Brief Reviews |
From the Lipid Research Laboratory, Division of Medicine, Hadassah University Hospital, Jerusalem, Israel.
Correspondence to Y. Stein, MD, Lipid Research Laboratory, Division of Medicine, Hadassah University Hospital, Ein Karem, POB 12220, Jerusalem 91120, Israel. E-mail ystein{at}hadassah.org.il
| Abstract |
|---|
|
|
|---|
Key Words: atherosclerosis prevention of CAD fatty streaks complex lesion gene therapy
| Introduction |
|---|
|
|
|---|
| Definition of Atherosclerotic Lesions |
|---|
|
|
|---|
| Studies in Experimental Animals |
|---|
|
|
|---|
A different approach to the study of regression was the long-term administration of L-arginine, the precursor of NO, to rabbits fed a cholesterol-rich diet.8 The L-arginine induced an improvement in endothelium-dependent relaxation that was accompanied by a reduction in the surface area of sudanophilic lesions, indicating the regression of preexisting lesions.8 The authors attribute the effect of L-arginine on lesion regression to the induction of apoptosis in macrophages.9 The application of MRI technology to study atherosclerosis in rabbits was reported during the past few years10 11 and permitted the estimation of atherosclerosis in vivo.12 The study12 was performed in cholesterol-fed rabbits that underwent aortic balloon injury; the regression of aortic atherosclerosis was initiated by return to chow diet for 20 months. MRI examination after 4 months of regression showed 56% stenosis, but after 20 months, it decreased to 45%. Similarly, average plaque thickness decreased from 0.85 to 0.6 mm between 4 and 20 months of regression.12 The WHHL rabbit, an LDL-receptordeficient model of atherosclerosis that develops aortic lesions on a chow diet, was used in the past decade to study the effects of drug intervention.13 Thus, statins were shown to reduce plasma cholesterol levels and to decrease the progression of atherosclerosis, but even after 8 months, they did not cause the regression of established lesions; this was also true in less recent studies (see Discussion in Shiomi and Ito13 ).
Monkeys
Regression studies of diet-induced
atherosclerosis in aorta and coronary arteries
in nonhuman primates began with the pioneering work of Armstrong et
al14 15 16
and were admirably reviewed by Wissler and
Vesselinovitch.17 Of special
significance is the conclusion that atherosclerosis in
monkeys bears a remarkable resemblance to that found in humans. The
results obtained show that return to a low-fat diet for 12 to 14 months
is accompanied by a 60% reduction in gross aortic intimal lesions, and
the addition of cholestyramine further reduces the amount of aortic
surface involvement.17 These
results were obtained in rhesus monkeys but not in cynomolgus monkeys,
in which the regression of atherosclerosis was not
quite so successful.18 One
difference between the 2 strains of monkeys is the abundance of immune
complexes in cynomolgus monkeys and the extension of plaques into the
media; the latter feature is not seen in human
atherosclerosis.17
An important distinction was made by Strong et al19 that to study the regression of advanced lesions, the period of induction of atherosclerosis must be increased. In experiments that last for up to 9 years, the induction period was increased to 5.4 years and regression was increased to 3.7 years. Return to basal diet resulted in a significant decrease of fatty streaks in most arterial segments. After 1.9 years, the raised lesions were less numerous, but no regression was noted. After 3.7 years on the regression diet, there was a nonsignificant decrease in the raised lesions.19 In that study, in addition to morphometry, CE content of arterial segments was determined. There was a 50% reduction after 1.9 years and a 75% reduction in CE after 3.7 years on the regression diet. The authors made an important caveat that although fatty streaks may regress almost completely, "regression of atherosclerotic lesions does not induce reversion of the arteries to a prediseased normal state."
These results just reviewed were derived mainly in male
monkeys, but during the past decade, the investigations were extended
to female monkeys and included the evaluation of hormonal therapy. It
seems of interest that these studies were carried out on cynomolgus
monkeys, which are apparently less prone to
regression.17 The animals
were ovariectomized and fed the atherogenic diet for 2 years.
