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Background Autonomic dysregulation represents a hallmark of coronary artery disease (CAD). Therefore, we investigated the effects of exercise-based cardiac rehabilitation (CR) on autonomic function and neuro-cardiovascular stress reactivity in CAD patients. Methods and Results Twenty-two CAD patients (4 women; 62±8 years) were studied before and following 6 months of aerobic- and resistance-training-based CR. Twenty-two similarly aged, healthy individuals (CTRL; 7 women; 62±11 years) served as controls. We measured blood pressure, muscle sympathetic nerve activity, heart rate, heart rate variability (linear and nonlinear), and cardiovagal (sequence method) and sympathetic (linear relationship between burst incidence and diastolic blood pressure) baroreflex sensitivity during supine rest. Furthermore, neuro-cardiovascular reactivity during short-duration static handgrip (20s) at 40% maximal effort was evaluated. Six months of CR lowered resting blood pressure (P<0.05), as well as muscle sympathetic nerve activity burst frequency (48±8 to 39±11 bursts/min; P<0.001) and burst incidence (81±7 to 66±17 bursts/100 heartbeats; P<0.001), to levels that matched CTRL and improved sympathetic baroreflex sensitivity in CAD patients (P<0.01). Heart rate variability (all P>0.05) and cardiovagal baroreflex sensitivity (P=0.11) were unchanged following CR, yet values were not different pre-CR from CTRL (all P>0.05). Furthermore, before CR, CAD patients displayed greater blood pressure and muscle sympathetic nerve activity reactivity to static handgrip versus CTRL (all P<0.05); yet, responses were reduced following CR (all P<0.05) to levels observed in CTRL. Conclusions Six months of exercise-based CR was associated with marked improvement in baseline autonomic function and neuro-cardiovascular stress reactivity in CAD patients, which may play a role in the reduced cardiac risk and improved survival observed in patients following exercise training.

Background: Pregnancy in women with mechanical valves has a high risk of both valve thrombosis and bleeding as well as adverse effects on the foetus. There is limited data on achieving optimal anticoagulation in pregnancy and management of valve thrombosis, to achieve a successful foetal outcome, while prioritizing the mother's health. While warfarin may carry a lower risk of valve thrombosis, warfarin is teratogenic in the first trimester and is associated with increased foetal loss throughout the pregnancy. Heparin does not cross the placenta but is associated with increased maternal morbidity and mortality., Case Summary: We describe the case of a pregnant patient with thrombosis of a mechanical mitral valve presenting with an embolic stroke at 22 weeks of pregnancy. The stroke was treated with clot retrieval and resulted in no residual neurological deficit. Two previous pregnancies had been managed with low molecular weight heparin, and both resulted in foetal loss. The patient was determined to continue this pregnancy. She was treated with intravenous unfractionated heparin during the remainder of the pregnancy. She developed worsening heart failure due to persisting valve thrombosis despite maintenance of therapeutic anticoagulation. The patient deteriorated rapidly prior to a planned early elective delivery. Emergency Caesarean section was required followed by valve replacement using extracorporeal membrane oxygenation support with an ultimately successful maternal and foetal outcome. Anticoagulation regimes and treatment of mechanical valve thrombosis in pregnancy are discussed., Discussion: The management of pregnant patients with mechanical valves is complex, especially when valve thrombosis and other complications occur. A multidisciplinary approach is essential and in this case led to successful outcome.

RNA fragments deriving from tRNAs (tRFs) exist in all branches of life and the repertoire of their biological functions regularly increases. Paradoxically, their biogenesis remains unclear. The human RNase A, Angiogenin, and the yeast RNase T2, Rny1p, generate long tRFs after cleavage in the anticodon region. The production of short tRFs after cleavage in the D or T regions is still enigmatic. Here, we show that the Arabidopsis Dicer-like proteins, DCL1-4, do not play a major role in the production of tRFs. Rather, we demonstrate that the Arabidopsis RNases T2, called RNS, are key players of both long and short tRFs biogenesis. Arabidopsis RNS show specific expression profiles. In particular, RNS1 and RNS3 are mainly found in the outer tissues of senescing seeds where they are the main endoribonucleases responsible of tRNA cleavage activity for tRFs production. In plants grown under phosphate starvation conditions, the induction of RNS1 is correlated with the accumulation of specific tRFs. Beyond plants, we also provide evidence that short tRFs can be produced by the yeast Rny1p and that, in vitro, human RNase T2 is also able to generate long and short tRFs. Our data suggest an evolutionary conserved feature of these enzymes in eukaryotes.

Background: The European General Practitioners Research Network (EGPRN) designed and validated a comprehensive definition of multimorbidity using a systematic literature review and qualitative research throughout Europe. This definition was tested as a model to assess death or acute hospitalization in multimorbid outpatients., Objective: To assess which criteria in the EGPRN concept of multimorbidity could detect outpatients at risk of death or acute hospitalization in a primary care cohort at a 6-month follow-up and to assess whether a large scale cohort with FPs would be feasible., Method: Family Physicians included a random sample of multimorbid patients who attended appointments in their offices from July to December 2014. Inclusion criteria were those of the EGPRN definition of Multimorbidity. Exclusion criteria were patients under legal protection and those unable to complete the 2-year follow-up. Statistical analysis was undertaken with uni- and multivariate analysis at a 6-month follow-up using a combination of approaches including both automatic classification and expert decision making. A Multiple Correspondence Analysis (MCA) completed the process with a projection of illustrative variables. A logistic regression was finally performed in order to identify and quantify risk factors for decompensation., Results: 19 FPs participated in the study. 96 patients were analyzed. 3 different clusters were identified. MCA showed the central function of psychosocial factors and peaceful versus conflictual relationships with relatives in all clusters. While taking into account the limit of a small cohort, age, frequency of family physician visits and extent of family difficulties were the factors which predicted death or acute hospitalization., Conclusion: A large scale cohort seems feasible in primary care. A sense of alarm should be triggered to prevent death or acute hospitalization in multimorbid older outpatients who have frequent family physician visits and who experience family difficulties.

