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Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease: Implications for Evaluation and Targets for Treatment of Dyslipidemia Based on Recent Guidelines

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Dyslipidemia and Its Role in the
Pathogenesis of Atherosclerotic
Cardiovascular Disease:
Implications for Evaluation
and Targets for Treatment of
Dyslipidemia Based on Recent
PerryWengrofsky, JustinLee and Amgad N.Makaryus
The clinical presentations of atherosclerotic disease are the result of a constella-
tion of diverse metabolic and immunologic mechanisms ultimately set into motion
by the formation of fatty acid streaks and the accompanying inflammatory cell
activation, endothelial damage, smooth muscle proliferation, vascular fibrosis, and
end-organ infarction and necrosis. At the heart of atherosclerosis are the byprod-
ucts of lipid metabolism, lipoproteins containing triglycerides, phospholipids,
and cholesterol, and the changes they undergo that eventually lead to macrophage
activation, foam cell formation, and other downstream atherosclerotic changes.
Understanding the functionality of cholesterol, triglycerides, and lipoproteins in the
cascade of atherosclerotic pathways has tremendous implications on current guide-
lines for the evaluation and targets in the management of dyslipidemia, and serves
as the foundation for future investigations into targets of atherosclerotic therapies.
Keywords: atherosclerosis, dyslipidemia, cardiovascular disease, guidelines
. Introduction
Atherosclerosis, the pathogenic process of vascular lipid deposition, arterial
luminal narrowing, and plaque expansion and instability, represents the major
driver of circulatory morbidity and mortality, including myocardial infarction,
ischemic cardiomyopathy, transient ischemic attacks, and ischemic and hemor-
rhagic stroke [1]. The acute and chronic clinical presentations of atherosclerotic
disease are the result of a constellation of diverse metabolic and immunologic
mechanisms ultimately set into motion by the formation of fatty acid streaks and
the accompanying inflammatory cell activation, endothelial damage, smooth
muscle proliferation, vascular fibrosis, and end-organ infarction and necrosis [2].
At the heart of atherosclerosis are the byproducts of lipid metabolism, lipoproteins
containing triglycerides, phospholipids, and cholesterol, and the changes they
undergo that eventually lead to macrophage activation, foam cell formation, and
other downstream atherosclerotic changes [3]. Lipoproteins are distinguished by
their lipid content, their position in lipid metabolic pathways, and overall athero-
genic risk [4, 5]. This chapter will review the role that the various lipoproteins play
in the pathophysiology of atherosclerosis as the fundamental triggers and players
in the immunologic, inflammatory, and thrombotic processes that characterize the
pathogenesis of atherosclerotic cardiovascular disease. Understanding the function-
ality of cholesterol, triglycerides, and lipoproteins in the cascade of atherosclerotic
pathways has tremendous implications on current guidelines for the evaluation and
targets in the management of dyslipidemia, and serves as the foundation for future
investigations into targets of atherosclerotic therapies.
. Lipoproteins and apolipoproteins
Lipoproteins are complex plasma particles containing a core of cholesterol esters
and triglycerides surrounded by free cholesterol, phospholipids, and apolipopro-
teins, and are classified based on size, density, and major lipid and apolipoprotein
content [6]. Apolipoproteins, structural proteins that bind triglyceride and choles-
terol and enable the formation of lipoproteins, enjoy important roles in lipoprotein
structure and metabolism by acting as ligands for lipoprotein receptors and activa-
tors or inhibitors of enzymes involved in lipoprotein metabolism [6, 7]. The size,
structure, and apolipoprotein content of the lipoproteins, namely chylomicrons
(CM), very-low-density lipoprotein (VLDL), intermediate-density lipoprotein
(IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and
lipoprotein(a) [Lp(a)], crystallize into individualized atherosclerotic risk profiles
for the specific lipoprotein [8, 9].
. Chylomicrons and chylomicron remnants
CMs, the largest and least dense of the lipoproteins, are triglyceride rich,
released from the intestine, and primarily responsible for delivery of dietary
cholesterol and triglycerides to peripheral tissue and the liver [6, 10]. Removal of
triglycerides from circulating CMs generates CM remnants that possess a consider-
ably higher cholesterol concentration [6, 11]. CMs and CM remnant size is linked to
ingested triglyceride levels and the structure is maintained by multiple apolipopro-
teins, predominantly apolipoprotein B-48 (Apo B-48) [6]. Apo B-48 is synthesized
in the intestine, and represents 48% of the amino acids in the peptide sequence of
apolipoprotein B-100 (Apo B-100), the apolipoprotein synthesized by the liver and
a major apolipoprotein involved in the atherosclerotic pathophysiology [12].
. Very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein
Triglyceride consumption by adipose tissue and the resulting cholesterol-rich
CM remnants subsequently reach the liver, which reorganizes triglycerides and
cholesterol in the form of VLDL that are secreted into circulation and allow for
lipoprotein lipase (LPL) mediated absorption of triglycerides by cardiomyocytes,
skeletal muscle, and adipose tissue [4, 6]. CMs, CM remnants, and VLDL contain
apolipoprotein C (Apo C), specifically Apo C-II, an essential cofactor for LPL,
and transposition of triglycerides from circulating lipoproteins to tissue steadily
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
increases the concentration of cholesterol and overall density of the lipoprotein
while simultaneously decreasing the size [6, 13]. The apolipoprotein that plays
the most atherogenic role of all the apolipoproteins and distinguishes VLDL from
chylomicrons and CM remnants is Apo B-100, a major structural apolipoprotein
and LDL receptor (LDLR) ligand [6, 14]. VLDL exists as the bridge between the
exogenous and endogenous pathways of lipid metabolism, with the lipid content
of CM remnants that reach the liver via gastrointestinal absorption at the begin-
ning of the exogenous pathway being repackaged and secreted by hepatocytes as
VLDL to initiate the endogenous pathway. IDLs, considered VLDL remnants, are
considerably smaller than the antecedent VLDL and exhibit similar apolipoprotein
composition, but they have similar triglyceride and cholesterol contents to the CM
remnants [4, 14, 15]. The decreased size and cholesterol along with the appropriate
apolipoprotein profile of Apo B-100 and Apo-E, another apolipoprotein ligand for
the LDLR, make IDL atherogenic, but the primary atherogenic lipoprotein that sets
off the cascade of atherosclerotic lipid, immunologic, and inflammatory pathways
remains LDL (Table).
. Low-density lipoprotein (LDL)
LDL, derived from LPL/Apo C-II-mediated triglyceride removal from VLDL
and IDL, is the lipoprotein responsible for cholesterol transport to peripheral tissue
and the lipoprotein that has been extensively studied and directly implicated in
the development of atherosclerosis [4, 5]. With an average size of 18–25nm, LDL
and the predominant apolipoprotein it contains, Apo B-100, undergo oxidation
and other molecular modifications that are responsible for endothelial damage,
macrophage chemoattraction, and pathologic arterial changes [1, 6, 16]. Individual
LDL particles can vary in size, with decreasing or small dense LDL being noticeably
more atherogenic than large LDL particles due to susceptibility to oxidation, ease
of extravasation and entrapment in the arterial wall, and avidity for binding with
vascular wall proteoglycans [6, 16, 17].
The metabolism of LDL, and thus the circulatory availability and arterial wall
extravasation ability of LDL, is determined by the quantity of hepatic LDLR, as the
concentration of LDL generated from the metabolism of VLDL and IDL is regulated
by the amount of IDL that is absorbed into the liver via the LDLR prior to LPL-
mediated triglyceride removal [6, 18]. Hepatic levels of LDLR are primarily modu-
lated by hepatocyte cholesterol levels, with adequate cholesterol levels stimulating
Lipoprotein Size (nm) Major lipid content Apolipoproteins
Chylomicron >75 Triglyceride Apo B-48, Apo C, ApoE, Apo A-I, A-II,
30–75 Triglyceride, cholesterol Apo B-48, ApoE
VLDL 30–75 Triglyceride Apo B-100, Apo C, ApoE
IDL 25–35 Triglyceride, cholesterol Apo B-100, Apo C, ApoE
LDL <25 Cholesterol Apo B-100
Lp(a) 30 Cholesterol Apo B-100, Apo(a)
HDL <15 Cholesterol,
Apo A-1, A-II
Apo C, ApoE
Table 1.
Lipoproteins—size, lipid, and apolipoprotein content.
LDLR targeting for degradation by PCSK9, a protein synthesized by hepatocytes
that binds the LDLR and promotes lysosomal LDLR degradation [5, 6, 19].
LDL subfraction sizes and the resulting atherogenicity need to be considered
when evaluating patients, as therapeutic regimens (such as niacin) have been known
to affect LDL particle size. It is also important to realize that while overall cholesterol
panel level changes may occur and appear to be in the right direction, it is actually
the atherogenicity of the particles specifically of LDL that drives the pathogenesis of
atherosclerosis [20]. Analysis, therefore, of LDL subfractions may be an important
component of lipid follow-up in patients with complex lipid disorders on combina-
tion pharmacologic therapy.
