Duration of Simultaneous Exposure to High-Risk and Lower-Risk Nephrotoxic Antimicrobials in the Neonatal Intensive Care Unit (NICU) and Future Adolescent Kidney Health.

OBJECTIVE: To determine whether greater duration of simultaneous exposure to antimicrobials with high nephrotoxicity risk combined with lower-risk antimicrobials (simultaneous exposure) in the neonatal intensive care unit (NICU) is associated with worse later kidney health in adolescents born preterm with very low birth weight (VLBW). STUDY DESIGN: Prospective cohort study of participants born preterm with VLBW (<1500 g) as singletons between January 1, 1992, and June 30, 1996. We defined simultaneous exposure as a high-risk antimicrobial, such as vancomycin, administered with a lower-risk antimicrobial on the same date in the NICU. Outcomes were serum creatinine, estimated glomerular filtration rate (eGFR), and first-morning urine albumin-creatinine ratio (ACR) at age 14 years. We fit multivariable linear regression models with days of simultaneous exposure and days of nonsimultaneous exposure as main effects, adjusting for gestational age, birth weight, and birth weight z-score. RESULTS: Of the 147 out of 177 participants who had exposure data, 97% received simultaneous antimicrobials for mean duration 7.2 days (SD 5.6). No participant had eGFR <90 ml/min/1.73 m2. The mean ACR was 15.2 mg/g (SD 38.7) and 7% had albuminuria (ACR >30 mg/g). Each day of simultaneous exposure was associated only with a 1.04-mg/g higher ACR (95% CI 1.01 to 1.06). CONCLUSIONS: Despite frequent simultaneous exposure to high-risk combined with lower-risk nephrotoxic antimicrobials in the NICU, there were no clinically relevant associations with worse kidney health identified in adolescence. Although future studies are needed, these findings may provide reassurance in a population thought to be at increased risk of chronic kidney disease.

Sex Differences in MicroRNA Expression and Cardiometabolic Risk Factors in Hispanic Adolescents with Obesity.

OBJECTIVE: To evaluate sex differences in microRNA (miRNA) expression, anthropometric measures, and cardiometabolic risk factors in Hispanic adolescents with obesity. STUDY DESIGN: Cross-sectional study of 68 (60% male) Hispanic adolescents with obesity, aged 13-17 years, recruited from a pediatric weight management clinic. We used small RNA sequencing to identify differentially expressed circulating miRNAs. We used ingenuity pathway analysis and David bioinformatic resource tools to identify target genes for these miRNAs and enriched pathways. We used standard procedures to measure anthropometric and cardiometabolic factors. RESULTS: We identified 5 miRNAs (miR-24-3p, miR-361-3p, miR-3605-5p, miR-486-5p, and miR-199b-3p) that differed between females and males. miRNA targets-enriched pathways included phosphatidylinositol 3-kinase-protein, 5' AMP-activated protein kinase, insulin resistance, sphingolipid, transforming growth factor-ß, adipocyte lipolysis regulation, and oxytocin signaling pathways. In addition, there were sex differences in blood pressure, skeletal muscle mass, lean body mass, and percent body fat. CONCLUSIONS: We have identified sex differences in miRNA expression in Hispanic adolescents relevant to cardiometabolic health. Future studies should focus on sex-specific mechanistic roles of miRNAs on gene pathways associated with obesity pathophysiology to support development of precision cardiometabolic interventions.

Influence of race on the effect of premature birth on salivary cortisol response to stress in adolescents.

BACKGROUND: Adolescents born preterm have altered hypothalamic-pituitary-adrenal axis function with a blunted cortisol stress response, however, the influences of intrauterine growth restriction and race are unclear. METHODS: We measured salivary cortisol before and 20 min after a maximal-exercise stress test and calculated the cortisol stress response. We used linear regression to compare cortisol stress responses between preterm and term groups, adjusting for birth weight z-score and maternal hypertension, and examined effect modification by race and sex. RESULTS: We evaluated 171 adolescents born preterm with very low birth weight and 50 born term. Adolescents born preterm had reduced cortisol stress response compared to term (0.03 vs. 0.08 µg/dL, p = 0.04). This difference was race dependent: non-Black adolescents born preterm had significantly reduced cortisol stress response compared to those born at term (adjusted ß: -0.74; 95% CI -1.34, -0.15), while there was no difference in Black adolescents (0.53; -0.16, 1.22). Sex did not modify the relationship. CONCLUSIONS: Adolescents born preterm exhibit a reduced salivary cortisol response to exercise stress, suggesting long-term alterations in the hypothalamic-pituitary-adrenal axis. This relationship was evident in non-Black but not in Black adolescents, suggesting that race may modify the influence of preterm birth on stress alterations of the hypothalamic-pituitary-adrenal axis.

