Blood volume contributes to the mechanical synchrony of the myocardium during moderate and high intensity exercise in women.

PURPOSE: Whether blood volume (BV) primarily determines the synchronous nature of the myocardium remains unknown. This study determined the impact of standard blood withdrawal on left ventricular mechanical dyssynchrony (LVMD) in women. METHODS: Transthoracic speckle-tracking echocardiography and central hemodynamic measurements were performed at rest and during moderate- to high-intensity exercise in healthy women (n = 24, age = 53.6 ± 16.3 year). LVMD was determined via the time to peak standard deviation (TPSD) of longitudinal and transverse strain and strain rates (LSR, TSR). Measurements were repeated within a week period immediately after a 10% reduction of BV. RESULTS: With intact BV, all individuals presented cardiac structure and function variables within normative values of the study population. Blood withdrawal decreased BV (5.3 ± 0.7 L) by 0.5 ± 0.1 L. Resting left ventricular (LV) end-diastolic volume (- 8%, P = 0.040) and passive filling (- 16%, P = 0.001) were reduced after blood withdrawal. No effect of blood withdrawal was observed for any measure of LVMD at rest (P ≥ 0.225). During exercise at a fixed submaximal workload (100 W), LVMD of myocardial longitudinal strain (LS TPSD) was increased after blood withdrawal (36%, P = 0.047). At peak effort, blood withdrawal led to increased LVMD of myocardial transverse strain rate (TSR TPSD) (31%, P = 0.002). The effect of blood withdrawal on TSR TPSD at peak effort was associated with LV concentric remodeling (r = 0.59, P = 0.003). CONCLUSION: Marked impairments in the mechanical synchrony of the myocardium are elicited by moderate blood withdrawal in healthy women during moderate and high intensity exercise.

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.

Marked improvements in cardiac function in postmenopausal women exposed to blood withdrawal plus endurance training.

The cardiac phenotype of a substantial fraction of the population, i.e., mature women, is mainly unresponsive to endurance training (ET), the most effective intervention to improve cardiorespiratory fitness. This study assessed whether a novel intervention comprising additional haemodynamic stimuli may overcome the generalized limitations to modify the cardiac phenotype of middle-aged and older women. Fifteen healthy postmenopausal women (52-75 yr) were recruited. Transthoracic echocardiography and central haemodynamics were assessed during incremental cycle ergometry (i) in baseline conditions, (ii) after standard (10%) blood withdrawal and (iii) subsequent 8-week ET. Main outcomes such as left ventricular (LV) function and structure and blood volume (BV) were determined. Phlebotomy induced a 0.5 ± 0.1 l reduction of BV, which was re-established after ET. Decrements in LV end-systolic volume (-27%) and increments in LV ejection fraction (+8%) during exercise as well as improved E/A ratio were detected after ET compared with baseline. In parallel, ET induced a 10% increment in LV mass without a concomitant increase in LV size. In conclusion, postmenopausal women exhibit large improvements in cardiac systolic and diastolic functions along with LV concentric remodelling in response to the sequenced combination of blood withdrawal and ET.

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.

AIMS: Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target. METHODS: 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome. RESULTS: Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age. CONCLUSIONS: This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.

Impact of Different Adipose Depots on Cardiovascular Disease.

ABSTRACT: Adipose tissue (AT)-derived factors contribute to the regulation of cardiovascular homeostasis, thereby playing an important role in cardiovascular health and disease. In obesity, AT expands and becomes dysfunctional, shifting its secretory profile toward a proinflammatory state associated with deleterious effects on the cardiovascular system. AT in distinct locations (ie, adipose depots) differs in crucial phenotypic variables, including inflammatory and secretory profile, cellular composition, lipolytic activity, and gene expression. Such heterogeneity among different adipose depots may explain contrasting cardiometabolic risks associated with different obesity phenotypes. In this respect, central obesity, defined as the accumulation of AT in the abdominal region, leads to higher risk of cardiometabolic alterations compared with the accumulation of AT in the gluteofemoral region (ie, peripheral obesity). The aim of this review was to provide an updated summary of clinical and experimental evidence supporting the differential roles of different adipose depots in cardiovascular disease and to discuss the molecular basis underlying the differences of adipose depots in the regulation of cardiovascular function.

Apold1 deficiency associates with increased arterial thrombosis in vivo.

