Influence of Blood Pressure Reduction on Pulse Wave Velocity in Primary Hypertension: A Meta-Analysis and Comparison With an Acute Modulation of Transmural Pressure.

BACKGROUND: Increased arterial stiffness and pulse wave velocity (PWV) of the aorta and large arteries impose adverse hemodynamic effects on the heart and other organs. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or is due to an alternate functional or structural change that might differ according to class of antihypertensive drug. METHODS: We performed a systematic review and meta-analysis of the effects of different antihypertensive drug classes and duration of treatment on PWV with and without adjustment for change in mean arterial blood pressure (BP; study 1) and compared this to the change in PWV after an acute change in transmural pressure, simulating an acute change in BP (study 2). RESULTS: A total of 83 studies involving 6200 subjects were identified. For all drug classes combined, the reduction of PWV was 0.65 (95% CI, 0.46-0.83) m/s per 10 mm Hg reduction in mean arterial BP, a change similar to that induced by an acute change in transmural pressure in a group of hypertensive subjects. When adjusted for change in mean arterial BP, the reduction in PWV after treatment with beta-blockers or diuretics was less than that after treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists or calcium channel antagonists. CONCLUSIONS: Reduction in PWV after antihypertensive treatment is largely explained by the reduction in BP, but there are some BP-independent effects. These might increase over time and contribute to better outcomes over the long term, but this remains to be demonstrated in long-term clinical trials.

Hemodynamic Determinants of Elevated Blood Pressure and Hypertension in the Middle to Older-Age UK Population: A UK Biobank Imaging Study.

BACKGROUND: Increased systemic vascular resistance and, in older people, reduced aortic distensibility, are thought to be the hemodynamic determinants of primary hypertension but cardiac output could also be important. We examined the hemodynamics of elevated blood pressure and hypertension in the middle to older-aged UK population participating in the UK Biobank imaging studies. METHODS: Cardiac output, systemic vascular resistance, and aortic distensibility were measured from cardiac magnetic resonance imaging in 31 112 (distensibility in 21 178) participants (46.3% male, mean age±SD 63±7 years). Body composition including visceral adipose tissue volume and abdominal subcutaneous adipose tissue volume were measured in 19 645 participants. RESULTS: Participants with higher blood pressure had higher cardiac output (higher by 17.9±26.6% in hypertensive compared with those with optimal blood pressure) and higher systemic vascular resistance (higher by 11.4±27.9% in hypertensive compared with those with optimal blood pressure). These differences were little changed after adjustment for body size and adiposity. The contribution of cardiac output relative to systemic vascular resistance was more marked in younger compared with older subjects. Aortic distensibility decreased with age and was lower in participants with higher compared with lower blood pressure but with a greater difference in younger compared with older subjects. CONCLUSIONS: In the middle to older-aged UK population, cardiac output plays an important role in contributing to elevated mean arterial blood pressure, particularly in younger compared with older subjects. Reduced aortic distensibility contributes to a rise in pulse pressure and systolic blood pressure at all ages.

Relation of Pulse Wave Velocity to Contemporaneous and Historical Blood Pressure in Female Twins.

BACKGROUND: An association between blood pressure and aortic stiffness is well known, but ambiguity remains as to whether one precedes the other. This study aimed to investigate the association of aortic stiffness with contemporaneous versus historic blood pressure and direction of causality between aortic stiffening and hypertension in female twins. METHODS: Aortic stiffness, measured by carotid-femoral pulse wave velocity (PWV), and mean arterial pressure (MAP) was recorded in 2037 female TwinsUK participants (mean age: 62.4±9.7 years) at a single time point. A subset of 947 participants had repeat PWV and MAP measures (mean interval 5.5±1.7 years) with additional historic MAP (mean interval 6.6±3.3 years before baseline). RESULTS: Cross-sectional multivariable linear regression analysis confirmed PWV significantly associated with age and MAP. In longitudinal analysis, annual progression of PWV was not associated with historic MAP (standardized beta coefficient [ß]=-0.02, P=0.698), weakly associated with baseline MAP (ß=0.09, P=0.049) but strongly associated with progression (from baseline to most recent measurement) of MAP (ß= 0.26, P<0.001). Progression of MAP associated with both baseline and progression of PWV (ß=0.13, P=0.003 and ß=0.24, P<0.001, respectively). CONCLUSIONS: Progression of aortic stiffness associates more strongly with contemporaneous MAP compared with historic MAP. In contrast, progression of MAP is associated with prior arterial stiffness. These findings suggest a bidirectional relationship between arterial stiffness and blood pressure, and that lowering blood pressure may prevent a cycle of arterial stiffening and hypertension.

