Respiratory modulation of sympathetic transduction to blood pressure in health and type 2 diabetes.

Type 2 diabetes (T2D) is often accompanied by hypertension, exaggerated blood pressure (BP) responses to sympatho-excitatory stressors, and raised cardiovascular disease risk. Appropriate respiratory-sympathetic coupling and sympathetic transduction to BP are important for short- and longer-term BP control. We tested the hypotheses that respiratory modulation of muscle sympathetic nerve activity (MSNA) and its transduction to BP would be impaired in T2D and associated with higher BP and respiratory-coupled BP variability. Resting MSNA, respiration and beat-to-beat BP were recorded in 20 T2D (49.1 ± 7.4 years; mean ± SD) and 13 healthy control (46.3 ± 9.4 years) participants. MSNA and the transduction of sympathetic bursts (signal-averaging) to mean arterial pressure (MAP) were compared at low and high lung volume phases. The peak MAP response following a sympathetic burst was lower during the high lung volume than low lung volume phase in controls (P = 0.005), whereas it was unchanged with phase in T2D participants (P = 0.522). Respiratory modulation of MSNA was impaired in T2D participants, who had an attenuated reduction in burst incidence from low to the high lung volume phase, versus controls (27.8 ± 38.4% vs. 49.4 ± 24.6%, respectively; P = 0.043). The T2D participants were grouped into unimpaired respiratory modulators (burst incidence modulation median or above) or impaired respiratory modulators (below median). Impaired modulators had higher systolic BP (133 ± 14 vs. 121 ± 11 mmHg, P = 0.046), greater Traube-Hering wave amplitudes (6.3 ± 2.4 vs. 4.6 ± 1.1 mmHg; P = 0.028) and higher BP variability (MAP average real variability, 2.0 ± 0.7 vs. 1.4 ± 0.3, P = 0.033). Respiratory modulation of MSNA and sympathetic transduction to BP are altered in T2D patients and may contribute to their increased hypertension and cardiovascular risk. KEY POINTS: Respiratory-sympathetic coupling and sympathetic transduction to blood pressure (BP) contribute to short- and longer-term BP control. Our understanding of these processes in health and type 2 diabetes (T2D), a condition with high prevalence of hypertension and cardiovascular risk, is incomplete. We found that respiration and sympathetic transduction to BP are coupled in healthy individuals. The mean arterial pressure response to a sympathetic burst was reduced during the high lung volume compared to the low lung volume phase. This coupling was absent in T2D. Respiratory modulation of muscle sympathetic nerve activity (MSNA) is impaired in T2D, with a blunted reduction of MSNA observed during the high lung volume phase. T2D patients with impaired respiratory MSNA modulation had augmented systolic BP, respiratory-related BP excursions (Traube-Hering waves) and BP variability. Abnormal respiratory modulation of MSNA and sympathetic transduction to BP in T2D may contribute to altered blood pressure control and cardiovascular risk in this population.

Sex differences in sympathetic transduction in black and white adults: implications for racial disparities in hypertension and cardiovascular disease risk.

The prevalence of hypertension in non-Hispanic black (BL) individuals is the greatest of any racial/ethnic group. Whereas women generally display lower rates of hypertension than men of the same background, BL women display a similar if not greater burden of hypertension compared with BL men. The risk for cardiovascular disease and related events is also highest in BL individuals. Given the importance of the sympathetic nervous system for the regulation of the cardiovascular system, a growing body of literature has investigated sympathetic function in BL and non-Hispanic white (WH) individuals. Here, we are focused on emerging evidence indicating that sympathetic function may be altered in BL individuals, with particular emphasis on the process by which bursts of muscle sympathetic nerve activity (MSNA) are transduced into vasoconstriction and increases in blood pressure (sympathetic vascular transduction). To synthesize this growing body of literature we discuss sex and race differences in 1) sympathetic outflow, 2) sympathetic vascular transduction, and 3) adrenergic receptor sensitivity. Sex differences are discussed foremost, to set the stage for new data indicating a sex dimorphism in sympathetic regulation in BL individuals. Specifically, we highlight evidence for a potential neurogenic phenotype including greater adiposity-independent sympathetic outflow and enhanced sympathetic vascular transduction in BL men that is not observed in BL women. The implications of these findings for the greater hypertension and cardiovascular disease risk in BL adults are discussed along with areas that require further investigation.

