Atherosclerosis and lipid metabolism

Atherosclerosis is a complex disease, characterized by an excessive inflammatory, fibro-fatty, proliferative response to damage of the artery wall involving several cell types, particularly smooth muscle cells, monocyte-derived macrophages, T-lymphocyte and platelets [7]. Hyperlipidemia constitutes a major etiopathological factor for atherosclerosis. The medicinal value of garlic is best known for its lipid lowering and antiatherogenic effects.

Animal studies

Several groups of investigators [8-14] studied the effects of long term (2–9 months) feeding of garlic and garlic preparations (2% garlic powder in diet) on experimental atherosclerosis induced by a high-cholesterol diet in rabbits. Most of these studies reported a statistically significant reduction in atheromatous lesions, particularly in the aorta, that averaged about 50%.

The chronic effects of garlic on lipid metabolism in rats were also encouraging. The duration of these studies was at least 4 weeks. Garlic (1–4% in diet) and garlic protein administration in hypercholesterolemic rats induced by a high-cholesterol diet, significantly reduced serum cholesterol, triglyceride and LDL cholesterol [11,15-20] but there was no effect on serum HDL. Total lipid content and cholesterol levels in liver were also decreased in rat after chronic garlic consumption. Abramoviz et al. (1999) investigated the effect of allicin as an active component of garlic on the formation of fatty streaks in aorta and lipid profile in mice [21]. While no significant differences were observed between blood lipid profiles, the microscopic evaluation of formation of fatty streaks in the aortic sinus showed that values for mice in the allicin treated groups were significantly lower by nearly 50%.

Aged garlic extract 'Kyolic' also significantly inhibited the development of thickened, lipid-filled lesions in the pre-formed neointimas produced by balloon-catheter injury of the right carotid artery in cholesterol-fed rabbits [22,23].

Human studies

Since 1975 there have been more than 46 (from medline search) human studies on lipid-lowering effects of garlic and garlic preparations. These studies, were mostly randomized, double blind, placebo-controlled using garlic powder rather than raw garlic of 4–16 weeks, in hyperlipidemic patients. Most of these studies showed significant decrease in serum cholesterol and serum triglyceride. Only about one-third of these studies measured lipoproteins, where significant favorable changes in LDL-cholesterol level (11–26% decrease) were consistently observed. A few studies using garlic powder (having low allicin yields) failed to show any lipid lowering effects [24,25]. During the last one decade (1993–2002), 18 clinical studies have been published regarding the hypolipedemic effect of garlic. Nine studies showed negative results and garlic powder was used in seven of these studies (Table- 1) [26-34]. The different composition and quantity of sulfur components of different garlic preparations used in various studies could account for the inconsistent findings. It highlights the need for standardization of different garlic preparations and to arrive at a valid conclusion. Other factors might include the subject recruitment, duration of study, dietary control, lifestyle and methods of lipid analyses [35,36].

Four meta-analysis of randomized, placebo-controlled human studies on hypocholesterolemic effects of garlic are available [35-38]. The analyses further detected that the extent of cholesterol-lowering properties of garlic differed markedly from one study to another. Warshafsky and his colleagues deduced from five randomized clinical trials that hypercholesterolemic patients treated with garlic had a mean plasma cholesterol concentration, that was 9% lower than that of patients treated with placebo [36]. Silagy and Neil (1994) analyzed sixteen trials, with data from 952 subjects in the meta-analysis [35]. Garlic, in powder and non-powder form, significantly lowered serum lipid levels over a 1–3 month period. Serum cholesterol fell by 8% with dried powder preparations and 15% with non-powder preparations. Serum triglyceride level also dropped significantly, while HDL-cholesterol was essentially unchanged. Amongst the garlic powder preparations these effects appeared to be similar across the daily dose range of 600–900 mg. Another meta-analysis [37] revealed that there was no significant difference in the mean concentrations of serum lipids, lipoproteins or apo A1 or B amongst the groups receiving garlic (900 mg/day of dried garlic powder standardized to 1.3% allicin) and placebo. In this meta-analysis, garlic was less effective in reducing total cholesterol than suggested by previous meta-analyses. However, in a more recent meta-analysis of thirteen trials [38], garlic reduced total cholesterol level from baseline significantly more than placebo, while six diet-controlled trials with the highest scores for methodological quality revealed a nonsignificant difference between garlic and placebo groups. The available data suggests that garlic is superior to placebo in reducing total cholesterol levels. However, the size of the effect is modest, and the robustness of the effect is debatable. Therefore, the hypocholesterolemic effect of garlic remains to be firmly established.

Possible mechanism/s

Protective effect of garlic on atherosclerosis has been attributed to its capacity to reduce lipid content in arterial wall. Garlic causes direct antiatherogenic (preventive) and antiatherosclerotic (causing regression) effects at the level of artery wall [39]. Garlic depressed the hepatic activities of lipogenic and cholesterogenic enzymes such as malic enzyme, fatty acid synthase, glucose-6 phosphate dehydrogenase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase [40]. Garlic also increased the excretion of cholesterol, as manifested by enhanced excretion of acidic and neutral steroids after garlic feeding [20]. LDL isolated from human subjects given AGE [41] and aqueous garlic extract [42] was found to be significantly more resistant to oxidation. These data indicate that suppressed LDL oxidation may be one of the powerful mechanisms accounted for the benefits of garlic in atherosclerosis [43]. Allicin was identified initially as the active compound responsible for antiatherosclerotic effect. However, recent in vitro studies revealed that water-soluble organosulfur compounds, especially S-allyl cysteine (SAC), present in aged garlic extract and diallyl-di-sulfide (DADS), present in garlic oil are also potent inhibitors of cholesterol synthesis [40,44].