Chocolate and Prevention of Cardiovascular Disease: A Systematic Review

However, the observational studies of stearic acid's association with CVD are inconclusive. (Table 2) Among retrospective studies, a Japanese case-control study of serum levels reported no association for stenosis [61], a Norwegian study found lower odds of MI [62], while a Costa Rican study of dietary intake found higher risk of MI [63] with higher intake of stearic acid. However, the results from the Costa Rican study should not be given much weight since retrospective self-report of dietary intakes are notoriously inaccurate and susceptible to reporting bias [64]. Nevertheless, higher rates of CHD and CAD progression was found in several prospective studies [65‐68], while stroke was not increased in another study [69].

On the other hand, several limitations exist for observational studies of stearic acid. First, researchers have cautioned that analyses of dietary stearic acid are very difficult due to high correlations of stearic acid intake with other fatty acids (often r = 0.7 to 0.9), thus impeding optimal study of associations [65]. Additionally, the larger prospective study that found higher risk of CHD also noted chocolate was a very small contributor (5%) of total stearic acid intake, with red meats as primary sources of stearic acid. Finally, since there exists high interconversion of stearic acid to unsaturated fatty acids [35, 42‐45], studies involving serum levels of stearic acid do not answer the relevant causal question of dietary intake of stearic acid and risk of disease. The associations of long-term serum stearic acid levels represent the effects of post-conversion stearic acid levels after a large proportion of the original dietary stearic acid has already been converted away to monounsaturated fat, which is well-established to exert protective effects against CVD [3, 27, 46‐49].

Thus, relatively little information can be inferred from observational studies of the association of stearic acid and CHD, and no epidemiologic study has, thus far, appropriately and optimally answered the causal question of the association of dietary stearic acid intake and risk of CVD. However, a sufficient body of strong evidence from short term randomized trials suggests stearic acid components in chocolate may be beneficial for cardiovascular health. However, further research in this area is warranted.

Chocolate flavonoids have shown good dose-response bioavailability in humans [11, 78, 79]. There exists several mechanisms of how flavonoids may be protective against CVD; these include: antioxidant, anti-platelet, anti-inflammatory effects, as well as possibly increasing HDL, lowering blood pressure, and improving endothelial function. The body of trials involving chocolate flavonoids is summarized in Table 1.

Central to the pathogenesis of atherosclerosis is the oxidation of low-density lipoprotein (LDL). The chemical structure of flavonoids gives the compound free radical scavenging ability, which means flavonoids may have antioxidant effects [80]. Various studies have confirmed the role of flavanoids as antioxidants in biological systems. Flavanoids in chocolate have been shown to exert potent antioxidant effects in vitro assays under artificial oxidative stress [13, 81‐84] as well increase antioxidant capacity as part of various chocolate feeding trials [79, 85‐89]. Additionally, because lipid soluble flavonoids may intercalate into the membranes of lipoprotein particles, studies have shown flavonoids to decrease lipid peroxidation of biological membranes [90]. Furthermore, a randomized trial also demonstrated that flavonoid-rich foods can protect human lymphocytes from oxidative damage in vivo [91].

Additionally, aggregation of platelets at the site of plaque rupture and endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Current research has shown that a number of components of chocolate, particularly catechin and epicatechin, have significant antiplatelet effects, quantitatively similar to that of aspirin [92]. Randomized trials studying platelet activation markers, microparticle formation and primary platelet aggregation as end points have found that daily intake of cocoa beverages produces a significant reduction in all these endpoints among healthy volunteers [93‐96]. There were also significant correlations between the reduction in these end points and the plasma concentrations of catechin and epicatechin [93‐96]. Another study found a significant reduction in platelet activation in groups consuming 100 g of dark chocolate when compared to those consuming similar amounts of white chocolate and milk chocolate [97]. In addition, randomized trials have also shown that consumption of high-flavanoid dark chocolate is associated with a significant improvement of endothelial function, marked by increase in brachial artery flow mediated dilation [98‐100], likely mediated by chocolate flavonoids increasing local production of nitric oxide [99, 100].

