As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.

Background: In‐stent restenosis (ISR) is commonly encountered even in the era of contemporary percutaneous coronary intervention (PCI). There is a paucity of data on the comparative outcomes of PCI for ISR lesions versus de novo lesions. Methods and Results: An electronic search was conducted for MEDLINE, Cochrane, and Embase through August 2022 for studies comparing the clinical outcomes after PCI for ISR versus de novo lesions. The primary outcome was major adverse cardiac events. Data were pooled using a random‐effects model. The final analysis included 12 studies, with a total of 708 391 patients, of whom 71 353 (10.3%) underwent PCI for ISR. The weighted follow‐up duration was 29.1 months. Compared with de novo lesions, PCI for ISR was associated with a higher incidence of major adverse cardiac events (odds ratio [OR], 1.31 [95% CI, 1.18–1.46]). There was no difference on a subgroup analysis of chronic total occlusion lesions versus none ( P _interaction =0.69). PCI for ISR was associated with a higher incidence of all‐cause mortality (OR, 1.03 [95% CI, 1.02–1.04]), myocardial infarction (OR, 1.20 [95% CI, 1.11–1.29]), target vessel revascularization (OR, 1.42 [95% CI, 1.29–1.55]), and stent thrombosis (OR, 1.44 [95% CI, 1.11–1.87]), but no difference in cardiovascular mortality (OR, 1.04 [95% CI, 0.90–1.20]). Conclusions: PCI for ISR is associated with higher incidence of adverse cardiac events compared with PCI for de novo lesions. Future efforts should be directed toward prevention of ISR and exploring novel treatment strategies for ISR lesions.