COCOA

Cocoa including very dark chocolate, and cocoa flavanol supplements, have strong evidence in reducing vascular inflammation. There is a large volume of both population study and clinical evidence showing positive effects on vascular health markers from moderate consumption of cocoa flavanols in the 200 to 700mg range, about 10g of cocoa powder or 35g of very dark chocolate. For instance, clinical trials in patients taking 40g cocoa with early phase heart disease have shown 7 to 11% reductions in some markers of blood platelet adhesion (Highlight 1) In particular, around a 1/5 lower level of CD36, a biomarker recent research papers highlight as key drivers of both metastasis and oncology drug resistance. Other studies in cardiovascular patients showing around a 1/4 reduction in overall blood platelet adhesion post surgery, even in patients with statins (see References).

A small but compelling 2023 clinical trial shows cocoa flavanol doses up to 800mg daily can radically reduce sICAM-1 (marker of intercellular adhesion) by up to half even in healthy subjects (Highlight 2). sICAM-1 is heavily implicated in cardiovascular disease and also incidence and progression including lung, breast and liver cancer. The same research found up to 2/3 reduction in 8-iso-PGF2 levels, a major biomarker for oxidative stress elevated in several cancers. Another meta-analysis across clinical trials confirms cocoa effects are consistent in lower VCAM-1 markers of platelet adhesion.

Cacao and its processed form cocoa contain active compounds and flavanols that can moderate markers of systemic inflammation such as MDA (malondialdehyde). A very recent meta-analysis found a medium to large suppression of MDA across clinical trials with various sources of cocoa. Higher relative levels are linked to increased progression, including breast, bladder and colorectal cancer. Also of note the reductions seen in all cause mortality including heart disease and stroke with lower MDA levels. Cancer brings much increased risks of adverse events in this areas.

Reduced levels of a gut metabolite (trimethyamine N-Oxide TMAO ) in otherwise healthy individuals improved vascular health measurements even at 2.5g daily of cocoa. Higher levels of TMAO and its precursor choline resulting from meat and dairy are associated in some research with much higher incidence rates of colorectal and advanced prosate cancers. On the other hand, recent studies show improved immunotherapy responses in advanced cancers including TNBC related to choline. Dietary increases in some patients from seafood and fish are discussed in some of these studies (see References),

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EXAMPLES OF IMPROVED OUTCOMES

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Highlighted Studies

In the current study, the expression of VLA-4, CD40, and CD36 on monocyte surfaces was significantly lower after the 4-wk C+M [ 20g cocoa x2 daily] intervention than after the M [skim milk] intervention. Serum concentrations of soluble adhesion molecules were in consonance with the data obtained in the cellular analysis. Soluble P-selectin and ICAM-1 concentrations were significantly lower after C+M intake than after M intake..,nutritional doses of cocoa may have an effect on all initial phas...

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..short-term cocoa consumption dose-dependently decreased the circulating levels of sICAM-1, sCD40L and 8-iso-PGF2 levels, improving oxidative stress, proinflammatory mediators and lipid peroxidation, with a significant effect on circulating levels of these markers for higher dosages of flavonoids. Moreover, the present study is also the first reporting dose-dependent effects of cocoa flavonoids on markers of endothelial damage and oxidative stress…the current results suggest that effec...

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As a result of the pooled estimates from the random-effects model, it was determined that MDA levels were reduced following DC/cocoa intake (SMD: −0.69) [ medium-large effect] and heterogeneity among the studies was significant [i.e variation of results]. Intervention duration and location of studies and participant’s BMI were the sources of heterogeneity. Greater effects were observed in doses ≤ 450 mg/d, duration > 4 weeks and in studies conducted in the Americas and also in ...

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..CF (cocoa flavanols 2x 450mg) improved vascular function and decreased systolic and diastolic blood pressure as well as arterial stiffness…consumption of CF for 1 month elicits significant changes in the gene expression and DNA methylation profile of healthy men which regulate integrity of immune‐endothelial cell barrier functions. Bioinformatic analysis revealed that genes affected by CF consumption are involved in the regulation of inflammation, cell adhesion, and chemotaxis of im...

