Health-promoting properties of artichoke in preventing cardiovascular disease by its lipidic and glycemic-reducing action

Abstract

The artichoke, Cynara scolymus, is one of the most ancient plants grown in the world, and its extracts, obtained from different parts of the plant (leaves, fruits and roots), have been used as medicaments from time immemorial. The pharmacological and therapeutic effects of the artichoke on the liver had already been well known in the 17th century. Modern studies started in the last century confirmed the stimulating properties of artichoke extracts on the liver and gallbladder. The ensuing wave of research was initially focused on the patent liver-stimulating, diuretic and choleretic effects exerted by artichoke preparations on both animals and man, then discovering such other therapeutic properties as the hypolipemizing activity, antioxidant activity and hypoglycemizing activity. This review enumerates the most significant studies that have highlighted these therapeutic properties. Complementary medicine information needs to be incorporated into clinical practice and patient and professional education, in addition to adequate education about proper nutrition. Awareness of the widespread use of complementary and alternative medicine by people with metabolic disorders is crucial for healthcare professionals in order to prevent cardiovascular disease.

Full text

Monaldi Arch Chest Dis
2013; 80: 17-26
REVIEWS
Introduction
Cynara scolymus extracts obtained from differ-
ent parts of the plant (leaves, fruits and roots) have
been used as medicaments since ancient times [1-3].
Traditional medicine made use of the artichoke a
choleretic, diuretic, laxative, appetite-stimulant,
anti-gout medication and depurative [4]. The inter-
est in the artichoke as a medicament was lost around
the mid-19
th
century, however, and was then revived
again in the first half of the 20
th
century, when
French scientists had described artichokes as poten-
tial drugs against liver disorders. In the 1960s, one
of the active ingredients found in the artichoke –
called cynarin – was identified and successfully
marketed as a liver-protecting agent. In a short time,
this active ingredient was isolated, and some Italian
researchers identified its chemical structure, thus en-
abling its synthesis. Some cynarin-based synthetic
preparations were used to treat liver and gallbladder
disorders, as well as to reduce lipid and cholesterol
values, even if, over the years, they were then re-
placed by drugs that were more specific for these
diseases. In the last ten years, however, the aqueous
extract from artichoke leaves has regained an ac-
knowledged medical value in Germany: it has been
officially certified as safe and effective if it is ob-
tained through a process complying with the rele-
vant international pharmaceutical regulations. The
extract has been used as a dietary supplement indi-
cated for treatment of hyperlipidemia [5, 6]. In addi-
tion, Pharmacopoeias have approved its use as a he-
patic stimulant and appetite stimulant, particularly
in children [7-10]. Artichoke leaves, whether fresh
or dry, are presently included in the official Euro-
pean monographs on herbal products, and the plant
is mentioned in the most important collections of
medicinal herbs and phytotherapy and general phar-
macognosy books [11-15], which approve use of ar-
tichoke as a choleretic, diuretic, hepatoprotective
and liver-stimulating substance. As far as Italy is
concerned, the artichoke is mentioned in the Italian
Health-promoting properties of artichoke
in preventing cardiovascular disease by its
lipidic and glycemic-reducing action
Proprietà di promozione sulla salute del carciofo mediante
prevenzione delle malattie cardiovascolari grazie alla sua
azione ipolipodemizzante ed ipoglicemizzante
Mariangela Rondanelli, Francesca Monteferrario, Simone Perna,
Milena Anna Faliva, Annalisa Opizzi
Department of Applied Health Sciences, Section of Human Nutrition and Dietetics, Faculty of Medicine, Azienda di Servizi alla
Persona di Pavia, University of Pavia.
Corresponding author: Mariangela Rondanelli; Department of Applied Health Sciences, Section of Human Nutrition and Dietetics,
Faculty of Medicine, Azienda di Servizi alla Persona di Pavia, University of Pavia, Istituto di Cura “Santa Margherita”, Via Emilia 32,
I-27100 Pavia, Italy; Tel. International +39-0382-381749, + 39- 3382559239, Fax International +39-0382-381218; E-mail address:
mariangela.rondanelli@unipv.it
ABSTRACT: Health-promoting properties of artichoke in
preventing cardiovascular disease by its lipidic and glycemic-
reducing action. M. Rondanelli, F. Monteferrario, S. Perna,
M.A Faliva, A. Opizzi.
The artichoke, Cynara scolymus, is one of the most an-
cient plants grown in the world, and its extracts, obtained
from different parts of the plant (leaves, fruits and roots),
have been used as medicaments from time immemorial. The
pharmacological and therapeutic effects of the artichoke on
the liver had already been well known in the 17
th
century.
Modern studies started in the last century confirmed the
stimulating properties of artichoke extracts on the liver and
gallbladder. The ensuing wave of research was initially fo-
cused on the patent liver-stimulating, diuretic and choleretic
effects exerted by artichoke preparations on both animals
and man, then discovering such other therapeutic properties
as the hypolipemizing activity, antioxidant activity and hy-
poglycemizing activity. This review enumerates the most
significant studies that have highlighted these therapeutic
properties. Complementary medicine information needs to
be incorporated into clinical practice and patient and pro-
fessional education, in addition to adequate education about
proper nutrition. Awareness of the widespread use of com-
plementary and alternative medicine by people with meta-
bolic disorders is crucial for healthcare professionals in or-
der to prevent cardiovascular disease.
Keywords: artichoke, caffeic acid derivatives, Cynara
scolimus, cholesterol, flavonoids, glycemia.
Monaldi Arch Chest Dis 2013; 80: 17-26.