Aging and sympathetic transduction to blood pressure in humans: methodological and physiological considerations.

Recent reports suggest that quantification of signal-averaged sympathetic transduction is influenced by resting muscle sympathetic nerve activity (MSNA) and burst occurrence relative to the average mean arterial pressure (MAP). Herein, we asked how these findings may influence age-related reductions in sympathetic transduction. Beat-to-beat blood pressure and MSNA were recorded during 5 min of rest in 27 younger (13 females: age, 25 ± 5 yr; BMI, 25 ± 4 kg/m2) and 26 older (15 females: age, 59 ± 5 yr; BMI, 26 ± 4 kg/m2) healthy adults. All MSNA bursts were signal averaged together. Beat-to-beat MAP values were then split into low (T1), middle (T2), and high (T3) tertiles, and signal-averaged transduction was calculated within each tertile. Resting MSNA was higher in older adults and MAP was similar between groups. Older adults exhibited blunted overall MAP transduction (younger, Δ1.5 ± 0.6 vs. older, Δ0.9 ± 0.7 mmHg; P = 0.005), which was irrespective of relation to prevailing MAP. A greater proportion of bursts occurred above the average MAP in older adults (P < 0.001), and a larger proportion of these bursts were associated with depressor responses (P = 0.005). Nonetheless, assessment of bursts above the average MAP associated with pressor responses revealed similar age-associated reductions in transduction (younger, Δ2.6 ± 1.6 vs. older, Δ1.7 ± 0.8 mmHg; P = 0.016). These findings indicate an age-related increase in burst occurrence above the average resting MAP, which alone does not explain blunted transduction, thereby supporting the physiological underpinnings of age-related decrements in sympathetic transduction to blood pressure.NEW & NOTEWORTHY The current study demonstrated that aging is associated with a greater prevalence of sympathetic bursts occurring above the average blood pressure, which offers both methodologically and physiologically relevant information regarding aging and sympathetic control of blood pressure. These data support age-related reductions in sympathetic transduction via a reduced pressor response to sympathetic bursts irrespective of the prevailing absolute blood pressure value, along with increases in sympathetic outflow necessary to maintain blood pressure.

Cardiac autonomic function is preserved in young adults with major depressive disorder.

The prevalence of major depressive disorder (MDD) is highest in young adults and contributes to an increased risk of developing future cardiovascular disease (CVD). However, the underlying mechanisms remain unclear. The studies examining cardiac autonomic function that have included young unmedicated adults with MDD report equivocal findings, and few have considered the potential influence of disease severity or duration. We hypothesized that heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) would be reduced in young unmedicated adults with MDD (18-30 yr old) compared with healthy nondepressed young adults (HA). We further hypothesized that greater symptom severity would be related to poorer cardiac autonomic function in young adults with MDD. Heart rate and beat-to-beat blood pressure were continuously recorded during 10 min of supine rest to assess HRV and cardiac BRS in 28 HA (17 female, 22 ± 3 yr old) and 37 adults with MDD experiencing current symptoms of mild-to-moderate severity (unmedicated; 28 female, 20 ± 3 yr old). Neither HRV [root mean square of successive differences between normal heartbeats (RMSSD): 63 ± 34 HA vs. 79 ± 36 ms MDD; P = 0.14] nor cardiac BRS (overall gain, 21 ± 10 HA vs. 23 ± 7 ms/mmHg MDD; P = 0.59) were different between groups. In young adults with MDD, there was no association between current depressive symptom severity and either HRV (RMSSD, R2 = 0.004, P = 0.73) or cardiac BRS (overall gain, R2 = 0.02, P = 0.85). Taken together, these data suggest that cardiac autonomic dysfunction may not contribute to elevated cardiovascular risk factor profiles in young unmedicated adults with MDD of mild-to-moderate severity.NEW & NOTEWORTHY This study investigated cardiac autonomic function in young unmedicated adults with major depressive disorder (MDD). The results demonstrated that both heart rate variability and cardiac baroreflex sensitivity were preserved in young unmedicated adults with MDD compared with healthy nondepressed young adults. Furthermore, in young adults with MDD, current depressive symptom severity was not associated with any indices of cardiac autonomic function.

