Muscle Oxygenation and Microvascular Reactivity Across Different Stages of CKD: A Near-Infrared Spectroscopy Study.

RATIONALE & OBJECTIVE: Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds progressively deteriorates with worsening CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with different stages of CKD versus controls. STUDY DESIGN: Observational controlled study. SETTING & PARTICIPANTS: 90 participants (18 per CKD stage 2, 3a, 3b, and 4, as well as 18 controls). PREDICTOR: CKD stage. OUTCOME: The primary outcome was muscle oxygenation at rest. Secondary outcomes were muscle oxygenation during occlusion-reperfusion and exercise, and muscle microvascular reactivity (hyperemic response). ANALYTICAL APPROACH: Continuous measurement of muscle oxygenation [tissue saturation index (TSI)] using near-infrared spectroscopy at rest, during occlusion-reperfusion, and during a 3-minute handgrip exercise (at 35% of maximal voluntary contraction). Aortic pulse wave velocity and carotid intima-media thickness were also recorded. RESULTS: Resting muscle oxygenation did not differ across the study groups (controls: 64.3% ± 2.9%; CKD stage 2: 63.8% ± 4.2%; CKD stage 3a: 64.1% ± 4.1%; CKD stage 3b: 62.3% ± 3.3%; CKD stage 4: 62.7% ± 4.3%; P=0.6). During occlusion, no significant differences among groups were detected in the TSI occlusion magnitude and TSI occlusion slope. However, during reperfusion the maximum TSI value was significantly lower in groups of patients with more advanced CKD stages compared with controls, as was the hyperemic response (controls: 11.2%±3.7%; CKD stage 2: 8.3%±4.6%; CKD stage 3: 7.8%±5.5%; CKD stage 3b: 7.3%±4.4%; CKD stage 4: 7.2%±3.3%; P=0.04). During the handgrip exercise, the average decline in TSI was marginally lower in patients with CKD than controls, but no significant differences were detected across CKD stages. LIMITATIONS: Moderate sample size, cross-sectional evaluation. CONCLUSIONS: Although no differences were observed in muscle oxygenation at rest or during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and was most prominent in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance. PLAIN-LANGUAGE SUMMARY: Previous studies in chronic kidney disease (CKD) have shown that vascular dysfunction in different circulatory beds progressively deteriorates with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with nondialysis CKD versus controls, as well as across different CKD stages. It showed that the microvascular hyperemic response after an arterial occlusion was significantly impaired in CKD and was worst in patients with more advanced CKD. No significant differences were detected in skeletal muscle oxygenation or muscle oxidative capacity at rest or during the handgrip exercise when comparing patients with CKD with controls or comparing across CKD stages. The impaired ability of microvasculature to respond to stimuli may be a component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.

Cerebral oxygenation during exercise deteriorates with advancing chronic kidney disease.

BACKGROUND: Cognitive impairment and exercise intolerance are common in chronic kidney disease (CKD). Cerebral perfusion and oxygenation play a major role in both cognitive function and exercise execution. This study aimed to examine cerebral oxygenation during a mild physical stress in patients at different CKD stages and controls without CKD. METHODS: Ninety participants (18 per CKD stage 2, 3a, 3b and 4 and 18 controls) underwent a 3-min intermittent handgrip exercise at 35% of their maximal voluntary contraction. During exercise, cerebral oxygenation [oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb) and total haemoglobin (tHb)] was assessed by near-infrared spectroscopy. Indices of microvascular (muscle hyperaemic response) and macrovascular function (carotid intima-media thickness and pulse wave velocity (PWV)) and cognitive and physical activity status were also evaluated. RESULTS: No differences in age, sex and body mass index were detected among groups. The mini-mental state examination score was significantly reduced with advancing CKD stages (controls: 29.2 ± 1.2, stage 2: 28.7 ± 1.0, stage 3a: 27.8 ± 1.9, stage 3b: 28.0 ± 1.8, stage 4: 27.6 ± 1.5; P = .019). Similar trends were observed for physical activity levels and handgrip strength. The average response in cerebral oxygenation (O2Hb) during exercise was lower with advancing CKD stages (controls: 2.50 ± 1.54, stage 2: 1.30 ± 1.05, stage 3a: 1.24 ± 0.93, stage 3b: 1.11 ± 0.89, stage 4: 0.97 ± 0.80 µmol/l; P < .001). The average tHb response (index of regional blood volume) showed a similar decreasing trend (P = .003); no differences in HHb among groups were detected. In univariate linear analysis, older age, lower estimated glomerular filtration rate (eGFR), Hb, microvascular hyperaemic response and increased PWV were associated with poor O2Hb response during exercise. In the multiple model, eGFR was the only parameter independently associated with the O2Hb response. CONCLUSIONS: Brain activation during a mild physical task appears to decrease with advancing CKD as suggested by the smaller increase in cerebral oxygenation. This may contribute to impaired cognitive function and reduced exercise tolerance with advancing CKD.

