Skeletal Muscle Oxygen Utilization Research Articles

Young users of electronic cigarettes exhibit reduced cardiorespiratory fitness.

Electronic nicotine delivery systems, often referred to as e-cigarettes, are popular tobacco products frequently advertised as safer alternatives to traditional cigarettes despite preliminary data suggesting a potential negative cardiovascular impact. Cardiorespiratory fitness is a critical cardiovascular health marker that is diminished in individuals who consume traditional tobacco products. Whether the use of e-cigarettes impacts cardiorespiratory fitness is currently unknown. Thus, the purpose of this study was to investigate the impact of regular e-cigarette use on cardiorespiratory fitness in young healthy adults. Twenty-six users of e-cigarettes (ECU, 13 males, and 13 females; age: 24 ± 3 yr; e-cigarette usage 4 ± 2 yr) and 16 demographically matched nonusers (NU, 6 males, and 10 females; age: 23 ± 3 yr) participated in this study. Cardiorespiratory fitness was measured by peak oxygen consumption (V̇o2peak) during a cardiopulmonary exercise test. Measurements of chronotropic response, hemodynamic, oxygen extraction, and utilization were also evaluated. Our results suggest that regular users of e-cigarettes exhibited significantly lower peak oxygen consumption when compared with nonusers, even when controlled by fat-free mass and lean body mass. Hemodynamic changes were not different between both groups during exercise, whereas lower chronotropic responses and skeletal muscle oxygen utilization were observed in users of e-cigarettes. Results from the present study demonstrate that young, apparently healthy, regular users of e-cigarettes exhibit significantly reduced cardiorespiratory fitness, lower chronotropic response, and impaired skeletal muscle oxygen utilization during exercise. Overall, our findings contribute to the growing body of evidence that supports adverse effects of regular e-cigarette use on cardiovascular health.NEW & NOTEWORTHY E-cigarettes are tobacco products frequently used by youth and young adults. Little is known about the long-term health effects of their prolonged use. Results from the present study demonstrate that young, apparently healthy, regular users of e-cigarettes exhibit significantly reduced cardiorespiratory fitness, a marker of cardiovascular health and a predictor of all-cause mortality. We also identified that the young users of e-cigarettes present with lower chronotropic response and impaired skeletal muscle oxygen utilization during exercise.

Contributors to Diminished Cardiorespiratory Fitness in Young Users of Electronic Cigarettes

Background: Cardiorespiratory fitness, an independent marker of cardiovascular health, represents the ability of respiratory, cardiovascular, and muscular systems to effciently deliver and utilize oxygen (O2) during exercise. Recently, reduced cardiorespiratory fitness was identified in young and healthy, regular users of electronic (e-) cigarettes; however, its limiting factors are not established. Thus, the purpose of this study was to investigate the contributors to impaired cardiorespiratory fitness in young regular users of e-cigarettes. Methods: An evaluation of hemodynamics, chronotropic response, and oxygen utilization during exercise was completed in nineteen regular users of e-cigarettes (EU, age: 23±3 yr; e-cigarette usage 4±2 yr.) and sixteen demographically matched non-users (NU, age: 23±3 yr.). Hemodynamics were accessed via a non-invasive signal morphology impedance cardiography device, while chronotropic responses were measured as changes in peak heart rate (HR). Oxygen extraction ratio (difference in arterial and venous O2 content) at baseline and peak exercise was also recorded. Fold changes from rest to peak exercise were assessed to provide insight into potential factors that limit cardiorespiratory fitness. Results: At peak exercise, users of e-cigarettes exhibited significantly higher chronotropic incompetence ( p=0.033) and lower ( p=0.047) peak HR than non-users, with no differences in other hemodynamic assessments. Significantly ( p=0.025) lower skeletal muscle O2 extraction (EU=51±11 vs. NU=61±10%) was also observed in users of e-cigarettes during peak exercise. Fold changes in chronotropic (HR; p=0.915) and hemodynamic (cardiac output; p=0.279) responses were similar between both groups, while significant ( p=0.048) differences in oxygen extraction ratio were identified between the users of e-cigarettes (0.5±0.3 fold change) and non-users (0.8±0.3 fold change). Conclusions: Results from our study demonstrate that young, regular users of e-cigarettes exhibit abnormal chronotropic responses and impaired skeletal muscle oxygen utilization during exercise when compared to non-users, suggesting reduced cardiovascular and muscle health. Overall, our findings contribute to the growing body of evidence that supports the negative effects of regular e-cigarette use on young individuals. Supported in part by a Rapid Response Project NIDA/FDA (PRM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Partial Pressure of End-Tidal Oxygen and Blood Lactate During Cardiopulmonary Exercise Testing in Healthy Older Participants and Patients at Risk of Cardiac Disease.

