Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?

BACKGROUND: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF. METHODS: Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions. RESULTS: PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug × exercise stage P=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL). CONCLUSIONS: Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04068844.

Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure.

BACKGROUND: Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT. METHODS: Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o2; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples t tests. RESULTS: V̇o2 was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; P=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; P=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; P=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; P=0.007). CONCLUSIONS: In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.

Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO2 ; P = 0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.

Aortic haemodynamics: the effects of habitual endurance exercise, age and muscle sympathetic vasomotor outflow in healthy men.

PURPOSE: We determined the effect of habitual endurance exercise and age on aortic pulse wave velocity (aPWV), augmentation pressure (AP) and systolic blood pressure (aSBP), with statistical adjustments of aPWV and AP for heart rate and aortic mean arterial pressure, when appropriate. Furthermore, we assessed whether muscle sympathetic nerve activity (MSNA) correlates with AP in young and middle-aged men. METHODS: Aortic PWV, AP, aortic blood pressure (applanation tonometry; SphygmoCor) and MSNA (peroneal microneurography) were recorded in 46 normotensive men who were either young or middle-aged and endurance-trained runners or recreationally active nonrunners (10 nonrunners and 13 runners within each age-group). Between-group differences and relationships between variables were assessed via ANOVA/ANCOVA and Pearson product-moment correlation coefficients, respectively. RESULTS: Adjusted aPWV and adjusted AP were similar between runners and nonrunners in both age groups (all, P > 0.05), but higher with age (all, P < 0.001), with a greater effect size for the age-related difference in AP in runners (Hedges' g, 3.6 vs 2.6). aSBP was lower in young (P = 0.009; g = 2.6), but not middle-aged (P = 0.341; g = 1.1), runners compared to nonrunners. MSNA burst frequency did not correlate with AP in either age group (young: r = 0.00, P = 0.994; middle-aged: r = - 0.11, P = 0.604). CONCLUSION: There is an age-dependent effect of habitual exercise on aortic haemodynamics, with lower aSBP in young runners compared to nonrunners only. Statistical adjustment of aPWV and AP markedly influenced the outcomes of this study, highlighting the importance of performing these analyses. Further, peripheral sympathetic vasomotor outflow and AP were not correlated in young or middle-aged normotensive men.

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men.

KEY POINTS: Intermittent hypoxia leads to long-lasting increases in muscle sympathetic nerve activity and blood pressure, contributing to increased risk for hypertension in obstructive sleep apnoea patients. We determined whether augmented vascular responses to increasing sympathetic vasomotor outflow, termed sympathetic neurovascular transduction (sNVT), accompanied changes in blood pressure following acute intermittent hypercapnic hypoxia in men. Lower body negative pressure was utilized to induce a range of sympathetic vasoconstrictor firing while measuring beat-by-beat blood pressure and forearm vascular conductance. IH reduced vascular shear stress and steepened the relationship between diastolic blood pressure and sympathetic discharge frequency, suggesting greater systemic sNVT. Our results indicate that recurring cycles of acute intermittent hypercapnic hypoxia characteristic of obstructive sleep apnoea could promote hypertension by increasing sNVT. ABSTRACT: Acute intermittent hypercapnic hypoxia (IH) induces long-lasting elevations in sympathetic vasomotor outflow and blood pressure in healthy humans. It is unknown whether IH alters sympathetic neurovascular transduction (sNVT), measured as the relationship between sympathetic vasomotor outflow and either forearm vascular conductance (FVC; regional sNVT) or diastolic blood pressure (systemic sNVT). We tested the hypothesis that IH augments sNVT by exposing healthy males to 40 consecutive 1 min breathing cycles, each comprising 40 s of hypercapnic hypoxia ( PETCO2 : +4 ± 3 mmHg above baseline; PETO2 : 48 ± 3 mmHg) and 20 s of normoxia (n = 9), or a 40 min air-breathing control (n = 7). Before and after the intervention, lower body negative pressure (LBNP; 3 min at -15, -30 and -45 mmHg) was applied to elicit reflex increases in muscle sympathetic nerve activity (MSNA, fibular microneurography) when clamping end-tidal gases at baseline levels. Ventilation, arterial pressure [systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP)], brachial artery blood flow ( Q̇BA ), FVC ( Q̇BA /MAP) and MSNA burst frequency were measured continuously. Following IH, but not control, ventilation [5 L min-1 ; 95% confidence interval (CI) = 1-9] and MAP (5 mmHg; 95% CI = 1-9) were increased, whereas FVC (-0.2 mL min-1  mmHg-1 ; 95% CI = -0.0 to -0.4) and mean shear rate (-21.9 s-1 ; 95% CI = -5.8 to -38.0; all P < 0.05) were reduced. Systemic sNVT was increased following IH (0.25 mmHg burst-1  min-1 ; 95% CI = 0.01-0.49; P < 0.05), whereas changes in regional forearm sNVT were similar between IH and sham. Reductions in vessel wall shear stress and, consequently, nitric oxide production may contribute to heightened systemic sNVT and provide a potential neurovascular mechanism for elevated blood pressure in obstructive sleep apnoea.

