The Cardiovascular Benefits of Garlic Consumption

The Cardiovascular Benefits of Garlic Consumption A positional paper for the general public Patrick Hargrave Spring 2005 A paper for Health and Fitness magazine or a Nutritional Journal

1 Cardiovascular disease is considered to be the major cause of death in the United

States. Whether the deaths are related to biological factors, such as genetics or high cholesterol levels, cardiovascular disease is a major concern for many Americans. With obesity on the rise and more than half the population experiencing heart problems, solutions to heart disease are becoming more and more necessary. As healthcare cost and insurance premiums continue to rise people are seeking alternative ways to help treat their ailing hearts. Cheaper methods of treating cardiovascular disease have begun to surface as terms such as alternative and naturopathic medicine become more and more popular. Whether it is yoga or taking vitamins or supplements of some variety, research is now being conducted at an increasingly rapid rate to discover alternative forms to treating and preventing cardiovascular disease. One such supplement in particular has drawn increased attention from researchers over the past decade. The natural herb garlic, is growing ever so popular amongst the elderly as well as the young as a way to treat and prevent various parameters, such as blood pressure, cholesterol levels, fatty streak formation on walls of arteries, and other biological factors that are associated with cardiovascular disease.

The cardiovascular benefits derived from garlic may be due to the bioavailability of the cultivated garlic supplement to yield the compound allicin (Lawson, 1998). Allicin is released when garlic is broken down. This compound that researchers discovered has many beneficial effects in terms of cardiovascular health. It has shown to have antiatherosclerotic (therapeutic), antiatherogenesis (preventative), as well as antithrombocytic (anticoagulant) properties. By examining past and recent studies on

2 humans as well as animals I will show the beneficial effects garlic has on cardiovascular health.

The effect of garlic on various factors of cardiovascular disease has puzzled researchers over the past decade. Its supplementation can come in various forms which makes corroborating multiple study results difficult. The most commonly used and researched form of cultivated garlic supplementation is aged garlic extract (AGE) taken in tablet form. This preparation of garlic supplementation has been the subject of many studies done in the 1990’s on its effects on cardiovascular health.

Garlic Studies on CVD 20 s d

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As eluded to in the figure above, multiple studies have been done on the effects of garlic, but have had inconclusive results. The graph depicts studies done throughout the

1990’s that have used the same aged garlic extract tablet (AGE) from Thailand called

Kwai. Although the graph does illustrate mixed effects from taking this form of a garlic supplement the results are more beneficial than the data suggest.

In the earlier studies conducted in the 90’s, garlic showed many beneficial effects in improving cardiovascular health. Jain et al. (1993) and Mader et al. (1990), both concluded that garlic helped treat cardiovascular disease by lowering cholesterol

3 levels. Jain et al. (1993) tested 53 men, mean age of 50, who had high cholesterol levels

(blood lipid contents greater than 220 mg/dl) and prescribed the subjects 900 mg garlic tablet daily for twelve weeks and observed the effects of the supplement on total cholesterol levels, low-density lipoproteins (bad cholesterol), high-density lipoproteins

(good cholesterol), and triglyceride levels. They found that total cholesterol decreased by

5.7%, LDL decreased 10.6%, and HDL and triglyceride levels were unchanged. Mader et al. (1990) prescribed an 800 mg garlic tablet daily for 12 weeks to 261 male and female hypercholesterolemic (total cholesterol and triglyceride levels greater than 200 mg/dl) patients and measured garlic’s effect on total cholesterol and triglyceride levels.

They observed that garlic did have beneficial effects as total cholesterol levels and triglyceride levels decreased significantly by 12% and 17% respectively.

Although these results were significant in favor of garlic, a limitation to these two studies should be noted. For both studies, the stabilization period was short, lasting only two weeks. This short period of time may not have been sufficient enough to stabilize the cholesterol levels of the subjects which could possibly have resulted in inaccurate blood cholesterol measurements.