The partial pressure of end-tidal oxygen (PETO2) and end-tidal oxygen concentration (ETO2) are among the indices that can be measured by exhaled gas analysis. Several observational studies have shown that skeletal muscle function is impaired in patients with cardiac disease; thus, the assessment of skeletal muscle function is important. Additionally, although it has recently been suggested that the difference in PETO2 from rest to the ventilatory anaerobic threshold (VAT) reflects oxygen availability in peripheral factors, primarily skeletal muscle, the evidence for this is not well established. Therefore, we hypothesized and investigated whether increased blood lactate (BLa) levels, resulting from decreased skeletal muscle and mitochondrial oxygen availability, and PETO2 dynamics during cardiopulmonary exercise testing (CPET) would be related. All participants performed the symptomatic limited CPET, and their BLa levels were measured. The difference in PETO2 and ETO2 from rest to VAT determined by the V-slope method (ΔPETO2 and ΔETO2) was calculated and compared with the increase in BLa due to exercise testing. We recruited 22 healthy older participants (nine males; 69.4 ± 6.8 years) and 11 patients with cardiovascular risk (eight males; 73.0 ± 8.8 years). ΔPETO2 and ΔETO2 did not differ between the two groups (P = 0.355 and P = 0.369, respectively), showing no correlation between increase in BLa from rest to VAT, but were significantly correlated with an increase in BLa from rest to the end of exercise (ΔPETO2, P = 0.030; ΔETO2, P = 0.029). The correlation was particularly pronounced among those at cardiovascular risk (ΔPETO2, P = 0.012; ΔETO2, P = 0.011). ΔPETO2 and ΔETO2 from rest to VAT during CPET may be useful as indices reflecting skeletal muscle oxygen utilization capacity.

Simulated Altitude Training and Sport Performance: Protocols and Physiological Effects

This article explores the physiological mechanisms and effects of simulated hypoxia environment training on sports performance. Different training protocols, including hypoxia high-intensity interval training (HHIIT), incremental hypoxia training, hypoxia submaximal exercise training and combined training, and hypoxia training in the recovery and sleep states, are discussed. HHIIT combines intermittent hypoxia exposure with high-intensity interval training, and has been shown to increase the maximum oxygen intake compare to the state of normoxia, improving cardiorespiratory fitness, skeletal muscle oxygen utilization, power performance, hematological adaptations, and sports performance. Incremental hypoxia training involves the gradual decrease in oxygen concentration while maintaining exercise intensity. It has been found to improve aerobic capacity; however, fewer effects were observed in hematological variables. Hypoxia submaximal exercise training and combined training in a hypoxia environment has shown to increase VO2 and VE, and only improve hemodynamic function in combined training with hypoxia. Hypoxia during the recovery state has been associated with improvements in maximum oxygen uptake, also providing benefits to sports performance. Overall, exposure to a hypoxia environment has been demonstrated to improve cardiorespiratory endurance, power performance, and specific physiological adaptations in training and resting states. However, the optimal training protocols and their effects on different sports and athlete proficiency require further research to optimize training and enhance athletic performance in hypoxia environments.

