Posted by: Joseph Dixon | May 25, 2014

Science: Unintended Consequences; Ancel Keys, Cholesterol, and the Transition to an Obese Society; Part X, The Framingham Study, the Mount Everest of Epidemiological Studies

Much of what we know about risk factors and Coronary Heart Disease (CHD) has come, first and foremost, from the Framingham study.   When Ancel Keys published in 1963 his fifteen year follow-up study on coronary heart disease in Minnesota Businessmen, he acknowledged that his study was too small, and also it did not follow a representative sample of men as most of the men in the study were from a high socio economic level (discussed in an earlier chapter). In the discussion section of the article, Dr. Keys compared the Minnesota study with that of several other studies ongoing at the time, including the Framingham study. Dr. Keys entered all the data from his subjects and data from the Framingham study (after 8 years of follow-up) and data from subjects from another study that was being conduct in Albany, New York, into table 5 of the article. The analysis of this table was straight-forward. Even back then, in the early portions of the Framingham study, it was clear that “the incidence (of CHD) rises sharply with increasing pre-disease serum cholesterol level.” In the last paragraph of the article, Dr. Keys wrote,

“Comparison with similar follow-up data from Framingham, Massachusetts, Albany, New York, and Chicago, show a high degree of concordance. In all series relative weight had least significance and the incidence of coronary heart disease rose continuously with the serum cholesterol level. With men classified according to pre-disease cholesterol level, about 80 per cent of the total variance in relative subsequent risk is accounted for by regression of risk on the cholesterol value raised to any power from 2 to 3 and the correlation between observed and predicted relative risk is of the order of r = 0.9.”

Of course, Ancel Keys went on to set up the Seven Countries study and Dr. Keys’ work was very instrumental in the design of the Framingham study as an epidemiological study to discover risk factors that contributed to the development of CHD.

Why was the Framingham study conducted?

Just in fall 2013 a review of the history of the Framingham study was published because it was the 65th anniversary of the start of the Framingham study (FS) in 1948.

The FS had its roots in the heart disease suffered by President Franklin D. Roosevelt, and the masses of Americans with heart disease (roughly half of all Americans) at that time. In 1948, President Harry Truman signed into law The National Heart Act, which was enacted because “the Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure…”   The city of Framingham was chosen as the site of a study because it was a small city comprised mainly of middle class residents of predominantly European origin (which resembled the population of the US at the time) and it was also close to Boston and the expertise of the Harvard Medical School.

The plan was to recruit 6000 out of the 10,000 adult residents of Framingham and follow them for as long as possible to determine what factors were important to the development of CHD. The first enrollees were examined on September 29, 1948.

By 1952 the first cohort of 5209 residents had been recruited, and the first scientific paper from the study was published in 1957. The paper reported that CHD was 4 times higher in residents with high blood pressure compared to residents with normal blood pressure, an observation that was quite unique at the time. Several hundred papers have been published from the Framingham Study.

In 1971 the Framingham study commenced the recruitment of the children of the original residents and their spouses. The second and third directors of the study (Thomas Dawber, M.D., William Kannel, M.D.) wished to find out how to prevent CHD, instead of finding treatments for patients who were already ill, as was the main emphasis of the practice of medicine at the time. In taking this approach, they were the first to use the term, “risk factor” in their work and publications. The Framingham Risk Score later became the basis for the risk calculator used by the National Cholesterol Education Program.

The first major findings in the FS centered around the role of hypertension in the development of CHD, and the investigators also studied how the heart itself changed with the disease. They reported the novel finding that residents with asymptomatic left-ventricular systolic dysfunction suffered heart failure at greatly increased rates.

In addition to direct measures of heart health, the FS pioneered the use of metabolic risk factors to predict disease. Following the lead of Ancel Keys, the Framingham investigators measured serum cholesterol, and then went on to measure lipoprotein fractions with ever increasing precision. In 1977 they reported the landmark observation that HDL cholesterol concentration was inversely related to the incidence of CHD. This was a major advance in the study of lipid metabolism and the development of CHD. Their observations were eventually supported by other studies such as:

Gerd Assmann, Helmut Schulte, Arnold von Eckardstein, Yadong Huang; High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 124 Suppl. (1996) S11-S20

Gerd Assman HDL Slide 1996

We now understand the different functions of HDL and LDL in the movement of cholesterol throughout the body, and this original observation from the Framingham study completely fits with the known functions of these lipoproteins.

