ArticlePDF AvailableLiterature Review

Abstract

Elevated plasma lipoprotein(a) (Lp(a)) levels are associated with an increased risk of cardiovascular disease (CVD). Hitherto, niacin has been the drug of choice to reduce elevated Lp(a) levels in hyperlipidemic patients but its efficacy in reducing CVD outcomes has been seriously questioned by recent clinical trials. Additional drugs may reduce to some extent plasma Lp(a) levels but the lack of a specific therapeutic indication for Lp(a)‐lowering limits profoundly reduce their use. An attractive therapeutic option is natural products. In several preclinical and clinical studies as well as meta‐analyses, natural products, including l‐carnitine, coenzyme Q 10, and xuezhikang were shown to significantly decrease Lp(a) levels in patients with Lp(a) hyperlipoproteinemia. Other natural products, such as pectin, Ginkgo biloba, flaxseed, red wine, resveratrol and curcuminoids can also reduce elevated Lp(a) concentrations but to a lesser degree. In conclusion, aforementioned natural products may represent promising therapeutic agents for Lp(a) lowering.
Received: 1 November 2017
|
Accepted: 7 December 2018
DOI: 10.1002/jcp.28134
REVIEW ARTICLE
Dietary natural products as emerging lipoprotein(a)lowering
agents
Amir Abbas MomtaziBorojeni
1
|
Niki Katsiki
2
|
Matteo Pirro
3
|
Maciej Banach
4,5
|
Khalid Al Rasadi
6
|
Amirhossein Sahebkar
7,8,9
1
Department of Medical Biotechnology,
Nanotechnology Research Center, Faculty of
Medicine, Mashhad University of Medical
Sciences, Mashhad, Iran
2
Second Propedeutic Department of Internal
Medicine, Medical School, Aristotle University
of Thessaloniki, Hippocration Hospital,
Thessaloniki, Greece
3
Unit of Internal Medicine, Angiology and
Arteriosclerosis Diseases, Department of
Medicine, University of Perugia, Perugia, Italy
4
Department of Hypertension, WAM
University Hospital in Lodz, Medical
University of Lodz, Lodz, Poland
5
Polish Mothers Memorial Hospital Research
Institute, Lodz, Poland
6
Department of Clinical Biochemistry, Sultan
Qaboos University Hospital, Muscat, Oman
7
Biotechnology Research Center,
Pharmaceutical Technology Institute,
Mashhad University of Medical Sciences,
Mashhad, Iran
8
Neurogenic Inflammation Research Center,
Mashhad University of Medical Sciences,
Mashhad, Iran
9
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
Correspondence
Amirhossein Sahebkar, Pharm.D., Ph.D.,
Department of Medical Biotechnology, School of
Medicine, Mashhad University of Medical
Sciences, Mashhad, P.O. Box: 9177948564, Iran.
Email: sahebkara@mums.ac.ir;
amir_saheb2000@yahoo.com;
amirhossein.sahebkar@uwa.edu.au
Abstract
Elevated plasma lipoprotein(a) (Lp(a)) levels are associated with an increased risk of
cardiovascular disease (CVD). Hitherto, niacin has been the drug of choice to reduce
elevated Lp(a) levels in hyperlipidemic patients but its efficacy in reducing CVD outcomes
has been seriously questioned by recent clinical trials. Additional drugs may reduce to
some extent plasma Lp(a) levels but the lack of a specific therapeutic indication for Lp(a)
lowering limits profoundly reduce their use. An attractive therapeutic option is natural
products. In several preclinical and clinical studies as well as metaanalyses, natural
products, including Lcarnitine, coenzyme Q
10
, and xuezhikang were shown to significantly
decrease Lp(a) levels in patients with Lp(a) hyperlipoproteinemia. Other natural products,
such as pectin, Ginkgo biloba,flaxseed,redwine,resveratrolandcurcuminoidscanalso
reduce elevated Lp(a) concentrations but to a lesser degree. In conclusion, aforemen-
tioned natural products may represent promising therapeutic agents for Lp(a) lowering.
KEYWORDS
cardiovascular disease, coenzyme Q10, Lcarnitine, lipoprotein(a), natural products, nutraceu-
ticals, resveratrol
1
|
INTRODUCTION
Lipoprotein(a) (Lp(a)), first discovered by Berg (1963), is a cholesterolrich
lowdensity lipoprotein (LDL)like particle (Berg et al., 1997), with a
diameter up to 25 nm and density higher than LDL (Krempler, Kostner,
Bolzano, & Sandhofer, 1980). Lp(a) is known to exert atherogenic and
prothrombotic properties (Marcovina,Koschinsky,Albers,&Skarlatos,
2003; Ellis, Boffa, Sahebkar, Koschinsky, & Watts, 2017; Pirro, Bianconi,
et al., 2017; Ferretti, Bacchetti, Johnston, et al., 2018). This lipoprotein is
mainly synthesized in hepatocytes and includes a central LDLlike
lipoprotein core containing a single molecule of apolipoprotein B (apoB)
covalently bound, in a 1:1 molar ratio, to glycoprotein apolipoprotein(a)
(apo(a)) by a disulfide bridge between cysteine residues of apo(a)
(Cys4057) and apoB100 (Cys4326). The presence of apo(a) represents
J Cell Physiol. 2019;114. wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc.
|
1
the major structural difference between Lp(a) and LDL, leading to diverse
physical and chemical properties (Clarke et al., 2009; Marcovina et al.,
2003; Siekmeier et al., 2010).
2
|
POPULATION, GENETIC VARIANTS,
AND LP(A) LEVELS
Plasma Lp(a) level is mostly hereditary and highly heterogeneous
between various individuals (Banach, 2016; Kotani, Serban, Penson,
Lippi, & Banach, 2016; Lanktree, Anand, Yusuf, & Hegele, 2010;
Tsimikas, 2017). Distribution of Lp(a) concentrations in different
populations is ethnic groupspecific (Lanktree et al., 2010). African
descendants have elevated plasma Lp(a) concentrations compared
with Asians and Caucasians (Berglund & Ramakrishnan, 2004). In the
general population, plasma Lp(a) levels can vary over 1,000fold,
ranging from <0.1 to >100 mg/dl (Boerwinkle et al., 1992). In this
context, although multiple acquired factors may have some influence
on plasma Lp(a) levels (Pirro, Bianconi, et al., 2017), dietary or other
lifestyle interventions have only a little impact, whereas genetic
variations mainly limited to the LPA gene, (the gene encoding apo(a)),
are believed to play a major role (Boerwinkle et al., 1992).
Single nucleotide polymorphisms (SNPs) in the LPA gene are strongly
associated with plasma Lp(a) levels (Clarke et al., 2009; Helgadottir et al.,
2012; Kamstrup, TybjærgHansen, Steffensen, & Nordestgaard, 2009).
The Precocious Coronary Artery Disease (PROCARDIS) study revealed
that two apo(a) SNPs accounted for 36% of the variation in Lp(a) levels
among European descendants (Clarke et al., 2009).
Allele size in the LPA gene is the other genetic factor that defines
plasma Lp(a) concentrations. Both the levels and atherogenicity of Lp(a),
evaluated by study of the carotid stenosis incidence, were found to be
influenced by genetic variants in the LPA gene, resulting in 30 different
isoforms of apo(a) (Kronenberg et al., 1999; Marcovina et al., 1996;
Sandholzer et al., 1991). The isoforms stem from variation in repeat
number of kringle IV type 2 (KIV2) domain, which is a highly
glycosylated repetitive domain in apo(a) structure. In general, proteins
with lower molecular weight are more efficiently synthesized and less
efficiently degraded than larger proteins. Therefore, apo(a) isoforms with
smallernumberofKIV2 repetitions have smaller sequences and are
associated with higher plasma Lp(a) levels and potentially more
atherothrombogenic activity (Kronenberg et al., 1999). The most
frequently used method to quantify plasma levels of Lp(a) is enzyme
immunoassay (enzymelinked immunosorbent assay) involving antibodies
that interact with the kringle region of apo(a) subunit. However, because
of the wide heterogeneity in apo(a) size, measurement of Lp(a) via
immunoassays is limited by inaccuracies and new approaches to measure
Lp(a) levels are being developed (Clarke et al., 2009).
3
|
LP(A) LEVELS AND CARDIOVASCULAR
DISEASE (CVD)
There is evidence, including genomewide association and Mendelian
randomization studies, that elevated plasma Lp(a) concentrations are
linked to CVD (Banach, Stulc, Dent, & Toth, 2016; Dubé, Boffa, Hegele,
& Koschinsky, 2012; Katsiki, AlRasadi, & Mikhailidis, 2017; Kronen-
berg & Utermann, 2013). In particular, increased plasma Lp(a) levels
represent a moderate, independent CVD risk factor (Emerging Risk
Factors Collaboration, 2009). Elevated plasma Lp(a) levels are
associated with coronary artery disease (Bennet et al., 2008;
Gurdasani et al., 2012; Mellwig et al., 2015), peripheral artery disease
(Gurdasani et al., 2012), cerebrovascular disease (Emerging Risk
Factors Collaboration, 2009; Gurdasani et al., 2012), abdominal aortic
aneurysm (Kotani et al., 2017), aortic valve calcification and stenosis
(Vongpromek et al., 2015), as well as venous thromboembolism (Lippi,
Franchini, & Targher, 2011). In this context, each 1 standard deviation
increase in logtransformed Lp(a) levels can raise the hazard ratio for
CVD by 1.11.2 (Emerging Risk Factors Collaboration, 2009) and is
parallel to as much as a 3.6fold increased risk for CVD events at high
Lp(a) concentrations (120 mg/dl; Kamstrup, Benn, TybjærgHansen, &
Nordestgaard, 2008).
Lp(a) increases CVD risk through multifaceted atherothrombotic
pathways, including binding of proinflammatory oxidized phospholi-
pids via apoB100 (Tsimikas et al., 2005), stimulation of the
expression of adhesion molecules such as vascular cell adhesion
protein 1 (VCAM1) and Eselectin (Allen et al., 1998), infiltration into
the arterial wall and impaired generation of plasmin due to a unique
structural mimicry between Lp(a) and plasminogen (Kang et al., 2002;
Tsimikas, Tsironis, & Tselepis, 2007). When Lp(a) immigrates into the
arterial intima, it attaches to the extracellular matrix via both apo(a)
and apoB components, leading to the enlargement of the athero-
sclerotic lesion (Nielsen, 1999).
In 2010/2011, the European Atherosclerosis Society (EAS;
Nordestgaard et al., 2010) and the National Lipid Association
(Davidson et al., 2011) guidelines recommended screening for
elevated Lp(a) levels in individual with intermediatetohigh risk of
CVD. These subjects include patients who present with premature
CVD, familial hypercholesterolemia (FH), family history of ele-
vated Lp(a), recurrent CVD despite statin therapy, and patients
with high CVD risk scores (Nordestgaard et al., 2010). An Lp(a)
level of 30 mg/dl has been stated as the risk threshold, and relative
risk of CVD increases continuously in patients with Lp(a) levels
above this threshold (Jacobson, 2013). Hence, lipidlowering
agents reducing Lp(a) levels to below 30 mg/dl can be considered
as promising therapies to decrease the risk of CVD. Recently, it has
been suggested that large absolute (rather than relative) reduc-
tions in Lp(a) are needed to lower CVD risk (Burgess et al., 2018).
Therefore, only individuals with very high Lp(a) baseline concen-
trations could indeed benefit in terms of CVD risk from Lp(a)
lowering therapeutic strategies.
4
|
LP(A)LOWERING THERAPIES
As recommended by the Canadian Cardiovascular Society, plasma
Lp(a) concentration should be <30 mg/dl (Anderson et al., 2013).
Niacin (nicotinic acid) monotherapy and niacincombination therapy
2
|
MOMTAZIBOROJENI ET AL.
are the only lipidlowering treatments that consistently, substan-
tially, durably, and dosedependently (from 1 to >3 g/day) reduce
elevated plasma Lp(a) levels by 2040% (Capuzzi et al., 1998;
Marcovina et al., 2003; Williams, 2002), accompanied by beneficial
effects on plasma lowdensity lipoproteincholesterol (LDLC), high
density lipoproteincholesterol (HDLC), and very lowdensity
lipoproteincholesterol (VLDL) levels (Stein et al., 1996). The clinical
use of niacin was limited due to its side effects through the
stimulation of prostaglandin D2 and E2 synthesis (Lippi & Targher,
2012). The main adverse event that reduced patients compliance
was flushing, an issue that was partly overcome by the combination
of niacinextended release with laropiprant (Yadav et al., 2012).
Although the EAS and the American Heart Association/American
Stroke Association guidelines recognized niacin as a drug of choice
for the treatment of elevated plasma Lp(a) concentrations (Gold-
stein et al., 2011; Nordestgaard et al., 2010), the two large
randomized controlled clinical trials with niacin (that is, the Heart
Protection Study 2Treatment of HDL to Reduce the Incidence of
Vascular Events [HPS2THRIVE] and the Atherothrombosis Inter-
vention in Metabolic Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes (AIMHIGH) trials; Investiga-
tors, 2011) did not find any significant effect of niacin on CVD risk
in statintreated patients with established CVD. Furthermore,
niacin was reported to increase the risk of side effects compared
withplacebointheHPS2THRIVE trial (HPS2THRIVE Collabora-
tive Group, 2014). Based on such negative results, niacin was
withdrawn from the EU market (http://www.ema.europa.eu/ema/
index.jsp?curl=pages/medicines/human/referrals/Tredaptive,_Pel-
zont_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0-
b01ac05805c516f) and its use was suspended worldwide.
Currently, statin therapy represents the firstline treatment to
decrease individuals CVD risk (Banach, Serban, et al., 2015; Lippi &
Targher, 2012) not only because of its LDLlowering activity but also
due to its several pleiotropic actions (Banach, Dinca, et al., 2016;
Bianconi, Sahebkar, Banach, & Pirro, 2017; Chrusciel et al., 2016;
Ferretti, Bacchetti, & Sahebkar, 2015; Ferretti, Bacchetti, Banach,
SimentalMendia, & Sahebkar, 2016; Momtazi, Derosa, Maffioli,
Banach, & Sahebkar, 2016; Panahi, Badeli, Karami, & Sahebkar,
2015; Parizadeh et al., 2011; RyszGorzynska et al., 2016; Sahebkar,
Kotani, et al., 2015; Sahebkar, Serban, Mikhailidis, et al., 2015;
Sahebkar, Pećin, et al., 2016b; Sahebka, Serban, et al., 2016d;
Sahebkar, Ponziani, Goitre, & Bo, 2015a; Sahebkar, Rathouska,
Derosa, Maffioli, & Nachtigal, 2016c; Serban et al., 2015). Inten-
sivestatin therapy leading to maximal LDLClowering in patients
with Lp(a) elevation is supported as a potential therapeutic choice by
a growing body of observational studies that have shown CVD risk
reduction parallel to LDLClowering in such patients (Banach,
Aronow, et al., 2015a; Nicholls et al., 2010). However, the effects
of statin therapy on plasma Lp(a) levels are scarce and controversial,
and in some cases even raised Lp(a) level is found after the initiation
of statin treatment (Sahebkar et al., 2017; Yeang et al., 2016). In
addition, statin intolerance and resistance may be present in some
dyslipidemic patients and therefore, alternative Lp(a)lowering
therapies are considered as an unmet clinical necessity (Kotani
et al., 2015).
