вход по аккаунту


Atherosclerosis Current concepts on pathogenesis and interventional therapies.

код для вставкиСкачать
Atherosclerosis: Current Concepts on
Pathogenesis and Interventional Therapies
Frank M. Yatsu, MD, and Marc Fisher, MD
Atherosclerosis, the primary pathological condition accounting for most stroke syndromes, has been the intense focus
of epidemiological, basic, and clinical investigations. Since these studies have direct bearing on the prevention of
atherothrombotic brain infarction, this review emphasizes those advances in treatment resulting from their findings.
The two most prominent theories on the pathogenesis of atherosclerosis relate to aberrations in lipoprotein metabolism
and to enhanced proliferation of smooth muscle cells; likely, the theories are complementary. As a practical guideline
for preventive therapy, the importance of using the total cholesterol level is stressed, although finer distinctions must
rely on the low-density and high-density lipoprotein concentrations and their normalization. Since prevention of
stroke may ultimately be its most effective therapy, consideration of cholesterol level, akin to strategies for preventing
coronary heart disease, and efforts to avert platelet adhesion or aggregation and coagulation are warranted.
Yatsu FM, Fisher M. Atherosclerosis: current concepts on pathogenesis and interventional therapies.
Ann Neurol 1989;26:3-12
Brown and Goldstein's major contributions on the role
of lipoprotein receptors in regulating cellular cholesterol metabolism have provided new understanding of
the molecular basis of atherogenesis and helped focus
attention on the potentially preventable nature of this
disease, the primary cause of stroke [l, 2}. Nearly
simultaneously, clinical studies disclosed the value of
reducing serum cholesterol in hypercholesterolemic
males in decreasing coronary heart disease (CHD) C3f.
These two events prompted this review of the current
status of our rapidly advancing understanding of atherogenesis. Emphasis is placed on those aspects of epidemiology, risk factors, molecular pathogenesis, and
potential interventional therapies that directly affect
reduction or prevention of atherothrombotic brain infarcts (ABIs).
Atherothrombotic stroke remains the most prominent stroke syndrome despite a 25% reduction in its
incidence over the past two to three decades {4-61. A
primary factor responsible for this decrease is control
of hypertension, but the role of the reduction in blood
cholesterol levels and smoking and other risk factors
cannot be minimized [ 3 , 7-151. Efforts to reduce atherosclerosis by reducing risk factors have been a longtime campaign of the American Heart Association and
others including the American Medical Association
C97. As greater insights into the pathogenesis of atherothrombotic stroke are gained, and particularly as we
learn to reduce atheroma by initiating regression, patients at risk for ABI should benefit.
A large number of investigations into the epidemiology of atherothrombotic strokes have been undertaken to uncover clues for prevention. The Framingham Study, in which over 5,000 individuals were
reexamined biannually, confirmed the conventional
roster of risk factors for atherothrombotic stroke,
which is more or less the same as that for CHD. These
factors include hypertension, smohng, diabetes mellitus, and previous strokes and cardiac disease [S-151.
Past epidemiological surveys have not demonstrated a
firm relationship between obesity, sedentary life, or
stress and atherothrombotic strokes, but because these
factors are risks for CHD, they likely play a role, as
recent studies suggest [13-151.
In addition to these clinical risk factors, an association exists between atherothrombotic stroke and
reduced serum levels of high-density lipoproteins
(HDLs) (16-211, an association also seen with C H D
122, 231. However, elevated levels of low-density lipoproteins (LDLs) do not correlate with the occurrence
of atherothrombotic stroke, unlike the situation with
CHD. Nevertheless, because generalized atherosclerosis reflects a common pathogenetic process, lack of
correlation between elevation of LDL and incidence of
ABI may reflect the age-related decline of LDL, while
reduction of HDL with ABI may represent persistence
of a preexisting abnormality into the later years, when
ABI tends to occur [24}. Despite the complexities of
the way in which lipoprotein is regulated, the postu-
From the Department of Neurology, University of Texas Health
Sciences Center, Houston, TX.
Address correspondence to Dr Yatsu, Department of Neurology,
University of Texas Healrh Sciences Center, 6431 Fannin Street,
suite 7.044-MSMB9 Houston, TX 77030.
Received Dec 31, 1987, and in revised form Apr 25 and Dec 28,
1988. Accepted for publication Jan 2, 1989.
Copyright 0 1989 by the American Neurological Association 3
lated roles of LDL and HDL suggest that measures to
reduce LDL and raise HDL to prevent ABI merit further exploration. Inexplicably, in the Framingham
Study, women with reduced levels of LDL were at
increased risk for ABI {231; however, an association
with reduced HDL may likely be contributory 1231.
Elevation of lipoprotein [a) may also correlate with the
incidence of ABI [25}.
Pathological, Histological, and Chemical
Features of Atherosclerotic Lesions
Atheromatous lesions are histologically similar in various arteries of the human body, although cerebral arterial lesions are predominantly fibrous and relatively
smooth, as opposed to being complex with ulcerations
and calcifications. Mature atheroma is composed
primarily of three constituents: (1) proliferated cells,
predominantly smooth muscle cells; (2) lipids, both
intracellular and extracellular, primarily cholesterolesters; and (3) connective tissue elements such as elastins and glycosaminoglycans 12, 261. In addition, the
mature atheroma is characterized by the presence of
monocyte-derived macrophages, which are frequently
lipid laden and hence called foam cells. Some foam
cells are also derived from arterial smooth muscle cells
127, 281.
Each of these various elements has been the focus of
intense research. The two most prominent theories of
atherogenesis relate to the role of smooth muscle cell
proliferation as an injury-healing response of the vessel
endothelium, and the lipid hypothesis, which postulates a primary role for abnormal lipoprotein metabolism and excess accumulation of arterial lipids, which
presumably provokes the atheromatous process. In addition, it is believed that reverse cholesterol transport
plays an important role in atheroma regression. Reverse transport refers to those mechanisms by which
tissue cholesterol is delivered from the periphery, including the vascular interstitium, to the liver for disposal, primarily as bile 129, 301.
