Association between CT Perfusion Parameters and Hemorrhagic Transformation after Endovascular Treatment in Acute Ischemic Stroke: Results from the ESCAPE-NA1 Trial.

BACKGROUND AND PURPOSE: Hemorrhagic transformation can occur as a complication of endovascular treatment for acute ischemic stroke. This study aimed to determine whether ischemia depth as measured by admission CTP metrics can predict the development of hemorrhagic transformation at 24 hours. MATERIALS AND METHODS: Patients with baseline CTP and 24-hour follow-up imaging from the ESCAPE-NA1 trial were included. RAPID software was used to generate CTP volume maps for relative CBF, CBV, and time-to-maximum at different thresholds. Hemorrhage on 24-hour imaging was classified according to the Heidelberg system, and volumes were calculated. Univariable and multivariable regression analyses assessed the association between CTP lesion volumes and hemorrhage/hemorrhage subtypes. RESULTS: Among 408 patients with baseline CTP, 142 (35%) had hemorrhagic transformation at 24-hour follow-up, with 89 (63%) classified as hemorrhagic infarction (HI1/HI2), and 53 (37%), as parenchymal hematoma (PH1/PH2). Patients with HI or PH had larger volumes of low relative CBF and CBV at each threshold compared with those without hemorrhage. After we adjustied for baseline and treatment variables, only increased relative CBF <30% lesion volume was associated with any hemorrhage (adjusted OR, 1.14; 95% CI, 1.02-1.27 per 10 mL), as well as parenchymal hematoma (adjusted OR, 1.23; 95% CI, 1.06-1.43 per 10 mL). No significant associations were observed for hemorrhagic infarction. CONCLUSIONS: Larger "core" volumes of relative CBF <30% were associated with an increased risk of PH following endovascular treatment. This particular metric, in conjunction with other clinical and imaging variables, may, therefore, help estimate the risk of post-endovascular treatment hemorrhagic complications.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Effect of incomplete reperfusion patterns on clinical outcome: insights from the ESCAPE-NA1 trial.

BACKGROUND: Incomplete reperfusion (IR) after mechanical thrombectomy (MT) can be a consequence of residual occlusion, no-reflow phenomenon, or collateral counterpressure. Data on the impact of these phenomena on clinical outcome are limited. METHODS: Patients from the ESCAPE-NA1 trial with IR (expanded Thrombolysis In Cerebral Infarction (eTICI) 2b) were compared with those with complete or near-complete reperfusion (eTICI 2c-3) on the final angiography run. Final runs were assessed for (a) an MT-accessible occlusion, or (b) a non-MT-accessible occlusion pattern. The primary clinical outcome was modified Rankin Scale (mRS) 0-2 at 90 days. Our imaging outcome was infarction in IR territory on follow-up imaging. Unadjusted and adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95% CI) were obtained. RESULTS: Of 1105 patients, 443 (40.1%) with IR and 506 (46.1%) with complete or near-complete reperfusion were included. An MT-accessible occlusion was identified in 147/443 patients (33.2%) and a non-MT-accessible occlusion in 296/443 (66.8%). As compared with patients with near-complete/complete reperfusion, patients with IR had significantly lower chances of achieving mRS 0-2 at 90 days (aIRR 0.82, 95% CI 0.74 to 0.91). Rates of mRS 0-2 were lower in the MT-accessible occlusion group as compared with the non-MT-accessible occlusion pattern group (aIRR 0.71, 95% CI 0.60 to 0.83, and aIRR 0.89, 95% CI 0.81 to 0.98, respectively). More patients with MT-accessible occlusion patterns developed infarcts in the non-reperfused territory as compared with patients with non-MT occlusion patterns (68.7% vs 46.3%). CONCLUSION: IR was associated with worse clinical outcomes than near-complete/complete reperfusion. Two-thirds of our patients with IR had non-MT-accessible occlusion patterns which were associated with better clinical and imaging outcomes compared with those with MT-accessible occlusion patterns.

Acute regulation of erythropoietin via lower body negative pressure: Influence of sex and age.