Cerebral Vasomotor Reactivity to Carbon Dioxide Using the Rebreathe Technique: Assessment of Within-day and Between-day Repeatability.

The cerebral vasodilator response to increased arterial carbon dioxide (CO2) concentration, termed cerebral vasomotor reactivity (CVMR), is used to assess cerebral vascular function. We sought to assess the within-day and between-day repeatability of CVMR to rebreathing-induced hypercapnia. Twelve healthy adults performed a within-day short interval protocol (17±2 minutes between trials), ten performed a within-day long interval protocol (145±16 minutes between trials), and seventeen performed a between-day protocol (5±2 days between visits). Repeatability of the slope of the percent change in middle cerebral artery mean blood velocity (%MCAvmean) and cerebral vascular conductance index (%CVCi), to the change in partial pressure of end-tidal CO2 (PETCO2) between the two trials/days was assessed. Within-day short interval %MCAvmean slope demonstrated fair to excellent repeatability (intraclass correlation, ICC=0.92 [95% confidence interval 0.72-0.98]; p<0.001) while %CVCi slope showed more variability (ICC=0.84 [0.47-0.95]; p=0.002]). Within-day long interval, %MCAvmean (ICC=0.95 [0.80-0.99]) and %CVCi (ICC=0.94 [0.71-0.99]) slopes showed good to excellent and fair to excellent repeatability respectively (p<0.001 for both). For between-day trials, better repeatability was observed for %CVCi (ICC=0.85 [0.57-0.95]; p<0.001) compared to %MCAvmean (ICC=0.76 [0.33-0.91]; p=0.004) slope. These findings indicate repeatable within- and between-day CVMR responses to rebreathe induced hypercapnia. However, a longer interval may be better for within-day repeat trials, particularly for CVCi measures.

Cardiovascular and cerebral vascular health in females with postacute sequelae of COVID-19.

Many individuals who had coronavirus disease 2019 (COVID-19) develop detrimental persistent symptoms, a condition known as postacute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted and central arterial stiffness would be elevated in patients with PASC compared with age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age-matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126 ± 19 vs.109 ± 8 mmHg; P = 0.010), central BP (P < 0.050), and PWV (7.1 ± 1.2 vs. 6.0 ± 0.8 m/s; P = 0.015) were higher in PASC group compared with controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P > 0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P > 0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected, effects that appear independent of symptom burden.NEW & NOTEWORTHY We demonstrate for the first time that resting blood pressure (BP) and central arterial stiffness are higher in females with PASC compared with controls. In contrast, peripheral and cerebral vascular functions appear unaffected. Moreover, there was no relationship between total PASC symptom burden and measures of BP, arterial stiffness, or vascular function. Collectively, these findings suggest that females with PASC could be at greater risk of developing hypertension, which appears independent of symptom burden.

Sympathetic transduction to blood pressure during euglycemic-hyperinsulinemia in young healthy adults: role of burst amplitude.

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the "net effect" of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC (P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts (P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.

Sympathetic transduction at rest and during cold pressor test in young healthy non-Hispanic Black and White women.