The influence of barosensory vessel mechanics on the vascular sympathetic baroreflex: insights into aging and blood pressure homeostasis.

Changes in the arterial baroreflex arc contribute to elevated sympathetic outflow and altered reflex control of blood pressure with human aging. Using ultrasound and sympathetic microneurography (muscle sympathetic nerve activity, MSNA) we investigated the relationships between aortic and carotid artery wall tension (indices of baroreceptor activation) and the vascular sympathetic baroreflex operating point (OP; MSNA burst incidence) in healthy, normotensive young (n = 27, 23 ± 3 yr) and middle-aged men (n = 22, 55 ± 4 yr). In young men, the OP was positively related to the magnitude and rate of unloading and time spent unloaded in the aortic artery (r = 0.56, 0.65, and 0.51, P = 0.02, 0.003, and 0.03), but not related to the magnitude or rate of unloading or time spent unloaded in the carotid artery (r = -0.32, -0.07, and 0.06, P = 0.25, 0.81, and 0.85). In contrast, in middle-aged men, the OP was not related to either the magnitude or rate of unloading or time spent unloaded in the aortic (r = 0.22, 0.21, and 0.27, P = 0.41, 0.43, and 0.31) or carotid artery (r = 0.06, 0.28, and -0.01; P = 0.48, 0.25, and 0.98). In conclusion, in young men, aortic unloading mechanics may play a role in determining the vascular sympathetic baroreflex OP. In contrast, in middle-aged men, barosensory vessel unloading mechanics do not appear to determine the vascular sympathetic baroreflex OP and, therefore, do not contribute to age-related arterial baroreflex resetting and increased resting MSNA.NEW & NOTEWORTHY We assessed the influence of barosensory vessel mechanics (magnitude and rate of unloading and time spent unloaded) as a surrogate for baroreceptor unloading. In young men, aortic unloading mechanics are important in regulating the operating point of the vascular sympathetic baroreflex, whereas in middle-aged men, these arterial mechanics do not influence this operating point. The age-related increase in resting muscle sympathetic nerve activity does not appear to be driven by altered baroreceptor input from stiffer barosensory vessels.

The influence of habitual endurance exercise on carotid artery strain and strain rate in young and middle-aged men.