. High-density lipoprotein (HDL)
HDL differs from VLDL, IDL, and LDL in size, lipid, and apolipoprotein con-
tent, role in cholesterol metabolic pathways, and antiatherogenic characteristics.
HDL is responsible for peripheral cholesterol uptake and delivery to the liver- and
cholesterol-derived hormone-producing organs, and it provides important anti-
oxidant and anti-inflammatory functions that can inhibit atherosclerosis [4, 6, 21].
Devoid of Apo B-100 that contributes to LDL oxidation and subsequent macro-
phage activation, HDL is associated with multiple subtypes of apolipoprotein A
(Apo A) that facilitates cholesterol transfer from peripheral tissue and activates
lecithin-cholesterol acyltransferance (LCAT), which allows for cholesterol esteri-
fication and movement of cholesterol from the HDL surface to the HDL core
[6, 22]. After cholesterol uptake from peripheral tissue and macrophages, HDL
facilitates transfer to the liver via scavenger receptor class B type I (SR-B1), where
the cholesterol can be converted into bile acids for excretion or be directly secreted
into bile [21, 23]. The apolipoprotein profile and receptors involved in cholesterol
movement from HDL sheds light on some of the physiologic pathways involved in
HDL attenuation of atherosclerosis and conversely the highly atherogenic contents
and formulation of LDL.
. Lipoprotein A [Lp(a)]
Lp(a) is the lipoprotein formed of a cholesterol-rich LDL molecule and apolipo-
protein a [Apo(a)], with levels that are very fluctuant but are generally dependent
on the rates of hepatic production of Apo(a) [6, 24]. The Apo-B100 and the Apo(a)
are connected via a disulfide bond, and given its size and cholesterol composition
essentially identical to that of LDL, Lp(a) is able to extravasate from plasma into the
arterial intima and interact with the extracellular matrix through LDL Apo B-100
and Lp(a) [2426]. In addition to Lp(a), extracellular matrix interactions that facili-
tate the trapping of cholesterol that sets the table for macrophage uptake and foam
cell formation, Lp(a) disrupts fibrinolysis and enhances coagulation, two functions
that promote atherosclerotic plaque instability and rupture [24, 27].
. Lipoproteins and the atherosclerotic thrombo-inflammatory process
. Endothelial changes and regional plaque distribution
Endothelial cells undergo a series of changes, both connected and unrelated to
lipoproteins that contribute to the different pathophysiologic mechanisms at play in
atherosclerosis and help to explain the typical regional distributions of atheroscle-
rotic lesions.
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
While LDL and other small and atherogenic lipoproteins undergo oxidative and
structural changes that eventually lead to trapping in the arterial intima that recruit
macrophages and other inflammatory cells, access to the intima extracellular matrix
is spearheaded by endothelial cell dysfunction and damage from oxidative injury
in conditions like smoking and hypertension, advanced glycation end products
in diabetes mellitus, and regional hemodynamic forces in particular parts of the
arterial tree [1, 28]. Oxidative insults to the endothelium impair production of nitric
oxide (NO), the potent modulator of vascular tone and inhibitor of the prolifera-
tion of vascular smooth muscle cells (VSMCs), and exhibits important roles in the
prevention of LDL oxidation and leukocyte extravasation from the bloodstream
to arterial intima [29]. Additional chemical mediators of endothelial dysfunction
include endothelin-1 (ET1) that interacts with NO in the regulation of arterial
tone, signals changes in endothelial expression of adhesion molecules, and recruits
important inflammatory cells such as macrophages while simultaneously regulating
extracellular matrix enzymes that contribute to intimal alterations [1, 30].
The endothelial changes that best illuminate the regional pathophysiology
of atherosclerosis are not the different levels of NO and other molecular signals,
but the regional reorganization of endothelial phenotypes in reaction to local
hemodynamic forces. Atherosclerotic plaques generally form at areas of arterial
curvature and bifurcation, the locations in the arterial circulation where there are
typical patterns of elevated shear stress [31]. Endothelial cells in regions of higher
shear stress display a cuboidal morphology, higher cell turnover, and impaired
endothelial barrier function that collectively promotes lipoprotein and inflamma-
tory cell migration, in comparison to endothelial cells in arterial beds with more
favorable hemodynamics that exhibit ellipsoidal morphology, coaxial alignment,
and an endothelial glycocalyx that protects against lipoprotein extravasation
While the size, oxidative profiles, and atherogenic risk of the lipoproteins, most
significantly LDL and Apo B-100, are the primary drivers of atherosclerosis, critical
endothelial changes that further exacerbate the migration of lipoproteins, leuko-
cytes, VSMCs, and fibroblasts are fundamental to the generation of plaques and the
clinical consequences of plaque expansion and rupture.
. Initiation of the atherosclerotic plaque: foam cell formation
With continued endothelial compromise in regions of arterial curvature and
bifurcation, circulating LDL, and to a lesser degree VLDL and IDL, increasingly
migrate from the plasma and are retained in the extracellular matrix of the tunica
intima [34, 35]. Subendothelial accumulation of LDL and VLDL remnants pre-
cipitates endothelial activation of the nuclear factor kappa B (NF-κB) pathway
that enhances endothelial expression of adhesion proteins such as VCAM-1 and
P-selection and pro-inflammatory receptors and cytokines that promote monocyte
migration [32, 34, 36, 37]. As LDL, VLDL, VLDL remnants, IDL, and Lp(a) collect
in the arterial intima, Apo B-100, most significantly in LDL, undergoes oxida-
tion to ox-LDL, a potent ligand of macrophage scavenger receptors [1, 5, 24, 38].
Endothelial activation and upregulation of adhesion molecules enables monocyte
rolling, activation, and transendothelial migration where they differentiate from
monocytes into macrophages [34, 39]. Retained ox-LDL interacts with two mac-
rophage receptors, class A and B scavenger receptors, and in distinct contrast to
cholesterol absorbed via the LDLR by the macrophage, ox-LDL does not cause a
negative feedback on scavenger receptor expression, perpetuating continued ox-
LDL and cholesterol uptake, resulting in the entrapment of newly formed foam cells
in the arterial intima secondary to compromised mobility [1, 34, 39, 40].
Despite the predominance of LDL in the cycle of endothelial damage, macro-
phage absorption, foam cell formation, and inflammatory transduction, VLDL
and Lp(a) play important roles in endothelial activation [4, 24]. Endothelial cell
exposure to the triglycerides of VLDL stimulates expression of selectins and other
proteins that promote monocyte entry into the arterial intima, and oxidized
VLDL increases expression of plasminogen activator inhibitor 1 (PAI-1), a protein
that attenuates plasminogen conversion to plasmin and thus plasmin-mediated
dismantling of cholesterol aggregates [4, 41, 42]. Lp(a) interactions with certain
macrophage surface integrin proteins promote monocyte extravasation and upon
macrophage absorption, upregulates expression of IL-1, tumor necrosis factor
(TNF) and monocyte chemoattractant protein (MCP-1) that recruits additional
macrophages, resulting in formation of more foam cells [24, 43].
. Plaque development: inflammatory cells and smooth muscle cells
In addition to uptake by macrophages, ox-LDL acts as an omnipotent chemo-
kine that induces the activity of multiple immunologic pathways and leads to the
migration and activation of additional monocytes and other inflammatory cells and
VSMCs [1, 32, 44]. While LDL, VLDL remnants, IDL, and Lp(a) retention leads to
foam cell formation as the integral first step in plaque development, subsequent leu-
kocyte adhesion and extravasation promotes clearance of foam cells and apoptotic
cell debris from dendritic cells and T cells via a complicated interaction between
the innate and adaptive immune systems [33, 4547]. Atherosclerotic lesion mac-
rophages differentiating into inflammatory M1 macrophages present antigens to
T cells, with resulting T cell activation and release of pro-inflammatory cytokines
such as IL-1 and IL-6, inducing local lesion inflammation, further foam cell forma-
tion, and subsequent foam cell apoptosis and necrosis (Figure ) [1, 48, 49].
In a similar pattern to macrophages, foam cells undergo phagocytosis by den-
dritic cells, where antigen presentation to T cells promotes release of pro-inflam-
matory cytokine, and continued phagocytosis compromises dendritic cell mobility
resulting in dendritic foam cell formation [45, 50, 51].
The cascade of endothelial dysfunction, lipoprotein accumulation, and inflam-
matory pathways results in dramatic changes in VSMC physiology [32, 52]. Native
arterial media VSMCs are activated and undergo proliferation, migration, and
phenotypic switching that ultimately plays the most critical roles in atherosclerotic
plaque stability or vulnerability [52–54]. VSMC proliferation and migration results
in increased production of extracellular matrix components, such as proteoglycans
and elastin, that attempts to compensate for the inward architectural distortions
caused by subendothelial lipoprotein accumulation, causing outward vascular
remodeling [32, 34, 55]. Collagen production by VSMCs is the most critical compo-
nent in the development of the fibrous cap in atherosclerotic plaques, with TGF-β
released from plaque macrophages signaling VSMC proliferation [34, 56, 57].
