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School of Biomolecular Sciences, Liverpool John Moore University, Liverpool L3 3AF, UK
ABSTRACT
Cardiovascular disease is a complex and multifactorial disease characterized by such factors as high cholesterol, hypertension, reduced fibrinolysis, increase in blood-clotting time and increased platelet aggregation. Dietary therapy is the first step in the treatment of hyperlipidemia; garlic has been used medicinally for centuries and is still included in the traditional medicine of many cultures. Historically, there has been great interest in the role of garlic in reducing cardiovascular risk factors. Evidence from numerous studies points to the fact that garlic can bring about the normalization of plasma lipids, enhancement of fibrinolytic activity, inhibition of platelet aggregation and reduction of blood pressure and glucose. However, some contradictory results have also emerged as a result of methodological shortcomings, the use of different formulations/preparations of garlic and different time scales of the studies. Accordingly, further clinical studies are required in which standardized formulations of garlic with known compositions can be used. Such formulations (e.g., Aged Garlic Extract) are now available and are being investigated. Evidence obtained from these studies indicates that garlic has potential in the prevention and control of cardiovascular disorders and is beneficial when taken as a dietary supplement.
KEY WORDS: • garlic • hypolipidemia • atherlosclerosis • clinical trials • diet
There are many factors associated with atherosclerosis and
cardiovascular disease, by far the greatest killers in modern society.
A high fat diet can lead to increases in serum cholesterol and plasma
fibrinogen levels and to a decrease in fibrinolytic activity and blood
coagulation time. Changes in blood coagulation time are involved in the
development of thrombi in atherosclerotic vessels, and elevated serum
cholesterol levels contribute significantly to the onset and
development of atherosclerosis and cardiovascular disease. Increased
levels of LDL are also linked with cardiovascular disease; more
specifically, it has been reported that oxidation of LDL particles is
likely a key step in the development of atherosclerotic plaques
(Luc and Fruchart 1991
). Increased levels of HDL are
negatively correlated with cardiovascular disease. There is also
considerable evidence supporting the involvement of platelets in the
development of atherosclerosis. Increased platelet activity has been
found in smokers, as well as in patients suffering from vascular
injury, hyperlipidemia and hypertension. These circulating platelets
can be deposited on the innermost lining of the arteries, thereby
forming plaques, which then lead to the thickening of the arterial
walls, hence narrowing of the blood vessels. These plaques can
aggregate, incorporating cholesterol, lipids and lipoproteins, thus
blocking the blood vessels. Alternatively, pieces of plaque may break
off and cause a blockage elsewhere in the blood stream. The blockage of
the coronary artery results in a heart attack, leading to a myocardial
infarction. In addition to hyperlipidemia, obesity, smoking, stress and
hypertension are also known to be the risk factors for atherosclerosis
(Hulley et al. 1980
). Both clinical and epidemiologic
studies have shown that hyperlipidemia and hypertension are perhaps the
greatest risk factors of atherosclerosis and its complications, such as
stroke and myocardial infarction (Hulley et al. 1980
).
Many studies have demonstrated that normalization of hypertension and
abnormal metabolism of lipids and lipoproteins, including cholesterol,
improves atherosclerotic coronary artery disease (Kleijnen et al. 1989
).
It has been believed for some time that dietary factors play a key role
in the development of some human diseases, including cardiovascular
disease. Several epidemiologic studies have indicated that certain
diets are associated with low risk of cardiovascular disease and that
these diets are rich in fruits, herbs and spices; the common spice
among them is garlic (Stavric 1994
). Considerable
anecdotal evidence supports the invaluable role that garlic has in the
therapy of many diseases (Bolton et al. 1982
). Over the
centuries, garlic has acquired a special position in the folklore of
many cultures as a formidable prophylactic and therapeutic medicinal
agent. It is cited in the Egyptian Codex Ebers, a
35-century-old document, as useful in the treatment of heart disorders,
tumors, worms, bites and other ailments. Hippocrates and Pliny the
Elder were both promoters of garlic’s medicinal virtues. Charak (ca.
3000 BC), the father of Ayurvedic medicine, claimed that garlic
maintains the fluidity of blood and strengthens the heart. The
first-century Indian physician Charaka claimed that garlic acted as
a heart tonic and prevented heart disease (Fenwick and Hanley 1985
). Over the last 20 years, this important and exciting role
of garlic has been and continues to be confirmed by basic and clinical
research reports from around the world.
Early work.