Each of these three general theories is reviewed further to gain insights into therapeutic interventions designed to reverse or prevent atheromas.
Injury-Healing Theory of Atherosclerosis, or
Smooth Cell Proliferation
The cellular participants in atherosclerotic plaque formation include endothelial and smooth muscle cells,
blood monocytedtissue macrophages, platelets, and
lymphocytes, while noncellular plaque constituents include lipids, proteoglycans, collagen, calcium, and
fibrous tissue elements 1311.
Studies of plaque evolution in experimental animals,
primarily swine and nonhuman primates, have shed
light on the cellular biological features of atherogenesis. In a nonhuman primate model, Faggiotto and col4 Annals of Neurology Vol 26 No 1 July 1989
leagues have shown that the earliest response (within
12 days) to dietary hypercholesterolemia is widespread
adhesion and subendothelial migration of monocytes
132, 333. Subsequently, these monocytes become tissue macrophages, accumulate intracellular lipid, and
assume the characteristic features of foam cells. Early
arterial lesions resemble fatty streaks, the earliest lesion of atherosclerosis. Over the next 3 to 4 months,
adventitial, lipid-laden smooth muscle cells migrate
and proliferate concurrently with monocyte/macrophage foam cells. At 5 to 8 months, endothelial cell
retraction with platelet accumulation and smooth muscle cell proliferation are observed, and the arterial lesions resemble fibrous plaques. These experiments
suggest that the early stages of atherogenesis have an
inflammatory component 134, 351. The various cellular
and noncellular elements and their dynamic interactions involved in the maturation of fatty streaks to
fibrous plaques and advanced atheromatous lesions
have been incorporated by Ross into the “response to
injury hypothesis of atherogenesis” [36, 371 (Fig 1).
Ross advocates a crucial role for the proliferative
response in atherosclerosis and concludes that various
conditions injurious to the vascular endothelium, such
as hypertension or increased levels of LDL, may initiate the cellular interactions leading to atherosclerotic
plaque formation 136, 371. Critical to the proliferative
response are postulated growth factors secreted by
various cells, such as platelets, which adhere and aggregate to the denuded endothelium and release plateletderived growth factor (PDGF) [381. PDGF is a
30,000-dalton protein made up of an A and a B subunit united by two sulfhydryl bonds. The B subunit is
strongly homologous with a protein (v-sis) coded for
by the simian sarcoma transforming virus 1381. In addition to platelets, other cells such as macrophages produce growth factors f381. Elucidation of the molecular
biological features of these growth factors could provide a means of controhng atherogenesis by gene regulation.
Lipid Hypothesis, or Abnormal Liproprotein
Metabolism in Atherogenesis
Cholesterol metabolism in the body can be analyzed in
terms of two pathways: (1) dietary intake and liver
synthesis and (2) reverse cholesterol transport from
tissue to bile.
Simply stated, the lipid hypothesis asserts that excess cholesterol in the serum, derived either from endogenous synthesis or dietary sources, initiates atherosclerosis by accumulating in endothelial cells and
provoking atheroma growth. Cholesterol, synthesized
in the liver at the rate of nearly one gram daily, is
packaged in a water-soluble protein of low density and
called very low-density lipoprotein, a term derived
from early techniques relying upon relative densities
Fig 1. Injury-healing hypothesis of atherosclerosis.According to
this hypothesis, advanced intimal proliferative lesions o f atherosclerosis may proceed bJ at least two pathways. The p a t h a y
demonstrated by the long arrows dramatizes changes seen in experimentally induced hypercholesterolemia. Endothelial injury
(A)provokes growth factor secretion (short arrow) from adhering platelets. Monocytes also attach to the endothelial cells (B)
which secrete their own growth factors (short arrow). Subendothelial migration of monocytes and their conversion to m c ropbages may lead to fatty-streak formation. Thesefatty streak
m y become converted to fibrousplaques (long arrow from C to
F ) through release ofgrowth factors bJ macrophages or endotbelial cells or both. Mamphages may lose their endothelial cover,
resulting in platelet attachment (D). Thus, there are three
sources for potentially atherogenic growth factors: platelets, mcrophzges, and endothelium (short arrows). Smooth muscle cells
in the proliferative lesion ( F ) m y form and secrete growth factors
such as platelet-dwved g m t h factor (short arrows). A n alternate pathway for the development of advanced atherosclerotic lesions is shown by the arrows from A to E to F.The endothelium may be injured but remin intact; the inmeased
endothelial turnover, however, may result in growth factor formation bJ endothelial cells (A). As a result, smooth muscle cells
are stimulated to migratefrom the media to the i n t i m , accompanied by endogenous production of platelet-hived growth factor
by smooth muscle as well as growthfator secretionfrom the “injure@ endothelial cells (E).These interactions could lead to
fibrow plaque formation and progression t o the advanced lesion
(F). LDL = low-density lipoprotein. (Reproduced b pmisszon
from Ross R 1361.)
for lipoprotein separation 139-417. In the bloodstream, rapid alteration of lipids by enzymes, such as
lipoprotein lipase and lecithin cholesterol acyl transferase, causes serial conversion of very low-density lipoproteins to an intermediate-density lipoprotein and
then to an LDL, which is the final vehicle for delivery
of cholesterol to peripheral tissues (Fig 2).
Elucidation of LDL‘s interaction with cell membranes led to an understanding at the molecular level
of cell receptors in general and offered clues to the
mechanisms involved in atherogenesis. The observation that normal fibroblasts down regulate endogenous
cholesterol synthesis in proponion to the amount of
cholesterol added (as LDL) to the incubating media,
whereas fibroblasts from patients with familial hypercholesterolemia do not, provided the clue that a membrane factor in these latter cells prevents cellular entry
O ~ L D L 142,431 ( ~ i 3).
Subsequent investigations yielded the observations
that the receptor is bound to the apoprotein B (B100)
of LDL and that the receptor itself is composed of five
distinct portions and has an approximately 800-aminoacid sequence (Fig 4). Molecular biological studies
have now determined the gene loci for the LDL receptor and the size of the D N A and the messenger RNA
and have identified specific molecular defects accounting for various genetic diseases that involve various
portions of the receptor [42,43] (Fig 5).
