Age-related Increases In Blood Pressure Research Articles

Abstract 130: Impact Of O-GlcNAcylation On Elastin Fragmentation In Aorta Of Aged Male And Female Fisher344 Rats

O-GlcNAcylation is a regulatory mechanism involving the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins, playing a crucial role in cellular processes. Within vascular smooth muscle cells (VSMCs), O-GlcNAc impacts vascular function and is associated with cardiovascular risk. Vascular aging is characterized by changes in VSMCs, such as stiffness and loss of elasticity. Elastin, a component of the extracellular matrix, undergoes fragmentation during aging, triggering detrimental cascades and damage to end-organs. This study explores the correlation between O-GlcNAc and elastin fragmentation as a hallmark of aging. Specifically, we hypothesized that higher levels of O-GlcNAc induces fragmentation. Male and female Fisher 344 rats were evaluated at 3-(3M) and 16-month-old (16M). Thoracic aortas were isolated and strain/stress was measured with a tissue puller (DMT ® ), and systolic blood pressure (SBP) was measured in the carotid artery. O-GlcNAc levels, elastase expression and activity, and elastin fragmentation were assessed using Western blot, immunofluorescence, and histology. Data were analyzed using Two-way ANOVA-Tukey post-hoc (p<0.05). Results showed an age-related increase in blood pressure with the SBP in 16M males ~30 mmHg higher than in 3M (87±3 vs. 117±4). In females, there was a modest increase of about 16 mmHg in 16M than 3M (83±4 vs. 99±4). Aortic thickness increased in 16M male (3M 99±4 vs. 16M 114±3) and female (3M 99±3 vs. 16M 123±3) compared to 3M, but no sex difference was observed. The number of fragmented elastin fibers/cm of aorta was higher in 16M females (7±3) than 3M (2±1) and the elastase activity is 40% higher in aorta and serum of 16M females.Functionally, the aorta of 3M male rats, but not 16 M, exhibited higher strain/stress than age-matched females (3M male 2.5±0.9 vs. female 1.6±0.6; 16M male 5.1±0.9 vs. female 4.6±0.6). Interestingly, aged females and males presented higher levels of O-GlcNAc, and pharmacological induction of O-GlcNAc using Thiamet G (1uM) increased aortic stiffness and elastin fragmentation in 3M male rats (2.1±0.9 vs. 3.6±0.9). These findings suggest that O-GlcNAc contribute to aortic stiffness and blood pressure during aging, possibly through inducing elastin fragmentation.

Pyridoxamine treatment ameliorates large artery stiffening and cerebral artery endothelial dysfunction in old mice

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.

Age-related blood pressure and electrocardiographic dispersion mapping changes observed in Magadan adolescents

Aim. To study age-related electrocardiographic (ECG) dispersion mapping (DM) changes in adolescents with normal blood pressure (BP). ECG-DM makes it possible to assess the severity of myocardial electrophysiological abnormalities, which have not reached clinical manifestations with a standard ECG recording.Material and methods. For the period of 2017-2020, the data of 1140 schoolchildren (590 boys and 550 girls) living in Magadan were analyzed. There were following inclusion criteria: age of 12-17 years, informed consent of parents, health status group 1-2, no prior chronic and acute diseases (vaccinations), and hypertension. Systolic (SBP) and diastolic blood pressure (DBP) were recorded 3 times on the A&D Company Ltd BP monitor (2017, Japan). ECG-DM parameters were obtained using the CardioVisor-06s system (2004, Russia, Moscow): Myocardium index (norm <15%), Rhythm index (norm <20%), right, left atrial (G1-G2) and right, left ventricular depolarization (G3-G4), right and left ventricular repolarization (G5-G6), ventricular depolarization symmetry (G7), intraventricular block (G8), ventricular hypertrophy (G9).Results. In the period from 12 to 17 years old, an age-related increase in BP and a decrease in heart rate were determined (p<0,001). Significant rates of BP increase were observed in girls at the age of 12-13 years (p<0,01), while in boys, yearly differences regard only SBP from 12 years (p<0,05), except for 14-15 years. Sex differences were established at the age of 13 for DBP (p=0,026), from the age of 14 according to SBP, with higher values in boys (p<0,05). From 12 to 17 years old, age-related changes were observed only in the Rhythm index (p<0,001), while the predominance of average normal values was established from the age of 14 in boys (p=0,008) and from 15 years old in girls (p=0,022) relative to younger age. There was also an increase in the proportion of persons with normal values in boys from 28,7 to 50,0%, in girls from 29,4 to 61,7% (p<0,05). The Myocardium index at all ages approached the upper normal limit without dependence on age and sex. According to G1-G9 indicators, normal and borderline values prevailed. The greatest similarity was observed in G1-G2 in 45,6-40,8% of boys and 48,3-46,5% of girls, as well as in G9 — 35,1-39,6% (p>0,05), respectively.The proportion of persons in G5-G6 was lower among boys (6,9 and 7,1%) compared with girls (14,2 and 13,1%) (p=0,002, p=0,010), while other indicators had no significant differences as follows: G3 (9,8 and 7,1%), G4 (4,9 and 4,0%), G7 (5,4 and 6,0%), G8 (1,4 and 1,1%) (p>0,05). Among boys according to G9, age differences were observed at 14-15 years old (p=0,026), while among girls — G1 at 16-17 years old (p=0,035).Conclusion. ECG-DM allows monitoring early cardiac dispersion changes in children aged 12-17 years with a normal blood pressure level and identifying among them those adolescents who need further examination.