Abstract 10465: Abnormal Post Exercise Skeletal Muscle Microvascular Response and Metabolism Correlate With Patient Reported Outcomes in Patients With Intermittent Claudication From Peripheral Artery Disease

Background and Aims: Intermittent claudication (IC) in patients with peripheral artery disease (PAD) is thought to be caused by reduced lower extremity macrovascular blood flow. However, the ankle-brachial index (ABI) (a macrovascular measure) does not correlate well with patient-reported outcome measures. We aimed to study microvascular and metabolic skeletal muscle responses to exercise in patients with IC using positron emission tomography (PET). Methods: We enrolled 19 patients with IC (ABI < 0.90 and imaging/angiographic evidence of PAD) and 12 healthy controls (HCs) (normal ABI). All subjects underwent rest perfusion imaging of the legs with 13 N-ammonia or 11 C-acetate PET followed by a graded treadmill test. Subjects exercised until limited by claudication or the end of the 20-minute protocol. Subjects then underwent immediately post-exercise PET imaging of the legs. Skeletal muscle blood flow (SMBF) was quantified in each leg at rest and immediately post-exercise. Skeletal muscle oxygen utilization (SMVO 2 ) normalized to SMBF was also quantified for patients who underwent imaging with 11 C-acetate. Peripheral artery questionnaire (PAQ) summary score was obtained for all subjects. Results: We found that SMBF was increased post-exercise in all subjects, and stress/rest SMBF was higher in the legs of subjects with PAD than in the legs of HCs ( Figure 1A ). We also found that stress SMVO 2 /SMBF was higher in legs of patients with PAD than in the legs of HCs ( Figure 1B ). There was a moderate, significant correlation between limb stress/rest SMBF and PAQ score ( Figure 1C ) and a strong, significant correlation between limb stress SMVO 2 /SMBF and PAQ score ( Figure 1D ). Conclusions: In conclusion, we found that SMBF increased in all subjects after treadmill exercise and paradoxically to the greatest degree in patients with IC. We also found that PET-derived markers of post-exercise microvascular perfusion and metabolism correlated with patient-reported outcomes.

Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 μL·min-1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD.NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 μM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Aerobic Metabolic Adaptations in Endurance Eccentric Exercise and Training: From Whole Body to Mitochondria.

A characteristic feature of eccentric as compared with concentric exercise is the ability to generate greater mechanical loads for lower cardiopulmonary demands. Current evidence concurs to show that eccentric training translates into considerable gains in muscle mass and strength. Less is known, however, regarding its impact on oxygen transport and on factors to be considered for optimizing its prescription and monitoring. This article reviews the existing evidence for endurance eccentric exercise effects on the components of the oxygen transport system from systemic to mitochondria in both humans and animals. In the studies reviewed, specially designed cycle-ergometers or downhill treadmill running were used to generate eccentric contractions. Observations to date indicate that overall, the aerobic demand associated with the eccentric training load was too low to significantly increase peak maximal oxygen consumption. By extension, it can be inferred that the very high eccentric power output that would have been required to solicit a metabolic demand sufficient to enhance peak aerobic power could not be tolerated or sustained by participants. The impact of endurance eccentric training on peripheral flow distribution remains largely undocumented. Given the high damage susceptibility of eccentric exercise, the extent to which skeletal muscle oxygen utilization adaptations would be seen depends on the balance of adverse and positive signals on mitochondrial integrity. The article examines the protection provided by repeated bouts of acute eccentric exercise and reports on the impact of eccentric cycling and downhill running training programs on markers of mitochondrial function and of mitochondrial biogenesis using mostly from animal studies. The summary of findings does not reveal an impact of training on skeletal muscle mitochondrial respiration nor on selected mitochondrial messenger RNA transcripts. The implications of observations to date are discussed within future perspectives for advancing research on endurance eccentric exercise physiological impacts and using a combined eccentric and concentric exercise approach to optimize functional capacity.

Age- And Sex-related Differences In Skeletal Muscle Oxygen Consumption Rate And Microvascular Reactivity

