Exercise Hyperemia Research Articles

The Efficacy Of Statin Administration On Vascular Function And Exercise Hyperemia In Patients With Heart Failure With Preserved Ejection Fraction

The Efficacy Of Statin Administration On Vascular Function And Exercise Hyperemia In Patients With Heart Failure With Preserved Ejection Fraction

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed. This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001). Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects. As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Muscle Blood Flow and Vasodilation are Blunted at the Onset of Exercise Following an Acute Bout of Ischemia-Reperfusion.

Ischemia-reperfusion injury (I/R) can inhibit endothelial function and impair nitric oxide bioavailability. We tested the hypothesis that I/R also blunts the rapid and steady-state hyperemic and vasodilatory response to handgrip exercise. Ten subjects (8M/2F; 24±4yr) performed handgrip exercises before and after I/R (20 min of ischemia/20 min of reperfusion) and time control (40 min supine rest) trials. Forearm blood flow (FBF) and vascular conductance (FVC) were assessed with Doppler ultrasound during single forearm contractions and 3 min of rhythmic handgrip exercise. Venous blood samples were drawn at rest and during exercise to assess plasma [nitrite]. Peak ΔFBF (from baseline) and ΔFVC following single contractions were attenuated following I/R (134±48 vs. 103±42 ml·min-1; 160±55 vs. 118±48 ml·min-1·100 mmHg-1, P<0.05 for both) but not following time control (115±63 vs. 124±57 ml·min-1; 150±80 vs. 148±64 ml·min-1·100 mmHg-1, P=0.16 and P=0.95, respectively). Steady-state ΔFBF and ΔFVC during rhythmic exercise were unchanged in both I/R (192 ± 52 vs. 190±53 ml·min-1; 208±56 vs. 193±60 ml·min-1·100 mmHg-1) and time control (188±54 vs. 196±48 ml·min-1; 206±60 vs. 207±49 ml·min-1·100 mmHg-1) trials (group x time interactions P=0.34 and 0.21, respectively). Plasma [nitrite] under resting conditions and during steady-steady state rhythmic exercise was attenuated following I/R (P<0.05 for both) but not time control (P=0.54 and 0.93). These data indicate I/R blunts hyperemia and vasodilation at the onset of muscle contractions but does not attenuate these responses during steady-state exercise.

Lower limb hyperthermia augments functional hyperaemia during small muscle mass exercise similarly in trained elderly and young humans.

What is the central question of the study? Ageing is postulated to lead to underperfusion of human limb tissues during passive and exertional hyperthermia, but findings to date have been equivocal. Thus, does age have an independent adverse effect on local haemodynamics during passive single-leg hyperthermia, single-leg knee-extensor exercise and their combination? What is the main finding and its importance? Local hyperthermia increased leg blood flow over three-fold and had an additive effect during knee-extensor exercise with no absolute differences in leg perfusion between the healthy, exercise-trained elderly and the young groups. Our findings indicate that age per se does not compromise lower limb hyperaemia during local hyperthermia and/or small muscle mass exercise. Heat and exercise therapies are recommended to improve vascular health across the lifespan. However, the haemodynamic effects of hyperthermia, exercise and their combination are inconsistent in young and elderly people. Here we investigated the acute effects of local-limb hyperthermia and exercise on limb haemodynamics in nine healthy, trained elderly (69±5 years) and 10 young (26±7 years) adults, hypothesising that the combination of local hyperthermia and exercise interact to increase leg perfusion, albeit to a lesser extent in the elderly. Participants underwent 90min of single whole-leg heating, with the contralateral leg remaining as control, followed by 10min of low-intensity incremental single-leg knee-extensor exercise with both the heated and control legs. Temperature profiles and leg haemodynamics at the femoral and popliteal arteries were measured. In both groups, heating increased whole-leg skin temperature and blood flow by 9.5±1.2°C and 0.7±0.2Lmin-1 (>3-fold), respectively (P<0.0001). Blood flow in the heated leg remained 0.7±0.6 and 1.0±0.8Lmin-1 higher during exercise at 6 and 12W, respectively (P<0.0001). However, there were no differences in limb haemodynamics between cohorts, other than the elderly group exhibiting a 16±6% larger arterial diameter and a 51±6% lower blood velocity following heating (P<0.0001). In conclusion, local hyperthermia-induced limb hyperperfusion and/or small muscle mass exercise hyperaemia are preserved in trained older people despite evident age-related structural and functional alterations in their leg conduit arteries.