. HDL and plaque development
The multifaceted pathways of atherosclerotic plaque development and the role
LDL and other Apo B-100 lipoproteins serve as a template for the important roles
and diverse protective mechanisms and functions of HDL in the pathogenesis
of atherosclerosis. Oxidation of Apo-B100 and the resulting accumulation and
macrophage phagocytosis of LDL and other lipoproteins can be mitigated by the
antioxidant activity of HDL, with its major apolipoproteins, Apo A-I and Apo A-II,
and HDL-associated enzymes such as paraoxonase possessing antioxidant activity
[21, 58, 59]. Resolving oxidative stress allows HDL to normalize endothelial function
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
by restoring production of NO [23, 60, 61]. HDL disrupts monocyte migration into
the arterial intima via inhibition of endothelial cell adhesion protein expression,
the fundamental first step in the formation of foam cells [62, 63]. HDL also inhibits
VSMC migration and mitigates coagulation system and platelet activation, which
come more into play in acute plaque rupture [4, 21, 64].
The major roles of HDL in atherosclerotic plaque development are inhibiting
foam cell formation by promoting cholesterol transfer from macrophages and atten-
uating local lesion inflammation. In a pattern similar to normal reverse cholesterol
transport from peripheral tissue to hepatocytes, HDL can remove cholesterol from
macrophages and foam cells in the arterial intima via passive aqueous diffusion or
cholesterol transporters, such as ATP-binding cassette transporters A1 (ABCA1)
and G1 (ABCG1) and scavenger-receptor BI (SR-BI) that utilize the cholesterol
concentration gradient [34, 65, 66]. HDL inhibits the M1 phenotype inflammatory
macrophages that dominate in atherosclerotic plaques and present antigens to T
cells while promoting M2 anti-inflammatory macrophages and modulating apopto-
sis of foam cells via antiapoptotic signaling pathways [6769].
. Atherosclerotic plaque progression, stability, and acute rupture
. Plaque progression: fibrous cap and necrotic lipid core
Smooth muscle proliferation within the atherosclerotic plaque is characterized
by the production of a subendothelial complex extracellular matrix making up the
Figure 1.
Small lipoproteins, most prominent LDL, penetrate the dysfunctional endothelial barrier and accumulate
in the arterial intima. LDL (Apo B-100 apolipoprotein component) undergoes oxidation to ox-LDL, which
triggers inflammatory cascade promoting migration of monocytes, VSMCs, and CD4 and CD8 T cells. ox-LDL
undergoes phagocytosis by macrophages (and VSMCs) to generate foam cells. Insufficient clearance of apoptotic
foam and inflammatory cells causes steady accumulation of subendothelial lipid necrotic core, which serves as
central component of developing atherosclerotic plaque.
fibrous cap that acts to wall off the inflammatory and highly thrombotic lesion col-
lection of cholesterol and cell debris that results from immune-mediated apoptosis
and destruction of foam cells [1, 70, 71].
As the plaque progresses, the thickening of the intima and the pathologic expansion
into the lumen displays areas of distinct cellular and lipid content, with the mature fibro-
atheroma consisting of an acellular lipid necrotic core of cell debris [71, 76]. The lipid
component of the necrotic core consists of foam cells and newly free cholesterol from
apoptotic macrophages that have been ineffectively cleared by efferocytosis [1, 71, 73].
The necrotic lipid core can undergo steady expansion with resulting plaque enlargement
and decreasing arterial lumen caliber due to diminished clearance capacity of cholesterol
by VSMCs and advanced plaque macrophages [34, 74].
The steady accumulation of free cholesterol and lipid material alongside necrotic
cellular products from apoptosis generates a continuous release of pro-inflammatory
stimuli that further promote additional foam cell destruction, a vicious cycle that is
contained by the thick collagenous fibrous cap [71, 75]. Vascular remodeling coun-
terbalances this continuous inflammatory process defined by intimal accumulation
and lesion expansion, which minimizes protrusion into the lumen and mitigates
clinical symptomology over the lifetime of the lesion (Figure ) [34, 71, 76].
. Stable and vulnerable plaques
The structural makeup of the plaque and relationship between fibrous cap thickness,
lipid and necrotic core size, inflammatory activity, and overlying endothelial integrity
translate to overall atherosclerotic plaque stability and risk of plaque compromise.
Figure 2.
Steady development of the necrotic lipid core leads to subendothelial expansion, which over time narrows the
diameter of the arterial lumen. VSMC migration, proliferation, and activation lead to deposition of fibrous
collagenous extracellular matrix material to create the fibrous cap of the atherosclerotic plaque. Overlying
dysfunction endothelial changes and breaks in the barrier allow for exposure of the contents of the cap and core
to interact with serum cells and proteins, leading to platelet adherence to intact but vulnerable plaques.
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
In stable atherosclerotic plaques, low-grade inflammation enables VSMC enrich-
ment, which increases the percentage of the plaque that is made up of the collagenous
fibrous cap [77, 78]. In general, the lines of demarcation between more stable and
more vulnerable plaques tend to center around the ratio between the solid fibrous tis-
sue and the extracellular lipid necrotic tissue, with stable and clinically silent plaques
typically displaying thick fibrous caps and minimal to no extracellular lipid and
necrotic foam cell debris [77, 79, 80]. While fibrous cap thickness and strength is a
critical determinant of overall plaque stability, the fibrous tissue laid down by VSMC
in the subendothelial part of the arterial intima is in a constant state of balance
between collagen synthesis and degradation mediated by inflammatory cytokines
that upregulate the expression of matrix metalloproteinases (MMPs) [1, 78, 81, 82].
MMPs can degrade fibrillar collagen, proteoglycans, and elastin over time, and the
resulting thinning and structural compromise of the fibrous cap transitions the
stable plaque to a vulnerable and high-risk plaque [77, 78, 83].
In parallel to the changes in the fibrous cap are dynamic swings in inflamma-
tory conditions in the necrotic lipid core, where increasing levels of VSMC and
macrophage apoptosis not only decrease the net number of cells that can synthesize
collagen and other stabilizing extracellular matrix components but also release
additional inflammatory cytokines that can further destabilize the plaque [78, 84].
Similar to the roles played in plaque development, T cells, both T helper CD4 T cells
and T cytotoxic CD8 cells, contribute to plaque destabilization via a perpetual loop
of macrophage and T cell recruitment, lipid uptake, foam cell formation, antigen
presentation, apoptosis, and lipid necrotic core expansion [78, 85, 86].
. Rupture and erosion of vulnerable plaques and acute thrombosis
The nonresolving inflammatory processes of lipoprotein accumulation, foam
cell formation, and immunologic activation leads to fibrocellular organization of
the plaque, with the plaque becoming increasingly unstable and prone to rupture
and acute thrombosis via fibrous cap thinning and lipid necrotic core expansion
[34, 77, 87]. The fibrous cap is thinned and weakened by MMPs, and disruption of
the collagenous cap and the overlying endothelium leads to exposure of the highly
thrombogenic and coagulable lipid necrotic core [1, 88]. Atherosclerotic plaques,
prior to any sort of structural compromise, are congregated by platelets that attach
to the dysfunctional endothelium of the plaque, and can participate in plaque-
associated thrombosis with and without rupture or erosion [88, 89].
Ruptured and eroded plaques trigger a rapid and dramatic thrombotic and
coagulation process, with activated platelets adhering to the exposed subendothelial
collagen of the thin fibrous cap via interactions between von Willebrand factor
(vWF) and glycoprotein (GP) Ib-V-IX, with adherent-activated platelets aggre-
gating via GP IIb/IIIa complexes [9092]. After adhesion, activated-aggregated
platelets release granules containing thromboxane A2, adenosine diphosphate
(ADP), and other pro-thrombotic and pro-inflammatory cytokines that recruit
inflammatory cells and amplify the platelet response (Figure ) [1, 90, 93].
Alongside platelet activation and thrombus formation is activation of the coagu-
lation system, with tissue factor (TF) receptors in the plaque binding circulating
factor VII(a) and triggering the extrinsic coagulation pathway to produce thrombin
[90, 94, 95]. Thrombin, a strong platelet agonist via protease-activated receptor
(PARs)-1 and 4, converts fibrinogen to fibrin for clot stabilization while simultane-
ously driving its own positive feedback loops through activation of factor XI and
other factors in the intrinsic coagulation pathway [90, 96, 97].
The constellation of plaque rupture, platelet activation and aggregation, and
coagulation system stimulation results in the formation of a thrombus on an
atherosclerotic plaque, causing partial to complete obstruction of the arterial
lumen, which has already been narrowed steadily over time by plaque progression
[1, 34, 90]. Postmortem pathological examination of these atherosclerotic plaque
thrombi show a directional morphology that highlights the stepwise process of
thrombus formation, with white platelet-rich heads adjacent to the focus of plaque
rupture, with red extensions from the white platelet head to the distal arterial wall
encompassing the fibrin and red blood cells that accumulate secondary to dimin-
ished blood flow from the obstructive thrombus [90, 98, 99].
