1. health and fitness
2. disease
3. cholesterol

European Heart Journal Supplements (2006) 8 (Supplement F), F4–F9
doi:10.1093/eurheartj/sul034
HDL and the progression of atherosclerosis: new
insights
Cesare R. Sirtori1,2
1
2
Department of Pharmacological Sciences, University of Milano, Via Balzaretti, 20133 Milano, Italy
University Center of Hyperlipidemias, Niguarda Hospital, Milano, Italy
KEYWORDS
Aims Lowering low-density lipoprotein (LDL) cholesterol or raising high-density
lipoprotein (HDL) cholesterol can result in significant cardiovascular benefit, both in
terms of reduction of events and also, to a variable extent, of atheromatous
lesions. LDL and HDL have opposite roles in body cholesterol regulation and, both
reduced deposition (LDL reduction) and increased removal (raised HDL) can improve
vascular disease. Very recently, studies using recombinant apolipoprotein AI liposomes
(in particular with the mutant apo AIMilano) have shown that direct infusion can effectively remove cellular cholesterol and dramatically reduce established atheromatous
plaques in animals and in coronary patients. It has thus become of growing interest,
the possibility of raising HDL by pharmacological treatments. This review will
attempt to investigate existing and novel methodologies for HDL raising.
Methods and results HDL raising can be achieved by using drugs active on the peroxisome proliferator activated receptor a (PPAR a) system, particularly using fibrates or
n-3 fatty acids and, possibly more effectively, by using nicotinic acid. The activity of
this agent has been traditionally linked to a reduced free fatty acid (FFA) mobilization
from adipose tissue. More recently, it has been noted that nicotinic acid can activate
the PPAR system, by stimulating all three PPAR isoforms (a, g, d). This mode of action
seems to more effectively explain the striking HDL-raising properties of the drug.
Conclusions Newly discovered mechanisms of nicotinic acid can explain, on the one
hand, reduced atherosclerosis progression in secondary prevention patients treated
with statins and, on the other hand, improved body cholesterol mobilization, effectively reducing cholesterol pool sizes.
Introduction: the HDL targets
Raising high-density lipoprotein (HDL) levels or providing
exogenous HDL (HDL therapy) are novel areas of therapeutic development in the cardiovascular field. They
are based on the strong scientific and clinical evidence
linking HDL to cardiovascular protection. Although
the ‘low HDL-cholesterol’ or ‘hypoalpha’ syndrome is
the most frequent lipoprotein abnormality in coronary
patients, it has not received as much attention as
the hyper LDL-cholesterolaemia. Way back from
Framingham Study analyses in 1977, an association was
Corresponding author.
E-mail address: [email protected]
reported between reduced HDL-cholesterol and
increased cardiovascular risk vs. an apparent protective
effect of elevated HDL-cholesterol in both sexes.1 A
raised cardiovascular risk was detected in subjects with
HDL-cholesterol levels below 50 mg/dL for females and
below 40 mg/dL for males, but there seemed to be
little benefit in HDL-cholesterol levels above 60 mg/dL
in either sex.
A direct comparison between the risk associated with
increased LDL-cholesterol and reduced HDL-cholesterol
had not been clearly provided by any epidemiological
study, until the recent ARIC investigation, assessing risk
in 12 339 middle-aged participants of both sexes, free
of coronary heart disease (CHD), with a 10-year follow-up
resulting in 725 CHD events.2 In males, comparing event
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]
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HDL-cholesterol;
LDL-cholesterol;
Cholesterol pool sizes;
HDL-mimetics;
Nicotinic acid;
Fibrates;
Statins
HDL and the progression of atherosclerosis
F5
Figure 1 Relative cardiovascular risk in male participants of the ARIC Study, as predicted by baseline LDL and HDL-levels. Risk from the lowest to the
highest quintile of LDL cholesterolaemia is multiplied by 2.6; from the highest to the lowest quintile of HDL cholesterolaemia by 2.9. Drawn from data
presented by Sharrett et al.2
Hypoalpha: the clinical condition
Hypoalpha asymptomatic patients show extensive coronary atheromas upon intravascular ultrasound (IVUS) evaluation vs. the case of patients with an isolated elevation of
LDL-cholesterol.7 Carotid intima media thickness (IMT)
studies8 indicate that individuals with reduced
HDL-cholesterol levels show IMTs similar to those with
familial hypercholesterolaemia. Further, hypoalpha
patients show reduced arterial vasodilation after various
stimuli, thus confirming endothelial protection by HDL.9
Growing evidence indicates that HDL-cholesterol raising
may possibly have a more powerful effect on arterial
protection than LDL-cholesterol lowering.