The cardiovascular effects of garlic have been documented in several
older publications (May 1926
, Schlesinger 1926
, Taubmann 1934
); however, it was
essentially rediscovered in the late 1960s and 1970s when it became the
subject of extensive scientific research. Because people who regularly
eat larger amounts of garlic and onions have lower lipid and
cholesterol levels than people who refrain from eating these vegetables
(Sainani et al. 1976
), much of the earlier work
investigated the effectiveness of raw garlic. In the late 1970s, a
number of studies were conducted in which raw garlic was given orally
for 2–3 mo to healthy subjects and patients with ischemic heart
disease. These studies demonstrated significant reductions in blood
cholesterol and triglyceride levels after garlic ingestion
(Agarwal 1996
). The only problem with these studies was
that the dosages required to obtain these effects were relatively high
(7–28 cloves/d). One of the main problems with these studies may be
that the percentage of active constituents in fresh garlic can vary by
a factor of 10 (Newall et al. 1995
). The debate on fresh
garlic is still very much alive, and some conflicting data are evident.
Chutani and Bordia (1981)
investigated the effect of
fried vs. raw garlic on fibrinolytic activity in humans and found that
both raw and fried garlic enhanced fibrinolytic activity within hours
of ingestion and that frying preserved this fibrinolytic activity.
Fourteen years later, Ali (1995)
examined the effect of
aqueous extract of raw garlic and boiled garlic on cyclooxygenase
activity in rabbit tissues. It was concluded that raw garlic inhibits
cyclooxygenase activity, whereas boiled garlic does not. Another study
by Ali and Thomson (1995)
reported that subjects who ate
3 g of fresh garlic daily for 16 wk had a 21% decrease in
cholesterol levels, although no significant decrease was seen before 4
wk. A significant reduction in serum thromboxane was also reported in
that study. Because the composition of raw garlic differs and large
amounts are required for it to be effective, historically, it has been
difficult to convince the general population to consume garlic
regularly. Standard garlic preparations that can be incorporated into
studies under control conditions should be developed. The last decade
has seen the vast majority of work in the garlic area; since then,
various commercial preparations of garlic have appeared on the market.
Work with garlic preparations.
Several clinical trials using commercially available garlic
preparations were conducted in the 1980s and early 1990s; most of these
used dried garlic powder (Kwai). The majority of these studies
demonstrated the lipid-lowering effects of garlic; some also showed
a significant decrease in serum triglyceride levels (Reuter et al. 1996
). It was also shown that garlic reduced blood
pressure, increased fibrinolytic activity and inhibited platelet
aggregation (Reuter et al. 1996
). However, in contrast,
recent studies with Kwai garlic powder have shown no significant effect
on cardiovascular variables (Issacsohn et al. 1998
)
Studies showing no effect of garlic.
Over the last 3 years, 5 clinical trials of garlic’s effect on
cardiovascular disease have been reported; all of these studies showed
garlic to be ineffective. Morris et al. (1995)
investigated the effects of garlic extract on platelet aggregation in a
randomized, placebo-controlled, double-blind trial. They
investigated effects of feeding garlic to healthy men on platelet
aggregation, serum thromboxane and lyso-platelet activating factor
as well as the effect on platelet aggregation in vitro. No significant
differences were observed except that the in vitro aggregation of
platelets with collagen decreased linearly with increasing amounts of
garlic extract, but the concentrations were higher than those
attainable in vivo (Morris et al. 1995
). Similarly,
Simons et al. (1995)
investigated the effects of garlic
powder (Kwai) on plasma lipids and lipoproteins in subjects with
mild-to-moderate hypercholesterolemia. This was a double-blind,
placebo-controlled, randomized crossover study in which the subjects
were asked to take 300 mg of garlic powder tablets three times per day.
This study found no demonstrable effect of garlic on lipids and
lipoproteins and also found no effect on the oxidizability of LDL
(Simons et al. 1995
). Another study in which the garlic
powder was standardized to allicin was reported by Neil et al (1996)
. This was a double-blind, randomized, 6-mo parallel
trial in which the effect of 900 mg/d of dried garlic powder
(standardized to 1.3% allicin) in reducing cholesterol was
investigated. The results of this study confirmed earlier work that
this form of dried garlic powder was less effective in reducing total
cholesterol than had been suggested by previous meta-analyses
(Neil et al. 1996
). Two trials reported this year, one
with garlic powder and the other with garlic oil, again failed to
demonstrate any significant reduction in serum lipids. Isaacsohn et al. (1998)
conducted a randomized, placebo-controlled
trial in which they investigated the effect of 900 mg/d of dried garlic
powder (Kwai) on serum cholesterol levels. Their conclusion was that at
this dosage for 12 wk, garlic powder was ineffective in lowering
cholesterol levels in patients with hypercholesterolemia.
Steam-distilled garlic oil preparation (5 mg twice per day for 12
wk) was used in a double-blind, randomized, placebo-controlled
trial by Berthold et al. (1998)
. The conclusion of this
study was that this commercial garlic oil preparation had no influence
on serum lipoproteins, cholesterol absorption or cholesterol synthesis.
The recent data from the clinical trials outlined above contradict some
of the results reported earlier. This could be due to several factors,
including a lack of consistency among studies in relation to dosage,
standardization of garlic preparations and period of treatment.