Pharmacopoeia X Edition [9] as a dry nebulization
extract titrated with caffeoylquinic acids calculated
as chlorogenic acid min. 13% and max. 18%.
Complementary medicine information needs to
be incorporated into clinical practice and patient and
professional education, in addition to adequate edu-
cation about proper nutrition [16]. Awareness of the
widespread use of complementary and alternative
medicine by people with metabolic disorders is cru-
cial for healthcare professionals in order to prevent
cardiovascular disease [17].
Chemistry of the biologically active molecules
found in the artichoke
From a chemical point of view, artichoke leaves
contain different molecules with important pharma-
cological activities: caffeic acid derivatives,
flavonoids, sesquiterpenic lactones, anthocyans, in
particular cyanidin and tannins, volatile oils, includ-
ing terpenoids, carotenoids, saturated, unsaturated
and polyunsaturated fatty acids, including linoleic,
palmitic, oleic and stearic acids, other unsaturated
compounds, like hydroxymethyl acrylic acid and
polyacetylene, citric, malic, lactic, succinic and
glycemic acids, monosaccharides, oligosaccharides
and polysaccharides of different kinds, such as, for
example, various sugars, mucilages, pectins, inulin,
amino acids and proteins, like L-asparagine, and a
large number of enzymes, including oxidase, perox-
idase, cynarase, ascorbinase, protease, ashes, potas-
sium, magnesium, calcium and traces of other met-
als.
Caffeic acid derivatives
Many of the pharmacological activities of arti-
choke leaf extracts were attributed – at least initially
– to the presence of caffeoylquinic acids (CQS). [18-
20]. In literature, these compounds are also called,
more generically, “caffeic acid derivatives” or “orto-
dihydrophenols”; they are synthetically obtained
from the condensation of a quinic acid molecule
with one or two caffeic acid molecules.
Historically, chemical investigations on these
component began in 1840, when a certain Mr. Grit-
teau isolated a substance that is known today as cy-
narin. The true nature of this substance was discov-
ered by Chabrol [21] and his collaborators in 1931.
Studies on the chemical nature of cynarin developed
over the years, and in 1965 some Authors [22]
demonstrated that this substance actually corre-
sponded to 1,5- dicaffeoylquinic acid. Today cy-
narin can also be obtained through an easy and
cheap semi-synthesis method that does not require
use of any chromatographic step [23]. This proce-
dure is based on the separation of the fraction rich in
1,5-dicaffeoylquinic acid, the isomerization of the
compound and, owing to its higher polarity, on the
simple isolation of cynarin from the reaction mix. In
addition to cynarin, other monocaffeoylquinic acids
have also been isolated from artichoke leaves:
chlorogenic acid (or 5-O-caffeoylquinic acid) and
crypto-chlorogenic acid (or 4-O- caffeoylquinic
acid) [24, 25].
The highest content in caffeoylquinic acids can
be found in the leaf at the end of the first vegetation
year [26]. But these acids can also be found in small
quantities in all the other parts of the plant. Pharma-
cologically, these compounds have exhibited
choleretic effects (that is, they stimulate the biliary
flow) and, in part, a cholesterol-reducing action.
Flavonoids
The chief flavonoids identified in leaves (0.1 to
1%) are luteolin [27-30] and three luteolin glyco-
sides: cynaroside (luteolin-7-O-glucopiranoside),
scolymoside (luteolin-7-O-rutinoside), and cy-
narotrioside (luteolin-7-O-rutinosil-4-O-glucopira-
noside). In addition, recent analyses also highlighted
the presence of rutin, apigenin, quercetin and other
flavonoids together with luteolin and its glycosides
[31, 32]. It now seems to have been ascertained that
these compounds – in particular luteolin – seem to
exert a pharmacological effect on cholesterolemia
through at least two different mechanisms: on the
one hand they modulate cholesterol absorption and,
on the other, they slow down endogenous choles-
terol synthesis by inhibiting HMG-CoA-reductase
synthesis. In addition, these substances can also en-
hance the production of biliary acids and exhibit a
marked antioxidant activity in the liver and serum.
Sesquiterpenic lactones
In addition to flavonoids and caffeoylquinic acid
derivatives, artichoke leaves also contain a number
of sesquiterpenic lactones (cynarotriol, cynaropi-
crin), which are responsible for the typical bitter
taste of the artichoke [27, 33]. The highest contents
in these substances were measured in young leaves
immediately after flowering; on the contrary, they
are absent in roots, ripe fruits and flowers. These
components are endowed with hypocholesterolem-
izing antiinflammatory activity.
Other components
Other components found in the artichoke in-
clude: anthocians, and in particular cyanidin and
tannins [34]; more than 30 volatile oils, including
terpenoids [35], carotenoids [36]; saturated, unsatu-
rated and polyunsaturated fatty acids, including
linoleic, palmitic, oleic and stearic acids [37]; other
unsaturated compounds, such as hydroxymethyl
acrylic acid and polyacetylene [38]; citric, malic,
lactic, succinic and glycemic acids [39]; monosac-
charides, oligosaccharides and polysaccharides of
different kinds, such as, for example, various sugars,
mucilages, pectins, inulin [40, 41]; amino acids and
proteins, like L-asparagine, and a large number of
enzymes [42], including oxidase, peroxidase, cy-
narase, ascorbinase, protease [43]; ashes, potassium,
magnesium, calcium and traces of other metals.
Pharmacology of the artichoke
The pharmacological and therapeutic character-
istics of cynarin and the other active ingredients
found in the artichoke leaves are described below
and schematically listed as follows: 1. Hypolipemic
and cholesterol biosynthesis-inhibiting properties. 2.