Apart from niacin, there are other developed and under
development drugs that were found to reduce elevated Lp(a) levels,
although their correlation with CVD risk is yet unknown. These drugs
include evolocumab and alirocumab (Sahebkar & Watts, 2013), the
two monoclonal antibodies targeting proprotein convertase subtili-
sin/kexin type9 (PCSK9) which can reduce Lp(a) up to 26% (Banach
et al., 2013; Dragan, Serban, & Banach, 2015; Kotani & Banach,
2017), cholesteryl ester transfer protein inhibitors (Banach et al.,
2013), mipomersen that is, an antisense oligonucleotide (ASO)
against apoB mRNA can reduce Lp (a) up to 26% (Raal et al.,
2010), ASO therapy (ISIS APO(a) Rx) directly against apo(a) mRNA
(Merki et al., 2011; Tsimikas et al., 2015), eprotirome that is, an
analogue of the thyroid hormone (Ladenson et al., 2010), tibolone
that is, a synthetic steroid drug with estrogenic and progestogenic
activities (Kotani et al., 2015), and lomitapide that is, a microsomal
triglyceride transfer protein inhibitor can reduce Lp(a) by 17%
(Samaha, McKenney, Bloedon, Sasiela, & Rader, 2008). In addition,
lipoprotein apheresis can be used to treat homozygous FH, severe
heterozygous FH and in some countries, it is approved for the
treatment of patients with high levels of Lp(a) >60 mg/dl (Leebmann
et al., 2013; Thompson &, Group HULAW, 2008). However, the
clinical use of these drugs is still limited. An alternative therapeutic
strategy to lower Lp(a) may involve natural products (Asgary,
RafieianKopaei, Shamsi, Najafi, & Sahebkar, 2014; Banach, Aronow,
et al., 2015a; Cicero et al., 2017; Panahi, Khalili, Hosseini,
Abbasinazari, & Sahebkar, 2014b; Sahebkar, Catena, et al., 2016a;
Serban et al., 2016).
The present review summarizes the Lp(a) reducing effects of
known LDLClowering natural products by discussing the evidence
from both preclinical and clinical studies.
5
|
LP(A)LOWERING NATURAL
PRODUCTS
5.1
|
LCarnitine
LCarnitine is derived from the amino acid lysine and plays a role in
mitochondrial fatty acid oxidation and adenosine triphosphate production
(Broderick, 2008). LCarnitineisknowntoberichinredmeatandcertain
fish, and at smaller amounts in dairy products and some fruits, such as
avocado (Rajasekar & Anuradha, 2007). Several experimental and clinical
studies investigated the effect of Lcarnitine on lipid metabolism and
found that Lcarnitine may be associated with reductions in Lp(a) levels
(Broderick, 2008; Rajasekar & Anuradha, 2007).
Recently we conducted a comprehensive systematic review and
metaanalysis of several randomized controlled trials and reported
that Lcarnitine supplementation (14 g/day) can significantly de-
crease Lp(a) levels (weighted mean difference [WMD], 8.82 mg/dl;
95% confidence interval [CI], 10.09 to 7.55; p<0.001) after 124
weeks in patients with Lp(a) hyperlipoproteinemia (i.e., serum Lp
(a) 30 mg/dl). Analysis of data based on the route of administration
MOMTAZIBOROJENI ET AL.
|
3
also suggested that oral administration significantly lowered Lp(a)
levels (WMD, 9.00 mg/dl; 95% CI, 10.29 to 7.72; p< 0.001), while
intravenous administration showed no significant effect (Serban
et al., 2016). Although the exact mechanism underlying the observed
Lp(a)lowering effect of Lcarnitine is yet unknown, it is suggested
that Lcarnitine may decrease the hepatic production of Lp(a) via
inducing the breakdown of fatty acids in the mitochondria
(Rajasekar & Anuradha, 2007). Overall, oral Lcarnitine might be an
effective natural strategy to reduce Lp(a) levels, although further
research is needed to establish this association.
5.2
|
Coenzyme Q
10
We recently carried out a systematic review and metaanalysis on the
results of six randomized controlled trials studying the effects of
coenzyme Q
10
supplementation (120300 mg/day) on serum Lp(a)
levels in 409 dyslipidemic patients (Serban et al., 2016b). Coenzyme Q
10
intake moderately but significantly reduced serum Lp(a) levels (WMD,
3.54 mg/dl; 95% CI, 5.50 to 1.58; p< 0.001), although it did not
affect other lipid parameters, including total cholesterol, LDLC, HDLC,
and TG (Serban et al., 2016). Lp(a)lowering effect of coenzyme Q
10
was
inversely associated with the supplemented doses; doses of coenzyme
Q
10
< 150 mg/day decreased Lp(a) levels at a greater degree than
doses 150 mg/day (WMD, 9.24 mg/dl; 95% CI, 15.19 to 3.29;
p= 0.002 and WMD, 2.75 mg/dl; 95% CI, 4.28 to 1.23; p< 0.001,
respectively; Serban et al., 2016). Furthermore, baseline Lp(a) levels
were found to affect the Lp(a)lowering impact of coenzyme Q
10
supplementation; baseline Lp(a) 30 mg/dl led to higher Lp(a) reduction
compared with baseline levels < 30 mg/dl (WMD, 11.72 mg/dl; 95% CI,
21.01 to 0.42; p=0.013 and WMD, 3.14 mg/dl; 95% CI, 4.92 to
1.35; p= 0.001, respectively; Serban et al., 2016b). Lp(a) levels were
decreased by 31.332.1% when baseline levels were 30 mg/dl and by
12.8% at baseline levels <30 mg/dl (Serban et al., 2016b).
In the same metaanalysis, it was hypothesized that different
coenzyme Q
10
formulations administered in the studies might
influence the relative bioavailability of coenzyme Q
10
by conse-
quently reducing coenzyme Q
10
absorption as the supplemented
doses are increased. Furthermore, it was observed that the highest
coenzyme Q
10
doses were used in the studies with the lowest
baseline Lp(a) levels, thus possibly maskingthe effect of the higher
doses (Serban et al., 2016). Treatment duration did not change the
effect of coenzyme Q
10
supplementation on Lp(a) concentrations;
administration for <8 weeks produced similar decreases in Lp(a)
levels compared with those lasting 8 weeks (WMD, 4.00 mg/dl;
95% CI, 5.45 to 2.54; p< 0.001 and WMD, 3.99 mg/dl; 95% CI,
11.15 to 3.18; p= 0.275), thus suggesting a lack of timedependent
Lp(a)lowering efficacy of coenzyme Q
10
(Serban et al., 2016).
Overall, coenzyme Q
10
supplementation can significantly reduce
(by 12.932.1%) plasma Lp(a) levels; the dose of coenzyme Q
10
and
the baseline Lp(a) concentrations may affect the degree of Lp(a)
lowering. It could be suggested that combination therapy of
coenzyme Q
10
with other lipidlowering drugs may be a promising
therapeutic option to further reduce plasma Lp(a) levels.
5.3
|
Xuezhikang
Red yeast rice, known as cholestin, is a yeast product that is grown on
rice and exerts documented cholesterollowering effects (Liu et al.,
2006; Pirro, Mannarino, Bianconi, et al., 2016; Pirro, Mannarino,
Ministrini, et al., 2016; Pirro, Vetrani, et al., 2017; Trimarco et al.,
2011) via suppressing cholesterol synthesis through the inhibition of
3hydroxy3methylglutarylcoenzyme A (HMGCoA) reductase
(Menéndez et al., 2001; Singh, Li, & Porter, 2006). Xuezhikang (XZK)
is a cholestin extract that contains a mixture of lovastatin (dominant
compound), plant sterols, and isoflavones (Heber et al., 1999; Jiang,
Hao, Deng, Zhou, & Lin, 1999). XZK exerts lipidlowering properties
and is also well tolerated in patients with statin intolerance (Becker
et al., 2009; Lu et al., 2008). A randomized study in patients with
coronary heart disease showed that consumption of XZK (1.2 g/day)
significantly reduced plasma Lp(a) levels by 23% after 6 weeks of
treatment (Liu, Zhao, Cheng, & Li, 2003).
5.4
|
Dietary fibers
Dietary fibers comprise a group of dietary components such as fruit,
vegetables, cereals, and whole grains. Dietary fibers can be totally
classified by their water solubility, including viscous or watersoluble
fibers such as pectin, fenugreek, and guar gum, and nonviscous or
waterinsoluble fibers, such as wheat bran (Dhingra, Michael, Rajput, &
Patil, 2012).
Experimental and clinical studies have shown that the intake of
viscous fibers or a mix of viscous and nonviscous fibers may protect
against atherosclerosis through decreases in LDLC (Anderson, 1995;
Glore, Van Treeck, Knehans, & Guild, 1994; Haskell, Spiller, Jensen,
Ellis, & Gates, 1992; Jenkins et al., 1993; VergaraJimenez, Furr, &
Fernandez, 1999; Vigne et al., 1987; ViudaMartos et al., 2010; Wu
et al., 2003). The exact mechanism of the cholesterollowering effect
of dietary fibers is yet unknown. Evidence suggests that fibers
mediate regulation of plasma cholesterol via their viscosity (gel
forming capacity; Glore et al., 1994) and by enhancing biodegrada-
tion of cholesterol into bile acids (Horton, Cuthbert, & Spady, 1994;
ViudaMartos et al., 2010) or via enhancing the hepatic clearance of
LDLC by LDLR (VergaraJimenez, Conde, Erickson, & Fernandez,
1998; ViudaMartos et al., 2010).
Pectin, fenugreek, and guar gum are watersoluble gelforming
fibers reducing plasma cholesterol via the formation of a viscous
matrix that prevents absorption of micelles containing cholesterol
and bile acids into the enterocyte (Jones, 2008). Reduction of bile
acid uptake leads to enhanced bile acid synthesis from hepatic
cholesterol via downregulation of liver cholesterol 7 αhydroxylase
(Buhman, Furumoto, Donkin, & Story, 2000; Moriceau et al., 2000;
Rodriguez, Jimenez, FernándezBolaños, Guillén, & Heredia, 2006),
which drops the intracellular cholesterol content and/or reduces the
uptake of intestinal cholesterol (Górecka, Korczak, Balcerowski, &
Decyk, 2002; ViudaMartos et al., 2010).
Apart from the aforementioned findings, pectin and fibernat were
found to decrease Lp(a) levels. In this context, Veldman et al. (1999)
4
|
MOMTAZIBOROJENI ET AL.
found that the supplementation of 15 g/day of pectin can reduce
plasma Lp(a) concentrations in hyperlipidemic patients by up to 27%
after a 4week intervention. Fibernat is a fiber cocktail containing
70% fenugreek, 15% guar gum, and 15% wheat bran (Venkatesan,
Devaraj, & Devaraj, 2003; Venkatesan, Devaraj, & Devaraj, 2007).
Venkatesan et al. (2007) showed that fibernat supplementation
(100 g·kg
1
·day
1
) for 6 weeks led to Lp(a) decreases by 24.7% in rats
fed an atherogenic diet. Such findings suggest that fibers may
influence plasma Lp(a) levels, although further research is needed to
evaluate the effects of dietary fibers on Lp(a) metabolism.
5.5
|
Ginkgo biloba
G. biloba (ginkgo) is one of the most famous herbal remedies and it
has been traditionally used by Chinese clinicians for the treatment of
a variety of pathological conditions, such as asthma, digestive, and
cognitive disorders including memory loss and dementia (Kiefer,
2004). Ginkgo leaves exert antioxidant and antiinflammatory
properties (Han, 2005; Yoshikawa, Naito, & Kondo, 1999).
Ginkgo extract was reported to affect Lp(a) levels thus exerting
antiatherosclerotic effects. In detail, 2 months of ginkgo intake (EGb
761; 240 mg/day) led to plasma Lp(a) concentration reduction by
23.4% (Schäfer et al., 2006). Furthermore, ginkgo decreased the
atherosclerotic plaque formation in patients undergoing coronary
artery bypass graft (Rodríguez et al., 2007).
Lp(a)lowering effects were suggested to be due to the anti
inflammatory properties of ginkgo (Lippi, Targher, & Guidi, 2007).
The extract of ginkgo with a higher amount of active terpenes and
bioavonoids was found to profoundly reduce proinflammatory
cytokines, such as interleukin 6 (IL6; He, Zhang, & Yuan, 2005;
Park et al., 2006; Pirro, Bianconi, et al., 2017). The expression of apo
(a) gene is known to be upregulated through acute phase response
via the enhancing effect of IL6 on Lp(a) transcription. Mechan-
istically, IL6 has a responsive element within the apo(a) gene and can
increase the expression of apo(a) in a dosedependent manner,
leading to a 24folds increase in the hepatic production of Lp(a)
(Ramharack, Barkalow, & Spahr, 1998). Overall, ginkgo extract
containing IL6 suppressing compounds can efficiently reduce
atherogenic Lp(a). Therefore, ginkgo may be considered as a potential
Lp(a)lowering agent but further investigations are needed to provide
a comprehensive understanding of this effect.
5.6
|
Flaxseed
Flaxseed (Linum usitatissimum) is a cholesterollowering plantbased
nutraceutical that was found to diminish the atherosclerotic lesion
progression (Babu, Mitchell, Wiesenfeld, Jenkins, & Gowda, 2000;
Dupasquier et al., 2006; Dupasquier et al., 2007; Lucas et al., 2002)
and also reduce CVD risk (RodriguezLeyva, Bassett, McCullough, &
Pierce, 2010). Experimental and human interventional studies also
showed Lp(a)lowering effects of flaxseed. In an animal study with
female hamsters, Campbell et al. (2013) reported that diet containing
15% and 22.5% flaxseed may reduce plasma Lp(a) levels by 51.1%
and 93.2%, respectively. A doubleblind, randomized, controlled trial
conducted by Bloedon et al., 2008 showed that 10 weeks
supplementation of ground flaxseed (40 g/day) can decrease plasma
Lp(a) concentrations by 14% in hypercholesterolemic patients. In
another doubleblind crossover study on postmenopausal women
with elevated Lp(a) levels, Arjmandi et al. (1998) demonstrated that 6
weeks consumption of whole flaxseed (38 g/day) can lower plasma Lp
(a) levels by 7.4%.
Flaxseed is known to be a rich source of dietary lignans,
potential lipidlowering and antioxidant phytoestrogens (Vanhar-
anta et al., 2002), which were associated with a reduced CVD risk
(Vanharanta et al., 1999). Flaxseed is also rich in αlinolenic acid
(ALA), the plant omega3(n3) fatty acid which has shown to reduce
plasma cholesterol levels (Chan, Bruce, & McDonald, 1991; Garg,
Wierzbicki, Thomson, & Clandinin, 1989; Harris, 1997) and CVD
risk (Hu et al., 1999; Mozaffarian et al., 2005; RodriguezLeyva
et al., 2010). Soluble fiber is the other main compound of flaxseed,
which is linked to lower cholesterol (Brown, Rosner, Willett, &
Sacks, 1999) and reduced CVD risk (Pereira et al., 2004). Such
findings can support the Lp(a)lowering effect of flaxseed, thus
emerging this functional food as a valuable lipidmanaging and
atheroprotective nutritional option.
5.7
|
Red wine and resveratrol
Moderate alcohol consumption, independently of the type of
alcoholic beverage, has been frequently associated with reduced
CVD risk (Ronksley, Brien, Turner, Mukamal, & Ghali, 2011). Alcohol
consumption may also increase HDLC and Apo AI concentrations
(Brien, Ronksley, Turner, Mukamal, & Ghali, 2011). Among the
alcoholic beverages, red wine contains abundant polyphenolic
compounds, which have been reported to inhibit the progression of
the atherosclerotic lesions (Auger et al., 2005), thus possessing
further benefits on decreasing CVD risk (Costanzo, Di Castelnuovo,
Donati, Iacoviello, & de Gaetano, 2011).