PURPOSE: To examine the influence of age and sex on non-invasive measurements of oxygen consumption rate and microvascular reactivity. METHODS: Seven young females (YF; mean ± SD, age = 20.9±2 y), 6 older females (OF; 57.5±10 y), 14 younger males (YM; 22.2±2 y), and 8 older males (OM; 59.5±5 y) visited the laboratory on one occasion during which skeletal muscle oxygen utilization and microvascular function were assessed following a 10-h fast using the near-infrared spectroscopy with vascular occlusion test (NIRS-VOT). During the NIRS-VOT, tissue saturation (StO2) was monitored, and the rate of decrease in StO2 (Slope 1) during cuff inflation (i.e., ischemia) was quantified, as were the reperfusion magnitude (RepMAG), rate of increase in StO2 (Slope 2), and the reperfusion area under the curve (StO2AUC) following cuff deflation. Two-way (age × sex) ANOVAs were used to examine the differences in Slope 1, RepMAG, Slope 2, and StO2AUC among the YW, OW, YM, and OM. Means ± 95% CIs are reported. RESULTS: There were significant age and sex effects for Slope 1 (p = 0.01 and 0.02, respectively), which was more negative (i.e., steeper) in males versus females (-0.132±0.12 vs. -0.108±0.15 %1s-1) and in the young versus older adults (-0.133±0.13 vs. -0.107±0.14 %1s-1). There was an age effect for RepMAG (p < 0.001), which was greater in the younger than older adults (50.7±4.0 vs. 38.5±4.6%). While there was no effect of age on Slope 2, Slope 2 was steeper (p = 0.002) in males than females (1.71±0.24 vs. 1.06±0.34 %1s-1). Finally, there were age (p = 0.02) and sex (p = 0.03) main effects for StO2AUC, which was greater in males versus females (1228.5±148.8 vs. 960.1±178.9 %1s) and in the young versus older adults (1240.7±148.8 vs. 947.9±178.9 %1s). CONCLUSIONS: Overall, our results suggest that there are age and sex-related differences in skeletal muscle oxygen consumption rate and microvascular reactivity, as assessed using the NIRS-VOT technique. However, because the degree of tissue desaturation is the stimulus for subsequent reperfusion responses and the rate of desaturation was greater in the younger than older adults and in males than females, it is not clear if the differences in Slope 2 and StO2AUC reflect differences in microvascular reactivity, per se. Additional studies are needed to more fully explore this interplay.

Studies into the determinants of skeletal muscle oxygen consumption: novel insight from near-infrared diffuse correlation spectroscopy.

Diffuse correlation spectroscopy (DCS) is emerging as a powerful tool to assess skeletal muscle perfusion. Near-infrared spectroscopy (NIRS) is an established technique for characterizing the transport and utilization of oxygen through the microcirculation. Here we compared a combined NIRS-DCS system with conventional measures of oxygen delivery and utilization during handgrip exercise. The data show good concurrent validity between convective oxygen delivery and DCS-derived blood flow index, as well as between oxygen extraction at the conduit and microvascular level. We then manipulated forearm arterial perfusion pressure by adjusting the position of the exercising arm relative to the position of the heart. The data show that microvascular perfusion can be uncoupled from convective oxygen delivery, and that tissue saturation seemingly compensates to maintain skeletal muscle oxygen consumption. Taken together, these data support a novel role for NIRS-DCS in understanding the determinants of muscle oxygen consumption at the microvascular level. Diffuse correlation spectroscopy (DCS) is emerging as a powerful tool to assess skeletal muscle perfusion. Combining DCS with near-infrared spectroscopy (NIRS) introduces exciting possibilities for understanding the determinants of muscle oxygen consumption; however, no investigation has directly compared NIRS-DCS to conventional measures of oxygen delivery and utilization in an exercising limb. To address this knowledge gap, nine healthy males performed rhythmic handgrip exercise with simultaneous measurements by NIRS-DCS, Doppler blood flow and venous oxygen content. The two approaches showed good concurrent validity, with directionally similar responses between: (a) Doppler-derived forearm blood flow and DCS-derived blood flow index (BFI), and (b) venous oxygen saturation and NIRS-derived tissue saturation. To explore the utility of combined NIRS-DCS across the physiological spectrum, we manipulated forearm arterial perfusion pressure by altering the arm position above or below the level of the heart. As expected, Doppler-derived skeletal muscle blood flow increased with exercise in both arm positions, but with markedly different magnitudes (below: +424.3±41.4ml/min, above: +306±12.0ml/min, P=0.002). In contrast, DCS-derived microvascular BFI increased to a similar extent with exercise, regardless of arm position (P=0.65). Importantly, however, the time to reach BFI steady state was markedly slower with the arm above the heart, supporting the experimental design. Notably, we observed faster tissue desaturation at the onset of exercise with the arm above the heart, resulting in similar muscle oxygen consumption profiles throughout exercise. Taken together, these data support a novel role for NIRS-DCS in understanding the determinants of skeletal muscle oxygen utilization non-invasively and throughout exercise.