. Atherosclerotic cardiovascular disease: presentation, evaluation, and
. Atherosclerotic cardiovascular disease (ASCVD)
ASCVD is the clinical manifestation of atherosclerosis and atherothrombosis,
the resulting symptomology and physical findings of acute and chronic end-organ
ischemia and infarction from the pathophysiologic thrombo-inflammatory pro-
cess of atherogenesis initiated by cholesterol and lipoprotein accumulation in the
arterial intima. Public health appreciation and scientific evidence for the role of
dyslipidemia in the progression of ASCVD has served as the impetus for organiza-
tions throughout the United States, Canada, and Europe to develop guidelines for
evaluation and management of dyslipidemia and ASCVD [100102]. Furthermore,
the severity and associated morbidity and mortality of the clinical manifestations
of ASCVD, including ischemic heart disease, such as stable angina, unstable angina,
Figure 3.
Rupture or erosion of the plaque’s fibrous cap enables exposure of highly thrombogenic and coagulable necrotic
lipid core content to circulating platelets and coagulation factors. Acute atherothrombosis results with dramatic
aggregation and activation of platelets and coagulation factors, resulting in acute occlusion of the implicated
arterial tree and downstream tissue ischemia and necrosis.
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial
infarction (STEMI), peripheral artery disease (PAD), and cerebrovascular disease,
both intracranial and extracranial, have prompted the development of condition
specific guidelines for primary prevention, acute management, and secondary
prevention [103114]. Guidelines for management of dyslipidemia in the context of
ASCVD are centered on the presence of pre-existing ASCVD, age, and underlying
comorbidities, most prominently diabetes.
. Coronary artery disease/ischemic heart disease
In the context of ASCVD, coronary artery disease (CAD), also referred to as
ischemic heart disease (IHD), covers a spectrum of acute and chronic conditions
resulting from myocardial oxygen demand and supply mismatch, generally caused
by atherosclerotic disease of native coronary arteries, both fixed lesions and acute
atherothrombosis [107, 115, 116].
Stable angina pectoris is a syndrome of recurrent and intermittent episodes of
chest pain during instances of increased myocardial oxygen demand and insufficient
oxygen supply from flow-limiting atherosclerotic coronary lesions [116, 117]. Stable
angina is the initial clinical manifestation of nearly half of all patients with CAD, and
given the high rates of myocardial infarction in patients with stable angina, extensive
guidelines on workup and management, including stress testing, coronary calcium
scoring by computed tomography, and cardiac catheterization and revascularization,
to mitigate the risk of future major cardiovascular events [107, 117, 118].
Acute coronary syndrome (ACS), the acute manifestations of CAD, include
unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), and
ST-elevation myocardial infarction (STEMI) are distinguished primarily by the
absence of presence of electrocardiographic (EKG) changes and troponin elevation
[115, 119]. The pathophysiology that differentiates stable angina from ACS is acute
plaque rupture or erosion that results in the acute worsening of coronary artery
flow, with subsequent symptomatic, electrocardiographic, and biochemical clinical
findings ranging from moderate to severe chest pain all the way to acute cardiogenic
shock and cardiac arrest [120, 121]. Myocardial infarction (MI), both NSTEMI and
STEMI, caused by acute atherothrombotic disease of an eroded or ruptured plaque,
is classified as a type I MI [115, 122]. It is distinguished from other etiologies of
cardiomyocyte damage, troponin elevation, and EKG changes such as other acute
stressors such as anemia, sepsis, or tachyarrhythmia that cause oxygen demand-
supply mismatch (type 2 MI), sudden cardiac death with symptoms suggestive of
MI but no blood specimen available for troponin analysis (type 3 MI), type 4 MI
as a complication of percutaneous coronary intervention (PCI), and type 5 MI as a
complication of coronary artery bypass grafting (CABG) [115, 122124]. The sever-
ity of clinical presentation, along with the acute and long-term risk after adequate
management of ACS, has led to countless clinical trials and guideline recommenda-
tions on the acute management, involving antiplatelet and anticoagulation therapy,
thrombolysis, PCI, and CABG [104106, 125–127].
. Cerebrovascular disease
Intracranial and extracranial atherosclerotic disease, the drivers of ischemic cere-
brovascular accident (CVA/stroke), can be the initial manifestation of atherosclerotic
cardiovascular disease or can present concurrently with atherosclerotic disease in
other arterial beds, including CAD or PAD [111, 112, 128]. Stroke is classified as either
hemorrhagic or ischemic, with hemorrhagic stroke accounting for less than 20% of all
strokes, with pathophysiology centered upon ruptured cerebral vessels that have been
damaged secondary to longstanding hypertension and amyloid angiopathy [129, 130].
While acute ischemic stroke can be caused by thromboembolic disease, particularly
in the setting of atrial fibrillation, acute ischemic stroke is generally caused by acute
thrombosis at the site of a cerebral atherosclerotic lesion, with neurologic motor and
sensory manifestations in the anatomical distributions innervated by the affected
region of the brain [112, 128, 131, 132]. In similar patterns to coronary artery disease,
atherosclerotic cerebrovascular disease carries severely high rates of morbidity and
mortality, with extensive evidence from clinical trials and guidelines directing highly
time sensitive interventions, including thrombolysis and thrombectomy, and the
general recommendations for primary and secondary prevention, including stroke-
related treatment of dyslipidemia [112, 113, 131, 133, 134].
. Peripheral artery disease
While clinicians classically associated peripheral artery disease (PAD) with
lower extremity atherosclerotic disease, PAD, also referred to as peripheral vas-
cular disease (PVD), encompasses atherosclerotic symptoms and disease of all
non-coronary and non-cerebrovascular arterial trees, including the upper and
lower extremities, renal, mesenteric, and aneurysms of the abdominal aorta and
its branching vessels [103, 108, 135]. The pathophysiology and the clinical presen-
tation of PAD are directly related to the organ system or extremity perfused by
the affected arterial tree, and similar to the contrast in stable angina versus acute
coronary syndrome, the symptomology can be both acute and chronic.
Lower extremity PAD can manifest in different ways, with the classical symp-
tom of claudication affecting a very small to large portion of the lower extremity,
with the affected area directly related to chronic arterial lumen narrowing from
local atherosclerotic lesions and the proximal or distal positioning of the plaque
[103, 136]. The most acute presentation of PAD is acute limb ischemia, the sudden
loss of limb perfusion with associated symptoms typically of severe pain, can be
caused by thromboembolism but more commonly is secondary to acute athero-
thrombosis from a ruptured or eroded atherosclerotic plaque [137139]. Acute limb
ischemia is distinct from critical limb ischemia (CLI), with CLI being classified
alongside chronic PAD as CLI progresses over several weeks to months, with clinical
symptoms of ischemic extremity pain at rest and/or development of ischemic tissue
loss such as non-healing ulcers or gangrene [140142]. The diagnosis and manage-
ment, both in the acute and chronic setting, involves assessing pulse and blood
pressure differences between upper and lower extremities using the ankle-brachial
index, vascular imaging, and revascularization, including thrombolysis, endovas-
cular repair, or open surgical correction [103, 108, 143145].
Non-lower extremity PAD, including renal artery disease, mesenteric arterial
disease, and aortic and branching vessel aneurysms represent additional manifesta-
tions of atherosclerotic cardiovascular disease with similar presentations of the
acute and chronic natures.
Atherosclerotic renal arterial disease classically manifests as chronic renal disease,
primarily presenting as a common cause of secondary hypertension from increased
activation of the renin-angiotensin-aldosterone system [108, 146, 147]. Additionally,
atherosclerotic renal arterial disease can appear as ischemic nephropathy with renal
parenchymal disease and manifestations of renal failure from chronic hypoperfu-
sion, microvascular damage, and tubulointerstitial injury [146, 148]. Atherosclerotic
renal arterial disease should be considered in patients with accelerated, resistant,
or malignant hypertension with new onset acute renal failure or congestive heart
failure, evaluated with renovascular imaging such as duplex ultrasonography
and angiography, and appropriately managed with either medical therapy or
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
revascularization, both endovascular and surgical [108, 149151]. Mesenteric isch-
emia can likewise present with chronic and acute symptoms, with chronic symptoms
of abdominal pain with eating, classically referred to as intestinal or postprandial
angina and representative of oxygen supply demand mismatch secondary to
increased intestinal metabolic activity and diminished mesenteric arterial perfusion
from underlying atherosclerosis flow-limiting lesions [108, 152]. Acute obstructive
intestinal ischemia can be secondary to thromboembolism or to acute thrombosis of a
ruptured or eroded atherosclerotic plaque, presenting classically with severe abdomi-
nal pain out of proportion to the physical exam, a critical condition that can result
in bowel necrosis and acute abdomen [153, 154]. Given the associated morbidity
and mortality, particularly of acute mesenteric ischemia, rapid general and vascular
surgery consultation, with prompt diagnostic imaging and intervention is critical for
appropriate evaluation and management [108, 155, 156].