A randomized crossover clinical trial on men with high CVD risk
found that red wine consumption (30 g/day) for 4 weeks could
reduce plasma Lp(a) levels by 12% when compared with the
consumption of dealcoholized red wine and/or gin (ChivaBlanch
et al., 2013). Furthermore, resveratrol (trans3,40,5trihydroxystil-
bene) is one of the predominant natural polyphenols present in red
wine (Sevov, Elfineh, & Cavelier, 2006). Cho et al. (2008) evaluated
the effect of a highfat diet containing 0.025% resveratrol on lipid
profile administered for 8 weeks in male Syrian golden hamsters.
Plasma Lp(a) levels were reduced by 60% in the resveratrolfed
group compared with the control group (Cho et al., 2008). None-
theless, the potential Lp(a)lowering efficacy of alcohol and/or
polyphenols deserves further investigation.
5.8
|
Curcuminoids
Curcuminoids are therapeutic ingredients of the famous dietary spice
turmeric, which are mainly derived from Curcuma longa. These
MOMTAZIBOROJENI ET AL.
|
5
polyphenolic natural products are known for various pharmaceutical
properties such as lipidlowering, antitumor, immunomodulatory,
antiinflammatory, antioxidant, antidepressant, and hepatoprotective
effects (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018; Iranshahi
et al., 2015; Lelli et al., 2017; Mirzaei et al., 2017; Momtazi and
Sahebkar, 2016; Momtazi & Sahebkar, 2016; Momtazi, Derosa, et al.,
2016; Momtazi, Shahabipou, et al., 2016; Panahi, Badeli, et al., 2015;
Panahi, Hosseini, et al., 2015; Rezaee, Momtazi, Monemi, & Sahebkar,
2016; Sahebkar, Cicero, et al., 2016; Sahebkar & Henrotin, 2016;
Sahebkar, 2014; Sahebkar, Serban, Ursoniu, & Banach, 2015;
Strimpakos & Sharma, 2008). With regard to lipids, curcuminoids
may decrease plasma triglycerides and cholesterol (DiSilvestro,
Joseph, Zhao, & Bomser, 2012; Mohammadi et al., 2013a; Panahi
et al., 2016; Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar,
2014a) and increase HDLC concentrations (Ganjali et al., 2017; Soni
& Kuttan, 1992) through modulation of the expression of genes and
the activity of enzymes involved in lipoprotein metabolism. In a
previous randomized controlled trial, we evaluated the effects of
curcuminoids on lipid profile in patients with metabolic syndrome
(Panahi et al., 2014b). The consumption of 1 g/day of curcuminoids
decreased serum Lp(a) levels by 9.7% at the end of the 8 weeks
compared with baseline levels (Panahi et al., 2014b).
5.9
|
Chenodeoxycholic acid (CDCA)
Bile acid CDCA is a natural farnesoid X receptor (FXR) agonist
(Bramlett, Yao, & Burris, 2000; Chiang, Kimmel, Weinberger, & Stroup,
2000), which reduces the biliary secretion of cholesterol and decreases
the cholesterol saturation of bile (Adler, Bennion, Duane, & Grundy,
1975; LaRusso, Hoffman, Hofmann, Northfield, & Thistle, 1975), leading
to the reduction of cholesterol and bile acid synthesis (Kallner, 1975;
LaRusso et al., 1975). Furthermore, CDCA has been found to decrease
hepatic production of VLDL (Angelin, Einarsson, Hellström, & Leijd,
1978; Miller & Nestel, 1974), HMGCoA reductase, LDLR, and PCSK9
(Langhi et al., 2008; Nilsson et al., 2007) in human, while plasma levels of
circulating LDLC have been often increased (Albers et al., 1982; Perez
Aguilar, Breto, Alegre, & Berenguer, 1985).
The most recent published human interventional study show that
CDCA treatment can strongly reduce plasma levels of circulating Lp
(a) that was along with reduction of plasma PCSK9 (Ghosh Laskar,
Eriksson, Rudling, & Angelin, 2017). This finding is supported by
other studies showing a decreased liver production of Lp(a) in
patients with biliary obstruction, in whom FXR signaling is activated
(Chennamsetty et al., 2011). Although exact Lp(a)lowering effect of
CDCA is unclear, the reduction in plasma PCSK9 during CDCA
treatment have probably an important role in Lp(a)lowering effect of
CDCA (Ghosh Laskar et al., 2017), as far as PCSK9 inhibitors are able
to reduce plasma Lp(a) levels.
5.10
|
Coffee
Coffee is an aqueous extract of the Coffea plants beans, which is
the most widely consumed caffeinecontaining beverage in
western societies (Doepker et al., 2016). Associations between
coffee consumption and plasma lipids levels have been previously
described, suggesting that coffee consumption may increase
plasma LDLC and total cholesterol concentrations in a dose
dependent manner (Cai, Ma, Zhang, Liu, & Wang, 2012; Jee
et al., 2001).
The lipidmodulating effects of coffee may be attributed to
kahweol and cafestol, the two diterpenes present in coffee (Heckers,
Gobel, & Kleppel, 1994; Weustenvanderwouw et al., 1994). The
amount of the diterpenes in the coffee is influenced by methods of
coffee preparation. In this context, coffee prepared by paper filters
that trap these diterpenes was shown to have no significant effects
on plasma cholesterol concentrations, while unfiltered coffee was
associated with elevated plasma LDLC levels (Cai et al., 2012;
Dusseldorp, Katan, Vliet, Demacker, & Stalenhoef, 1991; Heckers
et al., 1994; Jee et al., 2001; Urgert & Katan, 1997; Urgert et al.,
1995; Weustenvanderwouw et al., 1994).
Taking into consideration the negative effects of coffee on lipid
profile, the evaluation of Lp(a)modulating impact of coffee can be
valuable. Several trials investigated the effect of coffee consump-
tion on plasma Lp(a) concentrations. A recent comprehensive
systematic review showed that coffee affects plasma Lp(a)
depending on coffee source, dose, and duration of consumption,
method of preparation, and baseline Lp(a) levels. Interestingly,
shortterm coffee consumption was shown to reduce plasma
Lp(a) concentrations, whereas chronic intake was associated
with elevated plasma Lp(a) levels (Penson, Serban, Ursoniu, &
Banach, 2018).
Table 1 summarizes the changes in Lp(a) levels induced by
natural product supplementation in both clinical and preclinical
studies.
5.11
|
LDLClowering natural products with no
effect on plasma Lp(a)
Despite affecting LDLC, some natural products do not change
plasma Lp(a) levels. There are randomized controlled trials showing
that certain natural products, including berberine (Cicero, Rovati, &
Setnikar, 2007), brazil nut flour (Carvalho et al., 2015), ginger
(Tabibi et al., 2016), garlic (RyszGorzynska et al., 2016), tea
catechin (Inami et al., 2007), olive oil (Chan, Demonty, Pelled, &
Jones, 2007; Lichtenstein et al., 1993; Perona, Fitó, Covas, Garcia, &
RuizGutierrez, 2011), onion (EbrahimiMamaghani, SaghafiAsl,
Pirouzpanah, & AsghariJafarabadi, 2014), palm oil (Fattore, Bosetti,
Brighenti, Agostoni, & Fattore, 2014), rice bran oil (Jolfaie, Rouhani,
Surkan, Siassi, & Azadbakht, 2016), soy proteins and isoflavones
(Hall et al., 2006; MerzDemlow et al., 2000; Sacks et al., 2006;
Turhan, Duvan, Bolkan, & Onaran, 2009), phytosterols (Garoufi
et al., 2014; Nigon et al., 2001; Quílez et al., 2003), policosanol
(Dulin, Hatcher, Sasser, & Barringer, 2006; Reiner, TedeschiReiner,
&Romić, 2005), vitamin C (Loots, Oosthuizen, Pieters, Spies, &
Vorster, 2004), and B group of vitamins (Loots et al., 2004) do not
change Lp(a) concentrations.
6
|
MOMTAZIBOROJENI ET AL.
TABLE 1 Changes in Lp(a) levels in clinical and preclinical studies with natural product supplementation
Human interventional studies
Interventions Study design Trial protocol % of Lp(a) reduction Weighted mean difference References
LCarnitine Metaanalysis 14 g/day for 1 24 weeks 1329.3% 8.82 md/dl Serban et al. (2016)
Coenzyme Q
10
Metaanalysis 120300 mg/day for 412 weeks 12.528.6% 3.54 mg/dl Sahebkar, SimentalMendia, Stefanutti,
and Pirro (2016)
Pectin Randomized, placebocontrolled, and
doubleblind study
15 g/day for 4 weeks 27% 96 U/L Veldman et al. (1999)
Ginkgo biloba Longterm explorative clinical trial 2 × 120 mg/day for 2 months 23.4% 10.4 mg/dl Rodríguez et al. (2007); Schäfer
et al. (2006)
Xuezhikang Randomized and placebocontrolled trial 1.2 g/day for 6 weeks 23% 67.8 mg/L Liu et al. (2003)
Flaxseed Doubleblind, randomized, and controlled
clinical trial
40 g/day for 10 weeks 12% 4 mg/dl Bloedon et al. (2008)
Red wine Randomized crossover trial 30 g/day for 4 weeks 12% 4.2 mg/dl ChivaBlanch et al. (2013)
Curcuminoids Randomized controlled trial 1 g/day for 8 weeks 9.7% 8 mg/dl Panahi et al. (2014a)
Flaxseed Doubleblind crossover trial on
postmenopausal women
38 g/day for 6 weeks 7.4% 1.96 mg/dl Arjmandi et al. (1998)
Animal studies
Natural products Experimental model Dose of natural product Duration of treatment % of Lp(a) reduction Weighted mean difference References
Flaxseed Hamsters Diet containing 22.5% flaxseed 4 months 93.2% 0.3 mg/dl Campbell et al. (2013)
Diet containing 15% flaxseed 4 months 51.1% 2.15 mg/dl
Resveratrol Hamsters Diet containing 0.025% resveratrol 8 weeks 60% 8.83 mg/dl Cho et al. (2008)
Fibernat Rat 100 g·kg
1
·day
1
6 weeks 24.7% 6.8 mg/dl Venkatesan et al. (2007)
Note. Lp(a): lipoprotein(a).
MOMTAZIBOROJENI ET AL.
|
7
6
|
CONCLUDING REMARKS
Data from preclinical and clinical studies as well as metaanalyses
showed that natural products, including Lcarnitine, coenzyme Q
10
,
xuezhikang, pectin, fibernat, G. biloba, flaxseed, red wine, resveratrol,
curcuminoids, and CDCA exert significant Lp(a)lowering effects.
Efficient Lp(a)lowering therapy is achieved with an agent that can
reduce Lp(a) levels to <30 mg/dl in patients with Lp(a) hyperlipoprotei-
nemia(a) (Lp(a) 30 mg/dl). Niacin (from 1 to >3 g/day), which is
generally considered as a strong Lp(a)lowering agent, can reduce Lp
(a) by 2040%. Among the aforementioned natural products, Lcarnitine
(14g/day), coenzyme Q
10
(120300 mg/day), and xuezhikang (1.2 g/
day) were found to decrease elevated plasma Lp(a) levels to <30 mg/dl,
and by 1329%, 1229%, and 1329%, respectively, in patients with
hyperlipoproteinemia(a). Such natural products can be appropriate
alternatives for niacin which has limited clinical use due to adverse
effectssuchasflushing.LCarnitine, coenzyme Q
10
, and xuezhikang are
potential adjuncts to statins, known to lack any meaningful Lp(a)
lowering effects. Such natural products are known to be safe and can be
potentially useful in patients on residual cholesterol risk after statin
therapy, as well as in statinintolerant patients. Besides, many of the
natural products discussed in this review possess beneficial effects on
other lipids and lipoprotein indices (Cicero et al., 2017). However, the
effects of these natural products on CVD risk should be further
evaluated in robust randomized controlled trials. Other natural
products, including pectin, ginkgo, flaxseed, red wine, resveratrol,
curcuminoids, and CDCA have been shown to significantly lower
plasma Lp(a) levels in patients with Lp(a) <30 mg/dl but their efficacy in
hyperlipoproteinemia(a) is unknown.
CONFLICTS OF INTEREST
M. B. has served on the speakers bureau and as an advisory board
member for Amgen, Sanofi, Aventis, and Lilly. N. K. has given talks,
attended conferences, and participated in trials sponsored by Amgen,
Angelini, Astra Zeneca, Boehringer Ingelheim, Galenica, MSD,
Novartis, Novo Nordisk, Sanofi, and WinMedica. K. R. received
research grant from Sanofi, served on the speakers bureau and as an
advisory board member for Sanofi, Astra Zeneca, and Pfizer. The
authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
ORCID
Niki Katsiki http://orcid.org/0000-0003-0894-2644
Matteo Pirro http://orcid.org/0000-0002-5527-4821
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
REFERENCES
Abbas momtazi, A., & Sahebkar, A. (2016). Difluorinated curcumin: A
promising curcumin analogue with improved antitumor activity and
pharmacokinetic profile. Current Pharmaceutical Design,22(28),
43864397.
Abdollahi , E., Momtazi , A. A., Johnston , T. P., & Sahebkar , A. (2018).
Therapeutic effects of curcumin in inflammatory and immune
mediated diseases: A naturemade jackofalltrades? Journal of
Cellular Physiology,233(2), 830848.
Adler, R. D., Bennion, L. J., Duane, W. C., & Grundy, S. M. (1975). Effects of
low dose chenodeoxycholic acid feeding on biliary lipid metabolism.
Gastroenterology,68(2), 326334.
Albers, J. J., Grundy, S. M., Cleary, P. A., Small, D. M., Lachin, J. M., &
Schoenfield, L. J. (1982). National cooperative gallstone study.
Gastroenterology,82(4), 638646.
Allen, S., Khan, S., Tam, S., Koschinsky, M., Taylor, P., & Yacoub, M. (1998).
Expression of adhesion molecules by Lp (a): A potential novel mechanism
for its atherogenicity. The FASEB Journal,12(15), 17651776.
Anderson, J. W. (1995). Dietary fibre, complex carbohydrate and coronary
artery disease. The Canadian Journal of Cardiology,11, 55G62G.
Anderson, T. J., Grégoire, J., Hegele, R. A., Couture, P., Mancini, G. B. J.,
McPherson, R., Ur, E. (2013). 2012 update of the Canadian
Cardiovascular Society guidelines for the diagnosis and treatment of
dyslipidemia for the prevention of cardiovascular disease in the adult.
Canadian Journal of Cardiology,29(2), 151167.
Angelin, B., Einarsson, K., Hellström, K., & Leijd, B. (1978). Effects of
cholestyramine and chenodeoxycholic acid on the metabolism of
endogenous triglyceride in hyperlipoproteinemia. Journal of Lipid
Research,19(8), 10171024.
Arjmandi, B. H., Khan, D. A., Juma, S., Drum, M. L., Venkatesh, S., Sohn, E.,
Derman, R. (1998). Whole flaxseed consumption lowers serum LDL
cholesterol and lipoprotein(a) concentrations in postmenopausal
women. Nutrition Research,18(7), 12031214.
Asgary, S., RafieianKopaei, M., Shamsi, F., Najafi, S., & Sahebkar, A. (2014).
Biochemical and histopathological study of the antihyperglycemic
and antihyperlipidemic effects of cornelian cherry (Cornus mas L.) in
alloxaninduced diabetic rats. Journal of Complementary and Integrative
Medicine,11(2), 6369.
Auger, C., Teissedre, P.L., Gérain, P., Lequeux, N., Bornet, A., Serisier, S.,
Rouanet, J.M. (2005). Dietary wine phenolics catechin, quercetin, and
resveratrol efficiently protect hypercholesterolemic hamsters against
aortic fatty streak accumulation. Journal of Agricultural and Food
Chemistry,53(6), 20152021.