Central ANG-(1-7) infusion improves blood pressure regulation in antenatal betamethasone-exposed sheep and reveals sex-dependent effects on oxidative stress.

Fetal exposure to betamethasone (BMX) as a consequence of glucocorticoid administration to women threatening premature delivery may lead to long-term deleterious effects on the cardiovascular system and dysregulation of blood pressure in exposed adults. Indeed, adult offspring of BMX sheep exhibit increased mean arterial pressure (MAP) and attenuated baroreflex sensitivity (BRS) that are associated with lower medullary and cerebrospinal fluid (CSF) angiotensin-(1-7) [(ANG-(1-7)] content. Thus we determined the effects of ANG-(1-7) supplementation in the CSF on MAP, BRS, blood pressure (BPV) and heart rate variability (HRV) in conscious animals. The peptide or artificial CSF (aCSF) was infused continuously into the lateral ventricle (intracerebroventricular) of 4-mo-old male and female BMX sheep for 2 wk. Analysis of data from males and females combined revealed that intracerebroventricular ANG-(1-7) significantly lowered MAP and heart rate and improved BRS as compared with baseline; intracerebroventricular aCSF did not change these indexes. Similar patterns were observed for altered hemodynamics and autonomic function produced by intracerebroventricular ANG-(1-7) in both sexes. Oxidative stress and MAP kinase (MAPK) activation were lower in tissues from the dorsomedial medulla (DMM) of ANG-(1-7)-treated males but were unchanged in the treated females, when assessed at the end of the treatment period. We conclude that in the face of ANG-(1-7) deficiency in CSF and medullary tissue in BMX sheep intracerebroventricular supplementation of ANG-(1-7) lowers MAP and restores the impaired autonomic function to a similar degree in both males and females; however, the attenuation of MAPK and oxidative stress within the DMM was evident only in males. NEW & NOTEWORTHY We demonstrate that intracerebroventricular angiotensin-(1-7) [(ANG-(1-7)] treatment for 2 wk in antenatal betamethasone-exposed sheep provides beneficial effects on blood pressure and autonomic function. The physiological improvements are accompanied by an attenuation of oxidative stress in males but not females. The finding that ANG-(1-7) supplementation lowers blood pressure and restores the impaired autonomic function in a model of fetal programming previously shown to exhibit a deficiency in cerebrospinal fluid and brain tissue illustrates the potential for new therapeutic strategies for reducing cardiovascular dysfunction arising from prenatal events.

Children with orthostatic intolerance exhibit elevated markers of inflammation in the dorsal medulla.

Children with orthostatic intolerance (OI) have exaggerated decreases in heart rate variability (HRV) and suppression of baroreflex sensitivity (BRS) with standing. Accompanying brain transmitter and metabolite profiles are unknown. In this study, we used proton (1H) magnetic resonance spectroscopy (1H-MRS) to quantify markers of neuronal and glial integrity in a pilot study of children with OI compared with asymptomatic controls. Eighteen participants ages 10-18 yr were evaluated for blood pressure, heart rate (HR), and calculated indexes of autonomic function in supine and upright positions and, within an average of 2 wk, underwent 1H-MRS scans of dorsal medulla on a clinical 3T magnet while supine. As a result, of the 18 participants, 11 tested positive for OI and 7 did not. OI subjects exhibited higher HR and lower HRV and high-frequency α-index (HFα), an index of parasympathetic vagal tone, during standing compared with non-OI. HRV, sequence all (Seq All), high- and low-frequency (HFα and LFα) estimates of the spontaneous BRS decreased significantly, while BP variabilty increased significantly during standing only in subjects with OI. OI subjects had higher myoinositol (mIns) and total choline (tCho), markers of glial inflammation. Upright HFα and Seq All inversely correlated to supine tCho and mIns, respectively, independent of age and sex. In conclusions, in this pilot study, children with OI exhibit higher mIns and tCho in the dorsal medulla while supine that may reflect the well-established impairment in regulation of the autonomic nervous system upon standing. Neuroinflammation as an underlying cause or consequence of autonomic dysfunction is an intriguing possibility requiring further study.NEW & NOTEWORTHY (1H) magnetic resonance spectroscopy detected elevated markers of neuroinflammation in the dorsal medulla in children with impaired autonomic responses to head upright tilt. This first report of altered brain metabolites in this population provides a basis for future clinical studies using this methodology to aide in understanding complex autonomic disease states.

