Sustained Elevated Blood Pressure Accelerates Atherosclerosis Development in a Preclinical Model of Disease.
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ABSTRACT:
SUBMITTER: Gonzalez-Guerra A
PROVIDER: S-EPMC8395088 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D-deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or -sufficient diet for 8-10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ~2-fold greater atherosclerosis in the aortic arch and ~2-8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D-sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis.
| S-EPMC3551761 | biostudies-literature
Project description:ObjectiveEvidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level.ConclusionsWe show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.
| S-EPMC7447189 | biostudies-literature
Project description:Blood pressure (BP) increased with age and height development, but little was known about the effect of pubertal development on blood pressure in children. A cross-sectional study was performed among 4146 children aged 7-12 years old in China. Pubertal development was assessed based on breast stages and testicular volume. The associations of pubertal development with BP levels and the rate of elevated blood pressure (EBP) were quantified using multiple linear and logistic regressions. We found that pubertal developmental level was positively correlated with BP, and children who experienced puberty onset and early pubertal timing had higher BP levels and prevalence of EBP. After adjusting for covariates, children experienced puberty onset had 3.84 and 2.24 mmHg increase in systolic blood pressure and diastolic blood pressure, and 70%, 53%, and 62% increased odds of EBP, ESBP, and EDBP, respectively, compared with those without puberty onset. Similar results were observed for children who had early pubertal timing. The change of BP in puberty is greater and the association between pubertal development and BP is stronger in girls than boys. These findings suggested that pubertal development could be an important independent factor and one critical period for the EBP progress. Monitoring and management of pubertal development are necessary particularly among girls.
| S-EPMC8678653 | biostudies-literature
Project description:Background Emergency department (ED) visits for hypertension are rising, but the importance of elevated blood pressure (BP) measured during the ED visit is controversial. We evaluated the relationship between ED BP and mean BP over the subsequent year. Methods and Results We performed a retrospective cohort study from January 1, 2010 to December 31, 2013 of 8105 adult patients who made 1 visit to an academic medical center ED with ≥2 ED BPs and ≥2 BPs measured in the subsequent year. The primary exposure was lowest ED systolic BP. The primary outcome was mean systolic BP ≥140 mm Hg over the year following the index ED visit. Diastolic BP was examined as a secondary exposure and outcome. Multiple logistic regression was performed adjusting for several covariates, with interaction terms for hypertension diagnosis, ED disposition, pain-related ED chief complaint, and sex. Patients whose lowest ED systolic BP was 140 to 159 mm Hg had an adjusted odds ratio of having a mean SBP ≥140 mm Hg in the subsequent year of 10.9 (95% CI, 7.6-15.6). Patients without diagnosed hypertension and ED BP 140/90 to 159/99 mm Hg were more likely to have elevated BP in the following year. Hospitalization increased the likelihood of persistently elevated systolic BP but not diastolic BP. There was no effect modification by pain-related ED complaint. Conclusions When ED BP is consistently elevated, BP is highly likely to remain elevated in the subsequent year, regardless of pain, and particularly among patients without diagnosed hypertension. Further research is needed to determine the optimal management of elevated ED BP.
| S-EPMC7429032 | biostudies-literature
Project description:BackgroundPreeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension.Methods and resultsThe Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24-1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40-2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98-4.55]), heart failure (HR, 1.78 [95% CI, 1.43-2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24-2.04]), kidney disease (HR, 1.91 [95% CI, 1.18-3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21-1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35-3.41]), heart failure (HR, 1.43 [95% CI, 1.13-1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13-1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05-1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy.ConclusionsElevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.
| S-EPMC4151554 | biostudies-literature
Project description:Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood.The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ?120 mm?Hg, diastolic BP ?80 mm?Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ?90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47-2.38] and 1.57[1.22-2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92-1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50-0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied.Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood.
