The primary cause of mortality at 5 years following a cardiac transplantation is the development of atherosclerosis, termed coronary allograft vasculopathy (CAV). This pathology is characterized by diffused intimal hyperplasia and emanates from coronary arterial injuries caused by immune inflammatory cells. Neutrophils play an important role in this inflammatory process; however, their potential participation in the pathogenesis of CAV is poorly understood. Despite their essential contribution to the prevention of graft rejection, immunosuppressive drugs could have detrimental effects owing to their pro-inflammatory activities. Thus, we investigated the impact of different immunosuppressive drugs on the inflammatory response of neutrophils isolated from the blood of healthy volunteers. Under basal conditions, mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) had the most potent anti-inflammatory effect, decreasing both IL-8 release (≈−80%) and vascular endothelial growth factor (VEGF) release (≈−65%) and preserving the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA). In TNF-α-treated neutrophils, pre-incubation with everolimus provided the most potent effect, simultaneously reducing the release of both VEGF and IL-8 while doubling the release of IL-1RA. This latter effect of everolimus was maintained even when administered in combination with other immunosuppressive drugs. Sirolimus and everolimus decreased the tumor necrosis factor (TNF)-α-induced adhesion of neutrophils to human endothelial cells and human extracellular matrix. This effect was largely dependent on the ability of these compounds to alter β₂-integrin/CD18 activation. Our results suggest a potential mechanism for the beneficial effect of everolimus in the prevention of CAV in heart transplant recipients.

Background: Beyond the difference in marathon performance when comparing female and male runners, we tested the hypothesis that running strategy does not different according to sex. The goal of the present study is to compare the running strategy between the best female and male marathon performances achieved in the last two years. Methods: Two aspects of the races were analyzed: (i) average speed relative to runner critical speed (CS) with its coefficient of variation and (ii) asymmetry and global tendency of race speed (i.e., the race’s Kendall $\mathsf{\tau })$ . Results: The females’ best marathons were run at 97.6% ± 3% of CS for the new record (Brigid Kosgei, 2019) and at 96.1% ± 4.4% for the previous record (Paula Radcliffe, 2003). The best male performances (Eliud Kipchoge, 2018 and 2019) were achieved at a lower fraction of CS (94.7% ± 1.7% and 94.1% ± 2.3% in 2018 and 2019, respectively). Eliud Kipchoge (EK) achieved a significant negative split race considering the positive Kendall’s $\mathsf{\tau }$ of pacing (i.e., time over 1 km) ( $\mathsf{\tau }$ = 0.30; p = 0.007). Furthermore, EK ran more of the average distance below average speed (54% and 55% in 2018 and 2019, respectively), while female runners ran only at 46% below their average speed. Conclusions: The best female and male marathon performances were run differently considering speed time course (i.e., tendency and asymmetry), and fractional use of CS. In addition, this study shows a robust running strategy (or signature) used by EK in two different marathons. Improvement in marathon performance might depend on negative split and asymmetry for female runners, and on higher fractional utilization of CS for male runners.

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

Introduction Prolonged and strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Although a consensus exists regarding the decrease in diastolic function, the existence of a decrease in systolic function by a PSE remains controversial, probably due to the transient tachycardia and changes in loading conditions observed upon the completion of exercise. Therefore, the objective was to evaluate LV systolic function before and after a PSE using two-dimensional speckle tracking echocardiography not only at rest but also during incremental tests to adjust heart rates (HR). Methods and Results Sixteen healthy young men (23 ± 3 yr old) performed a 3-h period of intensity-controlled upright cycling. LV strain (S), systolic strain rate (SR), rotation, and systolic rotational rate were evaluated by two-dimensional speckle tracking echocardiography before and after a 3-h period of PSE at rest and during incremental tests. Posttest evaluation was performed once the HR had returned to the pretest value. Under resting conditions, parameters of systolic function were either unchanged or increased after the PSE. However, during the incremental test, all LV systolic SR and apical rotational rates were decreased after PSE (radial SR at workload 3 (W3): 2.21 ± 0.12.s⁻¹ vs 1.87 ± 0.10.s⁻¹, P < 0.01 and apical rotational rate at W3: 128 ± 28 deg.s⁻¹ vs 105 ± 26 deg.s⁻¹, P < 0.05). Regression analyses between LV systolic SR and HR showed lower y-intercepts without differences in slopes, suggesting a decrease of both global and regional systolic functions irrespective of HR after the PSE. Conclusion Our findings based on LV S and SR data during incremental tests demonstrate that the 3-h period of PSE induces LV systolic dysfunction.