Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial

FIGURE 1. Schematic of the fate of cocoa flavanols in the gastrointestinal tract. Only the monomeric flavanol (−)-epicatechin is absorbed in the small intestine and metabolized to the major SREMs (–)-epicatechin-3′-O-glucuronide, 3′-O-methyl-(–)-epicatechin-5-sulfate, and (–)-epicatechin-3′-sufate. Oligomeric procyanidins are neither absorbed nor metabolized in the small intestine. Both monomers and procyanidins are catabolized by gut microbes in the colon, leading to ring fission products including γVL, which, in turn, is absorbed and further metabolized to γVLMs. DP, degree of polymerization; SREM, structurally related (−)-epicatechin metabolite; γVL, 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone; γVLM, phase II γVL metabolite.

FIGURE 2. CONSORT study flow. CONSORT, Consolidated Standards of Reporting Trials; DP, degree of polymerization.

FIGURE 3. Changes in values of FMD from baseline at 2 h, 1 mo, and 2 h at 1 mo after supplementation of the following: 1) DP1–10, standardized cocoa extract that contains monomeric flavanols, mainly (−)-epicatechin, and procyanidins with a DP that ranges from 2 to 10; 2) a cocoa extract that contains predominantly procyanidins (DP2–10); or 3) a flavanol-free control (Control) (see Table 1 for their compositions). Time × intervention interaction, P = 0.101; main effect of intervention, P < 0.001; repeated-measurements ANCOVA with baseline values as covariates with Bonferroni post hoc test. Values are means ± SEMs. *P < 0.05 vs. DP2–10. #P < 0.05 vs. Control. DP, degree of polymerization; FMD, flow-mediated vasodilation.

FIGURE 4. (A) Changes in plasma SREMs from baseline at 2 h, 1 mo, and 2 h at 1 mo after supplementation of the following: 1) DP1–10, a standardized cocoa extract that contains monomeric flavanols, mainly (−)-epicatechin, and procyanidins with a DP that ranges from 2 to 10; 2) a cocoa extract that contains predominantly procyanidins (DP2–10); or 3) a flavanol-free control (Control) (see Table 1 for their compositions). Time × intervention interaction, P < 0.001; main effect of intervention, P < 0.001; repeated-measurements ANCOVA with baseline values as covariates with Bonferroni post hoc test. Amount of SREMs (B) and γVL metabolites (C) excreted over 24 h in urine on day 1 and the last day of study at 1 mo (time by intervention interactions P = 0.325 and P = 0.467 and main effects of intervention, each P < 0.001; repeated-measurements ANOVA with Bonferroni post hoc test). All values are means ± SEMs. *P < 0.05 vs. DP2–10; #P < 0.05 vs. Control. DP, degree of polymerization; SREM, structurally related (−)-epicatechin metabolite; γVL, 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone.

FIGURE 5. Changes in SBP (A) and PWV (B) from baseline at 2 h, 1 mo, and 2 h at 1 mo and total cholesterol (C) at 1 mo after supplementation of the following: 1) DP1–10, a standardized cocoa extract that contains monomeric flavanols, mainly (−)-epicatechin, and procyanidins with a DP that ranges from 2 to 10; 2) a cocoa extract that contains predominantly procyanidins (DP2–10); or 3) a flavanol-free control (Control) (see Table 1 for their compositions). Repeated-measurements ANCOVA (A, B) and univariate ANCOVA (C), with baseline values as covariates with Bonferroni post hoc test; time × intervention interactions, P = 0.291 (A) and P = 0.176 (B); main effects of intervention, P = 0.047 (A), P < 0.001 (B), and P = 0.007 (C) .Values are means ± SEMs. *P < 0.05 vs. DP2–10; #P < 0.05 vs. Control. DP, degree of polymerization; PWV, pulse wave velocity; SBP, systolic blood pressure.