Thereafter, regression was induced by lipid-lowering diet either alone
or in combination with hormonal
replacement.20 After 30
months on the various regression regimens, the plaque size and the
lumen in coronary arteries did not change from that in the
progression group. On the other hand, cholesterol content
of the aorta was reduced
50% by the lipid-lowering diet, but there
was no further improvement with hormonal therapy. These results showed
that estrogen replacement with or without progestin offered little or
no improvement of regression in ovariectomized
females.20 In an extension
of that study, the effect of hormonal replacement on connective tissue
was determined. Conjugated estrogen treatment inhibited collagen
accumulation that was associated with atherosclerosis
regression.21 Another
attempt to enhance regression of atherosclerosis in
cynomolgus monkeys was reported in a study designed to test the effect
of pravastatin on plaque characteristics independent of
cholesterol-lowering
effect.22 A 2-year induction
period was followed by a 2-year regression phase. The salient findings
were that although pravastatin did not affect plaque size
in coronary or iliac arteries, there were fewer
macrophages in the intima and media of the
pravastatin-treated monkeys, and a better dilator function
of the arteries was
noted.22
Swine
Minipigs have been used for the study of atherogenesis
for many years, and Cornhill et
al23 were the first to
introduce quantitative analysis with the help of
computer-stored digital images of Sudan-IVstained arteries. The
further development of this methodology generated
probability-of-occurrence maps that defined in statistical terms the
probability that sudanophilia will occur at a given point along the
surface of the arterial tree. This method permitted the
morphometric analysis of the Pathological Determinants of
Atherosclerosis in Youth (PDAY) Study (see
later).
The feeding of an atherogenic diet to miniature swine for 6 months resulted in the development of fatty streaks in the thoracic aorta and fibrous plaques in the abdominal aorta.24 During the next 9 months of regression on a conventional diet, serum lipid levels returned to baseline and there was regression of fatty streaks but not of fibrous plaques.24 The induction of atherosclerosis for 8 months, followed by a regression period of 4 months that included feeding of fish oil, did not induce the regression of atherosclerosis but prevented the progression of established lesions.25 In a later study,26 the effect of fish oil was examined in minipigs fed the atherogenic diet for 8 months followed by a normal diet alone or with fish oil. Although significant regression of lesions in the aorta and in carotid arteries occurred in animals on the regression diet, there was no potentiation of regression by the addition of fish oil.26
Hamsters
Among small rodents, hamsters have been used in studies
on atherogenesis because they respond to high-cholesterol
diets with an increase in plasma cholesterol levels.
However, when hamsters were fed 1% cholesterol for up to
20 months and their plasma cholesterol increased by
>5-fold, the cholesterol content of the total aorta
increased not more than 28% above that found in age-matched control
hamsters.27 This relative
resistance could be related to the commensurate 4-fold increase in
plasma HDL levels. Significant regression of fatty streaks was reported
in a study of 10 weeks of induction and 8 weeks of
regression.28 The regression
of fatty streaks was also found in another
study29 with a low-fat,
low-cholesterol diet with or without supplementation of
lovastatin. In a recent
study,30 the effect of
coconut oil versus olive oil on regression of lesions in the ascending
aorta and aortic arch was compared after 8 or 16 weeks. In the
ascending aorta, coconut oil increased the extent of lesions, whereas
with olive oil, no regression occurred up to 16 weeks. Different
results were reported for aortic arch, in which both coconut oil and
especially olive oil enhanced
regression.30
Transgenic Mice
The introduction of transgenic technology to the study
of atherosclerosis resulted in the creation of mice
that responded to a Western diet with lesions that resemble those found
in humans. The most commonly used models were either LDL
receptordeficient or apoE-deficient C57Bl mice, in which
overexpression of human apoA-I or apoA-IV resulted in significant
prevention of the development of
atherosclerosis.31 32 33 34 35
When regression was attempted by a reduction in plasma
cholesterol levels with the feeding of phytosterol, this
treatment slowed the development of atherosclerotic lesions in
apoE-deficient mice but did not affect
regression.36 In another
model of mouse atherogenesis, namely the apoE-3-Leiden transgenic mice,
withdrawal of the atherogenic diet fed for 14 weeks and feeding of a
standard diet for up to 16 weeks resulted in normalization of plasma
cholesterol levels after 4
weeks.37 At 4, 8, and 16
weeks on the standard diet, the size of the aortic plaques tended to
get smaller, but the difference did not reach statistical significance.