Depression in systemic lupus erythematosus: A manifestation of microcirculation dysfunction?

OBJECTIVES: Depression is highly prevalent among systemic lupus erythematosus (SLE) patients. Brain hypoperfusion in neuropsychiatric SLE patients might be associated with emotional difficulties. However, no previous study examined possible associations of depression with brain oxygenation during a mild physical stress in non-neuropsychiatric SLE patients. Our study aimed to identify possible differences in cerebral oxygenation during exercise in SLE patients with and without depressive symptoms using near-infrared spectroscopy (NIRS) and examine possible underlying mechanisms through evaluation of vascular cell adhesion molecule 1 (VCAM-1) levels. METHODS: SLE patients without a known neuropsychiatric history or treatment with antidepressants or antipsychotic drugs were enrolled. Participants were assigned into groups based on Beck's Depression Inventory I (BDI-I). Patients with BDI-I score ≥10 comprised the SLE-depression group and those with BDI-I score <9 the SLE-non-depression group. All participants underwent a protocol involving a seated rest, a 3-min handgrip exercise (at 30% of maximal strength), and a 3-min recovery. NIRS was used to monitor changes in cerebral oxygenated hemoglobin (O2Hb), deoxygenated (HHb), and total hemoglobin (tHb). VCAM-1 levels were measured in serum samples. RESULTS: Twenty-three patients were enrolled. During exercise, the SLE-depression group exhibited a significantly lower increase in cerebral O2Hb [(peak-O2Hb (p = 0.039); O2Hb-area under the curve, AUC, p = 0.027) vs. SLE-non-depression group. BDI-I score was inversely correlated with AUC (rho = -0.493, p = 0.017) and positively correlated with VCAM-1 levels (rho = 0.501, p = 0.034). CONCLUSION: This study suggests a possible association between emotional abnormalities and microvascular impairment (cerebral oxygenation and endothelial dysfunction) in SLE However, larger studies are needed to confirm these results.

Blunted cerebral oxygenation during exercise in systemic lupus erythematosus patients.

OBJECTIVES: Subclinical brain lesions have been reported in systemic lupus erythematosus (SLE) patients. Advanced neuroimaging techniques have revealed microstructural and microvascular alterations. Most studies examining structural or functional brain abnormalities were performed either at rest or during a mental task. Our study aimed to examine possible differences in cerebral oxygenation during exercise between SLE patients without known neuropsychiatric manifestations and age-matched controls, using near-infrared-spectroscopy (NIRS) and examine possible underlying mechanisms through evaluation of brain derived neurotrophic factor (BDNF) levels. METHODS: The protocol involved a seated rest, a 3-min submaximal (30%) handgrip exercise, and a 3-min recovery. Continuous-NIRS was used to monitor changes in cerebral-oxygenated (O2Hb), de-oxygenated (HHb) and total-haemoglobin (tHb). BDNF levels were measured in serum samples. RESULTS: Twenty-six SLE patients and 27 matched controls were enrolled. No differences were observed in baseline characteristics. During exercise, cerebral-O2Hb increased in both groups. However, SLE patients exhibited a significantly lower average- (1.20 ± 0.89 vs. 2.69 ± 2.46, p=0.001) and peak-O2Hb response (2.89 ± 1.56 vs. 5.83 ± 4.59, p=0.004) compared to controls. Serum BDNF levels were significantly lower in SLE patients compared to controls (p<0.01). CONCLUSIONS: To our knowledge, this is the first study to evaluate cerebral oxygenation during exercise using NIRS in SLE patients compared to age-matched controls. Our data show that SLE patients even without overt neuropsychiatric manifestations exhibit a blunted increase in cerebral-O2Hb during a submaximal exercise stimulus. Examining brain oxygenation during a simple exercise task may assist in identifying patients with early alterations in cerebral function.

Hemodialysis Effects on Autonomic Function: Results of Linear and Nonlinear Analysis of Heart Rate Variability at Rest and in Response to Physical and Mental Stress Tests.