New Findings: What is the topic of this review? This review focuses on how in vivo and molecular measurements of cardiac passive stiffness can predict exercise tolerance and how exercise training can reduce cardiac passive stiffness. What advances does it highlight? This review highlights advances in understanding the relationship between molecular (titin-based) and in vivo (left ventricular) passive stiffness, how passive stiffness modifies exercise tolerance, and how exercise training may be therapeutic for cardiac diseases with increased passive stiffness. Exercise can help alleviate the negative effects of cardiovascular disease and cardiovascular co-morbidities associated with sedentary behaviour; this may be especially true in diseases that are associated with increased left ventricular passive stiffness. In this review, we discuss the inverse relationship between exercise tolerance and cardiac passive stiffness. Passive stiffness is the physical property of cardiac muscle to produce a resistive force when stretched, which, in vivo, is measured using the left ventricular end diastolic pressure-volume relationship or is estimated using echocardiography. The giant elastic protein titin is the major contributor to passive stiffness at physiological muscle (sarcomere) lengths. Passive stiffness can be modified by altering titin isoform size or by post-translational modifications. In both human and animal models, increased left ventricular passive stiffness is associated with reduced exercise tolerance due to impaired diastolic filling, suggesting that increased passive stiffness predicts reduced exercise tolerance. At the same time, exercise training itself may induce both short- and long-term changes in titin-based passive stiffness, suggesting that exercise may be a treatment for diseases associated with increased passive stiffness. Direct modification of passive stiffness to improve exercise tolerance is a potential therapeutic approach. Titin passive stiffness itself may be a treatment target based on the recent discovery of RNA binding motif 20, which modifies titin isoform size and passive stiffness. Translating these discoveries that link exercise and left ventricular passive stiffness may provide new methods to enhance exercise tolerance and treat patients with cardiovascular disease., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

In the expanding repertoire of small noncoding RNAs (ncRNAs), tRNA-derived RNA fragments (tRFs) have been identified in all domains of life. Their existence in plants has been already proven but no detailed analysis has been performed. Here, short tRFs of 19-26 nucleotides were retrieved from Arabidopsis thaliana small RNA libraries obtained from various tissues, plants submitted to abiotic stress or fractions immunoprecipitated with ARGONAUTE 1 (AGO1). Large differences in the tRF populations of each extract were observed. Depending on the tRNA, either tRF-5D (due to a cleavage in the D region) or tRF-3T (via a cleavage in the T region) were found and hot spots of tRNA cleavages have been identified. Interestingly, up to 25% of the tRFs originate from plastid tRNAs and we provide evidence that mitochondrial tRNAs can also be a source of tRFs. Very specific tRF-5D deriving not only from nucleus-encoded but also from plastid-encoded tRNAs are strongly enriched in AGO1 immunoprecipitates. We demonstrate that the organellar tRFs are not found within chloroplasts or mitochondria but rather accumulate outside the organelles. These observations suggest that some organellar tRFs could play regulatory functions within the plant cell and may be part of a signaling pathway., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Beta-2 adrenergic receptors (β 2 ARs) are located throughout the body including airway and alveolar cells. The β 2 ARs regulate lung fluid clearance through a variety of mechanisms including ion transport on alveolar cells and relaxation of the pulmonary lymphatics. We examined the effect of an inhaled β 2 -agonist (albuterol) on alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume ( V C ) in healthy humans., Methods: We assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) at baseline, 30 minutes, and 60 minutes following nebulized albuterol (2.5 mg, diluted in 3 mL normal saline) in 45 healthy subjects. Seventeen subjects repeated these measures following nebulized normal saline (age = 27 ± 9 years, height = 165 ± 21 cm, weight = 68 ± 12 kg, BMI = 26 ± 9 kg/m 2 ). Cardiac output (Q), heart rate, systemic vascular resistance (SVR), blood pressure, oxygen saturation, forced expiratory volume at one-second (FEV 1 ), and forced expiratory flow at 50% of forced vital capacity (FEF 50 ) were assessed at baseline, 30 minutes, and 60 minutes following the administration of albuterol or saline., Results: Albuterol resulted in a decrease in SVR, and an increase in Q, FEV 1 , and FEF 50 compared to saline controls. Albuterol also resulted in a decrease in V C at 60 minutes post albuterol. Both albuterol and normal saline resulted in no change in DLCO or DM when assessed alone, but a significant increase was observed in DM when accounting for changes in V C ., Conclusion: These data suggest that nebulized albuterol improves pulmonary function in healthy humans, while nebulization of both albuterol and saline results in an increase in DM/ V C ., Competing Interests: Authors disclose no potential conflicts of interest.

In response to acute physiological stress, the sympathetic nervous system modifies neural outflow through increased firing frequency of lower-threshold axons, recruitment of latent subpopulations of higher-threshold axons, and/or acute modifications of synaptic delays. Aging and coronary artery disease (CAD) often modify efferent muscle sympathetic nerve activity (MSNA). Therefore, we investigated whether CAD (n = 14; 61 ± 10 yr) and/or healthy aging without CAD (OH; n = 14; 59 ± 9 yr) modified these recruitment strategies that normally are observed in young healthy (YH; n = 14; 25 ± 3 yr) individuals. MSNA (microneurography) was measured at baseline and during maximal voluntary end-inspiratory (EI) and end-expiratory (EE) apneas. Action potential (AP) patterns were studied using a novel AP analysis technique. AP frequency increased in all groups during both EI- and EE-apnea (all P < 0.05). The mean AP content per integrated burst increased during EI- and EE-apnea in YH (EI: Δ6 ± 4 APs/burst; EE: Δ10 ± 6 APs/burst; both P < 0.01) and OH (EI: Δ3 ± 3 APs/burst; EE: Δ4 ± 5 APs/burst; both P < 0.01), but not in CAD (EI: Δ1 ± 3 APs/burst; EE: Δ2 ± 3 APs/burst; both P = NS). When APs were binned into "clusters" according to peak-to-peak amplitude, total clusters increased during EI- and EE-apnea in YH (EI: Δ5 ± 2; EE: Δ6 ± 4; both P < 0.01), during EI-apnea only in OH (EI: Δ1 ± 2; P < 0.01; EE: Δ1 ± 2; P = NS), and neither apnea in CAD (EI: Δ -2 ± 2; EE: Δ -1 ± 2; both P = NS). In all groups, the AP cluster size-latency profile was shifted downwards for every corresponding cluster during EI- and EE-apnea (all P < 0.01). As such, inherent dysregulation exists within the central features of apnea-related sympathetic outflow in aging and CAD., (Copyright © 2016 the American Physiological Society.)