Antenatal Steroid Exposure, Aerobic Fitness, and Physical Activity in Adolescents Born Preterm with Very Low Birth Weight.

OBJECTIVE: To determine whether antenatal corticosteroid exposure is associated with aerobic fitness or physical activity participation in adolescents born preterm with very low birth weight (VLBW). STUDY DESIGN: Observational cohort study of 14-year-old adolescents (n = 173) born with VLBW between 1992 and 1996 at a regional perinatal center with 91 exposed to antenatal corticosteroids. Aerobic fitness was determined from peak oxygen uptake (V˙O2peak) obtained via maximal exercise testing on a cycle ergometer. Physical activity levels for the past year and past 2 months were estimated from a questionnaire. Between-group comparisons for continuous variables were evaluated using independent t tests or Mann-Whitney U tests. Generalized linear models were used to compare differences in fitness and physical activity between those exposed to antenatal corticosteroids and not exposed to antenatal corticosteroids, with race and sex in models. RESULTS: Regression analysis revealed an antenatal corticosteroids × sex × race interaction for V˙O2peak (P ≤ .001). Nonblack male adolescents exposed to antenatal corticosteroids had significantly greater V˙O2peak than nonblack male adolescents not exposed to antenatal corticosteroids expressed relative to body mass (mean difference [95% CI]; 8.5 [2.1-15.0] mL·kg-1·min-1) and lean body mass (9.0 [1.1-16.9] mL·kglean body mass-1·min-1). No antenatal corticosteroid group differences in V˙O2peak were evident in black male adolescents, or black and nonblack female adolescents. Male adolescents exposed to antenatal corticosteroids reported participating in significantly more total physical activity (medians: 14.6 vs 8.5) and vigorous physical activity (3.0 vs 0.95) per week for the past 2 months than male adolescents not exposed to antenatal corticosteroids. CONCLUSIONS: Exposure to antenatal corticosteroids was associated with greater physical activity participation and aerobic fitness in adolescents with VLBW, particularly in nonblack male adolescents, which may confer health benefits in this at-risk population.

Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm.

OBJECTIVES: To evaluate if obesity is associated with increased angiotensin II (Ang II) and decreased angiotensin-(1-7) or Ang-(1-7) in the circulation and urine among adolescents born prematurely. STUDY DESIGN: In a cross-sectional analysis of 175 14-year-olds born preterm with very low birth weight, we quantified plasma and urinary Ang II and Ang-(1-7) and compared their levels between subjects with overweight/obesity (body mass index ≥85th percentile, n = 61) and those with body mass index <85th percentile (n = 114) using generalized linear models, adjusted for race and antenatal corticosteroid exposure. RESULTS: Overweight/obesity was associated with higher systolic blood pressure and a greater proportion with high blood pressure. After adjustment for confounders, overweight/obesity was associated with an elevated ratio of plasma Ang II to Ang-(1-7) (ß: 0.57, 95% CI 0.23-0.91) and higher Ang II (ß: 0.21 pmol/L, 95% CI 0.03-0.39) but lower Ang-(1-7) (ß: -0.37 pmol/L, 95% CI -0.7 to -0.04). Overweight/obesity was associated with a higher ratio of urinary Ang II to Ang-(1-7) (ß: 0.21, 95% CI -0.02 to 0.44), an effect that approached statistical significance. CONCLUSIONS: Among preterm-born adolescents, overweight/obesity was associated with increased Ang II but reduced Ang-(1-7) in the circulation and the kidney as well as higher blood pressure. Obesity may compound the increased risk of hypertension and cardiovascular disease in individuals born prematurely by further augmenting the prematurity-associated imbalance in the renin-angiotensin system.

