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                   CHOLESTEROL in LIFE AHEAD  

Abstract:  Large differences in Total Cholesterol in blood can produce up to a 7 fold change, and large differences in HDL cholesterol can produce a 3 fold change in risk of heart disease.  But the effect of cholesterol on risk diminishes appreciably with increase in a person's age.  Substantial differences in cholesterol can be produced by diets differing in saturated fats and fiber.  Because Total and HDL cholesterol can be much affected by genetics, Life Ahead produces Cholesterol-Genetic factors that identify unusual health risks.  The harmful effect of cholesterol now can substantially reduced by use of Statin type drugs.   Cholesterol increases risk of heart disease via two quite separate mechanisms.  First, it produces the long term atherosclerosis that clogs arteries gradually over long periods of time.  Second, it produces in much shorter time the soft plaque that is prone to rupture and produce clots that obstruct narrowed arteries.

Background and Types of Cholesterol:  Cholesterol in serum or blood is a factor of major importance to risk of heart disease and Well-Days of life. Three types of cholesterol are:  (1) Total Cholesterol;  (2) LDL or low density Cholesterol, and (3) HDL or high density Cholesterol.  LDL plus HDL comprise about 87% of the Total Cholesterol and LDL is the key component that produces atherosclerosis. For a given Total Cholesterol the amount of LDL decreases by difference as HDL is increased, and HDL in addition appears to slow atherosclerosis.

The atherosclerosis producing property of cholesterol can be expressed either by using Total Cholesterol and HDL, or by using LDL cholesterol and HDL.  The use of LDL and HDL might be slightly more accurate.  But because the sum of LDL and HDL comprises most of Total cholesterol, the use of Total Cholesterol and HDL can produce near equivalent results.  Because most research results are based on Total Cholesterol and HDL rather than LDL and HDL, Life Ahead usually uses the Total Cholesterol- HDL combination to compute risks.

In the text the follows the italicized word Cholesterol refers to a combination of Total-LDL-HDL cholesterol factors.  A usual practice now is to value Cholesterol as Total Cholesterol and a ratio of Total Cholesterol divided by HDL.  This latter ratio is felt to have been an unfortunate choice of a statistic.  The ratio method may provide a rough measure of risk.  But the ratio assumes implicitly but incorrectly that the risk of each % change of HDL is equivalent to a similar opposing % change in Total Cholesterol.  It also implies - most incorrectly - that the level of total cholesterol and HDL does not matter. The level of cholesterol is of major significance.  And severe mathematical problems are encountered when attempting to use this ratio method over wide ranges of individual values.  Life Ahead thus uses the chemically and mathematically more appropriate combination of Total Cholesterol and the percent concentration of HDL in Total Cholesterol to value their effects on atherosclerosis and risk of disease.

Triglyceride is an associated factor that usually is related closely and inversely to HDL.  It is difficult to identify separate effects of HDL and Triglycerides at Triglyceride levels below about 150.  Thus Triglycerides is now used in Life Ahead as a further negative to health only when its level is quite high.

Cholesterol and Atherosclerosis:  LDL Cholesterol is the key agent that produces atherosclerosis and the narrowing of arteries so frequently found in industrialized societies. Atherosclerosis deposits build up gradually in direct relationship to the amount of LDL in the blood.  Twice the level of LDL in the blood will produce atherosclerosis about twice as fast.  But atherosclerosis deposits are not removed when LDL cholesterol is reduced.  Rather, they usually will either continue to build up more slowly, or start a slow decline.

An important factor producing coronary heart disease is the degree of artery narrowing caused by atherosclerosis deposits. The amount of this narrowing in turn is due NOT to the level of LDL cholesterol at some present age, but is produced by the sum or average of LDL cholesterol values at each previous year of life.  A low LDL value as a risk can be very misleading if earlier LDL values were much higher.  To avoid this problem Life Ahead provides an estimate of the actual amount of atherosclerosis accumulation at each age.  This is done partly via the Artery Blockage Model that is described separately.  Life Ahead identifies risk of Cholesterol as follows.