Structured, Progressive Exercise Training Improves Cardiovascular Psychophysiological Outcomes in Young Adult Women with a History of Adverse Childhood Experiences

Adverse childhood experiences (ACEs) represent psychosocial stressors that occur during critical developmental periods and are associated in a dose‐dependent manner with adverse cardiovascular outcomes in emerging adults, including greater age‐related increases in blood pressure (BP) and increased circulating endothelin‐1 (ET‐1), a psychosocial stress‐responsive, endothelium‐derived peptide and potent vasoconstrictor. ACEs have also been linked to lower resilience and hope, which is a motivational state based on goal‐directed energy (agency) and goal planning (pathways). Importantly, resilience and hope are each stable psychological traits that may protect against adversity. We examined the effects of a structured, progressive exercise training program on hope agency, hope pathways, resilience, BP, and circulating ET‐1 in young adult women with a history of moderate‐to‐severe (e.g., 4 or more) adverse childhood experiences (ACEs). We hypothesized that exercise training would increase resilience and hope, but lower systolic BP (SBP), diastolic BP (DBP), and circulating ET‐1. We further hypothesized that changes in hope and resilience would be associated with changes in BP and ET‐1 across the intervention period in the young women with ACEs. Forty‐two otherwise healthy young adult women with either four or more (ACE+) or with no ACEs (ACE–) were recruited and completed this study. Participants with ACEs (ACE+) were randomly assigned to either an exercise (n=14) or non‐exercise (n=14) control group, whereas women without a history of ACEs (ACE–) were assigned to a non‐exercise control (e.g., negative control group; n=14). Statistical analyses included two‐way mixed (group x time) effects and bivariate correlational analyses. Changes are reported as means ± SE. Agency did not change in any group (p = 0.14), but pathways improved only in the ACE+ exercise group (+1.6 ± 0.74 au; p = 0.03). ET‐1 decreased in the ACE+ exercise group only (‐0.31 ± 0.29 pg/ml, p= 0.04). While the interactions for resilience and SBP did not reach significance (p = 0.06 and 0.05, respectively), forced post‐hoc analyses indicated that resilience improved (+4.9 ± 1.9 au, p = 0.01) and SBP tended to improve (‐4.0 ± 2.0 mmHg; p = 0.05) in the ACE+ exercise group only. DBP did not change in any group (p = 0.43). There were significant inverse associations between changes in pathways and SBP (ρ = ‐0.43, p= 0.02) and pathways and ET‐1 (ρ = ‐0.56, p= 0.003), and a significant direct association between changes in SBP and ET‐1 (ρ = 0.49; p = 0.01) in the ACE+ young women. Associations among resilience and BP and ET‐1 were weaker and non‐significant (ρ = ‐0.17–0.29, p≥ 0.13). Our results suggest that structured, progressive exercise training promotes improvements in positive psychological factors, SBP, and circulating ET‐1 levels in young adults with a history of ACEs. Further, changes in pathways were related to changes in SBP and ET‐1 across the intervention period, suggesting a potential psychophysiological relationship between positive psychological traits and cardiovascular risk factors in young women with ACEs.