INTRODUCTION: Cardiac arrhythmias are the most common cause of death in hemodialysis. Autonomic dysfunction plays a central role in this arrhythmogenic background. Previous studies on hemodialysis-related changes in heart rate variability (HRV) give contradictory results. This study investigated HRV indices both at rest and in response to physical and mental stimulation maneuvers at multiple time-points around and during the hemodialysis procedure. METHODS: Autonomic function was assessed by linear and nonlinear HRV indices at predialysis, during dialysis (3 equal time-periods), postdialysis, and on the nondialysis day in 36 hemodialysis patients. Continuous measurement of beat-by-beat heart rate was recorded with Finometer-PRO (The Netherlands) at rest and after orthostatic, sit-to-stand, handgrip, and mental-arithmetic test. RESULTS: The RMSSD, SD1, and SD2 indices significantly increased during dialysis (early-HD, mid-HD, late-HD periods) compared with the predialysis levels (p < 0.05) and returned to baseline postdialysis (RMSSD: 54.39 ± 83.73 vs. 137.98 ± 109.53* vs. 119.85 ± 97.34* vs. 144.47 ± 88.74* vs. 85.82 ± 121.43msec, *p < 0.05 vs. predialysis and postdialysis). No differences were detected in the above indices between the predialysis and nondialysis day. However, postdialysis, the HRV responses to orthostatic and sit-to-stand tests were more exaggerated than in the predialysis measurements (p < 0.05). The HRV responses both at resting and physical tests in the nondialysis day were similar to the predialysis levels. HRV indices in the mental arithmetic test during hemodialysis were much higher than at the nondialysis day (RMSSD: 77.05 [180.41] versus 19.75 [105.47] msec; p = 0.031). CONCLUSIONS: Hemodialysis causes marked changes in the autonomic function. Resting HRV indices return to baseline postdialysis, but HRV responses to physical stress remain exaggerated and return to baseline on the nondialysis day. Detecting patients with significant autonomic dysfunction may help towards reduction of arrhythmia risk through individualized approaches.

Muscle Oxygenation, Neural, and Cardiovascular Responses to Isometric and Workload-matched Dynamic Resistance Exercise.

Differences in blood flow patterns and energy cost between isometric and dynamic resistance exercise may result to variant cardiovascular, neural, and muscle metabolic responses. We aimed to compare the cardiovascular, baroreceptor sensitivity, and muscle oxygenation responses between workload-matched, large muscle-mass isometric and dynamic resistance exercises. Twenty-four young men performed an isometric and a dynamic double leg-press protocol (4 sets×2 min) with similar tension time index (workload). Beat-by-beat hemodynamics, baroreceptor sensitivity, muscle oxygenation, and blood lactate were assessed. The increase in blood pressure was greater (p<0.05) in the 1st set during dynamic than isometric exercise (by ~4.5 mmHg), not different in the 2nd and 3rd sets, and greater in the 4th set during isometric exercise (by ~5 mmHg). Dynamic resistance exercise evoked a greater increase in heart rate, stroke volume, cardiac output, and contractility index (p<0.05), and a greater decline in peripheral resistance, baroreceptor sensitivity, and cardiac function indices than isometric exercise (p<0.05). Participants exhibited a greater reduction in muscle oxyhemoglobin and a greater increase in muscle deoxyhemoglobin in dynamic versus isometric exercise (p<0.001-0.05), with no differences in total hemoglobin and blood lactate. In conclusion, large muscle-mass, multiple-set isometric exercise elicits a relatively similar blood pressure but blunted cardiovascular and baroreceptor sensitivity responses compared to workload-matched dynamic resistance exercise. Differences in blood pressure responses between protocols appear small (~5 mmHg) and are affected by the number of sets. The muscle oxidative stimulus is greater during dynamic resistance exercise than workload-matched isometric exercise.

Brain oxygenation during multiple sets of isometric and dynamic resistance exercise of equivalent workloads: Association with systemic haemodynamics.

Brain function relies on sufficient blood flow and oxygen supply. Changes in cerebral oxygenation during exercise have been linked to brain activity and central command. Isometric- and dynamic-resistance exercise-(RE) may elicit differential responses in systemic circulation, neural function and metabolism; all important regulators of cerebral circulation. We examined whether (i) cerebral oxygenation differs between isometric- and dynamic-RE of similar exercise characteristics and (ii) cerebral oxygenation changes relate to cardiovascular adjustments occurring during RE. Fourteen men performed, randomly, an isometric-RE and a dynamic-RE of similar characteristics (bilateral-leg-press, 2-min×4-sets, 30% of maximal-voluntary-contraction, equivalent tension-time-index/workload). Cerebral-oxygenation (oxyhaemoglobin-O2Hb; total haemoglobin-tHb/blood-volume-index; deoxyhemoglobin-HHb) was assessed by NIRS and beat-by-beat haemodynamics via photoplethysmography. Cerebral-O2Hb and tHb progressively increased from the 1st to 4th set in both RE-protocols (p < 0.05); HHb slightly decreased (p < 0.05). Changes in NIRS-parameters were similar between RE-protocols within each exercise-set (p = 0.91-1.00) and during the entire protocol (including resting-phases) (p = 0.48-0.63). O2Hb and tHb changes were not correlated with changes in systemic haemodynamics. In conclusion, cerebral oxygenation/blood-volume steadily increased during multiple-set RE-protocols. Isometric- and dynamic-RE of matched exercise characteristics resulted in similar prefrontal oxygenation/blood volume changes, suggesting similar cerebral haemodynamic and possibly neuronal responses to maintain a predetermined force.

