Candela Diaz-Cañestro

Endurance Training and V˙o2max: Role of Maximal Cardiac Output and Oxygen Extraction

PURPOSE Although endurance training (ET) commonly augments maximal oxygen consumption (V˙O2max), it remains unclear whether such increase is associated with that of maximal cardiac output (Qmax) alone or along with arteriovenous oxygen difference (a-V˙O2diff). Herein, we sought to systematically review and determine the effects of ET on V˙O2max, Qmax, and a-V˙O2diff at maximal exercise, and on their associations, in healthy young subjects. METHODS We conducted a systematic search of MEDLINE, Scopus, and Web of Science (from their inception until September 2014) for articles assessing the effects of ET lasting ≥3 wk on V˙O2max and Qmax and/or a-V˙O2diff at maximal exercise in healthy young adults (mean age <40 yr). Meta-analyses were performed to determine standardized mean differences (SMD) in V˙O2max, Qmax, and a-V˙O2diff at maximal exercise between posttraining and pretraining measurements. Subgroup and meta-regression analyses were used to evaluate associations among SMD and potential moderating factors. RESULTS Thirteen studies were included after systematic review, comprising a total of 130 untrained or moderately trained healthy young subjects (mean age, 22-28 yr). Duration of ET programs ranged from 5 to 12.9 wk. After data pooling, V˙O2max (SMD = 0.75, P < 0.0001) and Qmax (SMD = 0.64, P < 0.0001), but not a-V˙O2diff at maximal exercise (SMD = 0.21, P = 0.23), were increased after ET. No significant heterogeneity was detected. With meta-regression, the SMD in Qmax was positively associated with the SMD in V˙O2max (B = 0.91, P = 0.007). The SMD in a-V˙O2diff at maximal exercise was not associated with the SMD in V˙O2max (B = 0.20, P = 0.40). CONCLUSIONS Based on a relatively small number of studies, improvement in V˙O2max following 5-13 wk of ET is associated with increase in Qmax, but not in a-V˙O2diff, in previously untrained to moderately trained healthy young individuals.

Flow-Mediated Dilation in Athletes: Influence of Aging.

PURPOSE Controversy exists on whether endothelial function is enhanced in athletes. We sought to systematically review the literature and determine whether endothelial function, as assessed by flow-mediated dilation (FMD), is greater in athletes across all ages relative to that in their age-matched counterparts. METHODS We conducted a systematic search on MEDLINE, Cochrane, Scopus, and Web of Science since their inceptions until July 2013 for articles evaluating FMD in athletes. A meta-analysis was performed to compare the standardized mean difference (SMD) in FMD of the brachial artery between athletes and age-matched control subjects. Subgroup analyses and meta-regression were used to identify sources of heterogeneity. RESULTS Twenty-one articles were included in this analysis, comprising 530 athletes (452 endurance trained, 49 strength trained, and 29 endurance and strength trained) and 376 control subjects. After data pooling, FMD was higher in athletes than that in control groups (SMD, 0.48; P = 0.008). In subgroup analyses, young athletes (<40 yr) presented increased baseline brachial artery diameter (mean difference, 0.40 mm; P < 0.00001) and similar FMD (SMD, 0.27; P = 0.22) compared with those in controls. In contrast, master athletes (>;50 yr) showed similar baseline brachial artery diameter (mean difference, 0.04 mm; P = 0.69) and increased FMD (SMD, 0.99; P = 0.0005) compared with those in controls. CONCLUSIONS The current meta-analysis provides evidence that master athletes but not young athletes exhibit greater FMD compared with that in age-matched healthy controls, thus suggesting that the association between high levels of exercise training and increased FMD is age dependent.