Important components of the pathophysiology that promotes arterial lumen
narrowing in atherosclerosis, namely chronic inflammation and extracellular
matrix degradation initiated by oxidized lipoprotein accumulation, are critical pro-
cesses that contribute to development of abdominal aortic aneurysms (AAA) [157].
While the precise mechanism of atherosclerosis and its relationship to the develop-
ment of aneurysms of the abdominal aorta and its branch vessels is yet unclear, the
high overlap of risk factors and similar pathophysiologic processes between the two
conditions has prompted development of guidelines for monitoring and manage-
ment of dyslipidemia in patients with known AAA, along with appropriate surveil-
lance imaging for assessment of aneurysmal diameter [108, 158].
. Evaluation, management, and prevention of dyslipidemia and
. Cholesterol monitoring, LDL, and evolution of dyslipidemia cardiovascular
risk algorithms
While the Apo B-100 cholesterol carrying lipoproteins all play roles in the
pathogenesis of atherosclerosis through the critical initiating steps of arterial
intima lipid accumulation and foam cell formation, cholesterol monitoring and
assessment of atherosclerotic cardiovascular risk has centered around surveillance
and management of serum LDL and LDL-cholesterol (LDL-C) levels based on the
abundant evidence available from epidemiologic and genetic hypercholesterolemia
studies, and randomized controlled trials [5, 159]. IDL, Lp(a), small VLDL, and
VLDL remnants all possess the requisite diameter (<70nm) and apolipoprotein
profile (Apo B-100) to freely enter the arterial intima, undergo oxidation, and
trigger macrophage phagocytosis, but LDL and LDL-C have been demonstrated to
be the most atherogenic of the lipoproteins, with probability of LDL retention and
risk of progressive plaque development increasing in parallel with LDL and LDL-C
levels in dose-dependent manners [5, 35, 159]. Genetic studies of patients with
familial hypercholesterolemia (FH), a spectrum of autosomal co-dominant dis-
orders with different loss or gain of function mutations involving genes involved
in LDL metabolism, most commonly presenting as a loss of function mutation
of the LDLR, carries a markedly increased risk for ASCVD in heterozygous FH
patients, with the rare patients who are homozygous FH developing ASCVD as
early as childhood and adolescence [5, 160, 161]. Large epidemiologic studies and
meta-analyses have also demonstrated linear associations between LDL-C levels
and risk of CAD death [5, 162]. The most compelling evidence for the association
between LDL-C and ASCVD comes from the library of evidence from randomized
controlled clinical trials showing risk reduction of major cardiovascular events and
progression of atherosclerotic plaques proportional to the decrease in LDL-C levels
from statin and non-statin therapies [5, 163, 164]. Additionally, LDL subfrac-
tion sizes and the resulting atherogenicity need to be considered when evaluated
patients, as studies have shown that while overall cholesterol panel levels may be
ameliorated with therapy, it is the atherogenicity of the particles, specifically of
LDL, that drives the pathogenesis of atherosclerosis [20]. Analysis, therefore, of
LDL subfractions is likely an important component of lipid panel monitoring in
these patients.
In parallel to the clinical studies and trials demonstrating the relationship
between LDL, LDL-C, and ASCVD were the development of algorithms for the
appropriate assessment and stratification of cardiovascular risk based on serum
lipid profiles and other modifiable and non-modifiable cardiovascular risk fac-
tors, including age, gender, family history, smoking, obesity, and hypertension.
Multiple ASCVD risk algorithms exist both in the US and Europe, and include the
Framingham Risk Score (FRS), the Reynolds Risk Score (RRS), the Systematic
Coronary Risk Evaluation (SCORE), the QRisk2, and the American College of
Cardiology/American Heart Association arteriosclerotic cardiovascular disease risk
estimator (AC/AHA-ASCVD) which has become the benchmark for risk stratifica-
tion and clinical decision-making on cholesterol therapies [167].
Prior to the assessment of ASCVD risk and decisions on dyslipidemia therapy
guidelines and recommendations for screening of cholesterol levels in adult
patients who are asymptomatic and without history of ASCVD are employed.
Differences exist in screening recommendations in the American, Canadian,
and European dyslipidemia guidelines that were published in 2018, 2016, and
2016, respectively [100102]. Canadian and European guidelines propose that
dyslipidemia screening be considered for men at or older than 40years of age,
but diverge on the initial age for women, with Canadian guidelines recommend-
ing at or older than 40years of age, and European guidelines recommending at
or older than 50years of age [100, 102]. According to American guidelines, as
recommended in the recently published “2018 AHA/ACC/ACCVPR/AAPA/ABC/
ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of
Blood Cholesterol,” screening for LDL-C and non LDL-C can begin in adults as
early as 20years of age, or childhood or adolescence for patients with a history of
FH [101].
. Dyslipidemia: primary prevention of ASCVD
Compared to prior US cholesterol guidelines, the new 2018 ACC/AHA [101]
guideline allows for more personalized targeted care for patients. By providing
a guided approach to treatment for clinicians, they and their patients are given
the tools necessary to understand and manage their risk related to cholesterol.
Additionally, these revised guidelines highlight the importance of theclinician-
patient discussion.” This patient risk discussion should include a review of risk
enhancers to arrive at an appropriate share decision-making approach that
addresses the patient’s values in terms of cost, potential for benefit, adverse effects,
and drug-drug interactions.
The 2018 ACC/AHA guideline recommends that primary management of dyslip-
idemia for the primary prevention of ASCVD be considered for adult patients based
on LDL-C levels and specific high-risk patient characteristics, most prominently a
comorbid diagnosis of DM.
Anticholesterol therapy is indicated for adult patients with LDL-C greater than
190mg/dL or for selected patients with moderately high LDL-C levels greater than
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
160mg/dL and a family history of premature ASCVD such as MI or CVA before
55years of age in a first-degree male relative or before 65years of age in a first-
degree female relative (Figure ).
Patients without LDL-C>190mg/dL or without LDL-C>160mg/dL and sig-
nificant family history of premature ASCVD are categorized based on the presence
of DM and their 10-year ASCVD risk as estimated by their ASCVD score.
Special attention is paid to DM in the context of the primary prevention of ASCVD
as DM is a major risk factor for ASCVD and contributes to and accelerates the patho-
genesis of atherosclerosis through multiple and diverse mechanisms [168, 169]. DM
amplifies the immune response of key inflammatory cells, most critically macrophages,
into the arterial intima in response to lipoprotein accumulation, and promotes the
instability of atherosclerotic plaques by increasing the size of the necrotic lipid cores
[169171]. For adult patients, age 40–75years, with DM, current guidelines recom-
mend initiation of moderate-intensity statin therapy with consideration for possible
high-intensity statin therapy depending on patient’s individualized risk assessment.
For adult patients, age 40–75years, without DM, decisions on lifestyle modifi-
cations and statin therapy are guided by the 10-year ASCVD risk as estimated by
Figure 4.
Management Algorithm of dyslipidemia for primary prevention of ASCVD (adapted from 2018 AHA/ACC/
ACCVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood
Figure 5.
Management algorithm of dyslipidemia for secondary prevention of ASCVD (adapted from 2018 AHA/ACC/
ACCVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood
the patient’s ASCVD score, with patients with a 10-year ASCVD risk score >7.5%
qualifying for moderate-intensity statin therapy, and for patient’ with a 10-year
ASCVD risk score >20% qualifying for moderate to high-intensity statin therapy.
Beyond the 10-year ASCVD risk score, clinician-patient discussions of dyslipidemia
and primary risk prevention should consider multiple factors, including patient
preference, likelihood of statin side effects, prospective benefit of intensive lifestyle
modifications, and presence or absence of risk-enhancing factors. Important risk-
enhancing factors to consider include metabolic syndrome, chronic kidney disease,
chronic inflammatory or infectious conditions such as rheumatologic disease or
HIV/AIDs, high-risk race or ethnicity, family history of premature ASCVD, and
presence of lipid levels or biomarkers associated with increased ASCVD risk such as
elevated Lp(a).
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
. Dyslipidemia: secondary prevention of ASCVD
Management of dyslipidemia for the secondary prevention of ASCVD is cen-
tered on encouragement of intensive healthy lifestyle modifications and risk assess-
ment for future ASCVD.Patients with high or very high-risk ASCVD are those with
multiple major ASCVD events or one major ASCVD event and multiple high-risk
conditions. Major ASCVD events include ACS within last 12months, MI, ischemia
CVA, PAD with claudication and ABI<0.85, and PAD with previous revasculariza-
tion or amputation. High-risk conditions are similar to the risk-enhancing factors
that were considered for the management of dyslipidemia in the context of primary
prevention of ASCVD, and include age>65, history of CABG or PCI outside of the
major ASCVD events, DM, hypertension, chronic kidney disease, current smoking
status, congestive heart failure, and persistently elevated LDL-C above 100mg/dL
despite maximal tolerate dose of statin therapy and ezetimibe, an anticholesterol
drug that decreased small intestine absorption of cholesterol (Figure ).
For patients with the aforementioned high-risk conditions who are on the maximal
tolerated dose of statin therapy and ezetimibe with persistently elevated LDL-C>70
or non HDL-C>100, the addition of PCSK9 inhibitors can be considered.
