In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l
in non-pregnant females and < 130 g.l
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,
<0.001). However, they were poorly related in liver disease (r=0.410,
=0.11) and heart failure patients (r=0.312,
=0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R
=0.109 and 0.052;
=0.11 and 0.16), whilst plasma volume did (R
change 0.724 and 0.805 in heart and liver disease respectively,
<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.
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":
) 15 sedentary individuals, <2 sessions/wk;
) 25 casual exercisers, 2-3 sessions/wk;
) 24 committed exercisers, 4-5 sessions/wk; and
) 13 competitive Masters athletes, 6-7 sessions/wk, plus regular competitions. Absolute (L/min) and relative (mL/kg/min) V̇o
were higher with increasing exercise "dose" (
= 0.0005 and
< 0.0001, respectively). Hemoglobin concentration, hematocrit, and absolute tHbmass and blood compartment volumes were not significantly different between groups (all,
> 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
< 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
< 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,
< 0.0340) and tHbmass and erythrocyte volume were also higher in Committed compared with Casual exercisers (both,
< 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.
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.
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
< 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
< 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
= 0.03). Multiple linear regression (adjusted
= 0.421
= 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.
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.
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.
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.
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
=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
=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).
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.
URL: https://www.
gov; Unique identifier: NCT04068844.
Cardiac Effects of Long-Duration Space Flight Shibata, Shigeki; Wakeham, Denis J.; Thomas, James D. ...
Journal of the American College of Cardiology,
08/2023, Letnik:
82, Številka:
8
Journal Article
Recenzirano
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.
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.
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.
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).
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.
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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.
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.
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.
BACKGROUNDThe 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 QUESTIONDoes reducing pulmonary capillary wedge pressure during exercise with NTG improve dyspnea on exertion in HFpEF? STUDY DESIGN AND METHODSThirty 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. RESULTSRatings 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. INTERPRETATIONThese 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.
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.
figure legend Experimental model and carbon dioxide tests. Arterial and jugular venous blood samples were collected alongside measurements of internal carotid and vertebral artery blood flow. These measurements were made during a transient and steady‐state carbon dioxide reactivity test under control (saline), nitric oxide synthase inhibition (L‐NMMA), or equipotent vasoconstrictor control conditions (phenylephrine).
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.
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 (V̇o
; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples
tests.
V̇o
was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min;
=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL;
=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min;
=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;
=0.007).
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.
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