NEW FINDINGS: What is the central question of this study? Carotid artery peak circumferential strain (PCS) and strain rate attenuate with age, but appear to be modulated by cardiorespiratory fitness status in young males. However, the relationship between habitual endurance exercise (running) and these parameters has not been studied in young and middle-aged men. What is the main finding and its importance? Young and middle-aged runners exhibited elevated PCS and systolic strain rate (S-SR) compared with non-runners, but habitual running did not influence diastolic strain rate (D-SR). Habitual exercise is associated with comparable improvements in carotid strain parameters in young and middle-aged men, but the age-related decline in PCS and S-SR might be more amenable to habitual endurance exercise than D-SR. ABSTRACT: Central arterial stiffness is an independent predictor of cardiovascular risk that can be modified by exercise training. However, conventional local measures of carotid artery stiffness display conflicting responses to habitual endurance exercise in young and older adults. Two-dimensional (2D)-Strain imaging of the common carotid artery (CCA) quantifies circumferential deformation (strain) of the arterial wall across the cardiac cycle, which is more sensitive at detecting age-related alterations in CCA stiffness than conventional methods. Therefore, the study was designed to examine the relationship between habitual endurance exercise (running) and CCA 2D-Strain parameters in young and middle-aged men. Short-axis ultrasound images of the CCA were obtained from 13 young non-runners [23 years of age (95% confidence interval: 21, 26 years of age)], 19 young runners [24 (22, 26) years of age], 13 middle-aged non-runners [54 (52, 56) years of age] and 19 middle-aged runners [56 (54, 58) years of age]. Images were analysed for peak circumferential strain (PCS; magnitude of deformation) and systolic and diastolic strain rates (S-SR and D-SR; deformation velocity), and group differences were examined via two-way ANOVA. PCS, S-SR and D-SR were attenuated in middle-aged men compared with young men (all P ≤ 0.001). PCS and S-SR were elevated in young and middle-aged runners when compared with non-runners (P = 0.002 and P = 0.009, respectively), but no age × training status interaction was observed. In contrast, there was no influence of habitual running on D-SR. Habitual exercise is associated with comparable improvements in CCA 2D-Strain parameters in young and middle-aged men, but the age-related decline in PCS and S-SR might be more amenable to habitual endurance exercise than D-SR.

Upward resetting of the vascular sympathetic baroreflex in middle-aged male runners.

This study focused on the influence of habitual endurance exercise training (i.e., committed runner or nonrunner) on the regulation of muscle sympathetic nerve activity (MSNA) and arterial pressure in middle-aged (50 to 63 yr, n = 23) and younger (19 to 30 yr; n = 23) normotensive men. Hemodynamic and neurophysiological assessments were performed at rest. Indices of vascular sympathetic baroreflex function were determined from the relationship between spontaneous changes in diastolic blood pressure (DBP) and MSNA. Large vessel arterial stiffness and left ventricular stroke volume also were measured. Paired comparisons were performed within each age category. Mean arterial pressure and basal MSNA bursts/min were not different between age-matched runners and nonrunners. However, MSNA bursts/100 heartbeats, an index of baroreflex regulation of MSNA (vascular sympathetic baroreflex operating point), was higher for middle-aged runners (P = 0.006), whereas this was not different between young runners and nonrunners. The slope of the DBP-MSNA relationship (vascular sympathetic baroreflex gain) was not different between groups in either age category. Aortic pulse wave velocity was lower for runners of both age categories (P < 0.03), although carotid ß-stiffness was lower only for middle-aged runners (P = 0.04). For runners of both age categories, stroke volume was larger, whereas heart rate was lower (both P < 0.01). In conclusion, we suggest that neural remodeling and upward setting of the vascular sympathetic baroreflex compensates for cardiovascular adaptations after many years committed to endurance exercise training, presumably to maintain arterial blood pressure stability. NEW & NOTEWORTHY Exercise training reduces muscle sympathetic burst activity in disease; this is often extrapolated to infer a similar effect in health. We demonstrate that burst frequency of middle-aged and younger men committed to endurance training is not different compared with age-matched casual exercisers. Notably, well-trained, middle-aged runners display similar arterial pressure but higher sympathetic burst occurrence than untrained peers. We suggest that homeostatic plasticity and upward setting of the vascular sympathetic baroreflex maintains arterial pressure stability following years of training.

Carotid artery wall mechanics in young males with high cardiorespiratory fitness.

