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In the present study, we, for the first time, report a significant and specific effect of commercially available FRC on endothelial and platelet function, in patients with CHF. Interestingly, chocolate not only improved this important cardiovascular surrogate marker acutely, but even more so, after longer-term ingestion for up to 4 weeks. Such a vascular positive effect of an orally available molecule is not trivial in CHF as unexpectedly statins proved to be ineffective in this patient population.[17,18]
While most studies, so far, investigated only the acute effects of FRC on endothelial function,[1] we here report long-term effects with daily ingestion of FRC using a double-blind randomized design, rarely applied in nutritional research. In addition, this is the first study on the effect of chocolate in patients with advanced heart disease such as CHF. Of note, CHF is associated with endothelial dysfunction, a condition confirmed in our patient population. Indeed, FMD averaged about 4%, which is markedly lower than that observed in healthy controls.[25] The molecular mechanisms of endothelial dysfunction in CHF might involve increased levels of cytokines, impaired endothelial-receptor-signal transduction pathways, and increased angiotensin-converting enzyme activity.[26–29] Furthermore, neurohumoral activation and increased levels of endothelium-derived vasoconstrictors occurs in CHF.[30] In addition, CHF is associated with enhanced generation of reactive oxygen species and oxidized LDL, further counteracting vasodilator properties of NO. Therefore, the fact that cocoa polyphenols improve endothelial function by increasing NO synthase (NOS) activity and by exerting antioxidative capacity might be of importance for HF patients, especially as there is a strong association between endothelial dysfunction and cardiovascular morbidity and mortality in these patients.[10] Finally, CHF patients, particularly at advanced stages, are prone to weight loss, anaemia, and cachexia, making nutritional issues important in the management of such patients.
In our study, ingestion of FRC was followed by a marked and significant increase in (−)-epicatechin plasma concentrations. In parallel, FMD improved significantly in the flavanol, but not in the control group. This effect likely involves increased NO bioavailability, since it is reduced in CHF,[31] and ingestion of cocoa high in flavanols rapidly enhances the pool of bioactive NO and improves FMD in patients with hypertension or diabetes.[15,32] Furthermore, after the infusion of L-NMMA, an inhibitor of the NO synthesis, the increase in plasma NO levels as well as the amelioration of endothelial dysfunction associated with cocoa are blunted.[32] Moreover, a diet high in flavanols has been associated with a high urinary excretion of NO metabolites[33] and purified (−)-epicatechin has been shown to mimic the endothelial effects of flavanol-rich cocoa.[33] In the short term, flavanols inhibit the inactivation of NO by free radicals via inhibition of NADPH oxidase, while in the long term, they seem to be able to express higher levels of protein eNOS.[34] Furthermore, pure (−)-epicatechin ingestion not only augments NO bioavailability, but also reduces the plasma levels of endothelin-1, a potent endothelium-derived vasoconstrictor.[35]
Besides their effects on endothelial NOS expression, cocoa flavanols also exert antioxidant effects in vitro, which could contribute to the results of our study. In humans, it has been shown that cocoa is able to counteract lipid peroxidation, thus lowering the levels of plasma F2-isoprostanes, important markers of in vivo lipid peroxidation,[36] as well as plasma levels of oxLDL,[37] and increases overall antioxidant capacity.[38] Although not obvious in the current study, we showed that in young healthy smokers, the same commercially available chocolate as used in the present study was able not only to improve endothelial function but also to improve antioxidant status.[39] We also evaluated the effect of the same commercially available chocolate on cardiac transplant recipients, where we demonstrated a reduction in oxidative stress, as assessed by plasma isoprostanes; this was paralleled by coronary vasodilatation, improvement in coronary vascular function, and decreased platelet adhesion.[16]
Beyond the acute effects on endothelial function, the sustained and even more pronounced effects of chronic cocoa ingestion were remarkable. Indeed, endothelial function was further improved after 2 and particularly after 4 weeks of daily ingestion of 80 g of FRC. It is of note that endothelial function measurements were performed in the morning after overnight fasting; thus, an acute effect of chocolate in these measurements can be excluded. Indeed, in line with this assumption, both at 2 and 4 weeks, (−)-epicatechin and its methyl metabolites were no longer detectable in plasma at the time of vascular function studies. Therefore, chronic flavanol supplementation must have changed the biology of the brachial artery and endothelial cells, in particular in the CHF patients studied. Although, we do not have a mechanistic prove, flavanols most likely must have induced the expression of endothelial NOS, an effect that was sustained beyond the short half-life of these cocoa-derived nutrients. In line with this interpretation, brachial artery diameter increased 2h after ingestion of FRC. Furthermore, plasma levels of oxidative stress markers as well as of C-reactive protein were similar at 2 and 4 weeks as they had been at baseline excluding a major contribution of reactive oxidant species. Finally, endothelium-independent relaxations to nitroglycerin were unaffected by the dietary intervention.