Neurological Progress: Yatsu and Fisher: Pathogenesis and Therapies of Atherosclerosis 5
Amino acids
Fig 2. Cholesterol influx. Cholesterol influx, or the delivgi of
cholesterol to peripheral tissues, represents both dietary and endogenously synthesized cholesterol. Dietary cholesterol is '$padaged"for uptake in chylomicra, which become serially altered and
metabolized in the circulation t o form so-called chylomicron remnants before their uptake and i3001ingt'with endogenously synthesized cholesterol in the liver. For peripheral utilization, cholesterol is packaged in a protein coat of very low-density lipoprotein
(VLDL), which is serially altered .by plasma enzymes to add and
delete lipidf and proteins to form an intermediate density lipoprotein, which is not shown in the diagram, andfinally low-density
lipoprotein (LDL), which has the single surface apoprotein B
requiredfor cellular uptake through LDL receptors.
Attempts have been made to unify the lipid hypothesis with the injury healing theory 1441. For example, Steinberg proposes that native LDL is modified
in vivo to an acetylated or oxidized form, which is
more readily absorbed by the macrophage scavenger
receptor than is native LDL 1441. Modified LDLproduced by incubating native LDL with endothelial
cells, smooth muscle cells, and macrophages-has cytotoxic and chemotactic properties that may initiate
and propagate many of the observed cellular events
associated with atherogenesis [45-47}.
Reverse Cholesterol Transport, or Cholesterol
Efflux from Tissue to Liver for Bile Formation
The efff ux or reverse cholesterol transport mechanism
of delivering cholesterol to the liver is poorly defined.
Reverse cholesterol transport is more than theoretically important to the cause and therapy of atherosclerosis because it offers a means of achieving atheroma
regression-that is, the leaching of lipids from atherosclerotic lesions.
The concept of reverse cholesterol transport grew
out of the observations that serum HDL correlates
6 Annals of Neurology Vol 26 No 1 July 1989
Pig 3. Route of low-density lipoprotein (LDL) receptor in mammalian cells. The LDL receptor begins its life in the endaplamic
reticulum, from which it travels to the Golgi complex and then
the cell surface. LDL (theprotein-cholesteryl ester complex) combines with the LDL receptor of the cell surface, migrates to the
coatedpit, and then is endqtosed as a coated vesicle. The LDL
receptor is recycledfrom the endosome to the cell surface, while the
LDL moiety is transferred to the lysosom, where tt is acted upon
at reducedpH .by hydrolytic enzymes. The cholestml is freed and
provokes three intracellular processes (demonstratedby the direction of the arrow for up or down regulation): ( 1 ) down regulation of 3-hydroxy-3-methylglutavyl
CoA reductase (HMG CoA
reductase), (2)down regulation of LDL receptors, and (3) up
regulation of acyl-CoA-cholesterol acyltransfwase (ACAT).
Thefirst two processes accomplish the task of reducing intracellular synthesis and uptake of cholesterol, and the last implements
the storage form of intracellular cholesterol. (Reproducedby permissionfrom Brozun MS, GokdsteinJ L (l}.Copyright 0 1986
by The Nobel Foundation.)
inversely with the incidence of CHD and that HDL is
both an effective acceptor of cholesterol from cells
loaded with cholesterol and an efficient donor of
cholesterol to liver hepatocytes for bile formation 14857). Two of the major HDLs are termed HDL3 and
HDL2. HDL3 particles have a diameter of 7 to 10 nm;
HDL2 particles are about twice that size. It is postulated that the conversion of HDL3 to HDL, may be
important in promoting reverse cholesterol transport.
The predominant apoprotein of the HDLs is apoprotein AI, while HDL2 possesses apoprotein E, which
may be Gritical for hepatic recognition that leads to bile
formation from cholesterol {58-60].
Monocyte-derived macrophage scavenging of excess
interstitial cholesterol and metabolically altered LDL is
believed to play a role in the process of reverse cholesterol transport 161-67). On the basis of OUT studies,
the smaller HDL3 is preferentially endocytosed by
macrophage receptors, packaged with both cholesterol
and apoprotein E, and exocytosed as a larger particle
identical with HDL2 or HDL1. We propose that this
HDL2 particle serves to enhance reverse cholesterol
transport and hepatic processing for bile formation.
- 1.
Ligand binding
292 amino
2. EGF precursor
-400 amino
3. 0-linked sugars
5 8 amino acids
22 amino acids
5. Cytoplasmic
50 amino acids
Fig 4. The law&nsity Itpoprotein (LDL) receptor. The LDL
receptor gene, on chromosome 19, spans approximately 45 kilobases and is & up of 18 exons separated by 17 intmns. The
receptor hax 5 domains. T h e j r s t (1) is the site for LDL binding. I t contains 292 amino acids and is notable for its highly
negatively charged amino acids. The second ( 2 ) domirz,which
has homology to tbe epidermal growthfactor (EGF) precursor,
contains approximately 400 amino acids. The third ( 3 ) domain
bears Winked sugavs and is 5 8 amino acids long. The fotrth
(4), or intrametabranous, segmenf is a 22-~mino-acidhydmphobicsequence. The$@ ( 5 ) domain is the cytopkasmic portion of
the LDL receptor and is 50 amino acids Eong. This sequence is
high& consemedpbylogeneticalIyjand is important in the receptor’s clwtering at coatedpits. (Reproducedly @mission fm
Brmun MS, GoUteinJL ill. Copyright 0 19886 by The Nobel
Furthermore, because calcium channel blockers stimulate scavenging of Cholesterol, use of these drugs may
augment reverse cholesterol transport, with resultant
atheroma regression [68}. Our in vitro and quantitative studies suggest that HDL3 conversion to HDL2 is
impaired in extracranial occlusive disease, suggesting
that reduced reverse cholesterol transport activity may
play a role in ABI.
