bluuebunny/crossref_metadata_2025_split huggingface dataset:
UTILIZATION OF ANTIHYPERTENSIVE DRUGS AS MONOTHERAPY AND COMBINED THERAPY IN BRAZIL: A POPULATION BASED STUDY
Authors: da Silva Brunna Raphaelly Amaral , Bricola Alice Aparecida Olim , Fontanella Andréia Turmina , Borges Rogério Boff , Costa Karen Sarmento 
Published: April 2021

Objective:
Our objective was to describe the use of antihypertensive drugs in Brazil with a focus on the combination of two drugs.

Design and method:
Secondary data analysis from the National Survey on Access Use and Promotion of Rational Use of Medicines (PNAUM 2014), a nationwide cross-sectional population-based study, focused on the use of medicines in Brazil with a total of 41,433 interviews. The sample consists of all antihypertensive drugs cited as used to treat hypertension. The I Brazilian Positioning about Combination of Antihypertensive Drugs 2013 was used as a criteria to identify the combinations as Preferential: ACEI (Angiotensin-converting enzyme inhibitors) + CCB (Calcium channel blockers), ACEI + Diuretic, ARB (Angiotensin II receptor blockers) + CCB (dihydropyridine derivates), ARB + Diuretic; Acceptable: Diuretic + BB (beta-Blockers), CCB (dihydropyridine derivates) + BB, CCB + Diuretic, RI (Renin inhibitor)+ Diuretic, RI + CCB, Diuretic Thiazide + Potassium-sparing Agent; Less usual: ACEI + BB, ARB + BB and Unusual combinations: CCB (non-dihydropyridine derivates) + BB, ACEI + ARB, ACEI + RI, ARB + RI, Antiadrenergic agents, centrally acting + BB. The Statistical Analysis System (SAS) version 9.4 was used.

Results:
A total of 45 antihypertensive drugs was related. Diuretics (47.2% 95%CI 45.5–48.8), ACEI (38.1% 95%CI 36.4–39.8) and ARB (37.1% 95%CI 35.5–38.7) were the most used drugs, regardless the treatment as monotherapy or combined therapy. As monotherapy the three classes cited was the most used, however in a different percentage: ACEI (37.1% 95%CI 35.0–39.4), ARB (28.1% 95%CI 26.1–30.2) and Diuretics (14.5% 95%CI 12.9–16.1). Considering people under therapy with two drugs and the I Brazilian Positioning about Combination of Antihypertensive Drugs criteria, the preferential combinations represented 66.3% (95%CI 63.8–68.8), acceptable 19.2% (95%CI 17.1–21.2), less usual 10.1% (95%CI 8.5–11.8), unusual combinations 1.4% (95% CI 0.9–1.9) and other combinations 3.0% (95%CI 1.9–4.1). The most preferential combinations were ARB + Diuretic 30.3% (95%CI 27.8–32.8) and ACEI + Diuretic 28.0% (95%CI 25.5–30.5). In general, Brazil is using antihypertensives according to the guidelines of hypertension.

Conclusions:
In general, Brazil is using antihypertensives according to the guidelines of hypertension.
INHIBITION OF ACE C-DOMAIN AND NEPRILYSIN AS A NEW THERAPY IN HYPERTENSION
Authors: Alves-Lopes Rheure , Montezano Augusto , Neves Karla , Harvey Adam , Rios Francisco , Arendse Lauren , Camargo Livia , Graham Delyth , Poglitsch Marko , Ehlers Mario , Sturrock Edward , Touyz Rhian 
Published: April 2021

Objective:
Dual inhibitors of neutral endopeptidase (NEP) and ACE (omapatrilat) have potent blood pressure-lowering actions, with angioedema as a side effect, due to bradykinin accumulation. Here we assessed whether a C-domain specific ACE inhibitor, lisinopril-trp (lis-trp), which specifically inhibits Ang II production while maintaining bradykinin metabolism, in combination with a NEP inhibitor (sacubitril), influences blood pressure, vascular function and the RAAS system in hypertension.

