Locomotor Muscle Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction

While there is emerging evidence of peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction (HFpEF) that may be related to systemic inflammation and redox imbalance, disease-related changes in locomotor muscle microvascular responsiveness have not been determined. This study combined passive leg movement and biomarker assessments of inflammation and oxidative damage to determine the magnitude and mechanisms of lower limb microvascular function in patients with HFpEF (71±1 years; n=44) compared with healthy, similarly aged controls (68±2 years; n=39). Leg blood flow, heart rate, mean arterial pressure, and stroke volume were assessed, and plasma biomarkers of inflammation and oxidative damage were also determined. A significantly attenuated passive leg movement–induced peak change in leg blood flow (263±25 versus 371±31 mL/min, HFpEF versus control) and leg vascular conductance (2.99±0.32 versus 3.88±0.34 mL/min per mm Hg, HFpEF versus control) was observed in patients compared with controls. Similarly, the total hyperemic response to passive leg movement, expressed as leg blood flow AUC and leg vascular conductance AUC , was ≈40% less in patients with HFpEF versus control. Significantly greater C-reactive protein, IL-6 (interleukin-6), and malondialdehyde were observed in patients with HFpEF but were not correlated with passive leg movement responses. These data provide new evidence of a decline in lower limb microvascular function within a milieu of vascular inflammation that may contribute to locomotor muscle dysfunction in patients with HFpEF.

Evidence of Reduced Peripheral Microvascular Function in Young Black Women Across the Menstrual Cycle

Black women (BLW) have a higher prevalence of cardiovascular disease (CVD) morbidity and mortality compared to white women (WHW). A racial disparity in CVD risk has been identified early in life as young adult BLW demonstrate attenuated vascular function compared to WHW. Previous studies comparing vascular function between premenopausal WHW and BLW have been limited to the early follicular (EF) phase of the menstrual cycle, which may not reflect their vascular function during other menstrual phases. Therefore, we evaluated peripheral microvascular function in premenopausal WHW and BLW using passive leg movement (PLM) during three menstrual phases: EF, ovulation (OV), and mid-luteal (ML). We hypothesized that microvascular function would be augmented during the OV and ML phases compared to the EF phase in both groups, but would be attenuated in BLW compared to WHW at all three phases. PLM was performed on 26 apparently healthy premenopausal women not using hormonal contraceptives: 15 WHW (23±3 years), 11 BLW (24±5 years). There was a main effect of race on the overall change in leg blood flow (∆LBF) (p=0.01) and leg blood flow area under the curve (LBF AUC) (p=0.02), such that LBF was lower in BLW. However, there was no effect of phase on ∆LBF (p=0.69) or LBF AUC (p=0.65), nor an interaction between race and phase on ∆LBF (p=0.37) or LBF AUC (p=0.75). Despite peripheral microvascular function being unchanged across the menstrual cycle, a racial disparity was apparent as microvascular function was attenuated in BLW compared to WHW across the menstrual cycle.

Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P =0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P =0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01308099.

Mechanisms of bone blood flow regulation in humans

Bone is a highly vascularized tissue. However, despite the importance of appropriate circulationfor bone health, regulation of bone blood flow remains poorly understood. Invasive animalstudies suggest that the sympathetic activity plays an important role in bone flow control.However, it remains unknown if bone vasculature evidences robust vasoconstriction in responseto sympathoexcitatory stimuli. Here, we characterized bone blood flow in young healthyindividuals (N=13,(4F)) in response to isometric handgrip exercise (IHE) and cold pressor test(CPT). These provide a strong stimulus for active vasoconstriction in the inactive muscle, andperhaps also in the bone. During sustained IHE to fatigue and CPT, we measured blood pressure,whole leg blood flow, and tibial perfusion using near-infrared spectroscopy. Tibia perfusion wasdetermined as oxy- and deoxy-hemoglobin. For both stimuli, tibial metabolism remainedconstant (i.e., no change in deoxyhemoglobin) and thus tibial arterial perfusion was representedby oxyhemoglobin. During IHE, oxyhemoglobin declined (beginning -0.20±1.04μM; end -1.13±3.71μM, both p<0.01) slower than whole leg blood flow (beginning -0.85±1.02cm/s; end -2.72±1.64cm/s, both =p<0.01). However, during CPT, both oxyhemoglobin (beginning -0.46 ±1.43μM; end -0.60±1.59μM, both p<0.01) and whole leg blood flow (beginning -1.52±1.63 cm/s;end -0.69±1.51cm/s, both p<0.01) declined with a similar time course, even though themagnitudes of decline were smaller than during IHE. These responses are likely due the differenttime courses of sympathetically mediated vasoconstriction in bone and muscle. These resultsindicate that sympathetic innervation of the bone vasculature serves a functional role in thecontrol of flow in young healthy individuals.