Membrane conductance (Dm) and capillary lung volume (Vc) derived from NO and CO lung transfer measurements in humans depend on the blood conductance (θ) values of both gases. Many θ values have been proposed in the literature. In the present study, measurements of CO and NO transfer while breathing 15% or 21% O2 allowed the estimation of θNO and the calculation of the optimal equation relating 1/θCO to pulmonary capillary oxygen pressure (PcapO2). In 10 healthy subjects, the mean calculated θNO value was similar to the θNO value previously reported in the literature (4.5mmHgmin(-1)) provided that one among three θCO equations from the literature was chosen. Setting 1/θCO=a·PcapO2+b, optimal values of a and b could be chosen using two methods: 1) by minimizing the difference between Dm/Vc ratios for any PcapO2, 2) by establishing a linear equation relating a and b. Using these methods, we are proposing the equation 1/θCO=0.0062·PcapO2+1.16, which is similar to two equations previously reported in the literature. With this set of θ values, DmCO reached the morphometric range., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To determine the sex difference in the impact of central venous pressure (CVP) on the pressor response induced by ischemic handgrip exercise., Methods: Twelve young healthy individuals (six males, 25 ± 3 years) performed ischemic handgrip exercise during mild levels of lower body negative pressure (LBNP, -5 mmHg) and during a 10° head-down tilt (HDT) to lower and increase CVP, respectively. The protocol consisted of 3 min of baseline ischemia, followed by 2 min of isometric handgrip exercise at 35 % of maximal voluntary contraction force, and 2 min of post-exercise circulatory occlusion. Mean arterial pressure (MAP) was assessed continuously by finger plethysmography and CVP was estimated from the venous pressure of the non-exercising dependent arm., Results: Baseline CVP was greater during HDT than LBNP (8.4 ± 1.8 vs. 6.5 ± 1.8 mmHg, p < 0.01). MAP was greater during LBNP than HDT throughout the protocol (p = 0.05). During ischemic handgrip exercise, CVP increased in males but not in females (Group × protocol interaction: p = 0.01). A group × condition interaction was also observed for MAP, with males showing a greater MAP during LBNP than HDT (110 ± 2 vs. 103 ± 2 mmHg, p < 0.01)., Conclusions: Baseline CVP inversely affected the pressor response to handgrip exercise in all individuals, with a greater MAP response observed during LBNP than HDT. Increase in CVP in males may be due to a greater splanchnic vasoconstrictor response to ischemic handgrip exercise. Therefore, combined baseline CVP and changes in CVP likely contributed to the greater MAP response observed during LBNP in males.

Sex and age affect the pulmonary circulation. Whether there may be racial differences in pulmonary vascular function is unknown. Thirty white European Caucasian subjects (15 women) and age and body-size matched 30 black sub-Saharan African subjects (15 women) underwent a cardiopulmonary exercise test and exercise stress echocardiography with measurements of pulmonary artery pressure (PAP) and cardiac output (CO). A pulmonary vascular distensibility coefficient α was mathematically determined from the natural curvilinearity of multipoint mean PAP (mPAP)-CO plots. Maximum oxygen uptake (V̇o2max) and workload were higher in the whites, while maximum respiratory exchange ratio and ventilatory equivalents for CO2 were the same. Pulmonary hemodynamics were not different at rest. Exercise was associated with a higher maximum total pulmonary vascular resistance, steeper mPAP-CO relationships, and lower α-coefficients in the blacks. These differences were entirely driven by higher slopes of mPAP-CO relationships (2.5 ± 0.7 vs. 1.4 ± 0.7 mmHg·l(-1)·min; P < 0.001) and lower α-coefficients (0.85 ± 0.33 vs. 1.35 ± 0.51%/mmHg; P < 0.01) in black men compared with white men. There were no differences in any of the hemodynamic variables between black and white women. In men only, the slopes of mPAP-CO relationships were inversely correlated to V̇o2max (P < 0.01). Thus the pulmonary circulation is intrinsically less distensible in black sub-Saharan African men compared with white Caucasian Europeans men, and this is associated with a lower exercise capacity. This study did not identify racial differences in pulmonary vascular function in women., (Copyright © 2015 the American Physiological Society.)