Abstract 10610: Schistosomiasis and Cardiovascular Disease in 1,000 HIV-Infected and Uninfected Tanzanian Adults: A Prospective Cohort Study

Background: Variations in immune phenotype are increasingly recognized as drivers of cardiovascular disease (CVD). For example, the inflammatory effect of HIV-infection is associated with a 2-fold higher risk of CVD. Conversely, schistosome infection induces an anti-inflammatory immune response, which may counter CVD pathways related to inflammation. Whether the immune regulatory effect of schistosome infection is sufficient to suppress the contrasting stimulatory effect of another disease such as HIV remains unknown and may provide critical insight into the immunologic basis of non-communicable diseases. Methods: In this prospective cohort study, we enrolled 1,000 HIV-infected and uninfected adults at a referral HIV clinic in a schistosome endemic area in Mwanza, Tanzania. Standardized history, echocardiography and serum were obtained. Blood pressure was monitored over two years. Regression models adjusted for age and sex were used to quantify associations. Results: We enrolled 503 schistosome infected and 497 uninfected adults with a median age of 36 [28- 43]. Schistosome infection was significantly associated with a lower prevalence of hypertension (39.6% vs 46.7%, p=0.016), myocardial diastolic dysfunction (8.1% vs 13.4%, p=0.015) and total-to-high density lipoprotein ratio (1.77 vs 1.82, p<0.0001) as compared to uninfected participants. Additionally, schistosome-infection was associated with significantly improved change in blood pressure over time (0.67 vs 3.35 mmHg increase, p=0.005). When stratified by concurrent HIV-infection, schistosome infection was associated with lower prevalence of diastolic dysfunction and total-to-HDL ratio in HIV- infected adults but lower prevalence of hypertension in those without HIV-infection. Conclusions: We provide the first evidence that schistosome infection may directly impact cardiac function and slow the age-related increase in blood pressure over time. Further, associations between schistosome and CVD differ by HIV status, implying that immune mediated interactions may have important physiologic ramifications for CVD. The patterns of these interactions may provide insight into the immunologic mechanisms of cardiovascular diseases.

Prenatal air pollution exposure to diesel exhaust induces cardiometabolic disorders in adulthood in a sex-specific manner

BackgroundResults from observational and experimental studies indicate that exposure to air pollutants during gestation reduces birth weight, whereas little is known on potential cardiometabolic consequences for the offspring at adulthood. ObjectivesOur aim was to evaluate the long-term effects of gestational exposure to diesel engine exhaust (DE) on adult offspring phenotype in a rabbit model. MethodsThe protocol was designed to mimic human exposure in large European cities. Females rabbits were exposed to diluted (1 mg/m3) DE (exposed, n = 9) or clean air (controls, n = 7), from 3 days after mating, 2 h/d and 5 d/wk in a nose-only inhalation system throughout gestation (gestation days 3–27). After birth and weaning, 72 offspring (47 exposed and 25 controls) were raised until adulthood (7.5 months) to evaluate their cardio-metabolic status, including the monitoring of body weight and food intake, fasting biochemistry, body composition (iDXA), cardiovascular parameters and glucose tolerance. After a metabolic challenge (high fat diet in males and gestation in females), animals were euthanized for postmortem phenotyping. ResultsSex-specific responses to maternal exposure were observed in adult offspring. Age-related increases in blood pressure (p = 0.058), glycaemia (p = 0.029), and perirenal fat mass (p = 0.026) as well as reductions in HDL-cholesterol (p = 0.025) and fat-to-body weight ratio (p = 0.011) were observed in exposed males, suggesting a metabolic syndrome. Almost only trends were observed in exposed females with higher triglycerides and decreased bone density compared to control females. Metabolic challenges triggered or amplified some biological responses, especially in females. ConclusionsIn utero exposure to air pollution predisposed rabbit offspring to cardiometabolic disorders in a sex-specific manner.

Age-related carotid extra-media thickening is associated with increased blood pressure and arterial stiffness.