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TABLE OF REFERENCES

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https://www.sciencedirect.com/science/article/pii/S00029165232664112.5In the current study, the expression of VLA-4, CD40, and CD36 on monocyte surfaces was significantly lower after the 4-wk C+M intervention than after the M intervention. Serum concentrations of soluble adhesion molecules were in consonance with the data obtained in the cellular analysis. Soluble P-selectin and ICAM-1 concentrations were significantly lower after C+M intake than after M intake. However, no changes were observed for the proinflammatory cytokine IL-6 or hs-CRP. In addition, besides the changes observed in the inflammatory variables, a significantly higher concentration of serum HDL cholesterol was observed as a consequence of C+M intake. our study is the first to report a positive effect of cocoa consumption on P-selectin concentrations...Another positive outcome of our study was the higher HDL-cholesterol concentration after C+M intake than after M intake. Although outcomes on lipid metabolism from cocoa feeding trials are still scarce, this finding seems to be in accordance with that of several studies that have reported higher HDL-cholesterol concentrations after cocoa or chocolate intake but no changes in LDL cholesterol
https://link.springer.com/article/10.1007/s40292-023-00571-82.5In this randomized, controlled, double-blind, crossover study we demonstrated for the first time that short-term cocoa consumption dose-dependently decreased the circulating levels of sICAM-1, sCD40L and 8-iso-PGF2 levels, therefore improving oxidative stress, proinflammatory mediators and lipid peroxidation, with a significant effect on circulating levels of these markers for higher dosages of flavonoids. Moreover, the present study is also the first reporting dose-dependent effects of cocoa flavonoids on markers of endothelial damage and oxidative stress. In line with this, and in contrast with the findings reported on endothelial function (only 10 g of cocoa with a very low caloric and flavanol intake per day were already significantly amelioring vascular function) the current results suggest that effects we observed were effective only for higher dosages of flavonoids.Exacly in line with our results, the recent COcoa Supplement and Multivitamin Outcomes Study (COSMOS) by Sesso et al. [27] strongly suggested that cocoa flavanols supplementation (500 mg), during a median follow-up of 3.6 y, significantly decreased CVD death by 27%. Our results support for the first time the possible fundamental role of the dose of flavonoids in the observed findings on inflammation, endothelial activation and lipid peroxidation. Indeed, althought a trend to decrease these markers is evident also for lower doses, we observed significant effects only after higher doses of flavonoid intake (≥ 200 mg of flavonoids 8-iso-PGF2 levels; ≥ 500 mg of flavonoids for sICAM-1 and sCD40L).
https://www.sciencedirect.com/science/article/pii/S0965229924000499#sec00402.5As a result of the pooled estimates from the random-effects model, it was determined that MDA levels were reduced following DC/cocoa intake (SMD: −0.69) [ medium-large effect] and heterogeneity among the studies was significant [i.e variation of results]. Intervention duration and location of studies and participant’s BMI were the sources of heterogeneity. Greater effects were observed in doses ≤ 450 mg/d, duration > 4 weeks and in studies conducted in the Americas and also in the overweight and obese participantsThis study summarized the pooled results of 33 CTs on the effects of DC/cocoa flavonoids on inflammation and oxidative stress in adults. These results showed that DC/cocoa intake significantly reduced plasma MDA and increased NO levels, indicating benefits for systemic oxidative status. However, no significant changes were observed for inflammatory markers like CRP, IL-6, and TNF-α. Subgroup analyses revealed significant effects in higher flavonoid dosages (>450 mg/day), shorter interventions (≤4 weeks), and trials conducted in Europe for CRP and IL-6. Also, greater effects were observed in non-healthy participants on IL-6 and TNF-α.