NEW FINDINGS: What is the central question of this study? Common carotid artery (CCA) two-dimensional strain imaging detects intrinsic arterial wall properties beyond conventional measures of arterial stiffness, but the effect of cardiorespiratory fitness on two-dimensional strain-derived indices of CCA stiffness is unknown. What is the main finding and its importance? Two-dimensional strain imaging of the CCA revealed greater peak circumferential strain and systolic strain rate in highly fit men compared with their less fit counterparts. Altered CCA wall mechanics might reflect intrinsic training-induced adaptations that help to buffer the increase in pulse pressure and stroke volume during exercise. ABSTRACT: The influence of cardiorespiratory fitness on arterial stiffness in young adults remains equivocal. Beyond conventional measures of arterial stiffness, two-dimensional strain imaging of the common carotid artery (CCA) provides new information related to the intrinsic properties of the arterial wall. Therefore, the aim of this study was to assess the effect of cardiorespiratory fitness on both conventional indices of CCA stiffness and two-dimensional strain parameters, at rest and after a bout of aerobic exercise in young, healthy men. Short-axis ultrasound images of the CCA were recorded in 34 healthy men {22 years old [95% confidence interval (CI), 19, 22]} before and immediately after 5 min of aerobic exercise (40% of maximal oxygen consumption). Images were analysed for arterial diameter, peak circumferential strain (PCS) and peak systolic and diastolic strain rates (S-SR and D-SR). Heart rate, systolic and diastolic blood pressure were simultaneously assessed, and Peterson's elastic modulus (Ep ) and ß-stiffness (ß1 ) were calculated. Participants were separated post hoc into moderate- and high-fitness groups [maximal oxygen consumption, 48.9 (95% CI, 44.7, 53.2) versus 65.6 ml kg-1  min-1 (95% CI, 63.1, 68.1), respectively; P < 0.001]. The Ep and ß1 were similar between groups at baseline (P > 0.13) but were elevated in the moderate-fitness group postexercise (P < 0.04). The PCS and S-SR were elevated in the high-fitness group at both time points [3.0% (95% CI, 1.2, 4.9), P = 0.002, and 0.401 s-1 (95% CI, 0.085, 0.72), P = 0.02, respectively]. No group differences were observed in CCA heart rate, systolic or diastolic blood pressure or D-SR throughout the protocol (P > 0.05). Highly fit individuals exhibit elevated CCA, PCS and S-SR, which might reflect training-induced adaptations that help to buffer the increase in pulse pressure and stroke volume during exercise.

Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia.

In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l-1 in non-pregnant females and < 130 g.l-1 in males) as due to impaired hemoglobin synthesis or increased erythrocyte loss or destruction. Rarely is a rise in plasma volume relative to circulating total hemoglobin mass considered as a cause. But does this matter? We explored this issue in patients, measuring hemoglobin concentration, total hemoglobin mass (optimized carbon monoxide rebreathing method) and thereby calculating plasma volume in healthy volunteers, surgical patients, and those with inflammatory bowel disease, chronic liver disease or heart failure. We studied 109 participants. Hemoglobin mass correlated well with its concentration in the healthy, surgical and inflammatory bowel disease groups (r=0.687-0.871, P<0.001). However, they were poorly related in liver disease (r=0.410, P=0.11) and heart failure patients (r=0.312, P=0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R2=0.109 and 0.052; P=0.11 and 0.16), whilst plasma volume did (R2 change 0.724 and 0.805 in heart and liver disease respectively, P<0.0001). Exemplar patients with identical (normal or raised) total hemoglobin masses were diagnosed as profoundly anemic (or not) depending on differences in plasma volume that had not been measured or even considered as a cause. The traditional inference that anemia generally reflects hemoglobin deficiency may be misleading, potentially resulting in inappropriate tests and therapeutic interventions to address 'hemoglobin deficiency' not 'plasma volume excess'. Measurement of total hemoglobin mass and plasma volume is now simple, cheap and safe, and its more routine use is advocated.

The effect of chronic habitual exercise on oxygen carrying capacity and blood compartment volumes in older adults.