Ageing results in higher blood pressure and arterial stiffening leading to increased cardiovascular disease (CVD) risk. The extra-media thickness (EMT) is a composite measure of the arterial adventitia, perivascular adipose tissue (PVAT) and the jugular vein, but the association among EMT and ageing, blood pressure and arterial stiffness is largely unknown. We hypothesized that EMT is associated with ageing, blood pressure and arterial stiffness. Fifty (18M/32F, age range 20-79years.) individuals underwent measures of EMT (media-adventitia border to jugular lumen interface) via ultrasonography, blood pressure (brachial; carotid), arterial stiffness (carotid beta-stiffness, distensibility and Young's modulus) and body composition (dual X-ray absorptiometry). Independent two-tailed t-tests compared characteristics between young and middle-aged/older adults (MA/O). Bivariate correlations assessed the relation between EMT, ageing, blood pressure and arterial stiffness endpoints. Partial correlations were used to adjust for age, sex, body mass index (BMI) and body fat percentage. Compared to young, MA/O adults had higher EMT, blood pressure, arterial stiffness, BMI and BF% (all, p≤0.05). Carotid EMT was positively correlated with age (r=0.46), brachial SBP (r=0.32), carotid SBP (r=0.42), PP (r=0.42), beta-stiffness (r=0.37) and Young's elastic modulus (r=0.43) (all, p≤0.05), and negatively correlated with carotid distensibility (r=-0.34, p≤0.05). All endpoints correlated with EMT remained after adjusting for BMI, BF% and sex (p≤0.05). These data suggest EMT is a clinically relevant target that may be associated with age-related CVD risk in humans, yet further investigation is required to elucidate the role of EMT in age-related increases in blood pressure and arterial stiffness.

The Long-Term Study of Urinary Biomarkers of Renal Injury in Spontaneously Hypertensive Rats

Background: The age-related increase in blood pressure in spontaneously hypertensive rats (SHRs) is associated to cardiac hypertrophy, heart failure, and renal injury. Here, we investigated for the first time the urinary enzymatic activities of glutamil aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), and Klotho urinary levels, proteins that are strongly expressed in the kidney, as early biomarkers of renal injury in SHRs. Methods: Male SHR and Wistar Kyoto (WKY) rats were studied from 2 to 8 months old. Systolic blood pressure (SBP), the heart rate (HR), metabolic variables, and urinary markers were measured monthly. At the end of the study, a histopathological evaluation of the kidney was performed. Results: Kidneys of SHR did not develop signs of relevant histopathological changes, but showed increased glomerular area and cellularity. Plasma creatinine was decreased, and creatinine clearance was augmented in SHR at the end of the study. Urinary excretion of Klotho was higher in SHR at 5 and 8 months old, whereas plasma Klotho levels were similar to WKY. GluAp, AlaAp, and DPP4 urinary activities were increased in SHR throughout the time-course study. A positive correlation between glomerular area and cellularity with creatinine clearance was observed. Urinary GluAp, AlaAp, DPP4, and Klotho showed positive correlations with SBP. Conclusions: GluAp, AlaAp, DPP4, and Klotho in the urine are useful tools for the evaluation of renal damage at early stages, before the whole histopathological and biochemical manifestations of renal disease are established. Moreover, these observations may represent a novel and noninvasive diagnostic approach to assess the evolution of kidney function in hypertension and other chronic diseases.

Abstract MP08: Testosterone Contributes To Renal Necrosis In Male Spontaneously Hypertensive Rats (SHR).