The measurement of esophageal pressure allows for the calculation of several important and clinically useful parameters of respiratory mechanics. Esophageal pressure is often measured with balloon-tipped catheters. These catheters may be handmade from natural latex condoms and polyethylene tubing. Given the potential of natural latex to cause allergic reaction, it is important to determine whether esophageal catheter balloons can be fabricated, by hand, using nonlatex condoms as construction materials. To determine the static and dynamic response characteristics of esophageal balloon catheters handmade from latex and nonlatex materials, six esophageal catheter balloons were constructed from each of the following condom materials: natural latex, synthetic polyisoprene, and polyurethane (18 total). Static compliance and working volume range of each balloon catheter was obtained from their pressure-volume characteristics in water. The dynamic response of balloon catheters were measured via a pressure "step" test, from which a third-order underdamped transfer function was modeled. The dynamic ranges of balloon catheters were characterized by the frequencies corresponding to ±5% amplitude- and phase-distortion (fA5% and fφ5%). Balloon catheters handmade from polyurethane condoms displayed the smallest working volume range and lowest static balloon compliance. Despite this lower compliance, fA 5% and fφ5% were remarkably similar between all balloon materials. Our findings suggest that polyisoprene condoms are an ideal nonlatex construction material to use when fabricating esophageal catheter balloons by hand., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

This study compared changes in cross-sectional area (CSA) and flow (Q) between the middle cerebral artery (MCA) and the internal carotid artery (ICA) at baseline and during 5 min of hypercapnia (HC; 6% CO2) and hypocapnia (HO; hyperventilation) and quantified how these changes contribute to estimates of cerebrovascular reactivity (CVR). Measures of MCA CSA were made using 3T magnetic resonance imaging. On a separate day, MCA flow velocity was measured with transcranial Doppler ultrasound and ICA diameters and flow velocity were measured with duplex ultrasound. Fourteen subjects (23 ± 3 yr, 7 females) participated, providing data for 11 subjects during HC and 9 subjects during HO. An increase in MCA CSA (P < 0.05) was observed within the first minute of HC. During HO, the decrease in MCA CSA (P < 0.05) was delayed until minute 4. No changes were observed in ICA CSA during HC or HO. The relative changes in QICA and QMCA were similar during HC and HO. Therefore, the MCA, but not ICA, dilates and constricts during 5 min of HC and HO, respectively. The consequent impact on QMCA significantly affects estimates of CVR, and reactivity cannot be attributed solely to changes in smaller arterioles., (Copyright © 2015 the American Physiological Society.)

Beyond their central role in protein synthesis, transfer RNAs (tRNAs) have many other crucial functions. This includes various roles in the regulation of gene expression, stress responses, metabolic processes and priming reverse transcription. In the RNA world, tRNAs are, with ribosomal RNAs, among the most stable molecules. Nevertheless, they are not eternal. As key elements of cell function, tRNAs need to be continuously quality-controlled. Two tRNA surveillance pathways have been identified. They act on hypo-modified or mis-processed pre-tRNAs and on mature tRNAs lacking modifications. A short overview of these two pathways will be presented here. Furthermore, while the exoribonucleases acting in these pathways ultimately lead to complete tRNA degradation, numerous tRNA-derived fragments (tRFs) are present within a cell. These cleavage products of tRNAs now potentially emerge as a new class of small non-coding RNAs (sncRNAs) and are suspected to have important regulatory functions. The tRFs are evolutionarily widespread and created by cleavage at different positions by various endonucleases. Here, we review our present knowledge on the biogenesis and function of tRFs in various organisms.

Cardiac and peripheral vasomotor factors contribute to the rapid pressor response at the onset of isometric handgrip exercise. We tested the hypothesis that age enhances the sympathetic and vasoconstrictor response at the onset of isometric handgrip exercise so that the pressor response is maintained, despite a diminished cardiac function. Twelve young and twelve older (24 ± 3 and 63 ± 8 yr) individuals performed 20-s isometric handgrip exercise at 30, 40, or 50% of maximal voluntary contraction force. Muscle sympathetic nerve activity (MSNA) was measured using microneurography. Mean arterial pressure (MAP) and cardiac output (Q) were assessed continuously by finger plethysmography and total peripheral resistance was calculated. MAP increased with the onset of handgrip; this increase was associated with handgrip intensity and was similar in both groups. Heart rate and Q increased with increasing handgrip intensity in both groups, but increases were greater in young vs. older individuals (age × handgrip intensity interaction, P < 0.05). MSNA burst frequency increased (P < 0.01), while MSNA burst incidence tended to increase (P = 0.06) with increasing handgrip intensity in both groups. The change in MSNA between baseline and handgrip, for both frequency and incidence, increased with increasing handgrip intensity for both groups. There was no effect of handgrip intensity or age on total peripheral resistance. The smaller heart rate and Q response during the first 20 s of handgrip exercise in older individuals was not accompanied by a greater sympathetic activation or vasoconstrictor response. However, increases in MAP were similar between groups, indicating that the pressor response at the onset of handgrip exercise is preserved with aging.

It has been reported that metabolic syndrome (MetS) impairs left ventricular (LV) diastolic function. The objective of this study was to determine whether exercise training can improve LV diastolic function in individuals with MetS. Twenty-eight individuals with MetS (9 males, aged 60 ± 5 years) underwent a 1-year combined endurance and resistance exercise training program; maximal aerobic capacity (V̇O2max), blood pressure, blood markers, and LV diastolic function were measured at weeks 0, 12, 24, and 52 throughout the training. Pulsed wave Doppler echocardiography across the mitral valve was used to assess peak early flow velocity (E) and peak atrial flow velocity (A) to determine the E/A ratio. Individuals with MetS had a reversed E/A ratio, suggesting impaired LV relaxation, the first stage of LV diastolic dysfunction. Exercise training reduced systolic blood pressure (SBP) (129 ± 14 to 120 ± 12 mm Hg; p < 0.01) and increased V̇O2max (29.2 ± 6.3 to 33.4 ± 6.5 mL·kg(-1)·min(-1); p < 0.01) and high-density lipoprotein cholesterol (1.04 ± 0.21 to 1.12 ± 0.25 mmol·L(-1); p = 0.02), but did not improve LV diastolic function. Individuals with an E/A ratio <1 at the start of training had a tendency toward an increased E/A ratio (p = 0.12) accompanied by significant decreases in SBP and increases in V̇O2max with exercise training. Combined resistance and aerobic exercise training improved cardiometabolic health but did not improve the impaired LV diastolic function of individuals with MetS.

