Professional Documents
Culture Documents
ATHEROSCLEROSIS:
THE
By Peter Libby
Scientists now agree that inflammation fuels the development and progression Igniting Trouble
of atherosclerosis: the dangerous accumulation of fat-laden deposits, or LACKING TOOLS to describe interac-
plaques, in the arteries. The old view that fat builds up on passive artery tions among cells and molecules, the an-
walls is no longer tenable. cients who first defined inflammation had
Inflammation can also cause certain plaques to rupture. Blood clots tend to focus on what they could see and feel.
to form over ruptured plaques and can then occlude arteries, leading to such Today we know that the outward signs
atherosclerotic complications as heart attack and stroke. reflect a pitched struggle playing out on a
Excess low-density lipoprotein (LDL), or bad cholesterol, in the blood can microscopic battlefield. After sensing
trigger arterial inflammation. And cholesterol-lowering therapies already (rightly or wrongly) that a microbial at-
cornerstones of treatment for atherosclerosis can reduce it. Strategies that tack has begun, certain white blood cells
interfere with inflammation in other ways are under study as well. the immune systems frontline warriors
A blood test that detects ongoing inflammation might prove useful as an convene in the apparently threatened tis-
adjunct to the cholesterol tests that doctors now employ to assess risk for sue. There they secrete an array of chem-
heart attack and stroke. icals intended to limit any infection. These
chemicals include oxidants (able to dam-
tivities in a tissue. gins when LDLs from the blood collect in Just as monocytes follow adhesion
The clearest picture of inflammations the intima, the part of the arterial wall molecules and chemokines into the inti-
role in the onset of atherosclerosis comes closest to the bloodstream [see illustra- ma, so do T lymphocytes, white blood
from investigations into low-density lipo- tion on next two pages]. At reasonable cells that represent a different branch of
protein, a.k.a. bad cholesterol. LDL par- concentrations in the blood, LDLs can the immune system. These lymphocytes
ticles, composed of fatty molecules (lipids) pass in and out of the intima, which con- also release cytokines that amplify in-
and protein, transport cholesterol (an- sists mainly of the endothelial cells that flammatory activities in artery walls. To-
other lipid) from their source in the liver line vessel walls, the underlying extracel- gether the foamy macrophages and a less-
and intestines to other organs. Scientists lular matrix (connective tissue), and a er number of T lymphocytes compose the
have long known that although the body smattering of smooth muscle cells (ma- so-called fatty streak, a precursor of the
CROSS SECTION
OF HEALTHY
CORONARY
ARTERY
Blood channel
Intima
Media
Adventitia
LDL
T cell
Endothelial cell
Monocyte
Adhesion Scavenger Foam cell
INTIMA
Modified LDL
molecule receptor Fatty droplet 1
Chemokine 2
3
Elastic tissue Inflammatory
Macrophage mediators
BIRTH OF A PLAQUE
1 Excess LDL particles accumulate in the
artery wall and undergo chemical
alterations. The modified LDLs then stimulate
2 In the intima, the monocytes mature into
active macrophages. The macrophages
and T cells produce many inflammatory
endothelial cells to display adhesion
molecules, which latch onto monocytes
(central players in inflammation) and T cells
mediators, including cytokines (best known
for carrying signals between immune system
cells) and factors that promote cell division.
3 The macrophages feast on LDLs,
becoming filled with fatty droplets. These
frothy-looking, fat-laden macrophages
(other immune system cells) in the blood. The The macrophages also display so-called (called foam cells) and the T cells constitute
endothelial cells also secrete chemokines, scavenger receptors, which help them ingest the fatty streak, the earliest form of
which lure the snared cells into the intima. modified LDLs. atherosclerotic plaque.
Cytokines that
disrupt smooth
muscle cells
Rupture
Tissue factor
Blood channel
Plaque
4 Thrombus
CUTAWAY VIEW OF
5 ARTERY AFFLICTED BY
ATHEROSCLEROSIS
KEITH KASNOT
The ancients who first DEFINED INFLAMMATION had to focus on what they
could see and feel. Today we know that the outward signs reflect
a pitched struggle playing out on a MICROSCOPIC BATTLEFIELD .
the problem, treated arteries often be- connections between other risk factors absence of infection. Nevertheless, cir-
come reoccluded fairly rapidly appar- and inflammation with the intensity ac- cumstantial evidence suggests that certain
ently in part because the treatments can corded to LDL, but they have uncovered microorganisms, such as herpesviruses or
elicit a robust inflammatory response. suggestive links. Diabetes, for instance, el- the bacterium Chlamydia pneumonia (a
evates glucose levels in the blood; this sug- frequent cause of respiratory infections),
Beyond Bad Cholesterol ar can enhance the glycation, and thus the could well induce or aggravate athero-
ALTHOUGH LDL frequently sparks the inflammatory properties, of LDL. Smok- sclerosis at times. C. pneumonia, for in-
sequence of events I have outlined, scien- ing causes oxidants to form and might stance, appears in many atherosclerotic
tists have identified several other factors hasten the oxidation of LDLs constituents, plaques, and its constituents can evoke
that unequivocally increase a persons thereby fostering arterial inflammation inflammatory responses by macrophages
risk for atherosclerosis or its complica- even in individuals with average LDL lev- and by vascular endothelial and smooth
tions. Many of these risk factors, and a els. Obesity contributes to diabetes and muscle cells.