Hemoglobin Dynamics in the Skeletal Muscle of Patients with Malignant Hematopoietic Disease.

Impaired oxygen utilization in skeletal muscle potentially contributes to muscle weakness in patients with malignant hematopoietic disease and may explain altered hemodynamic responses to exercise in these patients. We investigated whether changes in hemoglobin parameters in the tibialis anterior muscle in patients with malignant hematopoietic diseases were different from those in age-matched healthy controls and whether these results were associated with a decline in muscle strength. Near-infrared spectroscopy was used during and after a repeated isometric contraction task at 50% of maximal voluntary contraction in 16 patients and 21 age- and sex-matched healthy controls. In the healthy control group, there was a correlation between muscle strength and hemoglobin dynamics, (ΔtHbmean: r=0.42, p<0.05; ΔtHbmax: r=0.575, p<0.01, respectively) but not in patients with malignant hematopoietic disease. The results of this study may suggest that haemoglobin dynamics during and following exercise were different between patients with malignant hematopoietic disease and healthy controls.

Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation.

Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1α, which has been demonstrated to decrease the expression, was evaluated by methylation-specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1α in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1α in the muscle.

Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients With Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance

ObjectivesThe aim of this study was to examine skeletal muscle mitochondria content, oxidative capacity, and the expression of key mitochondrial dynamics proteins in patients with heart failure with preserved ejection fraction (HFpEF), as well as to determine potential relationships with measures of exercise performance. BackgroundMultiple lines of evidence indicate that severely reduced peak exercise oxygen uptake (peak VO2) in older patients with HFpEF is related to abnormal skeletal muscle oxygen utilization. Mitochondria are key regulators of skeletal muscle metabolism; however, little is known about how these organelles are affected in HFpEF. MethodsBoth vastus lateralis skeletal muscle citrate synthase activity and the expression of porin and regulators of mitochondrial fusion were examined in older patients with HFpEF (n = 20) and healthy, age-matched control subjects (n = 17). ResultsCompared with age-matched healthy control subjects, mitochondrial content assessed by porin expression was 46% lower (p = 0.01), citrate synthase activity was 29% lower (p = 0.01), and Mfn2 (mitofusin 2) expression was 54% lower (p <0.001) in patients with HFpEF. Expression of porin was significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.48, p = 0.003 and r = 0.33, p = 0.05, respectively). Expression of Mfn2 was also significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.40, p = 0.02 and r = 0.37, p = 0.03 respectively). ConclusionsThese findings suggest that skeletal muscle oxidative capacity, mitochondrial content, and mitochondrial fusion are abnormal in older patients with HFpEF and might contribute to their severe exercise intolerance.

Abstract 15962: VO2 Kinetics are Impaired in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

Background: VO2 kinetics, or mean response time (MRT), quantifies oxygen uptake at the onset of exercise reflecting the rapidity with which the cardiovascular system can match the metabolic demands of skeletal muscle. Slowed kinetics leads to myofibril oxygen deficit which must be buffered by increased glycolysis and depletion of high energy phosphate stores. To date no studies have assessed changes in VO2 kinetics in HFpEF but growing evidence suggests peripheral abnormalities in oxygen utilization play an important role in exertional intolerance. We hypothesized HFpEF patients would have prolonged MRT during exercise compared to healthy senior controls reflecting abnormalities in skeletal muscle oxygen utilization. Methods: Eight senior control and 13 carefully screened HFpEF subjects underwent cardiopulmonary exercise testing. AV nodal blocking agents were held 5 half-lives and subjects performed submaximal exercise at 30% of VO2max for 5 minutes. VO2 and cardiac output (Qc; acetylene rebreathe) were collected at rest and during exercise. MRT and O2 deficit were calculated from VO2 response curves plotted on a breath by breath basis. Results: HFpEF patients had lower peak VO2 compared to seniors (13.2 ± 3.1 vs 20.3 ± 3.5 ml/min/kg; p&lt;0.001). During fixed submaximal exercise, Qc, HR and VO2 were similar between groups. (Table) HFpEF patients had significantly prolonged MRT (69 v. 49s) compared to controls despite similar aerobic power and central cardiovascular and hemodynamic response. HFpEF patients also had a trend towards larger oxygen deficit (p=0.16) suggesting increased reliance on glycolytic metabolism during early exercise. Conclusions: HFpEF patients have slowed VO2 kinetics and an exaggerated O2 deficit during submaximal exercise. These findings establish abnormalities in muscle tissue oxygen utilization in HFpEF patients and suggest defects in oxygen metabolism are important contributors to exercise intolerance.