The two aforementioned studies conducted in the early 90’s found garlic to be beneficial in improving cardiovascular health but more recent studies conducted in the late 1990’s and 2001 disagreed with those findings and found that garlic had either no effect at all or the results were not significant. Gardner et al. (2001) tested 51 men and women age 50 with moderate hypercholesterolemia (130-190 mg/dl) for a period of 12 weeks and found that LDL levels decreased by only 6%, total cholesterol decreased by

4 4%, triglyceride levels by 6%, and increased HDL levels by 6% but the results were all insignificant compared to the baseline measurements.

These results of the Gardner et al. study agreed with findings of other studies that were conducted during the same time frame that used the same dosages and subject characteristics. Issachsohn et al. (1998) observed the effects of a 900 mg/day garlic tablet on 50 men and women age 57 with hyperlipidemia (high cholesterol levels). They found no significant changes: LDL increased by 2%, total cholesterol increased by 1%, and no change was observed in HDL and triglyceride levels. Neil et al. (1996) found similar results with their study of 53 year old male and female subjects with severe (total cholesterol , 252 mg/dl-348 mg/dl) hyperlipidemia. Subjects in this study were prescribed a 900 mg garlic tablet daily for 6 months. Although specific data could not be obtained for this study, no significant differences in total cholesterol, LDL, HDL, triglyceride levels were observed by the researchers.

These three studies used longer stabilization periods of 6-8 weeks as opposed to the short 2 week period from the earlier studies. This may have given researchers more accurate cholesterol level readings, which would lead to more accurate conclusions regarding garlic’s effect on lipid levels. The Neil et al. study was also conducted for a longer period of time (6 months) as opposed to the 3 and 4 months of the other disagreeing studies giving a longer perspective of garlic’s influence on CVD.

The group of studies conducted throughout the 1990s and 2001 had inconclusive results with close dosages and population characteristics. Therefore, several conclusions regarding the accuracy and validity of the studies must be observed. In a recent review conducted by Lawson (1998), attention was brought concerning the

5 bioavailability of the compound allicin in relation to the garlic supplements that were given to subjects during experiments in the late 90’s and 2001. Lawson discovered in his bioavailabilty experiment where he extracted allicin from the garlic tablets of studies done in throughout the nineties in order to test the actual amount of allicin in the garlic supplements. He discovered that the garlic tablets that were being prescribed to subjects in the early 90s had 3 times the bioavailability of allicin than the tablets being taken by subjects in the more recent studies (Lawson 2001). This would explain the insignificant results experienced by subjects in the later studies conducted and the beneficial results of garlic on cardiovascular health that researchers observed in the earlier studies.

The studies using garlic powder demonstrated that the release of allicin is a major factor in deriving cardiovascular benefits from garlic consumption. While garlic powder is the most widely used form of garlic supplementation it may lack efficiency in delivering allicin to the body. The high acidity of gastric juices in the stomach leads to the breaking down and dilution of allinase the enzyme that eventually forms allicin

(Zhang et al. 2001). As a result of garlic powder tablets and their susceptibility to gastric juices researchers have begun studying various alternatives to tablet supplementation which hope to yield more allicin release than the previous researched garlic tablets.

It has been established that the enzyme allicin is responsible for the beneficial effects of garlic on cardiovascular disease but the susceptibility of the garlic tablet to the digestive process causes less allicin to be released into the blood stream. It is this reason why a better protected garlic supplement in the from of a gel capsule filled with the same allicin releasing content will have greater cardiovascular benefits than a garlic tablet with the same allicin releasing potential.

6 To illustrate this hypothesis that the delivery of bioactive agents from garlic oil

gel capsules is more efficient than that of a garlic tablet, a study was conducted by Zhang

et al. (2001). They decided to test 78 (39 males, 39 females) healthy subjects, mean age

24, and examine the affects of garlic powder and garlic serum in gel capsules on their

cardiovascular health. A total of 78 healthy subjects were split into 3 groups. 26 subjects

took 8.2 mg/dl of a gel capsule serum garlic supplement, 26 took a placebo for 11 weeks,

and the other 26 subjects were given garlic powder of the same relative dose with the

same allicin releasing potential.