We previously published a sex difference in renal necrosis in SHR with males having a maturation induced increase in renal necrosis that is absent in females. Testosterone is known to drive an increase both in blood pressure (BP) with maturation in male SHR and necrosis of renal tubular epithelial cell in vitro. In the current study we tested the hypothesis that testosterone underlies the maturation induced increase in renal necrosis in male SHR. At 4 weeks of age, male SHR were randomly assigned to either sham or gonadectomy (ORX) groups (n=3). To control for the influence of high BP on renal necrosis, a third group was subjected to a sham surgery and treated with the anti-hypertensive medications hydrochlorothiazide (HCTZ; 55mg/kg/day) and reserpine (Res; 4.5 mg/kg/day) in drinking water starting at 9 weeks of age (n=4) to prevent age-related increases in BP. At 8 weeks of age, telemeters were implanted in all groups followed by a recovery for 1 week before BP was recorded. A separate set of rats were randomly assigned to Sham (n=3), ORX (n=4), or HCTZ/Res (n=4) and subjected to the exact same procedures as the previous set except for telemetry implantation. All rats were euthanized at 13 weeks of age and kidneys were collected for the quantification of renal necrosis using flow cytometric analysis of 7AAD + cells. Data were analyzed using one-way ANOVA and presented as mean ± standard error. BP was significantly lower in ODX and HCTZ/Res treated groups compared to sham (mean arterial blood pressure (mmHg): Sham= 139±2; HCTZ/Res= 117±3; ODX= 126±2; p=0.002; n=3-4). Renal necrosis was also significantly less in ORX rats, but not altered in HCTZ/Res treated groups compared to sham (renal necrosis expressed as % total gated kidney cells: Sham= 6±0.3%; HCTZ/Res=5±0.4%; ODX= 4±0.4%; P=0.003; n=6-7). Testosterone contributes to maturation induced increase in renal necrosis in male SHR.

Distinct Contribution of Systemic Blood Flow to Hypertension in an African Population Across the Adult Lifespan

Although hypertension in groups of African ancestry is volume-dependent, the relative impact of systemic flow (stroke volume, peak aortic flow [Q]) versus vascular mechanisms (systemic vascular resistance, aortic characteristic impedance [Zc], total arterial compliance) components of arterial load has not been evaluated across the adult age range. In participants of African ancestry (n=824, age=16-99 years, 68.3% female), using central arterial pressure and aortic velocity and diameter measurements in the outflow tract, we determined the hemodynamic correlates of age-related increases in blood pressure. Strong independent positive relations between age and stroke volume or peak aortic Q were noted (P<0.0001), effects associated with ventricular end diastolic volume and aldosterone-to-renin ratios. Age-related increases in mean arterial pressure were associated with stroke volume and not systemic vascular resistance. Although age-Q relations began from early adulthood, initially an inverse association between age and aortic Zc (P<0.0001) driven by increments in aortic root diameter (P<0.0001) prevented an enhanced systolic blood pressure and pulse pressure. When Zc began to positively relate to age (P<0.0001), age-Q relations translated into increases in forward wave pressures and hence systolic blood pressure and pulse pressure. Age relations with pulse pressure were as strongly determined by Q as by Zc or total arterial compliance (0.027±0.001 versus 0.028±0.001 and 0.032±0.003 mm Hg per yearly increase in pulse pressure produced by Q, Zc, and total arterial compliance; P<0.0001). Uncontrolled hypertension (confirmed with 24-hour blood pressure) was determined more by Q, Zc, and total arterial compliance than by increases in systemic vascular resistance (P<0.0005 for comparison). In conclusion, relationships between age and systemic blood flow contribute markedly to hypertension in groups of African origins.

Elevated Lipoprotein-Associated Phospholipase A2 Independently Affects Age-Related Increases in Systolic Blood Pressure: A Nested Case-Control Study in a Prospective Korean Cohort.

Inflammatory markers are susceptible to changes over time. Thus, we observed changes in inflammatory markers correlating with age-related increases in blood pressure (BP) through a prospective study. The aim of this study was to investigate changes in inflammatory markers that correlate with age-related increases in BP. The study included 1,500 nondiabetic and normotensive healthy subjects at baseline. Of these, 121 individuals who developed hypertension (defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) after 2 years formed the hypertension group. For each incident hypertension case, 2 age- and sex-matched control subjects were selected among those who did not develop hypertension (control group, n = 242). After baseline adjustment, the hypertension group exhibited greater increases in body mass index (BMI), systolic and diastolic BP, triglyceride, total cholesterol, glucose, Lp-PLA2 activity, and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α) levels compared to the control group. In the hypertension group, changes in (Δ) systolic BP correlated positively with Δ Lp-PLA2 activity, which correlated positively with Δ low-density lipoprotein (LDL−) cholesterol and Δ urinary 8-epi-PGF2α levels. Moreover, multiple linear regression revealed baseline systolic BP and Δ Lp-PLA2 activity to be independent predictors of Δ systolic BP in the hypertension group. Our results suggest that age-related increases in systolic BP may correlate strongly with elevated Lp-PLA2 activity and that Lp-PLA2 can be considered a biomarker for systolic BP elevation.