Absolute total hemoglobin mass (tHbmass) and blood compartment volumes are often considered to be higher in endurance athletes compared with nonathletes, yet little data support a fitness effect in older age. Therefore, we measured tHbmass and blood compartment volumes (carbon monoxide rebreathing) in 77 healthy individuals (23% female; aged, 60-87 yr). Participants were recruited into groups based upon their lifelong (>25 yr) exercise "dose": 1) 15 sedentary individuals, <2 sessions/wk; 2) 25 casual exercisers, 2-3 sessions/wk; 3) 24 committed exercisers, 4-5 sessions/wk; and 4) 13 competitive Masters athletes, 6-7 sessions/wk, plus regular competitions. Absolute (L/min) and relative (mL/kg/min) V̇o2peak were higher with increasing exercise "dose" (P = 0.0005 and P < 0.0001, respectively). Hemoglobin concentration, hematocrit, and absolute tHbmass and blood compartment volumes were not significantly different between groups (all, P > 0.1328). When scaled to body mass, tHbmass (Sedentary, 9.2 ± 1.7 mL/kg; Casual, 9.2 ± 1.3; Committed, 10.2 ± 1.4; Competitive, 11.5 ± 1.4, ANOVA P < 0.0001) and blood volume were significantly different between groups [Sedentary, 63.4 (59.2-68.5) mL/kg; Casual, 67.3 (64.4-72.6); Committed, 73.5 (67.5-80.2); Competitive, 83.4 (78.9-88.6), ANOVA P < 0.0001], whereby all values were highest in Masters athletes. However, when scaled to fat-free mass (FFM), tHbmass and blood compartment volumes were greater in Competitive compared with Casual exercisers (all, P < 0.0340) and tHbmass and erythrocyte volume were also higher in Committed compared with Casual exercisers (both, P < 0.0134). In conclusion, absolute tHbmass and blood compartment volumes are not different between groups, with dose-dependent differences only among exercisers when scaled for FFM, with the highest tHbmass and blood compartment volumes in competitive Masters athletes.NEW & NOTEWORTHY We observed that absolute oxygen carrying capacity (total hemoglobin mass, tHbmass) and blood compartment volumes were not associated with lifelong exercise dose. However, hematological adaptations associated with lifelong habitual exercise are only present among exercisers, whereby competitive Masters athletes have a greater oxygen carrying capacity (tHbmass) and expanded blood compartment volumes when scaled to fat-free mass.

Respiratory symptom perception during exercise in patients with heart failure with preserved ejection fraction.

We investigated whether central or peripheral limitations to oxygen uptake elicit different respiratory sensations and whether dyspnea on exertion (DOE) provokes unpleasantness and negative emotions in patients with heart failure with preserved ejection fraction (HFpEF). 48 patients were categorized based on their cardiac output (Q̇c)/oxygen uptake (V̇O2) slope and stroke volume (SV) reserve during an incremental cycling test. 15 were classified as centrally limited and 33 were classified as peripherally limited. Ratings of perceived breathlessness (RPB) and unpleasantness (RPU) were assessed (Borg 0-10 scale) during a 20 W cycling test. 15 respiratory sensations statements (1-10 scale) and 5 negative emotions statements (1-10) were subsequently rated. RPB (Central: 3.5±2.0 vs. Peripheral: 3.4±2.0, p=0.86), respiratory sensations, or negative emotions were not different between groups (p>0.05). RPB correlated (p<0.05) with RPU (r=0.925), "anxious" (r=0.610), and "afraid" (r=0.383). While DOE provokes elevated levels of negative emotions, DOE and respiratory sensations seem more related to a common mechanism rather than central and/or peripheral limitations in HFpEF.

Cardiac Effects of Long-Duration Space Flight.