The regulation of erythropoiesis via hemodynamic stimuli such as reduced central blood volume (CBV) remains uncertain in women and elderly individuals. This study assessed the acute effects of lower body negative pressure (LBNP) on key endocrine biomarkers regulating erythropoiesis, that is, erythropoietin (EPO) and copeptin, in young and older women and men (n = 87). Transthoracic echocardiography and hemodynamics were assessed throughout incremental LBNP levels for 1 hour, or until presyncope, with established methods. Venous blood samples were collected at baseline and immediately after termination of the orthostatic tolerance (OT) test for subsequent hormone analyses. The average age of young women and men (33.1 ± 6.0 vs. 29.5 ± 6.9 yr) and older women and men (63.8 ± 8.0 vs. 65.3 ± 8.9 yr) as well as their physical activity levels were matched within each age and sex group. CBV, as determined by right atrial volume, was reduced in all individuals at the end of the OT test (p < 0.001). The average OT time ranged from 50.1 to 58.1 min in all individuals. LBNP increased circulating EPO in young women (p = 0.023) but not in young men or older individuals. Copeptin was increased in all individuals with LBNP but was exclusively associated with EPO in men (r = 0.39, p = 0.013). The present study indicates that the acute hemodynamic regulation of EPO production is both sex- and age-dependent.

Challenges and opportunities in research funding for neurovascular diseases from a clinical researcher's perspective.

BACKGROUND & PURPOSE: Neurovascular research is underfunded, imposing substantial challenges on clinical researchers in the field of neurovascular diseases. We explored what physicians perceive to be the greatest challenges with regard to neurovascular research funding, and how they think the funding crisis in neurovascular research could be overcome. METHODS: We performed an international, multi-disciplinary survey among physicians involved in the medical care of patients with neurovascular diseases. After providing their demographic data, physicians were asked closed-ended questions on their personal opinion regarding challenges in neurovascular research funding, and how these challenges could be overcome. Physicians also described in their own words what they perceived to be the biggest challenges in obtaining funding. Data were analyzed using descriptive statistics and response clustering. RESULTS: Of 233 participating physicians (70.4% male,82.8% senior staff) from 48 countries, 217(97.4%) perceived the discrepancy between required and available funding to be a problem;172(73.8%) considered it a major problem. High competitiveness (61/118 available free text responses[51.7%]), time-consuming application processes (28/118[23.7%]) and administrative requirements (25/118[21.1%]) were identified as key obstacles. Traditional big funding agencies were perceived to be most capable of closing the neurovascular research funding gap, followed by specialty-specific organizations and industry, while philanthropy and crowdfunding were perceived to be less important. CONCLUSION: The gap between required and available funding was perceived to be a major problem in neurovascular research, with high competitiveness, time-consuming funding processes and excessive administrative requirements being the key obstacles to obtaining funding. Traditional funding agencies were perceived to be most capable of closing this funding gap.

Lean body mass and the cardiovascular system constitute a female-specific relationship.

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.

Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial.

BACKGROUND: Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care. METHODS: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual. FINDINGS: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis. FUNDING: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Ethical Justification for Deferral of Consent in the AcT Trial for Acute Ischemic Stroke.

The AcT trial (Alteplase Compared to Tenecteplase) compares alteplase or tenecteplase for patients with acute ischemic stroke. All eligible patients are enrolled by deferral of consent. Although the use of deferral of consent in the AcT trial meets the requirements of Canadian policy, we sought to provide a more explicit and rigorous approach to the justification of deferral of consent organized around 3 questions. Ultimately, the approach we outline here could become the foundation for a general justification for deferral of consent.

Differences in Cardiac Output and Aerobic Capacity Between Sexes Are Explained by Blood Volume and Oxygen Carrying Capacity.