Excess Systolic Hypertension in Post-Menopausal Women Originates in Their Early-30s, a Decade Before the Decline of Estrogen Concentrations Decline

Background: In young adults blood pressure, hypertension rates, and CVD risk are lower in women than similarly aged men. However, soon after menopause hypertension and CVD rates converge with, and overtake those of men. Thus, by their mid-50s, most women are hypertensive, and CVD becomes the leading cause of death. While this age-related increase in blood pressure and hypertension is largely attributed to menopause, and the concomitant decrease in estradiol concentrations, there is little empirical evidence to support this hypothesis. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) and Coronary Artery Risk Development in Young Adults (CARDIA) study was analyzed by segmented regression analysis to determine the relationship between systolic blood pressure and age. Data from NHANES was further stratified by Body Mass Index (BMI) and antihypertensive drug use to determine their impact on blood pressure. Estradiol concentrations (NHANES 2013-2016) were graphed against age to determine the start of menopause. Findings: Segmented regression analysis determined that the age-related increase in systolic blood pressure and systolic hypertension began when the women were in their early-30s, a decade before estrogen concentrations decline. BMI and antihypertensive drug use modified the response, but not the overall trend. Interpretation: Contrary to the commonly cited hypothesis, the age-related increase in hypertension is not related to menopause, nor decreased estradiol concentrations. Rather, the rise in systolic blood pressure and hypertension begins over a decade earlier, in a woman’s early-30s. These finding suggest that monitoring, and perhaps prophylactic treatment, of hypertension should begin at least a decade before menopause. Funding Statement: No funding was received for this study, nor for preparing and submitting the manuscript. Declaration of Interests: The Authors states that there is no conflict of interest. Ethics Approval Statement: Ethical approval for the study was provided by the University of Florida Institutional Review Board.

High Blood Pressure and Cardiovascular Disease.

Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD). Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure. Biologically, normal levels of BP are considerably lower than what has typically been characterized as normal in research and clinical practice. We propose that CVD is primarily caused by a right-sided shift in the population distribution of BP. Our view that BP is the predominant risk factor for CVD is based on conceptual postulates that have been tested in observational investigations and clinical trials. Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke. In multivariate modeling, the presumed attributable risk of high BP for stroke and coronary heart disease has increased steadily with progressive use of lower values for normal BP. Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies. Prevention of age-related increases in BP would, in large part, reduce the vascular consequences usually attributed to aging, and together with intensive treatment of established hypertension would eliminate a large proportion of the population burden of BP-related CVD.

Exercise Prevents Hypertension and Disrupts the Correlation Between Vascular Sympathetic Activity and Age-Related Increase in Blood Pressure in SHRs.

Hypertension usually accompanies the elevated sympathetic activity and sleep interruption. Few researches explored the dynamic changes and possible correlations in cardiovascular functions and sleep patterns during the development of hypertension. In contrast, exercise training provides several benefits on cardiovascular and sleep function in hypertensive subjects. However, controlling various factors during a long period of exercise training is difficult in hypertensive subjects, an animal model may be essential. This study aimed to explore dynamic changes in cardiovascular functions and sleep patterns during the development period of hypertension (10-20 weeks old) in spontaneously hypertensive rats (SHRs) and effects of exercise intervention. We used the treadmill exercise model for 8 weeks and started when SHRs were 12 weeks old. Electroencephalogram, electromyogram, electrocardiogram, and blood pressure (BP) were recorded simultaneously for 24 hours once a week over 11 weeks. Untrained SHRs revealed the age-related increments in BP, and the significant increasing slopes of differences on BP and vascular sympathetic activity were observed during the development period of hypertension. Compared with untrained rats, age-related increases in BP and vascular sympathetic activity were significantly suppressed in trained SHRs. Nevertheless, trained SHRs showed more quiet sleep time at partial weeks. The positive correlation between the differences from 10 weeks of vascular sympathetic activity and BP was disappeared in trained SHRs. There existed the significant correlation between the dynamic changes of vascular sympathetic activity and age-related elevation of BP during the development period of hypertension; however, exercise prevented hypertension and disrupted this correlation.