Dietary nitrate reduces skeletal muscle oxygenation response to physical exercise: a quantitative muscle functional MRI study.

Dietary inorganic nitrate supplementation (probably via conversion to nitrite) increases skeletal muscle metabolic efficiency. In addition, it may also cause hypoxia‐dependent vasodilation and this has the potential to augment oxygen delivery to exercising skeletal muscle. However, direct evidence for the latter with spatial localization to exercising muscle groups does not exist. We employed quantitative functional MRI (fMRI) to characterize skeletal muscle oxygen utilization and replenishment by assessment of tissue oxygenation maximal change and recovery change, respectively. Eleven healthy subjects were enrolled, of whom 9 (age 33.3 ± 4.4 years, five males) completed the study. Each subject took part in three MRI visits, with dietary nitrate (7cl concentrated beetroot juice) consumed before the third visit. During each visit fMRIs were conducted concurrently with plantar flexion exercise at workloads of 15% and 25% maximum voluntary contraction (MVC). No significant changes were found between visits 1 and 2 in the fMRI measures. A decrease in maximal change was found at 15% MVC in soleus between visits 2 and 3 (5.12 ± 2.36 to 2.55 ± 1.42, P = 0.004) and between visits 1 and 3 (4.43 ± 2.12 to 2.55 ± 1.42, P = 0.043), but not at 25% MVC or within gastrocnemius. There was no difference in recovery change between visits. We found that dietary nitrate supplementation reduces tissue oxygenation alterations during physical exercise in skeletal muscle. This effect is more prominent in muscles with predominantly type 1 fibers and at lower workloads. This indicates that in healthy subjects dietary nitrate predominantly affects skeletal muscle energy efficiency with no change in oxygen delivery.

Impaired Oxygen Utilization in Skeletal Muscle of CRPS I Patients

The purpose of this study was to evaluate oxygen extraction and utilization in end stage chronic complex regional pain syndrome type I (CRPS I) patients undergoing amputation and to relate these to muscle histology of the amputated limb. In 25 patients with severe CRPS I requiring amputation of the affected limb venous blood samples and in 11 patients skeletal muscle specimens were analyzed. The mean venous oxygen saturation (S(v)O(2)) value (94.3% ± 4.0%) of the affected limb was significantly higher than S(v)O(2) values found in healthy subjects (77.5% ± 9.8%) pointing to a severely decreased oxygen diffusion or utilization within the affected limb. Histologic analysis showed a significant decrease of type I fibers and a significant increase of type IIB fibers. Ultrastructural investigations of soleus skeletal muscle capillaries revealed thickened endothelial cells and thickened basement membranes. Muscle capillary densities were decreased in comparison with literature data. High venous oxygen saturation levels were partially explained by impaired diffusion of oxygen due to thickened basement membrane and decreased capillary density. This study shows that venous oxygen saturation is significantly increased in chronic end stage CRPS I patients corresponding with impaired oxygen diffusion. The abnormal skeletal muscle findings points to severe disuse but only partially explain the impaired diffusion of oxygen; mitochondrial dysfunction seems a likely explanation in addition.