Whether average sex differences in cardiorespiratory fitness can be mainly explained by blood inequalities in the healthy circulatory system remains unresolved. This study evaluated the contribution of blood volume (BV) and oxygen (O2) carrying capacity to the sex gap in cardiac and aerobic capacities in healthy young individuals. Healthy young women and men (n = 28, age range = 20-43 years) were matched by age and physical activity. Echocardiography, blood pressures, and O2 uptake were measured during incremental exercise. Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q), peak O2 uptake (VO2peak ), and BV were assessed with precise methods. The test was repeated in men after blood withdrawal and reduction of O2 carrying capacity, reaching women's levels. Before blood normalization, exercise cardiac volumes and output (LVEDV, SV, Q) adjusted by body size and VO2peak (42 ± 9 vs. 50 ± 11 ml⋅min-1⋅kg-1, P < 0.05) were lower in women relative to men. Blood normalization abolished sex differences in cardiac volumes and output during exercise (P ≥ 0.100). Likewise, VO2peak was similar between women and men after blood normalization (42 ± 9 vs. 40 ± 8 ml⋅min-1⋅kg-1, P = 0.416). In conclusion, sex differences in cardiac output and aerobic capacity are not present in experimental conditions matching BV and O2 carrying capacity between healthy young women and men.

Sex Differences in Orthostatic Tolerance Are Mainly Explained by Blood Volume and Oxygen Carrying Capacity.

OBJECTIVES: The reduced orthostatic tolerance (OT) that is characteristic of the female sex may be explained by multiple phenotypic differences between sexes. This study aimed to elucidate the mechanistic role of blood volume (BV) and oxygen carrying capacity on sex differences in OT. DESIGN: Experimental intervention. SETTING: University of Calgary, Main Campus, Calgary, AB, Canada. SUBJECTS: Healthy women and men (n = 90) throughout the adult lifespan (20-89 yr) matched by age and physical activity. INTERVENTIONS: Incremental lower body negative pressure (LBNP) in all individuals. Blood withdrawal and oxygen carrying capacity reduction in men to match with women's levels. MEASUREMENTS AND MAIN RESULTS: Transthoracic echocardiography and central blood pressures were assessed throughout incremental LBNP for 1 hour or until presyncope. Blood uniformization resulted in a precise sex match of BV and oxygen carrying capacity (p ≥ 0.598). A third of women (14/45) and two thirds of men (31/45) prior to blood uniformization completed the orthostatic test without presyncopal symptoms (p-for-sex < 0.001). After blood uniformization, seven out of 45 men completed the test (p-for-sex = 0.081). Left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) were progressively reduced with LBNP in both sexes, with women showing markedly lower volumes than men (p < 0.001). Blood uniformization did not eliminate sex differences in LVEDV and SV. CONCLUSIONS: Sex differences in OT are not present when BV and oxygen carrying capacity are experimentally matched between sexes throughout the adult lifespan.

Worldwide anaesthesia use during endovascular treatment for medium vessel occlusion stroke.

INTRODUCTION: The optimal anaesthesia approach for endovascular treatment (EVT) in acute ischaemic stroke is currently unknown. In stroke due to medium vessel occlusions (MeVO), the occluded vessels are particularly small and more difficult to access, especially in restless or uncooperative patients. In these patients, general anaesthesia (GA) may be preferred by physicians to prevent complications due to patient movement. We investigated physicians' approaches to anaesthesia during EVT for MeVO stroke. METHODS: In a worldwide, case-based, online survey, physicians' preferred anaesthesia approach during EVT for MeVO stroke was categorized as "initial GA", "initial GA if necessary" (depending on patient cooperation), "no initial GA, but conversion if necessary" (start with local anaesthesia or conscious sedation), and "no GA". Preferred anaesthesia approaches were reported overall and stratified by physician and patient characteristics. RESULTS: A total of 366 survey participants provided 1464 responses to 4 primary MeVO EVT case-scenarios. One-third of responses (489/1464 [33%]) favoured no initial GA, but conversion if necessary. Both initial GA and initial GA if necessary were preferred in 368/1464 (25%) of responses respectively. No GA was favoured in 244/1464 (17%). Occlusion location, respondent specialization (interventional neuroradiology), higher age, and female respondent sex were significantly associated with GA preference. GA was more often used in Europe than in other parts of the world (p < 0.001). CONCLUSIONS: Anaesthesia approaches in MeVO EVT vary across world regions and patient and physician factors. Most physicians in this survey preferred to start with local anaesthesia or conscious sedation and convert to GA if necessary.