However, the percent of macrophages in the lesions was
significantly reduced after 4 weeks and approached zero after 16
weeks.37 In another study,
an apoE-expressing retrovirus was used to transduce apoE-deficient
mouse bone marrow for transplantation into
apoE-/- recipient
mice.38 When mouse or human
apoE was expressed in these mice between 5 to 13 weeks of age, a
significant decrease in lesion area was seen. However, when
macrophage apoE was expressed at a later age (10 to 26 weeks),
there was no effect. The authors conclude that "macrophage
apo E can delay atherogenesis if expressed during foam cell formation,
but is not beneficial during the later stages of
atherogenesis."38 When
human apoE expression in the liver of
apoE-/- mice was achieved with the help of
second-generation adenoviruses, marked regression of preexisting fatty
streaks occurred in 12-week-old
mice.39 When the apoE was
expressed as above in 26-week-old mice, it induced a more moderate
regression of lesions during 6 weeks of the experimental period. During
that time, there also was a significant decrease in plasma
cholesterol levels. In a more complex study,
apoE-/- mice were generated on the nude
background as a new mouse model for
atherosclerosis.40
Human apoE cDNA was transferred to these mice with a first-generation
adenoviral vector. The nude athymic mice are deficient for cellular
immunity, and because of their immunodeficient background, the
adenovirus-mediated gene transfer and the expression of apoE lasted for
>4 months.40 In these
17-week-old mice, a dose-dependent regression of fatty streak lesions
occurred during 4 months after the gene
transfer.40 In another model
system, namely, LDL receptordeficient mice, liver-directed gene
transfer of apoA-I was
performed.41 Plasma levels
of human apoA-I peaked 7 days after injection and declined during the
subsequent week. A remarkable regression of lesions in the aortic root
was observed 4 weeks after the adenovirus injection. In the treated
mice, the percent lesion area occupied by macrophages and
macrophage-derived foam cells was significantly
reduced.41
| Studies in Humans |
|---|
|
|
|---|
The natural history of atherosclerosis in childhood and young adulthood was studied extensively in a multicenter cooperative project. The study, PDAY, examined the relation of risk factors for adult coronary artery disease (CAD) in almost 3000 persons aged 15 to 34 years who died of external causes.46 47 48 49 50 The study provided strong evidence that progression of the early lesions was positively associated with plasma LDL and VLDL levels and negatively associated with HDL levels. Smoking was associated with a 3-fold increase in raised lesions in the abdominal aorta in the 25- to 30-year-old group. Even though fatty streaks develop in many areas of abdominal aorta, only fatty streaks on the dorsolateral surface of distal aorta progress to become raised lesions.50 It seems plausible that the introduction of healthy lifestyle habits (diet low in fat and cholesterol, physical activity, balanced energy intake with expenditure, no smoking) in childhood could not only stop the progression but also promote the regression of lesions.46 48 49 50
Regression of Advanced Lesions
As mentioned in the introduction, in contradistinction
to studies in experimental animals that evaluated the regression of
atherosclerosis in the aorta and the coronary,
iliac, renal, femoral, and other arteries, human studies deal mainly
with coronary and carotid arteries. With the use of
quantitative coronary angiography (QCA), the regression of
atherosclerosis in humans has been defined indirectly
in terms of arteriographic improvement in stenosis, which is
expressed as increase in luminal area in the stenotic
vessel.51 The quantitative
term
(% S) used to designate progression with a plus sign or
regression with a minus sign denotes the average change in percent
stenosis over all the lesions measured per patient. With the
advent of effective lipid-lowering therapy, many randomized secondary
prevention angiographic trials were initiated and provided information
concerning the magnitude of regression. The regression trials of
coronary atherosclerosis using different
lipid-lowering drugs were summarized
extensively,52 53
so the individual trials are not reviewed here. A summary of 7 trials
showed an improvement in
(% S) that ranged from -0.7% to
-2.2% in stenosis in the treated patients, whereas the
(% S) worsened from +0.8% to +3.4% of luminal area in
controls.51 There are some
caveats that have to be taken into account when using this method;
improvement in lumen size can occur independent of changes in plaque
size due to remodeling of the vascular
wall54 or relaxation of the
vascular
tone.55 56
Spurious increase in the lumen may also result from lysis of occluding
or mural thrombi.