Endurance training and maximal oxygen consumption with ageing: Role of maximal cardiac output and oxygen extraction

Background The increase in maximal oxygen consumption (VO2max) with endurance training is associated with that of maximal cardiac output (Qmax), but not oxygen extraction, in young individuals. Whether such a relationship is altered with ageing remains unclear. Therefore, we sought systematically to review and determine the effect of endurance training on and the associations among VO2max, Qmax and arteriovenous oxygen difference at maximal exercise (Ca-vO2max) in healthy aged individuals. Design and methods We conducted a systematic search of MEDLINE, Scopus and Web of Science, from their inceptions until May 2015 for articles assessing the effect of endurance training lasting 3 weeks or longer on VO2max and Qmax and/or Ca-vO2max in healthy middle-aged and/or older individuals (mean age ≥40 years). Meta-analyses were performed to determine the standardised mean difference (SMD) in VO2max, Qmax and Ca-vO2max between post and pre-training measurements. Subgroup and meta-regression analyses were used to evaluate the associations among SMDs and potential moderating factors. Results Sixteen studies were included after systematic review, comprising a total of 153 primarily untrained healthy middle-aged and older subjects (mean age 42–71 years). Endurance training programmes ranged from 8 to 52 weeks of duration. After data pooling, VO2max (SMD 0.89; P < 0.0001) and Qmax (SMD 0.61; P < 0.0001) were increased after endurance training; no heterogeneity among studies was detected. Ca-vO2max was only increased with endurance training interventions lasting more than 12 weeks (SMD 0.62; P = 0.001). In meta-regression, the SMD in Qmax was positively associated with the SMD in VO2max (B = 0.79, P = 0.04). The SMD in Ca-vO2max was not associated with the SMD in VO2max (B = 0.09, P = 0.84). Conclusions The improvement in VO2max following endurance training is a linear function of Qmax, but not Ca-vO2max, through healthy ageing.

The Pathophysiological Role of Neutrophil Extracellular Traps in Inflammatory Diseases

Neutrophil pathogen-killing mechanism termed neutrophil extracellular traps (NETs) has been recently identified. NETs consist of chromatin and histones along with serine proteases and myeloperoxidase and are induced by a great variety of infectious and non-infectious stimuli. NETosis is a kind of programmed neutrophil death characterized by chromatin decondensation and release of nuclear granular contents, mainly driven by peptidylarginine deiminase 4 citrullination of histones. Although classically related to the protection against infectious pathogens, nowadays NETs have been described as a player of several pathophysiological processes. Neutrophil dysregulation has been demonstrated in the pathogenesis of most representative vascular diseases, such as acute coronary syndrome, stroke and venous thrombosis. Indeed, NETs have been identified within atherosclerotic lesions and arterial thrombi in both human beings and animal models. Moreover, an imbalance in this mechanism has been proposed as a critical source of modified and/or externalized autoantigens in autoimmune and inflammatory diseases. Finally, an update on the role of NETs in the pathogenesis of cancer has been included. In the present review, based on papers released on PubMed and MEDLINE up to July 2017, we point to update the knowledge on NETs, from their structure to their roles in infectious diseases as well as in cardiovascular diseases, autoimmunity, metabolic disorders and cancer, with a look to future perspectives and therapeutic opportunities.

Microvascular Dilator Function in Athletes: A Systematic Review and Meta-analysis

PURPOSE Despite the growing research interest in vascular adaptations to exercise training over the last few decades, it remains unclear whether microvascular function in healthy subjects can be further improved by regular training. Herein, we sought to systematically review the literature and determine whether microvascular dilator function is greater in athletes compared to age-matched healthy untrained subjects. METHODS We conducted a systematic search of MEDLINE, Cochrane, EMBASE, and Web of Science since their inceptions until October 2013 for articles evaluating indices of primarily microvascular endothelium-dependent or endothelium-independent dilation (MVEDD and MVEID, respectively) in athletes. A meta-analysis was performed to determine the standardized mean difference (SMD) in MVEDD and MVEID between athletes and age-matched controls. Subgroup analyses were used to study potential moderating factors. RESULTS Thirty-six studies were selected after systematic review, comprising 521 athletes (506 endurance-trained and 15 endurance- and strength-trained) and 496 age-matched control subjects. After data pooling, athletes presented higher MVEDD (31 studies; SMD, 0.47; P < 0.00001) and MVEID (14 studies; SMD, 0.51; P < 0.00001) compared with the control subjects. Similar results were observed in young (younger than 40 yr) and master (older than 55 yr) athletes when analyzed separately. CONCLUSION Both young and master athletes present enhanced microvascular function compared with age-matched untrained but otherwise healthy subjects. These data provide evidence of a positive association between exercise training and microvascular function in the absence of known underlying cardiovascular disease.

