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ATHEROSCLEROSIS - A LONG TERM BIOCHEMICAL PROCESS THAT SHORTENS LIVES
Atherosclerosis may be the single most important factor that limits the life of both men and women in developed country world populations of today. It is a basic cause of heart disease and strokes, kidney disease, high blood pressure and many other problems. Atherosclerosis involves the accumulation of deposits in arteries throughout the body that gradually clogs them. It produces is most lethal effect by clogging the tiny coronary arteries that supply the heart muscle with blood and oxygen.
Atherosclerosis is produced by a biochemical process. Because chemical processes follow predictable paths, its extent is potentially predictable. A major health goal today for nearly everyone is to slow our atherosclerosis. And a vast body or research now shows how atherosclerosis advances, and how it can be increased or slowed. A key objective in the development of Life Ahead has been that of achieving a better quantitative understanding of how atherosclerosis develops.
The landmark research on atherosclerosis was carried out by the International Atherosclerosis Project starting in the 1960’s. Some key results were provided in “Atherosclerosis in Persons with Coronary Heart Disease” by JP Strong and others. (Laboratory Investigation 18:527 and Atherosclerosis 23:451) The coronary arteries of several thousand men and women that died in 15 different countries throughout the world were autopsied. This included people that had died of coronary disease AND people that had died of other than cardiovascular causes. The amounts of atherosclerosis deposits in segments of each artery of each individual were analyzed to identify the percent of surface area covered by deposits, and artery wall thickness.
Their results provide a dramatic picture about how atherosclerosis develops during life and produces coronary disease. This picture is summarized in the Figure “Atherosclerosis” that accompanies. Each of 4 graphs plot the % of atherosclerosis in arteries vs. age for men and women. First note the lower lines in the two graphs at the top. This shows how atherosclerosis developed with age as a percent of surface area covered in the arteries of US men and women that died of other than cardiovascular diseases. (i.e accidents, cancer, etc). Results from this ‘non-cardiovascular’ group give us a picture of what usually is happening in the arteries of a population during life. The average extent of atherosclerosis developed steadily with age from less than 10% at age 30 to about 40% at age 65 for men. A similar trend but at a lower level is shown for women. But note from the upper lines that both men and women of all ages that died of coronary disease had average deposits of around 50-60% in their arteries. This was the classic research that demonstrated the role of atherosclerosis in causing coronary disease.
Figure "Atherosclerosis"
The plotted points and lines in these figures represent average values of large numbers of individuals. The actual artery deposits of individuals varied widely from these averages. For example some men who died of coronary disease had deposits of only 20%; others had deposits above 90%. Thus factors other than atherosclerosis are involved in producing heart disease. This will be discussed in the Health Library information accompanying. But atherosclerosis still ranks as a main factor that causes this all important disease.
The lower left plot shows that the rate at which atherosclerosis advances in men with age and time of exposure in years depends on average population total serum cholesterol. Populations with higher cholesterol had a much higher age-associated rate of atherosclerosis than did the populations of countries that have low average cholesterol levels. It is clear that cholesterol levels are a key factor in the production of atherosclerosis, and this same relationship is consistently found between cholesterol and risk of coronary disease. Much other research shows similarly that rate of heart attack occurrences is strongly related to cholesterol levels. The graph in the lower right figure shows that atherosclerosis is hastened by cigarette smoking. This explains why cigarette smokers can have a twice higher rate of coronary disease and death than do non-smokers.
Some important implications derive from this analysis. First, the atherosclerosis that is a key cause of heart and other related diseases usually develops only slowly in a population. Although the data are plotted vs. age, the more probable real causative factor is the duration in years of exposure to cholesterol that increased directly with age in this example. The lower line in the upper left plot suggests that deposits increased at an average rate of about 6% per year in men.
As atherosclerosis advances it thickens the artery wall and gradually reduces the area available for needed flow of blood. During the Korean War, 45 to 70% of young men averaging about age 25 had atherosclerosis, and 15-20% had diameter blockages of 50% or more. A Minnesota study found that 41% of a group of 30-49 year olds and 72% of 50-60 year olds had blockages of 50% or greater. Based on these and other data the Life Ahead Artery Blockage Model produces an estimate of average population artery blockage at age for a variety of causative factors. Atherosclerosis produces coronary heart disease via two major mechanisms. First, it blocks the artery cross section. This blockage can reach above 90% and effectively shut off blood flow to the heart per se. But more frequently a much lesser diameter blockage of only 40-50% provides a trap against which blood clots or pieces of ruptured plaque that break off the artery wall engage. Thus can suddenly shut off oxygen to the heart and cause a serious disease or fatal event. Life Ahead recognizes these mechanisms in forecasting risk of coronary disease.