Effect of home-based heat therapy on skeletal muscle blood flow during exercise in older adults

The arterial vasculature undergoes profound changes across the lifespan. This vascular aging manifests as structural (e.g., vascular rarefaction) and functional (e.g., endothelial dysfunction) maladaptations. These age-related maladaptations contribute to the hypo-perfusion of skeletal muscle during conditions that require an elevated blood supply and substrate delivery (e.g., exercise) by tipping the vasoactive balance in favor of vasoconstriction. Acute heat exposure increases body and tissue temperature, increases blood flow and shear stress throughout the arterial tree, and initiates a humoral response. Importantly, chronic exposure to these temperature-dependent stimuli may reverse age-related vascular dysfunction, thereby improving perfusion of active skeletal muscle (i.e., exercise hyperemia). However, the effect of chronic heat therapy on exercise hyperemia has never been explored. Therefore, the purpose of this pilot study was to test the hypothesis that home-based heat therapy would increase skeletal muscle blood flow in older adults performing plantar flexion exercise. Six older adults (5 women; 67 ± 4 years) performed graded (5, 9, and 14 kg) unilateral dynamic plantar flexion exercise before (pre) and after (post) 8 weeks of home-based heat therapy. Each session of heat therapy required participants to immerse their lower legs ~33 cm into a heated (~ 42°C) and circulated water bath 4 days per week, for 45 min per session. Dynamic plantar flexion exercise was performed using a duty cycle of 1 s contraction and 2 s relaxation. Superficial femoral artery blood velocity and diameter were measured via Duplex ultrasonography and used to calculate the change in blood flow measured from baseline to each stage of exercise. Vascular conductance was calculated as flow/pressure. The change in leg blood flow during exercise was increased following heat therapy ( P = 0.08 for main effect of time), an effect that was mediated by augmented vascular conductance (5 kg: pre, Δ143 ± 89 ml/min/mmHg vs post, Δ188 ± 89 ml/min/mmHg; 9 kg: pre, Δ225 ± 89 ml/min/mmHg vs post, Δ234 ± 89 ml/min/mmHg; 14 kg: pre, Δ264 ± 89 ml/min/mmHg vs post, Δ290 ± 89 ml/min/mmHg; P = 0.07). Our preliminary data suggest that home-based heat therapy increases skeletal muscle blood flow during exercise in older adults, and may serve as a pragmatic intervention to improve exercise and functional capacity in this population. Supported by: American Heart Association TPA958179 This is the full abstract presented at the American Physiology Summit 2023 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.

Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high-altitude.

Chronic exposure to hypoxia (high-altitude, HA; >4000m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (n=9) at sea-level (SL; 344 m) and following 21-28days at HA (∼4300m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF/MAP), and arterial and venous blood sampling (O2 delivery ( ) and uptake ( )) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local α- and β-adrenergic blockade (intra-arterial phentolamine and propranolol). HA reduced ΔFBF (25% MVC: SL: 138.3±47.6 vs. HA: 113.4±37.1mlmin-1 ; P=0.022) and Δ (25% MVC: SL: 20.3±7.5 vs. HA: 14.3±6.2mlmin-1 ; P=0.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SLα-β blockade : 164.1±71.7 vs. HAα-β blockade : 185.4±66.6mlmin-1 ; P=0.947) but resulted in an exaggerated relationship between and ( / slope: SL: 1.32; HA: slope: 1.86; P=0.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA. KEY POINTS: In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure. Exposure to chronic hypoxia (altitude, >4000m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise. In healthy male lowlanders exposed to chronic hypoxia (21-28days; ∼4300m), local adrenoreceptor blockade (combined α- and β-adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise. However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand. This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.