Aldosterone Induces Vasoconstriction in Individuals with Type 2 Diabetes: Effect of Acute Antioxidant Administration

Context Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species–dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. Objective We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response. Methods In a case–control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min–1 [L leg volume]–1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg–1 hour–1 followed by 25 mg kg–1 hour–1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. Results Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. Conclusion These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.

­Heart Failure with Preserved Ejection Fraction Diminishes Peripheral Hemodynamics and Accelerates Exercise-Induced Neuromuscular Fatigue

This study investigated the impact of heart failure with a preserved ejection fraction (HFpEF) on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (ejection-fraction: 61±2%, NYHA II-III) and eight healthy-controls performed dynamic single-leg knee-extension exercise [80% peak workload] to task-failure and maximal intermittent isometric quadriceps contractions (8×15-s, 20-s rest). Controls repeated knee-extension at the same absolute workload as the HFpEF. During knee-extension, leg blood flow was quantified using Doppler ultrasound. Pre- to post-exercise changes in quadriceps twitch-torque (ΔQtw, peripheral fatigue), voluntary-activation (ΔVA, central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24±5W) and controls (42±6W) had a similar time to task-failure (~10min), ΔQtw (~50%), and ΔVA (~6%) (P>0.3). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower leg blood flow response time (r=0.77). Knee-extension exercise at the same absolute workload resulted in a ~40% lower leg blood flow and greater ΔQtw (56±15 vs 11±10%) and ΔVA (5±3 vs 0±2%) in HFpEF than controls (P<0.05). Corticospinal excitability remained unaltered during exercise in both groups. Finally, despite a similar ΔVA, ΔQtw was larger in HFpEF compared to controls during isometric exercise (-49±9 vs -23±2%, P<0.05). In conclusion, HFpEF are characterized by a greater susceptibility to neuromuscular fatigue during exercise not limited by cardiac output. The patients' compromised peripheral hemodynamic response to exercise likely accounts, at least partly, for the attenuated fatigue resistance in this population.

Mechanisms underlying absent training-induced improvement in insulin action in lean, hyperandrogenic women with polycystic ovary syndrome (PCOS)

Women with polycystic ovary syndrome (PCOS) have been shown to be less insulin sensitive compared with control women, independent of BMI. Training is associated with molecular adaptations in skeletal muscle improving glucose uptake and metabolism in both healthy and type 2 diabetic individuals. In the present study, lean, hyperandrogenic women with PCOS (n=9) and healthy controls (CON, n=9) completed 14 weeks of controlled and supervised exercise training. In CON, the training intervention increased whole body insulin action by 26% and insulin-stimulated leg glucose uptake by 53%, together with increased insulin-stimulated leg blood flow and a more oxidative muscle fiber type distribution. In PCOS, no such changes were found, despite similar training intensity and improvements in maximal oxygen uptake. In skeletal muscle of CON, but not PCOS, training increased GLUT4 and HKII mRNA and protein expressions. These data suggest that the impaired increase in whole body insulin action in women with PCOS with training is caused by an impaired ability to upregulate key glucose handling proteins for insulin-stimulated glucose uptake in skeletal muscle, and insulin-stimulated leg blood flow. Still, other important benefits of exercise training appeared in women with PCOS, including an improvement of the hyperandrogenic state.

Mechanisms underlying absent training-induced improvement in insulin action in lean, hyperandrogenic women with polycystic ovary syndrome (PCOS)

Women with polycystic ovary syndrome (PCOS) have been shown to be less insulin sensitive compared with control women, independent of BMI. Training is associated with molecular adaptations in skeletal muscle improving glucose uptake and metabolism in both healthy and type 2 diabetic individuals. In the present study, lean, hyperandrogenic women with PCOS (n=9) and healthy controls (CON, n=9) completed 14 weeks of controlled and supervised exercise training. In CON, the training intervention increased whole body insulin action by 26% and insulin-stimulated leg glucose uptake by 53%, together with increased insulin-stimulated leg blood flow and a more oxidative muscle fiber type distribution. In PCOS, no such changes were found, despite similar training intensity and improvements in maximal oxygen uptake. In skeletal muscle of CON, but not PCOS, training increased GLUT4 and HKII mRNA and protein expressions. These data suggest that the impaired increase in whole body insulin action in women with PCOS with training is caused by an impaired ability to upregulate key glucose handling proteins for insulin-stimulated glucose uptake in skeletal muscle, and insulin-stimulated leg blood flow. Still, other important benefits of exercise training appeared in women with PCOS, including an improvement of the hyperandrogenic state.

Effect of histamine-receptor antagonism on leg blood flow during exercise

Leg blood flow during exercise was increased by taking antihistamines, which block the receptors for histamine, a molecule often associated with inflammatory and immune responses. The elevated blood flow occurred over exercise intensities ranging from 20 to 80% of peak capacity and during exercise of 60-min duration. These results suggest that exercise-induced elevations in histamine concentrations are involved in novel, poorly understood, and perhaps complex ways in the exercise response.