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Aims Intrinsic sex differences in fundamental blood attributes have long been hypothesized to contribute to the gap in cardiorespiratory fitness between men and women. This study experimentally assessed the role of blood volume and oxygen (O2) carrying capacity on sex differences in cardiac function and aerobic power. Methods and results Healthy women and men (n = 60) throughout the mature adult lifespan (42-88 yr) were matched by age and physical activity levels. Transthoracic echocardiography, central blood pressure and O2 uptake were assessed throughout incremental exercise (cycle ergometry). Main outcomes such as left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q), and peak O2 uptake (VO2peak), as well as blood volume (BV) were determined with established methods. Measurements were repeated in men following blood withdrawal and O2 carrying capacity reduction matching women’s levels. Prior to blood normalization, BV and O2 carrying capacity were markedly reduced in women compared with men (P < 0.001). Blood normalization resulted in a precise match of BV (82.36 ± 9.83 vs. 82.34 ± 7.70 ml·kg−1, P = 0.993) and O2 carrying capacity (12.0 ± 0.6 vs. 12.0 ± 0.7 g·dl−1, P = 0.562) between women and men. Body size-adjusted cardiac filling and output (LVEDV, SV, Q) during exercise as well as VO2peak (30.8 ± 7.5 vs. 35.6 ± 8.7 ml·min−1·kg−1, P < 0.001) were lower in women compared with men prior to blood normalization. VO2peak did not differ between women and men after blood normalization (30.8 ± 7.5 vs. 29.7 ± 7.4 ml·min−1·kg−1, P = 0.551). Conclusions Sex differences in cardiorespiratory fitness are abolished when blood attributes determining O2 delivery are experimentally matched between adult women and men. Translational Perspective Low cardiorespiratory fitness is strongly associated with all-cause and cardiovascular mortality in asymptomatic adults independently of traditional risk factors, relationships seemingly enhanced in middle-aged and older women. Yet, whether the primary hematological determinants of cardiorespiratory fitness that were established in studies comprising men explain the difference between sexes remains uncertain. Importantly, blood attributes are amenable to modification and thus potentially translated into effective targets to improve or preserve cardiovascular health in the general population. The present experimental study demonstrates that blood normalization between men and women eliminate sex differences in cardiorespiratory fitness.

ObjectiveThe contribution of body composition to sex differences in strong prognostic cardiorespiratory variables remains unresolved. This study aimed to elucidate whether body composition determines sex differences in cardiac and oxygen (O2) uptake responses to incremental exercise.MethodsHealthy, moderately active women and men (n = 60, age = 60.7 [12.3] years) matched by age and cardiorespiratory fitness were included. Body composition was determined via dual‐energy x‐ray absorptiometry. Transthoracic echocardiography and O2 uptake were assessed at rest and throughout incremental exercise with established methods. Major cardiac and pulmonary outcomes were normalized by body surface area (BSA), total lean body mass (LBM), or leg LBM.ResultsWomen presented with smaller anthropometrical indices (height, weight, BSA) and LBM compared with men (p < 0.001). Peak exercise cardiac dimensions and output (i.e., peak cardiac outout [Qpeak]), commonly normalized by BSA, were reduced in women relative to men (p ≤ 0.019). Cardiac sex differences were abolished after normalization by total or leg LBM (p ≥ 0.115). Strong linear relationships of total and leg LBM with Qpeak and peak oxygen uptake were detected exclusively in women (r ≥ 0.53, p ≤ 0.003), independent of body fat percentage.ConclusionsTotal and leg LBM stand out as strong independent determinants of cardiac and aerobic capacities in women, regardless of body fat percentage, relationships that are not present in age‐ and fitness‐matched men.

Recent evidence points toward a link between lean body mass (LBM) and cardiovascular capacity in women. This study aimed at determining the sex-specific relationship of LBM with central and peripheral circulatory variables in healthy women and men ( n =70) matched by age (60±12 years versus 58±15 years), physical activity, and cardiovascular risk factors. Regional (legs, arms, and trunk) and whole-body (total) body composition were assessed via dual-energy x-ray absorptiometry. Cardiac structure, function, and central/peripheral hemodynamics were measured via transthoracic echocardiography and the volume-clamp method at rest and peak incremental exercise. Regression analyses determined sex-specific relationships between LBM and cardiovascular variables. Regional and total LBM were lower in women than men ( P <0.001), with little overlap between sexes. Leg and arm LBM positively associated with left ventricular (LV) internal resting dimensions in women ( r ≥0.53, P ≤0.002) but not men ( P ≥0.156). Leg, arm, and total LBM only associated with LV relaxation in women ( r ≥0.43, P ≤0.013). All LBM variables strongly associated with LV volumes at peak exercise in women ( r ≥0.54, P ≤0.001) but not men and negatively associated with total peripheral resistance at peak exercise in women ( r ≥0.43, P ≤0.023). Adjustment by adiposity-related or cardiovascular risk factors did not alter results. In conclusion, leg and arm LBM independently associate with internal cardiac dimensions, ventricular relaxation, and systemic vascular resistance in a sex-specific manner, with these relationships exclusively present in women.

Background : Intravenous thrombolysis with alteplase is widely used in acute ischemic stroke patients presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared to alteplase. This study investigates whether intravenous tenecteplase is non‐inferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods : This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial with blinded endpoint assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non‐inferior to intravenous alteplase (0.9 mg/kg body weight, max dose 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a non‐inferiority margin of 5%, assuming incidence of 90‐day mRS 0–1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate < 5%. Results : The blinded primary endpoint is the proportion of subjects achieving a 90‐day mRS (modified Rankin scale) of 0–1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within 24‐hour period will be reported and coded using MedDRA. Outcomes are collected either centrally (primary, key secondary and safety endpoints) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusion : Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase vs. alteplase in patients with acute ischemic stroke presenting early after stroke onset. Clinical Trial Registration: NCT03889249 https://clinicaltrials.gov/ct2/show/NCT03889249 This article is protected by copyright. All rights reserved