Fetal programming and the angiotensin-(1-7) axis: a review of the experimental and clinical data.

Hypertension is the primary risk factor for cardiovascular disease that constitutes a serious worldwide health concern and a significant healthcare burden. As the majority of hypertension has an unknown etiology, considerable research efforts in both experimental models and human cohorts has focused on the premise that alterations in the fetal and perinatal environment are key factors in the development of hypertension in children and adults. The exact mechanisms of how fetal programming events increase the risk of hypertension and cardiovascular disease are not fully elaborated; however, the focus on alterations in the biochemical components and functional aspects of the renin-angiotensin (Ang) system (RAS) has predominated, particularly activation of the Ang-converting enzyme (ACE)-Ang II-Ang type 1 receptor (AT1R) axis. The emerging view of alternative pathways within the RAS that may functionally antagonize the Ang II axis raise the possibility that programming events also target the non-classical components of the RAS as an additional mechanism contributing to the development and progression of hypertension. In the current review, we evaluate the potential role of the ACE2-Ang-(1-7)-Mas receptor (MasR) axis of the RAS in fetal programming events and cardiovascular and renal dysfunction. Specifically, the review examines the impact of fetal programming on the Ang-(1-7) axis within the circulation, kidney, and brain such that the loss of Ang-(1-7) expression or tone, contributes to the chronic dysregulation of blood pressure (BP) and cardiometabolic disease in the offspring, as well as the influence of sex on potential programming of this pathway.

Comparison of Candesartan and Angiotensin-(1-7) Combination to Mito-TEMPO Treatment for Normalizing Blood Pressure and Sympathovagal Balance in (mREN2)27 Rats.

Hypertensive transgenic (mRen2)27 rats exhibit impaired baroreflex sensitivity (BRS) for control of heart rate (HR). Intracerebroventricular infusion of Ang-(1-7) improves indices of vagal BRS independent of lowering mean arterial pressure (MAP), whereas AT1 receptor blockade normalizes MAP and indices of sympathetic tone without correcting the vagal BRS. Scavenging cellular reactive oxygen species (ROS) with tempol in brain fails to correct either hypertension or sympathovagal balance in these animals, despite reports that mitochondrial ROS contributes to Ang II-infusion hypertension. To examine effects of a putative preferential mitochondrial ROS scavenger in the brain of (mRen2)27 rats, ICV infusions of Mito-TEMPO (3.2 µg/2.5 µL/h) were compared with artificial cerebrospinal fluid (aCSF; 2.5 µL/h) and combination AT1 receptor antagonist candesartan (CAN: 4 µg/2.5 µL/h) plus Ang-(1-7) (0.1 µg/2.5 µL/h) treatment. MAP was lower after CAN + Ang-(1-7) treatment, and both vagal and sympathetic components of BRS and sympathovagal balance were improved. By contrast, Mito-TEMPO improved sympathetic components of BRS and tended to improve overall sympathovagal balance but failed to alter MAP in this model of hypertension. Although further studies are required to determine whether Mito-TEMPO or CAN + Ang-(1-7) treatment at the doses used altered mitochondrial ROS, optimal therapeutic benefits are achieved by shifting the balance from Ang II toward Ang-(1-7) in this model of chronic RAS-dependent hypertension.

Renal function and blood pressure are altered in adolescents born preterm.