Antioxidant properties. 3. Hypoglycaemic proper-
ties. 4. Liver-protecting properties. 5. Choleretic
properties.
18
M. RONDANELLI ET AL.

1. Action on lipid metabolism
A large number of studies demonstrated that Arti-
choke extracts act on lipid metabolism by decreasing
production of cholesterol and endogenous triglycerides
and supporting their excretion or the natural re-distrib-
ution through the organism. They also strengthen bile
production by increasing the quantity of biliary acids
and cholesterol discharged with bile. Since bile is the
chief route to eliminate cholesterol, the stimulation of
biliary secretion by artichoke extracts results in causing
the physiological reduction of cholesterol in the liver
and serum. In literature, there are also a number of
studies highlighting a direct action of artichoke extracts
on the endogenous synthesis of cholesterol. A number
of reserchers investigated these activities closely
through both experimental and clinical settings. Del
Vecchio [44] had highlighted, in vitro, that the arti-
choke extract aided cholesterol esterification in serum,
while, together with this effect, Obrecht also observed
an action on atherosclerotic plaques. Preziosi and col-
leagues [45] tested the effects of an intravenous admin-
istration of cynarin and caffeic acid on serum choles-
terol of the rabbit. In these animals, significant results
were obtained following administration of doses of
over 100 mg/kg, and the reduction in cholesterol levels
lasted for more than 72 hours, with the maximum re-
duction occurring between the fourth and sixth hours
from administration [45, 46]. The action was more ef-
fective on esterified cholesterol rather than on free cho-
lesterol; the activity of caffeic acid was found to be
equivalent to that of cynarin, even if its duration was
shorter. The action of these two compounds seems to
be ascribable to inhibition of liver cholesterol biosyn-
thesis, rather than to the increase in serum cholesterol
solubilization or esterification power [47]. Gebhardt in-
vestigated the possible mechanisms of action of the dif-
ferent components of the artichoke cholesterol synthe-
sis inhibition [48]. An aqueous extract from artichoke
leaves was used in high doses to inhibit cholesterol
biosynthesis, in a dose-dependent manner, starting
from 14C-acetate in a culture of rat hepatocytes. The
failure in cholesterol synthesis seems to be linked to
some inhibition of HMG-CoA reductase by the arti-
choke extracts. This hypothesis was then compared
with the results obtained with mevastatin - an HMG-
CoA inhibitor. The comparison yielded similar results,
although the action of artichoke extracts lies in the
modulation of the activity of HMG-CoA reductase,
rather than in a true inhibition. The effects seem to be
induced chiefly by flavonoids, such as luteolin and cy-
naroside, and, to a lesser extent, by cynarin and caffeic
acid. These early studies were then followed by a con-
siderable number of investigations using both artichoke
extracts and cynarin alone, which demonstrated to pos-
sess good therapeutic efficacy in patients with normal
or high cholesterol and triglyceride levels in serum;
these results were then reviewed by Schilcher and Heil
in 1992, by Wegener [49] and Schmidt in 1995, by
Kraft [50] in 1997 and by Wegener and Fintelmann in
1999 [51]. The Table 1 and 2 provide an overview of
19
ARTICHOKE IN PREVENTING CVD: A REVIEW
Table 1. - Results of studies on the effects of cynarin and artichoke extracts on cholesterol serum from 1959 to 1994
(meta-analysis by Wegener and Schmidt).
Authors and Number Treatment Daily dose
Total Cholesterol (mg/dl)
publication year of patients length in weeks (mg)
From to Reduction %
Mancini et al. (1961) 23 8 1500 256 ± 40 192 ± 20 25
Caruzzo et al. (1969) 1 4 1000 n.a. Reduction Not available
Cairella and Volpari (1971) 24 4 1000 283 ± 7 247 ± 5 13
Hammerl et al. (1973) 132 52-80 60 310 214 31
Eberhardt (1973) 12/10 5 1500 234 ± 38 199 ± 54 15
Montini et al. (1975) 30/30 7 500 ca. 300 ca. 240 20
Pristautz (1975) 60 8.5 60 298 ± 6 266 ± 9 11
Heckers et al. (1977) 9 12 250 381 ± 31 375 ± 38 2
Adam and Kluthe (1979) 7 11 1000 275 ± 85 213 ± 53 23
Vorberg (1980) 50 4 1200 306 ± 50 260 ± 61 15
Wegener (1994) 170 6 1920 267 228 14.5
Wójcicki and Kadikow (1974) 20 3 500 (wk 1) 1085 ± 516 819 ± 179 25
450 (wk 2/3)
Wójcicki and Winter (1975) 10 4 900 203 ± 11 153 ± 11 25
Wójcicki et al. (1979) 43 4 750 293 ± 15 260 ± 12 11
Palacz et al. (1981) 43 52 900 – Slight reduction –
Wójcicki et al. (1981) 30 6 900 203 ± 6 179 ± 15 12

the results of the studies conducted to assess the effect
of the administration of the artichoke extract on lipid
metabolism in man.