Babu, U. S., Mitchell, G. V., Wiesenfeld, P., Jenkins, M. Y., & Gowda, H.
(2000). Nutritional and hematological impact of dietary flaxseed and
defatted flaxseed meal in rats. International Journal of Food Sciences
and Nutrition,51(2), 109117.
Banach, M. (2016). Lipoprotein (a)we know so much yet still have much
to learn. Journal of the American Heart Association,5(4
Banach, M., Aronow, W. S., Serban, C., Sahabkar, A., Rysz, J., Voroneanu,
L., & Covic, A. (2015). Lipids, blood pressure and kidney update 2014.
Pharmacological Research,95, 111125.
Banach, M., Dinca, M., Ursoniu, S., Serban, M. C., Howard, G., Mikhailidis,
D. P., Sahebkar, A. (2016). A PRISMAcompliant systematic review
and metaanalysis of randomized controlled trials investigating the
effects of statin therapy on plasma lipid concentrations in HIV
infected patients. Pharmacological Research,111, 343356.
Banach, M., Rizzo, M., Obradovic, M., Montalto, G., Rysz, J., P. mikhailidis,
D., & R. isenovic, E. (2013). PCSK9 inhibitiona novel mechanism to
treat lipid disorders? Current Pharmaceutical Design,19(21),
38693877.
Banach, M., Serban, C., Sahebkar, A., Mikhailidis, D. P., Ursoniu, S., Ray, K.
K., Serruys, P. W. (2015). Impact of statin therapy on coronary
plaque composition: A systematic review and metaanalysis of virtual
histology intravascular ultrasound studies. BMC Medicine,13, 229.
Banach, M., Stulc, T., Dent, R., & Toth, P. P. (2016). Statin nonadherence
and residual cardiovascular risk: There is need for substantial
improvement. International Journal of Cardiology,225, 184196.
8
|
MOMTAZIBOROJENI ET AL.
Becker,D.J.,Gordon,R.Y.,Halbert,S.C.,French,B.,Morris,P.B.,&Rader,D.
J. (2009). Red yeast rice for dyslipidemia in statinintolerant patients: A
randomized trial. Annals of Internal Medicine,150(12), 830839.
Bennet, A., Di Angelantonio, E., Erqou, S., Eiriksdottir, G., Sigurdsson, G.,
Woodward, M., Gudnason, V. (2008). Lipoprotein (a) levels and risk
of future coronary heart disease: Largescale prospective data.
Archives of Internal Medicine,168(6), 598608.
Berg, K. (1963). A new serum type system in manthe lp system. Acta
Pathologica et Microbiologica Scandinavica,59, 369382.
Berg, K., Dahlén, G., Christophersen, B., Cook, T., Kjekshus, J., & Pedersen,
T. (1997). Lp (a) lipoprotein level predicts survival and major coronary
events in the Scandinavian Simvastatin Survival Study. Clinical
Genetics,52(5), 254261.
Berglund, L., & Ramakrishnan, R. (2004). Lipoprotein(a): An elusive
cardiovascular risk factor. Arteriosclerosis, Thrombosis, and Vascular
Biology,24(12), 22192226.
Bianconi, V., Sahebkar, A., Banach, M., & Pirro, M. (2017). Statins,
haemostatic factors and thrombotic risk. Current Opinion in Cardiology,
32, 460466.
Bloedon, L. T., Balikai, S., Chittams, J., Cunnane, S. C., Berlin, J. A., Rader,
D. J., & Szapary, P. O. (2008). Flaxseed and cardiovascular risk factors:
Results from a double blind, randomized, controlled clinical trial.
Journal of the American College of Nutrition,27(1), 6574.
Boerwinkle, E., Leffert, C. C., Lin, J., Lackner, C., Chiesa, G., & Hobbs, H. H.
(1992). Apolipoprotein (a) gene accounts for greater than 90% of the
variation in plasma lipoprotein (a) concentrations. Journal of Clinical
Investigation,90(1), 5260.
Bramlett, K. S., Yao, S., & Burris, T. P. (2000). Correlation of farnesoid X
receptor coactivator recruitment and cholesterol 7αhydroxylase
gene repression by bile acids. Molecular Genetics and Metabolism,
71(4), 609615.
Brien, S. E., Ronksley, P. E., Turner, B. J., Mukamal, K. J., & Ghali, W. A.
(2011). Effect of alcohol consumption on biological markers asso-
ciated with risk of coronary heart disease: Systematic review and
metaanalysis of interventional studies. BMJ,342, d636.
Broderick, T. L. (2008). ATP production and TCA activity are stimulated by
propionylLcarnitine in the diabetic rat heart. Drugs in R & D,9(2),
8391.
Brown, L., Rosner, B., Willett, W. W., & Sacks, F. M. (1999). Cholesterol
lowering effects of dietary fiber: A metaanalysis. American Journal of
Clinical Nutrition,69(1), 3042.
Buhman, K. K., Furumoto, E. J., Donkin, S. S., & Story, J. A. (2000). Dietary
psyllium increases expression of ileal apical sodiumdependent bile
acid transporter mRNA coordinately with doseresponsive changes in
bile acid metabolism in rats. The Journal of Nutrition,130(9),
21372142.
Burgess, S., Ference, B. A., Staley, J. R., Freitag D. F., Mason, A. M., Nielsen,
S. F., Danesh, J. (2018). European prospective investigation into
cancer and nutritioncardiovascular disease (EPIC-CVD) consortium.
Association of LPA variants with risk of coronary disease and the
implications for lipoprotein(a)-lowering therapies: A mendelian
randomization analysis. JAMA Cardiol,3(7), 619627.
Cai, L., Ma, D., Zhang, Y., Liu, Z., & Wang, P. (2012). The effect of coffee
consumption on serum lipids: A metaanalysis of randomized
controlled trials. European Journal of Clinical Nutrition,66(8), 872877.
Campbell, S. C., Bakhshalian, N., Sadaat, R. L., Lerner, M. R., Lightfoot, S. A.,
Brackett, D., & Arjmandi, B. H. (2013). Flaxseed reverses athero-
sclerotic lesion formation and lowers lipoprotein(a) in ovarian
hormone deficiency. Menopause,20(11), 11761183.
Capuzzi, D. M., Guyton, J. R., Morgan, J. M., Goldberg, A. C., Kreisberg, R.
A., Brusco, O. A., & Brody, J. (1998). Efficacy and safety of an
extendedrelease niacin (Niaspan): A longterm study. The American
Journal of Cardiology,82(12), 74U81U.
Carvalho, R. F., Huguenin, G. V. B., Luiz, R. R., Moreira, A. S. B., Oliveira, G.
M. M., & Rosa, G. (2015). Intake of partially defatted Brazil nut flour
reduces serum cholesterol in hypercholesterolemic patientsa rando-
mized controlled trial. Nutrition Journal,14(1), 1.
Chan, J. K., Bruce, V. M., & McDonald, B. E. (1991). Dietary alphalinolenic
acid is as effective as oleic acid and linoleic acid in lowering blood
cholesterol in normolipidemic men. American Journal of Clinical
Nutrition,53(5), 12301234.
Chan, Y.M., Demonty, I., Pelled, D., & Jones, P. J. H. (2007). Olive oil
containing olive oil fatty acid esters of plant sterols and dietary
diacylglycerol reduces lowdensity lipoprotein cholesterol and de-
creases the tendency for peroxidation in hypercholesterolaemic
subjects. British Journal of Nutrition,98(03), 563570.
Chennamsetty, I., Claudel, T., Kostner, K. M., Baghdasaryan, A., Kratky, D.,
LevakFrank, S., Kostner, G. M. (2011). Farnesoid X receptor
represses hepatic human APOA gene expression. The Journal of
Clinical Investigation,121(9), 37243734.
Chiang, J. Y. L., Kimmel, R., Weinberger, C., & Stroup, D. (2000). Farnesoid
X receptor responds to bile acids and represses cholesterol 7α
hydroxylase gene (CYP7A1) transcription. Journal of Biological
Chemistry,275(15), 1091810924.
ChivaBlanch, G., UrpiSarda, M., Ros, E., ValderasMartinez, P., Casas, R.,
Arranz, S., Estruch, R. (2013). Effects of red wine polyphenols and
alcohol on glucose metabolism and the lipid profile: A randomized
clinical trial. Clinical Nutrition,32(2), 200206.
Cho, I. J., Ahn, J. Y., Kim, S., Choi, M. S., & Ha, T. Y. (2008). Resveratrol
attenuates the expression of HMGCoA reductase mRNA in
hamsters. Biochemical and Biophysical Research Communications,
367(1), 190194.
Chruściel, P., Sahebkar, A., RembekWieliczko, M., Serban, M. C., Ursoniu,
S., Mikhailidis, D. P., Banach, M. (2016). Impact of statin therapy on
plasma adiponectin concentrations: A systematic review and meta
analysis of 43 randomized controlled trial arms. Atherosclerosis,253,
194208.
Cicero, A. F., Rovati, L. C., & Setnikar, I. (2007). Eulipidemic effects of
berberine administered alone or in combination with other natural
cholesterollowering agents. ArzeneimittelForschung,57(01), 2630.
Cicero, A. F. G., Colletti, A., Bajraktari, G., Descamps, O., Djuric, D. M.,
Ezhov, M., Banach, M. (2017). Lipid lowering nutraceuticals in
clinical practice: Position paper from an International Lipid Expert
Panel. Archives of Medical Science,13(5), 9651005.
Clarke, R., Peden, J. F., Hopewell, J. C., Kyriakou, T., Goel, A., Heath, S. C.,
Farrall, M. (2009). Genetic variants associated with Lp (a)
lipoprotein level and coronary disease. New England Journal of
Medicine,361(26), 25182528.
Emerging Risk Factors Collaboration (2009). Lipoprotein (a) concentration
and the risk of coronary heart disease, stroke, and nonvascular
mortality. The Journal of the American Medical Association,302(4), 412.
Costanzo, S., Di Castelnuovo, A., Donati, M. B., Iacoviello, L., & de Gaetano,
G. (2011). Wine, beer or spirit drinking in relation to fatal and non
fatal cardiovascular events: A metaanalysis. European Journal of
Epidemiology,26(11), 833850.
Davidson, M. H., Ballantyne, C. M., Jacobson, T. A., Bittner, V. A., Braun, L.
T., Brown, A. S., Dicklin, M. R. (2011). Clinical utility of inflammatory
markers and advanced lipoprotein testing: Advice from an expert
panel of lipid specialists. Journal of Clinical Lipidology,5(5), 338367.
Dhingra, D., Michael, M., Rajput, H., & Patil, R. T. (2012). Dietary fibre in
foods: A review. JournalofFoodScienceandTechnology,49(3), 255266.
DiSilvestro, R. A., Joseph, E., Zhao, S., & Bomser, J. (2012). Diverse effects
of a low dose supplement of lipidated curcumin in healthy middle aged
people. Nutrition Journal,11(1), 79.
Doepker, C., Lieberman, H. R., Smith, A. P., Peck, J. D., ElSohemy, A., & Welsh,
B. T. (2016). Caffeine: Friend or foe? Food Science and Technology,7,737.
Dragan, S., Serban, M.C., & Banach, M. (2015). Proprotein convertase
subtilisin/kexin 9 inhibitors an emerging lipidlowering therapy?
Journal of Cardiovascular Pharmacology and Therapeutics,20(2),
157168.
MOMTAZIBOROJENI ET AL.
|
9
Dubé, J. B., Boffa, M. B., Hegele, R. A., & Koschinsky, M. L. (2012).
Lipoprotein (a): More interesting than ever after 50 years. Current
Opinion in Lipidology,23(2), 133140.
Dulin, M. F., Hatcher, L. F., Sasser, H. C., & Barringer, T. A. (2006).
Policosanol is ineffective in the treatment of hypercholesterolemia: A
randomized controlled trial. The American Journal of Clinical Nutrition,
84(6), 15431548.
Dupasquier, C. M. C., Dibrov, E., Kneesh, A. L., Cheung, P. K. M., Lee, K. G.
Y., Alexander, H. K., Pierce, G. N. (2007). Dietary flaxseed inhibits
atherosclerosis in the LDL receptordeficient mouse in part through
antiproliferative and antiinflammatory actions. American Journal of
Physiology Heart and Circulatory Physiology,293(4), H2394H2402.
Dupasquier, C. M. C., Weber, A. M., Ander, B. P., Rampersad, P. P.,
Steigerwald, S., Wigle, J. T., Pierce, G. N. (2006). Effects of dietary
flaxseed on vascular contractile function and atherosclerosis during
prolonged hypercholesterolemia in rabbits. American Journal of
Physiology Heart and Circulatory Physiology,291(6), H2987H2996.
Van dusseldorp, M., Katan, M. B., Van vliet, T., Demacker, P. N., &
Stalenhoef, A. F. (1991). Cholesterolraising factor from boiled coffee
does not pass a paper filter. Arteriosclerosis and Thrombosis,11(3),
586593.
EbrahimiMamaghani, M., SaghafiAsl, M., Pirouzpanah, S., & Asghari
Jafarabadi, M. (2014). Effects of raw red onion consumption on
metabolic features in overweight or obese women with polycystic
ovary syndrome: A randomized controlled clinical trial. Journal of
Obstetrics and Gynaecology Research,40(4), 10671076.
Ellis, K. L., Boffa, M. B., Sahebkar, A., Koschinsky, M. L., & Watts, G. F.
(2017). The renaissance of lipoprotein(a): Brave new world for
preventive cardiology? Progress in Lipid Research,68,5758.
Fattore, E., Bosetti, C., Brighenti, F., Agostoni, C., & Fattore, G. (2014).
Palm oil and blood lipidrelated markers of cardiovascular disease: A
systematic review and metaanalysis of dietary intervention trials. The
American Journal of Clinical Nutrition,99, 081190081350.
Ferretti, G., Bacchetti, T., Banach, M., SimentalMendia, L. E., & Sahebkar,
A. (2016). Impact of statin therapy on plasma MMP3, MMP9, and
TIMP1 concentrations. Angiology,68(10), 850862.
Ferretti, G., Bacchetti, T., Johnston, T. P., Banach, M., Pirro, M., &
Sahebkar, A. (2018). Lipoprotein(a): A missing culprit in the manage-
ment of athero-thrombosis? Journal of Cellular Physiology,233(4),
29662981.
Ferretti, G., Bacchetti, T., & Sahebkar, A. (2015). Effect of statin therapy
on paraoxonase1 status: A systematic review and metaanalysis of 25
clinical trials. Progress in Lipid Research,60,5073.
Ganjali, S., Blesso, C. N., Banach, M., Pirro, M., Majeed, M., & Sahebkar, A.
(2017). Effects of curcumin on HDL functionality. Pharmacological
Research,119, 208218.
Garg, M. L., Wierzbicki, A. A., Thomson, A. B. R., & Clandinin, M. T. (1989).
Dietary saturated fat level alters the competition between αlinolenic
and linoleic acid. Lipids,24(4), 334339.
Garoufi, A., Vorre, S., Soldatou, A., Tsentidis, C., Kossiva, L., Drakatos, A.,
Gourgiotis, D. (2014). Plant sterolsenriched diet decreases small,
dense LDLcholesterol levels in children with hypercholesterolemia: A
prospective study. Italian Journal of Pediatrics,40(1), 1.
Ghosh Laskar, M., Eriksson, M., Rudling, M., & Angelin, B. (2017).
Treatment with the natural FXR agonist chenodeoxycholic acid
reduces clearance of plasma LDL whilst decreasing circulating PCSK9,
lipoprotein (a) and apolipoprotein CIII. Journal of Internal Medicine,
281, 575585.