BACKGROUND: Preterm birth increases the risk of hypertension and kidney disease. However, it is unclear when changes in blood pressure (BP) and renal function become apparent and what role obesity and sex play. We hypothesized adolescents born preterm have higher BP and worse kidney function compared to term in an obesity- and sex-dependent manner. METHODS: Cross-sectional analysis of 14-year-olds born preterm with very low birth weight (n = 96) compared to term (n = 43). We used generalized linear models to estimate the associations among preterm birth and BP, estimated glomerular filtration rate (eGFR), and ln (x) urinary albumin-to-creatinine ratio (ACR), stratified by overweight/obesity (OWO, body mass index (BMI) ≥ 85th percentile) and sex. RESULTS: Compared to term, preterm-born adolescents had higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) (adjusted ß (aß) 3.5 mmHg, 95% CI - 0.1 to 7.2 and 3.6 mmHg, 95% CI 0.1 to 7.0), lower eGFR (ß - 8.2 mL/min/1.73 m2, 95% CI - 15.9 to - 0.4), and higher ACR (aß 0.34, 95% CI - 0.04 to 0.72). OWO modified the preterm-term difference in DBP (BMI < 85th percentile aß 5.0 mmHg, 95% CI 0.7 to 9.2 vs. OWO 0.2 mmHg, 95% CI - 5.3 to 5.6) and ACR (OWO aß 0.72, 95% CI 0.15 to 1.29 vs. BMI < 85th percentile 0.17, 95% CI - 0.31 to 0.65). Sex modified the preterm-term ACR difference (female aß 0.52, 95% CI 0.001 to 1.04 vs. male 0.18, 95% CI - 0.36 to 0.72). CONCLUSIONS: Prematurity was associated with higher BP and reduced renal function that were detectable in adolescence. OWO and sex may modify the strength of these relationships.

Sex-dependent expression of brain medullary MAP and PI3 kinases in adult sheep with antenatal betamethasone exposure.

Antenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, in utero BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin-angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown. Given the importance of these signaling pathways in the actions of Ang peptides as well as baroreflex function and autonomic integration, we applied both a kinase signaling array and associated individual immunoblots of the dorsomedial brain medulla from adult female and male sheep with antenatal BMX. MAPK and PI3K pathways were altered significantly in the BMX sheep in a sex-dependent manner. A protein array for kinases (PathScan® Intracellular Signaling Array Kit, Cell Signaling) and subsequent verification by immunoblot revealed that within the DMM, female BMX sheep exhibit lower expression of proteins in the PI3K pathway, while male BMX sheep show greater expression of p-MAPK pathway proteins extracellular signal regulated kinase (ERK) 1/2. We conclude that maladaptive changes in these two kinase pathways in the DMM may contribute to the chronic dysregulation of blood pressure in this model of fetal programming.

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction.

Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n = 26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 s vs 520 ± 257 s (p = 0.04) for the placebo group and 384 ± 129 s vs 483 ± 258 s for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 s vs 601 ± 38 s (p < 0.05) for the placebo group and 690 ± 38 s vs 772 ± 95 s for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight.

BackgroundExposure to antenatal corticosteroids (ANCS) is associated with adverse cardiometabolic outcomes in animal models; however, long-term outcomes in clinical studies are not well characterized. We hypothesized that exposure to ANCS would be associated with markers of increased cardiometabolic risk in adolescents born with very low birth weight (VLBW).MethodsIn an observational cohort of 186 14-year-old adolescents born with VLBW, we measured resting blood pressure (BP), BP response to cold, ambulatory BP, and anthropometrics; performed dual-energy X-ray absorptiometry; and analyzed blood samples for uric acid, cholesterol, glycated hemoglobin, and high-sensitivity C-reactive protein. Multivariate analyses were used to evaluate associations with ANCS, adjusting for race, sex, and maternal hypertensive pregnancy.ResultsThere were no ANCS group differences in BP measures or blood biomarkers. Compared with adolescents unexposed to ANCS, those exposed to ANCS were taller (exposed-unexposed mean difference 3.1 cm (95% confidence interval (CI) 0.7, 5.5)) and had decreased waist-to-height ratio (exposed-unexposed mean difference -0.03 (95% CI -0.058, -0.002)). Males exposed to ANCS had lower total cholesterol (exposed-unexposed mean difference -0.54 mmol/l (95%CI -0.83, -0.06)).ConclusionAmong adolescents born with VLBW, ANCS exposure was not associated with markers of increased cardiometabolic risk.

