Cardiorespiratory Fitness Is Associated with Decreased Platelet Reactivity

Purpose: Platelets are key mediators in cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a risk factor for CVD. The purpose of our study was to assess if CRF associates with platelet function.

Methods: Platelet assays and cardiopulmonary exercise testing were conducted in the Framingham Heart Study ( N = 3014). Linear mixed effects models estimated associations between CRF (assessed by peak oxygen uptake [V̇O 2 ]) and multiple platelet reactivity assays. Models were adjusted for multiple medications, risk factors, relatedness, and prevalent CVD.

Results: Nineteen associations passed the significance threshold in the fully adjusted models, all indicating higher CRF associated with decreased platelet reactivity. Significant traits spanned multiple platelet agonists. Strongest associations were observed in multiplate whole blood testing after TRAP-6 (e.g., velocity, beta = -0.563, 95% CI = -0.735 to -0.391, P = 1.38E-10), ADP (e.g., velocity, beta = -0.514, 95% CI = -0.681 to -0348, P = 1.41E-09), collagen (e.g., velocity, beta = -0.387, 95% CI = -0.549 to -0.224, P = 3.01E-06), ristocetin (e.g., AUC, beta = -0.365, 95% CI = -0.522 to -0.208, P = 5.17E-06) and arachidonic acid stimulation of platelets (e.g., velocity, beta = -0.298, 95% CI = -0.435 to -0.162, P = 3.39E-04), and light transmission aggregometry (LTA) after ristocetin stimulation (e.g., max aggregation, beta = -0.362, 95% CI = -0.540 to -0.184, P = 6.64E-05). One trait passed significance threshold in the aspirin subsample (LTA ristocetin primary slope, beta = -0.733, 95% CI = -1.134 to -0.333, P = 3.30E-04) and another in a model including von Willebrand Factor levels as a covariate (U46619, a thromboxane receptor mimetic, AUC in the Optimul assay, beta = -0.36, 95% CI = -0.551 to -0.168, P = 2.35E-04). No strong interactions were observed between the associations and sex, age, or body mass index in formal interaction analyses.

Conclusions: Our findings build on past work that shows CRF to be associated with reduced CVD by suggesting decreased platelet reactivity may play a mechanistic role. We found significant associations with multiple platelet agonists, indicating higher CRF may globally inhibit platelets; however, given multiple strong associations after TRAP-6 and ADP stimulation, PAR-1 and purinergic signaling may be most heavily involved. This is notable because each of these receptor pathways are tied to anticoagulant (DOAC/thrombin inhibitors) and antiplatelet therapies (P2Y12/PAR1/PAR4 inhibitors) for CVD prevention.