Therefore, notwithstanding the very marked clinical improvement and reduction in CAD mortality rates, as well as total mortality rates, with the effective lipid-lowering therapy, the extent of regression of lesions in the coronary arteries was disappointingly low. Hence, additional treatments were introduced to promote regression of lesions, especially in familial hypercholesterolemia (FH) patients.
LDL Apheresis
The term "LDL apheresis" was introduced by Stoffel
et al57 to describe the
selective removal of apoB-containing lipoproteins from plasma in vivo
through immunoabsorption. LDL apheresis has been used mainly for the
treatment of patients with FH or with very severe CAD and high plasma
LDL cholesterol levels that did not respond adequately to
dietary and drug intervention. In the first major multicenter study,
after 2 years of treatment, stenosis of coronary
arteries improved by 8% in one fourth of arterial
segments.58 In a randomized
study, FH heterozygotes with CAD received twice-weekly dextran-sulfate
LDL apheresis plus simvastatin, or colestipol and
simvastatin.59
QCA was performed in 39 patients before and after 2 years of treatment.
Six patients were found to be progressors and 9 were found to be
regressors, with
(S%) values of -1.8% on apheresis and -2.2%
on drugs. In this cohort, no advantage of LDL apheresis was
found.59 In another
study,60 42 men aged 30 to
67 years with CAD were treated with LDL apheresis (biweekly) and
simvastatin or simvastatin alone. After 2 years
of treatment, the mean plasma LDL cholesterol in the LDL
apheresis group was reduced by 63%, and that in the medication group
was reduced by 47%. Nine patients in the apheresis group and 11 in the
medication group were classified as progressors, and 2 and 5 patients,
respectively, were classified as regressors. In a prospective
study,61 25 FH heterozygotes
were treated with LDL apheresis and drugs and 11 patients were treated
with drugs only; the patients underwent QCA 2.5 years thereafter. The
frequency of regression or no progression was significantly higher in
the apheresis group. Another application of LDL apheresis was made in
long-term heart transplant survivors with angiographically documented
CAD and severe
hypercholesterolemia.62
In this study, before the initiation of LDL apheresis, the luminal
diameter of the coronary arteries decreased from 3.6±1.1 to
3.15±1 mm at 22 months after the heart transplantation. During
the next 22 months of LDL apheresis, the luminal diameter increased to
3.4±1.5 mm. This improvement could have been due to regression
and improved vascular
tone.62 The effectiveness of
LDL apheresis was recently
reviewed.63 64
| Conclusions |
|---|
|
|
|---|
The induction of advanced lesions in experimental animals is a much slower process than the induction of fatty streaks and requires prolonged exposure of the arterial wall to hypercholesterolemia. Attempts to regress these complex lesions were successful in the reduction of cholesterol content but to a much lesser extent of the nonlipid components of the lesions. The decrease in lesional cholesterol was related to the extent of lowering of plasma atherogenic lipoprotein levels and the duration of intervention.
In the evaluation of the results of treatment, it is important to distinguish between slowing of progression and true regression of lesions, which are 2 different processes dependent on different mechanisms.
It must be borne in mind that the current techniques to evaluate regression in humans are not optimal, because they do not allow differentiation of the lesions in vivo. Therefore, the knowledge accrued from the study of regression of advanced lesions in experimental animals is most relevant to the situation in humans. In long-term trials of secondary prevention of CAD, the increase in the partially obstructed lumen of coronary arteries, which is due in part to regression, was disappointingly small. Despite this, dietary and drug intervention did culminate in marked clinical improvement and reduction in CAD and total mortality rates in about one third of patients. These results were due in part to removal of cholesterol from the lesion, resulting in plaque stabilization, and in part to improvement in the vasomotor tone. It is expected that when a more aggressive lowering of LDL cholesterol to levels prevalent in primates will be the goal of treatment, better results will be achieved. However, because complete regression of complex atherosclerotic lesions is not currently achievable, the inescapable conclusion is that the future effort should be directed toward the primary prevention of CAD starting in adolescence, especially in individuals at high risk.
| Acknowledgments |
|---|
Received April 13, 2000; accepted July 31, 2000.
| References |
|---|
|
|
|---|
2.
Stein O, Hollander
G, Dabach Y, Halperin G, Stein Y. Use of
3H-cholesteryl linoleyl ether as a
quantitative marker for loss of cholesteryl ester during regression of
cholesterol-induced aortic atheromas in
rabbits.