BACKGROUND: Endothelial cells regulate the formation of blood clots; thus, genes selectively expressed in these cells could primarily determine thrombus formation. Apold1 (apolipoprotein L domain containing 1) is a gene expressed by endothelial cells; whether Apold1 directly contributes to arterial thrombosis has not yet been investigated. Here, we assessed the effect of Apold1 deletion on arterial thrombus formation using an in vivo model of carotid thrombosis induced by photochemical injury. MATERIAL AND METHODS: Apold1 knockout (Apold1-/- ) mice and wild-type (WT) littermates underwent carotid thrombosis induced by photochemical injury, and time to occlusion was recorded. Tissue factor (TF) activity and activation of mitogen-activated protein kinases (MAPKs) and phosphatidyl-inositol-3 kinase (PI3K)/Akt pathways were analysed by colorimetric assay and Western blotting in both Apold1-/- and WT mice. Finally, platelet reactivity was assessed using light transmission aggregometry. RESULTS: After photochemical injury, Apold1-/- mice exhibited shorter time to occlusion as compared to WT mice. Moreover, TF activity was increased in carotid arteries of Apold1-/- when compared to WT mice. Underlying mechanistic markers such as TF mRNA and MAPKs activation were unaffected in Apold1-/- mice. In contrast, phosphorylation of Akt was reduced in Apold1-/- as compared to WT mice. Additionally, Apold1-/- mice displayed increased platelet reactivity to stimulation with collagen compared with WT animals. CONCLUSIONS: Deficiency of Apold1 results in a prothrombotic phenotype, accompanied by increased vascular TF activity, decreased PI3K/Akt activation and increased platelet reactivity. These findings suggest Apold1 as an interesting new therapeutic target in the context of arterial thrombosis.

AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1ß (Interleukin-1ß).

Background and Purpose- Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD-a member of the AP-1 (activated protein-1) family of transcription factors-was recently shown to regulate inflammation by targeting IL (interleukin)-1ß synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods- WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1ß was investigated by treating JunD siRNA mice with an anti-IL-1ß monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results- In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1ß levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti-IL-1ß antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions- JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1ß.

Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke.

Aims: The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1ß inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1ß in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1ß inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy. Methods and results: Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1ß antibody or vehicle treatment. Following tMCAO, cerebral IL-1ß levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1ß antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1ß antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome. Conclusion: Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1ß blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1ß antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.

Exerkines and cardiometabolic benefits of exercise: from bench to clinic.

Regular exercise has both immediate and long-lasting benefits on cardiometabolic health, and has been recommended as a cornerstone of treatment in the management of diabetes and cardiovascular conditions. Exerkines, which are defined as humoral factors responsive to acute or chronic exercise, have emerged as important players conferring some of the multiple cardiometabolic benefits of exercise. Over the past decades, hundreds of exerkines released from skeletal muscle, heart, liver, adipose tissue, brain, and gut have been identified, and several exerkines (such as FGF21, IL-6, and adiponectin) have been exploited therapeutically as exercise mimetics for the treatment of various metabolic and cardiovascular diseases. Recent advances in metagenomics have led to the identification of gut microbiota, a so-called "hidden" metabolic organ, as an additional class of exerkines determining the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Furthermore, multiomics-based studies have shown the feasibility of using baseline exerkine signatures to predict individual responses to exercise with respect to metabolic and cardiorespiratory health. This review aims to explore the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk, and discuss the roadmaps for translating exerkine-based discovery into the therapeutic application and personalized medicine in the management of the cardiometabolic disease.

Lean body mass and the cardiorespiratory phenotype: An ethnic-specific relationship in Hans Chinese women and men.