Inhibition of Necrosis Via Necrox‐5 Attenuates The Development Of Hypertension In Male, But Not Female Spontaneously Hypertensive Rats (SHR)

It is well established that hypertension is accompanied by cell death, however, less is known regarding the role of cell death in blood pressure (BP) control. Necrosis is an uncontrolled pathologic form of cell death that is associated with inflammation. Therefore, the goal of the current study was to test the hypothesis that necrosis contributes to the development of hypertension in SHR. Initial studies measured renal necrosis in 13 wk old male and female SHR (n=9) using flow cytometry. Male SHR had greater renal necrosis compared to female SHR (3.7±0.4% vs. 0.4±0.2% of total renal cells, respectively; p&lt;0.0001). Additional male and female SHR were then randomized to receive vehicle or Necrox‐5 from 6–12 weeks of age (1 mg/kg via IP injection twice weekly; n=4); Necrox‐5 is a cell permeable inhibitor of necrosis that blocks oxidative stress induced necrotic cell death. BP was measured weekly via tail‐cuff analysis and via carotid catheter at sacrifice. Following 6 wks of treatment, kidneys were isolated and necrosis was measured by flow cytometry. Treatment with Necrox‐5 beginning at 6 wks of age attenuated maturation‐induced increases in BP in male SHR (Necrox‐5: 152±11 vs Control: 177±4 mmHg; p=0.07). BP in female SHR was not altered by chronic Necrox‐5 treatment (Necrox‐5: 152±14 vs. Control: 146±11 mmHg; p=0.72). In addition, the sex difference in BP apparent in control rats was abolished by Necrox‐5 treatment. Consistent with these results, Necrox‐5 treatment for 6 wks decreased renal necrosis only in males (Necrox‐5: 1.5±0.5% vs Control: 3±0% of total renal cells). Taken together, our data suggest that greater cell death in male SHR compared to female SHR contributes to sex differences in BP by exacerbating age‐related increases in BP in males.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease.

It is well-established that the age-related increase in blood pressure is augmented after menopause. Yet, the prevalence of hypertension is enhanced in low birth weight women relative to normal birth weight counterparts by 60years of age suggesting that adverse influences during fetal life heighten cardiovascular risk in later life. A changing hormonal milieu may contribute to increased cardiovascular risk that occurs after the menopausal transition. Low birth weight is associated with early age at menopause. A recent study indicates that a shift towards testosterone excess following early reproductive senescence may contribute to the etiology of age-dependent increases in blood pressure in a rodent model of low birth weight. This review will highlight current findings related to postmenopausal hypertension and discuss potential mechanisms that may contribute to the enhanced cardiovascular risk that develops with age in low birth weight women.

Associations among oxidative stress, Lp-PLA2 activity and arterial stiffness according to blood pressure status at a 3.5-year follow-up in subjects with prehypertension

Background and aimsWe aimed to determine changes in oxidative stress, lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and arterial stiffness in subjects with persistent prehypertensive symptoms during a 3.5-year follow-up period. MethodsWe divided 254 subjects with prehypertension according to their blood pressure (BP) status at 3.5 years of follow-up into three groups: reversed normotensive, persistent prehypertensive and developed hypertensive group. BP, serum lipid profile, oxidized LDL (ox-LDL), Lp-PLA2 activity and brachial-ankle pulse wave velocity (ba-PWV) were measured at baseline and the 3.5-year follow-up. ResultsThe reversed normotensive group showed a significant reduction in average BP (14.7/10.1 mmHg), whereas the developed hypertensive group showed a significant increase in average BP (15.2/11.5 mmHg). The persistent prehypertensive group showed increases in serum lipid profiles, circulating levels of Lp-PLA2 activity, ox-LDL and arterial stiffness as measured by ba-PWV at 3.5 years. The persistent prehypertensive and developed hypertensive groups showed greater increases in ox-LDL than the reversed normotensive group. The developed hypertensive group showed greater increases in Lp-PLA2, 8-epi-PGF2α, and ba-PWV than those observed in the reversed normotensive and persistent prehypertensive groups. In all subjects, changes (Δ) in systolic blood pressure (SBP) positively correlated with Δ Lp-PLA2, Δ ox-LDL, Δ urinary 8-epi-PGF2α and Δ ba-PWV. ConclusionsThis study indicates that in persistent prehypertension, increased ox-LDL hydrolysis by Lp-PLA2 enhances arterial stiffness without an age-related increase in BP.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during β-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10±0.01mmHg (%s)(-1) , n=23 vs. 0.06±0.01mmHg (%s)(-1) , n=18; P=0.003). Transduction was lowest in YW (0.02±0.01mmHg (%s)(-1) , n=23) and increased during β-blockade (0.11±0.01mmHg (%s)(-1) ; P<0.001). Transduction in PMW (0.07±0.01mmHg (%s)(-1) , n=23) was greater compared to YW (P=0.001), and was not altered during β-blockade (0.06±0.01mmHg (%s)(-1) ; P=0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55±1.5years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring.