In 2002 the FS began to recruit the third generation of participants, who are the grandchildren of the original residents. The multigenerational nature of the study lends itself to studies of the genetics of lipid metabolism and the development of CHD. Besides precisely defining the risk factor profiles for CHD, other major findings of the FS were:

1. Systolic pressure was superior to diastolic pressure in predicting CVD – April 1971

2. Type 2 Diabetes mellitus increases CVD mortality-Feb 1974

3. Non-rheumatic atrial fibrillation is a risk factor for stroke – Oct 1978

4. Postmenopausal estrogen use and smoking are linked to    CVD – Oct 1985

The observation from the Framingham study that HDL was protective against CHD explained some of the anomalies in the cholesterol story that were debated in the nutrition and medical fields. When serum cholesterol was very, very high, most likely it was due to a high LDL cholesterol. This corresponds with Ancel Keys’ observations that very high cholesterol concentrations were highly correlated with CHD across many countries. With intermediate cholesterol concentrations, the cholesterol in the blood could be the result of either changes in LDL cholesterol or HDL cholesterol. Therefore, with the insertion of the extra complexity that some cholesterol is hazardous and other cholesterol is protective, there was more variance in populations concerning the association of total cholesterol with CHD.

In fact, in some of the later reports from the Framingham Study, when the total cholesterol value was divided by the HDL cholesterol, the resulting value was a much better predictor of CHD than measuring LDL cholesterol (  )

This was confirmed recently by a study that was designed to test which lipoprotein or cholesterol parameter was more precise in its predictive value. Total cholesterol/HDL cholesterol was still as good as any other clinical chemistry measurement that is currently being performed in predicting the probability of CHD. (   )

New Knowledge about Blood Lipids and Lipoproteins from the Framingham Study and Concommitant Studies

We now know that there are two major pools of cholesterol in blood, with high levels of cholesterol in LDL being hazardous and high levels of cholesterol in HDL being protective.

LDL and HDL in Blood

Additional studies defined the roles of LDL and HDL lipoproteins.

LDL and HDL Roles Table

Roles of LDL and HDL in the Blood

LDL is formed from VLDL secreted by the liver. If LDL in blood is very high, LDL is able to enter the artery wall in the major conduit arteries of the heart. HDL, which is secreted in a cholesterol poor particle, permeates throughout the blood of the body and scours up any extra cholesterol (like a cholesterol vacuum cleaner) and delivers back to the liver. For many decades HDL keeps arteries from progressing to CHD. As with LDL receptors, the HDL concentration declines with age, therefore, this allows atherosclerotic disease to progress in older humans. Of course, humans with low HDL have higher risk for CHD.

Metabolism of HDL in Blood

Below is a theoretical breakdown of LDL and HDL cholesterol in blood with fairly extreme examples of a low serum total cholesterol with optimal levels of LDL and HDL cholesterol compared to a high serum total cholesterol with high risk factor levels of LDL and HDL cholesterol. At the bottom the Total cholesterol/HDL cholesterol is calculated and the high cholesterol example presents with an extremely high value of 8.

Theoretical LDL and HDL Breakdown

As the 1980s were approaching, more and more information was becoming available concerning risk factors for CHD. The Seven Countries study was responsible for showing that diet had a significant influence on CHD. The Framingham study more precisely defined the lipoprotein profiles that were either protective or hazardous.

But there were still many other factors that could influence health and disease. Obesity increased the development of CHD about 10%. Exercise was protective. And as we will find out later, other constituents in the diet could have effects on the development of CHD. But at this time, in the 1980s, most of the metabolic experimental evidence that was known concerned lipids. But many other discoveries were yet to come.


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