Arteriosclerosis. 1989;9:247252.
3.
Stein Y, Stein O,
Halperin G. The use of 3H-cholesteryl
linoleyl ether for the quantitation of plasma cholesteryl ester influx
into the aortic wall in hypercholesterolemic rabbits.
Arteriosclerosis. 1982;2:281289.
4. Zhu BQ, Sievers RE, Isenberg WM, Smith DL, Parmley WW. Regression of atherosclerosis in cholesterol-fed rabbits: effects of fish oil and verapamil. J Am Coll Cardiol. 1990;15:231237.[Abstract]
5. Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;85:12341241.
6.
Miyazaki A, Sakuma
S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H,
Sakamoto Y, Natio M, et al. Intravenous injection of rabbit
apolipoprotein A-I inhibits the progression of
atherosclerosis in cholesterol-fed rabbits.
Arterioscler Thromb Vasc Biol. 1995;15:18821888.
7. Rodrigueza WV, Klimuk SK, Pritchard PH, Hope MJ. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles. Biochim Biophys Acta. 1998;1368:306320.[Medline] [Order article via Infotrieve]
8.
Candipan RC, Wang
BY, Buitrago R, Tsao PS, Cooke JP. Regression or progression:
dependency on vascular nitric oxide.
Arterioscler Thromb Vasc Biol. 1996;16:4450.
9.
Wang BY, Ho HK, Lin
PS, Schwarzacher SP, Pollman MJ, Gibbons GH, Tsao PS, Cooke JP.
Regression of atherosclerosis: role of nitric oxide and
apoptosis. Circulation. 1999;99:12361241.
10. Skinner MP, Yuan C, Mitsumori L, Hayes CE, Raines EW, Nelson JA, Ross R. Serial magnetic resonance imaging of experimental atherosclerosis detects lesion fine structure, progression and complications in vivo. Nat Med. 1995;1:6973.[Medline] [Order article via Infotrieve]
11. Yuan C, Skinner MP, Kaneko E, Mitsumori LM, Hayes CE, Raines EW, Nelson JA, Ross R. Magnetic resonance imaging to study lesions of atherosclerosis in the hyperlipidemic rabbit aorta. Magn Reson Imaging. 1996;14:93102.[Medline] [Order article via Infotrieve]
12.
McConnell MV,
Aikawa M, Maier SE, Ganz P, Libby P, Lee RT. MRI of rabbit
atherosclerosis in response to dietary
cholesterol lowering.
Arterioscler Thromb Vasc Biol. 1999;19:19561959.
13. Shiomi M, Ito T. Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol. 1999;126:961968.[Medline] [Order article via Infotrieve]
14.
Armstrong ML,
Warner ED, Connor WE. Regression of coronary
atheromatosis in rhesus monkeys.
Circ Res. 1970;27:5967.
15.
Armstrong ML,
Megan MB. Lipid depletion in atheromatous
coronary arteries in rhesus monkeys after regression diets.
Circ Res. 1972;30:675680.
16. Armstrong ML. Connective tissue changes in regression. In: Schettler G, Goto Y, Hata Y, Klose GF, eds. Atherosclerosis IV. Berlin, Germany: Springer-Verlag; 1977:405413.
17. Wissler RW, Vesselinovitch D. Can atherosclerotic plaques regress? anatomic and biochemical evidence from nonhuman animals models. Am J Cardiol. 1990;65:33F40F.[Medline] [Order article via Infotrieve]
18. Vesselinovitch D, Wissler RW. Reversal of atherosclerosis: comparison of non-human primate models. In: Gotto AM Jr, Smith LC, Allen B, eds. Atherosclerosis V (Proceedings of the 5th International Symposium). New York, NY: Springer-Verlag; 1980:369374.
19.
Strong JP,
Bhattacharyya AK, Eggen DA, Malcom GT, Newman WP III, Restrepo C.
Long-term induction and regression of diet-induced atherosclerotic
lesions in rhesus monkeys, I: morphological and chemical evidence for
regression of lesions in the aorta and carotid and
peripheral arteries.
Arterioscler Thromb. 1994;14:958965.
20.