Rapid Onset Vasodilation: Impact of Cardiorespiratory Fitness

IntroductionHigher cardiorespiratory fitness is associated with greater vascular function that leads to improved regulation of skeletal muscle blood flow during exercise. Rapid onset vasodilation (ROV) describes the immediate increase in blood flow following a single contraction, which is integral to support greater blood flow during exercise. As such, blood flow regulation during exercise hyperemia is important. However, it is unclear if cardiorespiratory fitness plays a role in ROV of small muscle mass in young, healthy individuals.PurposeTo investigate the relationship of cardiorespiratory fitness on ROV following a single handgrip (HG) contraction in young, healthy adults.MethodsCardiorespiratory fitness (VO2peak) was assessed during a maximal cycle ergometer test in 14 volunteers (M/F, 6/8; 28 ± 5yrs; 24.8 ± 4.1kg/m2). Brachial velocity and diameter were measured using duplex Doppler ultrasound for 10 cardiac cycles prior to and 20 cardiac cycles following the first cardiac cycle after a single 30% of maximal voluntary handgrip contraction. Brachial artery blood flow (FBF) was calculated for each cardiac cycle: (diameter2/2)*π*velocity*60. Peak forearm (brachial) blood flow (FBFpeak) was determined as the maximal FBF from baseline following the first cardiac cycle after the single HG contraction. Time to peak blood flow response was determined as the time to reach FBFpeak and heart rate was measured using a three‐lead ECG. The relationship between FBFpeak and time to peak blood flow was tested using a multivariate regression analysis with cardiorespiratory fitness and sex as independent variables.ResultsCardiorespiratory fitness (VO2peak: 30.6 ± 8.0mL/kg/min); β for VO2peak= 0.162 [0.003, 0.327]) was the only predictor of time to peak blood flow response, F(1,12)= 4.602, p= 0.05, R2= 0.217, r= 0.526, while sex (β for time to peak= ‐106.5 [‐156.9, ‐56.2]) was the only predictor of FBFpeak, F(1,12)= 21.245, p&lt;0.001, R2= 0.609, r= 0.799, indicating that females had a lower FBFpeakoverall.ConclusionOur data suggests blood flow responsiveness (e.g., time to peak) is positively associated with cardiorespiratory fitness and these data contribute to our understanding of potential mechanisms between improved blood flow regulation commonly associated with greater cardiorespiratory fitness. More research is necessary to fully elucidate the role biological sex has on these relationships, but our data suggest there may be sex differences in certain blood flow responses.

Hypothetical Mechanism of Exercise-Induced Acute Kidney Injury Associated with Renal Hypouricemia.

Renal hypouricemia (RHUC) is a hereditary disease that presents with increased renal urate clearance and hypouricemia due to genetic mutations in the urate transporter URAT1 or GLUT9 that reabsorbs urates in the renal proximal tubule. Exercise-induced acute kidney injury (EIAKI) is known to be a complication of renal hypouricemia. In the skeletal muscle of RHUC patients during exhaustive exercise, the decreased release of endothelial-derived hyperpolarization factor (EDHF) due to hypouricemia might cause the disturbance of exercise hyperemia, which might increase post-exercise urinary urate excretion. In the kidneys of RHUC patients after exhaustive exercise, an intraluminal high concentration of urates in the proximal straight tubule and/or thick ascending limb of Henle’s loop might stimulate the luminal Toll-like receptor 4–myeloid differentiation factor 88–phosphoinositide 3-kinase–mammalian target of rapamycin (luminal TLR4–MyD88–PI3K–mTOR) pathway to activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and may release interleukin-1β (IL-1β), which might cause the symptoms of EIAKI.

Combined inorganic nitrate/nitrite supplementation blunts α-mediated vasoconstriction during exercise in patients with type 2 diabetes

AimsPatients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. MethodsForearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min−1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). ResultsΔFBF (156 ± 69 to 175 ± 73 ml min−1) and ΔFVC (130 ± 54 to 156 ± 63 ml min−1·100 mmHg−1, both P < 0.05) during exercise were augmented following BRA, but not BRP (P = 0.96 and 0.51). Phenylephrine-induced vasoconstriction during exercise was blunted following BRA (−17.1 ± 5.9 to −12.6 ± 3.1%, P < 0.01), but not BRP (P = 0.58) supplementation; the magnitude of sympatholysis was unchanged by either (beverage-by-time P = 0.15). BRA supplementation reduced dexmedetomidine-induced vasoconstriction during exercise (−23.3 ± 6.7 to −19.7 ± 5.2%) and improved the corresponding magnitude of sympatholysis (25.3 ± 11.4 to 34.4 ± 15.5%, both P < 0.05). ConclusionsBRA supplementation improves the hyperemic and vasodilatory responses to exercise in patients with T2DM which appears to be attributable to reduced α-adrenergic mediated vasoconstriction in contracting skeletal muscle.

