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Previous studies have reported detrimental effects of COVID-19 on the peripheral vasculature. However, reports on blood pressure (BP) are inconsistent, and measurements are made only in the laboratory setting. To date, no studies have measured ambulatory BP. In addition, in previous studies, time since COVID-19 diagnosis among participants varied across a wide range, potentially contributing to the inconsistent BP results. Thus, we aimed to perform a comprehensive assessment of BP and BP variability using ambulatory and laboratory (brachial and central) measurements in young adults who had COVID-19. We hypothesized that ambulatory BP would be elevated post-COVID-19 and that measures of BP would be inversely related with time since diagnosis. Twenty-eight young adults who had COVID-19 [11 ± 6 (range 3-22) wk since diagnosis] and 10 controls were studied. Ambulatory daytime, nighttime, and 24-h systolic BP, diastolic BP, and mean BP were not different between the control and COVID groups (e.g., daytime systolic BP: control, 122 ± 12 mmHg; COVID, 122 ± 10 mmHg

Exercise intolerance is a well-described characteristic of heart failure with preserved ejection fraction (HFpEF), but whether disease-related changes in autonomic function contribute to impaired cardiovascular control during exercise is not well understood. Thus, we used a combination of static handgrip exercise (HG) and post-exercise ischemia (PEI) to examine the pressor response to exercise and isolate the skeletal muscle metaboreflex, respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were assessed during 2-min of static HG at 30 and 40% of maximum voluntary contraction (MVC) and subsequent PEI in sixteen patients with HFpEF and seventeen healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared to controls during both 30%MVC (Δ11 ± 7 vs. Δ15 ± 8 mmHg) and 40%MVC (Δ19 ± 14 vs. Δ30 ± 8 mmHg), and a similar pattern of response was evident during PEI (30%MVC: Δ8 ± 5 vs. Δ12 ± 8 mmHg; 40%MVC: Δ13 ± 10 vs. Δ18 ± 9 mmHg) (group effect: p=0.048 and p=0.020 at 30% and 40% MVC, respectively). Changes in HR, CO, and TPR did not differ between groups during HG or PEI (p>0.05). Taken together, these data suggest a reduced pressor response to static muscle contractions in patients with HFpEF compared to similarly aged controls that may be mediated, in part, by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may contribute to the extreme exercise intolerance present in this patient group.

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients.NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

Reduced insulin sensitivity and impaired glycemic control are among the consequences of physical inactivity and have been associated with reduced cardiac baroreflex sensitivity (BRS). However, the effect of reduced insulin sensitivity and acute hyperglycemia following glucose consumption on cardiac BRS in young, healthy subjects has not been well characterized. We hypothesized that a reduction in insulin sensitivity via reductions in physical activity would reduce cardiac BRS at rest and following an oral glucose tolerance test (OGTT). Nine recreationally active men (23 ± 1 yr; >10,000 steps/day) underwent 5 days of reduced daily physical activity (RA5) by refraining from planned exercise and reducing daily steps (

Physical inactivity promotes the development of cardiovascular diseases. However, few data exist examining the vascular consequences of short-term reductions in daily physical activity. Thus we tested the hypothesis that popliteal and brachial artery flow-mediated dilation (FMD) would be reduced and concentrations of endothelial microparticles (EMPs) would be elevated following reduced daily physical activity. To examine this, popliteal and brachial artery FMD and plasma levels of EMPs suggestive of apoptotic and activated endothelial cells (CD31+/CD42b− and CD62E+ EMPs, respectively) were measured at baseline and during days 1, 3, and 5 of reduced daily physical activity in 11 recreationally active men (25 ± 2 yr). Subjects were instructed to reduce daily physical activity by taking +/CD42b− EMPs were significantly elevated with reduced activity (baseline: 17.6 ± 9.4, reduced activity day 5: 104.1 ± 43.1 per μl plasma, P < 0.05), whereas CD62E+ EMPs were unaltered. Collectively, our results provide evidence for the early and robust deleterious impact of reduced daily activity on vascular function and highlight the vulnerability of the vasculature to a sedentary lifestyle.

To date, no studies have examined whether there are either sex- or ovarian hormone-related alterations in arterial baroreflex resetting and function during dynamic exercise. Thus we studied 16 young men and 18 young women at rest and during leg cycling at 50% heart rate (HR) reserve. In addition, 10 women were studied at three different phases of the menstrual cycle. Five-second pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr were applied to determine full carotid baroreflex (CBR) stimulus response curves. An upward and rightward resetting of the CBR function curve was observed during exercise in all groups with a similar magnitude of CBR resetting for mean arterial pressure (MAP) and HR between sexes ( P > 0.05) and at different phases of the menstrual cycle ( P > 0.05). For CBR control of MAP, women exhibited augmented pressor responses to NP at rest and exercise during mid-luteal compared with early and late follicular phases. For CBR control of HR, there was a greater bradycardic response to NS in women across all menstrual cycle phases with the operating point (OP) located further away from centering point (CP) on the CBR-HR curve during rest (OP-CP; in mmHg: −13 ± 3 women vs. −3 ± 3 men; P < 0.05) and exercise (in mmHg: −31 ± 2 women vs. −15 ± 3 men; P < 0.05). Collectively, these findings suggest that sex and fluctuations in ovarian hormones do not influence exercise resetting of the baroreflex. However, women exhibited greater CBR control of HR during exercise, specifically against acute hypertension, an effect that was present throughout the menstrual cycle.