Sirtuin 5 as a novel target to blunt blood–brain barrier damage induced by cerebral ischemia/reperfusion injury

BACKGROUND In acute ischemic stroke (AIS) patients, impaired blood-brain barrier (BBB) integrity is associated with hemorrhagic transformation and worsened outcome. Yet, the mechanisms underlying these relationships are poorly understood and consequently therapeutic strategies are lacking. This study sought to determine whether SIRT5 contributes to BBB damage following I/R brain injury. METHODS AND RESULTS SIRT5 knockout (SIRT5-/-) and wild type (WT) mice underwent transient middle cerebral artery (MCA) occlusion (tMCAO) followed by 48h of reperfusion. Genetic deletion of SIRT5 decreased infarct size, improved neurological function and blunted systemic inflammation following stroke. Similar effects were also achieved by in vivo SIRT5 silencing. Immunohistochemical analysis revealed decreased BBB leakage and degradation of the tight junction protein occludin in SIRT5-/- mice exposed to tMCAO as compared to WT. In primary human brain microvascular endothelial cells (HBMVECs) exposed to hypoxia/reoxygenation (H/R), SIRT5 silencing decreased endothelial permeability and upregulated occludin and claudin-5; this effect was prevented by the PI3K inhibitor wortmannin. Lastly, SIRT5 gene expression was increased in peripheral blood monocytes (PBMCs) of AIS patients at 6h after onset of stroke compared to sex- and age-matched healthy controls. CONCLUSION SIRT5 is upregulated in PBMCs of AIS patients and in the MCA of WT mice exposed to tMCAO; SIRT5 mediates I/R-induced brain damage by increasing BBB permeability through degradation of occludin. This effect was reproduced in HBMVECs exposed to H/R, mediated by the PI3K/Akt pathway. Our findings shed new light on the mechanisms of I/R-dependent brain damage and suggest SIRT5 as a novel therapeutic target.

Arterial stiffness is strongly and negatively associated with the total volume of red blood cells

BACKGROUND Erythropoiesis is partly regulated through classic feedback pathways that govern blood volume (BV) as sensed by veno-atrial but also arterial stretch receptors. Hence, the total volume of red blood cells (RBCV) could be associated with arterial stiffness (AS), although such hypothesis has not yet been tested. Therefore, we sought to investigate the association of AS with hematological variables including RBCV. METHODS Fourteen healthy physically active individuals volunteered for the study (age=23±2). RBCV, plasma volume (PV), and BV were calculated from measures of hematocrit and total hemoglobin mass (Hbmass) determined by CO-rebreathing. Carotid compliance with ultrasonography and carotid-ankle pulse wave velocity (PWV) were determined at rest and immediately after a maximal exercise test. The rationale for assessment of AS after exercise derives from the potential marked role of AS in the regulation of erythropoiesis in the setting of reduced central venous pressure. RESULTS At rest, carotid compliance was positively associated with Hbmass, RBCV, BV, but not PV, with coefficients of determination (R(2)) ranging from 0.39 to 0.57. Following exercise, closer positive associations were observed between carotid compliance and Hbmass, RBCV, or BV. Moreover, carotid-ankle PWV was negatively associated with all hematological variables after exercise except for PV, with R(2) ranging from 0.49 to 0.75. Similar results were observed when adjusted by body weight. CONCLUSIONS AS is strongly and inversely associated with RBCV in healthy individuals. These findings suggest that AS may adversely intercede in the regulation of erythropoiesis through the alteration of mechanisms that control BV.