Effects of blood withdrawal on cardiac, hemodynamic, and pulmonary responses to a moderate acute workload in healthy middle-aged and older females.

OBJECTIVES: To investigate the effects of blood withdrawal on cardiac, hemodynamic, and pulmonary responses to submaximal exercise in females. DESIGN AND METHODS: 30 healthy females (63.8 ±â€¯8.3 years) were recruited for this experimental study. Transthoracic echocardiography, non-invasive blood pressure monitoring, and oxygen uptake were assessed during a fixed submaximal workload (100 W) prior to (day 1) and immediately after (day 2) a 10% reduction of blood volume. Main measurements included left ventricular end-diastolic volume, stroke volume, cardiac output, mean arterial pressure, systolic blood pressure, diastolic blood pressure, and oxygen uptake. Blood volume was determined via carbon monoxide rebreathing. RESULTS: Participant's blood volume ranged from 3.8 to 6.6 L. Following 10% reduction in blood volume (0.5 ±â€¯0.1 L), left ventricular end-diastolic volume (p ≤ 0.030) and stroke volume (p < 0.019) were reduced during submaximal exercise while cardiac output was unchanged (p = 0.139) due to increased heart rate (p < 0.026). Hemodynamic variables including mean arterial pressure (p < 0.015), systolic blood pressure (p < 0.005), and diastolic blood pressure (p < 0.038) were reduced while oxygen uptake was unaltered (p = 0.250). CONCLUSIONS: Blood withdrawal results in marked reductions in cardiac filling with compensatory chronotropic responses that preserve cardiac output at a moderate submaximal workload in healthy females. Thus, blood volume determines the relative exercise intensity, as typically determined by heart rate, of submaximal efforts in this population.

Sex differences in cardiorespiratory fitness are explained by blood volume and oxygen carrying capacity.

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.

Blood withdrawal acutely impairs cardiac filling, output and aerobic capacity in proportion to induced hypovolemia in middle-aged and older women.

Blood donation entails acute reductions of cardiorespiratory fitness in healthy men. Whether these effects can be extrapolated to blood donor populations comprising women remains uncertain. The purpose of this study was to comprehensively assess the acute impact of blood withdrawal on cardiac function, central hemodynamics and aerobic capacity in women throughout the mature adult lifespan. Transthoracic echocardiography and O2 uptake were assessed at rest and throughout incremental exercise (cycle ergometry) in healthy women (n = 30, age: 47-77 yr). Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q̇) and peak O2 uptake (V̇O2peak), and blood volume (BV) were determined with established methods. Measurements were repeated following a 10% reduction of BV within a week period. Individuals were non-smokers, non-obese and moderately fit (V̇O2peak = 31.4 ± 7.3 mL·min-1·kg-1). Hematocrit and BV ranged from 38.0 to 44.8% and from 3.8 to 6.6 L, respectively. The standard 10% reduction in BV resulted in 0.5 ± 0.1 L withdrawal of blood, which did not alter hematocrit (P = 0.953). Blood withdrawal substantially reduced cardiac LVEDV and SV at rest as well as during incremental exercise (≥10% decrements, P ≤ 0.009). Peak Q̇ was proportionally decreased after blood withdrawal (P < 0.001). Blood withdrawal induced a 10% decrement in V̇O2peak (P < 0.001). In conclusion, blood withdrawal impairs cardiac filling, Q̇ and aerobic capacity in proportion to the magnitude of hypovolemia in healthy mature women. Novelty: The filling of the heart and therefore cardiac output are impaired by blood withdrawal in women. Oxygen delivery and aerobic capacity are reduced in proportion to blood withdrawal.

Sex dimorphism in cardiac and aerobic capacities: The influence of body composition.

OBJECTIVE: The 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. METHODS: Healthy, 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. RESULTS: Women 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. CONCLUSIONS: Total 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.