Design and method:
Ang II was measured by LC-MS/MS (liquid chromatography). WT and AngII-dependent hypertensive mice (TTRhRen) received vehicle, sacubitril, lis-trp, lisinopril, sacubitril + lisinopril, sacubitril + lis-trp and omapatrilat for 4 weeks. Blood pressure (BP) was measured by tail-cuff and vascular function/structure of mesenteric arteries by myography.

Results:
Increased AngII levels in TTRhRen mice (pg/g: WT 254.90 ± 46.94 vs TTRhRen 623.70 ± 58.21) was reduced by lis-trp (309 ± 33.84), p < 0.05. Systolic BP was increased in TTRhRen mice (WT 107.5 ± 4.04 vs TTRhRen 135.3 ± 3.99) and reduced by sacubitril + lis-trp (117.0 ± 1.08) and omapatrilat (113.6 ± 2.52), p < 0.05. Hypercontractility in TTRhRen mice (WT 9.42 ± 0.20 vs TTRhRen 10.84 ± 0.19) was reversed by sacubitril + lis-trp (9.43 ± 0.39 p < 0.01), with no change in endothelial dysfunction (WT 92.72 ± 5.1 vs TTRhRen 65.05 ± 3.21 vs TTRhRen + sacubitril + lis-trp 61.04 ± 6.89, p < 0.05). Omapatrilat decreased contraction and improved vasodilation, which may contribute to angioedema. Additionally, sacubitril + lis-trp reversed hypertension-associated inward hypertrophic vaxscular remodelling (CSA um2: LinA3 2832000 ± 248200 vs sacubitril + lis-trp 1693000 ± 199700). These effects were similar to those of omapatrilat (CSA um2: 2286333 ± 44796.66).

Conclusions:
The combination of a C-domain selective ACEi plus a NEP inhibitor reduces blood pressure, normalises vascular contraction and prevents vascular remodelling in an endothelium-independent manner.
EFFECTS OF ANGIOTENSIN RECEPTOR BLOCKERS THERAPY ON LEFT VENTRICULAR HYPERTOPHY AND NT-PROBNP LEVEL IN HYPERTENSIVES
Authors: Popescu Liuba , Ciobanu Nicolae , Caraush Alexandru , Sasu Diana 
Published: April 2021

Objective:
To evaluate the effect of valsartan, eprosartan or losartan on LVH and NT-proBNP levels in patients with hypertension and preserved ejection fraction

Design and method:
This is randomized, prospective and double-blind study involved 154 hypertensive patients (56,5% men; mean age 53,6 ± 0,5 years) with concentric LVH remodeling (LV mass > 115 g/m2 and 95 g/m2 in men and women, respectively), which were eligible criterions to randomize to receive medication into three groups: valsartan (n = 48), eprosartan (n = 54), losartan (n = 52) over a follow-up period of 24 months. Echocardiography, ambulatory blood pressure monitoring and NT-proBNP assessments were performed at baseline and after 24 months treatment.

Results:
Despite similar effects on ambulatory blood pressure levels, significant differences on LV mass index were found between valsartan, eprosartan and losartan treatment (mean decrease 27.0 g/m2 vs 35 g/m2 and 24.0 g/m2, respectively, p < 0,001), and there was positive correlation of changes in ambulatory systolic blood pressure with LV mass index (r = 0,5; p < 0,001). Eprosartan-based therapy induced a greater reduction in NT-proBNP levels (-45,6%, p < 0,001) from baseline than in the valsartan (-28,9%, p < 0,01) and losartan group (- 26,5%,, p < 0,01).

Conclusions:
The findings of this study showed that all three agents progressively reduced LVH, but the reduction was significantly greater in the eprosartan group. Additionally, eprosartan was associated with a greater reduction of NT-proBNP levels.
STRUCTURAL BASIS FOR SUBSTRATE SPECIFICITY AND DOMAIN MOBILITY IN ACE – OPEN FOR BUSINESS
Authors: Sturrock Edward , Cozier Gyles , Lubbe Lizelle , Acharya Ravi 
Published: April 2021

Objective:
Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that is well known for its role in cardiovascular physiology. Through its cleavage of peptides angiotensin I and bradykinin, ACE is involved in the renin-angiotensin-aldosterone and kinin systems, respectively. However, ACE also catalyses the cleavage of a variety of substrates, and thus participates in numerous other physiological functions. The aim of this study was to investigate the hinging mechanism of ACE and the molecular basis for its hydolysis a wide range of substrates with exo- and endopeptidase activity.