It is impossible to draw any correlations among
the different results because of the lack of standardis-
ation of the methods and substances used in the stud-
ies. Nonetheless, all the studies, except one, demon-
strated statistically significant improvements in cho-
lesterol and triglycerides levels. As a matter of fact,
Heckers [52] administrated daily doses of 250 and
750 mg synthesis cynarin preparations for three
months in 17 outpatients affected by familial type IIa
or IIb hypercholesterolemia without observing any
significant improvements in cholesterol and triglyc-
erides levels, and came to the conclusion that cynarin
was relatively ineffective as a therapeutic regimen in
hyperlipemia. After the Polish investigator Wojcicki
and collaborators had conducted studies with cynarin
in the rat, they studied the influence of this com-
pound, and then of artichoke extracts, in men of dif-
ferent ages affected by primitive or secondary hyper-
cholesterolemia. First, they assessed the influence of
cynarin on serum lipid levels of 20 diabetic patients,
of 20 to 77 years of age, with clofibrate-resistant hy-
percholesterolemia [53]. Cynarin was administered
for 21 days: through i.m. injections (0.5 g/die) for the
first ten days and then through three tablets a day
(each containing 0.15 g cynarin) for the remaining
days. Both cholesterol and triglycerides decreased
considerably. Cynarin was then administered in pa-
tients affected by hypercholesterolemia alone. In this
case, the agent was administered through the intra-
venous route at a daily dose of 1 g for 21 days, and
then orally at a daily dose of 0.75 g for another 21
days. This study suggests that the hypocholes-
terolemizing action of cynarin could be enhanced by
treatment with higher doses and/or for longer periods
of time. Other investigations with cynarin [54] or ar-
tichoke extracts confirmed their beneficial effects in
patients affect by hyperlipemia. For example, the de-
crease in cholesterol, triglycerides (to –62% of the
baseline value), free fatty acids, phospholipids and
lipoproteins was observed in 30 healthy elderly indi-
viduals (aged 75 years on the average) following
daily administration of 0.45 or 0,9 g extract, contain-
ing 0.09% polyphenols, for six weeks. The adminis-
tration of different doses of two different artichoke
preparations for 27 or 45 weeks was compared in in-
dividuals with primary hypertriglyceridemia unaf-
fected by treatment with clofibrate; this study resulted
in the improvement of serum triglycerides levels in
39 out of 73 patients (58.5 %; mean value of the over-
all results), with the normalization of 12 cases
(16.8%). The fraction of phospholipids and free fatty
acids in blood was then assessed in 38 patients af-
fected by hypertriglyceridemia and treated with two
different doses of 0.25 g (no = 22) and 0.5 g (no = 16)
artichoke extract three times a day for 27 or 45 weeks.
Statistically significant improvements of cholesterol
in serum were observed after 45 weeks in the patients
treated with the higher dose (p <0.02). As far as phos-
pholipids were concerned, changes were observed
only in lecithin levels (p <0.02) in both treatment
groups; on the contrary, lysolecithin, sphyngomielin,
phosphatidylcholine, phosphatidylethanolamine,
lysophosphatidylethanolamine and cardiolipin levels
remained statistically unchanged. High LDL levels,
together with high cholesterol and triglycerides lev-
els, are a risk factor for various degenerative vascular
diseases, and in particular for arteriosclerosis. A mul-
ticentre, double-blind, randomised, placebo-con-
trolled clinical trial was published by Englisch and
collaborators in 2000 [55]. This trial analysed the ef-
ficacy and tolerability of an aqueous artichoke extract
with respect to hypercholesterolemia. The prepara-
tion was formulated in coated tablets containing 450
mg artichoke extract. The trial enrolled 143 adult pa-
tients (aged between 35 and 69 years) with total base-
line cholesterol levels higher than 280 mg/dl; they re-
ceived 1,800 mg artichoke extract or placebo a day
20
M. RONDANELLI ET AL.
Table 2. - Results of studies on the effects of cynarin and artichoke extracts on triglycerides serum from 1959 to 1994
(meta-analysis by Wegener and Schmidt).
Authors and Numebr Treatment Daily dose
Triglycerides (mg/dl)
publication year of patients length in weeks (mg)
from to Reduction %
Hammerl et al. 1973) 132 52-80 60 228 174 24
Mars and Brambilla 1974) 15/15 8.5 1000 237 ± 64 155 ± 47 35
Montini et al. 1975) 30/30 7 500 ca. 230 ca. 200 13
Pristautz 1975) 60 8.5 60 369 ± 11 303 ± 25 18
Vorberg 1980) 50 4 1200 196 ± 55 174 ± 80 11
Wójcicki and Kadikow 1974) 20 2 450 (wk 1) 704 ± 231 513 ± 177 27
500 (wk 2)
Wójcicki and Winter 1975) 10 4 900 143 ± 75 117 ± 43 18
Wójcicki et al. 1979) 43 4 750 547 ± 97 363 ± 43 33
Wójcicki et al. 1981) 30 6 900 135 ± 17 71 ± 8 47
Palacz et al. 1981) 43 52 900 – – 27.9

for more than 6 weeks and were forbidden to con-
sume such other medications as antibiotics or statins
during the experiment. Primary endpoints were cho-
lesterol and triglycerides levels in serum, and sec-
ondary endpoints were the values of liver enzymes.
The reductions in total cholesterol levels were ini-
tially comparable between the two groups, but after
the seconds week, the cholesterol level began to in-
crease in the group treated with placebo, while it de-
creased in the treated group. At the end of treatment,
the reduction in total cholesterol levels (-18.5% in
comparison with –8.6% in the placebo group) and
LDL cholesterol levels (-22.9% in comparison with
–6.3% in the placebo group) in the treated group was
statistically significant (p = 0.0011 and p = 0.0001, re-
spectively) in comparison with placebo. In the au-
thors’ opinion, these results are almost comparable to
those obtained with statins. The LDL/HDL ratio de-
creased by 20.2% in the treated group and by 7.2% in
the placebo group, although the HDL cholesterol lev-
els remained unchanged. Contrary to the results ob-
tained in other studies, triglycerides levels were not
affected by the administration of artichoke. Finally,
no statistically significant difference in liver enzymes
was observed between the two groups. Only two
cases of poor tolerability were reported in the 12 in-
dividuals who did not complete the trial. A recent trial
conducted by Bundy and Walzer [56] in 2008 exam-
ined 131 healthy adult individuals affected by slight
to moderate hypercholesterolemia., with total choles-
terol levels in plasma amounting to 6.0-8.0 mmol/l.
