Acute inflammation elicits decreased blood pressure but similar arterial stiffness in young African American adults.

African Americans (AA) have a higher risk for cardiovascular disease (CVD) as compared to their White (W) counterparts. CVD is characterized by increased blood pressure (BP), arterial stiffness and systemic inflammation. An acute inflammatory stimulus may explain physiological manifestations responsible for amplified CVD in AA that are not apparent at rest. The purpose of this study was to evaluate central and peripheral BP, central and local arterial stiffness, and indices of pulse wave morphology in young healthy AA and W participants in response to acute inflammation. Concentrations of the inflammatory cytokine interleukin-6 (IL-6) and measures of central and peripheral BP, central arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)), local carotid arterial stiffness (ß-stiffness, elastic modulus (Ep)), and indices of pulse wave morphology were assessed in 28 participants (21 ± 2 years, AA: n = 11) at baseline (BL), 24 h and 48 h post-inflammation. Changes in IL-6 concentrations (ΔIL-6) were significantly greater at 24 h as compared to 48 h post-inflammation (0.652 ± 0.644 vs. -0.146 ± 0.532 pg/µl, P ≤ 0.0001). Among AA participants, central and peripheral diastolic BP were significantly decreased at 24 h post-inflammation as compared to BL (aortic diastolic BP: -4 ± 4 mmHg, P = 0.016; brachial diastolic BP: -4 ± 4 mmHg, P = 0.014). AA participants also experienced a significant decrease in central and peripheral mean arterial BP at 48 h post-inflammation as compared to BL (aortic mean arterial pressure: -4 ± 4 mmHg, P = 0.009; brachial mean arterial pressure: -4 ± 4 mmHg, P = 0.012). Despite haemodynamic changes, there were no differences in central or local carotid arterial stiffness or indices of pulse wave morphology.

Naturally menstruating women exhibit lower cardiovagal baroreflex sensitivity than oral contraceptive users during the lower hormone phase.

The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2  = 0.15, P = 0.024), but not progesterone (R2  = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2  = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2  = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS. NEW FINDINGS: What is the central question of this study? Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)? What is the main finding and its importance? The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.

Race and sex differences in ROS production and SOD activity in HUVECs.

Black individuals and men are predisposed to an earlier onset and higher prevalence of hypertension, compared with White individuals and women, respectively. Therefore, the influence of race and sex on reactive oxygen species (ROS) production and superoxide dismutase (SOD) activity following induced inflammation was evaluated in female and male human umbilical vein endothelial cells (HUVECs) from Black and White individuals. It was hypothesized that HUVECs from Black individuals and male HUVECs would exhibit greater ROS production and impaired SOD activity. Inflammation was induced in HUVEC cell lines (n = 4/group) using tumor necrosis factor-alpha (TNF-α, 50ng/ml). There were no between group differences in ROS production or SOD activity in HUVECs from Black and White individuals, and HUVECs from Black individuals exhibited similar SOD activity at 24hr compared with 4hr of TNF-α treatment (p>0.05). However, HUVECs from White individuals exhibited significantly greater SOD Activity (p<0.05) at 24hr as compared to 4hr in the control condition but not with TNF-α treatment (p>0.05). Female HUVECs exhibited significantly lower ROS production than male HUVECs in the control condition and following TNF-α induced inflammation (p<0.05). Only female HUVECs exhibited significant increases in SOD activity with increased exposure time to TNF-α induced inflammation (p<0.05). HUVECs from White individuals alone exhibit blunted SOD activity when comparing control and TNF-α conditions. Further, compared to female HUVECs, male HUVECs exhibit a pro-inflammatory state.

Influence of sex and presence of cardiovascular risk factors on relations between cardiorespiratory fitness and cerebrovascular hemodynamics.

Cerebral hemodynamics and pulsatility are important mechanisms of cerebrovascular and brain health. Cardiorespiratory fitness may improve cerebrovascular pulsatility in healthy females, but not in males. Whether cardiovascular disease (CVD) risk factors modify sex-specific associations of fitness with cerebral hemodynamics and vascular contributors to cerebral hemodynamics is unknown. We assessed V̇o2peak and cerebrovascular hemodynamics in 157 adults without (42 ± 13 yr, BMI 24.5 ± 2.7 kg/m2), and 66 adults with modifiable CVD risk factors (54 ± 8 yr, BMI 29.9 ± 4.0 kg/m2). Intracranial [middle cerebral artery (MCA) pulsatility index (PI), mean velocity, conductance, and pulsatile damping] and extracranial hemodynamics [carotid artery wave transmission/reflection, PI, pulse wave velocity (PWV)-ß, and carotid-femoral PWV] were assessed via transcranial Doppler/ultrasound and tonometry. Cardiorespiratory fitness was assessed via V̇o2peak during an incremental exercise test. Multiple regression was used to assess contributions of V̇o2peak to cerebrovascular outcomes after adjustment for relevant covariates. V̇o2peak was inversely associated with MCA PI among females (ß = -0.39, P = 0.01) but not males (ß = -0.16, P = 0.25) without CVD risk factors. V̇o2peak was positively associated with MCA PI among females (ß = 0.44, P = 0.01) and not associated in males with CVD risk factors (ß = -0.06, P = 0.079). V̇o2peak was beneficially associated with vascular contributors to cerebral hemodynamics but had sex-specific associations with carotid stiffness and pulse pressure in females without CVD risk factors only. These results suggest that sex-specific associations between fitness and cerebral pulsatility among females without CVD risk factors may relate to the differential effects of fitness on carotid stiffness and pulse pressure. In addition, the presence of modifiable CVD risk factors may influence the protective relations of fitness on cerebrovascular hemodynamics.NEW & NOTEWORTHY We identify beneficial associations between cardiorespiratory fitness and lower carotid stiffness and pulse pressure as potential mechanisms underlying sex-specific associations of fitness and cerebral pulsatility in females without modifiable risk factors. Greater fitness is beneficially associated with conductance, pulsatile damping, and forward wave energy among adults without risk factors; however, associations are attenuated among adults with modifiable risk factors. These data suggest sex and risk factors may alter cerebrovascular sensitivity to cardiorespiratory fitness.

