering therapy.

Benefits of aggressive LDL-C lowering Content Points: In summary, the results of studies suggest that the benefits of aggressive LDL-C lowering can result in improvement in endothelial function, decreases in angina and reflex coronary constriction, as well as reduced need for revascularization.