The trial was aimed at assessing the effects of arti-
choke leaf extracts on lipid plasma levels and the gen-
eral wellbeing of the individuals. The volunteers were
randomised into two groups: one received 1,280 mg
artichoke extract every day for 12 weeks, and the
other a placebo. In the treated group, total cholesterol
levels in plasma decreased on the average by 4.2%,
while they increased in the control group (by 1.9% on
the average); this means that the difference between
the groups is statistically significant (p = 0.025). On
the other hand, there was no significant difference in
LDL cholesterol, HDL cholesterol and triglycerides
between the groups. Following either treatment, the
enrolled individuals reported an improvement of their
subjective sensation of wellbeing, without any signif-
icant difference between the groups. In conclusion,
consumption of the artichoke leaf extract resulted in a
modest but favourable, statistically significant, differ-
ence in total cholesterol after 12 weeks. Our present
knowledge has now ascertained that, in spite of the
presence of high quantities of lipids in the blood, the
first step towards the development of an atheroma-
tous plaque must take place in the vascular endothe-
lium owing to tissue lesions or oxidative processes.
Most of the recent in-vitro experiments have high-
lighted that the artichoke and its active ingredients not
only induce the reduction of circulating cholesterol
levels, but may also exert a positive effect on the vas-
cular endothelium performance, thus succeeding in
preventing atherosclerosis. Lupattelli and collabora-
tors [57] examined 18 moderately hypocholes-
terolemic individuals (LDL cholesterol ranging be-
tween 130 and 200 mg/dl, triglycerides between 150
and 250 mg/dl) and 10 individuals affected by high
hypercholesterolemia (LDL cholesterol >200 mg/dl,
triglycerides >250 mg/dl), aged between 36 and 60
years. The patients were not treated with a hypocho-
lesterolemizing therapy during the study period and
received 20 ml/die artichoke juice dissolved in water
for 6 weeks. In addition to the usual lipid parameters
in the blood, the levels of various soluble adhesion
molecules, such as VCAM-1, ICAM-1 and E-se-
lectin, were also measured; these molecules are hy-
per-expressed in dyslipidemic individuals. Finally,
the brachial arteria diameter and flow-mediated va-
sodilatation (FMV) of the brachial arteria – two mea-
sures of the arterial dilatation capacity – were veri-
fied. At the end of treatment, an increase in triglyc-
erides levels and a decrease in total and LDL choles-
terol (p <0.05 for all of them) were recorded in the
treated patients; even if the controls showed a signif-
icant decrease in the latter parameters (p <0,01 for
both). There was also a reduction in VCAM-1 and
ICAM-1 (p <0,05 for both), but not in E-selectin.
Brachial FMV increased significantly (p <0,01), and
a subsequent analysis demonstrated that the changes
in adhesion molecule levels and brachial FMV were
well correlated (p <0,05); on the contrary, no correla-
tion was observed between LDL cholesterol and
brachial FMV. In a subsequent discussion on these re-
sults, the Authors pointed out that the potential bene-
ficial effect of the artichoke on the vasodilatation ca-
pability, as observed in their study, seemed to be me-
diated by its antioxidant property, rather than by the
hypocholesterolemizing effect. The latest meta-
analysis on the hypocholesterolemizing action sec-
ondary to the administration of artichoke extract was
conducted by Pittler and collaborators [58]. In this
meta-analysis the authors reviewed 2 clinical trials
conducted with correct methods and involving 167
patients affected by moderate hypercholesterolemia.
The dry artichoke extract, titrated with caffeoylquinic
acid 15%, reduced total cholesterol from 7.74
mmol/l. to 6.31 mmol/l after 42 treatment days
(p<0.01), while the placebo reduced it from 7.69
mmol/l to 7.03 mmol/l. The adverse effects recorded
in either trial were almost negligible.
Finally, an interesting recent research random-
ized, double-blind, placebo-controlled clinical trial
was performed on 92 overweight subjects with pri-
mary mild hypercholesterolaemia for 8 weeks [59].
Verum supplementation with 2-daily oral assump-
tions (before lunch and dinner) of film-coated
tablets of 250 mg of standardized artichoke leaf ex-
tract (>20% caffeoylquinic acids, >5% flavonoids
and >5% cynaropicrin) was associated with a signif-
icant increase in mean high-density lipoprotein
(HDL)-cholesterol (p<0.001) and in mean change in
HDL-cholesterol (HDL-C) (p=0.004). A signifi-
cantly decreased difference was also found for the
mean change in total cholesterol (p=0.033), low-
density lipoprotein (LDL)-cholesterol (p<0.001), to-
tal cholesterol/HDL ratio (p<0.001) and LDL/HDL
ratio (p<0.001), when verum and placebo treatment
were compared.
These data indicates that dry artichoke extracts
can be useful to lower cholesterol levels, but other
adequately rigorous clinical trials still have to be
published to confirm these results. In short, the ac-
tion of the artichoke extract on cholesterolemia is
especially linked to the increase in choleresis and,
21
ARTICHOKE IN PREVENTING CVD: A REVIEW

therefore, to the excretion of biliary salts and acids
rich in cholesterol, but also to a direct action on the
liver, which it is known to play a major role in lipid.