Abstract MP27: Endothelial Nogo-B Modulates Ischemia Induced Collateral Artery Remodeling

Nogo-B, a member of the reticulon 4 family of proteins, is the dominant isoform expressed in endothelial cells (EC). We have shown that Nogo-B is necessary for blood flow recovery in ischemia. Mice lacking Nogo-B exhibit reduced arteriogenesis and angiogenesis that are linked to a decrease in macrophage infiltration and inflammatory gene expression in vivo. However, whether endothelial Nogo-B regulates arteriogenesis and/or angiogenesis is unknown. We generated an inducible EC-specific mouse overexpressing Nogo-B (Ng ECtg ) and investigated the arteriogenesis and angiogenesis in limb ischemia. Ischemia increased endothelial and serum Nogo-B expression. Blood flow recovery was markedly diminished after femoral artery ligation (FAL) in Ng ECtg compared to WT mice, in association with lower collateral density accessed by micro-CT arteriography. There was no reduction in capillary density or decrease in smooth muscle/pericyte and macrophage recruitment in Ng ECtg mice, suggesting EC Nogo-B overexpression regulates arteriogenesis but not angiogenesis. While Ng ECtg mice have normal number of native collateral artery, the early remodeling of the collateral artery was impaired after ischemia. Furthermore, in line with impaired remodeling, Ng ECtg mice have decreased functional (exercise) hyperemia response in the non-ischemic limb in vivo, and resistant arteries from Ng ECtg have diminished flow induced vasodilatation ex vivo compared to WT mice. Moreover, endothelial reconstitution of Nogo-B in global Nogo knockout background (NogoKO ECrc ) restored blood flow recovery after ischemia in vivo, further suggesting the EC specific function of Nogo-B in arteriogenesis. Mechanistically, we have shown that EC isolated from Ng ECtg mice have decreased nitric oxide release. Nogo-B overexpression negatively regulates eNOS phosphorylation, expression and golgi localization in EC. Future parabiosis study is warranted to elucidate the contribution of paracrine or EC intrinsic Nogo-B in modulating arteriogenesis and angiogenesis. In conclusion, our data showed for the first time that endothelial Nogo-B plays important roles in regulating collateral artery remodeling and blood flow through, at least in part, regulating NO bioavailability.

Aerobic High-Intensity Exercise Training Improves Cardiovascular Health in Older Post-menopausal Women.

The aim of this study was to determine the effect of a period of aerobic high intensity training on central- and peripheral cardiovascular parameters in older post-menopausal women. Eleven healthy post-menopausal (>10 years after menopause) women (mean age: 64 years; BMI: 25.3 kg m−2) completed an 8-week period of supervised, high intensity cycle training, with sessions conducted three times per week. Before and after the training period maximal oxygen uptake, body composition, popliteal artery flow mediated dilation, exercise hyperemia, arterial blood pressure, and plasma lipids were assessed. In addition, levels of estrogen related receptor α (ERRα) and vasodilator enzymes were determined in muscle biopsy samples. Training induced an 18% increase (P < 0.001) in maximal oxygen uptake. Plasma High-density lipoprotein (HDL) was higher (P < 0.05) after than before the training period. Fat mass was reduced (4.9%; P < 0.01), whereas lean body mass was unaltered. Mean arterial blood pressure was unchanged (91 vs. 88 mmHg; P = 0.058) with training. Training did not induce a change in popliteal flow mediated dilation. Exercise hyperemia at submaximal exercise was lower (P < 0.01; 11 and 4.6% at 10 and 16 W, respectively) after compared to before training. Muscle ERRα (~1.7-fold; P < 0.01) and eNOS (~1.4-fold; P < 0.05) were higher after the training intervention. The current study demonstrates that, in older post-menopausal women, a period of aerobic high intensity training effectively increases maximal oxygen uptake and improves the cardiovascular health profile, without a parallel improvement in conduit artery function.

Inorganic nitrate supplementation attenuates conduit artery retrograde and oscillatory shear in older adults.