Interventional Therapies to Prevent
Atherosclerosis and Induce Atheroma Regression
Epidemiological studies show strong associations between the presence of risk factors and atherosclerotic
complications of stroke and CHD, and impressive reductions in the incidence of these complications have
been achieved by reducing the incidence of these various risk factors (633. The most notable achievement in
reducing the occurrence and likely the severity of
strokes is detection and control of hypertension 1701.
In addition, results of the Lipid Research ClinicsCoronary Primary Prevention Trial (LRC-CPPT) indicate that reduction of serum cholesterol can reduce
CHD and, by extension, ABIs 13, 71, 72). In the
LRC-CPPT, over 3,000 asymptomatic middle-aged
men with hypercholesterolemia (> 260 mg/dl) were
assigned to a cholesterol-lowering diet either alone or
with cholestyramine. After 7 years on average, men
randomized to cholestyramine experienced significant
reductions in CHD. For the men on the low-cholesteroi diet plus cholestyramine, the decrease in coronary
end points was roughly parallel to the reduction in serum cholesterol. On average, LDL, the primary carrier
of cholesterol to tissue, declined by more than 20%
approximately 13% more than the reduction shown in
the diet-alone group, and this decline was associated
with a 24% reduction in CHD death and a 19% reduction in nonfatal cardiac myocardial infarctions.
In an editorial opposing the institution of cholesterol reduction in elderly patients suffering from
atherothrombotic brain infarction, we cited the lack of
studies showing any benefit of cholesterol reduction
plus the reality that many older individuals on fixed
incomes cannot afford the special diets f73f. Because
the LRC-CPPT study showed beneficial results, reconsideration of low-cholesterol diets for the elderly is
warranted. Although this recommendation is arguable
1741and may not be cost-effective in the elderly 175771, we believe it prudent to recommend cholesterollowering therapy to asymptomatic adults who are at
risk for atherosclerosis, such as those with hypertension, diabetes, and hyperlipidemia 17, 78-82).
The primary group requiring therapy are those adult
patients with serum cholesterol over 240 mg/dl. Simple dietary modifications that require dietetic consultation have been recommended by the American Heart
Association and by the Scientific Council of the American Medical Association 191. They include elimination
or reduction of animal meat, eggs, butter, and milk and
substitution of these items with fish or poultry, margarine, and skimmed or low-fat milk.
Drugs, available as an adjunct to the dietary restriction of cholesterol and saturated fats, accomplish their
task by either binding bile in the intestine, reducing
cholesterol synthesis in the liver, or enhancing cholesterol disposal by the liver. Drugs that bind bile (bile
sequestrants) include cholestyramine, which was used
in the LRC-CPPT 131. Cholestyrarnine reduces serum
cholesterol by interrupting the enterohepatic cycle for
bile, thereby stimulating the liver to process more
cholesterol for bile formation, which in turn reduces
s e m cholesterol 1831. Hepatic synthesis of cholesterol can be reduced with clofibrate (Atromid-S), nicotinic acid, and a variety of other drugs such as beta-
Neurological Progress: Yatsu and Fisher: Pathogenesis and Therapies of Atherosclerosis 7
FH 380-J.D
FH 7 6 3
FH 683
o f 4 bases)
Fig 5 . Mutations affeing the cytoplasmic domam of the lowhnsity lipoprotein (LDLJ receptor in threefamilial hypescholesterolemra IFH) homozygotes. Three examples of FH due to gene
d&cts codingfor the intracytopl~mic
portion of the LDL receptor have been sdentified by the preparation of genomic D N A
libraries and the isolation andsequencing of exons 17 and 18,
which encode the cytoplamzic domain. The defect z n FH 683 is a
conversion of the tryptophan codon to a nonsense (stop) codon.
With FH 763, a frameshi3 occurs, with the insertion of four
bases due to the duplication offour nucleotidesfollowing the codon for the sixth amino acid ofthe cytoplasmic tad. In FH
380-JD, a single base change leads t o the substitution of a cysteinefor a tyrosine residue at position 807, which is in the
mzale ofthe Lyytoplasmic tail domain. (Reproduced by pmzssaon
from Brown MS, GoldsteinJ L {I). Copyright 0 1986 by The
Nobel Foundation.)
sitosterol 1841. A promising new group of drugs
derived from fungi, including compactin and mevinolin (lovastatin), inhibit cholesterol synthesis [85). They
can both reduce endogenous cholesterol synthesis by
the liver and increase the hepatic receptors for LDL by
promoting LDL elimination via receptor-mediated endocytosis. Planned prospective studies of C H D using
lovastatin should clarify their likely beneficial effects.
The recent Helsinki Heart Study of gemfibrozil, which
lowers LDL and raises HDL, also supports the conclusions of the LRC-CPPT; gemfibrozil may be more
beneficial for those at risk for ABI, since atheroma
regression may be enhanced by elevation of HDL
[3, 81.
Another interventional approach to atherosclerosis
is to interfere with the cellular participants, as de-
8 Annals of Neurology
Vol 26 No 1 July 1989
scribed with the injury healing hypothesis. Drugs that
might be of use include platelet inhibitors such as aspirin, sulfinpyrazone, and dipyridamole 186). Antiplatelet therapy for atherogenesis was also suggested
by observations that swine with Von Wdlebrand’s disease placed on an atherogenic diet developed significantly less arterial atherosclerosis than normal swine
187). However, extensive screening of various platelet
inhibitors in a number of animal atherosclerosis models has produced conflicting results, and preliminary
results of studies assessing human carotid atherosclerosis progression by noninvasive testing have not yet
demonstrated significant retardation with platelet inhibitors [SS-9 1). These observations suggest that currently available platelet inhibition therapy by itself may
not directly inhibit atherogenesis. Nevertheless, use of
low-dose aspirin (325 mg daily) is worth considering
until definitive data are forthcoming.