Purpose: The objective of this study was to investigate the effect of changes in expiratory intrathoracic pressure on stroke volume (SV) at rest and during moderate exercise in patients with heart failure versus healthy individuals., Methods: SV was obtained by echocardiography during spontaneous breathing and during expiratory loads of 5 and 10 cm H2O produced by a ventilator in 11 patients with heart failure (61 ± yr, ejection fraction: 32 ± 4%, New York Heart Association, 32% ± 4%; NYHA class I-II) and 11 age-matched healthy individuals at rest and during exercise at 60% of aerobic capacity on a semirecumbent cycle ergometer., Results: At rest, expiratory loading did not change HR, SV index (SVI), or cardiac index (CI) in either group. During moderate exercise, expiratory loading increased SVI and CI in patients with heart failure but decreased SVI and CI in healthy individuals. There was a negative correlation between changes in gastric pressure and SVI (r = -0.51, P < 0.05) in healthy individuals, whereas there was a positive correlation between changes in gastric pressure accompanying expiratory loading and CI (r = 0.83, P < 0.01) in patients with heart failure., Conclusion: Expiratory loading during moderate exercise elicited increases in SVI and CI in patients with heart failure but decreased SVI and CI in healthy individuals. Improvements in cardiac function during submaximal exercise in patients with heart failure may be caused by a beneficial reduction in left ventricular preload.

It has been suggested that shallow slopes of mean pulmonary artery pressure (MPPA)–cardiac output (Q) relationships and pulmonary transit of agitated contrast during exercise may be associated with a higher maximal aerobic capacity V(O(2)max). If so, individuals with a higher V(O(2)max) could also exhibit a higher pulmonary vascular distensibility and increased pulmonary capillary blood volume during exercise. Exercise stress echocardiography was performed with repetitive injections of agitated contrast and measurements of MPPA, Q and lung diffusing capacities for carbon monoxide (D(L,CO)) and nitric oxide (D(L,CO)) in 24 healthy individuals. A pulmonary vascular distensibility coefficient α was mathematically determined from the slight natural curvilinearity of multipoint MPPA–Q plots. Membrane (D(m)) and capillary blood volume (V(c)) components of lung diffusing capacity were calculated. Maximal exercise increased MPPA, cardiac index (CI), D(L,CO) and (D(L,NO). The slope of the linear best fit of MPPA–CI was 3.2 ± 0.5 mmHg min l(-1) m(2) and α was 1.1 ± 0.3% mmHg(-1). A multivariable analysis showed that higher α and greater V(c) independently predicted V(O(2)max). All individuals had markedly positive pulmonary transit of agitated contrast at maximal exercise, with increases proportional to increases in pulmonary capillary pressure and V(c). Pulmonary transit of agitated contrast was not related to pulse oximetry arterial oxygen saturation. Therefore, a more distensible pulmonary circulation and a greater pulmonary capillary blood volume are associated with a higher V(O(2)max) in healthy individuals. Agitated contrast commonly transits through the pulmonary circulation at exercise, in proportion to increased pulmonary capillary pressures.

Objective: The aim of this study was to evaluate the long-term fate of the cryopreserved mitral homograft focusing on structural valve deterioration., Methods: Homograft replacement of the mitral valve was performed in 106 patients. The causes of mitral disease were rheumatic disease (n=75), endocarditis (n=24), and others (n=7). There were 40 partial homografts and 66 total homografts., Results: Mean follow-up was 9.3+4.7 years (up to 17.8 years). There were 5 early (<3 months) and 15 late deaths. There have been 5 early (<3 months) and 30 late reoperations. Five patients had endocarditis, and 5 patients had an ischemic/hemorrhagic event. Compared with baseline, follow-up echography showed progression of mitral regurgitation grade (from 0.4 to 1.3; P<.001) with stenosis (elevated gradient: from 3.9 to 7.0 mm Hg; P<.001) and decreased valve area (from 2.3 to 1.7 cm2, P<.001). Freedom from structural valve deterioration was 90%, 76%, and 65% at 5, 10, and 15 years, respectively. Structural valve deterioration was more frequent in total homografts (P=.018 vs partial homografts) and in case of pregnancy (P=.016 vs no pregnancy). Stenosis related to structural valve deterioration was more pronounced for age less than 40 years (P=.03) and ring size 30 mm or less (P=.002). Pathologic analysis of the explanted homografts almost invariably showed dense fibrosis with calcification and no cellularity., Conclusions: Mitral homografting was accomplished with early echographic results similar to those of valve repair. Structural valve deterioration produced mixed stenosis with insufficiency, and its incidence was comparable to that of bioprostheses structural valve deterioration. An improvement in the preservation mode of valvular homografts is warranted., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

This study investigated the effect of changes in inspiratory intrathoracic pressure on stroke volume at rest and during moderate exercise in patients with heart failure and reduced ejection fraction (HFREF) as well as healthy individuals. Stroke volume was obtained by echocardiography during 2 min of spontaneous breathing (S), two progressive levels of inspiratory unloading (UL1 and UL2) using a ventilator, and two progressive levels of inspiratory loading using resistors in 11 patients with HFREF (61 ± 9 years old; ejection fraction 32 ± 4%; NYHA class I-II) and 11 age-matched healthy individuals at rest and during exercise at 60% of maximal aerobic capacity on a semi-recumbent cycle ergometer. At rest, inspiratory unloading progressively decreased stroke volume index (SVI; S, 35.2 ± 5.4 ml m(-2); UL1, 33.3 ± 5.1 ml m(-2); and UL2, 32.2 ± 4.4 ml m(-2)) in healthy individuals, while it increased SVI (S, 31.4 ± 4.6 ml m(-2); UL1, 32.0 ± 5.9 ml m(-2); and UL2, 34.0 ± 7.2 ml m(-2)) in patients with HFREF (P = 0.04). During moderate exercise, inspiratory unloading decreased SVI in a similar manner (S, 43.9 ± 7.1 ml m(-2); UL1, 40.7 ± 4.7 ml m(-2); and UL2, 39.9 ± 3.7 ml m(-1)) in healthy individuals, while it increased SVI (S, 40.8 ± 6.5 ml m(-2); UL1, 42.8 ± 6.9 ml m(-2); and UL2, 44.1 ± 4. ml m(-2)) in patients with HFREF (P = 0.02). Inspiratory loading did not significantly change SVI at rest or during moderate exercise in both groups. It is concluded that inspiratory unloading improved SVI at rest and during moderate exercise in patients with HFREF, possibly due to a reduction in left ventricular afterload.