Glore, S. R., Van Treeck, D., Knehans, A. W., & Guild, M. (1994). Soluble
fiber and serum lipids: A literature review. Journal of the American
Dietetic Association,94(4), 425436.
Goldstein, L. B., Bushnell, C. D., Adams, R. J., Appel, L. J., Braun, L. T.,
Chaturvedi, S., Pearson, T. A. (2011). Guidelines for the primary
prevention of stroke. Stroke,42(2), 517584.
HPS2THRIVE Collaborative Group (2014). Effects of extendedrelease
niacin with laropiprant in highrisk patients. The New England Journal
of Medicine,2014(371), 203212.
Gurdasani, D., Sjouke, B., Tsimikas, S., Hovingh, G. K., Luben, R. N.,
Wainwright, N. W. J., Sandhu, M. S. (2012). Lipoprotein (a) and risk
of coronary, cerebrovascular, and peripheral artery disease. Arterio-
sclerosis, Thrombosis, and Vascular Biology,32(12), 30583065.
Górecka, D., Korczak, J., Balcerowski, E., & Decyk, K. (2002). Sorption of
bile acids and cholesterol by dietary fiber of carrots, cabbage and
apples. Electronic Journal of Polish Agricultural Universities,5,2.
Hall, W. L., Vafeiadou, K., Hallund, J., Bugel, S., Reimann, M., Koebnick, C.,
Williams, C. M. (2006). Soyisoflavoneenriched foods and markers
of lipid and glucose metabolism in postmenopausal women: Interac-
tions with genotype and equol production. American Journal of Clinical
Nutrition,83(3), 592600.
Han, Y. (2005). Ginkgo terpene component has an antiinflammatory
effect on Candida albicanscaused arthritic inflammation. International
Immunopharmacology,5(6), 10491056.
Harris, W. S. (1997). n3 fatty acids and serum lipoproteins: Human
studies. The American Journal of Clinical Nutrition,65(5), 1645S1654S.
Haskell, W. L., Spiller, G. A., Jensen, C. D., Ellis, B. K., & Gates, J. E. (1992).
Role of watersoluble dietary fiber in the management of elevated
plasma cholesterol in healthy subjects. The American Journal of
Cardiology,69(5), 433439.
He, M., Zhang, X. M., & Yuan, H. Q. (2005). Clinical study on treatment of
pulmonary interstitial fibrosis with ginkgo extract. Chinese Journal of
Integrated Traditional and Western Medicine,25(3), 222224.
Heber, D., Yip, I., Ashley, J. M., Elashoff, D. A., Elashoff, R. M., & Go, V. L.
W. (1999). Cholesterollowering effects of a proprietary Chinese red
yeastrice dietary supplement. The American Journal of Clinical
Nutrition,69(2), 231236.
Heckers, H., Göbel, U., & Kleppel, U. (1994). End of the coffee mystery:
Diterpene alcohols raise serum lowdensity lipoprotein cholesterol
and triglyceride levels. Journal of Internal Medicine,235(2), 192193.
Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Holm, H., Patel, R. S.,
Gudnason, T., Stefansson, K. (2012). Apolipoprotein (a) genetic
sequence variants associated with systemic atherosclerosis and
coronary atherosclerotic burden but not with venous thromboembo-
lism. Journal of the American College of Cardiology,60(8), 722729.
Horton, J. D., Cuthbert, J. A., & Spady, D. K. (1994). Regulation of hepatic
7 alphahydroxylase expression by dietary psyllium in the hamster.
Journal of Clinical Investigation,93(5), 20842092.
Hu, F. B., Stampfer, M. J., Manson, J. E., Rimm, E. B., Wolk, A., Colditz, G. A.,
Willett, W. C. (1999). Dietary intake of αlinolenic acid and risk of
fatal ischemic heart disease among women. The American Journal of
Clinical Nutrition,69(5), 890897.
Inami, S., Takano, M., Yamamoto, M., Murakami, D., Tajika, K., Yodogawa,
K., Mizuno, K. (2007). Tea catechin consumption reduces circulating
oxidized lowdensity lipoprotein. International Heart Journal,48(6),
725732.
Investigators, A.H. (2011). Niacin in patients with low HDL cholesterol
levels receiving intensive statin therapy. The New England Journal of
Medicine,2011(365), 22552267.
Iranshahi,M.,Chini,M.G.,Masullo,M.,Sahebkar, A., Javidnia, A., Chitsazian
Yazdi, M., Bifulco, G. (2015). Can small chemical modifications of
natural paninhibitors modulate the biological selectivity? The case of
curcumin prenylated derivatives acting as HDAC or mPGES1 inhibitors.
Journal of Natural Products,78(12), 28672879.
Jacobson,T.A.(2013).Lipoprotein(a),cardiovasculardisease,
and contemporary management. Mayo Clinic Proceedings,88(11),
12941311.
Jee,S.H.,He,J.,Appel,L.J.,Whelton,P.K.,Suh,I.,&Klag,M.J.(2001).Coffee
consumption and serum lipids: A metaanalysis of randomized controlled
clinical trials. American Journal of Epidemiology,153(4), 353362.
10
|
MOMTAZIBOROJENI ET AL.
Jenkins,D.,Wolever,T.,Rao,A.V.,Hegele,R.A.,Mitchell,S.J.,Ransom,T.,
Wursch, P. (1993). Effect on blood lipids of very high intakes of fiber in
diets low in saturated fat and cholesterol. New England Journal of
Medicine,329(1), 2126.
Jiang, J., Hao, X., Deng, C., Zhou, H., & Lin, J. (1999). Effects of Xuezhikang
on serum lipid profile, thromboxane A2 and prostacyclin in patients
with hyperlipidemia. Zhonghua Neike Zazhi,38(8), 517519.
Jolfaie, N., Rouhani, M., Surkan, P., Siassi, F., & Azadbakht, L. (2016). Rice
bran oil decreases total and LDL cholesterol in humans: A systematic
review and metaanalysis of randomized controlled clinical trials.
Hormone and Metabolic Research,48(07), 417426.
Jones, P. J. H. (2008). Dietary agents that target gastrointestinal and
hepatic handling of bile acids and cholesterol. Journal of Clinical
Lipidology,2(2), S4S10.
Kallner, M. (1975). The effect of chenodeoxycholic acid feeding on bile
acid kinetics and fecal neutral steroid excretion in patients with
hyperlipoproteinemia types II and IV. The Journal of Laboratory and
Clinical Medicine,86(4), 595604.
Kamstrup, P. R., Benn, M., TybjærgHansen, A., & Nordestgaard, B. G.
(2008). Extreme lipoprotein (a) levels and risk of myocardial infarction
in the general population. Circulation,117(2), 176184.
Kamstrup, P. R., TybjærgHansen, A., Steffensen, R., & Nordestgaard, B. G.
(2009). Genetically elevated lipoprotein (a) and increased risk of
myocardial infarction. Journal of the American Medical Association,
301(22), 23312339.
Kang, C., Dominguez, M., Loyau, S., Miyata, T., Durlach, V., & Anglé
sCano,
E. (2002). Lp (a) particles mold fibrinbinding properties of apo (a) in
sizedependent manner. Arteriosclerosis, Thrombosis, and Vascular
Biology,22(7), 12321238.
Katsiki, N., AlRasadi, K., & Mikhailidis, D. P. (2017). Lipoprotein (a) and
cardiovascular risk: The show must go on. Current Medicinal Chemistry,
24, 9891006.
Kiefer, M. (2004). Review about Ginkgo biloba special extract EGb 761
(Ginkgo). Current Pharmaceutical Design,10(3), 261264.
Kotani, K., & Banach, M. (2017). Lipoprotein(a) and inhibitors of
proprotein convertase subtilisin/kexin type 9. Journal of Thoracic
Disease,9(1), E78E82.
Kotani, K., Sahebkar, A., Serban, C., Andrica, F., Toth, P., Jones, S.,
Banach, M. (2015). Tibolone can decrease lipoprotein (a) concentra-
tions in postmenopausal women: a systematic review and meta
analysis of controlled trials. European Heart Journal,36(Suppl. 1), 286.
Kotani, K., Sahebkar, A., Serban, M. C., Ursoniu, S., Mikhailidis, D. P.,
Mariscalco, G., Banach, M. (2017). Lipoprotein(a) levels in patients
with abdominal aortic aneurysm. Angiology,68(2), 99108.
Kotani, K., Serban, M. C., Penson, P., Lippi, G., & Banach, M. (2016).
Evidencebased assessment of lipoprotein(a) as a risk biomarker for
cardiovascular diseasesSome answers and still many questions.
Critical Reviews in Clinical Laboratory Sciences,53(6), 370378.
Krempler, F., Kostner, G. M., Bolzano, K., & Sandhofer, F. (1980). Turnover
of lipoprotein (a) in man. Journal of Clinical Investigation,65(6),
14831490.
Kronenberg, F., Kronenberg, M. F., Kiechl, S., Trenkwalder, E., Santer, P.,
Oberhollenzer, F., Willeit, J. (1999). Role of lipoprotein(a) and
apolipoprotein(a) phenotype in atherogenesis. Prospective Results From
the Bruneck Study,100(11), 11541160.
Kronenberg, F., & Utermann, G. (2013). Lipoprotein (a): Resurrected by
genetics. Journal of Internal Medicine,273(1), 630.
Ladenson, P. W., Kristensen, J. D., Ridgway, E. C., Olsson, A. G., Carlsson,
B., Klein, I., Angelin, B. (2010). Use of the thyroid hormone analogue
eprotirome in statintreated dyslipidemia. New England Journal of
Medicine,362(10), 906916.
Langhi,C.,LeMay,C.,Kourimate,S.,Caron,S.,Staels,B.,Krempf,M.,
Cariou, B. (2008). Activation of the farnesoid X receptor represses
PCSK9 expression in human hepatocytes. FEBS Letters,582(6), 949955.
Lanktree, M. B., Anand, S. S., Yusuf, S., & Hegele, R. A. (2010).
Comprehensive analysis of genomic variation in the LPA locus and
its relationship to plasma lipoprotein (a) in South Asians, Chinese, and
European Caucasians. Circulation. Cardiovascular Genetics,3(1), 3946.
LaRusso, N. F., Hoffman, N. E., Hofmann, A. F., Northfield, T. C., & Thistle,
J. L. (1975). Effect of primary bile acid ingestion on bile acid
metabolism and biliary lipid secretion in gallstone patients. Gastro-
enterology,69(6), 13011314.
Leebmann, J., Roeseler, E., Julius, U., Heigl, F., Spitthoever, R., Heutling, D.,
Klingel, R. (2013). Lipoprotein apheresis in patients with maximally
tolerated lipidlowering therapy, lipoprotein(a)hyperlipoproteinemia,
and progressive cardiovascular disease: Prospective observational
multicenter study. Circulation,128(24), 25672576.
Lelli, D., Sahebkar, A., Johnston, T. P., & Pedone, C. (2017). Curcumin use
in pulmonary diseases: State of the art and future perspectives.
Pharmacological Research,115, 133148.
Lichtenstein, A. H., Ausman, L. M., Carrasco, W., Jenner, J. L., Gualtieri, L.
J., Goldin, B. R., Schaefer, E. J. (1993). Effects of canola, corn, and
olive oils on fasting and postprandial plasma lipoproteins in humans as
part of a National Cholesterol Education Program Step 2 diet.
Arteriosclerosis, Thrombosis, and Vascular Biology,13(10), 15331542.
Lippi, G., Franchini, M., & Targher, G. (2011). Screening and therapeutic
management of lipoprotein (a) excess: Review of the epidemiological
evidence, guidelines and recommendations. Clinica Chimica Acta,
412(11), 797801.
Lippi, G., & Targher, G. (2012). Optimal therapy for reduction of
lipoprotein (a). Journal of Clinical Pharmacy and Therapeutics,37(1),
13.
Lippi, G., Targher, G., & Guidi, G. C. (2007). Ginkgo biloba, inflammation and
lipoprotein(a). Atherosclerosis,195(2), 417418.
Liu, J., Zhang, J., Shi, Y., Grimsgaard, S., Alraek, T., & Fønnebø, V. (2006).
Chinese red yeast rice (Monascus purpureus) for primary hyperlipide-
mia: A metaanalysis of randomized controlled trials. Chinese Medicine,
1(1), 1.
Liu, L., Zhao, S.P., Cheng, Y.C., & Li, Y.L. (2003). Xuezhikang decreases
serum lipoprotein (a) and Creactive protein concentrations in
patients with coronary heart disease. Clinical Chemistry,49(8),
13471352.
Loots, D., Oosthuizen, W., Pieters, M., Spies, C., & Vorster, H. H. (2004).
Foodstate vitamin C complex may beneficially affect haemostasis and
fibrin network structure in hyperlipidaemic patients. Blood Coagulation
and Fibrinolysis,15(8), 677685.
Lu, Z., Kou, W., Du, B., Wu, Y., Zhao, S., Brusco, O. A., Capuzzi, D. M.,
Group CCSPS (2008). Effect of Xuezhikang, an extract from red yeast
Chinese rice, on coronary events in a Chinese population with
previous myocardial infarction. The American Journal of Cardiology,
101(12), 16891693.
Lucas, E. A., Wild, R. D., Hammond, L. J., Khalil, D. A., Juma, S., Daggy, B. P.,
Arjmandi, B. H. (2002). Flaxseed improves lipid profile without
altering biomarkers of bone metabolism in postmenopausal women.
The Journal of Clinical Endocrinology and Metabolism,87(4), 15271532.
Marcovina, S. M., Albers, J. J., Wijsman, E., Zhang, Z., Chapman, N., &
Kennedy, H. (1996). Differences in Lp [a] concentrations and apo [a]
polymorphs between black and white Americans. Journal of Lipid
Research,37(12), 25692585.
Marcovina, S. M., Koschinsky, M. L., Albers, J. J., & Skarlatos, S. (2003).
Report of the national heart, lung, and blood institute workshop on
lipoprotein (a) and cardiovascular disease: Recent advances and
future directions. Clinical Chemistry,49(11), 17851796.
Mellwig, K. P., Schatton, C., Biermann, B., Kottmann, T., Horstkotte, D., &
van Buuren, F. (2015). Lipoprotein(a): Influence on cardiovascular
manifestation. Clinical Research in Cardiology Supplements,10,3338.
Menéndez, R., Amor, A. M., Rodeiro, I., González, R. M., González, P. C.,
Alfonso, J. L., & Más, R. (2001). Policosanol modulates HMGCoA
MOMTAZIBOROJENI ET AL.
|
11
reductase activity in cultured fibroblasts. Archives of Medical Research,
32(1), 812.
Merki, E., Graham, M., Taleb, A., Leibundgut, G., Yang, X., Miller, E. R.,
Tsimikas, S. (2011). Antisense oligonucleotide lowers plasma levels of
apolipoprotein (a) and lipoprotein (a) in transgenic mice. Journal of the
American College of Cardiology,57(15), 16111621.
MerzDemlow, B. E., Duncan, A. M., Wangen, K. E., Xu, X., Carr, T. P.,
Phipps, W. R., & Kurzer, M. S. (2000). Soy isoflavones improve plasma
lipids in normocholesterolemic, premenopausal women. The American
Journal of Clinical Nutrition,71(6), 14621469.
Miller, N. E., & Nestel, P. J. (1974). Triglyceridelowering effect of
chenodeoxycholic acid in patients with endogenous hypertriglycer-
idaemia. The Lancet,304(7886), 929931.
Mirzaei, H., Shakeri, A., Rashidi, B., Jalili, A., Banikazemi, Z., & Sahebkar A.
2017. Phytosomal curcumin: A review of pharmacokinetic, experi-
mental and clinical studies. Biomedicine and Pharmacotherapy,85,
102112.