Non-Hispanic Black (BL) individuals have the highest prevalence of hypertension and cardiovascular disease (CVD) compared with all other racial/ethnic groups. Previous work focused on racial disparities in sympathetic control and blood pressure (BP) regulation between young BL and White (WH) adults, have mainly included men. Herein, we hypothesized that BL women would exhibit augmented resting sympathetic vascular transduction and greater sympathetic and BP reactivity to cold pressor test (CPT) compared with WH women. Twenty-eight young healthy women (BL: n = 14, 22 [Formula: see text] 4 yr; WH: n = 14, 22 [Formula: see text] 4 yr) participated. Beat-to-beat BP (Finometer), common femoral artery blood flow (duplex Doppler ultrasound), and muscle sympathetic nerve activity (MSNA; microneurography) were continuously recorded. In a subset (BL n = 10, WH n = 11), MSNA and BP were recorded at rest and during a 2-min CPT. Resting sympathetic vascular transduction was quantified as changes in leg vascular conductance (LVC) and mean arterial pressure (MAP) following spontaneous bursts of MSNA using signal averaging. Sympathetic and BP reactivity were quantified as changes in MSNA and MAP during the last minute of CPT. There were no differences in nadir LVC following resting MSNA bursts between BL (-8.70 ± 3.43%) and WH women (-7.30 ± 3.74%; P = 0.394). Likewise, peak increases in MAP following MSNA bursts were not different between groups (BL: +2.80 ± 1.42 mmHg; vs. WH: +2.99 ± 1.15 mmHg; P = 0.683). During CPT, increases in MSNA and MAP were also not different between BL and WH women, with similar transduction estimates between groups (ΔMAP/ΔMSNA; P = 0.182). These findings indicate that young, healthy BL women do not exhibit exaggerated sympathetic transduction or augmented sympathetic and BP reactivity during CPT.NEW & NOTEWORTHY This study was the first to comprehensively investigate sympathetic vascular transduction and sympathetic and BP reactivity during a cold pressor test in young, healthy BL women. We demonstrated that young BL women do not exhibit exaggerated resting sympathetic vascular transduction and do not have augmented sympathetic or BP reactivity during cold stress compared with their WH counterparts. Collectively, these findings suggest that alterations in sympathetic transduction and reactivity are not apparent in young, healthy BL women.

Impact of breakthrough COVID-19 cases during the omicron wave on vascular health and cardiac autonomic function in young adults.

We and others have previously shown that COVID-19 results in vascular and autonomic impairments in young adults. However, the newest variant of COVID-19 (Omicron) appears to have less severe complications. Therefore, we investigated whether recent breakthrough infection with COVID-19 during the Omicron wave impacts cardiovascular health in young adults. We hypothesized that measures of vascular health and indices of cardiac autonomic function would be impaired in those who had the Omicron variant of COVID-19 when compared with controls who never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7 females). Macro- and microvascular function were assessed using flow-mediated dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were assessed as indices of cardiac autonomic function. FMD was not different between control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive hyperemia (P = 0.884) and arterial stiffness were not different between groups (e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367). Finally, measures of HR variability and cardiac BRS were not different between groups (all, P > 0.05). Collectively, these data suggest preserved vascular health and cardiac autonomic function in young, otherwise healthy adults who had breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show for the first time that breakthrough cases of COVID-19 during the Omicron wave does not impact vascular health and cardiac autonomic function in young adults. These are promising results considering earlier research showing impaired vascular and autonomic function following previous variants of COVID-19. Collectively, these data demonstrate that the recent Omicron variant is not detrimental to cardiovascular health in young, otherwise healthy, vaccinated adults.

Augmented T-cell mitochondrial reactive oxygen species in adults with major depressive disorder.

The prevalence of major depressive disorder (MDD) is highest in young adulthood, an effect that has been magnified by the COVID-19 pandemic. Importantly, individuals with MDD are at a greater risk of developing cardiovascular disease (CVD). Accumulating evidence supports immune system dysregulation as a major contributor to the elevated CVD risk in older adults with MDD; however, whether this is present in young adults with MDD without comorbid disease remains unclear. Interestingly, recent data suggest augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) as a potent driver of immune dysregulation in animal models of psychiatric disease. With this background in mind, we tested the hypothesis that young adults with MDD would have augmented T-cell mitoROS and circulating proinflammatory cytokines compared with healthy young adults without MDD (HA). Whole blood was drawn from 14 young adults with MDD (age: 23 ± 2 yr) and 11 HA (age: 22 ± 1 yr). T-cell mitoROS (MitoSOX red; total: CD3+, T-helper: CD4+, T cytotoxic: CD8+) and serum cytokines were assessed by flow cytometry. Total T-cell mitoROS was significantly greater in adults with MDD compared with HA [median: 14,089 arbitrary units (AU); median: 1,362 AU, P = 0.01]. Likewise, both T-helper and T-cytotoxic cell mitoROS were significantly greater in adults with MDD compared with HA (both: P < 0.05). There were no differences in circulating cytokines between groups (all cytokines: P > 0.05). Collectively, these findings suggest that elevated T-cell mitoROS may represent an early marker of immune system dysregulation in young, otherwise healthy, adults with MDD.NEW & NOTEWORTHY To our knowledge, we provide the first evidence of augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) in young, otherwise healthy adults with MDD. Although the elevated T-cell mitoROS did not correspond to a proinflammatory profile, these findings suggest that elevated T-cell mitoROS may be an early marker of immune system dysregulation in young adults with MDD.

