Garlic and Cardiovascular Disease

By Dónal P. O'Mathúna, PhD. Dr. O'Mathuna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationships relevant to this field of study.

Cardiovascular disease (CVD) is a complex group of heart-related conditions that are the leading cause of death among Americans. For most of the twentieth century, deaths from CVD rose almost exponentially, although the numbers have dropped slightly in recent years. Nevertheless, CVD still accounts for more than one-third of all US deaths.1 One in three American adults have CVD, more than half of whom are under age 60. The current estimated direct and indirect cost of CVD in the United States is about $450 billion.1 Finding safe and effective strategies to prevent and treat CVD is, thus, a major health initiative.

Many factors contribute to the development of CVD, which encompasses high blood pressure, coronary heart disease, heart failure, stroke, and congenital cardiovascular defects.1 Epidemiological studies have noted the role of elevated serum lipids, including cholesterol and triglycerides, elevated blood pressure, increased platelet aggregation, increased plasma fibrinogen and coagulation factors, alterations in glucose metabolism, and smoking.2 Improvements have been associated with increased serum levels of high-density lipoprotein (HDL), normalization of abnormal lipid levels, inhibition of platelet aggregation and, in some studies, increased antioxidant status.

The latter is tied to the role of diet in CVD, including proposals that garlic may have a role in the prevention and treatment of CVD. Garlic continues to generate the highest dollar-value in US sales of herbal remedies, totaling over $26 million in 2005.3 It is also by far the most popular herb used by patients with CVD.4

History

Over the centuries, many cultures have viewed garlic as an important dietary supplement with beneficial health effects. Ancient Ayurvedic medicine texts refer to the beneficial effects of garlic for blood flow and strengthening of the heart.5 The Egyptian Codex Ebers (1500 BC) recommended garlic for treating heart disease and also for tumors, worms, bites, and many other conditions. The ancient Greek physician, Hippocrates (400 BC), and the Roman authority, Pliny the Elder (77 AD), similarly recommended garlic for the cardiovascular system. During the earliest Olympics, athletes were encouraged to consume copious quantities of garlic to increase their stamina.6

Clinical work as early as 1926 found garlic to have beneficial effects on cardiovascular disease. These effects were again noted in the 1960s and 1970s when a number of studies noted reductions in serum cholesterol and triglyceride levels.5 However, these early studies were conducted with raw garlic administered at very high doses (between seven and 28 cloves per day). This amount of raw garlic has serious social ramifications, regardless of any health benefits.

Pharmacology

To state the obvious, garlic has an odor problem! Because of this, much work has been done to find more palatable and less odorous formulations of garlic. The odor, as well as garlic's cardiovascular effects, is caused by sulfur-containing compounds.7 An intact clove of garlic contains almost all its sulfur in one storage compound called alliin (a name coming from garlic's botanical name, Allium sativum). Raw garlic also contains an enzyme called alliinase. When raw garlic is cut or crushed, the alliinase interacts with alliin to produce allicin.8 The distinctive aroma and taste of garlic is due to allicin, which is very volatile and unstable, breaking down either in a few hours at room temperature or after 20 minutes or less of cooking. Depending on whether it is cooked in water, oil, or alcohol, different sets of compounds are formed.

As allicin breaks down or is metabolized, dozens of other more stable sulfur compounds are formed. Many of these are biologically active. If garlic is macerated with oil, allicin is converted into compounds (most commonly, ajoene, and polysulfides) that can be stable for more than a year.9 The variety of ways garlic is processed and used leads to preparations with different ratios of different compounds, which may account for some of the inconsistency observed in clinical trials.

Mechanism of Action

Garlic is believed to impact the cardiovascular system via several mechanisms of action, reflecting the presence of several biologically active compounds. Ajoene and other compounds are known to inhibit platelet aggregation, which can help prevent CVD.7 Allicin also has anti-platelet aggregating activity; however, the instability of allicin makes it difficult to study its clinical effects and those of its derivatives. A number of constituents of garlic inhibit liver enzymes involved in making cholesterol, including HMG-CoA reductase (the same enzyme inhibited by statins), and others lower plasma cholesterol and triglyceride levels via mechanisms that are as yet unclear.10 Garlic also contains antioxidants that reduce the oxidation of LDL cholesterol, thus giving rise to beneficial effects that can counteract the development of atherosclerosis. Other constituents cause smooth muscle relaxation, which could contribute to reduced hypertension.