A direct correlation between HDL-cholesterol levels and
a series of parameters of coronary risk has been attempted
by a number of authors. Evidence has been provided for
an inverse correlation between HDL-cholesterol levels
and C-reactive protein levels in large series of patients.10
In a similar study, also in an Italian population, it could
be shown that hypoalpha patients have higher C-reactive
protein levels than patients with normal HDL, and the
highest levels are found in the hypoalpha patients with
coronary disease.11 There appears, however, to be a
threshold beyond which higher HDL-cholesterol levels
may not make a large difference; this may be the case discussed by Calabresi et al.,12 where plasma cytokine levels
(ICAM-I, VCAM-1, E-selectin) appeared to be dramatically
elevated in patients with HDL-cholesterol levels below
40 mg/dL, but were not further reduced with
HDL-cholesterol exceeding this level.
The importance of the acute raising of HDL levels was
recently demonstrated by the direct infusion of AIMilano
liposomes, resulting in significant atheroma regression by
IVUS evaluation in experimental animals13 as well as in
coronary patients.14 Conversely, extreme LDL-cholesterol
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rates in the lowest quintile of LDL-cholesterol (83 mg/dL)
vs. the highest quintile (185 mg/dL), a risk ratio of
2.6 could be found; conversely, from the highest
(59.4 mg/dL) to the lowest (28.6 mg/dL) quintile of HDLcholesterol, there was a 2.9-fold risk rise (Figure 1).
Multiplication of risk going from the highest to the
lowest HDL-cholesterol quintile is thus at least equivalent
(if not higher) vs. the multiplication of risk going from the
lowest to the highest LDL-cholesterol quintile. The difference in risk ratios for HDL-cholesterol vs. LDL-cholesterol
was even more dramatic for women: risk multiplication
from the lowest to the highest LDL-cholesterol levels in
fact was 2.9 vs. 5.8 for the highest vs. the lowest
HDL-cholesterol quintile. A detailed evaluation of the
comparative benefit of LDL lowering vs. HDL raising has
been recently provided.3
HDL-cholesterol as a risk-prediction marker has provided, at times, surprising findings: a post hoc evaluation of patients with acute coronary syndromes
participating in the MIRACL study has very recently
shown that baseline LDL-cholesterol and LDLcholesterol changes after atorvastatin treatment
were not predictive of subsequent events. In contrast,
HDL-cholesterol levels at baseline predicted a shortterm risk reduction of 1.4% for each 1 mg/dL increment of HDL-cholesterol.4 A similar reduction in risk
occurred when evaluating baseline ApoAI instead of
HDL-cholesterol. Use of ApoAI vs. HDL-cholesterol for
coronary risk evaluation has provided contrasting findings.5 Determination of ApoAI would have the advantage of little analytical influence from concomitant
hypertriglyceridaemia or non-fasting conditions.
However, a number of reports, including a very
recent one from the Women’s Health Study, have
shown that HDL-cholesterol levels are at least good
if not better predictors than ApoAI.6
F6
reduction by statins, as reported in the REVERSAL trial, did
not lead to any significant reduction in coronary atheromas
by IVUS evaluation.15
The clinical observation of rapid atheroma regression
following AIMilano liposome infusion has raised considerable enthusiasm on the concept of ‘HDL-therapy’, and
this has led to the development of a number of
approaches using the so-called ‘HDL mimetics’ (i.e.
large unilamellar vesicles)16 to small dextro-rotary peptides (D4F) and HDL with aminoacid or lipid modifications.17,18 At present, ApoAIMilano is the most
advanced and probably the most promising product
among these and is undergoing a late phase 2 clinical
trial, evaluating doses and safety.
Present-day HDL-cholesterol-raising drugs’
efficacy and differential mechanisms
per se can cause atheroma regression and directly
reduce cardiovascular events. Interestingly, in the
ARBITER 2 study, all patients were on statins, whereas
in the AFREGS, they were mainly on resins, and thus
the effects of nicotinic acid were assessed in their
absence.
There are at present two major drug classes for raising
HDL-cholesterol levels, plus one in development.
Fibrates have a well-defined stimulating activity on the
peroxisome proliferator receptor a (PPARa) system.21
By PPARa-associated mechanisms, fibrates stimulate triglyceride breakdown, i.e. they activate lipoprotein
lipase (LPL) and also reduce ApoCIII expression (an inhibitor of LPL); as a consequence, they raise HDL-cholesterol
levels. These mechanisms, together with antiinflammatory properties22 shared by other PPARa agonists, characterize their clinical action and potential
therapeutic benefit. Nicotinic acid still has an unclear
mechanism, which will be discussed in detail elsewhere
in this supplement. Finally, cholesterol ester transfer
protein (CETP) antagonists (JTI-7051 and torcetrapib),
by blocking the reverse cholesterol transport system,
raise HDL-cholesterol to very high levels,23 but their
therapeutic benefit is still unclear.