Placental insufficiency programs an increase in blood pressure associated with a twofold increase in serum testosterone in male growth-restricted offspring at 4 mo of age. Population studies indicate that the inverse relationship between birth weight and blood pressure is amplified with age. Thus, we tested the hypothesis that intrauterine growth restriction programs an age-related increase in blood pressure in male offspring. Growth-restricted offspring retained a significantly higher blood pressure at 12 but not at 18 mo of age compared with age-matched controls. Blood pressure was significantly increased in control offspring at 18 mo of age relative to control counterparts at 12 mo; however, blood pressure was not increased in growth-restricted at 18 mo relative to growth-restricted counterparts at 12 mo. Serum testosterone levels were not elevated in growth-restricted offspring relative to control at 12 mo of age. Thus, male growth-restricted offspring no longer exhibited a positive association between blood pressure and testosterone at 12 mo of age. Unlike hypertension in male growth-restricted offspring at 4 mo of age, inhibition of the renin-angiotensin system with enalapril (250 mg/l for 2 wk) did not abolish the difference in blood pressure in growth-restricted offspring relative to control counterparts at 12 mo of age. Therefore, these data suggest that intrauterine growth restriction programs an accelerated age-related increase in blood pressure in growth-restricted offspring. Furthermore, this study suggests that the etiology of increased blood pressure in male growth-restricted offspring at 12 mo of age differs from that at 4 mo of age.

7A.07

Objective: Obesity causes an increased blood pressure (BP). This effect may be diminished in communities of African descent. However, the impact of obesity on ambulatory or aortic BP, which are enhanced in groups of African ancestry, has not been assessed. We aimed to determine the extent to which obesity is related to variations in office, ambulatory and aortic BP in a community sample of African ancestry with a high prevalence of obesity. Design and method: In 1167 randomly selected participants of black South African ancestry >16 years of age (42.5% obese and 45.1% with abdominal obesity), we determined the impact of adiposity indexes on age-related increases in office, ambulatory (n = 767) and aortic (n = 1141) BP. Aortic BP was determined using radial applanation tonometry and SphygmoCor software. Results: Age was strongly related to all BP values and indexes of metabolic abnormalities (p < 0.0001). Independent of age, adiposity indexes were associated with insulin resistance, HDL cholesterol, glucose and triglyceride concentrations (p < 0.0001 for all). However, across the adult lifespan neither office, 24-hour, day, night, nor aortic BP were increased in participants with an increased waist circumference (WC), or body mass index (BMI)(> = 30 kg/m2) as compared to participants with a normal WC or BMI. Independent of age, WC accounted for only 0 to 1.02% of the variation in office, 24-hour or aortic BP and translated into only a 0.38 to 1.40 mm Hg increase in office or 24-hour systolic or diastolic BP for every 15.9 to 16.6 cm (1 SD) increase in WC. Neither WC (Odds ratio = 1.12, CI = 0.78 to 1.61, p = 0.54) nor BMI (Odds ratio = 1.11, CI = 0.78 to 1.58. p = 0.55) were associated with hypertension (38.5%) diagnosed according to 24-hour BP thresholds or the presence of treatment. Independent of age, adiposity indexes were not positively associated with factors that account for age-related increases in BP (aortic pulse wave velocity, and aortic forward and backward wave pressures). Conclusions: Although obesity and hypertension are prevalent in black African communities and obesity independently associates with metabolic abnormalities, obesity plays little role in the pathogenesis of hypertension in these communities.