The objective of this study was to determine whether changes in carboxyhaemoglobin (COHb) saturation following carbon monoxide (CO) rebreathing can be accurately detected by pulse CO-oximetry in order to determine blood volume. Noninvasive measurements of carboxyhaemoglobin saturation (SpCO) were continuously monitored by pulse CO-oximetry before, during and following 2 min of CO rebreathing. Reproducibility and accuracy of noninvasive blood volume measurements were determined in 16 healthy non-smoking individuals (15 males, age: 28 ± 2 years, body mass index: 25.4 ± 0.6 kg m(-2)) through comparison with blood volume measurements calculated from invasive measurements of COHb saturation. The coefficient of variation for noninvasive blood volume measurements performed on separate days was 15.1% which decreases to 9.1% when measurements were performed on the same day. Changes in COHb saturation and SpCO following CO rebreathing were strongly correlated (r = 0.90, p < 0.01), resulting in a significant correlation between invasive and noninvasive blood volume measurements (r = 0.83, p = 0.02). Changes in SpCO following CO rebreathing can be accurately detected by pulse CO-oximetry, which could potentially provide a simplified, convenient and reproducible method to rapidly determine blood volume in healthy individuals.

Background: The aim of this study was to determine the relationship between body position, pulmonary function (PF) and bronchial blood flow (Q(aw)) in a group of heart failure (HF) and control subjects., Methods: Thirty-six subjects were studied: 24 stable, ambulatory HF patients (HF: LVEF=27±6%, age=65±9 yr) and 12 age- and sex-matched controls (CTRL: LVEF=60±7%, age=62±8 yr). Measures of Q˙(aw) (soluble gas method) and PF were collected upright and following 30min in the supine position., Results: Q˙(aw) was similar between groups and remained unchanged with body position. Declines in forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1) with the supine position were observed in both groups; declines in forced expiratory flow 25-75% (FEF(25-75)) and FEF 75% (FEF75) with the supine position were observed in the HF group only. Changes in Q˙(aw) were related to changes in PF only in the HF patient groups (ΔFVC, % predicted, r = -0.45, p<0.04, ΔFEV1 r = -0.61, p<0.01, ΔFEV1% predicted, r = -0.45, p<0.04)., Conclusion: These data demonstrate that relationships between postural changes in Q˙(aw) and PF exist only in the HF population and that the bronchial circulation may contribute to postural PF decline in HF., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to determine the relationship between airway blood flow (Q(aw)), airway conductance (G(f-aw)) and pulmonary function in patients with stable HF., Methods: 12 controls (CTRL: age=63±9 years, FVC=98±15%pred, LVEF=61±6%) (all data presented as mean±SD), 16 patients with mild HF (HF-A, NYHA I-II: age=64±9 years, FVC=90±17%pred, LVEF=28±6%), and 14 patients with moderate/severe HF (HF-B, NYHA III-IV: age=65±6 years, FVC=84±12%pred, LVEF=26±6%) were studied. Q(aw) was assessed using soluble gas measurements; perfusion pressure across airway bed (ΔP(aw)) was estimated from systemic and pulmonary pressure measurements; G(f-aw) was calculated as Q(aw)/ΔP(aw); PF was assessed by spirometry., Results: While Q˙(aw) was not significantly different between CTRL (61.3±17.9 μL min(-1)mL(-1)), HF-A (70.1±26.9 μL min(-1)mL(-1)) and HF-B (56.2±14.9 μL min(-1)mL(-1)) groups, G(f-aw), was elevated in HF-A (1.1±0.4 μL min(-1)mL(-1)mm Hg(-1), p<0.03) and tended to be elevated in HF-B (1.2±0.6 μL min(-1)mL(-1)mm Hg(-1), p=0.07) when compared to CTRL (0.8±0.3 μL min(-1)mL(-1)mm Hg(-1)). Significant positive correlations were found between G(f-aw) and RV/TLC for HF-A (r=0.63, p<0.02) and HF-B (r=0.58, p<0.05)., Conclusions: These results support the hypothesis that increased bronchial conductance and bronchial congestion may be related to greater small airway obstruction and as such may play a role in the PF abnormalities and symptoms of congestion commonly observed in HF patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The purpose of this study is to examine the effects of a 3-month interval walking program on peak aerobic capacity and cardiovascular risk factors in middle-aged sedentary individuals. Participants were divided into 2 groups: a nontraining control group (n = 17) and an interval walking training group (n = 29). Participants in the interval walking training group were instructed to perform 5 or more sets of 3-min low-intensity walking interspersed by 3-min of moderate to high-intensity walking (>70% of peak aerobic capacity) on 4 or more days/week. Measurements of peak aerobic capacity, blood pressure, blood lipids, and glucose concentration were performed before and after training. Twenty-six individuals completed the interval walking program averaging 4 days/week for 34 min, of which 16 min were moderate to high-intensity walking, with a total energy expenditure of 776 kcal/week. Three months of interval walking increased peak aerobic capacity (from 20.4 ± 3.0 to 26.0 ± 5.2 mL/kg/min; P < .001) and reduced resting systolic blood pressure (127 ± 11 to 119 ± 11 mm Hg; P = .01). There was an inverse correlation between initial level and training-induced changes in glucose, HbA1c, high-density lipoprotein, and low-density lipoprotein. Conversely, 3 months of nontraining did not improve physical fitness or cardiovascular risk factors. Very modest amounts of aerobic exercise involving brief periods of interspersed higher intensity exercise can significantly increase peak aerobic capacity and reduce resting systolic blood pressure in middle-aged sedentary individuals and contribute to a normalization of cardiovascular risk factors in individuals with elevated initial values.

