Science links high LDL cholesterol with heart disease
Another argument that supports targetting LDL as the focal point for preventing cardiovascular disease lies with Michael S. Brown and Joseph L. Goldstein's revolutionary contribution to the understanding of how cholesterol is regulated in the body.
Brown and Goldstein discovered small proteins located on cell surfaces that function to take up circulating LDL from the bloodstream. They revealed details of the intricate connection between LDL receptors, the level of circulating LDL cholesterol, and the risk of atherosclerosis. If you recall, LDL receptors (located primarily on the surface of liver cells) help clear LDL from the bloodstream. Therefore, the greater the number of receptors, the lower the blood level of LDL. In 1984, Brown and Goldstein reported their groundbreaking discovery in Scientific American: "The LDL receptor hypothesis states that much of the atherosclerosis in the general population is caused by a dangerously high blood level of LDL resulting from failure to produce enough LDL receptors." The next year, they received the Nobel Prize in Physiology or Medicine for elucidating the role of LDL receptors in cholesterol metabolism and the atherosclerotic process.
Building on their work, researches have since been able to identify ways to increase the production of LDL receptors. In fact, several of the foods in the Cholesterol Down Plan help fight LDL by affecting these receptors. Eating almonds, for instance, helps increase the affinity of LDL particles for the receptors, and in test-tube experiments, an extract of Red Delicious apples has actually been shown to stimulate the growth of more LDL receptors on liver cells. Similarly, soy protein and its associated isoflavones were found to increase the production of LDL receptors in cells. The bottom line: increasing LDL receptors lowers your "bad" LDL cholesterol and is as easy as following the Cholesterol Down Plan.
Over the past several decades, scientific studies have continued to yield results supporting the fact that high LDL is the principal contributing factor in the development of atherosclerosis. Relevant research ranges from large-scale population studies (epidemiological research) to clinical intervention (such as studies showing that lowering LDL by means of powerful statin medications reduces heart disease) and animal research.
Large-scale research
Data derived from large-scale studies across different populations (comparing people from different countries, known as epidemiological research) shows that the higher the cholesterol level, the greater the degree of atherosclerosis evident in the population. This type of research illustrates that countries such as the United States - where the average LDL level has been estimated at approximately 123 mg/dL - have higher rates of heart disease than countries with lower average LDL numbers (under 100 mg/dL is considered by NCEP as an optimal goal for most individuals).
In 1994, two British scientists, Malcolm Law and Nicholas Wald, compiled an in-depth data analysis of the relationship between blood cholesterol level and rates of heart disease. Law and Wald estimated the average total cholesterol level of individuals residing in seventeen different countries over a forty-year time period and found tremendous variability: from 147 mg/dL (rural China) to 270 mg/dL (Finland) (a total cholesterol value of under 200 mg/dL is considered optimal by the American Heart Association). The three main conclusions were: the countries with the highest cholesterol levels had the greatest risk for heart disease; the increase in risk is specifically associated with an elevation in LDL cholesterol, which is determined by diet; and a difference in total cholesterol or LDL of just 23 mg/dL between countries was associated with a mean difference in death rates of 37 percent.
Another classic large-scale study, the famed "Seven countries Study," provides additional support for the contention that high LDL cholesterol is firmly linked to the development of heart disease. Pioneering nutrition researcher Ancel Keys analyzed and compared the diet and lifestyles of thousands of people living in Finland, Italy, Greece, the Netherlands, Japan, the United States, and Yugoslavia from 1958 to 1970. The data revealed that in countries where people consumed a diet high in saturated fat, there was a correspondingly high level of blood cholesterol and a significantly higher rate of heart attack and stroke. In fact, the death rate for heart disease in southern Europe (where the diet is low in saturated fat and the inhabitants have correspondingly low cholesterol levels) was half that of northern Europe and the United States. Thus, Key's research revealed for the first time that risk of death from cardiovascular disease is strongly related to the level of saturated fat in the diet and the corresponding amount of blood cholesterol.
Databases of American communities
On going studies of American communities have created enormously powerful databases that help scientists compile risk factors for the development of cardiovascular disease. Well-known studies such as the Multiple Risk Factor Intervention Trial (MRFIT), the Chicago Heart Association Detection Project in Industry (CHA), and the Peoples Gas Company Study (PG) have tracked thousands of Americans for years to find that a rise in cardiovascular disease risk is directly linked to high levels of blood cholesterol.