Aortic Distensibility Measured by Automated Analysis of Magnetic Resonance Imaging Predicts Adverse Cardiovascular Events in UK Biobank.

Background Automated analysis of cardiovascular magnetic resonance images provides the potential to assess aortic distensibility in large populations. The aim of this study was to compare the prediction of cardiovascular events by automated cardiovascular magnetic resonance with those of other simple measures of aortic stiffness suitable for population screening. Methods and Results Aortic distensibility was measured from automated segmentation of aortic cine cardiovascular magnetic resonance using artificial intelligence in 8435 participants. The associations of distensibility, brachial pulse pressure, and stiffness index (obtained by finger photoplethysmography) with conventional risk factors was examined by multivariable regression and incident cardiovascular events by Cox proportional-hazards regression. Mean (±SD) distensibility values for men and women were 1.77±1.15 and 2.10±1.45 (P<0.0001) 10-3 mm Hg-1, respectively. There was a good correlation between automatically and manually obtained systolic and diastolic aortic areas (r=0.980 and r=0.985, respectively). In regression analysis, distensibility associated with age, mean arterial pressure, heart rate, weight, and plasma glucose but not male sex, cholesterol or current smoking. During an average follow-up of 2.8±1.3 years, 86 participants experienced cardiovascular events 6 of whom died. Higher distensibility was associated with reduced risk of cardiovascular events (adjusted hazard ratio [HR], 0.61 per log unit of distensibility; P=0.016). There was no evidence of an association between pulse pressure (adjusted HR 1.00; P=0.715) or stiffness index (adjusted HR, 1.02; P=0.535) and risk of cardiovascular events. Conclusions Automated cardiovascular magnetic resonance-derived aortic distensibility may be incorporated into routine clinical imaging. It shows a similar association to cardiovascular risk factors as other measures of arterial stiffness and predicts new-onset cardiovascular events, making it a useful tool for the measurement of vascular aging and associated cardiovascular risk.

Cardiovascular health and risk of hospitalization with COVID-19: A Mendelian Randomization study.

BACKGROUND: Susceptibility to and severity of COVID-19 is associated with risk factors for and presence of cardiovascular disease. METHODS: We performed a 2-sample Mendelian randomization to determine whether blood pressure (BP), body mass index (BMI), presence of type 2 diabetes (T2DM) and coronary artery disease (CAD) are causally related to presentation with severe COVID-19. Variant-exposure instrumental variable associations were determined from most recently published genome-wide association and meta-analysis studies (GWAS) with publicly available summary-level GWAS data. Variant-outcome associations were obtained from a recent GWAS meta-analysis of laboratory confirmed diagnosis of COVID-19 with severity determined according to need for hospitalization/death. We also examined reverse causality using exposure as diagnosis of severe COVID-19 causing cardiovascular disease. RESULTS: We found no evidence for a causal association of cardiovascular risk factors/disease with severe COVID-19 (compared to population controls), nor evidence of reverse causality. Causal odds ratios (OR, by inverse variance weighted regression) for BP (OR for COVID-19 diagnosis 1.00 [95% confidence interval (CI): 0.99-1.01, P = 0.604] per genetically predicted increase in BP) and T2DM (OR for COVID-19 diagnosis to that of genetically predicted T2DM 1.02 [95% CI: 0.9-1.05, P = 0.927], in particular, were close to unity with relatively narrow confidence intervals. CONCLUSION: The association between cardiovascular risk factors/disease with that of hospitalization with COVID-19 reported in observational studies could be due to residual confounding by socioeconomic factors and /or those that influence the indication for hospital admission.

Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta-analysis.

AIMS: Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta-analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment. METHODS: Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials. Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1684 articles were retrieved of which 61 met the prespecified inclusion/exclusion criteria. PRA was measured in 30/61 studies. Diuretics led to a sustained increase in PRA which was similar for different classes of diuretic (standardised mean difference [95% confidence interval] 0.481 [0.362, 0.601], 0.729 [0.181, 1.28], 0.541 [0.253, 0.830] and 0.548 [0.159, 0.937] for thiazide, loop, mineralocorticoid receptor antagonists/potassium-sparing and combination diuretics respectively, Q = 0.897, P = .826), and did not relate to the average decrease in blood pressure. CONCLUSION: In antihypertensive drug trials, diuretics lead to a sustained increase in average PRA, which is similar across different classes of diuretic and unrelated to the average reduction in blood pressure.

Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization.

AIMS: Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness. METHODS AND RESULTS: We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001). CONCLUSION: The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness.

Association of pulse wave velocity and intima-media thickness with cardiovascular risk factors in young adults.

Pulse wave velocity (PWV), a measure of arterial stiffness, and intima-media thickening (IMT), a measure of early atherosclerosis, are intermediate markers of cardiovascular disease which are predictive of cardiovascular events. Traditionally, both were thought to result from accumulative exposure to traditional cardiovascular risk factors. However, their association with risk factors in young adults in low-income settings is unknown. We sought to investigate the association between PWV and IMT with traditional cardiovascular risk factors in the Andhra Pradesh Children and Parents Study cohort from Southern India. Male and female adults (N = 1440) aged between 20 and 24 years underwent measures of PWV and IMT. Exposure variables included smoking, body mass index (BMI), mean arterial pressure (MAP), glucose, homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, high-density lipoprotein cholesterol (HDL-cholesterol), and triglycerides. Association between outcome and exposure variables was assessed using linear regression analysis. Average values for PWV and IMT were 5.9 ± 0.6 m/s and 0.5 ± 0.1 mm. In univariable analysis, PWV associated with MAP, BMI, smoking, total cholesterol, glucose, and HOMA-IR and IMT associated with MAP, BMI, tobacco use, and HDL-cholesterol. In multivariable analysis, PWV remained strongly positively associated with MAP increasing by 0.5 m/s (P < .001) for a 10 mm Hg increase in MAP (R2  = .37). In contrast, IMT negatively associated with HDL-cholesterol (ß = -.10; P = .012, R2  = .02). There was weak evidence that PWV and IMT positively associated with BMI. In young adults from Southern India, PWV positively associated with blood pressure and IMT negatively associated with HDL-cholesterol. This suggests separate etiologies for atherosclerosis and arterial stiffening in young adults.

Pediatric heterozygous familial hypercholesterolemia patients have locally increased aortic pulse wave velocity and wall thickness at the aortic root.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects 1 in 250 people. Aortic stiffness, measured by pulse wave velocity (PWV), is an independent predictor for cardiovascular events. Young FH patients are a unique group with early vessel wall disease that may serve to elucidate the determinants of aortic stiffness. We hypothesized that young FH patients would have early changes in aortic stiffness compared to healthy, age- and sex-matched reference values. Thirty-three FH patients ( ≥ 7 years age; mean age 14.6 ± 3.3 years; 26/33 on statin therapy) underwent cardiac MRI. PWV was determined using propagation of flow waveform from aortic arch phase contrast images. Distensibility and aortic wall thickness (AWT) were measured at the ascending, proximal descending, and diaphragmatic aorta. Ventricular volumes and left ventricular (LV) myocardial mass were measured from 2D cine images. These parameters were compared to age- and sex-matched reference values. FH patients had significantly higher PWV (4.5 ± 0.8 vs. 3.5 ± 0.3 m/s; p < 0.001), aortic distensibility, and ascending aortic wall thickness (1.37 ± 0.18 vs. 1.30 ± 0.02 mm; p < 0.05) compared to reference. There was no difference in aortic area or descending aortic wall thickness between groups. Young FH patients had aortic changes with increased aortic pulse wave velocity in the setting of increased aortic distensibility, accompanied by increased thickness of the ascending aortic wall. Presence of these early findings in young patients despite the majority being on statin therapy support enhanced screening and aggressive treatment of familial hypercholesterolemia to prevent potential future cardiovascular events.

Evaluation of aortic 18F-NaF tracer uptake using PET/CT as a predictor of aortic calcification in postmenopausal women: A longitudinal study.