Other interventional possibilities are suggested by
the low incidence of C H D and atherosclerosis in
Greenland Eskimos {92]. The postulated mechanism
for this observation relates to the Eskimo diet, which is
rich in cold-water fish and their oils [93). These fish
oils contain large amounts of omega 3 series long-chain
fatty acids such as eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), as compared with the
omega 6 series long-chain fatty acids such as arachidonic acid contained in traditional land-based Western
diets. EPA and DHA appear to have remarkable inhibitory effects upon white blood cells and platelets as
well as producing omega 3 series prostaglandins and
leukotrienes 194-96). It has been hypothesized that
the clinically beneficial effects of these fish-derived
fatty acids upon atherosclerosis and related disorders is
attributable to these cellular and biochemical effects
1517, 98). We have recently reported that in a swine
hyperlipidemic atherosclerosis model the addition of
30 ml of cod liver oil per day markedly reduces the
extent of coronary atherogenesis, an observation seen
in other species such as rhesus monkey 199, loo}. Our
finding was independent of effects upon serum lipids
but was associated with a significant reduction in serum
thromboxane and platelet arachidonic acid levels.
Platelet EPA levels rose significantly during the course
of the experiment. The potential role of fish-derived
fatty acids in the prevention of human atherosclerosis
is being explored, and preliminary study of their use
after coronary angioplasty has shown a reduction in the
rate of restenosis {lOl).
We hypothesize that the effects of fish oil upon
white blood cell function is a major reason why this
therapy has a beneficial effect upon the atherosclerotic
process. Perhaps other relatively benign therapies that
inhibit white blood cell function, specifically that of
monocytedmacrophages, could prove valuable in preventing atherosclerosis 1102). Calcium channel blockers, as noted above, also have inhibitory effects upon
some macrophage function. Because calcium has been
implicated in platelet aggregation, release of PDGF,
smooth muscle cell proliferation, and binding of lipids
to macromolecules, calcium channel blockers could
also reduce atherogenesis 1103). It is not surprising
that calcium channel blockers have been observed to
retard atherosclerosis development in a number of experimental models [104- 1091, although these findings
are not uniform 1110, 1111. Whether calcium channel
blockers can be used in patients as a way of averting
atherosclerosis must await radomited human studies.
New and exciting therapies are becoming available for
testing and application in the primary and secondary
prevention of atherogenesis. They should have a major
impact on averting ABIs. For example, as more information about PDGF and other cell-derived growth factors becomes known, interventions that impede their
production and receptor binding will become available as therapy against atherosclerosis. Similarly, pharmacological interventions that retard proliferation of
arterial smooth muscle cells will offer another potentially novel approach to impeding atherosclerosis, as
will the reduction of LDL and elevation of HDL.
Finally, it is anticipated that simultaneous studies on
carotid atheromas and thrombogenesis, using increasingly sophisticated noninvasive tests, will identify cellular and other factors that provoke thrombus forma-
tion, the penultimate event in ABI. Whether or not
these latter factors relate to prostaglandin or leukotriene functions or other events including atheroma
rupture and surface receptor activity is as yet uncertain. However, simultaneous attack upon both atheroma formatiodregression and thrombogenesis on the
plaque are clearly appropriate therapeutic directions.
Meanwhile, patients must continue to be reminded of
the importance of reducing all known risk factors that
provoke the primary disease, atherosclerosis 1112115).
This study was supported in part by the Clayton Foundation for
Research (Houston, TX), the Cullen Trust for Health Care (Houscon, TX), the Herrnann Hospital Estate (Houston, TX), and the
United States Pubhc Health Service (Bethesda, MD).
1. Brown MS, Goldstein JL. A receptor-mediated pathway for
cholesterol homeostasis. Science 1986;232:34-47
2. Yatsu FM. Atherogenesis and stroke. In. Barnett HJM, Mohr
JP, Stein BM, Yatsu FM, eds. Stroke. Pathophysiology, diagnosis and management, vol 1. New York: Church11 Lvingstone, 198645-56
3. The Lipid Research Clinics Coronary Primary Prevention Trial
results. I. Red~ctionin incidence of coronary heart disease. II.
The relationship of reduction in incidence of coronary heart
disease to cholesterol lowering. JAMA 1984;251:351-364.
4. Hypertension Detection and Follow-up Program Cooperative
Group. Five-year findings of the Hypertensive Detection and
Follow-up Program. 111. Reduction in stroke incidence among
persons with high blood pressure. JAMA 1982;247:663-683
5. Whelton PK. Declining morrality from hypertension and
stroke. South Med J 1982;75:33-38
6. Yatsu FM, Becker C, McLeroy KR, et al. Community hospitalbased stroke programs: North Carolina, Oregon and New
York. I. Goals, objectives and data collection procedures.
Stroke 1986;17:276-284
7. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial
effects of combined cholestipoVniacin therapy on coronary
atherosclerosis and coronary venous bypass grafts. JAMA
8. Frick MH, El0 0, Haapa K,et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men
with dyslipidemia: safety of treatment, changes in risk factors
and incidence of coronary h e m disease. N Engl J Med
9. American Heart Association Committee Report. Rationale of
the diet-heart statement of the American Heart Association.
Circulation 1982;65:839-854
10. Kannel WB, Wolf PA, McGee DL, er al. Systolic blood pressure, arterial rigidity and risk of stroke. The Framingham
Study. JAMA 1981;245:1225-1229
11. Keys A. Coronary heart disease in seven countries. Circulation
1 9 7 0 ; 4 l ( ~ ~ p1):1-8
12. Skekelle RB,Shryock AM, Paul 0, et al. Diet, serum cholesterol, and death from coronary heart disease. The Western
Electric Study. N Engl J Med 1981;304:65-70
13. Astrup P, Kjeldsen K. Carbon monoxide, smoking and acherosclerosis. Med Clin North Am 1974;58:323-350
14. Horns DJ, Gerrard JM, Rao GH. Smoking and platelet labile
aggregation stimulating substance (LASS) synthesizing activity.