Skin microvascular dysfunction in systemic lupus erythematosus patients with and without cardiovascular risk factors.

OBJECTIVES: Patients with SLE have increased cardiovascular mortality. Alterations in both macro- and micro-circulation have been associated with cardiovascular disease. We sought to assess skin microvascular function by using laser speckle contrast analysis (LASCA) in patients with SLE, with and without cardiovascular disease and risk factors. METHODS: Continuous blood flow was recorded using a LASCA device during baseline, a 5-min arterial occlusion and a 5-min reperfusion period. RESULTS: Thirty-five patients with SLE (85.7% women) with a median disease duration 12.0 (6.5-17.5) years and a mean age of 46.3 (8.6) years and 31 controls matched for age, sex and BMI were enrolled. During reperfusion, SLE patients exhibited a smaller peak magnitude compared with controls (161.0 (47.1) vs 197.2 (41.4)%, respectively, P =0.002). Results remained unchanged among 24 SLE patients without cardiovascular disease compared with the control group (169.2 (48.1) vs 195.6 (34.0)%, respectively, P =0.002). CONCLUSION: Our study shows, for the first time, that patients with SLE, even without overt cardiovascular disease or risk factors, exhibit a blunted microvascular reactivity during reperfusion compared with controls. These results show that skin microvascular dysfunction is present in SLE independently of the CV burden that these patients bear and may represent an early sign of vascular damage.

Εndothelial and microvascular function in CKD: Evaluation methods and associations with outcomes.

BACKGROUND: Cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Endothelial dysfunction, the hallmark of atherosclerosis, is suggested to be involved pathogenetically in cardiovascular and renal disease progression in these patients. METHODS: This is a narrative review presenting the techniques and markers used for assessment of microvascular and endothelial function in patients with CKD and discussing findings of the relevant studies on the associations of endothelial dysfunction with co-morbid conditions and outcomes in this population. RESULTS: Venous Occlusion Plethysmography was the first method to evaluate microvascular function; subsequently, several relevant techniques have been developed and used in patients with CKD, including brachial Flow-Mediated Dilatation, and more recently, Near-Infrared Spectroscopy and Laser Speckle Contrast Analysis. Furthermore, several circulating biomarkers are commonly used in clinical research. Studies assessing endothelial function using the above techniques and biomarkers suggest that endothelial dysfunction occurs early in CKD and contributes to the target organ damage, cardiovascular events, death and progression towards end-stage kidney disease. CONCLUSIONS: Older and newer functional methods and several biomarkers have assessed endothelial dysfunction in CKD; accumulated evidence supports an association of endothelial dysfunction with outcomes. Future research with new, non-invasive and easily applicable methods could further delineate the role of endothelial dysfunction on cardiovascular and renal disease progression in patients with CKD.

Cardiorespiratory fitness in kidney transplant recipients compared to patients with kidney failure: a systematic review and meta-analysis.

Patients with kidney failure often present with reduced cardiovascular functional reserve and exercise tolerance. Previous studies on cardiorespiratory fitness examined with cardiopulmonary exercise testing (CPET) in kidney transplant recipients (KTR) had variable results. This is a systematic review and meta-analysis of studies examining cardiovascular functional reserve with CPET in KTR in comparison with patients with kidney failure (CKD-Stage-5 before dialysis, hemodialysis or peritoneal dialysis), as well as before and after kidney transplantation. Literature search involved PubMed, Web-of-Science and Scopus databases, manual search of article references and grey literature. From a total of 4,944 identified records, eight studies (with 461 participants) were included in quantitative analysis for the primary question. Across these studies, KTR had significantly higher oxygen consumption at peak/max exercise (VO2 peak/VO2 max) compared to patients with kidney failure (SMD = 0.70, 95% CI [0.31, 1.10], I2  = 70%, P = 0.002). In subgroup analyses, similar differences were evident among seven studies comparing KTR and hemodialysis patients (SMD = 0.64, 95% CI [0.16, 1.12], I2  = 65%, P = 0.009) and two studies comparing KTR with peritoneal dialysis subjects (SMD = 1.14, 95% CI [0.19, 2.09], I2  = 50%, P = 0.16). Across four studies with relevant data, oxygen consumption during peak/max exercise showed significant improvement after kidney transplantation compared to pretransplantation values (WMD = 2.43, 95% CI [0.01, 4.85], I2  = 68%, P = 0.02). In conclusion, KTR exhibit significantly higher cardiovascular functional reserve during CPET compared to patients with kidney failure. Cardiovascular reserve is significantly improved after kidney transplantation in relation to presurgery levels.

