Introduction

According to mainstream atherogenesis theory, the accumulation of oxidized LDL in the artery wall elicits an inflammatory response which results in an atherosclerotic plaque. HDL, the “good” cholesterol, is believed to protect against atherosclerosis by removing LDL from its site of deposition in the artery, a process called “reverse transport of cholesterol.”

There are several weaknesses with mainstream thought. Aggressive reduction of serum LDL-cholesterol using high dose statin therapy still leaves significant risk of adverse cardiovascular events in high-risk patients. Despite lowering serum LDL-cholesterol to less than 100 mg/dL, the estimated risk of adverse events in patients with established coronary artery disease is estimated to be 9% per year.1 This, coupled with the increased mortality associated with torcetrapib,2 a drug which raises serum HDL more effectively than any other, should prompt reexamination of mainstream atherogenesis theory. Further, oxidized LDL is widely distributed in both arteries and veins, the latter of which do not develop atherosclerosis.3 The sites of lipid accumulation in arteries, and thus the distribution of the putative precursor lesion, the fatty streak, correlates poorly with the distribution of atherosclerotic plaques.4,5 In fact, fatty streaks routinely resolve with leaving a trace.6 Mainstream theory does not explain the localization of plaques to the vicinity of changing arterial geometry, such as branches, curves, and dilatations.7 Mainstream theory provides no explanation for accelerated atherosclerosis associated with hypertension, except in the most ad hoc, nebulous, wishful thinking way.8 Reverse transport of cholesterol by HDL has little in vivo evidence to support it.4 Finally, mainstream theory cannot explain the presence of fibrous plaques in synthetic arteriovenous grafts.10

The hemorheologic–hemodynamic theory holds that atherosclerosis is a disease of stasis or pooling of blood, which promotes the organization of a thrombus into an atherosclerotic plaque. Stasis of blood predisposes to thrombosis, as described by Virchow in the 19th century. Risk factors for atherosclerosis create larger areas of decreased shear (flow) by increasing blood viscosity, arterial stiffness, or both. Both of these abnormalities are seen in association with aging, hypertension, diabetes mellitus, cigarette smoking, and obesity.10 The hemorheologic-hemodynamic theory proposes that the same pathologic process, thrombosis, leads to both plaque development and its complication, superimposed thrombosis and infarction. The name reflects the fact that the interaction of hemorheologic, i.e., blood flow, and hemodynamic, i.e., blood velocity, pulsatility, and arterial geometry, factors lead to atherosclerosis.