The Artichoke seems to be able to stimulate the
following mechanisms of cholesterol metabolism by
the liver: 1) more effective uptake and subsequent
intra-hepatocyte metabolism of chylomicron rem-
nants; 2) stimulation of apolipoprotein synthesis by
the liver, with the consequent improvement of lipid
metabolism; 3) increased uptake of LDLs and HDLs
by the liver with the improvement of their intra-he-
patocyte metabolism; 4) hepatic HDL synthesis
stimulation induced by increased formation of
apolipoproteins A1 and A2 by the liver. It is well
known that these apolipoproteins, also produced by
the intestine, are essential for the formation of cir-
culating HDLs; 5) increase in HTGL and LCAT syn-
thesis by the liver.
2. Antioxidant action
The artichoke leaf extract induces the concentra-
tion-dependent inhibition of induced oxidative
stress in human neutrophils. Cynarin, caffeic acid,
chlorogenic acid and luteolin have been found to be
the active ingredients that play the major role in the
antioxidant protective activity. The antiradical prop-
erties of aqueous and alcoholic artichoke extracts, as
well as their capability of inhibiting lipid peroxida-
tion, were recently confirmed. As demonstrated by
several studies conducted by Samochowiec [60], ar-
tichoke extracts possess efficacious properties
against the oxidative stress induced by inflamma-
tory process mediators and LDL oxidation. The rad-
ical-scavenger properties of the extract, documented
by in-vitro copper-induced oxidative prevention of
LDLs, are due to the presence of flavonoids and, in
particular, luteolin. Flavonoids act as hydrogen
donors (reducing action) and as chelating substances
capable of binding to catalyzing metals. In practice,
they act as antioxidants because they seize reactive
oxygen species (ROS) and transform them into less
aggressive radicals, thus sacrificing themselves and,
at the same time, saving physiological antioxidants
(carotenoids, glutathione, vit. C and vit. E). The ma-
jor role played by antioxidants in the reduction of
oxidative and degenerative damage to cells and,
consequently, to the tissue is by now widely known.
A recent Italian study conducted in 2008 [61] was
aimed at demonstrating the liver-protecting proper-
ties of polyphenolic artichoke extracts (AE) on rat
hepatocytes and human hepatoma cells. The hepato-
cytes were exposed to H2O2 generated in situ by
glucose-oxdase and then treated with AE, or pure
chlorogenic acid (Cha) or a well-known antioxidant,
N, N’-difenyl-p-phenylenediamine (DPPD). The ad-
dition of glucose-oxidase to the cell culture induced
deplezione intracellular gluthatione depletion
(GSH), malon dialdehyde accumulation (MDA) in
the cultures – an indicator of lipid peroxidation –
and cell death. These results demonstrated that cells
treated with AE were protected against the oxidative
stress caused by glucose-oxidase to a similar extent
to that of DPPD. In addition, AE, wa well as Cha,
prevented total loss of GSH and MDA accumula-
tion. On the contrary, hepatoma cell treatment with
AE for 24 hours determined reduced cell viability in
a dose-dependent manner; however, Cha did not ex-
ert any noteworthy effect on the cell death rate. The
results of this study indicate that AE has a potential
market as an antioxidant that protects hepatocytes
from oxidative stress. In addition, AE reduces via-
bility of human liver cancer cells by supporting their
apoptosis.
3. Hypoglycemizing action
A few compounds found in the artichoke exhib-
ited a significant hypoglycemizing activity in vitro.
Chlorogenic acid was identified by Arion and
collaborators as a powerful and specific glucose-6-
phosphate-translocase inhibitor [62]. This enzyme is
essential for the formation of endogenous glucose
during the gluconeogenesis process, as well as for
the glycolytic process. Chlorogenic acid also seems
to be able to reduce the absorption of the carrier-
favourite intestinal glucose.
All this may contribute to a slight reduction of
glycemia values, which is particularly significant in
non-insulin-dependent diabetic individuals. Matsui
and collaborators [63] isolated some caffeoylquinic
acid derivatives involved in the inhibitory activity of
α-glucosidase and demonstrated that caffeoylquinic
acids exerted a moderate hypoglycemizing effect.
Another compound that is found in artichoke leaves
in considerable quantities and affects glucide metab-
olism is inulin [64]; this compound belongs to the
family of fruit-oligosaccharides (FOS) and exerts
important effects on the intestinal transit, in which it
modulates cholesterol and triglycerides concentra-
tions in the blood and improves intestinal bacterial
flora composition. Various authors have described
the hypoglycemizing activity of the artichoke con-
sumed as food. Vinik [65] in 2002 and, more re-
cently, Nazni [66] in 2006 confirmed that the edible
parts of the plant have good hypoglycemizing prop-
erties, especially due to the presence of high quanti-
ties of alimentary fibre.
Moreover, recently a randomized, double-blind,
placebo-controlled clinical trial was performed in 39
overweight subjects for 2 months. The net change of
the glycaemia was reduced significantly only in the
intervention group; intervention consisted in 3-daily
oral assumptions (before breakfast, lunch and din-
ner) of film-coated tablets of 200 mg of standardized
Cynara scolymus flowering buds extract. Finally, in
the supplemented group, the homeostasis model as-
sessment (HOMA) decreased significantly after in-
tervention; these parameters did not change in the
controls [67].