Coronary Heart Disease, Total Cholesterol Risk and Age:  Risk of coronary disease from total cholesterol is estimated in Life Ahead at each age of life using the values from these profiles. This risk is now derived from the premier study of coronary disease vs. cholesterol levels that emerged from the MRFIT study (JD Neaton, Arch Intern Med 1992, 152:56).   This massive study included the deaths from coronary disease of 316,000 men for Total Cholesterol values from 130 to 340 during a subsequent 12 year period.  Increases over this wide range produced a steady stepwise increase in coronary death rates of  700% or 7 times at enormous significance.  No other study of cholesterol risk found even approaches the scope, size, and probably accuracy of this study.

The MRFIT analysis demonstrates the large potential role of total cholesterol in producing heart attack deaths. But a problem here is that the risk ratio of cholesterol declines with age. This fact long has long been recognized, and some time back some researchers even claimed “Cholesterol does not matter much when age moves much beyond age 50.”  The Pooling Study (AMA Monograph #60)  in which data of Framingham and four other large US studies of heart disease were  pooled to obtain better accuracy also confirms that the cholesterol risk factor does decline with age, but that it still remains as a significant factor at older ages.  The MRFIT study from far more data showed a similar result.  This age effect on risk ratios of coronary heart disease or death for a difference of about 100 mg/dl in total cholesterol from these studies and comparable values from the present formula used in Life Ahead follow:

Age                    37    42    47     52   56-7     62      70

Pooling study                     3.6    2.1    2.1    1.5

MRFIT Study           4.8   3.8   3.2    2.7    2.1

Life Ahead Formula    4.8   3.9   3.0    2.5    2.2    1.9     1.6

This change of risk ratio with age can be partly misleading because actual age related coronary risks are far higher at older than at younger ages.  Multiplying these ratios by age related risk of heart disease shows that the actual gross increase in risk for cholesterol is higher for the 1.6 ratio at age 70 than it is for the 4.8 ratio at age 37.  But these age related risks become significant in a lifecycle model because life expectancy and Well-Days depend importantly on risks during the last two decades of life.  No data were found that verify accurately the risks of cholesterol differences for individuals much beyond age 60, and thus present estimates of its risk for older persons requires as above some extrapolation.

Also note that different changes of risk ratios with age for different health factors can change their relative importance in producing Well-Days.  The above age-declining risk values for cholesterol are involved in identifying health values of diet.  Risks for a given amount and time of cigarette smoking decline somewhat similarly with age.  But risk ratios associated with cardiofitness and blood pressures do not decline with increase in age.  Thus the relative importance of maintaining cardiofitness and healthy blood pressures increases substantially as we become older. And this explains that risks of cholesterol enhancing diets can be lower than those inferred from simple risk factors determined at middle age.  The reason for the substantial variation of cholesterol related risk with age is not now understood.   

Coronary Heart Disease and HDL:  The Life Ahead formula for risk vs. HDL was derived from the Framingham and several other studies.  The basis used here as noted above was the percentage of HDL in total cholesterol.  A risk ratio of unity or 1.0 was given to values from the above average cholesterol profiles for men and women at age 50.  The formula for values differing from this where HDL% is the percent HDL in total cholesterol:

   A  =  Exp (4.492 - 0.665  *  Sqr ( HDL% ))                   

       HDL risk for men =       A / 3.795                    

       HDL risk for women =   A / 2.875

The effect of HDL as related to its % in total cholesterol follows:  A limiting risk at a maximum of 70 HDL and 80 HDL is assumed for men and women respectively.

HDL, % of Total Cholesterol            15         20       22.5       25       30     

HDL for 213 Total Cholesterol         32         43        48         53       64

Risk Factor for HDL                       1.79      1.20     1.00      0.85    0.62  

HDL thus can be a quite important independent risk factor.  A 3 fold change in coronary risk is associated with a two fold change in concentration of HDL in Total Cholesterol.

Triglycerides and Coronary Heart Disease:  More than adequate research now confirms that usually high levels of triglycerides do increase coronary risk further. As mentioned, data at lower levels of triglycerides interact with HDL so closely that a separation of separate effects could not be achieved.  It remains possible and perhaps probable that some of the benefit now accorded to high levels of HDL is due to associated lower levels of triglycerides.

But very high levels of triglycerides do convey separate and increased risk.  The present statistically based formula used in Life Ahead applies only to levels of triglycerides of 150 and above, and identifies risk vs an average population value assumed as 114:

Risk Ratio of Triglycerides = (Triglycerides, mg/dl / 114) ^ 0.27

Triglycerides, mg/dl         150      200     300      500
Risk Ratio                  1.08     1.16    1.30     1.49

Thus although levels of triglycerides much below 200 - assuming the effect of HDL is valued - do not suggest much concern, quite high levels do show appreciably increased risk.