https://pubmed.ncbi.nlm.nih.gov/16794458/2The consumption of a flavanol-rich cocoa beverage also resulted in significant inhibition of platelet aggregation, P/M and P/N, and platelet activation induced by collagen. The inhibitory effects were related to their flavanol content. There was also inhibition of monocyte and neutrophil activation, but here it was concluded that cocoa constituents other than flavanols may contribute to the inhibition that was observed. It can be concluded that cocoa flavanols, their metabolites and possibly other cocoa constituents can modulate the activity of platelets and leukocytes in vitro and ex vivo.The measurements of leukocyte activation performed ex vivo after the consumption of beverages containing either low or high levels of cocoa flavanols revealed additional interesting information. All 4 products consistently inhibited leukocyte activation, irrespective of their flavanol content. Clearly these results are very different to those obtained for platelets. They indicate that administration of cocoa products may have beneficial effects on leukocytes mediated via other constituents of cocoa in addition to flavanols. It is possible that the inhibitory effects of these unknown constituents are via direct inhibition of leukocyte function
https://pmc.ncbi.nlm.nih.gov/articles/PMC9787825/2Our clinical study showed that 1 month consumption of CF improved vascular function as reflected by increased in flow‐mediated dilation and decreased systolic and diastolic blood pressure as well as arterial stiffness.[ 2 ] Our current analysis now shows that the consumption of CF for 1 month elicits significant changes in the gene expression and DNA methylation profile of healthy men which regulate integrity of immune‐endothelial cell barrier functions. Bioinformatic analysis revealed that genes affected by CF consumption are involved in the regulation of inflammation, cell adhesion, and chemotaxis of immune cells. CF consumption may mediate vascular protective effects by modulating gene expression and DNA methylation towards a cardiovascular protective effect, in agreement with clinical results, by preserving integrity of immunological‐endothelial barrier functions...Identified genes are involved in regulation of immune response, cell adhesion, or cytoskeleton organization. These results reveal molecular mechanisms of CF which may mediate vascular protective effects, in agreement with clinical results, by preserving integrity of endothelial barrier functions.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.107.7138672It is noteworthy that the effect of dark chocolate on coronary vasomotion was observed in addition to current optimal therapy for heart transplantation patients, such as a statin, β-blocker, angiotensin-converting enzyme–inhibitor, or angiotensin receptor blocker if indicated. Given that several of these medications, specifically statins31 and blockers of the renin angiotensin system,32 are known to have beneficial effects on the vascular endothelium, coronary vasomotion, and platelet adhesion, the present results imply that the true effect of dark chocolate might provide a clinically relevant benefit not only in healthy subjects but also in patients treated with cardiovascular drugs.Activation of platelets is an essential step in acute coronary syndromes. The fact that shear stress–dependent platelet adhesion was reduced 2 hours after flavonoid-rich chocolate consumption in heart transplantation patients extends our previous findings in young healthy smokers, in whom a similar effect on platelet function was found.7 A high shear rate mimics severely stenotic or disrupted plaques, and thus, reduction of shear stress–dependent platelet adhesion is indicative of clinically relevant protective effects.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10223313/#sec4-nutrients-15-022991.5Regular intake of cocoa flavanols improves cardiovascular health by reducing TMAO and uric acid levels and increasing FMD values, additionally showing a direct association with polyphenol levels in serum. Concentrations of TMAO negatively correlated with polyphenol levels at the end of the intervention. Both cocoa flavanols and red berry anthocyanins improve gut microbiota metabolism by increasing carbohydrate fermentation, and therefore increase the synthesis of SCFAs. This increase in microbiota fermentation correlated negatively with SBP, DBP and TC/HDL ratio. Therefore, our study showed that both red berry anthocyanins and cocoa flavanols could modulate the gut microbiota metabolism in a positive way, and as a result have a protective effect on cardiovascular health in healthy adults. The intervention with cocoa flavanols showed better results, significantly lowering the levels of TMAO and uric acid and increasing FMD values. Additionally, we found a negative correlation between TMAO concentrations and polyphenol levels in blood, showing that individuals in whom higher concentrations of polyphenols were found after the intervention presented lower levels of TMAO