Design and method:
Minimally glycosylated N- and C-domain human ACE proteins (N389 and G13 respectively) and N389- S2-Sprime-nACE were produced by expression in cultured mammalian CHO cells and purified to homogeneity. ACE domains were crystallised and X-ray diffraction data were collected at the Diamond Light Source. Initial phases for the native structure were obtained by molecular replacement with PHASER.

Results:
In the present study, we present the high resolution crystal structures of native and S2-Sprime mutant ACE N-domains in an open conformation, and a closed C-domain structure where the C-terminus of a symmetry-related molecule is observed inserted into the active site cavity and binding to the zinc ion.

Conclusions:
Human ACE hydrolyzes a wide range of peptide substrates of varying lengths with carboxypeptidase, and endopeptidase activity. The crystal structures presented in this study shed light on how the ACE domains structurally achieves this diversity of activities. We have crystallized the first open nACE structure, demonstrating that ACE opens like ACE2 to give a wide groove that allows peptides to easily access the binding site. The shape of the groove encourages peptides to adopt an extended linear conformation, and there are likely to be interactions starting near the edge of the groove that are specific for the different peptide substrates that orientate and position them for the different types of hydrolysis. The cACE structure, showing C-terminal insertion from a symmetry related molecule, explains how sACE is capable of cleaving long peptides that are too big to be enclosed within the non-prime binding lobe.
SEX DIFFERENCES IN ANGIOTENSIN II-INDUCED HYPERTENSION AND KIDNEY INJURY: ROLE OF AT1A RECEPTORS IN THE PROXIMAL TUBULE OF THE KIDNEY
Authors: Leite Ana Paulo , Li Xia , Zhuo Jia 
Published: April 2021

Objective:
Sex differences are widely recognized to play a critical role in cardiovascular, blood pressure and renal responses to the vasoactive peptide angiotensin II (Ang II) via activation of AT1 (AT1a) receptors. However, it is not known whether there are sex differences in the pressor and renal responses to Ang II in the absence of AT1a receptors in the proximal tubules of the kidney. In the present study, we tested the hypothesis that there are significant sex differences in Ang II-induced hypertension and kidney injury using male and female wild-type and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-).

Design and method:
To test our hypothesis, twelve groups (n = 8–12 per group) of adult male and female wild-type and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic pump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in extrarenal tissues or the proximal tubules of the kidney, respectively.

Results:
Minor sex differences were found in body wt., heart wt., or kidney wt. between male and female wild-type and PT-Agtr1a-/- mice. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P < 0.01), while basal 24 h urinary Na+, K+, and Cl- excretion were significantly higher in male and female PT-Agtr1a-/- mice than wild-type controls (P < 0.01) without significant sex differences between different strains. Both male and female wild-type and PT-Agtr1a-/- mice developed time-dependent hypertension (P < 0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female wild-type and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in male and female PT-Agtr1a-/- mice (P < 0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in male and female wild-type and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P < 0.01).

Conclusions:
In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without significant sex differences involved.
DIETARY FIBRE REDUCES INTESTINAL PH AND EXHIBITS CARDIOVASCULAR‐PROTECTIVE EFFECTS THROUGH A PROTON‐SENSING RECEPTOR
Authors: Xie Liang , Dinakis Evany , Muralitharan Rikeish , Nakai Michael , Zhang Xiaoyue , Jama Hamdi , Paterson Madeleine , Robert Remy , Mackay Charles , Marques Francine 
Published: April 2021

Objective:
Dietary fibre lowers blood pressure (BP) and risk of cardiovascular disease and death via production of acidic metabolites by the gut microbiota. The mechanisms involved, however, are still elusive. Here, we aimed to understand the role of intestinal pH and the proton-sensing receptor GPR65 in the cardiovascular protection by dietary fibre.