Williams JK,
Anthony MS, Honore EK, Herrington DM, Morgan TM, Register TC, Clarkson
TB. Regression of atherosclerosis in female monkeys.
Arterioscler Thromb Vasc Biol. 1995;15:827836.
21.
Register TC,
Adams MR, Golden DL, Clarkson TB. Conjugate equine estrogens alone, but
not in combination with medroxyprogesterone
acetate, inhibit aortic connective tissue remodeling after plasma lipid
lowering in female monkeys. Arterioscler
Thromb Vasc Biol. 1998;18:11641171.
22.
Williams JK,
Sukhova GK, Herrington DM, Libby P. Pravastatin has
cholesterol-lowering independent effects on the artery wall
of atherosclerotic monkeys. J Am Coll
Cardiol. 1998;31:684691.
23.
Cornhill JF,
Barrett WA, Herderick EE, Mahley RW, Fry DL. Topographic study of
sudanophilic lesions in cholesterol-fed minipigs by image
analysis.
Arteriosclerosis. 1985;5:415426.
24.
Kobari Y, Koto M,
Tanigawa M. Regression of diet-induced atherosclerosis
in Gottingen miniature swine. Lab
Anim. 1991;25:110116.
25.
Sassen LM, Lamers
JM, Sluiter W, Hartog JM, Dekkers DH, Hogendoorn A, Verdouw PD.
Development and regression of atherosclerosis in pigs:
effects of n-3 fatty acids, their incorporation into plasma and aortic
plaque lipids, and granulocyte function.
Arterioscler Thromb. 1993;13:651660.
26.
Barbeau ML, Klemp
KF, Guyton JR, Rogers KA. Dietary fish oil. Influence on lesion
regression in the porcine model of atherosclerosis.
Arterioscler Thromb Vasc Biol. 1997;17:688694.
27. Stein O, Dabach Y, Hollander G, Halperin G, Thiery J, Stein Y. Relative resistance of the hamster to aortic atherosclerosis in spite of prolonged vitamin E deficiency and dietary hypercholesterolemia: putative effects of increased HDL? Biochim Biophys Acta. 1996;1299:216222.[Medline] [Order article via Infotrieve]
28. Nicolosi RJ, Wilson TA, Krause BR. The ACAT inhibitor CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters. Atherosclerosis. 1998;137:7785.[Medline] [Order article via Infotrieve]
29. Pitman WA, Osgood DP, Smith D, Schaefer EJ, Ordovas JM. The effects of diet and lovastatin on regression of fatty streak lesions and on hepatic and intestinal mRNA levels for the LDL receptor and HMG CoA reductase in F1B hamsters. Atherosclerosis. 1998;138:4352.[Medline] [Order article via Infotrieve]
30. Mangiapane EH, McAteer MA, Benson GM, White DA, Salter AM. Modulation of the regression of atherosclerosis in the hamster by dietary lipids: comparison of coconut oil and olive oil. Br J Nutr. 1999;82:401409.[Medline] [Order article via Infotrieve]
31. Rubin E, Krauss R, Spangler E, Verstuyft J, Clift S. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991;353:265267.[Medline] [Order article via Infotrieve]
32.
Plump A, Scott C,
Breslow J. Human apolipoprotein A-I gene expression increases high
density lipoprotein and suppresses atherosclerosis in
the apolipoprotein E-deficient mouse. Proc
Natl Acad Sci
U S A. 1994;91:96079611.
33. Paszty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994;94:899903.
34. Duverger N, Tremp G, Caillaud JM, Emmanuel F, Castro G, Fruchart JC, Steinmetz A, Denefle P. Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. Science. 1996;273:966968.[Abstract]
35. Cohen RD, Castellani LW, Qiao JH, Van Lenten BJ, Lusis AJ, Reue K. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J Clin Invest. 1997;99:19061916.[Medline] [Order article via Infotrieve]
36. Moghadasian MH, Godin DV, McManus BM, Frohlich JJ. Lack of regression of atherosclerotic lesions in phytosterol-treated apo E-deficient mice. Life Sci. 1999;64:10291036.[Medline] [Order article via Infotrieve]
37. Gijbels MJ, van der Cammen M, van der Laan LJ, Emeis JJ, Havekes LM, Hofker MH, Kraal G. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis. 1999;143:1525.[Medline] [Order article via Infotrieve]
38.
