| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
1 Correspondence: Department of Medicine, Massachusetts General Hospital, GRJ 1328, 55 Fruit St., Boston, Massachusetts, USA. E-mail: freeman{at}frodo.mgh.haarvard.edu
Editor’s Note:
This piece by Dr. Freeman summarizes "Cholesterol: From Biochemical Riddle to Blockbuster Drug for Heart Disease," the most recent Breakthroughs in Bioscience published by FASEB (http://www.faseb.org/opa/PDF/11419_FASEB.pdf). The Breakthroughs in Bioscience series is designed to bridge the gap of understanding between researchers and the public on major scientific developments. Breakthroughs are coordinated and edited by FASEB’s Office of Public Affairs, under the direction of the Breakthroughs in Bioscience Committee and its advisors. Breakthroughs provide literary support to associations and organizations who channel them into the public’s hands, enabling lay readership to appreciate the fine points of science in such clinically significant developments as outlined here.
Interestingly, when presenting famed researcher Konrad Bloch with his Nobel Prize for cardiovascular research in 1964, the Rector of the Caroline Institute said, "Your intellectual accomplishments and the immense technical difficulties you had to overcome can only be grasped by the specialist, but their significance can be understood by all. Within the foreseeable future, your discoveries may provide us with weapons against some of mankind’s gravest maladies, above all in relation to cardiovascular diseases. Achievements like yours make it not unrealistic to look forward to a time when mankind will not only live under vastly improved conditions, but will itself be better." (www.nobelprize.org) This Breakthrough shows at least the partial realization of that optimistic prognostication.
Michael Brown and Joseph Goldstein, winners of the 1985 Nobel Prize in Medicine for discovering the LDL-receptor and its role in regulating cholesterol, speculated on a drug therapy that could increase the number of LDL-receptors, simultaneous with a lesser demand for dietary regimens. They predicted (with good humor) "...it may one day be possible for many people to have their steak and live to enjoy it too" (1)
.
This year marks the 19th anniversary of the introduction of the first cholesterol-lowering HMG CoA reductase inhibitor, or statin, into clinical practice in the U.S. That first statin, lovastatin, is now available as a generic drug and several of the other statins will soon follow suit. These cholesterol-lowering drugs are among the most frequently prescribed medications in the world. Their impact on reducing coronary artery disease morbidity and mortality rates is among the best documented of clinical outcomes in medicine. All of this seems perfectly straightforward today, but one has only to go back 20 years to the pre-statin era to find a time when most patients with elevated serum cholesterol levels, even those who had previously experienced a heart attack, were not treated with any cholesterol-lowering medication. At that time, most Americans did not have their cholesterol levels routinely measured and very few had heard of the cholesterol-carrying lipoproteins [low density lipoprotein (LDL) and high density lipoprotein (HDL)] that transport the bulk of cholesterol in the blood. Although the link between elevated serum cholesterol levels and the risk of heart disease had been known for decades prior to lovastatin’s discovery, two seminal events occurring in the 1980’s, facilitated the translation of that knowledge into today’s clinical practice of routinely measuring and treating elevated serum cholesterol levels: the first event was the demonstration that a reduction in the level of total and LDL cholesterol results is a health benefit; and the second was the discovery and development of an effective and well-tolerated, pharmacological agent that could produce desirable cholesterol levels.
Prior to statin treatment, lowering an elevated LDL cholesterol level was not easy. Although dietary changes can sometimes produce profound reductions in blood cholesterol in any one individual, the typical response to dietary advice in human clinical trials is a cholesterol drop of 5-10%. Partly this is due to the difficulty of adhering to a low cholesterol/low saturated fat diet and partly this is because elegant homeostatic mechanisms defend cholesterol levels in the body via the regulation of its synthesis in many tissues, particularly the liver. The modest effects of diet on blood cholesterol made the performance of a large-scale trial to determine the impact of diet on heart disease prohibitively expensive and scientifically risky. The pre-statin cholesterol medications, chiefly resin-like polymers that bound bile acids in the gut and very high doses of the B vitamin, niacin, were able to reduce blood cholesterol levels only modestly and they did so at a side effect price that many patients and doctors found unacceptably high. Despite these barriers, the National Heart Lung Blood Institute undertook a landmark trial to test the cholesterol hypothesis of heart disease, using one of the bile acid resins, cholestyramine. Published in 1984, this study demonstrated a 19% reduction in coronary heart disease death or heart attack rates even though the total blood cholesterol level was only reduced by 8% in the drug-treated group (2)
. Although investigators in the field of cardiovascular disease immediately recognized the importance of this finding, the translation of these results into clinical practice was limited because of the difficulties associated with the use of the resin drugs and their modest impact on blood cholesterol levels.
With the discovery and development of the statins, the barrier blocking widespread cholesterol-lowering treatment was demolished. In relatively short order, several more landmark studies were published in the early and late 1990s that demonstrated that statins could reduce coronary heart disease death and heart attack rates by 20–50%, depending on the height of the initial blood cholesterol level and the presence or absence of other risk factors for heart disease (3
4
5
6
7
8
9
10)
. Statins were shown to work in men and women, the middle-aged and elderly, and those with and without preexisting heart disease or diabetes. The current debate in the cholesterol field is how much lower we should push LDL cholesterol values below the current nationally recognized optimum of 100 mg/dl (11)
. Without statins, and the basic and clinical science achievements of the mid and late 20th century that underlay their development, that conversation is barely imaginable.
As the 21st century opens, the problem of atherosclerosis is not, however, solved. Statin therapy markedly reduces future coronary events in patients who have had a previous heart attack, but it falls far short of providing a definitive cure. The basic science advances of the past 20 years have demonstrated a critical role of the immune system, particularly the macrophage and T lymphocyte, in promoting the development and then catastrophic rupture of the coronary plaque that causes heart attacks or sudden coronary death (12)
. These immunological responses appear to be initiated by high levels of cholesterol infiltrating the artery wall, but once the process has begun, even dramatic reductions in blood cholesterol appear to be incapable of completely halting it. The almost forgotten lipoprotein, HDL, has emerged as the next frontier in lipoprotein biology. HDL has been shown to modulate immune responses and to participate in a pathway that is designed to remove cholesterol from the artery wall. Animal data strongly suggest that were we able to effectively and intelligently disrupt the immunological processes directly, or via the enhancement of HDL function, we would have additional, valuable therapeutic approaches to preventing heart disease (12
,13)
. Combined with statin therapy, it is likely that these approaches could further dramatically reduce the atherosclerotic process at a time when our growing population of older, more obese, and diabetic Americans make likely the recrudescence of heart disease in the next few decades. As was true in the interregnum period from 1984 to 1987, we clearly know what we would like to do therapeutically; we simply do not yet have the tools in hand to do it. Those tools and the demonstration of their value are likely to follow in the next decade. When they do, they will follow in the basic and clinical science footsteps that produced the LDL cholesterol-lowering successes we now enjoy.
REFERENCES
Related Articles
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