Comparison between garlic gel capsule supplement and tablet supplement in men and women Cardiovascular Male garlic Female garlic Male garlic Female garlic disease factors capsule capsule tablet tablet Total .11* -.5* .19 -.22 cholesterol (mmol/l) HDL (mmol/l) -.08* .16* .05 .05 LDL (mmol/l) .29* -.63* .16 -.28 Triglycerides -.23 -.06 -.03 0 (mmol/l) Blood Glucose -.49# .16# -.31 .15 (mmol/l) *Denotes greater significance for women over men # Denotes greater significance for men over women

They found that in healthy males and females the garlic gel capsule worked more

efficiently than the garlic tablet in bypassing the body’s digestive processes. Although

the magnitude was small and insignificant for several factors, which could have been due

to the already healthy state (low levels of cholesterol) of the subjects, a striking

difference was observed between the reactions of men and women to the garlic gel

capsule. The women showed significant cardiovascular benefits of raised HDL levels,

and greater drops in LDL and total cholesterol levels over the men, while the men

7 showed a more significant drop in glucose levels over the women. This significant drop in glucose levels over the women observed by the researchers is due to the peripheral uptake of glucose and reduction in fasting plasma glucose levels that are both greater than in women (Zhang et al. 2001).

The significant benefit of lowered cholesterol levels seen in women is due to a lipid regulating process influenced by garlic called protein phosphorylation. Protein phosphorylation is caused by the enzyme AMP-dependent kinase (AMPK) which inhibits hydroxyl-methyl-CoA-reductase and acetyl-CoA-carboxylase which are both rate controlling enzymes for the synthesis of cholesterol and fatty acids (Zhang et al. 2001).

Therefore greater activation of AMPK in the liver cells of females amplifies the inhibitory effects of lipid biosynthesis thus leading to the significant decrease in total cholesterol and LDL levels.

The importance of the bioavailability of allicin from garlic supplements is a definitive factor in whether cardiovascular benefits are derived from a garlic supplement.

I have shown that greater yield of allicin is seen in supplements that are more protected from the gastric juices of the stomach i.e. gel capsule supplements. But as the beneficial effects have been seen with the aged garlic extract tablets as well as the garlic oil gel capsules, it is difficult to see a clear cut consensus on the positive results from these studies. All of these studies used garlic extracts from the more renowned cultivated garlic (allium sativum). But greater effects may be seen in the lesser known wild uncultivated garlic (allium ursinum). Due to higher angiotensin-converting enzyme

(ACE) inhibition and higher adenosine content over cultivated garlic, wild garlic will have greater pressure lowering effects than the previously studied cultivated garlic.

8 In a study conducted by Mohamadi et al. (2000) study involving 40 rats with cholesterol induced hypertension three different garlic preparations were fed to 30 rats while 10 remained as a control group. As seen below the rats who received garlic supplementation in their diets had significantly reduced systolic blood pressure over the control group. The three preparations of garlic: low allicin cultivated garlic (LACG), high allicin cultivated garlic (HACG), and wild garlic (WG), are represented in the graph below as being significantly effective in lowering blood pressure. The pressure lowering effects of wild garlic were significantly more effective than the LACG in lowering blood pressure and more effective than the HACG but by an insignificant amount (Mohamadi et al.).

Garlics Effect on SBP 190 )

g 185 Control H / 180

m LACG 175 m ( 170 HACG P

B 165 WG S 160 0 0.1 0.5 1 Garlic Concentration (w/w)

The greater decrease in systolic blood pressure as illustrated by the graph above suggest that the antihypertensive properties of garlic are dose related as a greater decrease in SBP was observed as garlic concentrations were increased. The greater pressure lowering effects of wild garlic over cultivated garlic is attributable to the ACE-inhibiting effects of gamma-glutamyl peptides (Mohammadi et al. 2000), which wild garlic contains twice as much of. These peptides inhibit synthesis of angiotensin II which binds to AT receptors (Mohammadi et al.) and causes thickening of artery walls that leads to greater blood viscosity. Therefore, greater circulation of these gamma-glutamyl peptides will

9 cause greater inhibition of angiotensin II binding thus decreasing viscosity and allowing blood to flow more smoothly throughout our bodies.

It is hard to accept that the beneficial affects of garlic on rats can be conducive to humans. But when comparing rat and human models of hypertension, both have similar pathogenic mechanisms and responses to treatment of hypertension (Mohammadi et al.