| S-EPMC3875837 | biostudies-literature
Project description:Estimates for prevalence of high blood pressure (BP) among adolescents in Africa vary widely and few studies, if any, have documented the results of the recommended stepwise BP screening. In this cross-sectional study in Tanzania, we aimed to estimate prevalence of sustained high BP in 3 public secondary schools using the American Academy of Pediatrics BP screening strategy. On Day 1, one screening automated office BP (AOBP) measurement (Step 1) was followed by two more AOBP measurements (Step 2). Repeat AOBP measurements were obtained after about one month on adolescents with high AOBP measurements on Day 1 (Step 3). Participants with sustained high BP underwent 24-h ambulatory BP monitoring (step 4). Of all 500 enrolled participants, the prevalence of high blood pressure at each step in the process was 36.6% (183), 25.6% (128), 10.2% (51), and 2.6%(13) respectively for Steps 1-4. All except 6 students completed all 4 steps of the BP screening algorithm as indicated. We conclude that diagnosis of hypertension in African adolescents should use multiple AOBP measurements over multiple days followed by 24-h ABPM. Screening for high BP in school settings appears to be feasible and could provide a platform for cardiovascular disease education and health promotion.
| S-EPMC8052360 | biostudies-literature
Project description:Miniature pigs have advantages over rodents in modeling atherosclerosis because their cardiovascular system and physiology are similar to that of humans. Apolipoprotein E (ApoE) deficiency has long been implicated in cardiovascular disease in humans. To establish an improved large animal model of familial hypercholesterolemia and atherosclerosis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 system (CRISPR/Cas9) was used to disrupt the ApoE gene in Bama miniature pigs. Biallelic-modified ApoE pigs with in-frame mutations (ApoEm/m ) and frameshift mutations (ApoE-/- ) were simultaneously produced. ApoE-/- pigs exhibited moderately increased plasma cholesterol levels when fed with a regular chow diet, but displayed severe hypercholesterolemia and spontaneously developed human-like atherosclerotic lesions in the aorta and coronary arteries after feeding on a high-fat and high-cholesterol (HFHC) diet for 6 months. Thus, these ApoE-/- pigs could be valuable large animal models for providing further insight into translational studies of atherosclerosis.
| S-EPMC6215431 | biostudies-literature
Project description:Little is known about prostaglandin F(2alpha) in cardiovascular homeostasis. Prostaglandin F(2alpha) dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory up-regulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNF(alpha), inducible nitric oxide enzyme and TGF(beta) are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.
| S-EPMC2673134 | biostudies-literature
Project description: INTRODUCTION: Published data on hypertension incidence and management in Anderson-Fabry disease are scant and the contribution of elevated blood pressure to organ damage is not well recognized.AimTherefore, we have assessed blood pressure values and their possible correlations with clinical findings in a well described cohort of Fabry patients.MethodsBetween January 2015 and May 2019, all adult Fabry patients (n = 24 females, n = 8 males) referred to our institute were prospectively enrolled. During the first examination patient's genotype and clinical characteristics were recorded. Blood pressure data were obtained by standard observed office measurements followed, within 6 months, by ambulatory blood pressure monitoring and home self-recordings. Organ involvement, including kidneys, heart and brain, was monitored over time. Consequently, patients were defined as clinically stable or progressive through the Fabry Stabilization Index.ResultsThe standard office measurements have diagnosed hypertension in three (9.37%) patients, but the ambulatory monitoring showed elevated blood pressure in six (18.75%) patients, revealing three cases of masked hypertension. All the hypertensive patients were females and, compared with normotensive subjects, they presented a lower glomerular filtration rate (p < 0.05) and a more advanced cardiac hypertrophy (p < 0.05). Four (66.7%) of them were diagnosed with a progressive form of the disease through the Fabry Stabilization Index while the majority of the normotensive group (84.6%, n = 19) was stable over time. No correlation was found between the prevalence of hypertension and the type of mutations causing Fabry disease.ConclusionHypertension can be found in a restricted portion of clinically stable Fabry patients. In contrast, patients presenting with a progressive organ involvement, particularly renal impairment, have a major risk of developing uncontrolled blood pressure, and should be followed carefully. Moreover, the ambulatory blood pressure monitoring proved to be useful to reveal masked hypertension, which can contribute to the progressive worsening of the organ damage. Therefore, a proper diagnosis and therapy of hypertension may improve the outcome of Fabry patients.
| S-EPMC8087548 | biostudies-literature