Thromb Res 1976;9:661-668
Neurological Progress: Yatsu and Fisher: Pathogenesis and Therapies of Atherosclerosis
15. Abbott RD, Yin Y, Reed DM, et al. Risk of stroke in male
cigarette smokers. N Engl J Med 1986;315:717-720
16. Bihari-Varga M, Szekely J, Gruber E. Plasma high density
lipoproteins in coronary, cerebral and peripheral vascular disease: the influence of various risk factors. Atherosclerosis
17. Murai A, Tanaka T, Miyahara T, Kameyama M. Lipoprotein
abnormalities in the pathogenesis of cerebral infarction and
transient ischemic attack. Stroke 1981;12:167-1 72
18. Nubiola AR, Masana L, Masdeu S, Rubies-Prat J. High density
lipoprotein cholesterol in cerebrovascular disease. Arch
Neurol 1981;38:468
19. Rossner S, Kjellin KG, Mettinger KL, et al. Normal serum
cholesterol but low high density lipoprotein cholesterol concentrations in young patients with ischaemic cerebrovascular
disease. Lancet 1978;1:5 77-5 79
20. Sirtori CR, Gianfranceschi G, Gritti I, et al. Decreased levels
of high-density lipoprotein cholesterol levels in male patients
with transient ischemic attacks. Atherosclerosis 1979;30:205211
21. Tagart H, Stout RW. Reduced high density lipoprotein in
stroke: relationship with elevated triglyceride and hypertension. Eur J Clin Invest 1979;9:219-221
22. Miller GM, Miller NE. Plasma high density lipoprotein concentration and development of ischaemic heart disease. Lancet
23. Gordon T, Kannel WB, Castelli WP, et al. Lipoproteins, cardiovascular disease and death. The Framingham Study. Arch
Intern Med 1981;141:1128-1131
24. Assmann G. High density lipoproteins and atherosclerosis.
Amsterdam: Elsevier Science, 1989:341-352
25. Zenker G, Koltringer P, Bone G, et al. Lipoprotein (a) as a
strong indicator for cerebrovascular disease. Stroke 1986;
26. Wissler RW. Conference on the biology of inflammation, cellcell interactions, connective tissue, and endothelial reactions.
Potential new approaches to atherosclerotic research. Arteriosclerosis 1983;3:398-402
27. Harmng HP, Kladetzky RG, Melnik B, Henericci M. Stimulation of the scavenger receptor on monocyte-macrophage
evokes release of arachdonic acid metabolites and reduced
oxygen species. Lab Invest 1986;55:209-216
28. Jonasson L, Holm J, Skalli 0, et al. Regional accumulations of
T cells, macrophages, and smooth muscle cells in the human
atherosclerotic plaque. Arteriosclerosis 1986;6:131- 138
29. Koo C, Innerarity TL, Mahley RW. Obligatory role of cholesterol and apolipoprotein E in the formation of large cholesterol-enriched and receptor-active high density lipoproteins. J
Biol Chem 1985;260:11934-11943
30. Yatsu FM, Alam R, Alani S. Scavenger activity in monocytederived macrophages from atherothrombotic strokes. Stroke
3 1. Mustard JF, Packham MA, Kinlough-Rathbone RC. Platelets,
atherosclerosis and clinical implications. In: Moore S, ed. Vascular injury and atherosclerosis. New York: Marcel Dekker,
32. Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate: I. Changes that lead to
fatty streak formation. Arteriosclerosis 1984;4:32 3- 340
33. Faggiotto A, Ross R, Harker L. Studies of hypercholesrerolemia in the nonhuman primate: 11. Fatty streak conversion
to fibrous plaque. Arteriosclerosis 1984;4:341-356
34. Joris I, Zand T, Nunnari JJ, et al. Studies on the pathogenesis
of atherosclerosis: I. Adhesion and emigration of mononuclear
cells in the aorta of hypercholesterolemic rats. Am J Pathol
35. Gerrity RG. The role of the monocyte in atherogenesis: I.
10 Annals of Neurology Vol 26 No 1 July 1989
Transition of blood-borne monocytes into foam cells in fatty
lesions. Am J Pathol 1981;103:181-190
36. Ross R. The pathogenesis of atherosclerosis-an update. N
Engl J Med 1986;314:488-500
37. Ross R, Glomset J. The pathogenesis of atherosclerosis. N
Engl J Med 1976;295:369-377
38. Ross R, Glomset J, Kariya B, Harker L. A platelet-dependent
serum factor that stimulates the proliferation of arterial smooth
muscle cells in vitro. Proc Natl Acad Sci USA 1974;71:12071210
39. Mahley RW. Cellular and molecular biology of lipoprotein metabolism in atherosclerosis. Diabetes 1981;3O(suppl 2):60-65
40. Mahley RW. Atherogenic hyperlipoproteinemia The cellular
and molecular biology of plasma lipoproteins altered by dietary
fat and cholesterol. Med Clin North Am 1982;66:375-400
41. Have1 RJ. Classification of the hyperlipidemias. Annu Rev
Med 1977;28:195-209
42. Brown MS, Kovanen PT, Goldstein JL. Regulation of plasma
cholesterol by lipoprotein receptors. Science 1981;212:628635
43. Brown MS, Goldstein JL. Lpoprotein metabolism in macrophages: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983;52:223-261
44. Steinberg D. Lipoproteins and the pathogenesis of atherosclerosis. Circulation 1987;76:508-5 14
45. Avogaro P, Bon GB, Cazzolato G. Presence of modified low
density lipoprotein in humans. Arteriosclerosis 1988;8:79-87
46. Steinbrecher VP, Parthasarathy S, Leake DS, et al. Modification of low density lipoprotein by endothelial cells involves
lipid peroxidation and degradation of low density lipoprotein
phospholipids. Proc Natl Acad Sci USA 1984;81:3883-3887
47. Qumn MT, Partbasarathy S, Steinberg D. Endothelial cellderived chemotactic factor for mouse peritoneal macrophages
and the effects of moddied forms of low density lipoprotein.