BACKGROUND: Lean body mass (LBM) and the functional capacity of cardiovascular (CV) and respiratory systems constitute a female-specific relationship in European-American individuals. Whether this recent finding be extrapolated to the world's largest ethnic group, that is, Hans Chinese (HC, a population characterized by low LBM), is unknown. METHODS: Healthy HC adults (n = 144, 50% ♀) closely matched by sex, age and physical activity were included. Total and regional (leg, arm and trunk) LBM and body composition were measured via dual-energy X-ray absorptiometry. Cardiac structure, stiffness, central/peripheral haemodynamics and peak O2 consumption (VO2peak) were assessed via transthoracic echocardiography and pulmonary gas analyses at rest and during exercise up to peak effort. Regression analyses determined the sex-specific relationship of LBM with cardiac and aerobic phenotypes. RESULTS: Total and regional LBM were lower and body fat percentage higher in women compared with men (P < 0.001). In both sexes, total LBM positively associated with left ventricular (LV) mass and peak volumes (r ≥ 0.33, P ≤ 0.005) and negatively with LV end-systolic and central arterial stiffness (r ≥ -0.34, P ≤ 0.004). Total LBM strongly associated with VO2peak (r ≥ 0.60, P < 0.001) and peak cardiac output (r ≥ 0.40, P < 0.001) in women and men. Among regional LBM, leg LBM prominently associated with the arterio-venous O2 difference at peak exercise in both sexes (r ≥ 0.43, P < 0.001). Adjustment by adiposity or CV risk factors did not modify the results. CONCLUSIONS: LBM independently determines internal cardiac dimensions, ventricular mass, distensibility and the capacity to deliver and consume O2 in HC adults irrespective of sex.

Sex-Specific Limitation of Cardiac Capacity During the Adult Life Span: Return to Fundamental Structure and Function.

Physiology underlying reduced cardiac pumping capacity in women compared with men and its interaction with aging remains unresolved. Herein, the pressure gradient (PG) driving venous return was manipulated to evidence whether cardiac structure and/or function explain sex differences in cardiac capacity. Healthy women/men matched by age and physical activity were included within young (n = 40, age = 25 ±â€…4 years) and older (n = 55, age = 60 ±â€…8 years) groups. Cardiac volumes/output (Q) were assessed up-to-peak exercise under 2 hemodynamic conditions ("low"/"high" PG between lower/upper body). Main outcomes included sex differences in delta ("high" - "low" PG) left ventricular (LV) end-diastolic volume (∆LVEDV), stroke volume (∆SV), and Q (∆Q). In young individuals, "high"-PG increased exercise LVEDV and SV in men (p ≤ .002), but not in women (p ≥ .562), relative to "low"-PG (control condition). Accordingly, peak ∆LVEDV, ∆SV, and ∆Q were enhanced in young men versus young women (p ≤ .019). Notwithstanding, right/left atrial volumes during exercise were similarly increased by "high"-PG in both young sexes (p ≤ .007). "High"-PG exclusively prolonged moderate exercise LV filling time in young men (p ≤ .036). In older individuals, "high"-PG did not modify exercise cardiac volumes and reduced LV diastolic function (p ≤ .049). In conclusion, the female young heart is unrestrained by venous return or structural factors external to the myocardium. As determined during moderate exercise, impaired LV filling time lengthening limits female-specific cardiac capacity. With older age, cardiac chambers are not distended and LV relaxation is impaired with increased PG in both sexes. During early but not late adulthood, a functional LV limitation may explain sex differences in cardiac capacity.

The Chinese cardiorespiratory and circulatory system at work in women and men: a case-control study.

Background: The physiology of prominent prognostic factors in the cardiorespiratory system remains unchartered in the world's largest ethnic group: Hans Chinese (HC). This study assessed and contrasted the fundamental variables in HC and European-American (EA) individuals. Methods: Healthy HC and EA adults (n = 140, 43% ♀) closely matched by age, sex and physical activity were included. Body composition (DXA) and haematological variables (haemoglobin mass, blood volume (BV)) were measured at rest. Pulmonary O2 uptake (VO2) measurements along with cycle ergometry designed for accurate transthoracic echocardiography were implemented to assess cardiorespiratory structure/function up to peak effort. Findings: HC presented with higher body fat and lower lean body mass (LBM) percentage than EA irrespective of sex (P ≤ 0.014). BV did not differ whereas blood haemoglobin concentration was lower in HC compared with EA, particularly in females (P = 0.009). Myocardial diastolic and overall function at rest was enhanced in HC versus EA (P < 0.001). During exercise, heart volumes and output per unit of body size did not differ between ethnicities, whereas larger heart volumes per unit of LBM were found in HC versus EA in females (P ≤ 0.003). At high exercise intensities, VO2 (-16%) and the arteriovenous O2 difference (-28%) were markedly reduced in HC compared with EA in females (P ≤ 0.024). In males, no physiological difference between HC and EA was observed during exercise. Interpretation: Notwithstanding lower LBM, HC are characterised by similar BV and cardiac capacity but reduced peak VO2 than EA in females, partly explained by low ethnic-specific blood O2 carrying capacity. Funding: Early Career Scheme (106210224, to D.M.) and Seed Fund (104006024, to D.M.).