Aging causes deleterious changes in resting conduit artery shear patterns and reduced blood flow during exercise partially attributable to reduced nitric oxide (NO). Inorganic nitrate increases circulating NO bioavailability and may, therefore, improve age-associated changes in shear rate as well as exercise hyperemia. Ten older adults (age: 67 ± 3 yr) consumed 4.03 mmol nitrate and 0.29 mmol nitrite (active) or devoid of both (placebo) daily for 4 wk in a randomized, double-blinded, crossover fashion. Brachial artery diameter (D) and blood velocity (Vmean) were measured via Doppler ultrasound at rest for the characterization of shear profile as well as during two handgrip exercise trials (4 and 8 kg) for calculation of forearm blood flow (Vmean × cross-sectional area, FBF) and conductance [FBF/mean arterial pressure, forearm vascular conductance (FVC)]. Plasma [nitrate] and [nitrite] increased following active (P < 0.05 for both) but not placebo (P = 0.68 and 0.40, respectively) supplementation. Neither mean nor antegrade shear rate changed following either supplement (beverage-by-time P = 0.14 and 0.21, respectively). Retrograde (-13.4 ± 7.0 to -9.7 ± 6.8·s-1) and oscillatory (0.20 ± 0.08 to 0.15 ± 0.09 A.U., P < 0.05 for both) shear decreased following active, but not placebo (P = 0.81 and 0.70, respectively), supplementation. The FBF response (Δ from rest) to neither 4-kg nor 8-kg trials changed following either supplement (beverage-by-time P = 0.53 and 0.11, respectively). Similarly, no changes were observed in FVC responses to 4-kg or 8-kg trials (beverage-by-time P = 0.23 and 0.07, respectively). These data indicate that inorganic nitrate supplementation improves conduit artery shear profiles, but not exercise hyperemia, in older adults.NEW & NOTEWORTHY We report for the first time, to our knowledge, that 4 wk of inorganic nitrate supplementation attenuates retrograde and oscillatory shear in the brachial artery of older adults. However, this was not associated with greater hyperemic or vasodilatory responses to exercise. In sum, these data highlight favorable changes in shear patterns with aging, which may reduce the risk of atherosclerotic cardiovascular disease.

Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese-HFpEF.

Key points Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored.Here we report that obese‐HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation.We also demonstrate that obese‐HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation – atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres.These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches. Peripheral skeletal muscle and vascular alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly identified, with limited therapeutic targets. This study used a cardiometabolic obese‐HFpEF rat model to comprehensively phenotype skeletal muscle mechanics, blood flow, microvasculature and fibre atrophy. Lean (n = 8) and obese‐HFpEF (n = 8) ZSF1 rats were compared. Skeletal muscles (soleus and diaphragm) were assessed for in vitro contractility (isometric and isotonic properties) alongside indices of fibre‐type cross‐sectional area, myosin isoform, and capillarity, and estimated muscle PO2. In situ extensor digitorum longus (EDL) contractility and femoral blood flow were assessed. HFpEF soleus demonstrated lower absolute maximal force by 22%, fibre atrophy by 24%, a fibre‐type shift from I to IIa, and a 17% lower capillary‐to‐fibre ratio despite increased capillary density (all P < 0.05) with preserved muscle PO2 (P = 0.115) and isometric specific force (P > 0.05). Soleus isotonic properties (shortening velocity and power) were impaired by up to 17 and 22%, respectively (P < 0.05), while the magnitude of the exercise hyperaemia was attenuated by 73% (P = 0.012) in line with higher muscle fatigue by 26% (P = 0.079). Diaphragm alterations (P < 0.05) included Type IIx fibre atrophy despite Type I/IIa fibre hypertrophy, with increased indices of capillarity alongside preserved contractile properties during isometric, isotonic, and cyclical contractions. In conclusion, obese‐HFpEF rats demonstrated blunted skeletal muscle blood flow during contractions in parallel to microvascular structural remodelling, fibre atrophy, and isotonic contractile dysfunction in the locomotor muscles. In contrast, diaphragm phenotype remained well preserved. This study identifies numerous muscle‐specific impairments that could exacerbate exercise intolerance in obese‐HFpEF.

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Cardiovascular responses to rhythmic handgrip exercise in heart failure with preserved ejection fraction.