Arterial stiffness and blood pressure are similar in naturally menstruating and oral contraceptive pill-using women during the higher hormone phases.

NEW FINDINGS: What is the central question of this study? Are there differences in blood pressure, arterial stiffness and indices of pressure waveforms between young oral contraceptive pill-using and naturally menstruating women during lower and higher hormone phases of their cycles? What is the main finding and its importance? Blood pressure, arterial stiffness and indices of pressure waveforms are influenced similarly by exogenous and endogenous hormones. However, lower levels of exogenous hormones moderately increase blood pressure among oral contraceptive pill-using women. ABSTRACT: Elevations in blood pressure (BP) are understood as having a bidirectional relationship with stiffening of central and peripheral arteries. Arterial stiffness is mitigated by oestrogen, which aides in arterial vasorelaxation. To evaluate whether BP, stiffness, and pressure waveforms were different between young healthy naturally menstruating (non-OCP) and oral contraceptive pill (OCP)-using women, we measured brachial and aortic BPs, carotid-to-femoral pulse wave velocity, carotid ß-stiffness, elastic modulus, central augmentation index and augmentation index normalized to a heart rate of 75 bpm, and forward and backward pressure waveforms in 22 women (22 (1) years, OCP: n = 12). To assess phasic differences, women were studied during the early follicular (≤5 days of menstruation onset) and early luteal (4 (2) days post-ovulation) phases of non-OCP and compared to the placebo pill (≤5 days of onset) and active pill (≤5 days of highest-dose active pill) phases of OCP. During the lower hormone phases, OCP users had significantly higher brachial systolic blood pressure (SBP) (119.3 (8.3) vs. 110.2 (8.3) mmHg, P = 0.02) and aortic SBP (104.10 (7.44) vs. 96.80 (6.39) mmHg, P = 0.03) as compared to non-OCP users; however, during the higher hormone phases, there were no differences in measures of brachial or aortic BP, arterial stiffness, or indices of BP waveforms between OCP and non-OCP users (P ≥ 0.05). In conclusion, exogenous and endogenous hormones have similar influences on BP and arterial stiffness; however, lower levels of exogenous hormones augment both central and peripheral BPs.

Similar inflammatory response and conduit artery vascular function between sexes following induced inflammation.

NEW FINDINGS: What is the central question of this study? Are there sex differences in vascular function following induced inflammation when oestrogen is typically similar between sexes? What is the main finding and its importance? The present study suggests no sex differences in conduit artery vascular responses to acutely induced inflammation during the low-oestrogen phase of the menstrual cycle in premenopausal women. However, women exhibit lower microvascular function than men. Overall, the results underpin the role of oestrogen in previously observed sex differences and the importance of reporting the phase in the hormonal cycle when women are studied. ABSTRACT: Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48 hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P < 0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P > 0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P > 0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P < 0.05; reactive hyperaemic area under the curve (in arbitrary units): women, BL 35,512 (14,916), 24H 34,428 (14,292) and 48H 39,467 (13,936); men, BL 61,748 (27,324), 24H 75,028 (29,051) and 48H 59,532 (13,960)]. When oestrogen concentrations are typically lower in women, women exhibit a similar inflammatory response and conduit artery function, but lower microvascular response to reactive hyperaemia, in comparison to age-matched men.

Vascular Health Triad in Humans With Hypertension-Not the Usual Suspects.