Hasty AH, MacRae
FL, Brandt SJ, Babaev VR, Gleaves LA, Fazio S. Retroviral gene therapy
in apoE-deficient mice: apoE expression in the artery wall reduces
early foam cell lesion formation.
Circulation. 1999;99:25712576.
39.
Tsukamoto K,
Tangirala R, Chun SH, Pur E, Rader DJ. Rapid regression of
atherosclerosis induced by liver-directed gene transfer
of apoE in apoE-deficient mice.
Arterioscler Thromb Vasc Biol. 1999;19:21622170.
40.
Desurmont C,
Caillaud JM, Emmanuel F, Benoit P, Fruchart JC, Castro G, Branellec D,
Heard JM, Duverger N. Complete atherosclerosis
regression after human apoE gene transfer in apoE-deficient/nude mice.
Arterioscler Thromb Vasc Biol. 2000;20:435442.
41.
Tangirala RK,
Tsukamoto K, Chun SH, Usher D, Pure E, Rader DJ. Regression of
atherosclerosis induced by liver-directed gene transfer
of apolipoprotein A-I in mice.
Circulation. 1999;100:18161822.
42. Stary HC. Macrophages in coronary artery and aortic intima and in atherosclerotic lesions of children and young adults up to age 29. In: Schettler G, Gotto AM,. Middelhoff G, Habenicht AJR, Jurutka KR, eds. Atherosclerosis VI. Berlin, Germany: Springer-Verlag; 1993:462466.
43. Stary HC. Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children. Atherosclerosis. 1987;64:91108.[Medline] [Order article via Infotrieve]
44. Napoli C, DArtmiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, Palinski W. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997;100:26802690.[Medline] [Order article via Infotrieve]
45. Napoli C, Glass CK, Witztum JL, Deutsch R, DArmiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerosis lesions in childhood: Fate of Early Lesions In Children (FELIC) Study. Lancet. 1999;354:12341241.[Medline] [Order article via Infotrieve]
46. McGill HC, McMahan CA, PDAY Research Group. Determinants of atherosclerosis in the young. Am J Cardiol. 1998;82:30T36T.[Medline] [Order article via Infotrieve]
47.
Pathobiological
Determinants of Atherosclerosis in Youth (PDAY)
Research Group. Natural history of aortic and coronary
atherosclerotic lesions in youth: findings from the PDAY Study.
Arterioscler Thromb Vasc Biol. 1993;13:12911298.
48.
McGill HC Jr,
McMahan CA, Malcom GT, Oalmann MC, Strong JP, for the PDAY Research
Group. Effects of serum lipoproteins and smoking on
atherosclerosis in young men and women.
Arterioscler Thromb Vasc Biol. 1997;17:95106.
49.
McGill HC Jr,
McMahan CA, Tracy RE, Oalmann MC, Cornhill JF, Herderick EE, Strong JP.
Relation of a postmortem renal index of hypertension to
atherosclerosis and coronary artery size in
young men and women. Pathobiological Determinants of
Atherosclerosis in Youth (PDAY) Research Groupl.
Arterioscler Thromb Vasc Biol. 1998;18:11081118.
50.
McGill HC Jr,
McMahan CA, Herderick EE, Tracy RE, Malcom GT, Zieske AW, Strong JP,
for the PDAY Research Group. Effects of coronary heart disease
risk factors on atherosclerosis of selected regions of
the aorta and right coronary artery.
Arterioscler Thromb Vasc Biol. 2000;20:836845.
51. Brown BG, Zhao XQ, Poulin D, Albers JJ. Regression of atherosclerosis: does it occur and does it have clinical meaning? Eur Heart J. 1995;16(suppl E):25.
52. Moncada S, Martin JF, Higgs A. Symposium on regression of atherosclerosis. Eur J Clin Invest. 1993;23:385398.[Medline] [Order article via Infotrieve]
53. Schell WD, Myers JN. Regression of atherosclerosis: a review. Progr Cardiovasc Dis. 1997;5:483496.
54. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:13711375.[Abstract]
55. Brown BG, Zhao XQ. Importance of endothelial function in mediating the benefits of lipid-lowering therapy. Am J Cardiol. 1998;82:49T-52T.[Medline] [Order article via Infotrieve]
56.
