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 (AT
R) 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.
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.
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.
The apelin/APJ axis may represent a new target for the development of novel therapeutic approaches for the treatment of hypertension and cardiovascular disease.
The renin-angiotensin-system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. Indeed, dysregulation of the RAS may lead to the development of ...cardiovascular pathologies including kidney injury. Moreover, the blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS that the system is comprised of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the non-classical RAS composed of the ACE2-Ang-(1-7)-Mas receptor axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and oxidative stress. Thus, a reduced tone of the Ang-(1-7) system may contribute to these pathologies as well. Moreover, the non-classical RAS components may contribute to the effects of therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury. The review considers recent studies on the ACE2-Ang-(1-7)-Mas receptor axis regarding the precursor for Ang-(1-7), the intracellular expression and sex differences of this system, as well as an emerging role of the Ang1-(1-7) pathway in fetal programing events and cardiovascular dysfunction.
Background Heart rate variability (HRV) is associated with vascular risk factors for dementia, but whether HRV is associated with specific domains of cognitive performance is unclear. Methods and ...Results In the Multi-Ethnic Study of Atherosclerosis (N=3018; mean age 59.3±9.2 years), we assessed the relationship of 10-second HRV to scores on tests of global cognitive performance (Cognitive Abilities Screening Instrument), processing speed (Digit Symbol Coding), and working memory (Digit Span). HRV was computed as the SD of normal-normal intervals (SDNN) and root mean square of successive differences (RMSSD) at Exam 1 (2000-2002) and Exam 5 (2010-2012). Cognitive tests were administered at Exam 5. We report regression coefficients (β 95% CI) representing cognitive test score change per 2-fold increase in HRV. After adjustment for age, race/ethnicity, sex, education, apolipoprotein E genotype, and cardiovascular risk factors and incident disease, higher Exam 1 (β=0.37 0.06, 0.67) and Exam 5 (β=0.31 0.04, 0.59) SDNN were associated with better Cognitive Abilities Screening Instrument performance. Higher Exam 1 (β=0.80 0.17, 1.43) and Exam 5 (β=0.63 0.06, 1.20) SDNN, and Exam 5 RMSSD (β=0.54 0.01, 1.08) were associated with better Digit Symbol Coding performance. Finally, higher Exam 5 SDNN was associated with better Digit Span performance (β=0.17 0.01, 0.33). Associations were attenuated after adjustment for resting heart rate. Conclusions Higher HRV is generally associated with better cognitive performance in this multi-ethnic cohort of aging adults, and further study of the relationship of autonomic function to cognition is warranted.
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).
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.
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).
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.
To evaluate sex differences in microRNA (miRNA) expression, anthropometric measures, and cardiometabolic risk factors in Hispanic adolescents with obesity.
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.
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-β, 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.
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.
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
β
(a
β
) 3.5 mmHg, 95% CI − 0.1 to 7.2 and 3.6 mmHg, 95% CI 0.1 to 7.0), lower eGFR (
β
− 8.2 mL/min/1.73 m
2
, 95% CI − 15.9 to − 0.4), and higher ACR (a
β
0.34, 95% CI − 0.04 to 0.72). OWO modified the preterm-term difference in DBP (BMI < 85th percentile a
β
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 a
β
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 a
β
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.
Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data ...suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term.
In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status.
Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm β 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3 than those born term (β 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002.
We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals.
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.
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.
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) (β: 0.57, 95% CI 0.23-0.91) and higher Ang II (β: 0.21 pmol/L, 95% CI 0.03-0.39) but lower Ang-(1-7) (β: -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) (β: 0.21, 95% CI −0.02 to 0.44), an effect that approached statistical significance.
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.
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