Hypertension (HTN) affects more than one-third of the US population and remains the top risk factor for the development of cardiovascular disease (CVD). Identifying the underlying mechanisms for developing HTN are of critical importance because the risk of developing CVD doubles with ∼20 mmHg increase in systolic blood pressure (BP). Endothelial dysfunction, especially in the resistance arteries, is the primary site for initiation of sub-clinical HTN. Furthermore, inflammation and reactive oxygen and nitrogen species (ROS/RNS) not only influence the endothelium independently, but also have a synergistic influence on each other. Together, the interplay between inflammation, ROS and vascular dysfunction is referred to as the vascular health triad, and affects BP regulation in humans. While the interplay of the vascular health triad is well established, new underlying mechanistic targets are under investigation, including: Inducible nitric oxide synthase, hydrogen peroxide, hydrogen sulfide, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor activated T cells. This review outlines the role of these unusual suspects in vascular health and function in humans. This review connects the dots using these unusual suspects underlying inflammation, ROS and vascular dysfunction especially in individuals at risk of or with diagnosed HTN based on novel studies performed in humans.

Interleukin-6 is higher in naturally menstruating women compared with oral contraceptive pill users during the low-hormone phase.

Endogenous sex hormone concentrations vary between healthy naturally menstruating (non-OCP) and oral contraceptive pill-using (OCP) women, as well as across cycles. The aim of this study was to investigate potential differences in concentrations of inflammatory cytokine interleukin-6 (IL-6) and vasoconstrictive substance endothelin-1 (ET-1) and measures of vascular function among relatively lower- and higher-hormone phases of non-OCP and OCP women. Concentrations of estrogen, progesterone, IL-6, and ET-1 and measures of vascular function were collected in 22 women (22 ± 1 yr, OCP: n = 12) during the early follicular (EF, ≤5 days of menstruation onset) and early luteal (EL, 4 ± 2 days postovulation) phases of non-OCP subjects and were compared to the placebo pill (PP, ≤5 days of PP onset) and active pill (AP, ≤5 days of highest-dose AP) phases of OCP subjects. Vascular function was assessed via brachial artery flow-mediated dilation (%FMD). Concentrations of endogenous estrogen and progesterone were higher in the EL phase compared with the EF phase of non-OCP (P = 0.01) but were similar between phases of OCP (P > 0.05). IL-6 was higher in non-OCP during the EF phase compared with the EL phase (P = 0.03) as well as compared with OCP during the PP phase (P = 0.002) but was similar between groups during the EL and AP phases, respectively (P > 0.05). Concentrations of ET-1 and measures of %FMD were similar between groups and unaffected by phase (P > 0.05). Thus, there exists variation in inflammation between young, healthy non-OCP and OCP women during the lower-hormone phase, despite similarities in vascular function and concentrations of ET-1 between groups and phases.NEW & NOTEWORTHY We demonstrate that despite having similar macrovascular function and concentrations of the vasoconstrictive substance endothelin-1 (ET-1) healthy naturally menstruating women display higher concentrations of circulating IL-6 during the lower-hormone phase of their menstrual cycle compared with 1) the higher-hormone phase of their menstrual cycle and 2) the lower-hormone phase of healthy women using oral contraceptive pills.

Race-specific changes in endothelial inflammation and microRNA in response to an acute inflammatory stimulus.

Both aberrant vascular reactivity to acute cardiovascular stress and epigenetic mechanisms such as microRNA (miR) may underlie the increased propensity for African Americans (AA) to develop cardiovascular disease. This study assessed racial differences in acute induced endothelial inflammation and related miRs. Cultured human umbilical vein endothelial cells (HUVECs) derived from AA and Caucasian Americans (CA) were exposed to influenza vaccine to determine changes in inflammatory markers, endothelial nitric oxide synthase (eNOS), and miR expression/release. Endothelial function [flow-mediated dilation (FMD)], circulating IL-6, and circulating miR were also measured in young, healthy AA and CA individuals before and after receiving the influenza vaccine. There were no significant racial differences in any parameters at baseline. The vaccine induced increases in IL-6 release (24%, P = 0.02) and ICAM-1 mRNA (40%, P = 0.03), as well as reduced eNOS mRNA (24%, P = 0.04) in AA HUVECs, but not in CA HUVECs (all P > 0.05). Intracellular levels of anti-inflammatory miR-221-3p and miR-222-3p increased specifically in CA HUVECs (72% and 53%, P = 0.04 and P = 0.06), whereas others did not change in either race. HUVEC secretion of several miRs decreased in both races, whereas the release of anti-inflammatory miR-150-5p was decreased only by AA cells (-30%, P = 0.03). In individuals of both races, circulating IL-6 increased approximately twofold 24 h after vaccination (both P < 0.01) and returned to baseline levels by 48 h, whereas FMD remained unchanged. Although macrovascular function was unaffected by acute inflammation in AA and CA individuals, AA endothelial cells exhibited increased susceptibility to acute inflammation and unique changes in related miR.NEW & NOTEWORTHY Used as an acute inflammatory stimulus, the influenza vaccine induced an inflammatory response and decreased eNOS gene expression in endothelial cells derived from African Americans, but not Caucasian Americans. Race-specific changes in intracellular expression and release of specific microRNAs also occurred and may contribute to an exaggerated inflammatory response in African Americans. In vivo, the vaccine caused similar systemic inflammation but had no effect on endothelial function or circulating microRNAs in individuals of either race.