Although the contribution of noncardiac complications to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) have been increasingly recognized, disease-related changes in peripheral vascular control remain poorly understood. We utilized small muscle mass handgrip exercise to concomitantly evaluate exercising muscle blood flow and conduit vessel endothelium-dependent vasodilation in individuals with HFpEF (n = 25) compared with hypertensive controls (HTN) (n = 25). Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), brachial artery blood velocity, and brachial artery diameter were assessed during progressive intermittent handgrip (HG) exercise [15-30-45% maximal voluntary contraction (MVC)]. Forearm blood flow (FBF) and vascular conductance (FVC) were determined to quantify the peripheral hemodynamic response to HG exercise, and changes in brachial artery diameter were evaluated to assess endothelium-dependent vasodilation. HR, SV, and CO were not different between groups across exercise intensities. However, although FBF was not different between groups at the lowest exercise intensity, FBF was significantly lower (20-40%) in individuals with HFpEF at the two higher exercise intensities (30% MVC: 229 ± 8 versus 274 ± 23 ml/min; 45% MVC: 283 ± 17 versus 399 ± 34 ml/min, HFpEF versus HTN). FVC was not different between groups at 15 and 30% MVC but was ∼20% lower in HFpEF at the highest exercise intensity. Brachial artery diameter increased across exercise intensities in both HFpEF and HTN, with no difference between groups. These findings demonstrate an attenuation in muscle blood flow during exercise in HFpEF in the absence of disease-related changes in central hemodynamics or endothelial function.NEW & NOTEWORTHY The current study identified, for the first time, an attenuation in exercising muscle blood flow during handgrip exercise in individuals with heart failure with preserved ejection fraction (HFpEF) compared with overweight individuals with hypertension, two of the most common comorbidities associated with HFpEF. These decrements in exercise hyperemia cannot be attributed to disease-related changes in central hemodynamics or endothelial function, providing additional evidence for disease-related vascular dysregulation, which may be a predominant contributor to exercise intolerance in individuals with HFpEF.

Functional sympatholysis is preserved in healthy young Black men during rhythmic handgrip exercise.

Black men have attenuated increases in forearm vascular conductance (FVC) and forearm blood flow (FBF) during moderate- and high-intensity rhythmic handgrip exercise compared with White men, but the underlying mechanisms are unclear. Here, we tested for the first time the hypothesis that functional sympatholysis (i.e., attenuation of sympathetic vasoconstriction in the exercising muscles) is impaired in Black men compared with White men. Thirteen White and 14 Black healthy young men were studied. FBF (duplex Doppler ultrasound) and mean arterial pressure (MAP; Finometer) were measured at rest and during rhythmic handgrip exercise at 30% maximal voluntary contraction. FVC was calculated as FBF/MAP. Sympathetic activation was induced via lower body negative pressure (LBNP) at -20 Torr for 2 min at rest and from the 3rd to the 5th min of handgrip. Sympathetic vasoconstriction was assessed as percent reductions in FVC during LBNP. The groups presented similar resting FVC, FBF, and MAP. During LBNP at rest, reductions in FVC were not different between White (-35 ± 10%) and Black men (-32 ± 14%, P = 0.616), indicating similar reflex-induced sympathetic vasoconstriction. During handgrip exercise, there were minimal reductions in FVC with LBNP in either group (White: -1 ± 7%; Black: +1 ± 8%; P = 0.523), indicating functional sympatholysis in both groups. Thus, contrary to our hypothesis, our findings indicate a preserved functional sympatholysis in healthy young Black men compared with White men, suggesting that this mechanism does not appear to contribute to reduced exercise hyperemia during moderate-intensity rhythmic handgrip in this population.

Prostaglandin contribution to postexercise hyperemia is dependent on tissue oxygenation during rhythmic and isometric contractions.