Exertional Desaturation in Idiopathic Pulmonary Fibrosis: The Role of Oxygen Supplementation in Modifying Cerebral-Skeletal Muscle Oxygenation and Systemic Hemodynamics.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown. OBJECTIVES: To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics. METHODS: In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored. RESULTS: In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 µmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. -1.7 ± 2.0 µmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance. CONCLUSIONS: IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients.

Measurement and Changes in Cerebral Oxygenation and Blood Flow at Rest and During Exercise in Normotensive and Hypertensive Individuals.

PURPOSE OF REVIEW: Summarize the methods used for measurement of cerebral blood flow and oxygenation; describe the effects of hypertension on cerebral blood flow and oxygenation. RECENT FINDINGS: Information regarding the effects of hypertension on cerebrovascular circulation during exercise is very limited, despite a plethora of methods to help with its assessment. In normotensive individuals performing incremental exercise testing, total blood flow to the brain increases. In contrast, the few studies performed in hypertensive patients suggest a smaller increase in cerebral blood flow, despite higher blood pressure levels. Endothelial dysfunction and increased vasoconstrictor concentration, as well as large vessel atherosclerosis and decreased small vessel number, have been proposed as the underlying mechanisms. Hypertension may adversely impact oxygen and blood delivery to the brain, both at rest and during exercise. Future studies should utilize the newer, noninvasive techniques to better characterize the interplay between the brain and exercise in hypertension.

Dietary nitrate improves muscle microvascular reactivity and lowers blood pressure at rest and during isometric exercise in untreated hypertensives.

OBJECTIVE: This double-blind, cross-over study examined in drug-naïve hypertensives the effects of a single dose of dietary nitrate (beetroot juice, BRJ) on (a) office/ambulatory BP and arterial stiffness, (b) muscle microvascular function, and (c) hemodynamic responses and cardiovagal baroreceptor sensitivity (cBRS) at rest and during isometric exercise. METHODS: Eighteen untreated hypertensives (44.0 ± 2.6 years) consumed randomly, a nitrate-rich (8.1 mmol-BRJnitrate ) and a nitrate-depleted (BRJplacebo ) BRJ. Office BP and pulse wave velocity were assessed before/after BRJ. An occlusion-reperfusion maneuver with continuous monitoring of muscle oxygenated hemoglobin (O2 Hb) and total hemoglobin (tHb), via NIRS, followed. Participants performed submaximal isometric handgrip with beat-by-beat monitoring of hemodynamics and cBRS. Ambulatory BP assessment followed. RESULTS: During reperfusion, following arterial occlusion, the magnitude and rate of muscle microvascular reoxygenation (O2 Hb) and red blood cell content (tHb) were higher in BRJnitrate vs BRJplacebo (P < 0.05), suggesting improved microvascular reactivity. Office/ambulatory BP were lower following BRJnitrate vs BRJplacebo (P < 0.05); pulse-wave-velocity was not altered. During isometric handgrip, BP and peripheral resistance rise were smaller in BRJnitrate vs BRJplacebo (P < 0.01-0.05), with no differences in cBRS. CONCLUSIONS: In drug-naïve hypertensives, a single dose of BRJ induces (a) short-term reductions in resting/ambulatory BP, (b) acute improvements in muscle microvascular function, and (c) attenuation in BP and peripheral resistance responses during isometric exercise.

Beetroot Increases Muscle Performance and Oxygenation During Sustained Isometric Exercise, but Does Not Alter Muscle Oxidative Efficiency and Microvascular Reactivity at Rest.