Chocolate may also influence levels of leukotrienes and prostacyclins. Leukotrienes are potent vasocontrictors, proinflammatory agents and stimulate platelet aggregation, whereas prostacyclin is a vasodilator and inhibits platelet aggregation. Consumption of chocolate with high procyanidin content (147 mg) was shown in a feeding trial to significantly lower the levels of leukotrienes (29%) and increase the levels of prostacyclin (32%) when compared to a group consuming a low procyanidin (3.3 mg) chocolate [101]. In vitro studies have indeed demonstrated chocolate components to inhibit lipoxygenase pathways, which gives rise to proinflammatory leukotrienes [102, 103]. Inflammation is now recognized as another independent mechanism in the pathogenesis of atherosclerosis, with various inflammatory markers having been shown to predict risk of future CVD events [104‐108]. In addition to anti-inflammatory effects on the lipoxygenase pathway, cocoa polyphenols have also been shown to decrease inflammation via several mechanisms, namely: inhibition of mitogen induced activation of T cells, polyclonal activation of B cells, reduced expression of interleukin-2 (IL-2) messenger RNA, and reduced secretion of IL-2 by T cells[109] Other have also found chocolate procyanidins can modulate of a variety of other cytokines (e.g. IL-5, TNF-α, TGF-β), reducing their inflammatory effects [110‐114].

Furthermore, multiple cocoa feeding trials have also found chocolate to increase HDL cholesterol [85, 86, 115], and decrease blood pressure [116‐119]. Finally, there are also suggestive findings in a few trials that indicate high-flavonoid chocolate may also lower LDL cholesterol [119], and improve insulin sensitivity [116].

Thus, the large body of evidence from laboratory findings and randomized trials suggest that high-flavonoid chocolate may protect against LDL oxidation, inhibit platelet aggregation, improve endothelial function, increase HDL, lower blood pressure, and reduce inflammation – thereby protective against risk of CVD.

Mechanistic studies involving stearic acid and flavonoids have only assessed effects on intermediate cardiovascular endpoints. However, one cannot always assume effects from short term trials effects will necessarily translate into long term effects on CVD outcomes. Therefore, one needs to examine observational studies followed to CVD events. While one small study found moderate consumption of candy and chocolate was associated with lower all-cause mortality [120], this analysis neither isolates chocolate nor CVD events. Thus, in absence of specific studies of chocolate flavonoids and risk of CVD, studies of all flavonoids are the best available evidence to infer risk.

The prospective studies of flavonoids and risk of CVD are summarized in Table 3. The earliest international ecologic study suggested flavonoid intake may be associated with lower rates of CHD mortality [121]. While some studies report flavonoid intake is not associated with CHD incidence [122‐124], two other prospective studies suggested flavonoids may lower risk of MI [125, 126]. For stroke, the evidence is fairly consistent. Other than one small early study which found a significantly lower risk of stroke with higher total flavonoid intake [127], most studies indicated no association for risk of stroke [124, 128‐130]. However, most of these studies had insufficient power to adequately study stroke, nor enough power to stratify on various subtypes of stroke with different etiologies.

However, the most extensively consistent finding is the association between flavonoid intake and CHD mortality. A total of eight cohort studies found risk of lower CHD mortality with total or specific flavonoid intake [71, 121, 123, 125, 126, 128, 130‐132], with one study finding marginally protective association among men with prior CVD conditions [123]. Only one study reported absolutely no association between flavonoid intake and CHD mortality [133]. However, as noted by the authors of one of the studies, a high background consumption of milk with tea intake may have led to the null finding [133], since milk intake has been shown to prevent the intestinal absorption of flavonoids [76].

A meta-analysis of the 7 prospective studies prior to September 2001 found that, overall, flavonoids may be protective against CHD mortality [17]. However, this meta-analysis did not include a large subsequent cohort study of 38,445 women [124], which found a non-significant inverse association between flavonoid intake and CHD mortality. However, results from our updated meta-analysis still indicate a significant protective association exists between flavonoid intake and risk of CHD mortality, RR = 0.81 (95% CI: 0.71–0.92), comparing highest vs. lowest tertiles.

However, a limitation of inference exists in that flavonoids consists of a wide variety of polyphenol compounds, the variety of which may differ between studies due to varying sources of dietary flavonoids. Nonetheless, dark chocolate does contain substantially more flavanols than tea, apple, onions, and red wine [12]. Additionally, chocolate has all the flavonoids of tea [134], has 4 times the catechins of tea [134], has many flavonoids not found in tea [135], and substantially contributes to the total flavonoid intake in the diet of many countries [136]. However, inference from observational studies on the protective effect of flavonoids in chocolate on CVD risk is somewhat indirect and may need to be examined by further studies.

Overall, these epidemiologic findings, combined with the large body of evidence from short term randomized chocolate feeding trials, suggests flavonoid intake from chocolate is likely protective against CVD, particularly CHD mortality. Additionally, given that dark chocolate has substantially higher levels of flavonoids than milk chocolate, and that milk may inhibit absorption of flavonoids – it would be more prudent to consume high flavonoid dark chocolate rather than milk chocolate.