4. Liver-protecting action
Among the many therapeutic properties that
have been traditionally ascribed to the artichoke, the
liver-protecting action is not certainly the least im-
portant, to the extent that its use was recommended
to patients affected by hepatitis, jaundice, cirrhosis
and liver steatosis. Cynarin and caffeoylquinic acids
are thought to be the substances that are chiefly re-
sponsible for the protective action against such he-
patotoxic agents as carbon tetrachloride. The liver-
protecting action manifests itself in the reduction of
liver malondialdehyde and blood enzymes AST
(Aspartate aminotransferase) and ALT (Alanine
22
M. RONDANELLI ET AL.

aminotransferase), whose increase in serum indi-
cates altered liver performance due to hepatotoxic
damage. The extracts with a higher content in phe-
nol derivatives exert a greater effect on the bile flow
and a better liver-protecting action. Nevertheless,
single administrations of chlorogenic acid in equiv-
alent quantities to those found in the extract do not
produce any choleretic or protective effects. At least
two of the earliest studies on the artichoke had tried
to demonstrate its usefulness in arsenic-poisoned in-
dividuals [68]. Artichoke leaf extracts were tested in
vivo by Maros [69] to verify their regeneration ef-
fects on liver cells. In one experiment, an aqueous
artichoke leaf extract, administered orally in par-
tially hepatectomized rats in 0.5 ml/day doses for 21
days, significantly increased liver tissue regenera-
tion as measured from the residual liver weight, mi-
totic index and liver cell rate. In other experiments
using the same methods the artichoke extract accel-
erated liver weight increase, induced marked hyper-
aemia and increased both binucleated hepatocyte
rate and the liver cell content in ribonucleic acid.
According to the majority of the recent research, lu-
teolin and other polyphenols [48] seem to affect he-
patocyte proliferation induced by different growth
factors, including insulin. The action against exoge-
nous toxic agents was also the subject of various in-
vestigations. Adzet and collaborators [70] reported
that an aqueous artichoke extract (containing 2.2%
caffeoylquinic acids and 0.9% luteolin), adminis-
tered orally in the rat in doses of 500 mg/kg body
weight 48 hours, 24 hours and 1 hour before induc-
ing acute liver intoxication with carbon tetrachlo-
ride, significantly improved the liver performance;
this was evidenced by the decrease in GSH (glu-
tathione) liver content and total bilirubin, direct
bilirubin, GOT and GPT levels in the plasma. Only
cynarin, of the three caffeoylquinic acids, exhibited
notable liver-protecting properties against release of
both GOT and GPT. Various polyphenol compo-
nents [48] of the artichoke leaf have been analysed
and seem to contribute to the liver-protecting and
antioxidant actions; this disagrees with the results
obtained by Adzet [70], who had ascertained that
only cynarin and, to a lesser extent, caffeic acid
were active. These results are of great clinical inter-
est, because this strong protective action is not prob-
ably limited to hepatocytes alone. For example, as
already mentioned, these substances also inhibit
LDL cholesterol oxidation and, consequently, may
prevent atherosclerosis. In 2003 Speroni and collab-
orators [71] tested four different marketed artichoke
leaf extracts, containing different quantities of ac-
tive ingredients, in an animal model. The study re-
sults demonstrated that the extract with the highest
content in phenols exerted the best results in terms
of biliary excretion and liver-protecting activities.
The histological examination of liver samples of
mice poisoned with CCl4 highlighted steatosis,
necrosis, small fibrosis areas and leukocyte migra-
tion; the hepatocytes showed dilatation of the endo-
plasmic reticulum with polyribosome detachment
and disaggregation, as well as cell swelling with
clarity of mitochondrial vacuoles. Similar aspects
also remain unchanged in samples taken from rats
treated with chlorogenic acid and cynarin. On the
contrary, the liver parenchyma of rats treated with
the extract having the highest content in phenols ex-
hibited an almost normal anatomy, without any ma-
jor damage to the endoplasmic reticulum or cell mi-
tochondria.
5. Choleretic action
The artichoke performs a “amphocholeretic”
role, regulating the biliary flow by either decreasing
an exceedingly high biliary secretion or increasing it
whenever it is reduced by toxic factors. The whole
phytocomplex enhances choleresis through the si-
multaneous stimulation of the enzymatic, functional
and antitoxic activities of the liver, liver regenera-
tion and blood flow increase. In fact, it joins the bil-
iary activity to the liver activity, thus justifying its
indication against dyspepsia accompanied by a sen-
sation of a full stomach, abdominal pain, meteorism,
nausea and vomiting.
Experiments conducted in vitro demonstrated
that the dry aqueous extract from artichoke leaves in
primary hepatocyte cultures can induce bile secre-
tion from biliary canaliculi, and that pure or more or
less diluted juices squeezed from fresh leaves exert
a dose-dependent choleretic effect on the isolated,
perfused rat liver; in an experiment conducted by
Matuschowski [72] in 1996, the bile flow increased
by 112 to 150%, with a peak after 20 minutes from
administration. The hepatobiliary and hepatoprotec-
tive effects of artichoke leaf preparations were
demonstrated not only by in-vitro experiments, but
also by a number in-vivo studies. Doses amounting
to 200 mg/kg of an hydro-alcoholic extract from
fresh artichoke leaves (19% of caffeoylquinic acids)
and to 25 mg/kg of an hydro-alcoholic extract from
fresh artichoke leaves – with the latter extract being
purified and enriched in phenolic compounds (46%
of caffeoylquinic acids) – were administered in the
rat by the parenteral route. Both extracts stimulated
choleresis by increasing the content in dry bile
residue and total cholate excretion (flow collection
through incannulation of the bile duct). These same
extracts, administered orally in doses of 400 mg/kg
for the total extract and 200 mg/kg for the enriched
extract, increased intestinal propulsion by 11% and
14% respectively, as was highlighted in the studies
conducted by Saenz Rodriguez and collaborators in
2002 [73] and in those conducted by Speroni in
2003 [71]. Much more recently, in 1993, the
choleretic action of the standardized extract was in-
vestigated by Kirchhoff [74] in a cross-over, double-
blind, randomised, placebo-controlled pilot study. A
single 1.92 g dose was administered in 20 male pa-
tients (mean age 26 years), divided into two groups:
the first group (A) received the active treatment and
then placebo after an 8-day washout period; the sec-
ond group (B) received placebo in the first stage and
the active treatment in the second. The mean in-
crease in secreted bile volume was considerably
higher in treated individuals (I-A and II-B) than in
the placebo groups (I-B and II-A); in particular, the
greatest effect was reached after 1 hour, but the ef-
fects were still evident after 3 hours (always p <0,01
times from the measurements between 30 and 180
minutes in comparison with the baseline values).