Impact of COVID-19 on cardiac autonomic function in healthy young adults: potential role of symptomatology and time since diagnosis.

Emerging evidence suggests that COVID-19 may affect cardiac autonomic function; however, the limited findings in young adults with COVID-19 have been equivocal. Notably, symptomology and time since diagnosis appear to influence vascular health following COVID-19, but this has not been explored in the context of cardiac autonomic regulation. Therefore, we hypothesized that young adults who had persistent symptoms following COVID-19 would have lower heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) compared with those who had COVID-19 but were asymptomatic at testing and controls who never had COVID-19. Furthermore, we hypothesized that there would be relationships between cardiac autonomic function measures and time since diagnosis. We studied 27 adults who had COVID-19 and were either asymptomatic (ASYM; n = 15, 6 females); 21 ± 4 yr; 8.4 ± 4.0 wk from diagnosis) or symptomatic (SYM; n = 12, 9 females); 24 ± 3 yr; 12.3 ± 6.2 wk from diagnosis) at testing, and 20 adults who reported never having COVID-19 (24 ± 4 yr, 11 females). Heart rate and beat-to-beat blood pressure were continuously recorded during 5 min of rest to assess HRV and cardiac BRS. HRV [root mean square of successive differences between normal heartbeats (RMSSD); control, 73 ± 50 ms; ASYM, 71 ± 47 ms; and SYM, 84 ± 45 ms; P = 0.774] and cardiac BRS (overall gain; control, 22.3 ± 10.1 ms/mmHg; ASYM, 22.7 ± 12.2 ms/mmHg; and SYM, 24.3 ± 10.8 ms/mmHg; P = 0.871) were not different between groups. However, we found correlations with time since diagnosis for HRV (e.g., RMSSD, r = 0.460, P = 0.016) and cardiac BRS (overall gain, r = 0.470, P = 0.014). These data suggest a transient impact of COVID-19 on cardiac autonomic function that appears mild and unrelated to persistent symptoms in young adults.NEW & NOTEWORTHY The potential role of persistent COVID-19 symptoms on cardiac autonomic function in young adults was investigated. We observed no differences in heart rate variability or cardiac baroreflex sensitivity between controls who never had COVID-19 and those who had COVID-19, regardless of symptomology. However, there were significant relationships between measures of cardiac autonomic function and time since diagnosis, suggesting that COVID-19-related changes in cardiac autonomic function are transient in young, otherwise healthy adults.

Sympathetic transduction in humans: recent advances and methodological considerations.

Ever since their origin more than one half-century ago, microneurographic recordings of sympathetic nerve activity have significantly advanced our understanding of the generation and regulation of central sympathetic outflow in human health and disease. For example, it is now appreciated that a myriad of disease states exhibit chronic sympathetic overactivity, a significant predictor of cardiovascular morbidity and mortality. Although microneurographic recordings allow for the direct quantification of sympathetic outflow, they alone do not provide information with respect to the ensuing sympathetically mediated vasoconstriction and blood pressure (BP) response. Therefore, the study of vascular and/or BP responses to sympathetic outflow (i.e., sympathetic transduction) has now emerged as an area of growing interest within the field of neural cardiovascular control in human health and disease. To date, studies have primarily examined sympathetic transduction under two distinct paradigms: when reflexively evoking sympatho-excitation through the induction of a laboratory stressor (i.e., sympathetic transduction during stress) and/or following spontaneous bursts of sympathetic outflow occurring under resting conditions (i.e., sympathetic transduction at rest). The purpose of this brief review is to highlight how our physiological understanding of sympathetic transduction has been advanced by these studies and to evaluate the primary analytical techniques developed to study sympathetic transduction in humans. We also discuss the framework by which the assessment of sympathetic transduction during stress reflects a fundamentally different process relative to sympathetic transduction at rest and why findings from investigations using these different techniques should be interpreted as such and not necessarily be considered one and the same.