Nutrient intake is accompanied by increases in central sympathetic outflow, a response that has been mainly attributed to insulin. Insulin-mediated sympathoexcitation appears to be blunted in insulin-resistant conditions, suggesting that aside from peripheral insulin insensitivity, such conditions may also impair the central action of insulin in mediating sympathetic activation. What remains unclear is whether an insulin-sensitive state, such as that induced by chronic endurance training, alters the central sympathetic effects of insulin during postprandial conditions. To examine this question plasma insulin and glucose, muscle sympathetic nerve activity (MSNA), heart rate, and arterial blood pressure were measured in 11 high-fit [HF; peak oxygen uptake (V̇o2peak) 65.9 ± 1.4 ml·kg−1·min−1] and 9 average-fit (AF; V̇o2peak 43.6 ± 1.3 ml·kg−1·min−1) male subjects before and for 120 min after ingestion of a mixed meal drink. As expected, the insulin response to meal ingestion was lower in HF than AF participants (insulin area under the curve0–120: 2,314 ± 171 vs. 4,028 ± 460 μIU·ml−1·120−1, HF vs. AF, P < 0.05), with similar plasma glucose responses between groups. Importantly, following consumption of the meal, the HF subjects demonstrated a greater rise in MSNA compared with the AF subjects (e.g., 120 min: Δ21 ± 1 vs. 8 ± 3 bursts/100 heart beats, HF vs. AF, P < 0.05). Furthermore, when expressed relative to plasma insulin, HF subjects exhibited a greater change in MSNA for any given change in insulin. Arterial blood pressure responses following meal intake were similar between groups. Collectively, these data suggest that, in addition to improved peripheral insulin sensitivity, endurance training may enhance the central sympathetic effect of insulin to increase MSNA following consumption of a mixed meal.

Although cerebral autoregulation (CA) appears well maintained during mild to moderate intensity dynamic exercise in young subjects, it is presently unclear how aging influences the regulation of cerebral blood flow during physical activity. Therefore, to address this question, middle cerebral artery blood velocity (MCA V), mean arterial pressure (MAP), and the partial pressure of arterial carbon dioxide (PaCO2) were assessed at rest and during steady-state cycling at 30% and 50% heart rate reserve (HRR) in 9 young (24 ± 3 yr; mean ± SD) and 10 older middle-aged (57 ± 7 yr) subjects. Transfer function analysis between changes in MAP and mean MCA V (MCA Vmean) in the low-frequency (LF) range were used to assess dynamic CA. No age-group differences were found in PaCO2 at rest or during cycling. Exercise-induced increases in MAP were greater in older subjects, while changes in MCA Vmean were similar between groups. The cerebral vascular conductance index (MCA Vmean/MAP) was not different at rest (young 0.66 ± 0.04 cm·s−1·mmHg−1 vs. older 0.67 ± 0.03 cm·s−1·mmHg−1; mean ± SE) or during 30% HRR cycling between groups but was reduced in older subjects during 50% HRR cycling (young 0.67 ± 0.03 cm·s−1·mmHg−1 vs. older 0.56 ± 0.02 cm·s−1·mmHg−1; P < 0.05). LF transfer function gain and phase between MAP and MCA Vmean was not different between groups at rest (LF gain: young 0.95 ± 0.05 cm·s−1·mmHg−1 vs. older 0.88 ± 0.06 cm·s−1·mmHg−1; P > 0.05) or during exercise (LF gain: young 0.80 ± 0.05 cm·s−1·mmHg−1 vs. older 0.72 ± 0.07 cm·s−1·mmHg−1 at 50% HRR; P > 0.05). We conclude that despite greater increases in MAP, the regulation of MCA Vmean is well maintained during dynamic exercise in healthy older middle-aged subjects.