During the discussion, the authors pointed out that
23
ARTICHOKE IN PREVENTING CVD: A REVIEW

this data was of an unquestionable clinical impor-
tance; in addition, the artichoke extract consumed
after a meal may be able to affect enzyme digestion
and the intestinal motor function for an actual
length of time of about 120-150 minutes. This
means that the extract can be recommended for
treatment of dyspepsia, especially when the cause
can by ascribed to dyskinesia of biliary ducts or fat
absorption disorders. Neither side effects nor
changes in laboratory parameters were observed
during this study. In 1998, Schulz reported the re-
sults of a small placebo-controlled clinical trial. The
administration of 1,920 mg artichoke extract in 20
volunteers increased bile flow by 127.3% and
151.5% after 30 and 60 minutes respectively. The
effects of the artichoke on gastrointestinal disorders
associated to poor elimination of biliary acids were
investigated in an observation study conducted by
Held [75] in 1991, in which 403 patients affected by
hepatic insufficiency and disorders in the biliary
duct were treated for 4 weeks with standardised ar-
tichoke extract containing 375 mg dry extract per
tablet. The overall results were considered as “very
good” by 37.4% of the patients (34.9% of the physi-
cians) and as “good” by 46.9% of the patients
(52.3% of the physicians). Twelve patients (2.9%)
dropped out of the study - 4 because of diarrhoea
and 2 because of excessive flatulence. The same ex-
tract was used in a similar study conducted by We-
gener in 1994. The extract was administered at the
average dose of 4.75 tablets a day (corresponding to
1,520 mg) in 170 patients affected by different gas-
trointestinal disorders, including dyspepsia (34%),
irritable colon (16%), constipation (22%), func-
tional biliary duct disorders (21%), and others. Af-
ter 6 weeks’ treatment, there was an unexpected
marked reduction of vomiting (95%), nausea (85%)
and abdominal pain (75.5%). Abdominal pain, inap-
petence and meteorism also improved. According to
the patients, the results were generally considered as
excellent (22%) or good (67%). Unwanted side ef-
fects (weakness and a sensation of hunger) were ob-
served only in 1.2% of the patients. Another large
multicentre phase IV clinical trial, with treatment
lasting 43.5 days on the average, was conducted by
Fintelmann and Menßen [76] in 1996 in 553 pa-
tients (mean age 54.7 years) suffering from dyspep-
sia. The administration of 3 to 6 tablets of standard-
ised extract containing 375 mg dry extract per tablet
resulted in the significant reduction of dyspeptic
symptoms within 6 treatment weeks and the im-
provement of general symptoms in 70% of the
cases. In comparison with baseline values, the sub-
jective reduction of symptoms was about 66% for
meteorism, 76% for abdominal pain, 82% for nau-
sea and 88% for vomiting. According to the physi-
cian’s opinion, the general average therapeutic effi-
cacy, on the basis of a classification scale ranging
from 1 (excellent) to 5 (poor), amounted to 1.95.
The effects were considered as “good” or “excel-
lent” in about 87% of the patients and occurred
within 10 days from treatment. Only slight side ef-
fects were recorded (weakness and flatulence).
Other more recent studies were also conducted to
ascertain the capability of the artichoke extract of
improving dyspepsia symptoms.
Riassunto
Il carciofo, Cynara scolymus, è una delle più an-
tiche piante coltivate nel mondo, ed suoi estratti, ot-
tenuti da diverse parti della pianta (foglie, frutti e
radici), sono stati utilizzati come medicamenti da
tempo immemorabile. Gli effetti farmacologici e te-
rapeutici del carciofo sul fegato erano già noti nel
17 ° secolo. Gli studi moderni, iniziati nel secolo
scorso, hanno confermato le proprietà stimolanti
degli estratti di carciofo sul fegato e sulla cistifellea.
La ricerca in questo campo è stata inizialmente con-
centrata sugli effetti diuretico e coleretico, esercitati
dagli estratti di carciofo sia sugli animali sia nel-
l’uomo. Poi sono state dimostrate altre importanti
proprietà terapeutiche, come l’attività ipolipemiz-
zante, l’attività antiossidante e ipoglicemizzante.
Questa review enumera gli studi più significativi che
hanno evidenziato queste proprietà terapeutiche.
Informazioni in merito alla possibilità terapeutiche
offerte dalla medicina complementare evidence-ba-
sed devono essere diffuse e tali possibilità terapeu-
tiche integrate nella pratica clinica, anche per le
persone con disturbi metabolici al fine di prevenire
le malattie cardiovascolari.
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