The placental syndromes gestational hypertension, preeclampsia and intrauterine growth restriction are associated with an increased cardiovascular risk to the mother later in life. In this review, we ...argue that a woman's pre-conception cardiovascular health drives both the development of placental syndromes and long-term cardiovascular risk but acknowledge that placental syndromes can also contribute to future cardiovascular risk independent of pre-conception health. We describe how preclinical studies in models of preeclampsia inform our understanding of the links with later cardiovascular disease, and how current pre-pregnancy studies may explain relative contributions of both pre-conception factors and the occurrence of placental syndromes to long-term cardiovascular disease.
α-Klotho Expression in Human Tissues Lim, Kenneth; Groen, Arnoud; Molostvov, Guerman ...
The journal of clinical endocrinology and metabolism,
2015-October, Letnik:
100, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Context:
α-Klotho has emerged as a powerful regulator of the aging process. To date, the expression profile of α-Klotho in human tissues is unknown, and its existence in some human tissue types is ...subject to much controversy.
Objective:
This is the first study to characterize systemwide tissue expression of transmembrane α-Klotho in humans. We have employed next-generation targeted proteomic analysis using parallel reaction monitoring in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health.
Results:
The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive, and neuronal tissues, was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, whereas liver did not reveal a detectable signal. These results were next confirmed by Western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho-expressing tissues were subjected to parallel reaction monitoring mass spectrometry (data deposited at ProteomeXchange, PXD002775) identifying peptides specific for the full-length, transmembrane α-Klotho isoform.
Conclusions:
The data presented confirm α-Klotho expression in the kidney tubule and in the artery and provide evidence of α-Klotho expression across organ systems and cell types that has not previously been described in humans.
Aims
Endothelial‐derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that ...was tested in two phase I studies.
Methods
Single escalating doses of GSK2256294 2–20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected.
Results
GSK2256294 was well‐tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half‐life averaging 25–43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose‐dependent, from an average of 41.9% on 2 mg (95% confidence interval CI –51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen.
Conclusions
GSK2256294 was well‐tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.
Pre‐eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an ...important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short‐ and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide–soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre‐eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S‐nitrosothiols; l‐arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3′,5′‐monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre‐eclampsia is explored.
Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and ...late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction.
We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction.
We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24–40 weeks.
Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 ± 1.35; P = .0001) and lower peripheral vascular resistance Z scores (–0.76 ± 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 ± 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores (–0.80 ± 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 ± 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03).
Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature.
Aortic stiffness is a strong predictor of cardiovascular disease endpoints. Cross-sectional studies have shown associations of various cardiovascular risk factors with aortic pulse wave velocity, a ...measure of aortic stiffness, but the long-term impact of these factors on aortic stiffness is unknown.
In 3,769 men and women from the Whitehall II cohort, a wide range of traditional and novel cardiovascular risk factors were determined at baseline (1991-1993) and aortic pulse wave velocity was measured at follow-up (2007-2009). The prospective associations between each baseline risk factor and aortic pulse wave velocity at follow-up were assessed through sex stratified linear regression analysis adjusted for relevant confounders. Missing data on baseline determinants were imputed using the Multivariate Imputation by Chained Equations.
Among men, the strongest predictors were waist circumference, waist-hip ratio, heart rate and interleukin 1 receptor antagonist, and among women, adiponectin, triglycerides, pulse pressure and waist-hip ratio. The impact of 10 centimeter increase in waist circumference on aortic pulse wave velocity was twice as large for men compared with women (men: 0.40 m/s (95%-CI: 0.24;0.56); women: 0.17 m/s (95%-CI: -0.01;0.35)), whereas the opposite was true for the impact of a two-fold increase in adiponectin (men: -0.30 m/s (95%-CI: -0.51;-0.10); women: 0.61 m/s (95%-CI: -0.86;-0.35)).
In this large prospective study, central obesity was a strong predictor of aortic stiffness. Additionally, heart rate in men and adiponectin in women predicted aortic pulse wave velocity suggesting that strategies to prevent aortic stiffening should be focused differently by sex.
The goal of this study was to determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors.
Several studies have ...shown that aPWV may be a useful risk factor for predicting CVD, but they have been underpowered to examine whether this is true for different subgroups.
We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with CVD outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects.