2000). Although human subjects are hard to come by, the biological similarities between humans and rats are similar and it is widely agreed upon in the scientific community that scientific discoveries on rats can be related to humans (Mohammadi et al.).

There are many possibilities that would result in the improvement of cardiovascular health from the intake of garlic. The reduction of total cholesterol levels as well as LDL, HDL, and triglyceride levels experienced by most subjects in the studies is a direct result of allicin release from the garlic. The lipid lowering effect of allicin may be due to its ability to reduce the oxidative properties of LDL in our blood. In 1993

Phelps and Harris took 6 volunteers who had hypercholesterolemia and prescribed them a

600mg/day tablet of a garlic powder supplement for two weeks. Although two weeks was not enough time to significantly have an influence on serum lipid levels or blood pressure they discovered that garlic did significantly reduce blood lipoprotein oxidation by 34% (Phelps & Harris 2003). Another discovery by Sendl et al. (1992) used liver homogenate to test inhibition of cholesterol synthesis and found that extracts from cultivated garlic and wild garlic of 166 mg/ml inhibited cholesterol synthesis 42%-52% with both extracts.

It is illustrated from the above mentioned studies that allicin has many therapeutic properties that help to alleviate blood coagulation as well as cholesterol synthesis. But

10 another main issue arises concerning the compounds preventative properties. Very few studies have been done to test preventative measures of the garlic extract and its influence on preventing fat formation around several key organs such as the liver and most importantly the arteries around the heart. One such study in a laboratory setting by

Abramowitz et al. (1999) tested 60 rabbits, 30 controlled, 30 treated with 9 mg/kg allicin solution for 15 weeks. They wanted to observe possible preventative effects of allicin on the formation of fatty streaks (atherosclerosis) on the aortic wall of the heart. They found that the area of fatty streak formation was significantly reduced by 3600 micron in the treatment group over the control group (figure 4 below). This result is very significant and meaningful when it comes to preventing cardiovascular disease.

Form ation of Fatty Streaks in Aortic Sinus 30000 )

20000 a 15000 allicin e r 10000 control A 5000 0 allicin control

Fat deposits surrounding the heart make it harder for the heart to work and pump blood throughout the body. If enough fat attaches to the artery walls coming off the heart, the heart becomes overworked and eventually stops working resulting in a heart attack. The discovery of this prevention along with the Sendl et al. discovery (1992) and

Phelps and Harris (1993) proved that garlic and its active compound allicin can be an effective preventative measure as fatty streak formation and cholesterol synthesis were significantly reduced.

11 Although the results in the Abramowitz et al. (1999) study above were significant in reducing the formation of fatty streaks inside the aortic wall, there were no observed significant effects on the LDL, HDL profiles in the blood of the rats. Despite this deficiency in effects on lipid levels it should be noted that the amount of blood that was drawn from the rats was minimal and cannot be represented as an accurate blood sample

(Abramowitz et al.).

The strength of the arguments for the beneficial affects of garlic on several factors involving heart disease is clearly evident. With several studies supporting garlic’s preventative, therapeutic, and anticoagulant properties with multiple doses as well as with different subjects the results seem to be conducive to the American public. Garlic has been shown to help subjects no matter whether their cholesterol levels were low (Zhang et al. 2001) or high (Mader et al. 1990, Jain et al. 1993). The inhibition of cholesterol synthesis (Sendl et al 1992), reduction in oxidation of LDL cholesterol (Phelps & Harris

1993), and the decline in fatty streak formation (Abramowitz et al. 1999), is evidence of the herbs preventative effects against cardiovascular disease.

Garlic also has proven to have therapeutic properties. In several studies involved in the early 90s where subjects were prescribed a garlic powder tablet daily, total cholesterol levels as well as LDL levels were shown to decrease significantly and certain studies showed triglyceride levels decreasing by a significant amount. Although studies in the later nineties found insignificant results with the same garlic preparation, an experiment by Lawson (2001) found that the Thai garlic supplement in the early nineties had three times the bioavailability of allicin that the tablets prescribed in the late nineties.