Benefits from Improving Cholesterol Values:  The above methods and formulae are intended to estimate the progress of atherosclerosis and risks associated with this from varying cholesterol factors.  But research shows clearly that atherosclerosis does not disappear in direct accord with a reduction in Total or LDL cholesterol.  Rather the deposits might continue to increase but at a slower rate, or start to slowly decline.  The important question debated by researchers for much a half century was “What effect will a reduction in Total or LDL cholesterol made during some year of life have on actual future coronary risk?”

Table C1 summarizes the key research from four decades of research on the benefits of cholesterol lowering.  The most effective agent by far is the use of Statin type drugs that from multiple studies show a consistent reduction in total cholesterol of 22%.  The 9 specific studies in C1 plus the Meta analysis of 13 studies provide the major result on Statins and other factors to date. LDL is reduced an average of 32% and HDL is increased by about 6%.  This produced an average actual reduction in risk of coronary disease of about 33% or 1/3rd within 2-3 years of therapy.  The average of 16 dietary trials of cholesterol reduction derived in the last listed meta study produced an average lowering of total cholesterol by 8.6% and this in turn produced from this a lesser reduction in risk ratio to 0.91 (limits 0.82-1.01).

Accompanying research showed that reduction of cholesterol via Statin drugs also reduced the progression of artery narrowing via atherosclerosis by 2-4%.  Although this reduction in narrowing was significant, its amount is much too small to explain the reduction in coronary risk measured.  The Artery Blockage Model suggests than a 10-15% difference in narrowing would be needed to explain a 1/3 reduction in risk. Thus cholesterol reduction must benefit by some mechanism other than atherosclerosis per se.

A question here becomes:  “How does the risk reduction from improving cholesterol for just 2-3 years compare with that expected from the long term risk of cholesterol in producing disease?"   From the multiple results in Table C1 Statin drugs reduce total cholesterol from 250 to 193.  This produces an expected risk factor from the MRFIT study data of 0.65.  But the drugs also increased HDL cholesterol from 48 to 51.  This increases the concentration of HDL at the final 193 total cholesterol from 19.3% to 26.3%.  Based on the long term results of HDL on risk using the above noted formula this should lower coronary risk by another factor of 0.61. The combination of 0.65 times 0.61 would be expected thus to produce a coronary risk of about 0.40 or a reduction in risk of 60%.  The actual risk from cholesterol lowering from drugs for these same changes in cholesterol was a reduction in risk of 33%.  Thus on a percentage basis the actual risk reduction from cholesterol by drugs was about half that expected from a long term change in cholesterol related risk. 

Actual average reduction in risk from reduction in cholesterol by diet in Table C1 was 0.91 or 9%. The change cholesterol of this amount from the above same bases would be expected to reduce risk by about 20%.  Although not as statistically firm as the data from drugs, the risk reduction from cholesterol lowering by diet also was about half of that expected from the long term effect of cholesterol on risk.  Changes in diet usually do not change the percentage value of HDL in total cholesterol much, and thus a change this factor would not be involved for most changes in diet.

Mechanisms of How Cholesterol Changes Risk:  How does cholesterol improvement achieve these benefits?   We have here a paradox.  First, cholesterol improvement reduces risk far more than would be expected from its benefit to atherosclerosis. But second, this benefit is only about half that expected from long term changes in cholesterol per se.  These observations provide interesting insight about the mechanism by which cholesterol probably produces its benefit. 

The extensive research of Dr. K L. Gould discussed in his landmark book “Coronary Artery Stenosis and Reversing Atherosclerosis” (Oxford Univ Press, NY)  showed that 65% of coronary attacks occur at the time artery narrowing still is less than 50%.  These attacks are caused by the rupture of and thrombosis of lipid-rich atherosclerosis plaque that tends to be freshly formed. These plaques tend to harden and become less vulnerable to rupture as they age.  It seems likely that the amount of the fresh plaque that is being formed at time will be proportional to cholesterol, and probably LDL, in the blood.  Thus an increase in risk-amount of  cholesterol can have a dual role.  It first increases the rate of the gradual artery narrowing that usually takes place slowly over decades of life. And second it produces at any point in time an increased level of vulnerable fresh plaque that can be prone to rupture. This process can explain at least qualitatively the above cited results.