Of 17,635 participants, a total of 1,785 (10%) had a CVD event. The pooled age- and sex-adjusted hazard ratios (HRs) per 1-SD change in loge aPWV were 1.35 (95% confidence interval CI: 1.22 to 1.50; p < 0.001) for coronary heart disease, 1.54 (95% CI: 1.34 to 1.78; p < 0.001) for stroke, and 1.45 (95% CI: 1.30 to 1.61; p < 0.001) for CVD. Associations stratified according to sex, diabetes, and hypertension were similar but decreased with age (1.89, 1.77, 1.36, and 1.23 for age ≤50, 51 to 60, 61 to 70, and >70 years, respectively; pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor of coronary heart disease (HR: 1.23 95% CI: 1.11 to 1.35; p < 0.001), stroke (HR: 1.28 95% CI: 1.16 to 1.42; p < 0.001), and CVD events (HR: 1.30 95% CI: 1.18 to 1.43; p < 0.001). Reclassification indices showed that the addition of aPWV improved risk prediction (13% for 10-year CVD risk for intermediate risk) for some subgroups.
Consideration of aPWV improves model fit and reclassifies risk for future CVD events in models that include standard risk factors. aPWV may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management.
Preeclampsia and fetal growth restriction during pregnancy are associated with increased risk of maternal cardiovascular disease later in life. It is unclear whether this association is causal or ...driven by similar antecedent risk factors. Clarification requires recruitment before conception which is methodologically difficult with high attrition rates and loss of outcome numbers to nonconception/miscarriage. Few prospective studies have, therefore, been adequately powered to address these questions. We recruited 530 healthy women (mean age: 35.0 years) intending to conceive and assessed cardiac output, cardiac index, stroke volume, total peripheral resistance, mean arterial pressure, and heart rate before pregnancy. Participants were followed to completion of subsequent pregnancy with repeat longitudinal assessments. Of 356 spontaneously conceived pregnancies, 15 (4.2%) were affected by preeclampsia and fetal growth restriction. Women who subsequently developed preeclampsia/fetal growth restriction had lower preconception cardiac output (4.9 versus 5.8 L/min;
=0.002) and cardiac index (2.9 versus 3.3 L/min per meter
;
=0.031) while mean arterial pressure (87.1 versus 82.3 mm Hg;
=0.05) and total peripheral resistance (1396.4 versus 1156.1 dynes sec cm
;
<0.001) were higher. Longitudinal trajectories for cardiac output and total peripheral resistance were similar between affected and healthy pregnancies, but the former group showed a more exaggerated fall in mean arterial pressure in the first trimester, followed by a steeper rise and a steeper fall to postpartum values. Significant relationships were observed between cardiac output, total peripheral resistance, and mean arterial pressure and gestational epoch. We conclude that in healthy women, an altered prepregnancy hemodynamic phenotype is associated with the subsequent development of preeclampsia/fetal growth restriction.
Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes ...associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data.
This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies.
Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9-58.3) per 100,000 person-years; n = 521, 85.8 (78.6-93.5) per 100,000 person-years; and n = 518, 99.3 (90.9-108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33-1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48-1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67-4.86), and unstable angina, aHR = 1.92 (1.33-2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49-7.19), and acute myocardial infarction, aHR = 2.46 (1.72-3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies.
Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.
The aim of the current investigation was to test the hypothesis that age-related changes in augmentation index (AIx) are more prominent in younger individuals (<50 years), whereas changes in aortic ...stiffness per se are more marked in older individuals (>50 years).
Aging exerts a number of deleterious changes in the cardiovascular system, and, in particular, on the large arteries. Previous studies have suggested that AIx and pulse wave velocity (PWV) increase linearly with age, yet epidemiological data concerning pulse pressure suggest that large artery stiffening predominantly occurs later in life.
Peripheral and central blood pressure, augmentation pressure (AP), and AIx were determined in 4,001 healthy, normotensive individuals, aged 18 to 90 years. Aortic and brachial PWV were also determined in a subset of 998 subjects.
Peripheral and central pulse pressure, AP, AIx, and aortic and brachial PWV all increased significantly with age; however, the age-related changes in AIx and aortic PWV were non-linear, with AIx increasing more in younger individuals, whereas the changes in PWV were more prominent in older individuals.
These data suggest that AIx might be a more sensitive marker of arterial stiffening and risk in younger individuals but aortic PWV is likely to be a better measure in older individuals.
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