We sought to examine the influence of exercise intensity on carotid baroreflex (CBR) control of heart rate (HR) and mean arterial pressure (MAP) at the onset of exercise in humans. To accomplish this, eight subjects performed multiple 1-min bouts of isometric handgrip (HG) exercise at 15, 30, 45 and 60% maximal voluntary contraction (MVC), while breathing to a metronome set at eupneic frequency. Neck suction (NS) of -60 Torr was applied for 5 s at end expiration to stimulate the CBR at rest, at the onset of HG (1 s), and after approximately 40 s of HG. Beat-to-beat measurements of HR and MAP were recorded throughout. Cardiac responses to NS at onset of 15% (-12 +/- 2 beats/min) and 30% (-10 +/- 2 beats/min) MVC HG were similar to rest (-10 +/- 1 beats/min). However, HR responses to NS were reduced at the onset of 45% and 60% MVC HG (-6 +/- 2 and -4 +/- 1 beats/min, respectively; P0.001). In contrast to HR, MAP responses to NS were not different from rest at exercise onset. Furthermore, both HR and MAP responses to NS applied at approximately 40s of HG were similar to rest. In summary, CBR control of HR was transiently blunted at the immediate onset of high-intensity HG, whereas MAP responses were preserved demonstrating differential baroreflex control of HR and blood pressure at exercise onset. Collectively, these results suggest that carotid-cardiac baroreflex control is dynamically modulated throughout isometric exercise in humans, whereas carotid baroreflex regulation of blood pressure is well-maintained.

We sought to examine the regulation of cerebral blood flow during 10 min of recovery from mild, moderate, and heavy cycling exercise by measuring middle cerebral artery blood velocity (MCA V). Transfer function analyses between changes in arterial blood pressure and MCA V were used to assess the frequency components of dynamic cerebral autoregulation (CA). After mild and moderate exercise, the decreases in mean arterial pressure (MAP) and mean MCA V (MCA Vm) were small. However, following heavy exercise, MAP was rapidly and markedly reduced, whereas MCA Vm decreased slowly (−23 ± 4 mmHg and −4 ± 1 cm/s after 1 min for MAP and MCA Vm, respectively; means ± SE). Importantly, for each workload, the normalized low-frequency transfer function gain between MAP and MCA Vm remained unchanged from rest to exercise and during recovery, indicating a maintained dynamic CA. Similar results were found for the systolic blood pressure and systolic MCA V relationship. In contrast, the normalized low-frequency transfer function gain between diastolic blood pressure and diastolic MCA V (MCA Vd) increased from rest to exercise and remained elevated in the recovery period ( P < 0.05). However, MCA Vd was quite stable on the cessation of exercise. These findings suggest that MCA V is well maintained following mild to heavy dynamic exercise. However, the increased transfer function gain between diastolic blood pressure and MCA Vd suggests that dynamic CA becomes less effective in response to rapid decreases in blood pressure during the initial 10 min of recovery from dynamic exercise.

The precise role of the sympathetic nervous system in the regulation of skeletal muscle blood flow during exercise has been challenging to define in humans, partly because of the limited techniques available for measuring blood flow in active muscle. Recent studies using near-infrared (NIR) spectroscopy to measure changes in tissue oxygenation have provided an alternative method to evaluate vasomotor responses in exercising muscle, but this approach has not been fully validated. In this study, we tested the hypothesis that sympathetic activation would evoke parallel changes in tissue oxygenation and blood flow in resting and exercising muscle. We simultaneously measured tissue oxygenation with NIR spectroscopy and blood flow with Doppler ultrasound in skeletal muscle of conscious humans ( n = 13) and anesthetized rats ( n = 9). In resting forearm of humans, reflex activation of sympathetic nerves with the use of lower body negative pressure produced graded decreases in tissue oxygenation and blood flow that were highly correlated ( r = 0.80, P < 0.0001). Similarly, in resting hindlimb of rats, electrical stimulation of sympathetic nerves produced graded decreases in tissue oxygenation and blood flow velocity that were highly correlated ( r = 0.93, P < 0.0001). During rhythmic muscle contraction, the decreases in tissue oxygenation and blood flow evoked by sympathetic activation were significantly attenuated ( P < 0.05 vs. rest) but remained highly correlated in both humans ( r = 0.80, P < 0.006) and rats ( r = 0.92, P < 0.0001). These data indicate that, during steady-state metabolic conditions, changes in tissue oxygenation can be used to reliably assess sympathetic vasoconstriction in both resting and exercising skeletal muscle.

TO THE EDITOR: We read with interest the recently published work of Park et al. (10) examining differential regional control of sympathetic nerve activity in end-stage renal disease (ESRD). These investigators compared integrated multiunit recordings of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) at rest between patients with ESRD and healthy age- and gender-matched control subjects, using the technique of microneurography. Similar to previous reports, the ESRD patients demonstrated greater resting MSNA compared with controls. However, SSNA was similar between the two groups, leading the authors to conclude that “. . . although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD.” Although we commend the authors for addressing this important issue, there are major limitations in comparing basal SSNA between groups that should be considered, despite the work of others who have performed similar analyses (5, 8, 11).