A general mechanism of HDL-cholesterol elevators is
that of stimulating fecal steroid excretion. This mechanism, of course, contrasts with that of statins, which
generally reduce fecal sterol elimination, most likely
because of their inhibition of biosynthesis, per se somewhat reducing sterol pools. Three studies that have
specifically investigated body cholesterol movements
after statins have produced negative findings. Grundy
and Bilheimer24 investigated fecal excretion of neutral
and acidic steroids in five heterozygote FH patients
before and during treatment with lovastatin. In three
out of five, neutral and acidic steroid excretions were
reduced, whereas there were no alterations in the
other two (Figure 2A). These findings were replicated
by carrying out a whole-body cholesterol turnover study
in nine hypercholesterolemic patients before and after
Figure 2 Comparison between fecal steroid excretions as neutral steroids or bile acids following treatment with (A) HMGCoA reductase inhibitor (lovastatin), drawn from data presented by Grundy et al.24; (B) torcetrapib with and without atorvastatin (fecal steroid excretion corrected by the plant sterol
intake elimination), drawn from data presented by Brousseau et al.30; (C) infusion of recombinant proapoA-I (4 g of protein) in familial hypercholesterolemic subjects, reproduced from Eriksson et al.28 with permission from Lippincott, Williams & Wilkins (www.lww.com).
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HDL can directly remove cellular cholesterol and exert a
variety of vascular protective effects (antioxidant, antiinflammatory, pro-fibrinolytic, and others). Use of drugs
raising HDL-cholesterol by different mechanisms (from
fibrates to nicotinic acid) has gained support from a
variety of clinical studies, some of which are indicative
of reduced cardiovascular events/atheroma reduction
following treatment. The direct provision of biosynthetic
or plasma-extracted HDL, e.g. with AIMilano, can improve
the extent and severity of vascular lesions, with the
potential benefit of acting in a short time frame.
The clear evidence of beneficial effect of HDL-therapy
has encouraged a re-evaluation of established treatments
aimed to elevate HDL-cholesterol levels in order to
reduce cardiovascular risk. Two recent studies, Arterial
Biology for the Investigation of the Treatment Effects of
Reducing Cholesterol (ARBITER) 2, evaluating IMT in
coronary patients already at optimal LDL-cholesterol
levels,19 and the Armed Forces Regression Study
(AFREGS), in coronary patients not on statins,20 clearly
showed that drug-induced HDL-cholesterol elevations
C.R. Sirtori
HDL and the progression of atherosclerosis
The mechanism of HDL-raising by nicotinic
acid: new insights
Nicotinic acid, had shown its lipid-lowering properties
well over 50 years ago. These occur at relatively high
dosages (above 1 g/day) and are best achieved with
retard formulations, which also provide the optimal
tolerability.32 Traditionally, the mechanism of the
lipid-lowering effect, in particular, triglyceride reduction
and the remarkable HDL-raising property, have been
ascribed to an antilipolytic activity.32 This has been
recently attributed to the interaction with a well-defined
G/protein-coupled receptor in adipose tissue.33–35 Very
recently, it has been also indicated that the GPR109A
receptor (HM74A in humans and PUMA-G in mice) mediates the skin-flushing response to nicotinic acid.36
Previous studies by the present author’s group,37 using
a very powerful long-acting inhibitor of lipolysis (acipimox), showed that this drug has an antilipolytic activity
at least 10-fold higher vs. nicotinic acid and, in addition,
it maintains the activity for a prolonged period. Acipimox
blocks lipolysis for up to 9–12 h vs. the very transient
inhibitory activity of standard formulations of nicotinic
acid (less than 3 h). The antilipolytic activity of standard
nicotinic acid is also immediately followed by a rebound
of free fatty acid (FFA) levels at least 2-fold higher
vs. baseline.37 Acipimox, in spite of this extraordinary
antilipolytic activity, proved to be a poorly active lipidlowering medication, with a modest triglyceridereducing effect and a HDL-raising activity not better
than þ10%.38,39 It seems, therefore, rather unlikely
that these striking differences in antilipolytic and
lipid-lowering activities could address to the antilipolytic
effect as a major mechanism of nicotinic acid. In
addition, very recently, Lena Vega et al.40 showed that
Niaspanw, a very well tolerated, prolonged-release formulation of nicotinic acid, also inhibits lypolysis not
longer than 3–4 h, and 9 h after administration, FFA
levels are clearly above baseline. In spite of this, the
triglyceride-lowering effect and, in particular, the
HDL-cholesterol-raising activity (þ21% in non-diabetic
subjects and þ 28% in diabetic patients) are certainly
far better than those of acipimox.