The role of prostaglandins (PGs) in exercise hyperemia is controversial. We tested their contributions in moderate intensity forearm exercise, whether their release is oxygen (O2)‐dependent or affected by aging. A total of 12 young (21 ± 1 years) and 11 older (66 ± 2 years) recreationally active men performed rhythmic and isometric handgrip contractions at 60% maximum voluntary contraction for 3 min during air breathing after placebo, after cyclooxygenase (COX) inhibition with aspirin, while breathing 40% O2 and during their combination (aspirin + 40% O2). Forearm blood flow (FBF) was recorded with venous occlusion plethysmography (forearm vascular conductance (FVC): FBF/mean arterial pressure). Venous efflux of PGI2 and PGE2 were assessed by immunoassay. Postcontraction increases in FVC were similar for rhythmic and isometric contractions in young and older men, and accompanied by similar increases in efflux of PGI2 and PGE2. Aspirin attenuated the efflux of PGI2 by 75%–85%, PGE2 by 50%–70%, (p < .05 within group; p > .05 young versus. older), and postcontraction increases in FVC by 22%–27% and 17%–21% in young and older men, respectively (p < .05 within group and young versus. older). In both age groups, 40% O2 and aspirin + 40% O2 caused similar inhibition of the increases in FVC and efflux of PGs as aspirin alone (p < .05 within group). These results indicate that PGs make substantial contributions to the postcontraction hyperemia of rhythmic and isometric contractions at moderate intensities in recreationally active young and older men. Given PGI2 is mainly released by endothelium and PGE2 by muscle fibers, we propose PG generation is dependent on the contraction‐induced falls in O2 at these sites.

The Role of Lifelong Physical Activity on Cardiovascular Function

IntroductionAgeing is associated with vascular dysfunction and a reduced capacity of the central circulation to deliver O2 to the contracting muscles. The purpose of present study was to investigate the role of lifelong physical activity level on vascular function and hemodynamics during whole‐body exercise.MethodsVascular function was determined by femoral arterial Ach infusion (10, 25 and 100 μg/min/kg leg mass) and central (ICG) and limb (thermodilution) hemodynamics were measured during incremental cycling to exhaustion with and without simultaneous arm cycling (50w) were determined in 9 young (Y) (23±1 years; mean±SEM), 9 lifelong sedentary elderly (SE) (66±2 years), 8 lifelong moderately‐active elderly (MAE) (64±2 years) and 8 lifelong very active elderly (VAE) (65±2 years) men. Data was analyzed with one‐way repeated measure ANOVA (within groups) and two‐way ANOVA (between groups).ResultsThe vasodilatory response to ACh was lowest in the SE, higher in MAE and VAE (P &lt;0.05) and highest in the Y (P &lt;0.05). During incremental cycling, peak workload was higher in the VAE (313±10 W) and MAE (274±14 W) compared to Y and SE (247±13; 191±3 W; P&lt;0.05). Leg blood flow (LBF) increased similarly in VAE, MAE and SE, but peak values were higher in VAE, MAE and Y compared to SE (7.8±0.5; 7.9±0.9; 8.6±0.4 vs. 6.4±0.4 L/min; P&lt;0.05). Leg a‐vO2 difference was higher in VAE and MAE compared to the Y and SE at all workloads (P&lt;0.05), whereas leg VO2 was higher in VAE, MAE and Y compared to SE at exhaustion (P&lt;0.05). During combined arm and leg cycling LBF, leg a‐vO2 difference and VO2 was lower in Y and SE compared to leg cycling alone (P&lt;0.05). Mean arterial pressure increased in all groups, but was lower in Y (P&lt;0.05).ConclusionsThese results demonstrate that lifelong moderate physical activity can maintain aerobic power despite a lower vascular function and exercise hyperemia by an increase in O2 extraction.

