By Kilmer McCully, M.D.
Homocysteine participates in the aggregation of lipoproteins by reacting with the protein to form cross-linkages, leading to aggregation, spontaneous precipitation and phagocytosis by macrophages to form foam cells. Thus in persons with elevated homocysteine levels, there is an increased ability of lipoproteins to form aggregates, leading to foam cell formation from macrophages by phagocytosis.
In addition, lipoproteins containing homocysteine have altered antigenic structure, leading to the formation of antibodies that complex with lipoproteins. A similar process has been identified with lipoproteins within foam cells, since oxidation reactions create modified or oxidized lipoproteins that incite autoantibody formation. In the presence of invading micro-organisms, the complexes with lipoproteins theoretically become enlarged and subject to precipitation and phagocytosis by macrophages.
This leads to the concept of the creation of vulnerable plaques within arteries. In the case of a massive invasion of micro-organisms, or when the immune system is impaired, the complexes of micro-organisms with lipoproteins, enhanced by the effect of excess homocysteine, obstruct the vasa vasorum, the small arterioles, venules and capillaries that normally nourish the wall of the artery.
Obstruction of the blood flow causes ischemia of the artery wall ( lack of blood supply ), increasing the tendency to cell death and rupture of the capillaries. These large complexes are phagocytosed by macrophages to form foam cells that accumulate, initially in the adventitia, but then migrating into the intima, where lipoproteins, inflammatory cells, and lipid deposits, including cholesterol, accumulate.
This process is probably increased and enhanced in cases where autoantibodies are formed to homocysteinylated lipoproteins and oxidized lipoproteins. The result is a vulnerable plaque that by rupturing causes thrombosis, obstruction of the arterial lumen, and death of the heart, brain, kidney or other tissue supplied by the artery.
The vasa vasorum are functionally end arteries, since flow ceases at the point where the pressure within these blood vessels is opposed by the pressure within the arterial lumen. Thus, the process of plaque formation is potentially enhanced in areas of increased blood pressure, such as disrupted laminar flow, turbulence, angulation of arterial lumen, and increased systemic pressure. In fact, these are the areas in the arteries where vulnerable plaques are most commonly observed.
One can readily understand that this interpretation explains many of the observations about vulnerable plaques and the pathophysiological processes found in vascular disease.
It explains how risk factors, such as stress, B vitamin deficiency, elevated blood pressure, smoking, and kidney failure lead to increased disease risk through formation of homocysteinylated lipoprotein aggregates. It explains the resistance of persons with elevated lipoprotein levels to infectious diseases. It explains how cholesterol becomes deposited in plaques. It explains the inflammatory process and the release of inflammatory cytokines, C-reactive protein, fever, leukocytosis, and the frequent occurrence of bacteriemia and sepsis in myocardial infarction complicated by shock. It explains the observation of microbial remnants in plaques. And it explains the inflammatory nature of cardiovascular disease.
Suggestions for prevention and therapy of vascular disease readily follow from this interpretation of the origin of vulnerable plaques. Risk factors that lead to elevated homocysteine levels need to be addressed by smoking cessation, dietary B vitamins, stress reduction, and control of diabetes and hypertension. The immune system needs to be enhanced by intake of vitamin A, vitamin D, pyridoxine ( vitamin B6 ), and other factors that are needed for proper immune function.
Appropriate antibiotic therapy is needed in heart attack and stroke patients that have evidence of active infection. Dietary improvement is needed to supply the nutrients that are needed to minimize homocysteine elevation and to support anti-oxidant function. Attempts to prevent cardiovascular disease and prolong life may be more successful by understanding the fallacies of the "diet-heart" hypothesis and determining what is harmful to the immune system and what may strengthen it.
Kilmer S. McCully, M.D.
Chief, Pathology and Laboratory Medicine Service
West Roxbury Veterans Affairs Medical Center
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