OBJECTIVE: To examine the effects of beetroot juice (BRJ) on (i) in vivo skeletal muscle O2 consumption (mVO2) and microvascular reactivity at rest and (ii) muscle performance, muscle oxygenation, and mVO2 during sustained isometric handgrip exercise (IHG). METHODS: Sixteen young males consumed, randomly, a nitrate-rich (8.1 mmol BRJnitrate) or nitrate-depleted (BRJplacebo) BRJ. After 2.5 hours, they performed an occlusion-reperfusion maneuver at rest, a 3-minute sustained IHG, and a sustained IHG to exhaustion with arterial occlusion. Changes in muscle oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), microvascular red blood cell content (tHb), and mVO2 were measured using near-infrared spectroscopy. Force output was recorded. RESULTS: During occlusion, the O2Hb decline did not differ between BRJnitrate and BRJplacebo (magnitude: -30.3 ± 1.6 vs. -31.1 ± 1.5 ΔµΜ; slope: -0.107 ± 0.007 vs. -0.111 ± 0.007 µΜ second-1). During reperfusion, all microvascular reactivity indices were not altered after BRJnitrate (e.g., O2Hbslope: 1.584 ± 0.093 vs. 1.556 ± 0.072 µΜ second-1). During the second and third minute of IHG, O2Hb and tHb were higher in BRJnitrate versus BRJplacebo (p < 0.05), and force output was higher during the third minute (10.8 ± 0.7 vs. 9.5 ± 1.2 kg; p < 0.05); HHb did not differ between trials. In IHG with arterial occlusion, BRJnitrate prolonged the time to fatigue (94.1 ± 5.8 vs. 80.1 ± 3.3 seconds; p < 0.01), with no effects on O2Hb decline (O2Hbslope: -0.226 ± 0.015 vs. -0.230 ± 0.026 µΜ s-1) and mVO2 (14.1 ± 1.0 vs. 14.3 ± 1.6 µmol l-1 minute-1). CONCLUSION: Acute BRJ ingestion in moderately trained individuals (i) did not alter in vivo skeletal muscle microvascular reactivity (index of microvascular function at rest) and basal oxidative efficiency, (ii) increased muscle oxygenation during IHG (possibly via enhanced O2 delivery), and (iii) provided ergogenic benefits during sustained IHG with no effects on muscle oxidative efficiency. The ergogenic effects of BRJ appeared independent of its tissue perfusion benefits.

Amiodarone plus Ranolazine for Conversion of Post-Cardiac Surgery Atrial Fibrillation: Enhanced Effectiveness in Reduced Versus Preserved Ejection Fraction Patients.

PURPOSE: Ranolazine (RAN) added to amiodarone (AMIO) has been shown to accelerate termination of postoperative atrial fibrillation (POAF) following coronary artery bypass surgery in patients without heart failure (HF). This study aimed to investigate if treatment efficacy with AMIO or AMIO + RAN differs between patients with concomitant HF with reduced or preserved ejection fraction (HFrEF or HFpEF). METHODS: Patients with POAF and HFrEF (n = 511, 446 males; 65 ± 9 years) and with HFpEF (n = 301, 257 males; 66 ± 10 years) were enrolled. Onset of AF occurred 2.15 ± 1.0 days after cardiac surgery, and patients within each group were randomly assigned to receive either AMIO monotherapy (300 mg in 30 min + 1125 mg in 36 h iv) or AMIO+RAN combination (500 mg po + 375 mg, after 6 h and 375 mg twice daily thereafter). Primary endpoint was the time to conversion of POAF within 36 h after initiation of treatment. RESULTS: AMIO restored sinus rhythm earlier in HFrEF vs. in HFpEF patients (24.3 ± 4.6 vs. 26.8 ± 2.8 h, p < 0.0001). AMIO + RAN converted POAF faster than AMIO alone in both HFrEF and HFpEF groups, with conversion times 10.4 ± 4.5 h in HFrEF and 12.2 ± 1.1 h in HFpEF patients (p < 0.0001). Left atrial diameter was significantly greater in HFrEF vs. HFpEF patients (48.2 ± 2.6 vs. 35.2 ± 2.9 mm, p < 0.0001). No serious adverse drug effects were observed during AF or after restoration to sinus rhythm in any of the patients enrolled. CONCLUSION: AMIO alone or in combination with RAN converted POAF faster in patients with reduced EF than in those with preserved EF. Thus, AMIO + RAN seems to be a valuable alternative treatment for terminating POAF in HFrEF patients.