The lower rate of atherosclerosis for women explains why they die of coronary disease less often than men. But an immediate question here is "How can this be, because the actual cholesterol level of women at these ages is similar to that of men?". An answer requires that something else must be modifying the rate at which atherosclerosis develops in women, and that this modifying factor must reduce the effect of cholesterol in producing atherosclerosis by nearly three fold. Today's research has shown that the potency of cholesterol in producing atherosclerosis and heart disease is strongly related to its state of oxidation. Estrogen - a key biochemical difference between men and women - is a strong antioxidant that is known to reduce atherosclerosis. Smoking is a strong pro-oxidant and this can explain in part why smoking enhances the atherosclerosis reaction. The combined effect of estrogen and smoking thus produces a 4-5 fold difference in the rate at which cholesterol produces atherosclerosis. The antioxidant model in Life Ahead that is described elsewhere identifies a 4 fold potential difference in in rate of atherosclerosis and heart disease at a given level of cholesterol. And a variety of antioxidants including vitamins can produce part and perhaps much of this very large potential effect. This means that even though cholesterol is a key and probably the primary biochemical factor here, the actual extent of atherosclerosis and risk of heart disease can vary 4 fold or more for a given level of cholesterol. These factors and their quantified effects are now explained by and incorporated into the Life Ahead Model.
It can be shown further that atherosclerosis deposits increase with serum cholesterol-years or the product of serum cholesterol times years of exposure. An example of this is a ‘cholesterol-age’ guide that heart disease becomes likely when total cholesterol times age totals about 1600. A very few individuals with a serious genetic defect have cholesterol levels of 800. They usually suffer coronary disease in their 20’s. Individuals with very high cholesterol of 400 usually suffer in their 40’s. Those having only a 200 cholesterol level usually make it into their 80’s before this disease strikes. But this is only a very crude guide. A much more quantified if still approximate analysis of how various types of cholesterol and many other factors clog arteries via atherosclerosis is provided in the description oft he Life Ahead Artery Blockage Model.
Atherosclerosis deposits once formed can be difficult to remove. Thus a second implication is that atherosclerosis is produced during any specific year will depend on the cholesterol during that year. If cholesterol is say 250 or higher in early years atherosclerosis will develop substantially during those years. A reduction in cholesterol to say 180 at mid-life will slow its progress. But the deposits laid down during the 250+ cholesterol years will mostly remain, the narrowing of arteries will persist, and this will produce an increased risk of disease. Thus a person that now has180 cholesterol but who had earlier high cholesterol can have more narrowed arteries and much higher atherosclerosis and risk of disease than another person that always had 180 cholesterol. This shows the fallacy of a cholesterol risk factor based just on today’s cholesterol. Life Ahead recognizes this problem by producing a lifetime profile of probable actual cholesterol values vs. age from results on overall populations together with any available information on earlier-years cholesterol provided. And Life Ahead computes risk of every disease at every year of life from factors that actually existed during that year.
Atherosclerosis can regress. Although this fact was disputed in past years, today’s research shows that the deposits will recede but slowly after a substantial reduction in cholesterol is achieved. Life Ahead research described for the Artery Blockage Model suggests that atherosclerosis always is developing based on cholesterol and other factors, but also is being removed by the body defenses at a rate of about 4% per year. Thus if the development rate of atherosclerosis drops below about 4% per year, the deposits can gradually recede. Thus the very substantial reductions in cholesterol obtainable now by drugs can initiate a continuing reduction in atherosclerosis and reduce risk of disease or its recurrence. Life Ahead forecasts the reductions both in risk of disease and in reductions in atherosclerosis that accompany a lowering of cholesterol at any age in life. A key source on this subject used for Life Ahead was the important book of K Lance Gould “Coronary Artery Stenosis and Reversing Atherosclerosis”, Oxford University Press, NY.
Note that DURATION of exposure – and not just age - is the key probable casual factor determining extent of the atherosclerosis that is a key cause heart disease. DURATION of exposure also is a key factor in the development of cancer. A new contribution of Life Ahead is that it tracks duration of exposure and the increase in risk from this for each succeeding year of life for the important factors that produce the major life limiting diseases. This vitally important factor usually is overlooked in statistical models and in many studies of health. As will be shown elsewhere, the effects of estrogen, antioxidants and many other factors that operate via the atherosclerosis mechanism to produce cardiovascular diseases also must depend directly on their duration of exposure.