In an effort to ascertain the long-term impact of high cholesterol on risk of death from heart disease or other causes of death, scientists performed an analysis combining data from groups of younger men (eighteen to thirty-nine years at baseline) drawn from the MRFIT, CHA, and PG studies. The men (approximately 80,000) were evaluated at baseline and then cause of death was determined at the long-term follow-up, which differed among studies (twenty-five years for CHA, thirty-four years for PG, and sixteen years for MRFIT). The main findings were as follows: there was a strong relationship between high blood cholesterol level in younger men and long-term risk of death from heart disease, and young men with favorable total cholesterol values (<200 mg/dL) lived a substantially longer period of time (3.8 to 8.7 years longer) compared to those men with an initial total cholesterol level greater than 240 mg/dL. Note that although LDL was not recorded in these studies, a high total cholesterol value implies high LDL, as LDL carries the bulk of the cholesterol in the bloodstream.
Another large-scale study specifically examined the relationship between LDL cholesterol level and risk of heart disease. Researchers from the National Heart, Lung, and Blood Institute recruited a total of 12,339 healthy, middle-aged men and women (forty-five to sixty-four years old) from communities in North Carolina, Mississippi, Minnesota, and Maryland to participate in the Atherosclerosis Risk in Communities Study (ARIC). Heart attacks and death from heart-disease-related events were determined over a ten-year follow-up period. There was a strong association between high LDL cholesterol and risk of death. What's more, in both men and women, a much lower risk of death was observed in subjects with an LDL value of less than 100 mg/dL, prompting the researchers to categorize an LDL cholesterol value of less than 100 mg/dL as optimal.
New and exciting data from the same ARIC study recently surfaced that graphically illustrates the dramatic lifelong benefit of even moderate reduction in LDL levels. A small percentage of the black volunteers had a genetic mutation that kept the LDL level of these particular subjects approximately 28 percent lower (average LDL was 100 mg/dL) than other study subjects (average LDL was 138 mg/dL). During the fifteen years of follow-up, only one of the eighty-five volunteers with the genetic mutation developed heart disease, compared to 10 percent of black subjects without the gene mutation. Remarkably, this 28 percent reduction in LDL translated into a reduction of almost 90 percent in the risk of heart disease. These results show the value of lowering your LDL level and keeping it down for life.
Reduce your risk
According to new research estimates, for every 1 percent reduction in LDL cholesterol, you reduce your risk of developing heart disease by approximately 2 percent. That means that if you can get your LDL down from, say, 160 mg/dL to 120 mg/dL, you would cut your risk of a heart attack by more than half.
Source: Alan R. Tail, 'Protease variants, LDL and coronary heart disease." New England Journal of Medicine 354 (2006): 1310-1312; Terje R. Pederson, et al, "Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian simvastatin survival study (45)," Atherosclerosis Supplements 5 (2004): 99-106.
Animal studies
The data drawn from animal research also provide sufficient evidence to incriminate LDL as the main villain in heart disease. For instance, experimental animals fed a high-fat diet to induce an elevated level of circulating LDL exhibit high rates of atherosclerosis, similar to that of their human counterparts with high LDL levels.
In a classic study of diet - included atherosclerosis in hamsters conducted by a group of Romanian researchers, male hamsters were fed a diet high in saturated fat and cholesterol. After four weeks, their LDL shot up fourfold; after ten months, it had reached thirteen times the control hamsters level. The resulting atherosclerosis process was immediately evident in the hamsters aortas, where huge masses of plaque had amassed that would eventually lead to blood clots and, finally, heart attacks.
Another more recent study in baboons showed that a diet high in cholesterol and saturated fat resulted in a significant elevation of LDL cholesterol. Ten baboons were placed on the artery - clogging diet for a period of seven weeks. A section of the baboons' arteries was then surgically removed and examined microscopically. Along with the significant elevation of LDL cholesterol, researchers discovered severe inflammation within the arteries and evidence that a series of events termed "endothelial dysfunction" had occurred, a situation that promotes early atherosclerotic changes. Granted, hamsters are hamsters, baboons are baboons, and humans are humans, but the research shows that our bodies work similarly: across the board, increased levels of LDL mean an increased risk of atherosclerosis. For further evidence of the connection between the two, let's turn to compelling new findings taken from results of five large-scale scientific research studies employing statin drug therapy.
Statin studies show the benefits of lower LDL
Each of these studies clearly demonstrates the health benefits of lowering LDL cholesterol to values well under the previous goal for high-risk patients of less than 100 mg/dL. In fact, they are what prompted the government to issue its ATP III½ revision, including the new ultra - low LDL target. The five studies are the Heart Protection Study (HPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), the Antihypertensive and Lipid - Lowering Treatment to Prevent Heart Attack Trial - Lipid Lowering Trial (ALLHAT-LLT), the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection - Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22).
Source: Cholesterol Down, Foreword by Jennifer H. Mieres, M.D. |
