A chocolate a day keeps the doctor away?

Epidemiological studies linking cardiovascular benefits to chocolate consumption have proliferated in recent years generating significant interest in the health benefits of chocolate in both the medical community and the lay press. Studies of the Kuna Indians in Panama, who consume large amounts of a natural cocoa beverage, have found lower blood pressures, better renal function and decreased cardiovascular mortality relative to Panamanian control populations (Katz et al. 2011). Similar investigations in American and European populations have demonstrated significant associations between chocolate intake and improved blood pressure as well as cardiovascular and all-cause mortality (Katz et al. 2011). A recent meta-analysis demonstrated a chocolate-associated reduction in cardiovascular disease risk of 37% and a reduction in stroke risk of 29% (Heiss et al. 2010; Buitrago-Lopez et al. 2011). The tantalizing epidemiological evidence has led to in vitro, animal and human studies designed to identify clinical benefits from chocolate and elucidate the mechanisms and active compounds responsible for those benefits. Numerous small-scale, brief clinical intervention studies using dark chocolate in normal volunteers and subjects at risk for or with established cardiovascular disease have been performed. These trials have demonstrated improvements in peripheral and coronary vascular endothelial function, blood pressure, lipids, glucose tolerance and inflammatory markers (Katz et al. 2011). As chocolate is a complex mixture of compounds, identification of any single agent mediating these beneficial effects is challenging. (–)-Epicatechin, one of several flavonoids found in red wine, green tea, apples and in particularly high concentrations in dark chocolate, has emerged as a likely candidate. One study of normal volunteers demonstrated that serum (–)-epicatechin levels increased after dark chocolate administration and that administration of pure (–)-epicatechin (the only study in humans to date) recapitulated the vascular effects seen with dark chocolate (Katz et al. 2011). Studies using dark chocolate in humans and pure (–)-epicatechin in vitro and in animal models have identified a variety of mechanisms that could underlie clinical benefits. Increased levels of nitric oxide, prostacyclin, circulating angiogenic cells and reductions in endothelin-1, platelet activation, inflammatory cytokines, reactive oxygen species, metalloproteinases and growth factors have all been observed. In a recent issue of The Journal of Physiology, Nogueira et al. (2011) make an important contribution to this list by presenting evidence that (–)-epicatechin also acts via effects on mitochondria. In their study, mice treated with (–)-epicatechin demonstrated improvements in mitochondria that included increased volume, cristae density and protein content for oxidative phosphorylation complexes and organelle membrane in skeletal and cardiac muscle. In addition, notable increases were seen in skeletal muscle capillary density. All of these observed effects were further enhanced in mice subjected to an exercise training regimen. Improvement in mitochondrial function could explain the findings from two other recent studies as well. In one, treatment of rats with 10 days of (–)-epicatechin reduced myocardial infarct size 48 h after ischaemia reperfusion injury (Yamazaki et al. 2008). In another, rats treated with (–)-epicatechin for 10 days prior to permanent coronary occlusion had markedly decreased myocardial infarct size at 48 h and 3 weeks and preserved cardiac haemodynamics at 3 weeks (Yamazaki et al. 2010). Mitochondrial dysfunction is important in ischaemic cardiac injury and epicatechin mediated improvements in mitochondrial function could be responsible for the finding of reduced infarct size in these studies. Evidence of the contribution of mitochondrial dysfunction in the development and maintenance of cardiovascular and metabolic diseases has increased rapidly in recent years, as has interest in therapies that target mitochondrial dysfunction (Rosca & Hoppel, 2010). The findings from Nogueira et al. and other recent studies suggest a possible clinical role for (–)-epicatechin in the treatment of human diseases, particularly those with skeletal muscle and cardiovascular pathologies. One could hypothesize benefits from (–)-epicatechin treatment in conditions such as type 2 diabetes, hypertension, coronary artery disease, left sided heart failure and right heart failure secondary to pulmonary arterial hypertension (PAH). (–)-Epicatechin as a treatment for PAH is particularly intriguing. PAH is a disease of progressively increasing pulmonary artery pressure leading eventually to right heart failure and death. Initial endothelial injury leads to endothelial dysfunction and disordered cellular growth causing pulmonary vascular remodelling and elevated pulmonary vascular resistance. Idiopathic PAH is rare, but PAH is also recognized as a complication of common diseases such as connective tissue disease, congenital heart disease, HIV infection and cirrhosis. Available therapies for PAH augment vasodilator/antiproliferative mediators or block vasoconstrictor/proliferative mediators. However, these therapies are expensive, carry significant risk of adverse effects and some are difficult to administer. Even with optimal management, treatment benefits to patients are minimal. A research priority in PAH is the development of novel therapeutic approaches that target pathways other than pulmonary vasoconstriction, such as mitochondrial dysfunction (Archer et al. 2010). (–)-Epicatechin may be particularly well suited to fill this need. Not only does (–)-epicatechin improve endothelial function through the same pathways as established PAH therapies (nitric oxide, endothelin-1, prostacyclin), but there is now also evidence that it improves mitochondrial abnormalities like those observed in patients with PAH (Archer et al. 2010). Challenges to using (–)-epicatechin for the treatment of human disease remain significant. At this time, dark chocolate is the best studied and most reliable method to deliver (–)-epicatechin to patients. Though tasty, long-term chocolate consumption as a treatment for disease is impractical for many reasons including its high calorie content and possible variable composition. The availability of purified (–)-epicatechin for clinical studies in humans would facilitate future investigations. Furthermore, studies that have been performed to date are small, uncontrolled and have evaluated only surrogate markers for cardiovascular disease. Well-designed, randomized, controlled, long term studies with clinically meaningful endpoints are needed to better clarify the potential benefits of dark chocolate and epicatechin to human health.