Cholesterol, Genetics and the Life Ahead Cholesterol Genetic Factors:  Many individuals with unhealthy cholesterol values probably derive this problem mostly from genetics and family history.  A common statement once was:  “Cholesterol is 1/3rd diet and 2/3rds genetics.”  The Life Ahead computer program provides an extensive valuation of the known factors that can modify levels of serum cholesterol.   These include age, sex, detail of fats and fiber in diet, exercise, and alcohol.  Expected values of cholesterol from the average population profile at age modified by all of these factors are thus computed if a diet entry is included.

Life Ahead then compares these estimated values of Cholesterol at present or various ages with any actual cholesterol values entered. Ratios of actual to predicted values for Total Cholesterol and HDL cholesterol are computed and identified as Total Cholesterol Genetic Factor and the HDL Genetic Factor respectively.   If either of these factors are more than 10% above or below average, they are noted in the program output as non-actionable factors.  A high Total Cholesterol Genetic Factor or a low HDL Genetic Factor identifies additional unwanted risks.  Keep in mind that a high Total Cholesterol factor is a negative, and a high HDL factor is positive to health.

Although these genetic factors may not be modifiable by change in habits, they can reveal an inherent health risk that previously has not been identified. An unfavorable genetic risk reveals that more effort on diet, exercise, an/or other habits than usual may be needed in order to avoid a major cardiovascular disease event or death.  Also, many people that have a high Total Cholesterol from genetics find that they can achieve much larger reductions from changes in diet than do those with normal cholesterol.  This should increase their focus on dietary modification.  Genetic factors for cholesterol more favorable than usual suggest that an individual probably has more flexibility in diet options for health than do those with average or high genetic factors.

And finally, anyone that has an unfavorable Cholesterol and Cholesterol Genetic factor should seek a doctor’s approval to use the Statin drugs that are remarkably successful in controlling cholesterol.

What Can be Done to Improve Cholesterol:  The key actionable habit that can improve Total or LDL cholesterol is DIET.  More about this is included in “More Healthful Diets---“ and in “Dietary Fats, Fiber, and Cholesterol”.  Modest changes in diet usually will not change Total Cholesterol by very much.  But large changes in diet can produce very substantial differences.  For example, the DEMO diets in Life Ahead show that a change from the “#1 or Average” to “#2 or Good” diet produced a reduction from 210 to 201 mg/dl of Total Cholesterol.  But the change from #1 to the “#3 or Poor” diet increased Total Cholesterol from the 210 to an estimated 248.  Thus over wide ranges in diet that are not uncommon, Total Cholesterol probably can change as much as 50 mg/dl  

Exercise can improve cholesterol, but not by very much. Cardiofitness can improve Total Cholesterol but not by very much.  Results from four direct studies showed that each improvement of 1 in CFR or 1% in cardiofitness improved HDL by only 0.1 mg/dl. Thus a substantial improvement in fitness of 20 CFR will improve HDL by only 2 mg/dl. This change in HDL in turn will reduce risk of the disease by 6%.  In contrast, an improvement of 20 in CFR will reduce actual risk of coronary disease by about 75%.  See “Exercise and Cardiofitness, A Summary.”  Some proponents of HDL have suggested the benefit of exercise in reducing coronary risk is achieved mostly via its role in reducing HDL.  More accurately, the benefit that derives from efficient exercise in modifying HDL explains less than one tenth of the overall benefit of efficient exercise in reducing risk of this disease.

A small part of the benefit of alcohol may be achieved via its modification of HDL.  1 drink per day will increase HDL by 4.0 mg/dl, and modest multiples of drinks will increase HDL by multiples of this amount. Thus the HDL change from each drink per day will account for reducing coronary disease risk by about 12% or a factor of 0.88. The Life Ahead analysis finds a lowest risk factor from alcohol of 0.50 at about 35 grams of alcohol or 1.25 drinks per day. At this level of drinking the HDL contribution may explain 1/5th of the total benefit of alcohol.  But as alcohol consumption moves higher its effect on coronary risk reverses to a net increase in risk at much over 2 drinks per day.  Considered overall, the change in HDL produced by alcohol explains very little of the benefits that a modest consumption of alcohol can provide.  And HDL provides a false indicator of the negative benefit to health of alcohol consumptions above 2 drinks per day.