Proc Natl Acad Sci USA 1985;82:5949-5953
48. D e b a t r e J, Wolfbauer G, Phillips MC, Rothblat GH. Role
of apolipoproteins in cellular cholesterol efflux. Biochim Biophys Acta 1986;875:419-428
49. Fielding CJ, Fielding PE. Cholesterol transport between cells
and body fluids. Med Clin North Am 1982;66:363-373
50. Glomset JA. The plasma lecithin: cholesterol acyltransferase.J
Lipid Res 1968;9:155-167
51. Schmia G, Niemann R, Brennhausen B, et al. Regulation of
hgh density lipoprotein receptors in cultured macrophages:
role of acyl-CoA: cholesterol acyltransferase. EMBO J 1985;
52. Stein 0, Halperin G, Stein Y. Cholesteryl ester efflux from
extracellular and cellular elements of the arterial wall. Arteriosclerosis 1986;6:70-78
53. Tall AR, Small DM. Body cholesterol removal: role of plasma
high-density lipoproteins. Adv Lipid Res 1980;17:1
54. Wallentin L, Sundin B. HDL2 and HDL3 lipid levels in coronary heart disease and other causes. Atherosclerosis 1986;59:
55. Basu SK, Goldstein JL, Brown MS. Independent pathways for
secretion of cholesterol and apolipoprotein E by macrophages.
Science 1983;219:871-873
56. Brunzell JD, Sniderman AD, Albers JJ, Kwiterovich PO.
Apoproteins B and A-I and coronary artery disease. Arteriosclerosis 1984;4:79-83
57. Norum RA, Lakier JB, Goldstein S, et al. Familial deficiency
of apolipoprotein A-I and C-111 and precocious coronary heart
disease. N Engl J Med 1982;306:1513-1519
58. Innerarity TL, Arnold KS, Weisgraber KH, Mahley RW.
Apolipoprotein E is the determinant that mediates the receptor uptake of beta-VLDL by mouse macrophages. Arteriosclerosis 1986;6:114-122
59. Koo C, Innerarity TL, Mahley RW. Obligatory role of cholesterol and apolipoprotein E in the formation of large cholesterol-enriched and receptor active high densiry lipoproteins. J
Biol Chem 1985;260:11934-11943
60. Kottke BA. Lipid markers for atherosclerosis. Am J Cardiol
61. Curtiss LK. New mechanisms for foam cell generation in
atherosclerotic lesions. J Clin Invest 1987;80:367-373
62. Phillips DR, Arnold K, Innerarity TL. Platelet secretory products inhbit lipoprotein metabolism in macrophages. Nature
1985;3 16:?46-?48
63. Tabas I, Wedand DA, Tall DR. Inhibition of acyl coenzyme A:
cholesterol acyl transferase in J774 macrophages enhances
down-regulation of the LDL receptor and HMG-CoA-reductase and prevents LDL-induced cholesterol accumulation.
J Biol Chem 1986;261:3147-3155
64. Van Lenten BJ, Fogelman AM, Jackson RL, et al. Receptormediated uptake of remnant lipoproteins by cholesterolloaded human monocyte-macrophages. J Biol Chem 1985;
65. Via DP, Plant AL, Craig IF, et al. Metabolism of normal and
modified LDLs by macrophage cell lines of murine and human
origin. Biochim Biophys Acta 1985;833:417-428
66. Schmia G, Assmann G, Robenek H, Brennhausen B. Tangier
disease: a disorder of intracellular membrane traffic. Proc Natl
Acad Sci USA 1985;82:6305-6309
67. Soutar AK, Knight BL. Degradation by cultured monocytederived macrophages from normal and familial hypercholesterolemic subjects of modified and unmodified low-density lipoproteins. Biochem J 1982;204:549-556
68. Yatsu FM, Alam R, Alam S. Enhancement of cholesteryl ester
metabolism in cultured human monocyte-derived macrophages by verapamil. Biochm Biophys Acta 1985;847:77-81
69. Dayton S, Pearce ML, Hashimoto S, et al. A controlled clinical
trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969;4O(suppl 2):l-63
70. Taguchi J, Freis ED. Partial reduction of blood pressure and
prevention of complications in hypertension. N Engl J Med
71. Turpeinen 0. Effect of cholesterol-lowering diet on mortality
from coronary heart disease and other causes. Circulation
72. Yano K, Rhoads GG, Kagan A, et al. Dietary intake and the
risk of coronary heart disease in Japanese men living in Hawaii.
Am J Clin Nutr 1978;31:1270-1279
73. Yatsu FM. Dietary cholesterol: does it aggravate strokes due to
atherosclerosis? Neurology 1981 ;31:1270
74. Kronmal RA. Commentary on the published results of the
Lipid Research Clinics Coronary Primary Prevention Trial.
JAMA 1985;253:2091-2092
75. Multiple Risk Factor Intervention Trial Research Group. Risk
factor changes and mortality results. JAMA 1982;248:14651477
76. Olson RE. Mass intervention versus screening and selective
intervention for the prevention of coronary heart disease.
JAMA 1986;255 :2204-2207
7 7. Oster G, Epstein AM. Cost-effectiveness of antihyperlipemic
therapy in the prevention of coronary heart disease. JAMA
78. Gotto AM, Shepherd J, Scott LW, Manis E. Primary hyperlipoproteinemia and dietary management. In: Levey RI, Rifkind BM, eds. Nutrition and coronary heart disease, vol 1.
New York Raven, 1979:247
79. Consensus Conference. Lowering blood cholesterol to prevent
heart disease. JAMA 1985;253:2080-2086
80. Pet0 R, Yusuf S. Summary of results from dietary and drug
intervention trials. In: Proceedings of the NIH Consensus De-
velopment Conference: Lowering Blood Cholesterol to Prevent Heart Disease. Bethesda, M D National Institutes of
Health, 1984:24
SalonenJT, Puska P, Mustaniemi H. Changes in morbidity and
mortality during comprehensive community program to control cardiovascular disease during 1972-1977 in North Karelia. Br Med J 1979;2:1178
Stallones RA. Mortality and the multiple risk factor intervention trial. Am J Epidemiol 1983;117:647-650
Subbiah MT, Yunker RL, Rymaszewski 2, et al. Cholestyramine treatment in early life of LDL receptor deficient
Watanabe rabbits: decreased aortic cholesteryl ester accumulation and atherosclerosis in adult life. Biochim Biophys Acta
Illingworth DR, Connor WE. Disorders of lipid metabolism.