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)-1β 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-1β 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-1β 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-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β 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-1β 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-1β 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-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.

Maximal cardiac output in athletes: Influence of age

Background The decline in maximal oxygen consumption (VO2max) with age seems to be exacerbated in endurance-trained athletes (EA) relative to untrained healthy subjects. Whether maximal cardiac output (Qmax) parallels this group-specific decline with age remains uncertain. Therefore, we sought to systematically review the literature and determine whether Qmax is similarly enhanced in EA across all ages relative to age-matched untrained counterparts. Design and methods We conducted a systematic search of MEDLINE, Cochrane and Web of Science from their inceptions until June 2014 for articles evaluating Qmax in athletes. A meta-analysis was performed to determine the standardized mean difference (SMD) in Qmax between EA and age-matched untrained healthy subjects. Included studies had to (i) comprise EA and control groups matched for body size or (ii) present Qmax values normalized for body size. Subgroup and meta-regression analyses were used to study the influence of age and potential moderating factors. Results Eighteen studies were selected after systematic review, comprising 268 EA and 232 age-matched untrained subjects. Nine studies involved young EA (mean age ≤40 years) while nine studies involved master EA (mean age >55 years). After data pooling, young and master EA groups showed higher Qmax compared with control groups (SMD = 1.49 and SMD = 1.68, respectively; both p < 0.0001). The SMD in Qmax between EA and control groups was similar in studies in young EA compared with studies in master EA (p = 0.61). Moreover, the SMD in VO2max between EA and control groups did not differ in studies in young EA compared with studies in master EA (p = 0.37). In meta-regression analyses, the difference in percentage of body fat between EA and control groups was inversely associated with the SMD in Qmax (B = − 0.17, p = 0.01) and the SMD in VO2max (B = −0.20, p = 0.01). Mean age was not associated with the SMD in Qmax (B = −0.001, P = 0.90) nor with the SMD in VO2max (B = 0.01, P = 0.58). Conclusions Based on current published studies, the enhanced Qmax observed in EA compared with untrained healthy subjects matched for body size is not affected by age but may be related, at least in part, to the improved body composition of EA.

Determinants of exercise intolerance in heart failure with preserved ejection fraction: A systematic review and meta-analysis

BACKGROUND Severe exercise intolerance (EI), demonstrated by impaired peak oxygen consumption, intrinsically characterizes heart failure with preserved ejection fraction (HFpEF). Controversy exists on the determinants of EI in patients with HFpEF according to case-control studies. The purpose of this study is to systematically review and clarify the main (Fick) determinants of EI in HFpEF. METHODS We conducted a systematic search of MEDLINE, Scopus and Web of Science since their inceptions until January 2017 for articles assessing peak cardiac output and/or arteriovenous oxygen difference (a-vO2diffpeak) with incremental exercise in patients diagnosed with HFpEF and age-matched control individuals. Meta-analyses were performed to determine the standardized mean difference (SMD) in peak cardiac index (CIpeak) and a-vO2diffpeak between HFpEF and control groups. Subgroup and meta-regression analyses were used to evaluate potential moderating factors. RESULTS Ten studies were included after systematic review, comprising a total of 213 HFpEF patients and 179 age-matched control individuals (mean age=51-73years). After data pooling, CIpeak (n=392, SMD=-1.42; P<0.001) and a-vO2diffpeak (n=228, SMD=-0.52; P=0.002) were impaired in HFpEF patients. In subgroup analyses, a-vO2diffpeak was reduced in HFpEF versus healthy individuals (n=114, SMD=-0.85; P<0.001) but not compared with control patients without heart failure (n=92, SMD=-0.12; P=0.57). The SMD in a-vO2diffpeak was negatively associated with age (B=-0.05, P=0.046), difference in % females (B=-0.01, P=0.026) and prevalence of hypertension (B=-0.01, P=0.015) between HFpEF and control groups. CONCLUSIONS HFpEF is associated with a predominant impairment of CIpeak, accompanied by sex- and comorbidity-dependent reduced oxygen extraction at peak exercise.