Effects of oral lycopene supplementation on vascular function in patients with cardiovascular disease and healthy volunteers: a randomised controlled trial

Abstract

Aims: The mechanisms by which a 'Mediterranean diet' reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV).

Methods and results: We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: -45% to -10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: -1.6 to -0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: -30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function.

Conclusions: Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs.

Trial registration: ClinicalTrials.gov NCT01100385.

Conflict of interest statement

Competing Interests: The authors declare the following: Cambridge Theranostics donated drugs and placebo to the study. Ateronon, a food supplement, is a registered trademark of CamNutra. The authors acknowledge unrestricted educational donations made by Cambridge Theranostics and CamNutra to Addenbrooke’s Charitable Trust. The donations were unrelated to the trial, which was not funded by either company. The commercial companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flow diagram of subjects through the study.

The safety population consisted of anyone who received at least 1*Reasons for failure to enrol included not meeting inclusion criteria, an inability to attend laboratory for assessments within the appropriate timeframe, patient withdrawal, inability to lie flat for a period of time for the studies, or an inability to cannulate the brachial artery. **Quality control evaluation done by two independent parties. Reasons for non-evaluable data and consequent exclusion from final forearm blood flow (FBF) analysis (before unblinding and statistical analysis) included incomplete data sets, non-evaluable sets, and FBF procedure variation.

Figure 2. Schematic of forearm blood flow protocol.

ACh: Acetylcholine; SNP: Sodium Nitroprusside; L-NMMA: NG-monomethyl-L-arginine; H: Haemodynamic measurements.

Figure 3. Changes in Forearm Blood Flow.

Infused arm forearm blood flow values in cardiovascular disease patients (A–C) and healthy volunteers (D–F) before dose on day 1 (broken lines) and after dose on day 56 (solid lines) for lycopene (red lines) and placebo (blue lines) in response to acetylcholine (ACh; graphs A and C); sodium nitroprusside (SNP; graphs B and D), and NG-monomethyl-L-arginine (L-NMMA; graphs C and F) infusions. Values represent mean with standard error (SE) bars. Comparisons were made using a repeat measures ANOVA with terms for drug/placebo, visit day, infusion dose within day, and interaction of treatment and dose within day, in which baseline saline was treated as infusion dose zero. P-values presented are for lycopene vs. placebo overall for the higher dose challenge agent.

Figure 4. Post-hoc analysis of infused arm FBF values in response to ACh.

Forearm blood flow (FBF) values are represented as percentage change from preceding saline baseline with standard error bars. P-values were generated from comparisons made using unpaired, 2 tailed Student t-tests. (A) At the start of the study, patients with cardiovascular disease (CVD) in the lycopene group (broken red line) had significantly impaired vasodilatory responses to acetylcholine (ACh; 30% lower, 95%CI: −58% to −3%, P = 0.03) compared with healthy volunteers (HVs) at baseline (broken blue line). (B) After treatment with lycopene, the same patients (solid red line) show no significant changes in FBF values compared with HVs at baseline (broken blue line) (2% lower, 95% CI: −30% to +30%, P = 0.85).

Figure 5. Post-hoc correlation between serum lycopene concentrations and EDV.

Relationship between absolute change in serum lycopene concentrations and absolute change in endothelial dependent vasodilatation (EDV; forearm blood flow response to 15 µg/min acetylcholine measured as %change from preceding saline baseline) for all trial subjects. Absolute change in serum lycopene calculated as final visit serum lycopene minus baseline serum lycopene. Absolute change in EDV calculated as final visit EDV minus baseline EDV. r: correlation coefficient calculated using Pearson correlation analysis.