In view of the scepticism on the antilipolytic mechanism
of nicotinic acid, other investigators have explored
alternative pathways. Rubic et al.41 have recently shown
that by exposing human monocytoid cells to nicotinic
acid, this resulted in markedly increased expression of
ABCA1 and PPARg. ABCA1 activation is opposite to the
effect reported by Sone et al.42 in a macrophage cell
line exposed to fluvastatin, both in basal conditions and
after stimulation with 22-hydroxycholesterol.
However, potentially the most exciting findings have
been recently reported by Watt et al.43 in muscles of
healthy individuals before exercise. Volunteers were
administered nicotinic acid with the objective of reducing lipolysis during the ensuing exercise. The administration of nicotinic acid, surprisingly, led to a marked
increase of PPARa and PPARd mRNA levels in muscle
(Figure 3). This rise was similar to that noted after exercise and was accompanied by an increased expression of
the PPAR co-activator 1-a (PGC1a) mRNA. The authors
concluded that ‘nicotinic acid ingestion decreased FFA
availability but it promoted induction of PPARa/d and
PGC1a gene expression to a similar degree as prolonged
exercise’.43 The induction of PPARg has been very
recently ascribed to an indirect mechanism of nicotinic
acid, i.e. an induction of the prostaglandin synthesis
pathway via the HM74A receptor.44,45
These very exciting data point out that possibly nicotinic
acid may act as a ‘fraudulent fatty acid’.46 Fraudulent
fatty acids are fatty acid-like molecules not metabolized
by mitochondria but activating the peroxisomal system,
thus leading to metabolic consequences similar to those
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15 months of lovastatin therapy (40 mg/day),25 again
showing no significant changes in the sizes of rapidly,
slowly, and total body exchangeable sterol pools.
Finally, in a study in normolipidemic volunteers26 on
lovastatin (40 mg bid) in the presence of either a lowor high-cholesterol diet, as expected, biliary cholesterol
secretion, fecal output of endogenous neutral sterols,
cholesterol balance, and systemic cholesterol input
(sum of cholesterol synthesis þ absorbed dietary cholesterol) were reduced. Vascular benefits of statins should,
therefore, be attributed to a stabilization of body cholesterol pools, and biliary cholesterol lowering may also
potentially be of benefit in gallstone patients.27
Two studies have evaluated the effects of a direct infusion of reconstituted HDL using human ApoAI formulated
into liposomes on fecal steroid excretion. In patients with
severe FH, single dose (4 g of protein) of recombinant
pro-ApoAI induced a clear increase of cholesterol mobilization, resulting in increased fecal neutral steroids and
bile acids28 (Figure 2B). In a second study,29 the effects
of an i.v. infusion of human ApoAI phosphatidylcholine
(PC) discs (molar ratio 1:150) were compared with
those of pro-ApoAI/PC discs, in normolipidemic recipients. In both conditions, there was an increase of small
pre-b-HDL in plasma and lymph, an increase of both
plasma lathosterol and fecal neutral steroids and, more
so, of bile acids, in particular, chenodeoxycholate and
derivatives (þ302% at 24 h and still 192% at the seventh
day after the end of the infusion).
Contrasting findings have, instead, been provided with
torcetrapib, the most advanced CETP antagonist. In a
study where torcetrapib was given together with atorvastatin, the association, as expected, led to a reduction of
fecal steroid elimination.30 Torcetrapib per se did not,
however, modify fecal neutral sterol or bile acid
excretion, thus indicating that possibly a tissue cholesterol redistribution effect may occur, as suggested by
the authors, or other mechanisms may be in play
(Figure 2C).
The effects of nicotinic acid on fecal steroid excretion
were evaluated in detail in one study, in which a
reduction of cholesterol biosynthesis was noted and,
more significantly, an increase of fecal neutral and
acidic steroids, witnessing enhanced cholesterol mobilization.31 The drug also reversed the apparent increase in
sterol pools after cholestyramine treatment.
F7
F8
C.R. Sirtori
Figure 3 Real-time PCR analysis of PPARa and PPARd from muscle of healthy individuals before and after 3 h of moderate exercise with (NA) or without
(CON) prior administration of nicotinic acid (10 mg/kg)43 [&Society for Endocrinology (2004), reproduced with permission]. Suppression of plasma FFAs
upregulates PPARa and PPARd and PPAR coactivator 1alpha in human skeletal muscle, but not lipid regulatory genes. P , 0.05, different from the
corresponding value for CON. †P , 0.05, different from the pre-exercise value.
exerted by nicotinic acid. In particular, among fraudulent
fatty acids, nicotinic acid (or most likely nicotinoyl CoA,
the major metabolite) is the only one activating all three
peroxisomal isotypes as well as ABCA1.
The very novel findings with nicotinic acid, indicative of a
more extensive mode of action vs. presently available
HDL-raising drugs, are an additional area of interest for
studies on the potential of HDL raising in the clinic.
Conflict of interest: none declared.
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