Another study by Mohammadi et al. (2000) showed that the beneficial effects of garlic

12 appeared to be dose related as greater pressure lowering effects were found in rats with greater garlic and allicin concentrations in their diets. This important discovery that allicin was the compound in garlic that yields its cardiovascular benefits led the way for more complete studies to be conducted in order to evaluate the affects of greater allicin bioavailability on cardiovascular disease factors.

Zhang et al. showed that the bioavailability of allicin is more potent when garlic was protected from the stomachs digestive process. This lead to greater decreases in

LDL, total cholesterol, and triglyceride levels in males and females over the control group and the garlic powder supplement group.

These studies showed the bioavailability of allicin to be a deciding factor in garlic’s therapeutic methods but the preventative and anticoagulant properties of the herb were also proven. Sendl et al. proved that garlic can inhibit cholesterol synthesis by 50%.

Phelps and Harris proved that even in the short term, garlic inhibited LDL oxidation by

34% and Abramowitz et al. discovered that allicin was highly effective in alleviating high blood pressure, addressing garlic’s anticoagulant properties. In light of overwhelming support for the therapeutic, preventative, and anticoagulant properties of garlic from studies thus far and due to the lack of contradictory bioavailability studies I believe it can be stated that greater cardiovascular benefits may be derived from taking a garlic supplement that is high in allicin and is better protected from the gastric juices of the stomach.

13 References

Abramowitz D., Gavri S., Harats D., Levkovitz H., Mirelman D., Miron T., et al. (1999). Allicin-induced decrease in formation of fatty streaks (atherosclerosis) in mice fed a cholesterol-rich diet. Coron Artery Dis (Coronary artery disease.) 1999 Oct; 10(7): 515-9

Gardner C., Chatterjee L., Carlson J. (2001). The effect of a garlic preparation on plasma lipid levels in moderately hypercholesterolemic adults. Atherosclerosis 154, 213-220

Harris WS., Phelps S. (1993). Garlic Supplementation and lipoprotein oxidation susceptibility. In: Lipids (May) 285; 475-7

Isaachsohn, J.L., Moser, M., Stein, E. A., Dudley, K., Davey, AJ.A., Liskov, E., & Black, H.R. (1998). Garlic powder and plasma lipids and lipoproteins: A multi-centered randomized, placebo-controlled trial. Archives of Internal Medicine, 158(11), 1189-1194.

Jain, A. K., Vargas, R., Gotzkowsky, S., & McMahon, F.G. (1993). Can garlic reduce levels of serum lipids? A controlled clinical study. The American Journal of Medicine, 94(6), 632-635.

Lawson, L.D. (2001). Garlic for total cholesterol reduction. Annals of Internal Medicine, 135(1), 65-66.

Lawson, L.D. (1998). Garlic: A review of its medicinal effects and indicated active compounds. In: L.D. Lawosn & R. Bauer, Phytomedicines of Europe: Chemistry and Biological Activity. American Chemical Society Symposium series 691 (pp. 176-209). Washington DC: American Chemical Society, 176-209.

Mader, F.H. (1990). Treatment of hyperlipidemia with garlic-powder tablets. Arznemittel Forschung, 40(10), 1111-1116.

Mohammadi A., Jarrel S., Shi S., Andrawis N., Myers A., Clouatre D., & Preuss H. (2000). Effects of Wild versus Cultivated Garlic on Blood Pressure and Other Parameters in Hypertensive Rats. Heart Dis (Heart disease (Hagerstown, Md.)) 2000 Jan-Feb; 2(1): 3-9 Niel, H.A., Silagy, C.A., Lancaster, T., Hodgeman, J., Vos, K., Moore, J.W., et al. (1996). Garlic powder in the treatment of moderate hyperlipidemia: A controlled trial and meta-analyses of randomized clinical trials. Journal of the Royal College of Physicians of London, 30(4), 329-334.

14 Sendl A, Schliack M, Losu R, Stanislaus F, Wagner H. Inhibition of cholesterol synthesis in vitro by extracts and isolated compounds prepared from garlic and wild garlic. Athersclerosis 1992; 94: 79-85.

Zhang et al. (2001). Gender may affect the action of garlic Oil on plasma cholesterol and Glucose levels of normal subjects. Journal of Nutrition, 131, 1471-1478