Introduction: Fighter aircraft pilots are exposed to repetitive headward acceleration (+Gz) during air combat maneuvering. The objective of this study was to compare physiologic responses and the calculated +Gz tolerances of multiple successive +Gz exposures with the responses of the first +Gz exposure., Methods: There were 13 subjects who performed simulated air combat maneuvering (SACM) profiles composed of 10 rapid-onset rate +Gz cycles with different combinations of short- or long-duration +Gz plateaus (8 or 20 s) and +Gz pauses (1 or 15 s). +Gz, plateaus were individually set at levels inducing strong physiologic responses while the +Gz pause was set at 1.4 Gz. Head-level systolic pressure, ear opacity, and vision quality were measured., Results: The nadirs of head-level systolic pressure, ear opacity, and visual quality during each +Gz plateau were higher in subsequent cycles compared to the first +Gz cycle. There was an average increase in calculated +Gz tolerance of 0.35 +/- 0.21 Gz following the first +Gz cycle. SACMs with short +Gz pauses produced greater increases in +Gz tolerance than SACMs with long +Gz pauses., Discussion: Cardiovascular and visual responses were improved over the course of successive +Gz cycles, indicating that the risk of +Gz-induced loss of consciousness was not increased beyond the first +Gz cycle. The increase in +Gz tolerance beginning with the second cycle is attributed to a carryover of compensatory responses, primarily vasoconstriction, with possible contribution from greater venous return and baroreflex enhancement.

Background: Ventilatory efficiency (VE/VCO(2) ratio) and the partial pressure of end-tidal carbon dioxide (P(ET)CO(2)), obtained during moderate to high levels of physical exertion demonstrate prognostic value in heart failure (HF). The present investigation assesses the clinical utility of these variables during low-intensity exercise., Methods and Results: One hundred and thirty subjects diagnosed with HF underwent a 2-minute, constant-rate treadmill session at 2 miles per hour. Both the VE/VCO(2) ratio and P(ET)CO(2) were recorded during exercise (30-second average) and their change (Delta) from rest. B-type and atrial natriuretic peptide (BNP and ANP) were also determined. Only P(ET)CO(2) and DeltaP(ET)CO(2) emerged from the multivariate Cox regression. Receiver operating characteristic curve analysis revealed the prognostic classification schemes were significant with thresholds of < or >or=34 mm Hg (hazard ratio: 4.2, 95% CI: 2.2-8.0, P < .001) and < or >or=1 mm Hg (hazard ratio: 3.5, 95% CI: 1.9-6.6, P < .001) being optimal for P(ET)CO(2) and DeltaP(ET)CO(2), respectively. Moreover, subjects with a P(ET)CO(2)>or=34 mm Hg had a significantly lower BNP (214.1 +/- 431.9 vs. 1110.5 +/- 1854.0 pg/mL, P=.005) and ANP (108.2 +/- 103.6 vs. 246.2 +/- 200.4 pg/mL, P < .001)., Conclusions: The results of this pilot study indicate ventilatory expired gas analysis during a short bout of low-intensity exercise may provide insight into prognosis and cardiac stability.

The reduced arterial oxygen tension at high altitude impairs the ability to work. Acetazolamide improves arterial oxygen saturation (SaO(2)) by increasing ventilation but is associated with an increased work and cost of breathing. Depending on the settings, sildenafil can also increases SaO(2) possibly through a reduction in pulmonary hypertension and interstitial edema, which could improve ventilation-perfusion matching. The objective of this study is to determine the effects of acetazolamide and sildenafil on ventilatory control and breathing efficiency (V(E)/VCO(2)) during submaximal steady-state hypoxic exercise in healthy individuals. Following 18 h of hypoxic exposure in an altitude tent at an oxygen concentration of 12.5% (simulated altitude of 4,300 m), 15 participants performed 10 min of hypoxic exercise on a stationary bicycle at 40% of their sea level peak oxygen uptake (VO(2)) while randomly receiving sildenafil 40 mg (SIL), acetazolamide 125 mg (ACZ) or a placebo (PLA). There was no difference in VO(2) during exercise between conditions while SaO(2) was greater with acetazolamide compared to both placebo and sildenafil. Acetazolamide increased ventilation (PLA 49.0 +/- 3.2, SIL 47.7 +/- 3.1, ACZ 52.1 +/- 3.0 l/min) and reduced end-tidal CO(2) (P(ET)CO(2)) (PLA 32.1 +/- 0.8, SIL 32.8 +/- 0.9, ACZ 29.2 +/- 0.7 mmHg) compared to placebo and sildenafil. Breathing was less efficient with acetazolamide (increased V(E)/VCO(2)) in comparison to placebo and sildenafil (PLA 41.5 +/- 1.0, SIL 40.4 +/- 1.3, ACZ 45.4 +/- 1.0) while sildenafil did not change V(E)/VCO(2) during hypoxic exercise. In conclusion, acetazolamide increased ventilation and reduced breathing efficiency while sildenafil did not affect breathing efficiency despite a trend toward a blunted ventilatory response, possibly due to a reduction in pulmonary hypertension and/or ventilatory drive, during submaximal hypoxic exercise in healthy individuals.