https://www.sciencedirect.com/science/article/pii/S0022316623007770#s00071.5A significant difference between the cocoa flavanol intervention and placebo groups was found for C-reactive protein (WMD = −0.83 mg/dL) and vascular cell adhesion molecule 1 (VCAM-1) After correcting for multiple comparisons, the associations observed for C-reactive protein and VCAM-1 remained significant.Fasting insulin concentrations and HOMA-IR were each significantly lower in the cocoa flavanol groups than the placebo group , whereas the quantitative insulin sensitivity check index and insulin sensitivity index were significantly improved among the cocoa flavanol groups compared with placebo.. The WMDs between the cocoa flavanol and placebo groups were −2.33 μIU/mL for fasting insulin and −0.93 for HOMA-IR
https://ajcn.nutrition.org/article/S0002-9165(22)00275-1/fulltext1.5Cocoa extract was not significantly associated with all-cause mortality, but there was a significant 27% reduction in the secondary outcome of CVD mortality—the only secondary endpoint to reach nominal statistical significance—that may have reflected combined effects among individual CVD outcomes. There was an apparent split in the Kaplan-Meier curves for CVD death after year 1 and a reasonable biological rationale expected for atherosclerosis-related outcomes. However, we did not statistically confirm latency because of imprecision in our HR estimates from randomization to year 1 and the limited duration of the COSMOS trial intervention. We believe it is important to extend mortality follow-up to fully evaluate the long-term effects of cocoa extract on total and cause-specific mortality.In conclusion, cocoa extract supplementation did not significantly reduce our primary outcome of total cardiovascular events after 3.6 y of treatment and follow-up, but we found a statistically significant 27% reduction in the secondary outcome of CVD death and a potential reduction in total cardiovascular events in per-protocol analyses. Longer-term follow-up of the trial cohort and ongoing ancillary mechanistic studies in COSMOS may further elucidate the relation between cocoa extract supplementation and clinical cardiovascular events.
https://www.mdpi.com/2072-6643/16/12/19191.5..cocoa polyphenol intake reduced total cholesterol (−8.35 mg/dL) and LDL-c (−9.47 mg/dL), but it did not reduce triglycerides and HDL-c; (iii) cocoa consumption was associated with a reduction in fasting blood glucose (−4.91 mg/dL), but not in HbA1c; and (iv) our meta-analysis showed that cocoa consumption reduced both SBP (−2.52 mmHg) and DBP levels (−1.58 mmHg), especially at higher amounts of polyphenol intake. In summary, cocoa consumption showed a protective effect on major cardiometabolic risk markers with a clinically significant impact in terms of cardiovascular risk reduction.We conclude that the consumption of cocoa as a dietary supplement in cocoa extract capsules or dark-chocolate products has a protective effect on most cardiometabolic risk markers evaluated in this analysis, including total cholesterol, LDL-c, fasting blood glucose, SBP, and DBP...the consumption of polyphenol-rich cocoa could be part of a strategy aimed at promoting cardiovascular health.
https://www.sciencedirect.com/science/article/pii/S0002916523066601?via%3Dihub1.5consumption of cocoa caused an aspirin-like effect on platelet function, as measured in terms of platelet-related primary hemostasis. We hypothesize that flavonoids in cocoa account for at least some of the platelet-inhibitory effects observed in this study. It is unlikely that the sustained effect of cocoa on markers of platelet activation is attributable to the caffeine fraction of the cocoa beverage, because the caffeine-containing beverage stimulated rather than decreased epinephrine-induced activated glycoprotein IIb-IIIa expression and microparticle formation. Indeed, flavonoids decrease platelet aggregation in vitroIn this study, we showed that platelet activation and reactivity to physiologic agonists were inhibited 2 and 6 h after the ingestion of a cocoa beverage by healthy subjects without a history of cardiovascular disease. The highly enriched flavonoid composition of the cocoa used in this study may have contributed to the inhibition of platelet activity after its consumption. The timing of the effects observed is consistent with the kinetics of epicatechin absorption from chocolate. Thus, suppression of platelet function is one mechanism by which cocoa and chocolate could offer cardiovascular benefits.

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