Impairments in microvascular function and skeletal muscle oxygenation in women with gestational diabetes mellitus: links to cardiovascular disease risk factors.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a risk factor for the development of endothelial dysfunction and cardiovascular disease. However, in vivo microvascular endothelial function in GDM has not been investigated. This study aimed to examine, using near-infrared spectroscopy (NIRS), whether: (1) there are differences in microvascular reactivity and skeletal muscle oxygen consumption (m[Formula: see text]) at rest and during exercise between GDM and uncomplicated pregnancies; and (2) there is an association of NIRS indices with macrovascular function and cardiovascular disease risk factors. METHODS: Twenty-nine pregnant women (13 with GDM and 16 women with uncomplicated pregnancy, 28 ± 2 gestational weeks) underwent arterial stiffness (pulse wave velocity [PWV]) and 24 h ambulatory BP (24 h BP) evaluation. NIRS continuously monitored, non-invasively, changes in muscle oxygenated and deoxygenated haemoglobin and tissue O2 saturation index (TSI, %) during arterial occlusion/reperfusion and intermittent handgrip exercise. m[Formula: see text] and vascular reactivity indices were calculated. RESULTS: During occlusion and reperfusion, women with GDM exhibited slower TSI response (occlusion slope: -0.06 ± 0.02 vs -0.10 ± 0.04, in GDM and controls, respectively; reperfusion slope: 0.65 ± 0.26 vs 1.05 ± 0.41, respectively), lower m[Formula: see text] (1.3 ± 1.2 vs 3.8 ± 2.3 µmol l-1 min-1) and blunted hyperaemia (ΔTSI 6.8 ± 2.9 vs 9.5 ± 3.4) compared with controls (p < 0.01). Despite similar handgrip strength in the GDM and control groups (29.1 ± 8.1 vs 26.2 ± 10.4 kg, respectively), during repeated forearm contractions, women with GDM presented a blunted TSI response (6.5 ± 3.9 vs 19.2 ± 10.9; p < 0.01) and a reduced capacity to maintain the predetermined handgrip (23.4 ± 2.9 vs 27.4 ± 3.8%, p < 0.05). NIRS indices correlated with PWV, 24 h BP and blood glucose concentration earlier in pregnancy (r = 0.40-0.60; p < 0.05). CONCLUSIONS/INTERPRETATION: Women with GDM exhibited a characteristic blunted TSI curve, showing alterations in muscle oxygenation and microvascular responsiveness compared with women with uncomplicated pregnancies. These alterations were manifested during exercise and possibly contribute to the reduced exercise tolerance in GDM. NIRS indices correlated with macrovascular indices (arterial stiffness) and 24 h BP.

Global Metabolic Stress of Isoeffort Continuous and High Intensity Interval Aerobic Exercise: A Comparative 1H NMR Metabonomic Study.

The overall metabolic/energetic stress that occurs during an acute bout of exercise is proposed to be the main driving force for long-term training adaptations. Continuous and high-intensity interval exercise protocols (HIIE) are currently prescribed to acquire the muscular and metabolic benefits of aerobic training. We applied 1H NMR-based metabonomics to compare the overall metabolic perturbation and activation of individual bioenergetic pathways of three popular aerobic exercises matched for effort/strain. Nine men performed continuous, long-interval (3 min), and short-interval (30 s) bouts of exercise under isoeffort conditions. Blood was collected before and after exercise. The multivariate PCA and OPLS-DA models showed a distinct separation of pre- and postexercise samples in three protocols. The two models did not discriminate the postexercise overall metabolic profiles of the three exercise types. Analysis focused on muscle bioenergetic pathways revealed an extensive upregulation of carbohydrate-lipid metabolism and the TCA cycle in all three protocols; there were only a few differences among protocols in the postexercise abundance of molecules when long-interval bouts were performed. In conclusion, continuous and HIIE exercise protocols, when performed with similar effort/strain, induce comparable global metabolic response/stress despite their marked differences in work-bout intensities. This study highlights the importance of NMR metabonomics in comprehensive monitoring of metabolic consequences of exercise training in the blood of athletes and exercising individuals.

Exaggerated haemodynamic and neural responses to involuntary contractions induced by whole-body vibration in normotensive obese versus lean women.