The existence of resistance training-induced left ventricular (LV) concentric hypertrophy is equivocal. Although some have described significant LV hypertrophy, others have suggested that training-induced LV hypertrophy is proportional to increased fat free mass (FFM) and thus a normal physiologic response to training. Method limitations, steroid use, and type of training may contribute to discrepant findings. Thus, LV structure and volumes are determined using magnetic resonance imaging. Body composition was determined using dual-energy x-ray absorptiometry in 9 elite Olympic weight lifters and 10 age- and weight-matched recreationally active controls. LV structure and volumes were determined by acquiring 6 short- and 3 long-axis magnetic resonance imaging scans of the left ventricle, whereas LV wall thickness was defined as the average of 6 midventricular segment thickness measurements. Weight lifters had the same age, weight, and FFM, but were shorter and had a greater body mass index than controls. LV mass was not different in weight lifters and controls, but was lower in weight lifters when indexed to FFM (2.56 +/- 0.07 vs 2.30 +/- 0.05, p = 0.01). LV mass correlated with FFM (r = 0.49, p = 0.04). However, LV mass was lower in weight lifters for a given FFM. LV wall thickness, as well as end-diastolic, end-systolic, and stroke volumes, were not different between groups. In conclusion, these results refute the hypothesis that resistance training induces LV concentric hypertrophy and suggest that Olympic weight lifting is associated with increases in FFM without a concomitant increase in LV mass.

The shift from upright to supine posture increases stroke volume in healthy young adults, primarily through increased end-diastolic volume. Aging is associated with increased ventricular stiffness and impaired diastolic function. The purpose of this study was to determine whether the stroke volume change between the upright and supine posture was blunted in healthy older men and whether the early mitral inflow response to this postural change was reduced by aging. Pulsed Doppler echocardiography and tissue Doppler imaging were used to assess stroke volume and left ventricular function during upright and supine posture in 10 young and 12 older healthy men. Cardiac output was greater in the supine versus upright condition in both groups. In young men supine posture was associated with a large increment in stroke volume (63.1 +/- 7.2 upright to 98.6 +/- 11.7 ml supine; P < 0.05) and a decrease in heart rate. In older men, the stroke volume increment was smaller (63.9 +/- 3.6 upright to 82.0 +/- 5.7 ml supine; P < 0.05) and heart rate decreased less than young men when comparing upright to supine posture. Increased stroke volume was associated with higher peak early diastolic filling velocity (E) in young men and higher peak late diastolic filling velocity (A) in older men. These findings indicate that healthy aging attenuates the increase in early filling associated with moving from an upright to a supine posture. Furthermore, healthy older men are more dependent upon atrial diastolic filling to augment end-diastolic and stroke volume, which may be due to age-associated increases in left ventricular filling pressure and impaired compliance.

Cortical and trabecular bone loss can lead to osteoporosis in chronic forms of anorexia nervosa (AN). As there is some debate about the reversibility of this condition, we performed a longitudinal follow-up study of 27 cases in which clinical, biological, X-ray and lumbar and femoral neck dual photon absorptiometry examinations were conducted every 6 months for up to 30 months. Three groups were distinguished: G1, untreated amenorrheic AN (N = 14, total follow-up 126 months); G2, effectively treated AN (N = 11, total follow-up 192 months), with two subgroups: fluoride (N = 5) and estrogen (N = 6); and G3, remitting AN with normalization of the gonadic function (N = 2, total follow-up 36 months). Results were adjusted for each patient to a 6-month variation. Semestrial variations in lumbar bone mineral density (BMD) were -2.1 +/- 1.3%, +2.8 +/- 1.5%, and -0.3 +/- 1.3% (mean +/- SEM), respectively for G1, G2 and G3; those for femoral neck BMD semestrial variations were -5.9 +/- 2.1%, -3.8 +/- 1.2% and -1.0 +/- 0.6%. Femoral neck and lumbar BMD variations for G1 were mainly correlated positively with bone-forming markers (serum osteocalcin, alkaline phosphatase) and negatively with initial lumbar BMD. Estrogen alone increased lumbar BMD by +1.4 +/- 2.3% every 6 months but did not stabilize femoral neck BMD (-3.5 +/- 1.4%). Fluoride increased lumbar BMD by 4.8 +/- 1.8%. Both lumbar and femoral neck BMD were stabilized in the remission group (-0.3 +/- 1.3% and -1.0 +/- 0.6%), despite half of the follow-up time with amenorrhea. In conclusion, untreated AN is associated with a marked trabecular and cortical bone loss (4-10% per year), which can lead to osteoporotic fractures. In prevention of bone loss, the efficacy of estrogen is difficult to investigate in AN, even with a well-controlled trial. Our study could provide argument that, when the observance of this preventive treatment is assessed, lumbar BMD can be stabilized in chronic forms of AN.

Anorexia nervosa affects 0.5% to 1% of female adolescents. The course is chronic in 50% of cases, causing substantial bone loss with osteoporotic fractures after a few years of amenorrhea. This is probably an underestimated problem. The diagnosis of anorexia nervosa is readily missed, as illustrated by five cases reported herein. The five patients were females aged 17 to 44 years who were only slightly underweight (mean weight, 43.6 kg; body mass index < 20 kg/m2). The first fracture occurred seven to 24 years after the onset of anorexia nervosa. Three patients had vertebral crush fractures, and two had peripheral insufficiency fractures. Bone mineral density measured by absorptiometry was very low (mean lumbar z-score, -3.7 SD). Three patients, who were all members of health care professions, knew that they had anorexia nervosa but failed to report this condition. In the other two patients, the amenorrhea had been mistakenly ascribed to other causes (Stein-Leventhal syndrome and psychogenic anovulation). None of the patients was receiving medical follow-up. Anorexia nervosa should be considered routinely in women who are slightly underweight. The patients often deny abnormal menstruation or eating behaviors. The diagnosis rests on determination of the body mass index, a thorough history emphasizing current and past gonadal dysfunction, and evaluation of the diagnostic criteria for anorexia nervosa. Osteoporosis is probably a common but underestimated complication of anorexia nervosa, particularly before the menopause. Enhanced awareness of this condition should allow earlier detection of a greater number of cases.