CORP: Standardizing methodology for assessing spontaneous baroreflex control of muscle sympathetic nerve activity in humans.

The use of spontaneous bursts of muscle sympathetic nerve activity (MSNA) to assess arterial baroreflex control of sympathetic nerve activity has seen increased utility in studies of both health and disease. However, methods used for analyzing spontaneous MSNA baroreflex sensitivity are highly variable across published studies. Therefore, we sought to comprehensively examine methods of producing linear regression slopes to quantify spontaneous MSNA baroreflex sensitivity in a large cohort of subjects (n = 150) to support a standardized procedure for analysis that would allow for consistent and comparable results across laboratories. The primary results demonstrated that 1) consistency of linear regression slopes was considerably improved when the correlation coefficient was above -0.70, which is more stringent compared with commonly reported criterion of -0.50, 2) longer recording durations increased the percentage of linear regressions producing correlation coefficients above -0.70 (1 min = 15%, 2 min = 28%, 5 min = 53%, 10 min = 67%, P < 0.001) and reaching statistical significance (1 min = 40%, 2 min = 69%, 5 min = 78%, 10 min = 89%, P < 0.001), 3) correlation coefficients were improved with 3-mmHg versus 1-mmHg and 2-mmHg diastolic blood pressure (BP) bin size, and 4) linear regression slopes were reduced when the acquired BP signal was not properly aligned with the cardiac cycle triggering the burst of MSNA. In summary, these results support the use of baseline recording durations of 10 min, a correlation coefficient above -0.70 for reliable linear regressions, 3-mmHg bin size, and importance of properly time-aligning MSNA and diastolic BP. Together, these findings provide best practices for determining spontaneous MSNA baroreflex sensitivity under resting conditions for improved rigor and reproducibility of results.

Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19.

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19.NEW & NOTEWORTHY This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.

Influence of sex on heightened vasoconstrictor mechanisms in the non-Hispanic black population.

Cardiovascular disease (CVD) affects individuals of all races and ethnicities; however, its prevalence is highest in non-Hispanic black individuals (BL) relative to other populations. While previous research has provided valuable insight into elevated CVD risk in the BL population, this work has been almost exclusively conducted in men. This is alarming given that BL women suffer from CVD at an equivalent rate to BL men and each has a greater prevalence when compared to all other ethnicities, regardless of sex. The importance of investigating sex differences in mechanisms of cardiovascular function is highlighted by the National Institute of Health requiring sex to be considered as a biological variable in research studies to better our "understanding of key sex influences on health processes and outcomes." The mechanism(s) responsible for the elevated CVD risk in BL women remains unclear and is likely multifactorial. Limited studies in BL women suggest that, while impaired vasodilator capacity is involved, heightened vasoconstrictor tone and/or responsiveness may also contribute. Within this mini-review, we will discuss potential mechanisms of elevated rates of hypertension and other CVDs in BL individuals with a particular focus on young, otherwise healthy, college-aged women. To stimulate academic thought and future research, we will also discuss potential mechanisms for impaired vascular function in BL women, as well as possible divergent mechanisms between BL men and women based on either preliminary data or plausible speculation extending from findings in the existing literature. Last, we will conclude with potential future research directions aimed at better understanding the elevated risk for hypertension and CVD in BL women.

Assessment of resistance vessel function in human skeletal muscle: guidelines for experimental design, Doppler ultrasound, and pharmacology.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.