Although many of these studies using garlic powder claimed the
potential of allicin, it is recognized that allicin is unstable and is
not absorbed on ingestion; studies on the fate of allicin are rare
(Lawson et al. 1992
). In addition, garlic preparations
that are produced by heat or solvent extraction processes are stated to
contain alliin but to be devoid of allinase; hence no allicin may be
formed. Garlic oil macerates and steam-distillation products are
rich in secondary metabolites such as ajoene. However, it is unclear to
what extent these secondary compounds are formed in the body after the
ingestion of garlic and whether their actions can be compared with
those of fresh garlic (Newall et al. 1995
).
In contrast to the above studies, there have also been some recent clinical trials showing garlic to be cardioprotective. These studies have incorporated a different garlic proprietary, commercially available product, which is particularly rich in S-allyl cysteine, a water-soluble, sulfur-containing amino acid; however, it also contains other compounds.
Studies showing garlic to be cardioprotective.
Aged garlic extract (Kyolic) was found to be effective in lowering
serum cholesterol and triglycerides in hyperlipidemic patients in a
randomized study conducted by Lau et al (1987)
. Subjects
took four 1-mL capsules containing 250 g/L dry weight of the active
garlic components. More recently, Steiner et al. (1996)
reported the results of a double-blind crossover study in
moderately hypercholesterolemic men in which the authors compared the
effect of aged garlic extract and placebo administration on blood
lipids. Aged garlic extract (7.2 g) was given as a dietary supplement
for 6 mo. In that study, reductions of 6% in total cholesterol, 4% in
LDL and 5.5% in systolic blood pressure were obtained. Because oxygen
radical injury and lipid peroxidation have been suggested as major
causes of various diseases including atherosclerosis, Ide et al. (1997)
reported that aged garlic extract inhibits oxidative
modification of low density lipoprotein (LDL), hence slowing down or
preventing atherosclerosis. In support of these findings, Bordia et al. (1996)
investigated the effect of garlic on platelet
aggregation in healthy subjects and patients with coronary artery
disease. They found that long-term administration of a low dosage
of garlic led to inhibition of platelet aggregation. The modulation of
lipid profiles by garlic in combination with fish oil has also been
reported by Morcos (1997)
, using a single-blind,
placebo-controlled crossover study involving 40 subjects. After 1 mo,
decreases of 11% in cholesterol, 34% in triglycerides, 10% in LDL
and 19% in cholesterol/HDL ratio were observed.
Overall, the studies to date give a conflicting message, which can be confusing for consumers and health care professionals. These differences are probably due to the following: 1) the amount of active constituents in raw garlic can vary; 2) because different garlic preparations have been used, there is a need to establish active constituents; and 3) standardized commercial preparations must be used such that bioavailability, toxicology and tolerance data are available.
Most of the published studies have been performed in subjects in whom
cardiovascular disease is apparent. It is perhaps more important to
investigate whether garlic taken as a dietary supplement can either
delay or prevent cardiovascular disease. Such studies are now being
performed and published. One of the early studies was conducted by
Legnani et al. (1993)
in which the authors investigated
the acute and chronic effects of dried garlic powder on platelet
aggregation in apparently healthy subjects. At a dose of 900 mg/d, a
significant reduction in platelet aggregation occurred. More recently
Effendy et al. (1997)
investigated the effect of aged
garlic extract, "Kyolic," on the development of experimental
atherosclerosis in rabbits. Their conclusion was that Kyolic treatment
reduced fatty streak development, vessel wall cholesterol accumulation
and the development of fibro-fatty plaques in neointimas of
cholesterol-fed rabbits, thus providing protection against the
onset of atherosclerosis.
We also recently conducted a clinical trial in our laboratory and asked
the question, "Is aged garlic extract a cardioprotective agent?"
This trial was conducted in apparently healthy subjects who took 5 mL/d
of aged garlic extract for 3 mo. Blood samples were taken at the
beginning and the end of the study. There was a significant reduction
in platelet aggregation and also a significant reduction in the
circulating levels of thromboxane B2 at the end
of the aged garlic extract ingestion. No significant differences were
found in the circulating levels of 6-keto
PGF1
; therefore, we concluded that aged garlic
extract when taken as a dietary supplement can act as a
cardioprotective agent.
Summary
Despite conflicting studies, possibly due to the use of different preparations and different experimental protocols, the historical perspective on garlic points toward its positive role in either preventing or delaying cardiovascular disease, i.e., reducing serum lipids, blood pressure and platelet aggregation. However, further controlled human studies with standardized preparations and known and established active constituents are required to establish the true usefulness of this remarkable herb in reducing or preventing cardiovascular disease.
FOOTNOTES
1 Presented at the conference "Recent Advances on the Nutritional Benefits Accompanying the Use of Garlic as a Supplement" held November 15–17, 1998 in Newport Beach, CA. The conference was supported by educational grants from Pennsylvania State University, Wakunaga of America, Ltd. and the National Cancer Institute. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors: John Milner, The Pennsylvania State University, University Park, PA and Richard Rivlin, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY. 
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