Mohammadi, A., Sahebkar, A., Iranshahi, M., Amini, M., Khojasteh, R.,
GhayourMobarhan, M., & Ferns, G. A. (2013a). Effects of supple-
mentation with curcuminoids on dyslipidemia in obese patients: A
randomized crossover trial. Phytotherapy Research,27(3), 374379.
Momtazi, A. A., Derosa, G., Maffioli, P., Banach, M., & Sahebkar, A. (2016).
Role of microRNAs in the therapeutic effects of curcumin in non
cancer diseases. Molecular diagnosis & therapy,20(4), 335345.
Momtazi, A. A., & Sahebkar, A. (2016). Difluorinated curcumin: A
promising curcumin analogue with improved antitumor activity and
pharmacokinetic profile. Current Pharmaceutical Design,22,
43864397.
Momtazi, A. A., Shahabipour, F., Khatibi, S., Johnston, T. P., Pirro, M., &
Sahebkar, A. (2016). Curcumin as a microRNA regulator in cancer: A
review. Reviews of Physiology, Biochemistry and Pharmacology,171,
138.
Moriceau, S., Besson, C., Levrat, M.A., Moundras, C., Rémésy, C., Morand,
C., & Demigné, C. (2000). Cholesterollowering effects of guar gum:
Changes in bile acid pools and intestinal reabsorption. Lipids,35(4),
437444.
Mozaffarian, D., Ascherio, A., Hu, F. B., Stampfer, M. J., Willett, W. C.,
Siscovick, D. S., & Rimm, E. B. (2005). Interplay between different
polyunsaturated fatty acids and risk of coronary heart disease in men.
Circulation,111(2), 157164.
Nicholls, S. J., Tang, W. H. W., Scoffone, H., Brennan, D. M., Hartiala, J.,
Allayee, H., & Hazen, S. L. (2010). Lipoprotein (a) levels and longterm
cardiovascular risk in the contemporary era of statin therapy. Journal
of Lipid Research,51(10), 30553061.
Nielsen, L. B. (1999). Atherogenecity of lipoprotein (a) and oxidized low
density lipoprotein: Insight from in vivo studies of arterial wall influx,
degradation and efflux. Atherosclerosis,143(2), 229243.
Nigon, F., SerfatyLacrosnière, C., Beucler, I., Chauvois, D., Neveu, C., Giral,
P., Bruckert, E. (2001). Plant sterolenriched margarine lowers
plasma LDL in hyperlipidemic subjects with low cholesterol intake:
Effect of fibrate treatment. Clinical Chemistry and Laboratory Medicine,
39(7), 634640.
Nilsson, L.M., Abrahamsson, A., Sahlin, S., Gustafsson, U., Angelin, B.,
Parini, P., & Einarsson, C. (2007). Bile acids and lipoprotein
metabolism: Effects of cholestyramine and chenodeoxycholic acid
on human hepatic mRNA expression. Biochemical and Biophysical
Research Communications,357(3), 707711.
Nordestgaard, B. G., Chapman, M. J., Ray, K., Borén, J., Andreotti, F.,
Watts, G. F., TybjærgHansen, A. (2010). Lipoprotein (a) as a
cardiovascular risk factor: Current status. European Heart Journal,31,
ehq386ehq2853.
Panahi, Y., Badeli, R., Karami, G. R., & Sahebkar, A. (2015). Investigation of
the efficacy of adjunctive therapy with bioavailabilityboosted
curcuminoids in major depressive disorder. Phytotherapy research:
PTR,29(1), 1721.
Panahi, Y., Hosseini, M. S., Khalili, N., Naimi, E., Majeed, M., & Sahebkar, A.
(2015). Antioxidant and antiinflammatory effects of curcuminoid
piperine combination in subjects with metabolic syndrome: A
randomized controlled trial and an updated metaanalysis. Clinical
Nutrition,34(6), 11011108.
Panahi, Y., Khalili, N., Hosseini, M. S., Abbasinazari, M., & Sahebkar, A.
(2014a). Lipidmodifying effects of adjunctive therapy with curcumi-
noidspiperine combination in patients with metabolic syndrome:
Results of a randomized controlled trial. Complementary Therapies in
Medicine,22(5), 851857.
Panahi, Y., Khalili, N., Hosseini, M. S., Abbasinazari, M., & Sahebkar, A.
(2014b). Lipidmodifying effects of adjunctive therapy with curcumi-
noidspiperine combination in patients with metabolic syndrome:
Results of a randomized controlled trial. Complementary Therapies in
Medicine,22(5), 851857.
Panahi, Y., Kianpour, P., Mohtashami, R., Jafari, R., SimentalMendía, L. E.,
& Sahebkar, A. (2016). Curcumin lowers serum lipids and uric acid in
subjects with nonalcoholic fatty liver disease: A randomized con-
trolled trial. Journal of Cardiovascular Pharmacology,68(3), 223229.
Parizadeh, S. M. R., Azarpazhooh, M. R., Moohebati, M., Nematy, M.,
GhayourMobarhan, M., Tavallaie, S., Ferns, G. A. A. (2011).
Simvastatin therapy reduces prooxidantantioxidant balance: Results
of a placebocontrolled crossover trial. Lipids,46(4), 333340.
Park, Y. M., Won, J. H., Yun, K. J., Ryu, J. H., Han, Y. N., Choi, S. K., & Lee, K.
T. (2006). Preventive effect of Ginkgo biloba extract (GBB) on the
lipopolysaccharideinduced expressions of inducible nitric oxide
synthase and cyclooxygenase2 via suppression of nuclear factor
kappaB in RAW 264.7 cells. Biological and Pharmaceutical Bulletin,
29(5), 985990.
Penson, P., Serban, M.C., Ursoniu, S., Banach, M., & Lipid and Blood
Pressure Metaanalysis Collaboration (LBPMC) Group (2018). Does
coffee consumption alter plasma lipoprotein (A) concentrations? A
systematic review. Critical Reviews in Food Science and Nutrition,
58(10), 17061714.
Pereira, M. A., OReilly, E., Augustsson, K., Fraser, G. E., Goldbourt, U.,
Heitmann, B. L., Ascherio, A. (2004). Dietary fiber and risk of
coronary heart disease: A pooled analysis of cohort studies. Archives of
Internal Medicine,164(4), 370376.
Perona, J. S., Fitó, M., Covas, M.I., Garcia, M., & RuizGutierrez, V. (2011).
Olive oil phenols modulate the triacylglycerol molecular species of
human very lowdensity lipoprotein. A randomized, crossover,
controlled trial. Metabolism: Clinical and Experimental,60(6), 893899.
Pirro, M., Bianconi, V., Paciullo, F., Mannarino, M. R., Bagaglia, F., & Sahebkar,
A. (2017). Lipoprotein(a) and inflammation: A dangerous duet leading to
endothelial loss of integrity. Pharmacological Research,119, 178187.
Pirro, M., Mannarino, M. R., Bianconi, V., SimentalMendía, L. E., Bagaglia,
F., Mannarino, E., & Sahebkar, A. (2016). The effects of a nutraceutical
combination on plasma lipids and glucose: A systematic review and
metaanalysis of randomized controlled trials. Pharmacological Re-
search,110,7688.
Pirro, M., Mannarino, M. R., Ministrini, S., Fallarino, F., Lupattelli, G.,
Bianconi, V., Mannarino, E. (2016). Effects of a nutraceutical
combination on lipids, inflammation and endothelial integrity in
patients with subclinical inflammation: A randomized clinical trial.
Scientific Reports,6, 23587.
Pirro, M., Vetrani, C., Bianchi, C., Mannarino, M. R., Bernini, F., & Rivellese,
A. A. (2017). Joint position statement on "Nutraceuticals for the
treatment of hypercholesterolemia" of the Italian Society of Diabe-
tology (SID) and of the Italian Society for the Study of Arteriosclerosis
(SISA). Nutrition, Metabolism, and Cardiovascular Diseases,27(1), 217.
PérezAguilar, F., Bretó, M., Alegre, B., & Berenguer, J. (1985). Increase in
serum total cholesterol and lowdensity lipoprotein cholesterol by
highdose chenodeoxycholic acid in patients with radiolucent gall-
stones significantly reversed during preventive low dose after
gallstone dissolution. Digestion,31(4), 225233.
12
|
MOMTAZIBOROJENI ET AL.
Quí
lez, J., Rafecas, M., Brufau, G., Garcí
aLorda, P., Megí
as, I., Bulló, M.,
SalasSalvadó, J. (2003). Bakery products enriched with phytosterol
esters, αtocopherol and βcarotene decrease plasma LDLcholesterol
and maintain plasma βcarotene concentrations in normocholester-
olemic men and women. The Journal of Nutrition,133(10), 31033109.
Raal, F. J., Santos, R. D., Blom, D. J., Marais, A. D., Charng, M.J., Cromwell,
W. C., Crooke, S. T. (2010). Mipomersen, an apolipoprotein B
synthesis inhibitor, for lowering of LDL cholesterol concentrations in
patients with homozygous familial hypercholesterolaemia: A rando-
mised, doubleblind, placebocontrolled trial. The Lancet,375(9719),
9981006.
Rajasekar, P., & Anuradha, C. V. (2007). LCarnitine inhibits protein
glycation in vitro and in vivo: Evidence for a role in diabetic
management. Acta Diabetologica,44(2), 8390.
Ramharack, R., Barkalow, D., & Spahr, M. A. (1998). Dominant negative
effect of TGFbeta1 and TNFalpha on basal and IL6induced
lipoprotein(a) and apolipoprotein(a) mRNA expression in primary
monkey hepatocyte cultures. Arteriosclerosis, Thrombosis, and Vascular
Biology,18(6), 984990.
Reiner, Ž., TedeschiReiner, E., & Romić,Ž. (2005). Effects of rice
policosanol on serum lipoproteins, homocysteine, fibrinogen and C
reactive protein in hypercholesterolaemic patients. Clinical Drug
Investigation,25(11), 701707.
Rezaee, R., Momtazi , A. A., Johnston , T. P., & Sahebkar , A. (2016).
Curcumin: a potentially powerful tool to reverse cisplatininduced
toxicity. Pharmacological research,117, 218227.
Rodriguez, R., Jimenez, A., FernándezBolaños, J., Guillén, R., & Heredia, A.
(2006). Dietary fibre from vegetable products as source of functional
ingredients. Trends in Food Science & Technology,17(1), 315.
RodriguezLeyva, D., Bassett, C. M. C., McCullough, R., & Pierce, G. N.
(2010). The cardiovascular effects of flaxseed and its omega3 fatty
acid, alphalinolenic acid. Canadian Journal of Cardiology,26(9),
489496.
Rodríguez, M., Ringstad, L., Schäfer, P., Just, S., Hofer, H. W., Malmsten,
M., & Siegel, G. (2007). Reduction of atherosclerotic nanoplaque
formation and size by Ginkgo biloba (EGb 761) in cardiovascular high
risk patients. Atherosclerosis,192(2), 438444.
Ronksley, P. E., Brien, S. E., Turner, B. J., Mukamal, K. J., & Ghali, W. A.
(2011). Association of alcohol consumption with selected cardiovas-
cular disease outcomes: A systematic review and metaanalysis. BMJ,
342, d671d671.
RyszGórzynska, M., GlubaBrzózka, A., Sahebkar, A., Serban, M. C.,
Mikhailidis, D. P., Ursoniu, S., Banach, M. (2016). Efficacy of statin
therapy in pulmonary arterial. Scientific Reports,6, 30060.
Sacks, F. M., Lichtenstein, A., Van Horn, L., Harris, W., KrisEtherton, P., &
Winston, M., Committee AHAN (2006). Soy protein, isoflavones, and
cardiovascular health an American Heart Association science advisory
for professionals from the nutrition committee. Circulation,113(7),
10341044.
Sahebkar, A. (2014). Lowdensity lipoprotein is a potential target for
curcumin: Novel mechanistic insights. Basic and Clinical Pharmacology
and Toxicology,114(6), 437438.
Sahebkar, A., Catena, C., Ray, K., VallejoVaz, A., Reiner, Ž., Sechi, L., &
Colussi, G. (2016). Impact of statin therapy on plasma levels of
plasminogen activator inhibitor1. A systematic review and meta
analysis of randomised controlled trials. Thrombosis and Haemostasis,
116(1), 162171.
Sahebkar, A., Cicero, A. F. G., Simental-Mendía, L. E., Aggarwal, B. B., &
Gupta, S. C. (2016). Curcumin downregulates human tumor necrosis
factor-αlevels: A systematic review and meta-analysis of randomized
controlled trials. Pharmacological Research,107, 234242.
Sahebkar, A., & Henrotin, Y. (2016). Analgesic efficacy and safety of
curcuminoids in clinical practice: A systematic review and meta
analysis of randomized controlled trials. Pain Medicine,17(6),
11921202.
Sahebkar, A., Kotani, K., Serban, C., Ursoniu, S., Mikhailidis, D. P., Jones, S.
R., Banach, M. (2015). Statin therapy reduces plasma endothelin1
concentrations: A metaanalysis of 15 randomized controlled trials.
Atherosclerosis,241(2), 433442.
Sahebkar, A., Pećin, I., TedeschiReiner, E., Derosa, G., Maffioli, P., &
Reiner, Ž. (2016). Effects of statin therapy on augmentation index as a
measure of arterial stiffness: A systematic review and metaanalysis.
International Journal of Cardiology,212, 160168.
Sahebkar, A., Ponziani, M. C., Goitre, I., & Bo, S. (2015). Does statin
therapy reduce plasma VEGF levels in humans? A systematic review
and metaanalysis of randomized controlled trials. Metabolism: Clinical
and Experimental,64(11), 14661476.
Sahebkar, A., Rathouska, J., Derosa, G., Maffioli, P., & Nachtigal, P. (2016).
Statin impact on disease activity and Creactive protein concentra-
tions in systemic lupus erythematosus patients: A systematic review
and metaanalysis of controlled trials. Autoimmunity Reviews,15(4),
344353.
Sahebkar, A., Serban, C., Mikhailidis, D. P., Undas, A., Lip, G. Y. H.,
Muntner, P., Banach, M. (2015). Association between statin use and
plasma ddimer levels: A systematic review and metaanalysis of
randomised controlled trials. Thrombosis and Haemostasis,114(3),
546557.
Sahebkar, A., Serban, C., Ursoniu, S., Mikhailidis, D. P., Undas, A., Lip, G. Y.
H., Banach, M. (2016). The impact of statin therapy on plasma levels
of von Willebrand factor antigen. Systematic review and meta
analysis of randomised placebocontrolled trials. Thrombosis and
Haemostasis,115(3), 520532.
Sahebkar, A., Serban, M. C., Ursoniu, S., & Banach, M. (2015). Effect of
curcuminoids on oxidative stress: A systematic review and meta
analysis of randomized controlled trials. Journal of Functional Foods,
18, 898909.
Sahebkar, A., SimentalMendía, L. E., Stefanutti, C., & Pirro, M. (2016).
Supplementation with coenzyme Q10 reduces plasma lipoprotein(a)
concentrations but not other lipid indices: A systematic review and
metaanalysis. Pharmacological Research,105, 198209.
Sahebkar, A., SimentalMendía, L. E., Watts, G. F., Serban, M. C., & Banach,
M. (2017). Comparison of the effects of fibrates versus statins on
plasma lipoprotein(a) concentrations: A systematic review and meta
analysis of headtohead randomized controlled trials. BMC Medicine,
15(1), 22.
Sahebkar, A., & Watts, G. F. (2013). New therapies targeting apoB
metabolism for high-risk patients with inherited dyslipidaemias: What
can the clinician expect? Cardiovascular Drugs and Therapy,27(6),
559567.
