Cocoa Flavanols Linked to Vascular Protection in ESRD

Sanjeet Bagcchi, MBBS

January 07, 2016

Ingestion of cocoa flavanols (CF) can attenuate hemodialysis (HD)-induced and chronic endothelial dysfunction in patients with end-stage renal disease (ESRD) and improve vascular function in high-risk patients, according to a new study published online December 17 in the Clinical Journal of the American Society of Nephrology.

Cocoa flavanols are plant-derived polyphenols that are present in cocoa.

Tienush Rassaf, MD, from the Department of Cardiology, West German Heart and Vascular Center, Essen, Germany, and colleagues note that ESRD is regarded as an important cardiovascular risk factor. "This leads to a dramatic increase in morbidity and mortality in this population, which is eight times greater than in the general population," the researchers write. In ESRD, vascular dysfunctions are linked with heart failure and sudden cardiac deaths.

"Elevated cardiac troponin levels reflect this, an important predictor of all-cause mortality in ESRD," the researchers note. They also point out that in patients with ESRD, impaired bioavailability of nitric oxide further perpetuates vascular dysfunctions. "Importantly, HD acutely impairs endothelial function through reduction of [nitric oxide] bioactivity," they explain.

Dietary supplements rich in CF could lead to improvement in vascular function; however, studies assessing the effect on vascular dysfunction in patients with ESRD are "sparse." Therefore, the researchers conducted a randomized, double-blind, placebo-controlled trial during 2012 to 2013 to assess "the impact of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD." They enrolled 57 participants undergoing HD for underlying renal diseases, including hypertensive and diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.

Of the 57 participants, the researchers randomly assigned 52 to a chronic parallel group trial. They provided 26 participants with beverages rich in CF (900 mg CF per study day) and 26 participants with a nutrient-matched, CF-free placebo. In the study, "[p]rimary and secondary outcome measures included changes in [flow-mediated dilation (FMD)] and hemodynamics," Dr Rassaf and colleagues explain.

The patients tolerated ingestion of CF well, and acute ingestion led to an FMD improvement by 53% (3.2% ± 0.6% to 4.8% ± 0.9% vs placebo, 3.2% ± 0.7% to 3.3% ± 0.8%; P < .001), without affecting heart rate and blood pressure.

Compared with placebo, after a 30-day ingestion of CF, the researchers noted an increase in baseline FMD of 18% (3.4% ± 0.9% to 3.9% ± 0.8% vs placebo, 3.5% ± 0.7% to 3.5% ± 0.7%; P < .001); this was associated with a decrease in diastolic blood pressure (73 ± 12 to 69 ± 11 mm Hg vs placebo, 70 ± 11 to 73 ± 13 mm Hg; P = .03) and an increase in heart rate (70 ± 12 to 74 ± 13 bpm vs placebo, 75 ± 15 to 74 ± 13 bpm; P = .01).

The researchers also note that during HD, acute ingestion of CF led to an alleviation of HD-induced vascular dysfunction (3.4% ± 0.9% to 2.7% ± 0.6% vs placebo, 3.5% ± 0.7% to 2.0% ± 0.6%; P < .001), and the effect was sustained "throughout the study" (acute-on-chronic, 3.9% ± 0.9% to 3.0% ± 0.7% vs placebo, 3.5% ± 0.7% to 2.2% ± 0.6%; P = .01).

According to Dr Rassaf and colleagues, the study yields four major findings: in patients with ESRD, ingestion of CF (at 900 mg per day) is well tolerated, endothelial dysfunction is partly reversed by acute and chronic ingestion of CF, chronic ingestion of CF leads to decrease in diastolic blood pressure without "affecting markers of aortic stiffness," and CF ingestion mitigates vascular dysfunction induced by HD.

"The exact mechanisms through which CF exert putative cardioprotective effects still remain incompletely elucidated," the authors write. "Impacts on [nitric oxide] homeostasis with increased nitrosothiol plasma levels, cellular signal cascades, altered gene-expression and enzyme activity are considered potential pathways. In the present study we did not observe differences in plasma nitrite or nitrate levels possibly due to small sample size or due to activation of [inducible nitric oxide synthase] as suggested for ESRD patients," the researchers explain.

In an accompanying editorial, Carmine Zoccali, MD, and Francesca Mallamaci, MD, from the Ospedali Riuniti, Reggio Calabria, Italy, write, "While the evidence that flavonoids exert favorable effects on the cardiovascular system in studies based on surrogates like FMD or pulse wave velocity and may lower [blood pressure] in human hypertension seems robust and credible, until now there is no large trial based on clinical end-points showing a benefit by these compounds. Thus, although likely, the therapeutic benefit of flavonoids for the prevention and treatment of cardiovascular disease remains an open question."

However, in the last 2 decades, no meaningful cardiovascular prognosis has been noted in patients with ESRD, they point out. The nephrology community needs to be attentive to a "promising intervention" such as CF, considering the serious burden of cardiovascular disease among patients receiving HD, they write. The findings of this study might be a turning point in the battle against cardiovascular disease in patients undergoing HD, provided other studies (based on same surrogates) and a trial based on clinical end-points confirm the findings, they conclude.

This work was funded in part by the European Commission. MARS Symbioscience provided the CF test products and analytical standards. The authors and editorialists have disclosed no relevant financial relationships.

CJASN. Published online December 17, 2015. Abstract

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