When analyzed with careful quantification it appears that there is little an individual can do that will improve HDL very much. And this measure does not identify usefully the benefits of either exercise, cardiofitness, or alcohol.

Life Ahead Well-Days and Cholesterol:  Life Ahead computes a risk of cardiovascular and all other included diseases at each age of life using the above described profile values of cholesterol and all other included factors. The base for this computation is the actual death and disease rates of the US population, and all risk factors are unity at values of this base population.  The artery blockage model estimates average population artery narrowing by year and enters a risk modifier if narrowing is more or less than average.  An effect on risk of the artery blockage model becomes significant only if cholesterol levels were changed significantly from usual profile during life.   If a Diet Entry is not asked, no change in cholesterol is assumed for Good Habits. Thus the benefits for good habits can be much underestimated when no diet entry is made. 

The Cholesterol-Age Profiles:  Because cholesterol produces accumulating deposits at each year of life, it is necessary to know its level at each year to reflect how much deposit probably has or will be formed during this year.  Thus Life Ahead produces an age-profile of each type of cholesterol for each age of life. Because individuals usually will not have actual values of cholesterol available for every year, a best estimate for the profile is produced from average population trends with age and actual values available. These population trends are modified for any earlier than present value of cholesterol that is entered into the program.  The Life Ahead Life Cycle model computes all risks of disease and death for each year of life in every valuation.

The disease and death values used in Life Ahead Version 2 are for an average US Population during 1995-1998. (The structure of the model is such that it should also develop correct risks for populations of earlier and later years.)  Thus a base profile for the average individual is produced for each year of age from population average cholesterol values vs. age published by the National Institutes of Health (NIH) for these years.  Values in mg/dl from this average population profile are:

                               Men                    Women

Age                   10    30    50    80     10   30    50    80

Total Cholesterol    150   192   213   208    154   187   218   231

LDL Cholesterol       90   124   142   138     83   110   136   147

HDL Cholesterol       44    46    48    48     54    56    58    59         

If a diet entry is made with no actual cholesterol entry, the first pass computation develops an estimate of likely cholesterol values from average profile and diet and all other factors.  If any actual cholesterol values are entered, the Genetic Factors for Total and HDL cholesterol are computed to reconcile the computed results for diet with those for actually entered cholesterol values.  The computed result for Good Habits then assumes that any deficiencies in dietary values of  fats, fiber, and all other dietary factors vs. desirable targets will be corrected.  Thus if a Total Cholesterol Genetic factor is high, practical modifications of diet and other habits will be able to reduce the Good Habit factor for Total Cholesterol only to a higher value than that computed for a person having a normal Total Cholesterol Genetic Factor.  This recognizes that the individual with the high genetic factor has an added quantifiable risk, and if cholesterol remains unfavorable, should be discussing use of cholesterol modifying drugs with a doctor.

Life Ahead now computes differences for changes in cholesterol due to diet or other changes assuming the basic long term effects (i.e. the MRFIT study) of these factors.  As noted above, this will overestimate benefits or debits of substantial changes cholesterol as those for Statin drugs for a some years following the changes.  However, as years progress this error probably will become small first because actual values should move closer to those now computed as atherosclerosis progresses toward estimate over longer time, and second because the effects of Total Cholesterol become smaller with increase in user age.  Thus effects of this approximation on Well-Days should be minimal.

Note the Life Ahead does not usually attempt to compute differences in health risk for various assumed values of cholesterol that often is done via statistical type models.  Individuals do not have any real option for changing their cholesterol by specified amounts other than by modifying factors such as diet and exercise or taking drugs, and thus any such computations are hypothetical. And changing cholesterol by these actionable means also involves changes risks from other factors.  But the program will display an estimate of benefits or debits to outlook for a specified serum cholesterol difference if this is specifically desired.

You can use the Life Ahead program to obtain an estimate of how different entered cholesterol values at present age will change risks of major disease and Well-Days of expected life.  (Cholesterol values entered can be deleted and changed if desired).  Just use the demo program and a diet entry of Demo diet weekly #1 to view the effects on a typical US man or woman of age 50, or enter your own age and physical activity and other factors for a more accurate effect for you.  To download the free Life Ahead program access

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