In: Riikind BM, Levey RI, eds. Endocrinology and merabolism. New York: Grune, 1977327
Bilheimer DW, Grundy SM, Brown MS, Goldstein JL.
Mevinolin and colestipol stimulate receptor-mediated dearance in famlal hypercholesterolemia heterozygotes. Proc Natl
Acad Sci USA 1983;80:4124-4128
Hollander W, Kirkpatrick B, Paddock J, et al. Studies on the
progression and regression of coronary and peripheral atherosclerosis in the cynomologus monkey: I. Effects of dipyridamole and aspirin. Exp Mu1 Pathol 1979;3055-73
Fuster V, Bowie EJW, Gass DN, et al. Arteriosclerosis in von
Willebrand and normal pigs: spontaneous and high cholesterol
diet induced. J Clin Invest 1978;61:722-730
Pick P, Chediak J, Glick G. Aspirin inhibits development of
coronary atherosclerosis in cynomologus monkeys fed an
atherogenic diet. J Clin Invest 1979;63:158-162
Saunders RN. Evaluation of platelet inhibiting drugs in models
of atherosclerosis. Annu Rev Pharmacol Toxic01 1982;22:
Roederer GD, Langlois YE, Jagar KA, et al. The natural history of carotid arterial disease in asymptomatic patients with
cervical bruits. Stroke 1984;15:605-613
Bogousslavsky J, Despland PA, Re& F. Asymptomatic tight
stenosis of the internal carotid artery: long-term prognosis.
Neurology 1986;36:861-863
Dyerberg J, Bang HO, Stoffersen E. Eicosapentaenoic acid and
prevention of thrombosis and atherosclerosis? Lancet
Yamaguchi K, Mizota M, Hashizume H, Kumagai A. Antiatherogenic action of eicosapentaenoic acid in multiple oral
doses. Prostaglandins Leukotrienes Med 1987;28:35-43
Lee TH, Hoover RL. Williams JD, et al. Effect of dietary
enrichment with eicosapentaenoic and docosahexanoic acids
on in vitro neurophil and monocyte leukotriene generation
and neutrophil function. N Engl J Med 1985;312:1217-1224
Knapp HR, Reilly IAFG, Alessandrini P, FitzGerald GA. In
vivo indices of platelet and vascular function during fish-oil
administration in patients with atherosclerosis. N Engl J Med
Fisher M, Upchurch KS, Levine PH, et al. Effects of dietary
fish oil supplementation on polymorphonuclear leukocyte potential. Inflammation 1987;10:387-392
Fisher M, Levine PH, Weiner BH. The potential clinical
benefits of fish consumption. Arch Intern Med 1986;140:
Herold PM, Kinsella JE. Fish oil consumption and decreased
risk of cardiovascular disease: a comparison of findings from
animal and human feeding trials. Am J Clin Nutr 1986;43:
Weiner BH, Ockene IS, Levine PH, et al. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model. N
Engl J Med 1986;315:841-846
Neurological Progress: Yatsu and Fisher: Pathogenesis and Therapies of Atherosclerosis 11
100. Davis HR, Bridenstine RT, Vesselinovitch D, Wissler RW.
Fish oil inhibits development of atherosclerosis in rhesus rnonkeys. Arteriosclerosis 1987;7:441-449
101. Dehmer G, Popma JJ, van den Berg EK, et al. Reduction in
the rate of early restenosis after coronary angioplasty by a &et
supplemented with n-3 fatty acids. N Engl J Med 1988;319:
102. Wright B, Zeidman I, Greig R, Poste G. Inhibition of macrophage activation by calcium channel blockers and calmoddin
antagonists. Cell Immunol 1985;95:46-53
103. Parmley WW, Blumlein S, Sievers R. Modification of experimental atherosclerosis by calcium channel blockers. Am J Cardiol 1985;55:165B-171B
104. Henry PD. Atherosclerosis, calcium and calcium antagonists.
Circulation 1985;72:456-458
105. Betz E, Hammerle H, Strohschneider T. Inhibition of smooth
muscle cell proliferation and endothelid permeability with
flunarizine in vitro and in experimental atheromas. Res Exp
Med 1985;185:325-340
106. Kramsch DM, Aspen AJ, Apstein CS. Suppression of experimental atherosclerosis by the calcium antagonist lanthanum.
Possible role of calcium in atherogenesis. J Clin Invest 1980;
107. M ah o w RM, Blaton Y. Regression of atherosclerotic lesions.
Arteriosclerosis 1984;4:292-295
12 Annals of Neurology Vol 26 NO 1 July 1989
108. Sugano M, Nakashima Y , Matsushima T, et al. Suppression of
atherosclerosis in cholesterol-fed rabbits by diltiazem injection. Arteriosclerosis 1986;6:237-24 1
109. Wissler RW. Current status of regression stuhes: progression
and regression of atherosclerotic lesions. Adv Exp Med Biol
110. Natio M, Kuzuya F, Asai K, et al. Ineffectiveness of calciumantagonist nicardipine and diltiazem on experimental atherosclerosis in cholesterol-fed rabbits. Angiology 1984;36:622627
111. Stender S, Stender I, Nordestgaard B, Kjeldsen K. No effect
of nifedipine on atherogenesis in cholestetol-fed rabbits. Arteriosclerosis 1984;4:389-394
112. Anda RF, Remington RP, Sienko DG, Davis RM. Are physicians advising smokers to quit? JAMA 1987;257:19.16-1919
113. Parthasrathy S, Young SG, Witztum JL, et al. CoI inhibits
oxidative modification of low density lipoprotein. J Clin Invest
114. Leon AS, Connett J, Jacobs DR Jr, Rauramaa R. Leisure-time
physical activity levels and risk of coronary heart disease and
death. The Multiple Risk Factor 1ntervl:ntion Trial. JAMA
115. Strategy for the prevention of coronary heart disease: a policy
statement of the European Atherosclerosis Society. Eur Heart
J 1987;8:77-88
Без категории
Размер файла
1 347 Кб
current, atherosclerosis, intervention, therapie, pathogenesis, concept
Пожаловаться на содержимое документа