Samaha, F. F., McKenney, J., Bloedon, L. T., Sasiela, W. J., & Rader, D. J.
(2008). Inhibition of microsomal triglyceride transfer protein alone or
with ezetimibe in patients with moderate hypercholesterolemia.
Nature Clinical Practice Cardiovascular Medicine,5(8), 497505.
Sandholzer, C., Hallman, D., Saha, N., Sigurdsson, G., Lackner, C., Csaszar,
A., Utermann, G. (1991). Effects of the apolipoprotein (a) size
polymorphism on the lipoprotein (a) concentration in 7 ethnic groups.
Human Genetics,86(6), 607614.
Schäfer, P., Rodríguez, M., Just, S., Ullrich, T., Winkler, K., Knes, O.,
Siegel, G. (2006). The effect of Ginkgo biloba (EGb 761) on
arteriosclerotic nanoplaque formation and size in a longterm clinical
trial. Desalination,191(13), 426431.
Serban, C., Sahebkar, A., Ursoniu, S., Mikhailidis, D. P., Rizzo, M., Lip, G. Y.
H., Banach, M. (2015). A systematic review and metaanalysis of the
effect of statins on plasma asymmetric dimethylarginine concentra-
tions. Scientific Reports,5, 9902.
Serban,M.C.,Sahebkar,A.,Mikhailidis,D.P.,Toth,P.P.,Jones,S.R.,
Muntner, P., Banach,M.(2016).ImpactofLcarnitine on plasma
lipoprotein(a) concentrations: A systematic review and meta
analysis of randomized controlled trials. Scientific Reports,6,
19188.
MOMTAZIBOROJENI ET AL.
|
13
Sevov, M., Elfineh, L., & Cavelier, L. B. (2006). Resveratrol regulates the
expression of LXRαin human macrophages. Biochemical and
Biophysical Research Communications,348(3), 10471054.
Siekmeier, R., Scharnagl, H., Kostner, G., Grammer, T., Stojakovic, T., &
März, W. (2010). Variation of Lp (a) plasma concentrations in health
and disease. The Open Clinical Chemistry. The Journal,3,7289.
Singh, D. K., Li, L., & Porter, T. D. (2006). Policosanol inhibits cholesterol
synthesis in hepatoma cells by activation of AMPkinase. Journal of
Pharmacology and Experimental Therapeutics,318(3), 10201026.
Soni, K. B., & Kuttan, R. (1992). Effect of oral curcumin administration on
serum peroxides and cholesterol levels in human volunteers. Indian
Journal of Physiology and Pharmacology,36, 273273.
Stein, E. A., Davidson, M. H., Dujovne, C. A., Hunninghake, D. B., Goldberg,
R. B., Illingworth, D. R., Tobert, J. A. (1996). Efficacy and tolerability
of lowdose simvastatin and niacin, alone and in combination, in
patients with combined hyperlipidemia: A prospective trial. Journal of
Cardiovascular Pharmacology and Therapeutics,1(2), 107116.
Strimpakos, A. S., & Sharma, R. A. (2008). Curcumin: Preventive and
therapeutic properties in laboratory studies and clinical trials.
Antioxidants and Redox Signaling,10(3), 511546.
Tabibi, H., Imani, H., Atabak, S., Najafi, I., Hedayati, M., & Rahmani, L.
(2016). Effects of ginger on serum lipids and lipoproteins in peritoneal
dialysis patients: A randomized controlled trial. Peritoneal Dialysis
International,36(2), 140145.
Thompson, G. R., HEARTUK LDL Apheresis Working Group (2008).
Recommendations for the use of LDL apheresis. Atherosclerosis,
198(2), 247255.
Trimarco, B., Benvenuti, C., Rozza, F., Cimmino, C. S., Giudice, R., & Crispo,
S. (2011). Clinical evidence of efficacy of red yeast rice and berberine
in a large controlled study versus diet. Mediterranean Journal of
Nutrition and Metabolism,4(2), 133139.
Tsimikas, S. (2017). A test in context: Lipoprotein(a): Diagnosis, prognosis,
controversies, and emerging therapies. Journal of the American College
of Cardiology,69(6), 692711.
Tsimikas, S., Brilakis, E. S., Miller, E. R., McConnell, J. P., Lennon, R. J.,
Kornman, K. S., Berger, P. B. (2005). Oxidized phospholipids, Lp(a)
lipoprotein, and coronary artery disease. The New England Journal of
Medicine,353(1), 4657.
Tsimikas, S., Tsironis, L. D., & Tselepis, A. D. (2007). New insights into the
role of lipoprotein (a)associated lipoproteinassociated phospholi-
pase A2 in atherosclerosis and cardiovascular disease. Arteriosclerosis,
Thrombosis, and Vascular Biology,27(10), 20942099.
Tsimikas, S., Viney, N. J., Hughes, S. G., Singleton, W., Graham, M. J., Baker,
B. F., Witztum, J. L. (2015). Antisense therapy targeting
apolipoprotein (a): A randomised, doubleblind, placebocontrolled
phase 1 study. The Lancet,386(10002), 14721483.
Turhan, N. O., Duvan, C. I., Bolkan, F., & Onaran, Y. (2009). Effect of
isoflavone on plasma nitrite/nitrate, homocysteine, and lipid levels in
Turkish women in the early postmenopausal period: A randomized
controlled trial. Turkish Journal of Medical Sciences,39(3), 367375.
Urgert, R., & Katan, M. B. (1997). The cholesterolraising factor from
coffee beans. Annual Review of Nutrition,17, 305324.
Urgert, R., Van der weg, G., Kosmeijerschuil, T. G., Van de bovenkamp, P.,
Hovenier, R., & Katan, M. B. (1995). Levels of the cholesterolelevating
diterpenes cafestol and kahweol in various coffee brews. Journal of
Agricultural and Food Chemistry,43(8), 21672172.
Vanharanta, M., Voutilainen, S., Lakka, T. A., van der Lee, M., Adlercreutz,
H., & Salonen, J. T. (1999). Risk of acute coronary events according to
serum concentrations of enterolactone: A prospective population
based casecontrol study. The Lancet,354(9196), 21122115.
Vanharanta, M., Voutilainen, S., Nurmi, T., Kaikkonen, J., Roberts, L. J.,
Morrow, J. D., Salonen, J. T. (2002). Association between low serum
enterolactone and increased plasma F2isoprostanes, a measure of
lipid peroxidation. Atherosclerosis,160(2), 465469.
Veldman, F. J., Nair, C. H., Vorster, H. H., Vermaak, W. J. H., Jerling, J. C.,
Oosthuizen, W., & Venter, C. S. (1999). Possible mechanisms through
which dietary pectin influences fibrin network architecture in
hypercholesterolaemic subjects. Thrombosis Research,93(6), 253264.
Venkatesan, N., Devaraj, S. N., & Devaraj, H. (2007). A fibre cocktail of
fenugreek, guar gum and wheat bran reduces oxidative modification
of LDL induced by an atherogenic diet in rats. Molecular and Cellular
Biochemistry,294(12), 145153.
Venkatesan, N., Niranjali devaraj, S., & Devaraj, H. (2003). Increased
binding of LDL and VLDL to apo B, E receptors of hepatic plasma
membrane of rats treated with fibernat. European Journal of Nutrition,
42(5), 262271.
VergaraJimenez, M., Conde, K., Erickson, S. K., & Fernandez, M. L. (1998).
Hypolipidemic mechanisms of pectin and psyllium in guinea pigs fed
high fatsucrose diets: Alterations on hepatic cholesterol metabolism.
Journal of Lipid Research,39(7), 14551465.
VergaraJimenez, M., Furr, H., & Fernandez, M. L. (1999). Pectin and
psyllium decrease the susceptibility of LDL to oxidation in guinea pigs.
The Journal of Nutritional Biochemistry,10(2), 118124.
Vigne, J. L., Lairon, D., Borel, P., Portugal, H., Pauli, A.M., Hauton, J. C., &
Lafont, H. (1987). Effect of pectin, wheat bran and cellulose on serum
lipids and lipoproteins in rats fed on a lowor highfat diet. British
Journal of Nutrition,58(03), 405413.
ViudaMartos, M., LópezMarcos, M. C., FernándezLópez, J., Sendra, E.,
LópezVargas, J. H., & PérezÁlvarez, J. A. (2010). Role of fiber in
cardiovascular diseases: A review. Comprehensive Reviews in Food
Science and Food Safety,9(2), 240258.
Vongpromek, R., Bos, S., Ten kate, G. J. R., Yahya, R., Verhoeven, A. J. M.,
De feyter, P. J., Mulder, M. T. (2015). Lipoprotein (a) levels are
associated with aortic valve calcification in asymptomatic patients
with familial hypercholesterolaemia. Journal of Internal Medicine,
278(2), 166173.
Weustenvanderwouw, M., Katan, M. B., Viani, R., Huggett, A. C., Liardon,
R., Lundlarsen, P. G., Beynen, A. C. (1994). Identity of the
cholesterolraising factor from boiled coffee and its effects on liver
function enzymes. Journal of Lipid Research,35(4), 721733.
Williams, L. (2002). Third report of the National Cholesterol Education
Program (NCEP) expert panel on detection, evaluation, and treatment
of high blood cholesterol in adults (Adult Treatment Panel III) final
report. Circulation,106(25), 3143.
Wu, H., Dwyer, K. M., Fan, Z., Shircore, A., Fan, J., & Dwyer, J. H. (2003).
Dietary fiber and progression of atherosclerosis: The Los Angeles
Atherosclerosis Study. The American Journal of Clinical Nutrition,78(6),
10851091.
Yadav, R., France, M., Younis, N., Hama, S., Ammori, B. J., Kwok, S., &
Soran, H. (2012). Extendedrelease niacin with laropiprant: A review
on efficacy, clinical effectiveness and safety. Expert Opinion on
Pharmacotherapy,13(9), 13451362.
Yeang, C., Hung, M. Y., Byun, Y. S., Clopton, P., Yang, X., Witztum, J. L., &
Tsimikas, S. (2016). Effect of therapeutic interventions on oxidized
phospholipids on apolipoprotein B100 and lipoprotein(a). Journal of
Clinical Lipidology,10(3), 594603.
Yoshikawa, T., Naito, Y., & Kondo, M. (1999). Ginkgo biloba leaf extract:
Review of biological actions and clinical applications. Antioxidants and
Redox Signaling,1(4), 469480.
How to cite this article: MomtaziBorojeni AA, Katsiki N,
Pirro M, Banach M, Rasadi KA, Sahebkar A. Dietary natural
products as emerging lipoprotein(a)lowering agents. J Cell
Physiol. 2019;114. https://doi.org/10.1002/jcp.28134
14
|
MOMTAZIBOROJENI ET AL.
... At present, drugs used to reduce the level of blood lipids mainly include statins (atorvastatin, lovastatin, etc.), fibrates (bezafibrate, lifibrate, etc.), and resin (cholestyramine, colestipol, etc.). Nevertheless, these synthetic medicines are often associated with some serious side effects such as diarrhea, nausea, gallstones, myositis, and abnormal liver function [5][6][7]. Therefore, it is urgent to discover new lipid-lowering agents with more therapeutic value and less tolerable side effects from natural products. ...
... Compound 6 was indicated to be Rconfiguration at C-13, and its optical rotation was ([α] 25 D +2.6 (c 0.10, MeOH)), compared with compound 5 ([α] 25 D +4.0 (c 0.10, MeOH)). Thus, the structure of 6 was identified to be (R)-11-hydroxy-11-(o-tolyl) undecanoic acid (6). ...
... Compound 6 was indicated to be R-configuration at C-13, and its optical rotation was ([α] 25 D +2.6 (c 0.10, MeOH)), compared with compound 5 ([α] 25 D +4.0 (c 0.10, MeOH)). Thus, the structure of 6 was identified to be (R)-11-hydroxy-11-(o-tolyl) undecanoic acid (6). ...
Article
Full-text available
Six new aromatic acids (1–6) and three new leucine derivatives containing an unusual oxime moiety (7–9) were isolated and identified from the deep-sea-derived actinomycetes strain Streptomyces chumphonensis SCSIO15079, together with two known compounds (10–11). The structures of 1–9 including absolute configurations were determined by detailed NMR, MS, and experimental and calculated electronic circular dichroism spectroscopic analyses. Compounds 1–9 were evaluated for their antimicrobial and cytotoxicity activities, as well as their effects on intracellular lipid accumulation in HepG2 cells. Compounds 3 and 4, with the most potent inhibitory activity on intracellular lipid accumulation at 10 μM, were revealed with potential antihyperlipidemic effects, although the mechanism needs to be further studied.
... 25 In addition, phenolic compounds in terms of their inhibitory effects on inflammatory cytokines like interleukin 6 can reduce Lp(a) gene expression. 26 Therefore, the internal septum of walnut may be used alone or in combination with other lipid-lowering drugs to prevent primary and secondary ...
Article
Introduction: Dyslipidemia and diabetes mellitus are two important risk factors for coronary artery disease and stroke. Traditionally, herbal remedies like walnut were used to treat dyslipidemia. The study aimed to evaluate the effect of Juglans regia L. (J. regia L.) internal septum extract (ISE) on lipid profile of patients with type 2 diabetes. Methods: After preparing hydroalcoholic ISE, Folin-Ciocalteau (FC) and AlCl3 colorimetric methods were used to determine total phenolic content (TPC) and total flavonoid content (TFC), respectively. In a randomized, double-blind placebo-controlled trial, 86 diabetic patients with dyslipidemia were randomly divided into equal groups and received ISE or placebo capsules 1500 mg/day for 12 weeks. Lipid profile, LFT, SCr, urea, hemoglobin A1c (HbA1c), blood pressure (BP), weight, waist and waist to hip ratio (WHR) were determined at baseline and after 12 weeks. The paired sample t-test and independent sample t-test were performed to compare the differences within and among the groups, respectively. This study was registered in the Iranian registry of clinical trials (IRCT ID: IRCT20201227049850N1). Results: The Mean (SD) of TPC and TFC were measured based on 74.57 (5.20) milligram gallic acid equivalent/gram of dry extract (mg GAE/g DE) and 14.11 (2.73) mg quercetin equivalent/g of DE (mg QE/g DE), respectively. During the trial, 26 patients lost follow-up, and the study continued with remaining 60 patients. After intervention, there were no significant differences in LDL-C (p=0.44), total cholesterol (TC) (p=0.42), high-density lipoprotein cholesterol (HDL-C) (p=0.99), triglyceride (TG) (p =0.32) and Lp(a) (p=0.55) between two groups. Moreover, no significant (p>0.05) changes were observed in HbA1c, LFT, SCr, urea, BP, weight, waist, and WHR among the groups after 12 weeks. Conclusion: Our findings showed J. regia L. ISE had no significant effect on lipid profile compared to placebo. Moreover, no adverse effect was observed on liver and kidney function tests.
... Although an elevated Lp(a) level is independently associated with the incidence of cardiovascular events in the general BioMed Research International population and it is an established predictor of cardiovascular events in patients with ASCVD [55,56], the possibilities of decreasing elevated Lp(a) are still quite limited [57][58][59][60][61][62][63]. Unlike LDL-C and triglycerides, Lp(a) is relatively refractory to diet [64], lifestyle changes [65], and most drug interventions. ...