INTRODUCTION: Aortic calcification as detected by computed tomography is associated with arterial stiffening and is an important predictor of cardiovascular morbidity and mortality. Uptake of 18F-sodium fluoride (18F-NaF) in the aortic wall reflects metabolically active areas of calcification. The aim of this study was to determine if 18F-NaF uptake in the aorta is associated with calcification and progression of calcification as detected by computed tomography. METHODS: Twenty-one postmenopausal women (mean age 62 ± 6 years) underwent assessment of aortic 18F-NaF uptake using positron emission tomography/computer tomography at baseline and a repeat computed tomography scan after a mean follow-up of 3.8 ± 1.3 years. Tracer uptake was quantified by calculating the target-to-background (TBR) ratios at baseline and follow-up. Calcification was assessed at baseline and follow-up using computed tomography. RESULTS: Over the follow-up period, aortic calcium volume increased from 0.46 ± 0.62 to 0.71 ± 0.93 cm3 (P < 0.05). However, the change in calcium volume did not correlate with baseline TBR either unadjusted (r = 0.00, P = 1.00) or adjusted for age and baseline calcium volume (beta coefficient = -0.18, P = 0.42). TBR at baseline did not differ between participants with (n = 16) compared to those without (n = 5) progression in calcium volume (2.43 ± 0.46 vs. 2.31 ± 0.38, P = 0.58). In aortic segments identified to have the highest tracer uptake at baseline, calcium volume did not significantly change over the follow-up period (P = 0.41). CONCLUSION: In a cohort of postmenopausal women, 18F-NaF uptake as measured by TBR in the lumbar aorta did not predict progression of aortic calcification as detected by computed tomography over a four-year follow-up.

Hemodynamic Mechanism of the Age-Related Increase in Pulse Pressure in Women.

We examined the influence of arterial stiffening and ventricular ejection dynamics on the age-related increase in central pulse pressure. A total of 2033 women aged 18 to 91 years from the Twins UK cohort were studied. Aortic flow and central blood pressure were measured by Doppler sonography and carotid tonometry, respectively. Measured values of central pulse pressure were compared with values predicted from aortic pulse wave velocity and ventricular ejection characteristics. Central pulse pressure at the first shoulder ( P1) increased with age from 29.2±8.0 in those <40 years to 44.2±13.8 mm Hg in those >70 years (means±SD; P<0.001), an increase explained almost entirely by the concomitant increase in aortic pulse wave velocity. Pulse pressure, at the second pressure peak ( P2, usually equal to peak central pulse pressure) increased to a greater extent with age: from 29.1±7.8 mm Hg for those <40 years to 60.2±20.5 mm Hg for those >70 years ( P<0.001). The ratio of P2/P1 closely mirrored the ratio of ejection volume to ejection velocity at corresponding time points, and the proportionately greater increase in P2 compared with P1 was explained by increased ventricular ejection up to the time of P2. This increased from 52.5±13.1 to 59.3±17.8 mL ( P<0.001) in parallel with an age-related increase in stroke volume and body mass index. These results suggest that the age-related change in central pulse wave morphology is driven mainly by an increase in arterial stiffening and altered pattern of ventricular ejection.

Gut microbial diversity is associated with lower arterial stiffness in women.

Aims: The gut microbiome influences metabolic syndrome (MetS) and inflammation and is therapeutically modifiable. Arterial stiffness is poorly correlated with most traditional risk factors. Our aim was to examine whether gut microbial composition is associated with arterial stiffness. Methods and results: We assessed the correlation between carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, and gut microbiome composition in 617 middle-aged women from the TwinsUK cohort with concurrent serum metabolomics data. Pulse wave velocity was negatively correlated with gut microbiome alpha diversity (Shannon index, Beta(SE)= -0.25(0.07), P = 1 × 10-4) after adjustment for covariates. We identified seven operational taxonomic units associated with PWV after adjusting for covariates and multiple testing-two belonging to the Ruminococcaceae family. Associations between microbe abundances, microbe diversity, and PWV remained significant after adjustment for levels of gut-derived metabolites (indolepropionate, trimethylamine oxide, and phenylacetylglutamine). We linearly combined the PWV-associated gut microbiome-derived variables and found that microbiome factors explained 8.3% (95% confidence interval 4.3-12.4%) of the variance in PWV. A formal mediation analysis revealed that only a small proportion (5.51%) of the total effect of the gut microbiome on PWV was mediated by insulin resistance and visceral fat, c-reactive protein, and cardiovascular risk factors after adjusting for age, body mass index, and mean arterial pressure. Conclusions: Gut microbiome diversity is inversely associated with arterial stiffness in women. The effect of gut microbiome composition on PWV is only minimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing.

