Senolytic and anti-inflammatory efficacy of quercetin in men and women undergoing coronary artery by-pass surgery

Recent studies suggest that vascular senescence and its associated inflammation could fuel the so-called inflammaging to favor atherogenesis; whether these pathways can be inactivated in CAD patients (male and female) is unknown. We performed a randomized, double-blind trial involving patients undergoing an elective coronary artery by-pass graft surgery. The patients were randomly assigned to receive either quercetin (500 mg twice daily) or placebo starting two days before surgery. The primary efficacy end point was a reduction in post-operative systemic inflammation. The secondary efficacy end-point was an improved endothelial function ex vivo of discarded segments of internal thoracic artery (ITA). The exploratory end-point was to acquire a vascular transcriptomic signature per treatment and sex by single nucleus RNA sequencing. A total of 97 patients (78 men) were recruited, 50 were assigned to the placebo group and 47 to the quercetin group. In the intent-to-treat population (ITT), quercetin tended to reduce C-reactive protein at hospital discharge (F value 3.39; p=0.073); this tendency was confirmed by a plasma proteomic analysis revealing a significant shift of differentially expressed inflammatory proteins between sexes (-48 in men and +12 in women). Quercetin increased endothelial sensitivity to acetylcholine-dependent relaxation (F value 4.01; p=0.0487). In a sub-group analysis, this effect of quercetin remained significant in men (F value 3.92; p=0.0513) but not in women (F value 0.17; p=0.678). The transcriptomic signature of the ITA revealed overexpression of classic cellular senescence pathways of both replicative- and stress-induced senescence, together with an inflammatory signature typical of inflammaging and oxidative stress; quercetin reversed this signature towards reduced senescence, stress and inflammation. In female ITA, the response to quercetin was heterogeneous and limited in efficacy, with a “cooling” of the endothelium, but a promotion of the inflammaging signature in fibroblasts. No adverse events were reported. Quercetin reduced global post-operative inflammation and improved endothelial dysfunction in the ITT population; men benefited from quercetin but not women. This study suggests that a hit-and-run senolytic strategy to reduce the vascular inflammaging may benefit men more than women with CAD.