Recent experiments have shown that human red blood cells release hydrogen sulfide (H2S) from various sulfur compounds derived from garlic.11 H2S is a naturally occurring cell signaling molecule with several cardioprotective effects, including relaxing vascular smooth muscle, decreasing blood pressure, and protecting against oxidative damage. Not only does this new research shed insight on garlic's mechanism of action, it may also lead to a means of standardizing garlic preparation.11

Clinical Studies

Many laboratory and animal tests have demonstrated that garlic and its constituents have biological activities related to CVD; however, controversy continues over the clinical significance of these results. An editorial in February 2007 asking whether garlic prevents CVD concluded that "the jury is still out."12 Results of trials have been contradictory. Another problem has been that while early studies often found beneficial effects, more recent trials have not. The more recent trials were usually larger, longer, and of higher methodological quality.

The impact of garlic on total serum cholesterol levels is the property that has received most research.9 Two meta-analyses published in 1993 and 1996 generated much interest in garlic because they reported 9% and 12% reductions in total cholesterol levels, respectively.13 Since 1993, 27 randomized, controlled trials of garlic's impact on serum cholesterol have been published; 16 showed no effect on cholesterol, but 11 showed some reduction.9 All the trials showing effectiveness had participants with elevated cholesterol levels, while those which were not effective used participants with normal or mildly elevated cholesterol levels.2 However, a 2002 review noted that in spite of earlier beneficial results, "in the last five years, no randomized, double-blind, placebo-controlled study could be found in which the results indicated a clear beneficial effect of a garlic preparation alone on blood lipids."13 Since that time, five more randomized, controlled trials found no effect from garlic supplementation in hypercholesterolemic patients.9 The most recent controlled trial randomly allocated 192 adults with moderately-elevated cholesterol levels to receive either raw garlic, one of two garlic supplements, or placebo for 6 months.14 No significant differences were found between the serum cholesterol or other lipid levels measured.

Many studies have examined the role of garlic preparations in lowering blood pressure. A 1994 meta-analysis of 10 randomized, controlled trials reported an overall significant reduction in systolic and diastolic blood pressure of 8 and 5 mmHg, respectively.9 However, a 2001 meta-analysis found 23 placebo-controlled studies of which only 4 found statistically significant reductions in blood pressure.15 This review concluded that the overall effect on blood pressure was clinically insignificant, with a subsequent 2002 review concluding that a variety of garlic preparations were of no greater benefit than placebo in treating hypertension.9 A 2007 study randomly divided 75 hypertensive patients into three groups: patients received one garlic clove, garlic tablets (2.4 mg allicin), or placebo.16 No significant differences were noted in blood pressure measurements within one hour of consumption.

Although many of garlic's components have demonstrated antioxidant effects, very few studies have been conducted on the clinical significance of these effects. The results of studies measuring serum antioxidant capacity for those taking garlic have been variable. The particular garlic preparation employed is of significant import. A product (called AGE) made by soaking garlic slivers in alcohol for 20 months, which removes almost all allicin, leaves several compounds that appear to have greater antioxidant capacity.6 The clinical impact of these preparations on CVD is not known.

Almost all the trials examining garlic's impact on fibrinolysis have had positive effects. Fibrinolysis leads to the breakdown of blood clots, and impairment of this process increases the risk of cardiovascular disease. Fibrinolytic activity, acute and chronic, has been increased with all types of garlic preparations in most of the studies examining this factor.6 Another aspect of blood clotting, platelet aggregation, also is affected by garlic. Seven clinical trials have examined this area since 1993, and all found beneficial effects.2 However, a review published in 2000 by the Agency for Healthcare Research and Quality (AHRQ) concluded that these results must be taken as preliminary.17 While all the studies identified for this review had positive results, they were very small, of limited duration, and some had serious methodological flaws.

Adverse Effects

Garlic is well-known for its problematic breath and body odor after oral ingestion. These are the most commonly reported complaints from trial participants.18 Eating raw garlic and high doses of some supplements also can cause mouth and gastrointestinal irritation, heartburn, nausea, vomiting, and diarrhea.14 Some people also are susceptible to allergic reactions to garlic, with one observational study estimating that 1.1% of people were susceptible to allergic reactions at therapeutic doses.18

The effects of garlic on platelet aggregation and fibrinolysis may increase the risk of bleeding; although few studies or case reports have found this to occur. Some case reports of postoperative bleeding have been reported.18 However, a randomized, controlled trial found no change in bleeding events among people taking warfarin when given either garlic (AGE formulation) or placebo.19 There have been theoretical concerns that allicin may stimulate enzymes involved in the metabolism of many drugs. Conversely, a number of small observational studies showed that garlic did not change the metabolism or pharmacokinetics of drugs metabolized via these enzymes.18 However, a number of patients taking HIV protease inhibitors had their drug serum levels reduced after taking garlic, suggesting that some sort of interaction occurs between these compounds.

