Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease

Abstract

Purpose: The grape and wine polyphenol resveratrol exerts cardiovascular benefits but evidence from randomized human clinical trials is very limited. We investigated dose-depending effects of a resveratrol-containing grape supplement on stable patients with coronary artery disease (CAD) treated according to currently accepted guidelines for secondary prevention of cardiovascular disease.

Methods: In a triple-blind, randomized, placebo-controlled, one-year follow-up, 3-arm pilot clinical trial, 75 stable-CAD patients received 350 mg/day of placebo, resveratrol-containing grape extract (grape phenolics plus 8 mg resveratrol) or conventional grape extract lacking resveratrol during 6 months, and a double dose for the following 6 months. Changes in circulating inflammatory and fibrinolytic biomarkers were analyzed. Moreover, the transcriptional profiling of inflammatory genes in peripheral blood mononuclear cells (PBMCs) was explored using microarrays and functional gene expression analysis.

Results: After 1 year, in contrast to the placebo and conventional grape extract groups, the resveratrol-containing grape extract group showed an increase of the anti-inflammatory serum adiponectin (9.6 %, p = 0.01) and a decrease of the thrombogenic plasminogen activator inhibitor type 1 (PAI-1) (-18.6 %, p = 0.05). In addition, 6 key inflammation-related transcription factors were predicted to be significantly activated or inhibited, with 27 extracellular-space acting genes involved in inflammation, cell migration and T-cell interaction signals presenting downregulation (p < 0.05) in PBMCs. No adverse effects were detected in relation to the study products.

Conclusions: Chronic daily consumption of a resveratrol-containing grape nutraceutical could exert cardiovascular benefits in stable-CAD patients treated according to current evidence-based standards, by increasing serum adiponectin, preventing PAI-1 increase and inhibiting atherothrombotic signals in PBMCs.

Fig. 1

Design of the trial. (a) Inclusion/Exclusion criteria. (b) Flow of participants through the trial. A, placebo group; B, conventional grape extract group (GE); C, resveratrol-containing grape extract group (GE-RES); RAS-blockers, renin-angiotensin system blockers; ESC, European Society of Cardiology

Fig. 2

Changes of plasminogen activator inhibitor type 1 (PAI-1) and inflammatory-related markers from baseline after 6 and 12 months. Patients consumed 1 capsule/day for the first 6 months (350 mg/day) and 2 capsules/day (700 mg/day) for the following 6 months. Percent changes are expressed as mean ± SD. Intra-group changes over time: *p < 0.05; ^# p = 0.05. Differences versus group A (placebo): ^a p < 0.05

Fig. 3

Effect on serum adiponectin concentration. Filled symbols and lines designate individual subjects. Open symbols designate mean ± SD concentration at baseline and 12 months

Fig. 4

Predicted pathways by the Ingenuity Pathway Analysis software (IPA) according to microarrays results in peripheral blood mononuclear cells (PBMCs). Green and red colors designate down- and upregulation of gene expression, respectively. Transcription factors involved in the predicted pathway are listed in Table 4. Expression changes in extracellular-space genes and their functions are listed in Supplementary Tables 2 and 3, respectively