Arterial stiffening is a heritable trait associated with arterial dilation but not wall thickening: a longitudinal study in the twins UK cohort.

Aims: Vascular ageing is characterized by arterial stiffening, dilation, and arterial wall thickening. We investigated the extent to which these changes are related and their heritability during 5 year follow-up in the Twins UK cohort. Methods and results: Carotid-femoral pulse wave velocity (PWVcf), carotid diameter, carotid distensibility, and carotid intima-media thickness (IMT) were measured in 762 female twins (mean age 57.9 ± 8.6 years) at two time-points over an average follow-up of 4.9 ± 1.5 years. Magnetic resonance imaging (MRI) was performed in a sub-sample of 38 women to measure aortic pulse wave velocity (PWVaorta), diameter, and wall thickness. Heritability of changes in arterial wall properties was estimated using structural equation modelling. Annual increases in PWVcf, carotid diameter, distensibility, and IMT were 0.139 m/s, 0.028 mm, -0.4 kPa-1, and 0.011 mm per year, respectively. In regression analysis, predictors of progression in PWVcf included age, mean arterial pressure (MAP), and heart rate (HR) at baseline, and progression in MAP, HR, and body mass index (BMI). Predictors of progression in IMT included progression in MAP, BMI, and triglyceride levels. Progression of PWV and distensibility correlated with progression in carotid diameter but not with IMT. Heritability of progression of PWVcf, diameter, and IMT was 55%, 21%, and 8%, respectively. In a sub-sample of women that underwent MRI, aortic wall thickness increased by 0.19 mm/year, but aortic wall thickening was not correlated with an increase in lumen diameter or PWVaorta. Conclusion: Arterial stiffening, as measured by PWVcf, and dilation are heritable but independent of arterial wall thickening. Genetic and cardiovascular risk factors contribute differently to progression of PWV and IMT.

Aortic length measurements for pulse wave velocity calculation: manual 2D vs automated 3D centreline extraction.

BACKGROUND: Pulse wave velocity (PWV) is a biomarker for the intrinsic stiffness of the aortic wall, and has been shown to be predictive for cardiovascular events. It can be assessed using cardiovascular magnetic resonance (CMR) from the delay between phase-contrast flow waveforms at two or more locations in the aorta, and the distance on CMR images between those locations. This study aimed to investigate the impact of different distance measurement methods on PWV. We present and evaluate an algorithm for automated centreline tracking in 3D images, and compare PWV calculations using distances derived from 3D images to those obtained from a conventional 2D oblique-sagittal image of the aorta. METHODS: We included 35 patients from a twin cohort, and 20 post-coarctation repair patients. Phase-contrast flow was acquired in the ascending, descending and diaphragmatic aorta. A 3D centreline tracking algorithm is presented and evaluated on a subset of 30 subjects, on three CMR sequences: balanced steady-state free precession (SSFP), black-blood double inversion recovery turbo spin echo, and contrast-enhanced CMR angiography. Aortic lengths are subsequently compared between measurements from a 2D oblique-sagittal plane, and a 3D geometry. RESULTS: The error in length of automated 3D centreline tracking compared with manual annotations ranged from 2.4 [1.8-4.3] mm (mean [IQR], black-blood) to 6.4 [4.7-8.9] mm (SSFP). The impact on PWV was below 0.5m/s (<5%). Differences between 2D and 3D centreline length were significant for the majority of our experiments (p < 0.05). Individual differences in PWV were larger than 0.5m/s in 15% of all cases (thoracic aorta) and 37% when studying the aortic arch only. Finally, the difference between end-diastolic and end-systolic 2D centreline lengths was statistically significant (p < 0.01), but resulted in small differences in PWV (0.08 [0.04 - 0.10]m/s). CONCLUSIONS: Automatic aortic centreline tracking in three commonly used CMR sequences is possible with good accuracy. The 3D length obtained from such sequences can differ considerably from lengths obtained from a 2D oblique-sagittal plane, depending on aortic curvature, adequate planning of the oblique-sagittal plane, and patient motion between acquisitions. For accurate PWV measurements we recommend using 3D centrelines.

Molecular Mechanisms of Arterial Stiffening.

Stiffening of large arteries is a hallmark of vascular aging and one of the most important determinants of the age-related increase in blood pressure and cardiovascular disease events. Despite a substantial genetic component, the molecular mechanisms underlying phenotypic variability in arterial stiffness remain unknown. Previous genetic studies have identified several genetic variants that are associated with measures of arterial stiffness. Here, we review the relevant advances in the identification of pathways underlying arterial stiffness from genomic studies.