Ischemic Heart Failure Etiology Affects Phase II VO2 Kinetics in Heart Transplant Recipients

Heart transplant recipients (HTR) have severely reduced peak aerobic power (VO2peak) and delayed oxygen (VO2) kinetics. The role that pre-transplant heart failure etiology has on VO2peak and VO2 kinetics in HTR has not been well studied. PURPOSE: The objective of this study was to examine the role that heart failure etiology has on VO2peak and phase II VO2 kinetics in HTR. We hypothesized that HTR with pre-transplant ischemic heart failure (I-HTR) would have a reduced VO2peak and attenuated phase II VO2 kinetics compared with HTR with pre-transplant non-ischemic heart failure (NI-HTR). METHODS: 11 clinically stable I-HTR (mean ± SD, age: 65 ± 5 years; 9 males and 2 females) and 6 NI-HTR (age, 46 ±11 years; 4 males and 2 females) were included in this study. All participants performed an incremental exercise test on a cycle ergometer during which time expired gases were collected. On a separate day, participants completed step-transition exercise to 25% VO2peak that lasted ∼5 minutes. This intensity was below the ventilatory threshold. Phase II VO2 kinetics was estimated with a monoexponential model that included a time delay, amplitude term, and a time constant. Data were analyzed using analysis of variance. The alpha level was set “a priori” at p <0.05. RESULTS: No significant difference was found for VO2peak between the groups (I-HTR: 1.8 ± 0.6 L/min versus NI-HTR: 1.8 ± 0.7 L/min, p> 0.05). The phase II VO2 time constant was 45 ± 18 seconds for I-HTR and 25 ± 11 seconds for NI-HTR (p <0.05). The time delay was 52 ± 23 seconds and 61 ± 23 seconds (p >0.05) for I-HTR and NI-HTR, respectively. Finally, the amplitude response was 0.34 ± 0.15 L/min (I-HTR) and 0.41 ± 0.26 L/min (NI-HTR, p >0.05). CONCLUSION: I-HTR have a slower phase II VO2 time constant compared to NI-HTR despite no differences in VO2peak. The delayed response may be related to pre- and post-transplant abnormalities in cardiovascular and skeletal muscle function that result in reduced oxygen delivery and/or skeletal muscle oxygen utilization. Future studies are required to determine if exercise training can reverse the abnormal VO kinetics found in I-HTR.

Effects of captopril on forearm oxygen consumption during dynamic handgrip exercise in patients with congestive heart failure.

The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently decreased because of decreased skeletal muscle oxygen utilization. In this study we examined whether forearm oxygen utilization is decreased during dynamic handgrip exercise in patients with CHF and whether captopril improves forearm oxygen utilization. They were divided into 3 groups according to the level of plasma renin activity (PRA) and New York Heart Association functional classification (NYHA): Group 1 consisted of 7 normal (control) subjects (PRA: 0.5 +/- 0.2 ng/ml/h, NYHA: 0); Group 2, 7 patients with severe CHF (PRA: 11.3 +/- 3.9 ng/ml/h, NYHA: 3.6 +/- 0.3); Group 3, 4 patients with mild CHF (PRA: 2.4 +/- 0.2 ng/ml/h, NYHA: 2 +/- 0). Forearm blood flow was measured by a strain gauge plethysmograph at rest and during dynamic handgrip exercise. Regional arterial venous oxygen content was measured and forearm oxygen consumption was calculated by the Fick principle. Forearm blood flow was less (p less than 0.05) at rest and during exercise in patients with severe CHF than in control subjects; this was compensated for by increased oxygen extraction, thus maintaining forearm oxygen consumption at a normal level at rest and during submaximal exercise. During maximal exercise, oxygen extraction was not different between normal control subjects and patients with severe CHF, thus forearm oxygen consumption was significantly less (p less than 0.01) in patients with severe CHF than in control subjects. In patients with mild CHF, forearm blood flow, oxygen extraction and oxygen consumption were not different from those in normal control subjects. Captopril (25 mg orally) did not alter forearm hemodynamics at rest and during exercise in control subjects and patients with mild CHF. In patients with severe CHF, captopril lowered systolic and mean blood pressure (p less than 0.05). Captopril increased forearm oxygen extraction (p less than 0.05) and tended to increase blood flow and thus increased oxygen consumption (p less than 0.01) during maximal exercise. Our data indicate that oxygen utilization was impaired in patients with severe CHF and that captopril improved forearm oxygen utilization during maximal handgrip exercise in patients with severe CHF.