Article
Full-text available
Background: Obesity, especially severe obesity, is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. Bariatric surgery is a durable and effective weight loss therapy for patients with severe obesity and weight-related comorbidities. Elevated plasma levels of lipoprotein (a) (Lp(a)) are causally associated with ASCVD. The aim of this meta-analysis was to analyze whether bariatric surgery is associated with Lp(a) concentrations. Methods: A literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to May 1st, 2021. A random-effects model and the generic inverse variance weighting method were used to compensate for the heterogeneity of studies in terms of study design, treatment duration, and the characteristics of the studied populations. A random-effects metaregression model was used to explore the association with an estimated effect size. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias in the meta-analysis. Results: Meta-analysis of 13 studies including 1551 patients showed a significant decrease of circulating Lp(a) after bariatric surgery (SMD: -0.438, 95% CI: -0.702, -0.174, p < 0.001, I 2: 94.05%). The results of the metaregression did not indicate any significant association between the changes in Lp(a) and duration of follow-up after surgery, reduction in body mass index, or baseline Lp(a) concentration. The reduction in circulating Lp(a) was robust in the leave-one-out sensitivity analysis. Conclusion: Bariatric surgery significantly decreases circulating Lp(a) concentrations. This decrease may have a positive effect on ASCVD in obese patients.
... On the other hand, fibrates 95 , and most hormones (except growth hormone) 32,96 may reduce Lp(a) levels. Niacin 97 , mipomersen 98 , lomitapide 99 , proprotein convertase subtilisin kexin 9 (PCSK9) [100][101][102] and (cholesteryl transfer protein) CETP inhibitors 103 , aspirin 32 , antibodies to interleukin-6 32 , nutraceuticals [104][105][106][107] , tibolone 108 and ezetimibe 109 , also, decrease Lp(a) levels. Vitamin C 110 and bile acid sequestrants 111 have a neutral effect on plasma Lp(a) levels. ...
Article
Over the past few years, there has been an undiminished interest on lipoprotein(a) [Lp(a)]. High Lp(a) levels have been proposed as an independent causal risk factor for atherosclerotic cardiovascular disease (CVD). The main question that remains to be answered, however, is the potential clinical benefit of Lp(a) reduction. This will contribute to the enrichment of our knowledge on the exact pathophysiological role of this lipoprotein. This narrative review aims to summarize currently available data on the structure, metabolism, and pathogenicity of Lp(a).
... The deficiency of these nutrients in the body may increase the risk of developing a variety of conditions, including cardiovascular diseases [52,66]. Antioxidant supplementation has been extensively researched, but the findings remain inconclusive, especially in the case of vitamin E [13,67,68]. ...
Article
Full-text available
Dietary supplements are products containing nutrients sold in various medicinal forms, and their widespread use may stem from the conviction that a preparation that looks like a drug must have therapeutic properties. The aim of this scoping review is to present what is known about the effects of using selected dietary supplements in the context of chronic diseases, as well as the risks associated with their use. The literature shows that the taking of vitamin and mineral supplements by healthy people neither lowers their risk of cardiovascular diseases nor prevents the development of malignancies. Many scientific societies recognize that omega-3 fatty acids lower blood triglycerides, but whether taking them prevents heart disease is less clear-cut. Taking weight loss supplements is not an effective method of fighting obesity. Often, some supplements are increasingly sold illegally, which is then also associated with the higher risk that they may be adulterated with banned substances, thus making them even more dangerous and potentially life-threatening. Supplements are necessary in cases of nutrient deficiency; however, even though prescription is not required, their use should be recommended and monitored by a physician.
... Commonly, it has been known that dyslipidemia is associated with overproduction of many atherogenic lipoproteins as well as it lead to decrease the high density lipoproteins (HDL) and increases low density lipoproteins (LDL) [3]. Many compounds have been approved to be used in treatment or control dyslipidemia; natural agents are widely used for this prospect [4][5][6][7]. The target for these agents mainly is to reduce LDL and increase HDL. ...
Article
Full-text available
In the present study, we examined the synergetic effect of forskolin and mevastatin administration on lipid profile and lipid metabolism in omental adipose tissue in dyslipidemic rats. The study was conducted on forty male albino rats. The rats were randomly classified into four main groups of ten animals in each group as follows: group A, served as control nontreated; group B, rats that received Triton WR 1339 (500 mg/kg); group C, rats that received Triton WR 1339 with forskolin (100% FSK extract 0.5 mg/kg/day) for four weeks; and group D, dyslipidemic rats received both mevastatin and forskolin. At the end of the experimental period, blood and omental adipose tissue samples were collected, preserved, and used for biochemical determination of lipid profile and mRNA expression profile of adenylate cyclase (AC), hormone-sensitive lipase, respectively (HSL), and adenosine monophosphate-activated protein kinase (AMPK). The results showed a significant decline in the serum concentration of total cholesterol, LDL-cholesterol, and triglycerides, although there was a significant increase in serum levels of HDL-cholesterol and glycerol in rats received forskolin alone or with mevastatin when compared with control and dyslipidemic groups. The mRNA expression levels of AC, HSL, and AMPK were significantly increased in omental adipose tissue of rats received forskolin when compared with other groups. In conclusion, forskolin acts synergistically with mevastatin to lower lipid profile and improve lipid metabolism in dyslipidemic rats through upregulation of AMPK expression.
Article
Full-text available
Rejuvenation refers to the transition from an adult state to a juvenile state. Trunk truncation at the base of the tree can result in tree rejuvenation. However, little is known about the association of rejuvenation with leaf biomass and flavonoid accumulation. The results of this study showed that, compared with control leaves, leaves of renewed Ginkgo biloba shoots were larger, thicker, and more lobed and had higher fresh/dry weights and chlorophyll contents. The leaf biomass per hectare of rejuvenated trees was twofold higher than that of the untruncated controls. Moreover, we observed a marked increase in the accumulation of flavonol glycosides via metabolomic analysis and detected upregulated expression of genes involved in flavonoid biosynthesis, including CHS, FLS, F3’H, DFR, and LAR. Overexpression of GbCHS in ginkgo calli confirmed that GbCHS plays an important role in flavonoid biosynthesis. Interestingly, the contents of gibberellins significantly increased in the rejuvenated leaves. Moreover, exogenous gibberellin treatment significantly increased GbCHS expression and flavonoid contents. Our findings show that truncation can stimulate tree rejuvenation by altering hormone levels, representing an effective and feasible approach for enhancing the biomass and flavonoid content of G. biloba leaves.
Article
Full-text available
Myocarditis is an inflammatory disease of the myocardium that mostly affects young adults. The disease is commonly caused by viral infection, medications, autoimmune disorders, and inflammatory conditions. Nearly 50% of the cases of myocarditis are due to post-viral immune response in a setting of an identifiable or non-identifiable infection. The clinical manifestation is nonspecific ranging from asymptomatic courses to sudden death in infants and young patients. This review describes the properties of phytochemicals as plant-derived active ingredients which can be used in the prevention and treatment of myocarditis and its associated risk factors. Meanwhile, it has illustrated epidemiological analyses, mechanism of action, and the metabolism of phytochemicals in animal and human clinical trials. We also mentioned the precise mechanism of action by which phytochemicals elicit their anti-viral, anti-inflammatory, antioxidant, and immunomodulatory effects and how they regulate signal transduction pathways. Nevertheless, comprehensive clinical trials are required to study the properties of phytochemicals in vivo, in vitro, and in silico for a proper management of myocarditis. Our findings indicate that phytochemicals function as potent adjunctive therapeutic drugs in myocarditis and its related complications.
Article
Full-text available
Background and aims The increasing prevalence of diabetes mellitus is causing a massive growth of peripheral artery disease incidences, a disabling complication of diabetic atherosclerosis, which leads often to the amputation of the affected limb. Critical limb ischemia is the terminal disease stage, which requires a prompt intervention to relieve pain and save limbs. However, patients undergoing revascularization often suffer from cardiovascular, cerebrovascular and major adverse limb events with poor outcomes. Furthermore, the same procedure performed in apparently similar patients has various outcomes and lack of an outcome predictive support causes a high lower limb arterial revascularization rate with disastrous effects for patients. We collected the main risk factors of major adverse limb events in a more readable and immediate format of the topic, to propose an overview of parameters to manage effectively peripheral artery disease patients and to propose basics of a new predictive tool to prevent from disabling vascular complications of the disease. Methods Most recent and updated literature about the prevalence of major adverse limb events in peripheral artery disease was reviewed to identify possible main predictors. Results In this article, we summarized major risk factors of limb revascularization failure and disabling vascular complications collecting those parameters principally responsible for major adverse limb events, which provides physio-pathological explanation of their role in peripheral artery disease. Conclusion We evaluated and listed a panel of possible predictors of MALE (Major Adverse Limb Event) in order to contribute to the development of a predictive score, based on a summary of the main risk factors reported in scientific articles, which could improve the management of peripheral artery disease by preventing vascular accidents.
Article
Objective To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia, and preliminarily explore its lipid-lowering mechanism.MethodsA total of 90 early menopausal women with hypercholesterolemia were enrolled from December, 2014 to May, 2016 from Beijing Anzhen Hospital, Capital Medical University, who were randomly allocated to receive Xuezhikang (1200 mg/d, orally) or atorvastatin (10 mg/d, orally) according to a random number table. Serum levels of some related biomarkers, including cholesterol synthesis markers (squalene, dihydrocholesterol, dehydrocholesterol, and lathosterol), and absorption markers (campesterol, stigmasterol, and sitosterol) as well as safety indices were obtained at baseline and after 8 weeks of the intervention.ResultsEight weeks after treatment, both Xuezhikang and atorvastatin significantly reduced the levels of total cholesterol, triglycerides, low density cholesterol compared to baseline (all P<0.01). Xuezhikang significantly reduced the levels of squalene, dehydrocholesterol and lathosterol compared to baseline (all P<0.01), but atorvastatin only significantly reduced the level of squalene (P<0.01), compared to baseline. All cholesterol absorption markers showed no significant differences before and after treatment (P>0.05), however, a more obvious downward trend was shown in the Xuezhikang group. In addition, all the safety indices showed no significant differences between the two groups. Although the creatinekinase level in the Xuezhikang group was significantly higher, it remained within the safe range.Conclusions Xuezhikang may have more comprehensive effects on the markers of cholesterol synthesis and metabolism in early menopausal women with hypercholesterolemia through ergosterol and flavonoids in its “natural polypill.”
Article
Full-text available
Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10⁻³⁷), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10⁻¹²). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
Article
Full-text available
In recent years there has been a growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies nutraceuticals might help to obtain the theraputic lipid goals and reduce the cardiovascular residual risk. Some nutraceuticals have essential lipid lowering-properties confirmed in studies, some might have also possible positive effects on non-lipid cardiovascular risk factors and have proven to improve early markers of vascular health such as endothelial function and pulse wave velocity. However the clinical evidence supporting the use of single or a combination of lipid-lowering nutraceuticals is largely variable and for many of them very limitted and therefore often debatable. The purpose of this Position Paper is to provide consensus-based recommendations for optimal management of lipid-lowering nutraceuticals in patients with dyslipidemia still not being on statin therapy, on statin or combination therapy without lipid goals achieved, and for those with statin intolerance. This statement is intended for physicians and other health care professional that are engaged in the diagnosis and management of patients with lipid disorders, especially in the setting of primary care. Key words: dyslipidemia, lipid, nutraceuticals, position paper, recommendations.
Article
Full-text available
Evidence that elevated lipoprotein(a) (Lp[a]) levels contribute to cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) is substantial. Development of isoform-independent assays, in concert with genetic, epidemiological, translational, and pathophysiological insights, have established Lp(a) as an independent, genetic, and likely causal risk factor for CVD and CAVS. These observations are consistent across a broad spectrum of patients, risk factors, and concomitant therapies, including patients with low-density lipoprotein cholesterol <70 mg/dl. Statins tend to increase Lp(a) levels, possibly contributing to the “residual risk” noted in outcomes trials and at the bedside. Recently approved proprotein convertase subtilisin/kexin-type 9 inhibitors and mipomersen lower Lp(a) 20% to 30%, and emerging RNA-targeted therapies lower Lp(a) >80%. These approaches will allow testing of the “Lp(a) hypothesis” in clinical trials. This review summarizes the current landscape of Lp(a), discusses controversies, and reviews emerging therapies to reduce plasma Lp(a) levels to decrease risk of CVD and CAVS.
Article
Background: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. Methods and Results: In this multicenter, prospective, randomized trial, 180 patients with hyper cholesterolemia and hypertriglyceridernia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total. low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 248, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol ( P <.05). More patients discontinued treatment because of an adverse event in the niacin ( P <.03) and combination groups ( P =.06) than the simvastatin group. Conclusions: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration.
Article
Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran).
Article
Lipoprotein(a) Lp(a) is a cholesterol-rich, LDL-like particle that is independently associated with an increased risk for ischemic heart disease, atherosclerosis, thrombosis, and stroke. Genetic variation in the Lp(a) locus and some other genes related to Lp(a) synthesis and metabolism play a critical role in regulating plasma Lp(a) levels. The pathophysiological potential of Lp(a) is related to proatherogenic and prothrombotic effects on the vasculature. Different molecular mechanisms underlying the atherothrombotic potential of Lp(a), free apolipoprotein(a), and oxidized-Lp(a) have been proposed. However, plasma Lp(a) assay is complicated by problems associated with quantification and standardization owing to the polymorphic nature of this lipoprotein. This review has focused on the physicochemical properties of Lp(a), the genetic aspects of Lp(a), the need for accurate determination of Lp(a), the synthesis and recent findings on metabolism of Lp(a). Lastly, the patho-physiological mechanisms by which Lp(a) may increase athero-thrombosis and an overview on the therapeutic modalities to interfere with Lp(a) are summarized. This article is protected by copyright. All rights reserved.
Article
Purpose of the review. Statins reduce cholesterol synthesis and promote low-density lipoprotein clearance from circulation. Beyond their cholesterol-lowering action, statins may interfere with haemostasis. This review aims to provide an update on the impact of statin treatment on markers of haemostasis and platelet function and on thrombosis-related outcomes. Recent findings. Different coagulation factors are modulated by statins, leading to inhibition of coagulation and increased fibrinolysis. Also, an impact of statins on platelet function has been documented. From a clinical perspective, several observational studies have revealed a reduced incidence of venous thromboembolism (VTE) in patients receiving statins, which has been argued in some available studies and meta-analyses. Furthermore, a beneficial effect of early statin initiation following acute coronary syndrome (ACS) for short-term prevention of thrombosis-related events has been documented but the available data is still not consistent. Summary. Although statins influence the levels of a multitude of haemostatic factors in an anti-thrombotic direction, data supporting their use for VTE prevention is contrasting, and the impact of statins on early vascular events following ACS is still debated. Whether the robust long-term beneficial effects of statins in reducing cardiovascular risk may be also explained by persistent changes in haemostatic factors needs further exploration.
Article
Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function.
Article
Background. Curcuminoids are natural products with potent anti-inflammatory and antioxidant properties. There have been a number of reports on the analgesic effects of curcuminoids in clinical trials, yet data have not been fully conclusive. Objectives. To provide the highest level of evidence on the efficacy of curcuminoids in patients with painful conditions through meta-analysis of data from randomized controlled trials (RCTs). Methods. A systematic review and meta-analysis was conducted using data reported by RCTs. The primary efficacy measure was pain intensity or algofunctional status. Treatment effect was summarized with standardized mean difference (SMD) calculated from differences in means of pain measures between treatment and control groups using a random- effects model. Results. A total of eight RCTs met our inclusion criteria that included 606 randomized patients. Curcuminoids were found to significantly reduce pain (SMD:20.57, 95% CI:21.11 to20.03, P50.04). This pain-relieving effect was found to be independent of administered dose and duration of treatment with curcuminoids, and was free from publication bias. Curcuminoids were safe and well tolerated in all evaluated RCTs. Conclusion. Curcuminoids supplements may be a safe and effective strategy to improve pain severity, by warranting further rigorously conducted studies to define the long-term efficacy and safety.