Design and method:
Intestinal pH of C57BL/6 (WT) mice was measured after a 7-day dietary intervention with different levels of dietary fibre. The impact of pH and GPR65 on production of an inflammatory cytokine, TNFa, was determined by flow cytometry. We also determined the cardiovascular phenotype of male and female naïve WT and Gpr65-/- mice, including BP, tissue weights, sodium handling and immune cell infiltration.

Results:
Compared to the control diet, high fibre diet significantly reduced pH in caecum (control 6.84 ± 0.12 vs high fibre 6.03 ± 0.07; P < 0.001) and colon (7.10 ± 0.12 vs 5.95 ± 0.12, P < 0.001), while a diet lacking fibre significantly elevated pH (caecum, 7.37 ± 0.05, P = 0.001; colon, 7.53 ± 0.07, P = 0.030). Acidic pH inhibited the production of the pro-inflammatory TNFa by both CD4+ and CD8+ T cells (pH 6 vs pH 7; P < 0.001). Deletion of GPR65 increased TNFa production, particularly at acidic pH (CD4+, P = 0.002; CD8+, P < 0.001). Compared to WT controls, male and female Gpr65-/- mice had higher BP (mean arterial pressure; males WT 76.57 ± 3.26 vs Gpr65-/- 87.69 ± 2.18, P = 0.013; females WT 73.40 ± 2.41 vs Gpr65-/- 82.27 ± 2.56, P = 0.018; mmHg), and significant cardiac (Males, P < 0.001; Females, P = 0.001), renal (Males, P = 0.003; Females, P = 0.003) and splenic (Males, P = 0.002; Females, P = 0.002) hypertrophies when adjusted to tibia length. Male Gpr65-/- mice exhibited compromised capability in handling sodium (P < 0.001) and water (P = 0.028). Furthermore, male Gpr65-/- mice had increased infiltrations of CD4+ T cells (P = 0.015) and gamma-delta T cells (P = 0.038) in the kidneys, suggesting an increased susceptibility to renal inflammation.

Conclusions:
We determined that dietary fibre reduces large intestine pH. Low pH inhibits TNFa production in a partially GPR65-dependent way. Gpr65-/- mice exhibited spontaneous cardiovascular disorders including higher BP. This supports that the cardiovascular protection by dietary fibre is likely to be through pH regulation and GPR65. This is a highly novel mechanism that regulates BP.
ARTERIAL HYPERTENSION IN YOUNG PEOPLE REVEALING SYSTEMIC AFFECTIONS
Authors: Thabet Maissa , Romdhane Wiem , Anoun Jihed , Zorgati Hend , Hassine Imen Ben , Karmeni Monia , Fredj Fatma Ben , Mzabi Anis , Laouani Chadia 
Published: April 2021

Objective:
Arterial hypertension in young patients can reveal or be a complication involving multiple mechanisms (coarctation of the aorta, inflammatory stenosis and / or thrombosis of the renal artery, vasculitis of arteries of different sizes, glomerular nephropathies, fibrosis retro peritoneal …) many systemic conditions.

Design and method:
We retrospectively studied hypertension in 16 patients under 40. Data were collected retrospectively from 16 patients, under 40 years old, and hospitalized d in an internal medicine department for systemic diseases.

Results:
These were 2 men and 14 women. The average age was 34 years and 8 months (range 16–40 years).
The systemic conditions identified were: systemic lupus erythematosus (7 cases), Takayasu disease (4 cases), systemic sclerosis (1 case), Sjögren syndrome (1 case), Behçet's disease (1 case), Buerger's disease (1 case) and cryoglobulinemia (1 case).