Antenatal steroid exposure and heart rate variability in adolescents born with very low birth weight.

BACKGROUND: Reduced heart rate variability (HRV) suggests autonomic imbalance in the control of heart rate and is associated with unfavorable cardiometabolic outcomes. We examined whether antenatal corticosteroid (ANCS) exposure had long-term programming effects on HRV in adolescents born with very low birth weight (VLBW). METHODS: Follow-up study of a cohort of VLBW 14-y olds born between 1992 and 1996 with 50% exposed to ANCS. HRV in both the time and frequency domains using Nevrokard Software was determined from a 5-min electrocardiogram tracing. RESULTS: HRV data from 89 (35 male, 53 non-black) exposed (ANCS+) and 77 (28 male, 29 non-black) unexposed (ANCS-) adolescents were analyzed. HRV did not differ between ANCS+ and ANCS- black participants. However, in non-black participants, a significant interaction between ANCS and sex was observed, with ANCS- females having significantly greater HRV than ANCS+ females and males, and ANCS- males for both time and frequency domain variables. CONCLUSION: Among non-black adolescents born with VLBW, ANCS exposure is associated with reduced HRV with apparent sex-specificity. Reduced HRV has been associated with development of adverse cardiometabolic outcomes, thus supporting the need to monitor these outcomes in VLBW adolescents as they mature.

Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm.

BACKGROUND: Antenatal corticosteroid (ANCS) treatment hastens fetal lung maturity and improves survival of premature infants, but the long-term effects of ANCS are not well-described. Animal models suggest that ANCS increases the risk of cardiovascular disease through programmed changes in the renin-angiotensin (Ang)-aldosterone system (RAAS). We hypothesized that ANCS exposure alters the RAAS in adolescents born prematurely. METHODS: A cohort of 173 adolescents born prematurely was evaluated, of whom 92 were exposed to ANCS. We measured plasma and urine Ang II and Ang-(1-7) and calculated Ang II/Ang-(1-7) ratios. We used general linear regression models to estimate the difference in the RAAS between the ANCS-exposed and unexposed groups, adjusting for confounding variables. RESULTS: In unadjusted analyses, and after adjustment for sex, race, and maternal hypertension, ANCS exposure was associated with increased urinary Ang II/Ang-(1-7) (estimate 0.27 (95% CI 0.03, 0.5), P = 0.03), increased plasma Ang-(1-7) (0.66 (0.26, 1.07), P = 0.002), and decreased plasma Ang II/Ang-(1-7) (-0.48 (-0.91, -0.06), P = 0.03). CONCLUSION: These alterations indicate an imbalance in the urinary RAAS, promoting the actions of Ang II at the expense of Ang-(1-7), which over time may increase the risk of renal inflammation and fibrosis and ultimately hypertension and renal disease.

Clinical, hemispheric, and autonomic changes associated with use of closed-loop, allostatic neurotechnology by a case series of individuals with self-reported symptoms of post-traumatic stress.

BACKGROUND: The objective of this pilot study was to explore the use of a closed-loop, allostatic, acoustic stimulation neurotechnology for individuals with self-reported symptoms of post-traumatic stress, as a potential means to impact symptomatology, temporal lobe high frequency asymmetry, heart rate variability (HRV), and baroreflex sensitivity (BRS). METHODS: From a cohort of individuals participating in a naturalistic study to evaluate use of allostatic neurotechnology for diverse clinical conditions, a subset was identified who reported high scores on the Posttraumatic Stress Disorder Checklist (PCL). The intervention entailed a series of sessions wherein brain electrical activity was monitored noninvasively at high spectral resolutions, with software algorithms translating selected brain frequencies into acoustic stimuli (audible tones) that were delivered back to the user in real time, to support auto-calibration of neural oscillations. Participants completed symptom inventories before and after the intervention, and a subset underwent short-term blood pressure recordings for HRV and BRS. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and for the last four sessions. RESULTS: Nineteen individuals (mean age 47, 11 women) were enrolled, and the majority also reported symptom scores that exceeded inventory thresholds for depression. They undertook a median of 16 sessions over 16.5 days, and 18 completed the number of sessions recommended. After the intervention, 89% of the completers reported clinically significant decreases in post-traumatic stress symptoms, indicated by a change of at least 10 points on the PCL. At a group level, individuals with either rightward (n = 7) or leftward (n = 7) dominant baseline asymmetry in temporal lobe high frequency (23-36 Hz) activity demonstrated statistically significant reductions in their asymmetry scores over the course of their first four sessions. For 12 individuals who underwent short-term blood pressure recordings, there were statistically significant increases in HRV in the time domain and BRS (Sequence Up). There were no adverse events. CONCLUSION: Closed-loop, allostatic neurotechnology for auto-calibration of neural oscillations appears promising as an innovative therapeutic strategy for individuals with symptoms of post-traumatic stress. TRIALS REGISTRATION: ClinicalTrials.gov #NCT02709369 , retrospectively registered on March 4, 2016.