Integrated multiomics approach identifies calcium and integrin-binding protein-2 as a novel gene for pulse wave velocity.

BACKGROUND: Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV. METHODS AND RESULTS: We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [ß = -0.359, standard error (SE) = 0.07, P = 4.8 × 10]. The same variant was also associated with increased CIB2 expression in leucocytes (ß = 0.034, SE = 0.008, P = 4.95 × 10) and skin (ß = 0.072, SE = 0.01, P = 2.35 × 10) and with hypomethylation of the gene promoter (ß = -0.899, SE = 0.098, P = 3.63 × 10). CONCLUSION: Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms.

Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort.

We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39-81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean±SD follow-up of 4.3±1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase (P=0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (ß=0.19, P=0.008) and collagen type IV α 1 (ß=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (ß=-0.20, P=0.005), angiotensin-converting enzyme (ß=-0.15, P=0.035), and B-cell CLL/lymphoma11B (ß=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (ß=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV α 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.

Thoracic but not abdominal phase contrast magnetic resonance-derived aortic pulse wave velocity is elevated in patients with abdominal aortic aneurysm.

OBJECTIVES: Increased stiffening of the aortic wall could contribute to the development of abdominal aortic aneurysm (AAA). We investigated regional aortic wall pulse wave velocity (PWV) in patients with AAA. METHODS: Forty-six men diagnosed with a small AAA and 42 control men were recruited from the AAA surveillance and screening programmes at Guy's and St Thomas' Hospital. Phase-contrast cardiovascular MRI was performed to determine regional PWV along the thoracic (PWVTHOR) and abdominal aorta (PWVABD). PWV over the total aorta (PWVTOTAL) was calculated from the combined regions. RESULTS: PWVTOTAL was significantly higher in patients with AAA compared to controls (10.0 ±â€Š2.1 versus 8.4 ±â€Š1.6 m/s, respectively; P < 0.0001). The difference in total aortic PWV between groups was explained by increased thoracic PWV in patients with AAA compared to controls (PWVTHOR 9.9 ±â€Š2.8 versus 8.1 ±â€Š2.5 m/s, respectively; P < 0.01). In contrast, there was no difference in PWV measured over the abdominal region in AAA patients compared with controls (PWVABD 10.7 ±â€Š3.3 and 10.1 ±â€Š3.3 m/s, in AAA and control groups, respectively; P = 0.40). In multiple regression analysis, including the whole cohort, abdominal aortic diameter remained significantly associated with PWVTOTAL and PWVTHOR (standardized regression coefficients 0.22 and 0.19, respectively; each P < 0.05 after adjustment for age and mean arterial pressure), but not with PWVABD. CONCLUSION: AAA patients have a greater PWV in the thoracic but not abdominal aorta compared to control individuals. Greater abdominal aortic diameter in patients with AAA is likely to offset effects of intrinsic stiffening of the abdominal aorta on PWV.

Metabolomic study of carotid-femoral pulse-wave velocity in women.

OBJECTIVE: Carotid-femoral pulse-wave velocity (PWV) is a measure of aortic stiffness that is strongly associated with increased risk of cardiovascular morbidity and mortality. The aim of the current study was to identify the molecular markers and the pathways involved in differences in PWV in women, in order to further understand the regulation of arterial stiffening. METHODS: A total of 280 known metabolites were measured in 1797 female twins (age range: 18-84 years) not on any antihypertensive medication. Metabolites associated with PWV (after adjustment for age, BMI, metabolite batch, and family relatedness) were entered into a backward linear regression. Transcriptomic analyses were further performed on the top compounds identified. RESULTS: Twelve metabolites were associated with PWV (P < 1.8 × 10). One of the most strongly associated metabolites was uridine, which was not associated with blood pressure (BP) and traditional risk factors but correlated significantly with the gene-expression levels of the purinergic receptor P2RY2 (Beta = -0.010, SE = 0.003, P = 0.007), suggesting that it may play a role in regulating endothelial nitric oxide synthase phosphorylation. On the other hand, phenylacetylglutamine was strongly associated with both PWV and BP. CONCLUSION: Circulating levels of uridine, phenylacetylglutamine, and serine appear strongly correlated with PWV in women.