What is the central question of this study? In obesity, the exaggerated blood pressure response to voluntary exercise is linked to hypertension, yet the mechanisms are not fully elucidated. We examined whether involuntary contractions elicit greater haemodynamic responses and altered neural control of blood pressure in normotensive obese versus lean women. What is the main finding and its importance? During involuntary contractions induced by whole-body vibration, there were augmented blood pressure and spontaneous baroreflex responses in obese compared with lean women. This finding is suggestive of an overactive mechanoreflex in the exercise-induced hypertensive response in obesity. Passive contractions did not elicit differential heart rate responses in obese compared with lean women, implying other mechanisms for the blunted heart rate response reported during voluntary exercise in obesity. In obesity, the exaggerated blood pressure (BP) response to exercise is linked to hypertension, yet the mechanisms are not fully elucidated. In this study, we examined whether involuntary mechanical oscillations, induced by whole-body vibration (WBV), elicit greater haemodynamic responses and altered neural control of BP in obese versus lean women. Twenty-two normotensive, premenopausal women (12 lean and 10 obese) randomly underwent a passive WBV (25 Hz) and a control protocol (similar posture without WVB). Beat-by-beat BP, heart rate, stroke volume, systemic vascular resistance, cardiac output, parasympathetic output (evaluated by heart rate variability) and spontaneous baroreceptor sensitivity (sBRS) were assessed. We found that during WBV, obese women exhibited an augmented systolic BP response compared with lean women that was correlated with body fat percentage (r = 0.77; P < 0.05). The exaggerated BP rise was driven mainly by the greater increase in cardiac output index in obese versus lean women, associated with a greater stroke volume index in obese women. Involuntary contractions did not elicit a differential magnitude of responses in heart rate, heart rate variability indices and systemic vascular resistance in obese versus lean women; however, they did result in greater sBRS responses (P < 0.05) in obese women. In conclusion, involuntary contractions elicited an augmented BP and sBRS response in normotensive obese versus lean women. The greater elevations in circulatory haemodynamics in obese women are suggestive of an overactive mechanoreflex in the exercise-induced hypertensive response in obesity.

Low vitamin C values are linked with decreased physical performance and increased oxidative stress: reversal by vitamin C supplementation.

PURPOSE: It has been suggested that part of the failure of antioxidant supplementation to reduce oxidative stress and promote health is that it has been administered in humans with normal levels of antioxidants. METHODS: To test this hypothesis, we screened 100 males for vitamin C baseline values in blood. Subsequently, the 10 individuals with the lowest and the 10 with the highest vitamin C values were assigned in two groups. Using a placebo-controlled crossover design, the 20 selected subjects performed aerobic exercise to exhaustion (oxidant stimulus) before and after vitamin C supplementation for 30 days. RESULTS: The low vitamin C group had lower VO2max values than the high vitamin C group. Vitamin C supplementation in this group marginally increased VO2max. Baseline concentration of F2-isoprostanes and protein carbonyls was higher in the low vitamin C group compared to the high vitamin C group. Vitamin C supplementation decreased the baseline concentration of F2-isoprostanes and protein carbonyls in both groups, yet the decrease was greater in the low vitamin C group. Before vitamin C supplementation, F2-isoprostanes and protein carbonyls were increased to a greater extent after exercise in the high vitamin C group compared to the low vitamin C group. Interestingly, after vitamin C supplementation, this difference was narrowed. CONCLUSION: We show for the first time that low vitamin C concentration is linked with decreased physical performance and increased oxidative stress and that vitamin C supplementation decreases oxidative stress and might increase exercise performance only in those with low initial concentration of vitamin C.

The rat closely mimics oxidative stress and inflammation in humans after exercise but not after exercise combined with vitamin C administration.

PURPOSE: The purpose of the present study was to directly compare oxidative stress and inflammation responses between rats and humans. METHODS: We contrasted rat and human oxidative stress and inflammatory responses to exercise (pro-oxidant stimulus) and/or vitamin C (anti-oxidant stimulus) administration. Vitamin C was administered orally in both species (16 mg kg(-1) of body weight). Twelve redox biomarkers and seven inflammatory biomarkers were determined in plasma and erythrocytes pre- and post-exercise or pre- and post-exercise combined with vitamin C administration. RESULTS: Exercise increased oxidative stress and induced an inflammatory state in rats and humans. There were only 1/19 significant species × exercise interactions (catalase), indicating similar responses to exercise between rats and humans in redox and inflammatory biomarkers. Vitamin C decreased oxidative stress and increased antioxidant capacity only in humans and did not affect the redox state of rats. In contrast, vitamin C induced an anti-inflammatory state only in rats and did not affect the inflammatory state of humans. There were 10/19 significant species × vitamin C interactions, indicating that rats poorly mimic human oxidative stress and inflammatory responses to vitamin C administration. Exercise after acute vitamin C administration altered redox state only in humans and did not affect the redox state of rats. On the contrary, inflammation biomarkers changed similarly after exercise combined with vitamin C in both rats and humans. CONCLUSIONS: The rat adequately mimics human responses to exercise in basic blood redox/inflammatory profile, yet this is not the case after exercise combined with vitamin C administration.