Augmented pressor and sympathoexcitatory responses to the onset of isometric handgrip in patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) exhibit greater daytime blood pressure (BP) variability, increasing their cardiovascular risk. Given the number of daily activities that incorporate short-duration isometric muscle contractions (e.g., carrying groceries), herein we investigated BP and muscle sympathetic nerve activity (MSNA) responses at the onset of isometric handgrip (HG). We tested the hypothesis that, relative to control subjects, patients with T2D would exhibit exaggerated pressor and MSNA responses to the immediate onset of HG. Mean arterial pressure (MAP) and MSNA were quantified during the first 30 s of isometric HG at 30% and 40% of maximal voluntary contraction (MVC) and during a cold pressor test (CPT), a nonexercise sympathoexcitatory stimulus. The onset of 30% MVC HG evoked similar increases in MAP between groups (P = 0.17); however, the increase in MSNA was significantly greater in patients with T2D versus control subjects with the largest group difference at 20 s (P < 0.001). At the onset of 40% MVC HG, patients with T2D demonstrated greater increases in MAP (e.g., 10 s, T2D: 9 ± 1 mmHg, controls: 5 ± 2 mmHg; P = 0.04). MSNA was also greater in patients with T2D at 40% MVC onset but differences were only significant at the 20-30 s timepoint (T2D: 15 ± 3 bursts/min, controls: -2 ± 4 bursts/min; P < 0.001). Similarly, MAP and MSNA responses were augmented during the onset of CPT in T2D patients. These findings demonstrate exaggerated pressor and MSNA reactivity in patients with T2D, with rapid and robust responses to both isometric contractions and cold stress. This hyper-responsiveness may contribute to daily surges in BP in patients with T2D, increasing their short-term and long-term cardiovascular risk.

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.

Augmented resting beat-to-beat blood pressure variability in young, healthy, non-Hispanic black men.

NEW FINDINGS: What is the central question of this study? The prevalence of hypertension in black individuals exceeds that in other racial groups. Despite this well-known heightened risk, the underlying contributory factors remain incompletely understood. We hypothesized that young black men would exhibit augmented beat-to-beat blood pressure variability compared with white men and that black men would exhibit augmented total peripheral resistance variability. What is the main finding and its importance? We demonstrate that young, healthy black men exhibit greater resting beat-to-beat blood pressure variability compared with their white counterparts, which is accompanied by greater variability in total peripheral resistance. These swings in blood pressure over time might contribute to the enhanced cardiovascular risk profile in black individuals. ABSTRACT: The prevalence of hypertension in black (BL) individuals exceeds that in other racial groups. Recently, resting beat-to-beat blood pressure (BP) variability has been shown to predict cardiovascular risk and detect target organ damage better than ambulatory BP monitoring. Given the heightened risk in BL individuals, we hypothesized young BL men would exhibit augmented beat-to-beat BP variability compared with white (WH) men. Furthermore, given studies reporting reduced vasodilatation and augmented vasoconstriction in BL individuals, we hypothesized that BL men would exhibit augmented variability in total peripheral resistance (TPR). In 45 normotensive men (24 BL), beat-to-beat BP (Finometer) was measured during 10-20 min of quiet rest. Cardiac output and TPR were estimated (Modelflow method). Despite similar resting BP, BL men exhibited greater BP standard deviation (e.g. systolic BP SD; BL, 7.1 ± 2.2 mmHg; WH, 5.4 ± 1.5 mmHg; P = 0.006) compared with WH men, which was accompanied by a greater TPR SD (P = 0.003), but not cardiac output SD (P = 0.390). Other traditional measures of variability provided similar results. Histogram analysis indicated that BL men exhibited a greater percentage of cardiac cycles with BPs higher (> +10 mmHg higher) and lower (< -8 mmHg lower) than mean systolic BP compared with WH men (interaction, P < 0.001), which was accompanied by a greater percentage of cardiac cycles with high/low TPR (P < 0.001). In a subset of subjects (n = 30), reduced sympathetic baroreflex sensitivity was associated with augmented BP variability (r = -0.638, P < 0.001), whereas cardiac baroreflex sensitivity had no relationship (P = 0.447). Herein, we document an augmented beat-to-beat BP variability in young BL men, which coincided with fluctuations in vascular resistance and reduced sympathetic BRS.

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.