BACKGROUND: Ventricular mass responds to changes in physical activity and loading, with cardiac hypertrophy after exercise training, and cardiac atrophy after sustained inactivity. Ventricular wall stress (ie, loading) decreases during microgravity. Cardiac atrophy does not plateau during 12 weeks of simulated microgravity but is mitigated by concurrent exercise training. OBJECTIVES: The goal of this study was to determine whether the current exercise countermeasures on the International Space Station (ISS) offset cardiac atrophy during prolonged space flight. METHODS: We measured left ventricular (LV) and right ventricular (RV) mass and volumes (via magnetic resonance imaging) in 13 astronauts (4 females; age 49 ± 4 years), between 75 and 60 days before and 3 days after 155 ± 31 days aboard the ISS. Furthermore, we assessed total cardiac work between 21 and 7 days before space flight and 15 days before the end of the mission. Data were compared via paired-samples t-tests. RESULTS: Total cardiac work was lower during space flight (P = 0.008); however, we observed no meaningful difference in LV mass postflight (pre: 115 ± 30 g vs post: 118 ± 29 g; P = 0.053), with marginally higher LV stroke volume (P = 0.074) and ejection fraction postflight (P = 0.075). RV mass (P = 0.999), RV ejection fraction (P = 0.147), and ventricular end-diastolic (P = 0.934) and end-systolic volumes (P = 0.145) were not different postflight. There were strong positive correlations between the relative change in LV mass with the relative changes in total cardiac output (r = 0.73; P = 0.015) and total cardiac work (r = 0.53; P = 0.112). CONCLUSIONS: The current exercise countermeasures used on the ISS appear effective in offsetting reductions in cardiac mass and volume, despite overall reductions in total cardiac work, during prolonged space flight.

Reducing Pulmonary Capillary Wedge Pressure During Exercise Exacerbates Exertional Dyspnea in Patients With Heart Failure With Preserved Ejection Fraction: Implications for V˙/Q˙ Mismatch.

BACKGROUND: The primary cause of dyspnea on exertion in heart failure with preserved ejection fraction (HFpEF) is presumed to be the marked rise in pulmonary capillary wedge pressure during exercise; however, this hypothesis has never been tested directly. Therefore, we evaluated invasive exercise hemodynamics and dyspnea on exertion in patients with HFpEF before and after acute nitroglycerin (NTG) treatment to lower pulmonary capillary wedge pressure. RESEARCH QUESTION: Does reducing pulmonary capillary wedge pressure during exercise with NTG improve dyspnea on exertion in HFpEF? STUDY DESIGN AND METHODS: Thirty patients with HFpEF performed two invasive 6-min constant-load cycling tests (20 W): one with placebo (PLC) and one with NTG. Ratings of perceived breathlessness (0-10 scale), pulmonary capillary wedge pressure (right side of heart catheter), and arterial blood gases (radial artery catheter) were measured. Measurements of V˙/Q˙ matching, including alveolar dead space (Vdalv; Enghoff modification of the Bohr equation) and the alveolar-arterial Po2 difference (A-aDO2; alveolar gas equation), were also derived. The ventilation (V˙e)/CO2 elimination (V˙co2) slope was also calculated as the slope of the V˙e and V˙co2 relationship, which reflects ventilatory efficiency. RESULTS: Ratings of perceived breathlessness increased (PLC: 3.43 ± 1.94 vs NTG: 4.03 ± 2.18; P = .009) despite a clear decrease in pulmonary capillary wedge pressure at 20 W (PLC: 19.7 ± 8.2 vs NTG: 15.9 ± 7.4 mm Hg; P < .001). Moreover, Vdalv (PLC: 0.28 ± 0.07 vs NTG: 0.31 ± 0.08 L/breath; P = .01), A-aDO2 (PLC: 19.6 ± 6.7 vs NTG: 21.1 ± 6.7; P = .04), and V˙e/V˙co2 slope (PLC: 37.6 ± 5.7 vs NTG: 40.2 ± 6.5; P < .001) all increased at 20 W after a decrease in pulmonary capillary wedge pressure. INTERPRETATION: These findings have important clinical implications and indicate that lowering pulmonary capillary wedge pressure does not decrease dyspnea on exertion in patients with HFpEF; rather, lowering pulmonary capillary wedge pressure exacerbates dyspnea on exertion, increases V˙/Q˙ mismatch, and worsens ventilatory efficiency during exercise in these patients. This study provides compelling evidence that high pulmonary capillary wedge pressure is likely a secondary phenomenon rather than a primary cause of dyspnea on exertion in patients with HFpEF, and a new therapeutic paradigm is needed to improve symptoms of dyspnea on exertion in these patients.

Aortic stiffness contributes to greater pressor responses during static hand grip exercise in healthy young and middle-aged normotensive men.