Exercise Hyperemia is Preserved During Augmented Basal Oxygen Delivery in Humans

The coupling between skeletal muscle blood flow and metabolic demand is largely attributed to feedback regulation of oxygen delivery. However, the relative importance of feedforward mechanisms in increasing blood flow in proportion to contractile work is unknown. We hypothesized that the change in blood flow following initiation of exercise is preserved independent of the level of baseline oxygen delivery, and that reciprocal reductions in oxygen extraction occur during elevations in resting blood flow. In 6 young healthy adults (4M/2F, 22±1 y) we quantified forearm blood flow (FBF; Doppler ultrasound), oxygen extraction (O2 extraction; based on venous O2 content), and forearm oxygen consumption (mVO2; Fick equation). Measurements were taken at rest and during 5 minutes of rhythmic handgrip exercise under control conditions and during intra‐arterial infusion of the vasodilator sodium nitroprusside (SNP) to pharmacologically manipulate oxygen delivery (O2D) prior to initiation of contractions. We elevated resting blood flow to levels that matched (MAT) and exceeded (EXC) steady‐state hyperemia during control (CON) exercise trials. Steady‐state FBF and O2D during dynamic forearm contractions at an intensity equivalent to 10% of participants maximal voluntary contraction under CON conditions were 159 ± 24 ml · min−1 and 32 ± 4.9 ml O2 · min−1, respectively. As intended, SNP infusion increased resting FBF (152 ± 26 ml · min−1) and O2D (31 ± 5.3 ml O2 · min−1) to levels similar to those observed during CON exercise in MAT (both P = NS), and further elevated FBF (196 ± 19 ml · min−1) and O2D (40 ± 4.0 ml O2 · min−1) to levels exceeding CON exercise in EXC (both P &lt; 0.05). However, resting O2 extraction decreased in MAT (9 ± 5 %) and EXC (7 ± 4 %) compared to CON (49 ± 7 %; P &lt; 0.05), and thus resting mVO2 was not different between conditions (range: ~2–3 ml O2 · min−1; P = NS). Despite elevating resting FBF and O2D to levels adequate to sustain muscle contractile work, the change in FBF in response to exercise remained intact during MAT (Δ FBF; 112 ± 20 ml · min−1) and EXC (Δ FBF; 133 ± 18 ml · min−1) compared to CON (Δ FBF; 123 ± 24 ml · min−1; all P = NS). As predicted, O2 extraction remained lower during steady‐state exercise in the MAT (45 ± 7 %) and EXC (39 ± 7 %) conditions compared to CON (66 ± 3 %; P &lt; 0.05). However, the change in O2 extraction from rest to steady‐state exercise was not reduced (Δ O2 extraction: CON; 17 ± 5, MAT; 36 ± 5, EXC; 32 ± 5 %; P = NS), and thus mVO2 was not different between conditions (CON; 21 ± 2.9, MAT; 24 ± 4.5, EXC; 27 ± 5.6 ml O2 · min−1; P = NS). We conclude that changes in blood flow and oxygen extraction remain intact when oxygen delivery is artificially elevated prior to exercise, which highlights the importance of feedforward mechanisms capable of initiating changes in skeletal muscle blood flow independent of oxygen delivery.Support or Funding InformationNIH HL119337

Vascular function is related to blood flow during high-intensity, but not low-intensity, knee extension exercise.

While vascular function, assessed as the ability of the vasculature to dilate in response to a stimulus, is related to cardiovascular health, its relationship to exercise hyperemia is unclear. This study sought to determine if blood flow during submaximal and maximal exercise is related to vascular function. Nineteen healthy adults completed multiple assessments of vascular function specific to the leg, including passive leg movement (PLM), rapid onset vasodilation (ROV), reactive hyperemia (RH), and flow-mediated dilation (FMD). On a separate day, exercise blood flow (Doppler ultrasound) was assessed in the same leg during various intensities of single-leg, knee-extension (KE) exercise. Vascular function, determined by PLM, ROV, and RH, was related to exercise blood flow at high intensities, including maximum work rate (WRmax) (r = 0.58-0.77, P < 0.001), but not low intensities, like ~21% WRmax (r = 0.12-0.34, P = 0.12-0.62). Relationships between multiple indices of vascular function and peak exercise blood flow persisted when controlling for quadriceps mass and exercise work rate (P < 0.05), indicating vascular function is independently related to the blood flow response to intense exercise. When divided into two groups based upon the magnitude of the PLM response, subjects with a lower PLM response exhibited lower exercise flow at several absolute work rates, as well as lower peak flow (P < 0.05). In conclusion, leg flow during dynamic exercise is independently correlated with multiple different indices of microvascular function. Thus microvascular function appears to modulate the hyperemic response to high-intensity, but not low-intensity, exercise.NEW & NOTEWORTHY While substantial evidence indicates that individuals with lower vascular function are at greater risk for cardiovascular disease, with many redundant vasodilator pathways present during exercise, it has been unclear if low vascular function actually impacts blood flow during exercise. This study provides evidence that vascular function, assessed by multiple noninvasive methods, is related to the blood flow response to high-intensity leg exercise in healthy young adults. Importantly, healthy young adults with lower levels of vascular function, particularly microvascular function, exhibit lower blood flow during high-intensity, and maximal knee extension exercise. Thus it appears that in addition to increasing one's risk of cardiovascular disease, lower vascular function is also related to a blunted blood flow response during high-intensity exercise.