. Current and future therapy targets for dyslipidemia ASCVD
. Statins
Dyslipidemia therapy for the primary and secondary prevention of ASCVD,
both current and therapies under investigation for future use, are centered on tar-
geting LDL-C given the extensive evidence demonstrating the relationship between
LDL and ASCVD, and no class of medications has been shown to be more effective
at lowering LDL-C than statins, the foundation of lipid and cholesterol lowering
therapy [101, 172, 173].
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the synthetic
pathway of cholesterol, resulting in lowering of tissue cholesterol, most critically
intrahepatic cholesterol, and reflex increase in hepatic expression of surface LDLR and
accompanying enhancement of receptor-mediated uptake of LDL and other circulat-
ing lipoproteins [172, 174]. Beyond the inhibition of hepatic cholesterol synthesis and
the resulting reduction in circulating LDL, statins have demonstrated other important
benefits in atherosclerotic plaque progression and the risk of acute atherothrombosis
[174, 175]. Statins promote plaque stabilization by reducing inflammation and increas-
ing collagen content in atherosclerotic plaques, slow the progression of overall plaque
volume, and diminish high-risk or vulnerable plaque features [174176].
Statin dosing intensity is categorized by expected reduction in LDL-C, with
high-intensity statins typically lowering LDL-C by at least 50%, moderate-intensity
statins typically lowering LDL-C by 30–49%, and low-intensity statins typically
lowering LDL-C by less than 30%.
. Nonstatins
There are different classes of non-statin medications used in the management
of dyslipidemia, including bile acid sequestrants (cholestyramine, colestipol, and
colesevelam), niacin, and fibrate, with ezetimibe and the PCSK9 inhibitors being
the non-statin classes of medications that incorporated into the guidelines for
dyslipidemia management in the primary and secondary prevention of ASCVD in
combination therapy with statins [100].
Ezetimibe decreases small intestine cholesterol absorption by inhibiting the
Niemann-Pick C1-Like 1 (NPC1L1) transporter [172, 177]. While the exact mecha-
nisms of the effect of ezetimibe on atherosclerosis by itself are not as well defined
as the effects of statins on atherosclerotic plaque progression and stabilization, the
addition of ezetimibe to statins has been shown to regress plaque burden, reduce
plaque volume, and promote plaque stabilization [178, 179]. PSCK9 works by
interacting in with hepatic LDLR and enhancing the degradation of the receptor
by hepatic lysosomes, with PSCK9 inhibitors thus mitigating the PSCK9-mediated
turnover of hepatic LDLR and prolonging LDLR lifespan and uptake of circulating
LDL-C [180]. PSCK9 inhibitors, namely alirocumab and evolocumab, in combina-
tion with statins have been shown to increase plaque calcification (a marker of
plaque stability), and promote VSMC and collagen plaque content while simultane-
ously decreasing the size of the lipid necrotic core [181, 182].
. New and future therapeutic targets and approaches to dyslipidemia and
Beyond the dramatic reductions in LDL-C and mechanisms of atherosclerotic
plaque stabilization and slowing of progression effected by statins, ezetimibe, and
PSCK9 inhibitors and their codification in the management algorithms for dyslip-
idemia and ASCVD: the other inflammatory, lipoprotein, and metabolic pathways
involved in the pathophysiology of atherosclerosis serve as potential targets for
therapies in the primary and secondary prevention of dyslipidemia and ASCVD.
The antiatherogenic properties of HDL, both in terms of its antioxidant and choles-
terol efflux capacities, have led to investigations for the therapeutic potential of recon-
stituted HDL and methods to improve endogenous HDL functionality [23, 183]. Apo
A-1 and apolipoprotein E (Apo E) are the atheroprotective apolipoprotein components
of HDL, but studies involving Apo A-1/HDL mimetic peptides transcriptional upregu-
lators of Apo A-1 did not result in significant regression of coronary atherosclerotic
lesions despite the enhanced HDL-C efflux [184]. Apo E consists of three isoforms
(Apo E2, Apo E3, and Apo E4) and promotes clearance of circulating TG-rich lipopro-
tein remnants, cholesterol efflux from macrophages preventing foam cell formation,
and diminishes expression of adhesion molecules necessary for macrophage migration
into the arterial intima [184186]. ApoE exerts additional atheroprotective functions
via tampering the inflammatory response by inhibiting T cells, lipoprotein oxidation,
and resulting proliferation and migration of VSMCs, suppressing platelet aggregation,
and restoring endothelial function by promoting release of NO [184, 187190]. Given
ApoE diverse protective properties at various stages of the atherosclerotic thrombo-
inflammatory process, studies investigating the potential value of reconstituted HDL
with favorable ApoE content or methods to promote increased ApoE profiles among
endogenous HDL can serve substantial roles for the future management of dyslipid-
emia and ASCVD.
Given the extensive inflammatory pathways and processes underlying the patho-
genesis of atherosclerosis, considerable work has been and is currently dedicated
to anti-inflammatory targets of therapy in dyslipidemia and ASCVD, with drugs in
various stages of research and development. The role of lipoprotein oxidation, most
significantly LDL to ox-LDL, has prompted the study of therapeutic antioxidants in
the management of dyslipidemia, and has shown promising benefits in secondary
prevention of ASCVD after ACS within 12months [191, 192]. The increase of ox-LDL
levels due to phospholipase A2 activity which enzymatically generate phospholipids
with atherogenic modifications has led to study of the role of phospholipase 2 inhibi-
tors in the prevention of atherosclerosis [193]. Many other inflammatory pathway
targets have been investigated for the management of dyslipidemia and ASCVD
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease…
including leukotriene pathway inhibitors (promote atherosclerotic plaque develop-
ment and progression via chemoattraction of macrophages and other inflammatory
cells and increasing endothelial permeability), chemokine CC motif ligand 2 (CCL2),
also known as MCP1 (chemokine recruiter of plaque destabilizing macrophages),
and blockade of potent inflammatory markers TNF and IL-1 [191, 194196].
. Conclusion
Atherosclerotic cardiovascular disease encompasses conditions carrying tremen-
dous morbidity and mortality, and is the acute and chronic clinical manifestations
of a progressive pathogenic process that is initiated by the inflammatory responses
to dyslipidemia. The diverse metabolic and immune mechanisms at play in the
thrombo-inflammatory pathophysiology of atherosclerosis are driven by disrup-
tions in the body’s native metabolism of cholesterol, triglycerides, and lipoproteins,
with comorbid conditions and risk factors such as smoking, hypertension, and
obesity promoting critical changes in cholesterol and lipoproteins that initiate a
vicious cycle of lipoprotein accumulation, foam cell formation, and inflamma-
tory reaction. The fact that so many immune cell lines and metabolic factors play
important roles in the development of atherosclerosis serves as a pool of current
and potential future targets for therapies in the primary and secondary prevention
of dyslipidemia and ASCVD.
Author details
PerryWengrofsky1, JustinLee2 and Amgad N.Makaryus3,4*
1 Department of Internal Medicine, State University of NewYork,
Downstate Medical Center, Brooklyn, NY, USA
2 Division of Cardiovascular Disease, Department of Medicine,
State University of NewYork, Downstate Medical Center, Brooklyn, NY, USA
3 Department of Cardiology, Nassau University Medical Center, East Meadow, NY,
4 Donald and Barbara Zucker School of Medicine at Hofstra/Northwell,
Hempstead, NY, USA
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... Dyslipidemia is clinically considered one of the most important risk factors for cardiovascular disease (K. L. Li et al., 2018;Wengrofsky et al., 2019). Beneficial clinical effects have been seen with lower LDL-C and TC levels, which play an important role in the pathogenesis of the cardiovascular disease (Wengrofsky et al., 2019). ...
... L. Li et al., 2018;Wengrofsky et al., 2019). Beneficial clinical effects have been seen with lower LDL-C and TC levels, which play an important role in the pathogenesis of the cardiovascular disease (Wengrofsky et al., 2019). In low risk patients, the use of non-pharmacological agents such as diet can help improve dyslipidemia (Sikand et al., 2018). ...
Objective The purpose of the current study is to conduct a meta-analysis of published randomized controlled trials to explore the quantitative effect of quinoa supplementation on serum lipid concentrations. Methods Online databases, including Web of Science, Scopus, and PubMed, were systematically searched. A comprehensive literature review was performed based on English reports of randomized controlled trials of quinoa on lipid profiles in adults, which were published up to July 2020. Weighted mean differences (WMD) with a 95% confidence interval (CI) were assigned as the ultimate effects of using random models. Study quality was assessed by using the Cochran score, and a meta-analysis was conducted. Results Five RCTs with eight intervention arms, including 291 participants, were selected for the present meta-analysis. The intervention period was between 4 and 12 weeks. The results showed doses higher than 50 g of quinoa consumption and duration more than six weeks of intervention significantly reduced serum triglyceride (TG) levels (WMD: -0.864 mg/dl; 95% CI: -1.286, -0.442, P < 0.001) and (WMD: -0.623 mg/dl; 95% CI: -1.015, -0.232, P = 0.002), respectively. In general, quinoa supplementation did not have a significant effect on concentrations of high-density lipoprotein cholesterol (HDL-C) levels (WMD: -0.145 mg/dl; 95% CI: -0.377, 0.086, P = 0.218), low-density lipoprotein cholesterol (LDL-C) levels, (WMD: 0.082 mg/dl; 95% CI: -0.150, 0.314, P = 0.489), and total cholesterol (TC) levels)WMD: -0.036 mg/dl; 95% CI: -0.267, 0.195, P = 0.759(. Conclusion This study reveals quinoa supplementation in doses higher than 50 g/day and the duration more than six weeks significantly reduced TG levels. However, further studies in this area are recommended to understand the potential mechanisms of quinoa on blood lipids.