Conclusions:
Hypertension in young patients revealing a systemic disorder is rare and has complex mechanisms. Its etiological treatment depends on the specific context of each identified condition, on surgical treatment and / or long-term medical treatment.
HYPERTENSION DURING EARLY PREGNANCY IMPAIRS GENETIC PRIMING OF UTERINE ARTERIES PRIOR TO REMODELLING IN RODENTS
Authors: Scott Kayley , Morgan Hannah , McBride Martin , Graham Delyth , Delles Christian 
Published: April 2021

Objective:
During pregnancy the uterine spiral arteries undergo major vascular remodelling to ensure sufficient uteroplacental perfusion to support the fetus. In pregnancies complicated by hypertensive disorders this remodelling is deficient leading to impaired uteroplacental blood flow and poor maternal and fetal outcomes. Evidence suggests that the uterine arteries can be ‘primed’ by changes in gene expression and maternal factors to ensure appropriate remodelling takes place.
This study aimed to examine the early-pregnancy associated gene expression changes in the uterine arteries (UAs) of stroke-prone spontaneously hypertensive rats (SHRSP) compared to their normotensive counterparts, Wistar-Kyoto rats (WKY).

Design and method:
SHRSP and WKY females were time-mated with males of the relevant strain. On gestational day (GD)6.5 dams were sacrificed, the UA collected and processed for RNA-sequencing alongside age-matched virgin controls (n = 3/group). Structure & function were assessed by wire and pressure myography. Gene expression changes were investigated using Ingenuity Pathway Analysis (IPA®) with padj > 0.05.

Results:
No structural or functional differences were observed in UAs between strains (SHRSP, WKY) or pregnancy (NP, P) using myography. SHRSP UAs showed a greater number of differentially expressed genes (DEGs) across pregnancy than WKY. WKY UAs exhibited an expression pattern of reduced Ca2+ handling and RAAS components with an increase in ATP production between NP and P states. SHRSP P UAs showed an increased expression of DEGs related to immune response, ROS production and downstream effectors of the RAAS in comparison to SHRSP NP UAs. These changes were not shared between strains.

Conclusions:
These results suggest SHRSP UAs experience gene expression changes in inflammation and oxidative stress pathways in early pregnancy that may induce failed priming of the UA. This may subsequently contribute to adverse vascular remodelling and placental ischaemia in later gestation characteristic of hypertensive pregnancies.
DIETARY SODIUM INTAKE DOES NOT ALTER RENAL POTASSIUM HANDLING AND BLOOD PRESSURE IN HEALTHY YOUNG MALES
Authors: Olivier Valerie , Pechere Antoinette , Feraille Eric 
Published: April 2021

Objective:
High salt intake and potassium deficiency are involved in the pathogenesis of hypertension and cardiovascular diseases. The effects of sodium intakes on renal handling of potassium are scarcely studied. The objective of this study is to assess the renal handling of potassium in condition of low, normal and high sodium intake.

Design and method:
In a cross-over study, we assessed the effect of sodium on renal potassium handling in 16 healthy males assigned to three 7-day periods on low (LSD, 3 g NaCl/d), normal (NSD, 6 g NaCl/d) and high (HSD, 15 g NaCl/d) sodium diet with constant potassium intake. Contributions of distal NaCl co-transporter and epithelial sodium channel in the collecting system on potassium and sodium handling were assessed at steady-state by acute response to 100 mg oral hydrochlorothiazide and with addition of 10 mg of amiloride to hydrochlorothiazide, respectively.

Results:
Diurnal blood pressure slightly increased from 119.30 ± 7.95 mmHg under LSD to 123.00 ± 7.50 mmHg, (P = 0.02) under HSD, while estimated glomerular filtration rate increased from 133.20 ± 34.68 ml/min under LSD to 187.00 ± 49.10 under HSD, (P = 0.005). Twenty-four hours potassium excretion remained stable on all sodium intakes (66.28 ± 19.12 mmol/24 h under LSD; 55.91 ± 21.17 mmol/24 h under NSD and 66.81 ± 20.72 under HSD, P = 0.9). The hydrochlorothiazide-induced natriuresis was the highest under HSD (30.22 ± 12.53 mmol/h), and the lowest under LSD (15.38 ± 8.94 mmol/h, P = 0.02). Hydrochlorothiazide increased kaliuresis and amiloride decreased kaliuresis similarly on all 3 diets.