Distinct neurohumoral biomarker profiles in children with hemodynamically defined orthostatic intolerance may predict treatment options.

Studies of adults with orthostatic intolerance (OI) have revealed altered neurohumoral responses to orthostasis, which provide mechanistic insights into the dysregulation of blood pressure control. Similar studies in children with OI providing a thorough neurohumoral profile are lacking. The objective of the present study was to determine the cardiovascular and neurohumoral profile in adolescent subjects presenting with OI. Subjects at 10-18 yr of age were prospectively recruited if they exhibited two or more traditional OI symptoms and were referred for head-up tilt (HUT) testing. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured in the supine position and after 15 min of 70° tilt. Heart rate and blood pressure were continuously measured. Of the 48 patients, 30 patients had an abnormal tilt. Subjects with an abnormal tilt had lower systolic, diastolic, and mean arterial blood pressures during tilt, significantly higher levels of vasopressin during HUT, and relatively higher catecholamines and ANG II during HUT than subjects with a normal tilt. Distinct neurohumoral profiles were observed when OI subjects were placed into the following groups defined by the hemodynamic response: postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), syncope, and POTS/syncope. Key characteristics included higher HUT-induced norepinephrine in POTS subjects, higher vasopressin in OH and syncope subjects, and higher supine and HUT aldosterone in OH subjects. In conclusion, children with OI and an abnormal response to tilt exhibit distinct neurohumoral profiles associated with the type of the hemodynamic response during orthostatic challenge. Elevated arginine vasopressin levels in syncope and OH groups are likely an exaggerated response to decreased blood flow not compensated by higher norepinephrine levels, as observed in POTS subjects. These different compensatory mechanisms support the role of measuring neurohumoral profiles toward the goal of selecting more focused and mechanistic-based treatment options for pediatric patients with OI.

Apelin-13 in blood pressure regulation and cardiovascular disease.

PURPOSE OF REVIEW: Despite extensive pharmacological treatment, hypertension and heart failure still pose as high health and economic burden. Thus, novel therapeutic approaches are needed to promote more effective treatment of hypertension and cardiovascular disease. In this review we summarized recent evidence supporting the therapeutic potential of apelin-13, a recently discovered endogenous ligand for the G-protein coupled receptor APJ. RECENT FINDINGS: Systemic administration of apelin-13 or its posttranslationally modified form, pyroglutamate apelin-13, exert vasodilatory and antihypertensive effects. Yet, central application of apelin increases blood pressure and its systemic effects may be compromised in the presence of endothelial dysfunction. In addition, positive inotropic effects by exogenous apelin in the normal and failing heart, as well as cardioprotective effects after myocardial infarction, strongly suggest its therapeutic potential in preventing and treating heart failure and consequences of myocardial ischemia. However, therapeutic use of apelin is limited primarily by its short half-life and parenteral administration, and significant effort has been directed to the development of novel agonists, delivery methods, and improving the efficacy of agonists at APJ. SUMMARY: The apelin/APJ axis may represent a new target for the development of novel therapeutic approaches for the treatment of hypertension and cardiovascular disease.

Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(®)), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8-17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 µV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01.

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity.

As they age, Sprague-Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are 2-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor messenger RNA is significantly lower in aged rats, whereas CB2 receptor messenger RNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmole) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mm Hg after 60 minutes; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.