... Elevated triglycerides may also be an independent risk factor for CAD, especially in women. 7 On the other hand, high-density lipoprotein (HDL-C) seems to play a protective role and is inversely related to risk CAD. 8 Many attempts have been made to treat or lower lipid levels, and research has shown that lowering cholesterol may help prevent primary and secondary coronary heart disease. 9 Smoking has a significant impact on lipid profile and platelet activity and increases the risk of coronary artery disease (CAD) by 2 to 3 times. ...
Full-text available
Background: Coronary Artery Disease (CAD) develops as a result of atherosclerosis. Atherosclerosis is a condition that leads to clogged arteries and can be caused by a variety of factors. Several studies have shown that various factors contribute to the development and progression of CAD. The aim of this study is to investigate the serum levels of MBL-2, TNC and TAC in patients with CAD and the relationship between these biochemical parameters and the progression of CAD. Methods: In this study, 60 serum samples were obtained from CAD patients as the case group and 20 healthy serum samples as the control group. Serum levels of MBL-2 and TNC were measured by the ELISA method. Serum TAC level was determined by calorimetry (spectrophotometry). In addition, MDA serum level was measured by reaction with thiobarbituric acid (TBA). Results: The mean age in the case and control groups was 58.4±9.5 years and 85±9.8 years, respectively. There was no significant difference in age, sex and family history in CAD patients (P 0.05), but there was a significant difference in blood pressure and smoking history (P 0.05). Serum cholesterol, triglyceride and LDL levels were significantly increased in the case group compared to the control group, while serum HDL-C levels were significantly decreased in the case group. Serum levels of MBL-2, TNC and MDA, were significantly increased in the case group compared to the control group. The serum level of TAC was significantly lower in the case group than in the control group. Conclusion: This study suggests that it is possible to diagnose patients with coronary artery disease (CAD) in the early stages of their disease and take preventive measures by measuring these parameters in serum. However, more research is needed before these serum parameters can be considered diagnostic biomarkers or therapeutic targets.
... Существенные различия между группами были зарегистрированы по полу, ИМТ и эмоциональному напряжению, что указывает на их особую важность у молодых людей в снижении адаптивного и компенсаторного потенциала ССС и развитии ССЗ.4. ОбсуждениеВ свете наших результатов присутствует связь между появлением сердечнососудистых заболеваний и стрессом, гипертонией, низкой ежедневной физической активностью, курением и генетической предрасположенностью.Адаптационный потенциал ССС зависит от ИМТ> тревожности> курения> генетической предрасположенности> гипертонии> быстрого питания.Повышение ДАД наблюдалось у трех молодых людей, что является скрытым признаком начальной гипертонии , вероятно, из-за нарушения эластичности сосудов после дисфункции эндотелиальных клеток, которая, по данным литературы чаще всего вызвана гиперлипидемией и гипергликемией.[22][23][24] В проанализированных данных наблюдалась недостаточность адаптивного потенциала, связанная с полом, что свидетельствует о более высоком риске развития сердечно-сосудистых заболеваний у молодых мужчин.[28] ...
Conference Paper
Full-text available
Аннотация Общие-сведения: В настоящее время отмечается прогрессивный рост сердечно-сосудистых-заболеваний (ССЗ) среди молодежи. Цели: Оценить адаптивные и компенсаторные механизмы сердечно- сосудистой-системы (ССС) у лиц молодого возраста. Методы: В исследовании приняли участие 29 добровольцев, разделенных на две группы по величине адаптационного потенциала (АП). Группа 1 (n = 16), значения АП были меньше 2,6, группа 2 (n = 13) значения АП были 2,6 и более. Возраст участников 18-25 лет (медиана 21,0). Всем участникам измеряли частоту сердечных сокращений (ЧСС), артериальное давление (САД/ДАД), рост, вес, объемы талии и бедер. Были рассчитаны АП (R.М. Baevsky et al., 1987), индекс Кердо, индекс массы тела и соотношение талии/бедер. Было проведено анкетирование респондентов обеих групп, направленное на сбор информации о факторах риска, связанных с образом жизни: курение табака, факторы, связанные с нездоровым питанием (низкая частота употребления фруктов/овощей/высокая частота жирной пищи), недостаток физической активности, уровень личностной и ситуативной тревожности посредством специально разработанных и стандартизированных личных интервью с помощью бумажных-анкет и Google-форм. Для математического анализа был выбран критерий χ2 Pearson («Statistica 7»). Результаты: Нарушения АП у молодежи выявлены у 44,8%. Гемодинамический анализ и адаптационные способности ССС показали, что у участников 1-й группы с нормальным АП были более низкие уровни САД, ДАД и ЧСС, а также меньшие нарушения вегетативной регуляции ССС, чем у лиц 2-й группы. Выявлены наиболее значимые факторы риска развития ССЗ у лиц данной возрастной группы. Заключение: Нарушения АП у молодых сопровождаются преобладанием симпатических влияний в регуляции функций ССС у 44,8%. В снижении адаптивно-компенсаторного потенциала ССС и развитии ССЗ у молодых людей наиболее значимыми являются факторы пола, избыточной массы тела, и тревожности.
... In the last few decades, cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide [1]. Dyslipidemia promotes atherosclerosis and causes CVD [2]. The discovery of statins was a significant milestone in lipid-lowering pharmacology. ...
Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity. The most common side effect is statin-associated muscle symptoms. Uncommon side effects include new-onset diabetes mellitus and elevation in liver enzymes. These effects can lead to noncompliance and premature discontinuation of the medication. Hence, it is crucial to identify patients with true statin-associated side effects (SASE) to ensure optimal statin use. The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of SASE. In patients with true SASE, timely intervention with modified statin or non-statins is beneficial. Herein, we discuss key clinical trial data on statins and non-statins, and describe our center’s approach toward patients with SASE.
... According to their size, structure, and apolipoprotein content, lipoproteins are classified as chylomicrons, very-LDLs, intermediate-density lipoproteins, LDLs, HDLs, and lipoprotein (a). 10 ...
Full-text available
Dyslipidemia refers to an abnormal amount of lipid in the blood, and the total cholesterol level is defined as the sum of high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and very-LDL cholesterol concentrations. In Korea, the westernization of lifestyle habits in recent years has caused an increase in the incidence of dyslipidemia, which is an important risk factor of cardiovascular disease (CVD). Several studies have been conducted on how dyslipidemia affects not only CVD, but also chorioretinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Recently, a pathological model of AMD was proposed under the assumption that AMD proceeds through a mechanism similar to that of atherosclerotic CVD. However, controversy remains regarding the relationship between chorioretinal diseases and lipid levels in the blood, and the effects of lipid-lowering agents. Herein, we summarize the role of lipids in chorioretinal diseases. In addition, the effects of lipid-lowering agents on the prevention and progression of chorioretinal diseases are presented.
... Dyslipidemia -abnormal elevations in cholesterol, triglycerides, or both, or decreased high-density lipoprotein cholesterol (HDL-C) levels 1 -is a well-established modifiable risk factor for the development of atherosclerosis and subsequent life-threatening complications such as cardiovascular disease (CVD), to include both coronary heart disease (CHD) and stroke. [1][2][3][4] In the United States, CVD remains the leading cause of death, responsible for 840,768 deaths in 2016 with an estimated annual cost of 351.2 USD billion. 5 Due to the fact that 40% of these annual cardiovascular deaths are preventable it is important that modifiable risk factors, such as dyslipidemia, are detected by recommended screening and managed with lifestyle modifications and appropriate medical management. ...
Full-text available
Background Physical activity is widely known to positively affect serum lipids. Yet, no study has utilized a path analysis methodology, which is more efficacious at analyzing complex relationships than simple regressions, to incorporate the cumulative effects of physical activity and waist circumference on lipids. Purpose: Our objective was to analyze the effects of moderate and vigorous physical activity, combined with waist circumference and sex, on serum lipids. Methods: A cross-sectional analysis of US male and female adults from 2011 to 2016 NHANES data was collected. Path analyses for each lipid value included physical activity (moderate and vigorous in MET per minute), waist circumference (per cm), and sex and were performed using R 3.6.1. Results: Our sample size was 16,221 (N = 225,364,595). Vigorous intensity exercise was associated with decreased high-density lipoproteins (HDL) and triglycerides (TG), while indirectly influencing total cholesterol, low-density lipoproteins, HDL and TG through decreased waist circumference. Moderate physical activity had no statistically significant impact on lipids or waist circumference. Discussion: Vigorous physical activity positively affects dyslipidemia when combining sex and decreasing waist circumference. This impact was not present when moderate physical activity was applied. Translation to Health Education Practice: Physicians and Health Educators should encourage patients to perform vigorous physical activity and weight loss to improve lipids.