few still under study, exhibit intriguing in- vascular inflammation. High blood pres- Infections might also act from a dis-
flammatory properties. Before I describe sure may not exert direct inflammatory tance, in what I call an echo effect. When
some of those features, I must first point effects, but a hormone partly responsible the body fights infections, inflammatory
out that LDL probably plays an even larg- for much human hypertension an- mediators can escape into the blood and
er role in initiating and perpetuating ath- giotensin II appears to incite inflamma- travel to distant sites. These substances
erosclerosis than is generally recognized. tion as well; elevated levels of this hor- can, in theory, stimulate the white cells in
A much repeated statistic says that mone, then, might give rise to hyperten- atherosclerotic plaques, thereby prompt-
half of all patients who have angina or
THE AUTHOR
have had a heart attack do not have PETER LIBBY, who earned his M.D. from the University of California, San Diego, is chief of
above-average LDL levels a finding fre- cardiovascular medicine at Brigham and Womens Hospital, Mallinckrodt Professor of Med-
quently interpreted to mean that in such icine at Harvard Medical School, and co-editor of the sixth edition of Heart Disease, a clas-
individuals, LDL exerts no influence on sic cardiology textbook (see More to Explore, on page 55). He regards lifestyle modifi-
the atherosclerosis at the root of those cation as the cornerstone of cardiovascular prevention and practices what he preaches
disorders. But typical LDL levels in West- by running recreationally, albeit, he says, more avidly than swiftly.
IN THE PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE, BY PAUL M. RIDKER IN CIRCULATION, VOL. 103, PAGES 18131818; APRIL 3, 2001
lowest C-reactive protein levels. And subjects having the highest values for both cholester- prostaglandins, which generate pain and
ol and C-reactive protein confronted the greatest risk of all. Encouraged by such results, fever. Strong data from well-performed
researchers now hope to undertake a large study assessing whether basing treatment clinical trials indicate that aspirin shields
decisions on combined C-reactive protein and cholesterol testing will save lives. P.L. against heart attacks and, in some pa-
tients, against mini strokes (technically,
9
transient ischemic attacks, or TIAs). But
NINA FINKEL; SOURCE: HIGH-SENSITIVITY C-REACTIVE PROTEIN: POTENTIAL ADJUNCT FOR GLOBAL RISK ASSESSMENT
8.7 the low doses that afford this protection
probably reduce the clotting propensity of
8
blood instead of quieting inflammation.
7.2 Scientists have little clinical data relat-
7
ing to the effects of other NSAIDs on ath-
erosclerosis, and some evidence suggests
6.0 6
6.0 that selective inhibitors of the prosta-
glandin-producing enzyme COX-2 might
5.1 5 actually enhance thrombus development
Relative Risk
(as Quin 3
w
m t
cho easuiles o 2 2 e Pro
les red f C
h ctiv without undermining overall immunity.
ter
ol t by th oles 1 1 Rea
o H e r ter Low o f C-
DL atio ol est est iles But I suspect that a more practical strate-
cho of
les tota Low Quint
ter
ol) l
gy would concentrate on defusing the trig-
gers at the root of arterial inflammation.
THE NEW PICTURE of atherosclerosis explains why many heart attacks come from
out of the blue: the plaques that rupture do not necessarily
protrude very far into the blood channel and so MAY NOT CAUSE ANGINA.
cussion) might help by limiting inflam- of heart attack relative to the rate in a mations dark side including its ability
mation, thereby minimizing plaque build- matched group of patients who received to contribute to atherosclerosis and other
up and make existing plaques less likely no treatment. Such results need to be con- chronic disorders. Scientists continue to
to rupture. firmed in a much larger trial before doc- pursue a deeper understanding of inflam-
Recent analyses of the statins (widely tors can confidently treat patients on the mations role in atherosclerosis and to de-
prescribed lipid-controlling drugs) sup- basis of the combined test, although some cipher the devilishly intricate interactions
port this notion. They confirm that the physicians already incorporate tests of C- that ignite and drive the inflammatory
drugs can decrease inflammation in pa- reactive protein in their practices. processes in the arteries. These insights
tients. Experiments on isolated cells and Noninvasive methods for specifically should enable us to make further inroads
laboratory animals indicate as well that identifying vulnerable plaques might also against a disease of growing worldwide
the drugs anti-inflammatory effects may help pinpoint individuals who lack strong importance that causes extensive disabil-
not depend entirely on changing the con- warning signs of risk for heart attack or ity and takes far too many lives. SA