Distinct changes in serum metabolites and lipid species in the onset and progression of NAFLD in Obese Chinese.

Introduction: Metabolic disturbances are major contributors to the onset and progression of non-alcoholic fatty liver disease (NAFLD), which includes a histological spectrum ranging from single steatosis (SS) to non-alcoholic steatohepatitis (NASH). This study aimed to identify serum metabolites and lipids enriched in different histological stages of NAFLD and to explore metabolites/lipids as non-invasive biomarkers in risk prediction of NAFLD and NASH in obese Chinese. Methods: Serum samples and liver biopsies were obtained from 250 NAFLD subjects. Untargeted metabolomic and lipidomic profiling were performed using Liquid Chromatography-Mass Spectrometry. Significantly altered metabolites and lipids were identified by MaAsLin2. Pathway enrichment was conducted with MetaboAnalyst and LIPEA. WGCNA was implemented to construct the co-expression network. Logistic regression models were developed to classify different histological stages of NAFLD. Results: A total of 263 metabolites and 550 lipid species were detected in serum samples. Differential analysis and pathway enrichment analysis revealed the progressive patterns in metabolic mechanisms during the transition from normal liver to SS and to NASH, including N-palmitoyltaurine, tridecylic acid, and branched-chain amino acid signaling pathways. The co-expression network showed a distinct correlation between different triglyceride and phosphatidylcholine species with disease severity. Multiple models classifying NAFLD versus normal liver and NASH versus SS identified important metabolic features associated with significant improvement in disease prediction compared to conventional clinical parameters. Conclusion: Different histological stages of NAFLD are enriched with distinct sets of metabolites, lipids, and metabolic pathways. Integrated algorithms highlight the important metabolic and lipidomic features for diagnosis and staging of NAFLD in obese individuals.

Sex-specific improvement in cardiac phenotype in older females combining blood withdrawal and exercise training.

This study determined whether an intervention combining hematological and exercise stimuli may overcome the prevailing limitations to improve the cardiac phenotype and orthostatic tolerance (OT) of females with advanced age. Healthy females (n = 15) and males (n = 14) matched by age (63.7 ± 7.0 vs. 63.6 ± 8.7 yr) and moderate physical activity were recruited. OT, transthoracic echocardiography, and central hemodynamics were assessed during incremental lower body negative pressure (LBNP) levels (up to -50 mmHg) for 1 h or until presyncope, prior to and after an intervention comprising standard (10%) blood withdrawal and an 8-wk exercise training program designed to maximize central hemodynamic adaptations. OT time was lower in females compared with males (48.1 ± 10.6 vs. 57.0 ± 4.8 min, P = 0.008) before the intervention. Improved OT time (+11%) in females (48.1 ± 10.6 vs. 53.5 ± 6.1 min, P = 0.021) but not in males (57.0 ± 4.8 vs. 56.7 ± 5.6 min, P = 0.868) was found following the intervention, resulting in similar OT time between females and males (P = 0.156). The intervention induced improvements in left ventricular (LV) diastolic function (+13% for myocardial e') along with increased LV mass (+13%) in females (P ≤ 0.039) but not in males (P ≥ 0.257). During the initial LBNP stages (0 to -20 mmHg), LV stroke volume and cardiac output were exclusively increased in females after the intervention (P ≤ 0.034). In conclusion, the cardiac phenotype of females with advanced age can be structurally and functionally modified in parallel to improved OT via short-term hematological and central hemodynamic stimuli.NEW & NOTEWORTHY Based on previous studies, main features of the cardiac phenotype in females with advanced age are generally unresponsive to lifestyle interventions. The present findings reveals that the cardiac phenotype of middle-age and older females is amenable to large modification in a short-term period when hematological stimuli are combined with those induced by exercise training. The same intervention only induced minor adaptations in males matched by age and potential confounding factors.

Impaired cardiac mechanical synchrony revealed with increased myocardial work in women with advanced age.