... Chylomicrons contain high levels of TGs, which are released from the intestine. They are primarily responsible for delivering dietary cholesterol and TGs to peripheral tissue and the liver [13]. Atherosclerosis can be developed when lipid metabolism is disturbed, leading to alterations in plasma Lp function as well as its levels. ...
Background Cardiovascular diseases are the leading deadly cause in the modern world and dyslipidemia is one of the major risk factors. Objective The current therapeutic strategies for cardiovascular diseases involve the management of risk factors especially dyslipidemia and hypertension. Recently, the updated guidelines of dyslipidemia management were presented, and the newest data were included in terms of diagnosis, imaging and treatment. Methods In this targeted literature review, the researchers presented the newest evidence on dyslipidemia management by including the current therapeutic goals for dyslipidemia. In addition, the novel diagnostic tools based on theranostics are shown. Finally, the future perspectives on treatment based on novel drug delivery systems and their potential to be used in clinical trials were also analyzed. Results It should be noted that dyslipidemia management can be achieved by the strict lifestyle change, by adopting a healthy life and the choice of the most suitable drug.
Cardiovascular Diseases (CVD) have a high disease burden in India. Dyslipidemia, a major CVD risk factor, requires effective management. Our review describes the appropriateness of the international dyslipidemia guidelines in the Indian context. A systematic search was performed in PubMed, Google Scholar, Cochrane Library and Science Direct to obtain relevant articles. Dyslipidemia management guidelines by western medical associations are based on their studies, with ethnic minorities underrepresented and biological features of other racial groups inadequately incorporated. The Lipid Association of India (LAI) came up with a consensus statement guided by an expert panel to adapt the western guidelines to Indians. However, absence of Indian guidelines has led to physicians basing treatment on individual preference, contributing to heterogeneity. Our review underscores the need for formulating Indian dyslipidemia management guidelines and CV risk estimation algorithms, highlighting the scope for further research. This could supplement the clinical expertise of LAI and enhance patient experience.
The human prostate is an androgen-dependent gland where an imbalance in cell proliferation can lead to benign prostatic hyperplasia (BPH), which results in voiding lower urinary tract symptoms in the elderly. In the last decades, novel evidence has suggested that BPH might represent an element into the wide spectrum of disorders conforming the Metabolic Syndrome (MS). The dyslipidemic state and the other atherogenic factors of the MS have been shown to induce, maintain and/or aggravate the pathological growth of different organs, with data regarding the prostate being still limited. We here review the available epidemiological and experimental studies about the association of BPH with dyslipidemias. In particular, we have focused on Oxidized Low-Density Lipoproteins (OxLDL) as a potential trigger for vascular disease and cellular proliferation in atherogenic contexts, analyzing their putative molecular mechanisms, including the induction of specific extracellular vesicles (EVs)-derived miRNAs. In addition to the epidemiological evidence, OxLDL is proposed to play a fundamental role in the upregulation of prostatic cell proliferation by activating the Rho/Akt/p27Kip1 pathway in atherogenic contexts. miR-21, miR-141, miR-143, miR-145, miR-155, and miR-221 would be involved in the transcription of genes related to the proliferative process. Although much remains to be investigated regarding the impact of OxLDL, its receptors, and molecular mechanisms on the prostate, it is clear that EVs and miRNAs represent a promising target for proliferative pathologies of the prostate gland.
Background: Globally, dyslipidemia has been shown to be an independent predictor of many cardiovascular and cerebrovascular events, which lead to recent advocacy towards dyslipidemia prevention and control as a key risk factor and its prognostic significance to reduce the burden of stroke and myocardial infarction. Aim: This study aimed to evaluate hyperlipidemia as a risk factor connected with stroke and CVD. Moreover, having identified this risk factor, the study evaluates how hyperlipidemia has been examined earlier and what can be done in the future. Methods: All prospective studies concerning hyperlipidemia as risk factors for stroke and CVD were identified by a search of PubMed/MEDLINE and EMBASE databases with keywords hyperlipidemia, risk factors, stroke, and cardiovascular disease. Results: The constant positive association between the incidence of coronary heart disease and cholesterol concentration of LDL is apparent in observational studies in different populations. Thus, the reduction of LDL cholesterol in those populations, particularly with regard to initial cholesterol concentrations, can reduce the risk of vascular diseases. However, the impact of using lipid-lowering drugs, such as statins, has been demonstrated in several studies as an important factor in decreasing the mortality and morbidity in rates of patients with stroke and CVD. Conclusion: After reviewing all the research mentioned in this review, it can be confirmed that hyperlipidemia is a risk factor for stroke and correlated in patients with CVD.
Full-text available
Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1−/− × Apoe−/− mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis.
Background: Despite adverse prognoses of type 2 myocardial infarction and myocardial injury, an effective, practical risk stratification method remains an unmet clinical need. We sought to develop an efficient clinical bedside tool for estimating the risk of major adverse cardiovascular events at 180 days for this patient population. Methods: The derivation cohort included patients with type 2 myocardial infarction or myocardial injury admitted to a tertiary hospital between 2012 and 2013 (n = 611). The primary outcome was a major adverse cardiovascular event (death or readmission for heart failure or myocardial infarction). The score included clinical variables significantly associated with the outcome. External validation was conducted using the UTROPIA cohort (n = 401). Results: The TARRACO Score included cardiac troponin (cTn) concentrations and 5 independent clinical predictors of adverse cardiovascular events: age, hypertension, absence of chest pain, dyspnea, and anemia. The score exhibited good discriminative accuracy (area under the curve = 0.74; 95% CI, 0.70-0.79). Patients were classified into low-risk (score 0-6) and high-risk (score ≥7) categories. Major adverse cardiovascular events rates were 5 times more likely in high-risk patients compared with those at low risk (78.9 vs 15.4 events/100 patient-years, respectively; logrank P < .001). The external validation showed equivalent prognostic capacity (area under the curve=0.71, 0.65-0.78). Conclusion: A novel risk score based on bedside clinical variables and cTn concentrations allows risk stratification for death and cardiac-related rehospitalizations in patients with type 2 myocardial infarctions and myocardial injury. This score identifies patients at the highest risk of adverse events, a subset of patients who may benefit from close observation, medical intensification, or both.
Cardiovascular disease (CVD) continues to be a leading cause of death worldwide with atherosclerosis being the major underlying pathology. The interplay between lipids and immune cells is believed to be a driving force in the chronic inflammation of the arterial wall during atherogenesis. Atherosclerosis is initiated as lipid particles accumulate and become trapped in vessel walls. The subsequent immune response, involving both adaptive and immune cells, progresses plaque development, which may be exacerbated under dyslipidemic conditions. Broad evidence, especially from animal models, clearly demonstrates the effect of lipids on immune cells from their development in the bone marrow to their phenotypic switching in circulation. Interestingly, recent research has also shown a long-lasting epigenetic signature from lipids on immune cells. Traditionally, cardiovascular therapies have approached atherosclerosis through lipid-lowering medications because, until recently, anti-inflammatory therapies have been largely unsuccessful in clinical trials. However, the recent Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) provided pivotal support of the inflammatory hypothesis of atherosclerosis in man spurring on anti-inflammatory strategies to treat atherosclerosis. In this review, we describe the interactions between lipids and immune cells along with their specific outcomes as well as discuss their future perspective as potential cardiovascular targets.
Inflammation and lipid accumulation are two basic hallmarks of atherosclerosis as a chronic disease. Inflammation not only is a local response but can also be considered as a systemic process followed by an elevation of inflammatory mediators. Monocytes are a major source of proinflammatory species during atherogenesis. In atherosclerosis, modified low-density lipoproteins (LDLs) are removed by macrophages; these are recruited in the vessel wall, inducing the release of inflammatory cytokines in inflamed tissue. Hence, inflammatory cholesterol ester-loaded plaque is generated. High-density lipoprotein-cholesterol (HDL-C) exhibits antiatherosclerotic effects by neutralizing the proinflammatory and pro-oxidant effects of monocytes via inhibiting the migration of macrophages and LDL oxidation in addition to the efflux of cholesterol from these cells. Furthermore, HDL plays a role in suppressing the activation of monocytes and proliferation-differentiation of monocyte progenitor cells. Thus, accumulation of monocytes and reduction of HDL-C may participate in atherosclerosis and cardiovascular diseases (CVD). Given that the relationship between the high number of monocytes and low HDL-C levels has been reported in inflammatory disorders, this review focused on understanding whether the monocyte-to-HDL ratio could be a convenient marker to predict atherosclerosis development and progression, hallmarks of CV events, instead of the individual monocyte count or HDL-C level.