Central arterial stiffness can influence exercise blood pressure (BP) by increasing the rise in arterial pressure per unit increase in aortic inflow. Whether central arterial stiffness influences the pressor response to isometric handgrip exercise (HG) and post-exercise muscle ischemia (PEMI), two common laboratory tests to study sympathetic control of BP, is unknown. We studied 46 healthy non-hypertensive males (23 young and 23 middle-aged) during HG (which increases in cardiac output [Q̇c]) and isolated metaboreflex activation PEMI (no change or decreases in Q̇c). Aortic stiffness (aortic pulse wave velocity [aPWV]; applanation tonometry via SphygmoCor) was measured during supine rest and was correlated to the pressor responses to HG and PEMI. BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA) were continuously recorded at rest, during HG to fatigue (35 % maximal voluntary contraction) and 2-min of PEMI. aPWV was higher in middle-aged compared to young males (7.1 ± 0.9 vs 5.4 ± 0.7 m/s, P < 0.001). Middle-aged males also exhibited greater increases in systolic pressure (∆30 ± 11 vs 10 ± 8 mmHg) and MSNA (∆2313 ± 2006 vs 1387 ± 1482 %/min) compared to young males during HG (both, P < 0.03); with no difference in the Q̇c response (P = 0.090). Responses to PEMI were not different between groups. Sympathetic transduction during these stressors (MSNA-diastolic pressure slope) was not different between groups (P > 0.341). Middle-aged males displayed a greater increase in SBP per unit change of Q̇c during HG (∆SBP/∆Q̇c; 21 ± 18 vs 6 ± 10 mmHg/L/min, P = 0.004), with a strong and moderate relationship between the change in systolic (r = 0.53, P < 0.001) and diastolic pressure (r = 0.34, P = 0.023) and resting aPWV, respectively; with no correlation during PEMI. Central arterial stiffness can modulate pressor responses during stimuli associated with increases in cardiac output and sympathoexcitation in healthy males.

Distinct contributions of skin and core temperatures to flow-mediated dilation of the brachial artery following passive heating.

We measured acute vascular responses to heat stress to examine the hypothesis that macrovascular endothelial-dependent dilation is improved in a shear-dependent manner, which is further modified by skin temperature. Twelve healthy males performed whole body heating (+1.3°C esophageal temperature), bilateral forearm heating (∼38°C skin temperature), and a time-matched (∼60 min) control condition on separate days in a counterbalanced order. Bilateral assessments of blood flow and brachial artery flow-mediated dilation (FMD) were performed before and 10 min after each condition with duplex Doppler ultrasound. To isolate the influence of shear stress, a pneumatic cuff was inflated (∼90 mmHg) around the right forearm during each condition to attenuate heat-induced rises in blood flow and shear stress. After forearm heating, FMD increased [cuffed: 4.7 (2.9)% to 6.8 (1.5)% and noncuffed: 5.1 (2.8)% to 6.4 (2.6)%] in both arms (time P < 0.01). Whole body heating also increased FMD in the noncuffed arm from 3.6 (2.2)% to 9.2 (3.2)% and in the cuffed arm from to 5.6 (3.0)% to 8.6 (4.9)% (time P < 0.01). After the time control, FMD decreased [cuffed: 6.3 (2.4)% to 4.7 (2.2)% and noncuffed: 6.1 (3.0)% to 4.5 (2.6)%] in both arms (time P = 0.03). Multiple linear regression (adjusted R2 = 0.421 P = 0.003) revealed that changes in esophageal temperature, skin temperatures, and heart rate explained the majority of the variance in this model (34%, 31%, and 21%, respectively). Our findings indicate that, in addition to shear stress, skin and core temperatures are likely important contributors to passive heating-induced vascular adaptations.NEW & NOTEWORTHY The primary determinant of vascular adaptations to lifestyle interventions, such as exercise and heat therapy, is repeated elevations in vascular shear stress. Whether skin or core temperatures also modulate the vascular adaptation to acute heat exposure is unknown, likely due to difficulty in dissociating the thermal and hemodynamic responses to heat. We found that skin and core temperatures modify the acute vascular responses to passive heating irrespective of the magnitude of increase in shear stress.