Formulation

The two most commonly used powdered formulations are dried garlic powder and aged garlic extract (AGE). During the aging process, the volatile components are lost, thus leading to AGE being called odorless garlic. Garlic oil also is available, made using three different methods, with each leading to different mixtures of sulfur compounds. The most commonly used dosage form in clinical trials is a standardized garlic powder extract called Kwai (200-400 mg tid).

Conclusion

Overall, garlic preparations have some value as a complementary agent in reducing some risk factors associated with cardiovascular disease. The evidence from studies conducted in the 1990s suggested a broad range of modest benefits. However, additional, recent, higher-quality studies have found more limited benefits. Cholesterol-lowering and hypertension-reducing effects have not been replicated in the more recent trials. Garlic does contain a number of antioxidants, and has anticoagulant effects which may translate into beneficial cardiovascular effects. Given its relatively good safety profile, garlic may provide some protection against CVD.

Recommendation

Given the many associations between garlic and cardiovascular health, and the results of some research studies, garlic can be recommended as part of an overall heart-healthy diet. One clove a day should provide sufficient sulfur compounds, though this is debated and very much open to personal taste. The use of garlic supplements in place of effective treatments for CVD should be discouraged. Earlier claims that garlic reduces cholesterol levels or blood pressure have not been borne out in recent studies. While garlic supplements are generally safe, people taking garlic should be closely monitored for allergies and interference with concurrent anticoagulant or HIV protease therapy. The diversity of garlic formulations available makes it difficult to recommend specific brands.

References

1. American Heart Association, American Stroke Association. Heart disease and stroke statistics: 2008 update. Available at: www.americanheart.org/presenter.jhtml?identifier=3000090. Accessed January 13, 2008.

2. Rahman K, Lowe GM. Garlic and cardiovascular disease: A critical review. J Nutr. 2006;136:736S-740S.

3. Blumenthal M, et al. Total sales of herbal supplements in United States show steady growth. HerbalGram. 2006;71:64-66.

4. Pharand C, et al. Use of OTC and herbal products in patients with cardiovascular disease. Ann Pharmacother. 2003;37:899-904.

5. Rahman K. Historical perspective on garlic and cardiovascular disease. J Nutr. 2001;131:977S-979S.

6. Banerjee SK, Maulik SK. Effect of garlic on cardiovascular disorders: A review. Nutr J. 2002;1:4-18.

7. Rahman K. Effects of garlic on platelet biochemistry and physiology. Mol Nutr Food Res. 2007;51:1335-1344.

8. Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr. 2006;136:716S-725S.

9. Pittler MH, Ernst E. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res. 2007;51:1382-1385.

10. Allison GL, et al. Aged garlic extract and its constituents inhibit platelet aggregation through multiple mechanisms. J Nutr. 2006;136:782S-788S.

11. Benavides GA, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA. 2007;104:17977-179782.

12. Charlson M, McFerren M. Garlic: What we know and what we don't know. Arch Intern Med. 2007;167:325-326.

13. Brace LD. Cardiovascular benefits of garlic (Allium sativum L). J Cardiovasc Nurs. 2002;16:33-49.

14. Gardner CD, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: A randomized clinical trial. Arch Intern Med. 2007;167:346-353.

15. Ackermann RT, et al. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001;161:813-824.

16. Capraz M, et al. Garlic, hypertension and patient education. Int J Cardiol. 2007;121:130-131.

17. Mulrow C, et al. Garlic: Effects on cardiovascular risks and disease, protective effects against cancer, and clinical adverse effects. Rockville, MD: Agency for Healthcare Research and Quality; 2000. AHRQ publication 01-E023. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.28361. Accessed Jan. 12, 2008.

18. Borrelli F, et al. Garlic (Allium sativum L.): adverse effects and drug interactions in humans. Mol Nutr Food Res. 2007;51:1386-1397.

19. Macan H, et al. Aged garlic extract may be safe for patients on warfarin therapy.J Nutr. 2006;136:793S-795S.