BACKGROUND: Whether the synchronous nature of the myocardium is sex-dependent or affected by the aging process remains unknown. This study aimed to determine the influence of sex and age on cardiac mechanical synchrony during controlled hemodynamic stress. METHODS: Transthoracic speckle-tracking echocardiography analyses and central hemodynamics were assessed at rest and during moderate- to high-intensity exercise in healthy young (<45 yr) and older (≥45 yr) women (n = 32) and men (n = 34) matched by age, physical activity and exercise capacity. Left ventricular mechanical dyssynchrony (LVMD) was determined as the time to peak standard deviation (TPSD) of longitudinal and transverse strain and strain rates (LSR, TSR). RESULTS: Physical activity, aerobic capacity, heart rate, blood pressure and LVMD at rest were similar between women and men in each age group (P > 0.05). The rate pressure product, an index of myocardial work, did not differ between sex and age groups at rest and during exercise at a given percentage of peak heart rate (P > 0.05). A consistent age effect was observed for transverse LVMD (P-for-age ≤ 0.011). Specifically, older women presented with marked increments (≥42 %) in TSR TPSD at all exercise levels compared with younger women (P ≤ 0.005). Sex per se did not generally affect LVMD. CONCLUSION: A prevailing impairment of cardiac mechanical synchrony in the transverse axis of the left ventricle is revealed during conditions of elevated hemodynamic stress in women with advanced age.

A machine-learning algorithm integrating baseline serum proteomic signatures predicts exercise responsiveness in overweight males with prediabetes.

The molecular transducers conferring the benefits of chronic exercise in diabetes prevention remain to be comprehensively investigated. Herein, serum proteomic profiling of 688 inflammatory and metabolic biomarkers in 36 medication-naive overweight and obese men with prediabetes reveals hundreds of exercise-responsive proteins modulated by 12-week high-intensity interval exercise training, including regulators of metabolism, cardiovascular system, inflammation, and apoptosis. Strong associations are found between proteins involved in gastro-intestinal mucosal immunity and metabolic outcomes. Exercise-induced changes in trefoil factor 2 (TFF2) are associated with changes in insulin resistance and fasting insulin, whereas baseline levels of the pancreatic secretory granule membrane major glycoprotein GP2 are related to changes in fasting glucose and glucose tolerance. A hybrid set of 23 proteins including TFF2 are differentially altered in exercise responders and non-responders. Furthermore, a machine-learning algorithm integrating baseline proteomic signatures accurately predicts individualized metabolic responsiveness to exercise training.

Sex-Specific Effect of Blood Oxygen-Carrying Capacity on Orthostatic Tolerance in Older Individuals.

Blood oxygen (O2)-carrying capacity is reduced with aging and has been previously linked with the capacity to withstand the upright posture, that is, orthostatic tolerance (OT). This study experimentally tested the hypothesis that a definite reduction in blood O2-carrying capacity via hemoglobin manipulation differently affects the OT of older women and men as assessed by lower body negative pressure (LBNP). Secondary hemodynamic parameters were determined with transthoracic echocardiography throughout incremental LBNP levels for 1 hour or until presyncope in healthy older women and men (total n = 26) matched by age (64 ± 7 vs 65 ± 8 years, p < .618) and physical activity levels. Measurements were repeated within a week period after a 10% reduction of blood O2-carrying capacity via carbon monoxide rebreathing and analyzed via 2-way analysis of covariance. In the assessment session, OT time was similar between women and men (53.5 ± 6.1 vs 56.4 ± 6.0 minutes, p = .238). Following a 10% reduction of blood O2-carrying capacity, OT time was reduced in women compared with men (51.3 ± 7.0 vs 58.2 ± 2.8 minutes, p = .003). The effect of reduced O2-carrying capacity on OT time differed between sexes (mean difference [MD] = -5.30 minutes, p = .010). Prior to presyncope, reduced O2-carrying capacity resulted in lower left ventricular end-diastolic volume (MD = -8.11 mL∙m-2, p = .043) and stroke volume (MD = -8.04 mL∙m-2, 95% confidence interval = -14.36, -1.71, p = .018) in women relative to men, even after adjusting for baseline variables. In conclusion, present results suggest that reduced blood O2-carrying capacity specifically impairs OT and its circulatory determinants in older women.