The improvement in platelet function shortly after cocoa ingestion confirms our previous studies in young healthy smokers[39] and heart transplant recipients.[16] However, we were not able to show any long-term effect after 2 or 4 weeks. This may be due to the fact that blood samples were collected after an overnight fast, and thus, the polyphenols had already been metabolized and excreted as reflected by the lack of detection of these substances in the blood samples. Our findings are not surprising, since platelets are anucleated cells and hence unable to induce protein production, for instance, an increased transcription and translation of endothelial NOS expression. Hence, it appears that flavanols can activate NO release from platelets as previously described,[40] but—in contrast to endothelial cells—are unable to exert sustained effects in these anucleated cells.
Neurohumoral activation, in particular activation of the sympathetic nervous system, is a hallmark of CHF. Thus, we further investigated the effect of FRC on baroreceptor function by the α-coefficient method. However, no effect of the dietary intervention has been noted, neither in the short nor in the long term. This is surprising, since NO has been involved in baroreceptor signalling.[41] An explanation might be the use of β-blocking agents in all of our patients according to guidelines, thus masking a possible effect of FRC. Alternatively, the limited number of observations may also contribute to the negative findings, as baroreflex function was only measured in 11 patients.
Epidemiological and small intervention studies suggest a small, but distinct BP-lowering effect of chocolate consumption.[2,3,42,43] However, these studies were performed in patients with elevated or mildly elevated BP. Moreover, the effect of BP lowering was higher in subjects with higher baseline BP.[43] As it is typical in CHF, baseline BP of our patients was low and averaged 110/65 mmHg. We did not observe any relevant effect of FRC consumption on systolic or diastolic BP, neither acutely nor after 2 and 4 weeks, despite a substantial increase in plasma epicatechin levels and that of its metabolites. This might be explained by the low baseline BP as well as by the fact that antihypertensive drugs had been used. Intervention studies demonstrated improved insulin sensitivity after chocolate consumption, especially in hypertensives.[14,42] Interestingly, in this study, we observed a decrease in insulin sensitivity after 4 weeks in the control group, a decrease not seen in patients consuming FRC. This may potentially point towards an additional beneficial effect of FRC in CHF patients. It is of note that despite the high caloric load of our commercially available FRC, no weight gain and no change in blood lipids were noted.
There are some limitations of the study. We did not control for habitual food intake, especially for other cocoa products. Furthermore, patients were free to schedule study chocolate intake; thus, other foods might have influenced bioavailability. Although we think it is unlikely, we cannot exclude that the results are biased by the individuals' diet. We are aware that our results are based on a rather small sample size; thus, effects on secondary endpoints such as BP, oxidative stress parameters, and others might not have been detected.
In conclusion, this is the first study demonstrating beneficial cardiovascular effects of commercially available FRC in patients with CHF. Flavanol-rich chocolate not only led to peripheral vasodilatation, improvement in endothelial function, and enhancement in platelet function shortly after chocolate ingestion but also to an amelioration in endothelial function in the long term after 2 and 4 weeks of daily chocolate ingestion. It is of note that endothelial function was improved on top of optimal medical treatment with drugs known to improve vascular function alone.
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Acknowledgments
We thank Rosy Hug for her contributions to operational management.
Funding
Partly supported by an unrestricted grant from Nestlé Research Center, Switzerland, as well as by funds of the Zurich Heart House—Foundation for Cardiovascular Research, Zurich, and a strategic alliance with Pfizer, Inc., New York, USA. Nestlé reviewed and approved the manuscript; otherwise, the funding sources were not involved in the design and conduct of the study; as well as in collection, management, analysis, and interpretation of the data.
Eur Heart J. 2012;33(17):2172-2180. © 2012 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.
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) doing studies that validate certain postulations. For a long time now people have been interested in Flavanol rich foods. This is a good indicator that they actually have bio- activity and that it is positive.