Conclusions:
Neither spontaneous nor diuretic-induced potassium excretion were influenced by sodium intake in healthy male subjects. However, the respective contribution of the distal convoluted tubule and the collecting duct to renal sodium handling was dependent on dietary sodium intake.
INTERRELATION OF INDICATORS OF LEFT VENTRICULAR-ARTERIAL COUPLING AND PARAMETERS OF LOCAL ARTERIAL STIFFNESS IN THE POSTINFARCTION PERIOD
Authors: Salyamova Lyudmila , Kvasova Olga , Galimskaya Vera , Khromova Angelina , Burko Nadezhda , Oleynikov Valentin 
Published: April 2021

Objective:
To study the correlations between the parameters of the left ventricular-arterial coupling (LVAC) and the parameters of local arterial stiffness in patients after STEMI 6 months after revascularization.

Design and method:
125 patients (mean age 51.2 ± 8.8 years) after STEMI were included in the study. The diagnosis was confirmed by biomarkers of myocardial necrosis, ECG, coronary angiography. Echocardiography was performed at the 7–9th day and 6 months after STEMI (MyLab, Esaote, Italy), followed by calculation of LVAC indices: arterial elastance (Ea), left ventricular elastance (Ees), LVAC index (Ea/Ees). The study of the right and left common carotid arteries (CCA) was carried out on a MyLab ultrasound scanner (Esaote, Italy) using high-frequency RF signal technology. The following parameters were recorded: QIMT - intima-media thickness, DC - lateral distensibility coefficient, stiffness index β, loc Psys - local SBP, locPdia - local DBP, locPWV - local pulse wave velocity, AP - amplification pressure.

Results:
In the study of the correlation of LVAC indices with the CCA rigidity parameters recorded on 7–9th day from the STEMI, a relationship was revealed only between Ees and LocPsys (r = 0.40; p = 0.01), Ees and LocPdia (r = 0, 26; p = 0.004). After 6 months of follow-up, a closer relationship between the LVAC and the parameters of the local CCA stiffness was diagnosed. The Ea indicator correlated with DC (r = -0.23; p = 0.009), PWV (r = 0.21; p = 0.02), LocPsys (r = 0.33; p = 0.0002), LocPdia (r = 0.26; p = 0.004) and AP (r = 0.19; p = 0.03). The Ees indicator was found to be associated with LocPsys (r = 0.38; p = 0.00001), LocPdia (r = 0.27; p = 0.002), AP (r = 0.22; p = 0.01).

Conclusions:
After 6 months, there was a closer correlation between the LVAC indices and the parameters of local pressure and rigidity. This is probably partly due to the remodeling of the cardiovascular system in the postinfarction period and the inclusion of compensatory-adaptive mechanisms that ensure the contractile function of the heart.
BLOOD PRESSURE RESPONSES TO STRESS AFTER CHRONIC PHYSICAL EXERCISE: A SYSTEMATIC REVIEW WITH META-ANALYSIS
Authors: Mariano Igor , Amaral Ana Luiza , Ribeiro Paula , Puga Guilherme 
Published: April 2021

Objective:
To assess the effects of physical exercise interventions on blood pressure (BP) responsiveness to laboratory stress tests.

Design and method:
This is a systematic review with meta-analysis that examined the effect of at least 4 weeks of exercise training on adults BP responsiveness to stressor tasks. For quantitative analysis, a random-effects model by Hunter Smith method was used. The searches were performed in 4 digital databases (PUBMED, LILACS, EMBASE and PsycInfo) and 19 studies and 2 event abstracts were included, totaling 857 individuals (12 studies and 516 individuals, in the quantitative phase).

Results:
Regarding qualitative analyses, 66.7% of the full text and abstracts showed favorable BP responses (either in SBP, DPB and/or MBP) after chronic exercise training, and the most frequent stressor test was the Arithmetic task, used in 33.3% of studies. Besides that, no asymmetries were found in the funnel graphs that would infer publication bias. Favorable metanalytic results for the exercises were found in systolic BP (SBP; mean effect size = -0.47 [-0.69; -0.24]) and diastolic BP (DBP; mean effect size = -0.35 [-0.58; -0.12).

Conclusions:
In summary, chronic physical exercise lowers SBP and DBP responsiveness to laboratory stress tests. So, these results associated with information from previous studies reinforce the idea that physical exercise is a valid strategy to control not only BP at rest but also its levels under stress, reducing hypertensive peaks of these individuals.