The traditional view of atherosclerosis is that it is caused by an accumulation of lipids in the endothelial lining of arteries. These lipids we are told, are derived mainly from dietary cholesterol and transported to the artery walls by low density lipoprotein (LDL). Once the LDL particle has been taken up by the endothelial cells of arteries, they accumulate and cause cellular dysfunction. This triggers an inflammatory response and the influx of immune cells causes the development of foam cells and then a hardened plaque. It is this plaque that is supposed to block the artery and causes cardiovascular disease through increased blood pressure caused by resistance within the vascular system. This theory is still widely believed by many medical doctors and research scientists as a fact, and is found promulgated unquestionably in most academic medical text books.
However, closer examination of the observable evidence shows the theory to be constructed like a house of cards. The most obvious problem is that dietary cholesterol does not increase plasma levels of cholesterol. However, it is true that other factors such as the development of metabolic syndrome can alter plasma levels of lipoproteins. Characterised by insulin resistance, metabolic syndrome is a condition that results in accumulation of abdominal adiposity, oxidative stress and metabolic abnormalities. In particular, lipoprotein metabolism becomes dysfunctional and this can alter plasma levels of cholesterol. If we reject dietary cholesterol as a cause of atherosclerosis, can we claim that the lipoprotein changes resulting from metabolic syndrome may be the likely cause of atherosclerosis? Does the rest of the theory hold water if we side step the initial step and assume an alternative cause of the lipoprotein changes?
Unfortunately for proponents of the theory, other aspect are also problematic. Firstly, it is evident that the correlation between atherosclerosis and cardiovascular disease is not consistent with the theory. For example, some individuals have highly developed atherosclerotic plaques, yet do not suffer from any obvious cardiovascular symptoms, while others have no atherosclerosis and yet die of myocardial infarction. This is problematic because it highlights that atherosclerosis is not necessary for the development of cardiovascular disease, which logic suggests removes atherosclerosis as a driver of the disease. The Japanese are known to have very low levels of cardiovascular disease, and yet suffer from atherosclerosis to the same extent as other Western nations. Therefore, atherosclerosis may or may not be a contributory factor in cardiovascular disease, but is certainly not essential to the aetiology.
Secondly, interest has grown in the role played by oxidative stress in the development of endothelial dysfunction. Mechanistically, free radicals inhibit the formation of nitric oxide through inhibition of the synthesising enzyme nitric oxide synthase. Nitric oxide is required for the dilation of blood vessels, and as levels fall, the endothelial lining of arteries loses the ability to dilate in response to blood flow, resulting in increased blood pressure. Over time this triggers a dysfunction in the endothelial cells causing them to lose elasticity, in a manner similar to that in atherosclerosis. Metabolic syndrome causes systemic oxidative stress and is also associated with raised level of plasma LDL. That lipoprotein changes are present in metabolic syndrome may therefore be inconsequential to the aetiology of cardiovascular disease. Support for this comes from studies questioning the strength of the association between LDL and atherosclerosis.
A number of well designed trials have demonstrated that diets high in antioxidants can improve endothelial function and lower blood pressure. In addition, fish oils are also able to improve endothelial function through other mechanisms. For example in one study1, researchers raised levels of non-esterified fatty acids with a heparin injection in healthy subjects in order to stimulate the postprandial rise in fatty acids that might occur following a typical Western meal. Free fatty acids increase following a meal because endogenous de novo lipogenesis and exogenous dietary fat enters the circulation and is de-esterified through the action of lipoprotein lipase. Free fatty acids are known to cause an increase in blood pressure through inhibition of nitric oxide synthesis. While saturated fat ingestion caused a deterioration in endothelial function as measured by a reduced flow mediated dilation, ingestion of n-3 fatty acids with the saturated fat improved flow.
Therefore atherosclerotic-like inelasticity in arteries may not require the presence of LDL at all in order to develop, but may result from the long-term dysfunction to the endothelium caused by oxidative stress. The weak association between LDL and atherosclerosis reported in some studies may result from the deterioration of lipoprotein metabolism during the development of metabolic syndrome, but LDL may not actually be involved in the aetiology of cardiovascular disease at all. Instead it might be the oxidative stress that develops from the abdominal obesity in metabolic syndrome that is the cause of the endothelial dysfunction, through reductions in the production of nitric oxide. It is not clear why fish oils prevent reductions in flow mediated dilation, but studies show that they do not affect nitric oxide synthesis. Instead fish oils may be metabolised by cytochrome P450 to epoxides. Epoxides are known to cause dilation of blood vessels.
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