Hambrecht R, Wolf
A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of
exercise in coronary endothelial function in
patients with coronary artery disease.
N Engl J Med. 2000;342:454460.
57. Stoffel W, Borberg H, Greve V. Application of specific extracorporeal removal of low density lipoproteins in familial hypercholesterolaemia. Lancet. 1981;2:10051007.[Medline] [Order article via Infotrieve]
58. Schuff-Werner P, Gohlke H, Bartmann U, Baggio G, Corti MC, Dinsenbacher A, Eisenhauer T, Grutzmacher P, Keller C, Kettner U, Kleophas W, Koster W, Olbricht CJ,. Richter WO, Seidel D, the Help-Study Group. The HELP-LDL-Apheresis Multicentre Study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease, II: final evaluation of the effect of regular treatment on LDL-cholesterol plasma concentrations and the course of coronary heart disease. Eur J Clin Inv. 1994;24:724732.[Medline] [Order article via Infotrieve]
59. Thompson GR, Maher VMG, Matthews S, Kitano Y, Neuwirth C, Shortt MB, Davies G, Rees A, Mir A, Prescott RJ, de Feyter P, Henderson A. Familial hypercholesterolaemia regression study: a randomised trial of low-density-lipoprotein apheresis. Lancet. 1995;345:811816.[Medline] [Order article via Infotrieve]
60.
Kroon AA,
Aengevaeren WR, van der Werf T, Uijen GJ, Reiber JH, Bruschke AV,
Stalenhoef AF. LDL-Apheresis Atherosclerosis Regression
Study (LAARS): effect of aggressive versus conventional lipid lowering
treatment on coronary atherosclerosis.
Circulation. 1996;93:18261835.
61. Nishimura S, Sekiguchi M, Kano T, Ishiwata S, Nagasaki F, Nishide T, Okimoto T, Kutsumi Y, Kuwabara Y, Takatsu F, Nishikawa H, Daida H, Yamaguchi H. Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS). Atherosclerosis. 1999;144:409417.[Medline] [Order article via Infotrieve]
62. Park JW, Merz M, Braun P. Regression of transplant coronary artery disease during chronic low-density lipoprotein-apheresis. J Heart Lung Transplant. 1997;16:290297.[Medline] [Order article via Infotrieve]
63. Thiery J, Seidel D. Safety and effectiveness of long-term LDL-apheresis in patients at high risk. Curr Opin Lipid. 1998;9:521526.[Medline] [Order article via Infotrieve]
64. Kajinami K, Mabuchi H. Therapeutic effects of LDL apheresis in the prevention of atherosclerosis. Curr Opin Lipidol. 1999;10:401406.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
K. Prasad Flax Lignan Complex Slows Down the Progression of Atherosclerosis in Hyperlipidemic Rabbits Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2009; 14(1): 38 - 48. [Abstract] [PDF] |
||||
![]() |
K. Prasad A Study on Regression of Hypercholesterolemic Atherosclerosis in Rabbits by Flax Lignan Complex Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 304 - 313. [Abstract] [PDF] |
||||
![]() |
L. Verna, C. Ganda, and M. B. Stemerman In Vivo Low-Density Lipoprotein Exposure Induces Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1 Correlated With Activator Protein-1 Expression Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1344 - 1349. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Verschuren, R. Kleemann, E. H. Offerman, A. J. Szalai, S. J. Emeis, H. M. G. Princen, and T. Kooistra Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3-Leiden Transgenic Mice Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 161 - 167. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Levin, E. D. Bischoff, C. L. Daige, D. Thomas, C. T. Vu, R. A. Heyman, R. K. Tangirala, and I. G. Schulman Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 135 - 142. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. P. Choudhury, V. Fuster, J. J. Badimon, E. A. Fisher, and Z. A. Fayad MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1065 - 1074. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. X. Rong, J. Li, E. D. Reis, R. P. Choudhury, H. M. Dansky, V. I. Elmalem, J. T. Fallon, J. L. Breslow, and E. A. Fisher Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content Circulation, November 13, 2001; 104(20): 2447 - 2452. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. Palinski, F. P. D'Armiento, J. L. Witztum, F. de Nigris, F. Casanada, M. Condorelli, M. Silvestre, and C. Napoli Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits Circ. Res., November 23, 2001; 89(11): 991 - 996. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |