Association between time-of-day for eating, exercise, and sleep with blood pressure in adults with elevated blood pressure or hypertension: a systematic review.

The purpose of this review is to synthesize results from studies examining the association between time-of-day for eating, exercise, and sleep with blood pressure (BP) in adults with elevated BP or hypertension. Six databases were searched for relevant publications from which 789 were identified. Ten studies met inclusion criteria. Four studies examined time-of-day for eating, five examined time-of-day for exercise, and one examined time-of-day for sleep and their associations with BP. Results suggested that later time-of-day for eating ( n  = 2/4) and later sleep mid-point ( n  = 1/1) were significantly related to higher BP in multivariable models, whereas morning ( n  = 3/5) and evening ( n  = 4/5) exercise were associated with significantly lower BP. Although this small body of work is limited by a lack of prospective, randomized controlled study designs and underutilization of 24 h ambulatory BP assessment, these results provide preliminary, hypothesis-generating support for the independent role of time-of-day for eating, exercise, and sleep with lower BP.

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.

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.

Daily Stress and Microvascular Dysfunction: The Buffering Effect of Physical Activity.

Although often short-lived, emotional responsiveness to daily stressors ( i.e. , routine and sometimes unexpected everyday hassles) is associated with increased cardiovascular disease (CVD), morbidity, and mortality. Here, we present the novel hypothesis that a disruption of microvascular homeostasis is a key antecedent. In addition, we postulate that physical activity may mitigate the psychobiological consequences of daily stress, thereby limiting pathophysiological CVD-related sequelae.

Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder.

Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [NG-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before (P = 0.023), but not after (P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline (R2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before (P < 0.01), but not after (P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression.NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.

Microvascular ß-Adrenergic Receptor-Mediated Vasodilation Is Attenuated in Adults With Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with sympathetic overactivity and alterations in peripheral adrenergic receptor function; however, no studies have directly assessed vasoconstrictor responsiveness in adults with MDD. We tested the hypotheses that ß-adrenergic receptor-mediated vasodilation would be blunted in adults with MDD compared with healthy nondepressed adults (HA) and would functionally contribute to exaggerated norepinephrine-induced vasoconstriction. METHODS: In 13 HA (8 female; 24±4 years) and in 12 adults with MDD (8 female; 22±3 yrs), red blood cell flux was measured during graded intradermal microdialysis perfusion of the ß-adrenergic receptor agonist isoproterenol (10-10 to 10-4 mol/L) and, separately, during the perfusion of norepinephrine (10-12 to 10-2 mol/L), alone and in combination with the ß-adrenergic receptor antagonist propranolol (2 mmol/L). Nonadrenergic vasoconstriction was assessed via perfusion of angiotensin II (10-12 to 10-4 mol/L). RESULTS: Isoproterenol-induced vasodilation was blunted in adults with MDD (188.9±70.1 HA versus 128.3±39.4 au MDD, P=0.025). Net norepinephrine-induced vasoconstriction was exaggerated in adults with MDD (-0.16±0.54 HA versus -0.75±0.56 au MDD, P=0.014); however, there were no group differences in angiotensin II-induced vasoconstriction. Propranolol potentiated norepinephrine-induced vasoconstriction in HA (-0.16±0.54 norepinephrine versus -1.60±1.40 au propranolol, P<0.01) but had no effect in adults with MDD (-0.75±0.56 norepinephrine versus -1.58±1.56 au propranolol, P=0.08). CONCLUSIONS: ß-adrenergic receptor-mediated microvascular vasodilation was blunted in adults with MDD and contributed to exaggerated adrenergic vasoconstriction. The relative loss of the vasoprotective effect of ß-adrenergic receptor-mediated vasodilation may contribute to increased peripheral resistance, thereby driving the development of hypertension in adults with MDD.

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.

Influence of Age and Estradiol on Sympathetic Nerve Activity Responses to Exercise in Women.

INTRODUCTION: Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses. METHODS: Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 µg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts. RESULTS: Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P < 0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P < 0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol. CONCLUSIONS: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

COVID-19-Related Daily Stress Processes in College-Aged Adults: Examining the Role of Depressive Symptom Severity.

Exposure to daily stressors specific to the COVID-19 pandemic (e.g., threat of infection) is associated with emotional distress, heightened stress reactivity, and increased depressive symptomology. Herein, we examined whether current depressive symptomology modulates the association between COVID-19-related daily stressor exposure and negative affective reactivity in young, otherwise healthy, college-aged adults. Fifty-eight adults (21 men; 22±3years) completed a daily web-based interview for eight consecutive days to assess COVID-19-related daily stress exposure and emotional responsiveness (September-November 2020). Depressive symptom severity was assessed using the Patient Health Questionnaire-9 (PHQ-9), and a score of ≥10 (range: 0-27) was used to define adults with a depressive episode (n=20). Participants reported at least one COVID-19-related stressor on 35.8% of interview days. Depressive symptomology did not predict the likelihood of exposure to a COVID-19-related stressor (p=0.46; OR=1.52; 95% CI: 0.492-4.718). However, negative affect (NA) was greater on days with an exposure to any COVID-19-specific daily stressor in adults with moderate-to-severe depressive symptoms (b=0.28, SE=0.093, p=0.003) but not in those without (b=0.009, SE=0.074, p=0.90), such that negative affective reactivity to COVID-19-related stressors was amplified in adults with a current depressive episode (p=0.019). Depressive symptomology did not moderate positive affective reactivity (p=0.686). Taken together, these data suggest that exposure to daily stressors related to COVID-19 further worsens NA in adults with a current depressive episode, potentially rendering them more susceptible to adverse mental health outcomes during the pandemic.

Hydrogen sulfide-dependent microvascular vasodilation is improved following chronic sulfhydryl-donating antihypertensive pharmacotherapy in adults with hypertension.

Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H2S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H2S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10-10 to 10-1 M) alone (control) and in combination with an inhibitor of enzymatic H2S production [10-3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028 M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16-wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H2S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55 AU post; P = 0.04) and increased the H2S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H2S-dependent mechanisms.NEW & NOTEWORTHY This is the first study to prospectively assess the effects of sulfhydryl antihypertensive treatment on microvascular endothelial function in adults with hypertension. Our data suggest that 16 wk of SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in middle-aged adults with hypertension, in part via H2S-dependent mechanisms.

Cerebrovascular reactivity is blunted in young adults with major depressive disorder: The influence of current depressive symptomology.

BACKGROUND: In middle-aged adults with depression, cerebral vasodilatory reactivity is blunted; however, this has not been examined in treatment-naïve young adults with major depressive disorder (MDD). We tested the hypothesis that cerebrovascular reactivity would be blunted in young adults (18-30 yrs) with MDD compared to healthy non-depressed adults (HA) and would be attenuated to a greater extent in adults with symptomatic MDD (sMDD) compared to adults with MDD in remission (euthymic MDD; eMDD). METHODS: Sixteen adults with MDD [21±3yrs; n = 8 sMDD (6 women); n = 8 eMDD (5 women)] and 14 HA (22±3yrs; 9 women) participated. End-tidal carbon dioxide concentration (PETCO2; capnograph), beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), and internal carotid artery (ICA) diameter and blood velocity (Doppler ultrasound) were continuously measured during baseline and rebreathing-induced hypercapnia. Cerebrovascular reactivity was calculated as the relative increase in vascular conductance during hypercapnia. RESULTS: In adults with MDD, cerebrovascular reactivity in the MCA (∆39±9 HA vs. ∆31±13% MDD, p = 0.04), but not the ICA (∆36±24 HA vs. ∆34±18% MDD, p = 0.84), was blunted compared to HA. In the MCA, cerebrovascular reactivity was reduced in adults with sMDD compared to adults with eMDD (∆36±11 eMDD vs. ∆25±13% sMDD, p = 0.02). LIMITATIONS: The cross-sectional nature approach limits conclusions regarding the temporal nature of this link. CONCLUSION: These data indicate that MCA cerebrovascular reactivity is blunted in young adults with MDD and further modulated by current depressive symptomology, suggesting that the management of depressive symptomology may secondarily improve cerebrovascular health.

Thermoregulatory reflex control of cutaneous vasodilation in healthy aging.

Reflex cutaneous vasodilation during heating is attenuated in healthy human aging secondary to blunted increases in efferent skin sympathetic nervous system activity (SSNA) and reductions in end-organ sensitivity. Whether age-related alterations in the mean body temperature ( T - b) threshold for increasing SSNA and/or the sensitivity of responses are evident with aging have not been examined. We tested the hypotheses that the Tb threshold for SSNA and cutaneous vascular conductance (CVC) would be increased, but the sensitivity would be reduced, with aging. Reflex vasodilation was induced in 13 young (23 ± 3 y) and 13 older (67 ± 7 y) adults using a water-perfused suit to systematically increase mean skin and esophageal temperatures. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome were continuously measured. SSNA was normalized to baseline; CVC was normalized as a percentage of maximal CVC. Baseline T - b was lower in older adults (36.0 ± 0.4°C vs 36.4 ± 0.3°C; p = 0.005). During passive heating, the ∆ T - b thresholds for increasing SSNA and CVC were greater (1.3 ± 0.4°C vs 0.9 ± 0.3°C; p = 0.007 and 1.3 ± 0.4°C vs 0.8 ± 0.3°C; p = 0.002, respectively) in older adults. The slope of the relation between both SSNA (0.31 ± 0.23 vs 0.13 ± 0.10 V⋅s⋅°C -1; p = 0.01) and CVC (87.5 ± 50.1 vs 32.4 ± 18.1%max⋅°C-1; p = 0.002) vs T - b was lower in older adults. The relative T - b threshold for activation of SSNA and the initiation of reflex cutaneous vasodilation is higher in older adults, and once activated, the sensitivity of both responses is diminished, supporting the concept that the efferent component of the thermoregulatory reflex arc is impaired in healthy aging. Abbreviations: CI: confidence interval; CVC: cutaneous vascular conductance; SSNA: skin sympathetic nervous system activity; T - b: mean body temperature; Tes: esophageal temperature; T - sk: mean skin temperature.

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.

Reproducibility of the neurocardiovascular responses to common laboratory-based sympathoexcitatory stimuli in young adults.

The magnitude of blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to laboratory stressors is commonly used to compare neurocardiovascular responsiveness between groups and conditions. However, no studies have rigorously examined the reproducibility of BP and MSNA responsiveness. Here, we assess the within-visit reproducibility of BP (finger photoplethysmography) and MSNA (microneurography) responses to isometric handgrip (HG) and postexercise ischemia (PEI) in young healthy adults (n = 30). In a subset (n = 21), we also examined the between-visit reproducibility of responsiveness to HG, PEI, and the cold pressor test (CPT). Intraclass correlation coefficients (ICCs) were used as a primary reproducibility measure (e.g., ICC >0.75 is considered very good). Within a visit, the increase in mean arterial pressure during HG [ICC = 0.85 (0.69-0.93); P < 0.001] and PEI [ICC = 0.85 (0.69-0.93); P < 0.001] demonstrated very good reproducibility. Furthermore, the between-visit reproducibility of the pressor response to HG [ICC = 0.85 (0.62-0.94); P < 0.001], PEI [ICC = 0.84 (CI = 0.58-0.94); P < 0.001], and the CPT [ICC = 0.89 (0.72-0.95) P < 0.001]) were also very good. However, there was greater variability in both the within- [HG: ICC = 0.58 (-0.22-0.85), P = 0.001; PEI: ICC = 0.33 (-0.24-0.69), P = 0.042] and between-visit reproducibility of MSNA responsiveness [HG: ICC = 0.87 (0.53-0.96), P = 0.001; PEI: ICC = 0.24 (-0.62-0.78), P = 0.27; CPT: ICC = 0.77 (0.29-0.93), P = 0.007]. The magnitude of the BP response to several standard laboratory stimuli was very good, whereas the variability of the MSNA response to these perturbations was generally less consistent, particularly during PEI. These data provide novel insight for both study design and data interpretation when comparing neurocardiovascular responsiveness between different conditions, groups, or studies, as well as before and after interventions/treatments.NEW & NOTEWORTHY The magnitude of the increases in blood pressure and muscle sympathetic nerve activity in response to sympathoexcitatory stimuli such as static handgrip, postexercise ischemia, and the cold pressor test are commonly used to assess neurocardiovascular responsiveness. However, limited studies have comprehensively examined the reproducibility of these responses. We demonstrate that the reproducibility of the pressor response to these perturbations was very good within an individual, whereas the reproducibility of the MSNA response was less consistent.

AHA/ACC-defined stage 1 hypertensive adults do not display cutaneous microvascular endothelial dysfunction.

In 2017, the American Heart Association (AHA) and American College of Cardiology (ACC) redefined stage 1 hypertension to systolic blood pressure (BP) 130-139 mmHg or diastolic BP 80-89 mmHg; however, the degree to which microvascular endothelial dysfunction is evident in adults with stage 1 hypertension remains equivocal. We tested the hypotheses that cutaneous microvascular endothelial dysfunction would be present in adults with stage 1 hypertension (HTN1) compared with normotensive adults (NTN; BP <120/<80 mmHg) but would be less severe compared with adults with stage 2 hypertension (HTN2; systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and that this graded impairment would be mediated by reductions in nitric oxide (NO)-dependent dilation. This retrospective analysis included 20 NTN (5 men; 45-64 yr; BP 94-114/60-70 mmHg), 22 HTN1 (11 men; 40-74 yr; BP 110-134/70-88 mmHg), and 44 HTN2 (27 men; 40-74 yr; BP 128-180/80-110 mmHg). BP and nocturnal dipping status were also assessed using 24-h ambulatory BP monitoring. Red cell flux (laser Doppler flowmetry) was measured during intradermal microdialysis perfusion of acetylcholine (ACh; 10-10 to 10-1M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mM). ACh-induced dilation was impaired in HTN2 (P < 0.01), but not in HTN1 (P = 0.85), compared with NTN. Furthermore, reductions in NO-dependent dilation were evident in HTN2 (P < 0.01) but not in HTN1 (P = 0.76). Regardless of BP, endothelium-dependent dilation was impaired in nondippers (nighttime drop in systolic BP <10%) compared with dippers (nighttime drop in systolic BP ≥10%, P < 0.05). In conclusion, functional impairments in NO-mediated endothelium-dependent dilation were not evident in HTN1. However, regardless of BP classification, the lack of a nocturnal dip in BP was associated with blunted endothelium-dependent dilation.NEW & NOTEWORTHY This is the first study to pharmacologically assess the mechanistic regulation of endothelial function in adults with hypertension, classified according to the 2017 clinical guidelines set for by the American Heart Association (AHA) and American College of Cardiology (ACC). Compared with that in normotensive adults, nitric oxide-mediated endothelium-dependent dilation is impaired in adults with stage 2, but not stage 1, hypertension. Adults lacking a nighttime dip in blood pressure demonstrated reductions in endothelium-dependent dilation.

Greater Daily Psychosocial Stress Exposure is Associated With Increased Norepinephrine-Induced Vasoconstriction in Young Adults.

Background Epidemiological data suggest a link between psychological stress and increased cardiovascular disease risk; however, the underlying mechanisms remain incompletely understood. The purpose of this investigation was to directly examine the influence of daily psychosocial stress on microvascular adrenergic vasoconstrictor responsiveness in healthy adults. We hypothesized increased daily psychosocial stress would be positively related to increased norepinephrine-induced vasoconstriction. Methods and Results Eighteen healthy adults (19-36 years; 10 women) completed a daily psychosocial experiences telephone interview for 8 consecutive evenings in order to document their exposure and emotional responsiveness to common stressors (eg, arguments, work stress) over the preceding 24 hrs. On the last interview day, red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of norepinephrine (10-12 to 10-2 mol/L) and expressed as a percentage of baseline vascular conductance. Exogenous norepinephrine elicited progressive and robust vasoconstriction in all individuals (maximal vasoconstriction: 71±4%base; cumulative vasoconstriction [area under the curve]: 118±102 arbitrary units). Participants experienced a stressor on 51±5% of days and a total of 5.2±0.9 stressors over the 8-day time frame. Increased daily frequency of stressor exposure was positively related to both maximal (R2=0.26; P=0.03) and cumulative (R2=0.31; P=0.02) vasoconstrictor responsiveness. Likewise, the total number of stressors was associated with increased maximal (R2=0.40; P<0.01) and cumulative (R2=0.27; P=0.03) norepinephrine-induced vasoconstriction. Neither stressor severity nor stress-related emotions were related to vasoconstrictor responsiveness. Conclusions Collectively, these data suggest that daily psychosocial stressor exposure by itself is sufficient to adversely influence microvascular vasoconstrictor function, regardless of the perceived severity or emotional consequences of the stressor exposure.

Peripheral microvascular serotoninergic signaling is dysregulated in young adults with major depressive disorder.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2) NO-dependent and 3) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1) serotonin (10-10 to 10-1 mol/L) alone and in combination with a nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 µmol/L); and 2) paroxetine (n = 6; 10-9 to 10-2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment.NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Chronic statin therapy is associated with enhanced cutaneous vascular responsiveness to sympathetic outflow during passive heat stress.

KEY POINTS: Impairments in both central sympathetic and peripheral microvascular function contribute to blunted reflex cutaneous vasodilatation during heat stress in healthy older adults. Hypercholesterolaemia is associated with decrements in neurovascular function; however, little is known about the impact of hypercholesterolaemia on the integrated responses to heat stress. Further, whether chronic statin therapy alters skin sympathetic outflow or its relation to cutaneous vascular conductance during heat stress is unknown. We demonstrate that reflex cutaneous vasodilatation is impaired in older hypercholesterolaemic adults but not in formerly hypercholesterolaemic adults currently treated with a statin compared to age-matched controls. Additionally, chronic statin treatment-induced improvements in reflex vasodilatation are mediated, in part, by increases in end-organ responsiveness to efferent sympathetic outflow during whole-body heating. These data add to the growing body of literature substantiating the beneficial pleiotropic neurovascular effects of chronic statin treatment and provide further support for the use of statins to confer additional cardioprotective benefits in older adults. ABSTRACT: Attenuated reflex cutaneous vasodilatation in healthy human ageing is mediated by alterations in both central (sympathetic outflow) and peripheral (microvascular endothelial) function. Hypercholesterolaemia is associated with further impairments in neurovascular function. HMG-CoA reductase inhibitors (statins) improve cutaneous endothelium-dependent dilatation; however, whether statin therapy alters skin sympathetic nervous system activity (SSNA) or its relation to cutaneous vascular conductance (CVC) during passive heat stress is unknown. We hypothesized that (1) hypercholesterolaemic older adults would demonstrate blunted increases in both SSNA and CVC during passive heating and (2) chronic statin treatment would improve the response range and sensitivity of the SSNA:CVC relation. Reflex vasodilatation in response to a 1.0°C rise in oral temperature (Tor ; water perfused suit) was induced in 13 healthy normocholesterolaemic adults (62 ± 2 years; LDL = 113 ± 7 mg/dl), 10 hypercholesterolaemic adults (60 ± 1 years; LDL = 183 ± 2 mg/dl), and 10 previously hypercholesterolaemic adults (64 ± 1 years; LDL = 102 ± 2 mg/dl) treated with lipophilic statin (10-40 mg daily). SSNA (peroneal microneurography) and red cell flux (laser-Doppler flowmetry) in the innervated dermatome (dorsum of foot) were continuously measured. Reflex vasodilatation was blunted in hypercholesterolaemic adults, but not in statin-treated adults, compared to normocholesterolaemic adults (at ∆Tor  = 1.0°C: normal = 36 ± 1%CVCmax , high = 32 ± 1%CVCmax , statin = 38 ± 1%CVCmax ; P < 0.01). ∆SSNA was not different (at ∆Tor  = 1.0°C: normal: ∆ = 393 ± 96%, high: ∆ = 311 ± 120%, statin: ∆ = 256 ± 90%; P = 0.11). The slope of the SSNA:CVC relation was blunted in hypercholesterolaemic adults (0.02 ± 0.03%CVCmax /%baseline ) compared to both normocholesterolaemic (0.09 ± 0.02%CVCmax /%baseline ; P = 0.024) and statin-treated (0.12 ± 0.05%CVCmax /%baseline ; P = 0.03) adults. Chronic statin treatment improves reflex cutaneous vasodilatation in formerly hypercholesterolaemic older adults by increasing end-organ responsiveness to sympathetic outflow during passive heat stress.

Self-Reported Everyday Psychosocial Stressors Are Associated With Greater Impairments in Endothelial Function in Young Adults With Major Depressive Disorder.

Background Despite the epidemiological associations between psychological stress, depression, and increased cardiovascular disease risk, no studies have examined the relation between naturally occurring psychosocial stressors and directly measured microvascular function in adults with major depressive disorder ( MDD ). We tested the hypothesis that young adults with MDD exposed to everyday psychosocial stressors would exhibit more severe impairments in endothelium-dependent dilation ( EDD ) compared with: (1) healthy nondepressed adults ( HCs ); and (2) adults with MDD without acute psychosocial stress exposure. Methods and Results Twenty HCs (22±1 years) and 23 otherwise healthy adults with MDD (20±0.3 years) participated in the study. Participants completed a psychosocial experiences survey to document their exposure to any of 6 stressors over the preceding 24 hours (eg, arguments, work stressors). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of acetylcholine (10-10 to 10-1mol/L). EDD was expressed as a percentage of maximum vascular conductance (flux/mm Hg). Multiple linear regression was used to determine the associations between stress, EDD , and MDD . Adults with MDD reported a greater number and severity of psychosocial stressors compared with HCs (all P<0.05). EDD was blunted in adults with MDD ( HCs : 91±2 versus MDD : 74±3%; P<0.001). Exposure to any stressor was related to more severe impairments in EDD in patients with MDD (no stressor: 81±3 versus 1+ stressors: 69±5%; P=0.04) but not in HCs ( P=0.48). Conclusions These data indicate that exposure to everyday psychosocial stressors is associated with greater impairments in endothelial function in patients with MDD , suggesting a potential mechanistic link between daily stress and depression in increased cardiovascular risk.

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder.

RATIONALE: In rodent models of depression, oxidative stress-induced reductions in NO bioavailability contribute to impaired endothelium-dependent dilation. Endothelial dysfunction is evident in major depressive disorder (MDD); however, the molecular mediators remain undefined. OBJECTIVE: We sought to translate preclinical findings to humans by testing the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential modulatory influences of sex, in MDD. METHODS AND RESULTS: Twenty-four treatment-naive, otherwise healthy, young adults with MDD (14 women; 18-23 years) and 20 healthy adults (10 women; 19-30 years) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine, alone and in combination with an NO synthase inhibitor (L-NAME), a superoxide scavenger (Tempol), and an NADPH oxidase inhibitor (apocynin), as well as during perfusion of the endothelium-independent agonist sodium nitroprusside. Tissue oxidative stress markers (eg, nitrotyrosine abundance, superoxide production) were also quantified. Endothelium-dependent dilation was blunted in MDD and mediated by reductions in NO-dependent dilation. Endothelium-independent dilation was likewise attenuated in MDD. In MDD, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation. Acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Expression and activity of oxidative stress markers were increased in MDD. In a subset of adults with MDD treated with a selective serotonin reuptake inhibitor for their depressive symptoms and in remission (n=8; 7 women; 19-37 years), NO-mediated endothelium-dependent dilation was preserved, but endothelium-independent dilation was impaired, compared with healthy adults. CONCLUSIONS: Oxidative stress-induced reductions in NO-dependent dilation, as well as alterations in vascular smooth muscle function, directly contribute to microvascular dysfunction in MDD. Strategies targeting vascular oxidative stress may be viable therapeutic options for improving NO-mediated endothelial function and reducing cardiovascular risk in MDD.