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.

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.

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.

Ethnicity differences in geometric remodelling and myocardial composition in hypertension unveiled by cardiovascular magnetic resonance.

AIMS: Hypertensive patients of African ancestry (Afr-a) have higher incidences of heart failure and worse clinical outcomes than hypertensive patients of European ancestry (Eu-a), yet the underlying mechanisms remain misunderstood. This study investigated right (RV) and left (LV) ventricular remodelling alongside myocardial tissue derangements between Afr-a and Eu-a hypertensives. METHODS AND RESULTS: 63 Afr-a and 47 Eu-a hypertensives underwent multi-parametric cardiovascular magnetic resonance. Biventricular volumes, mass, function, mass/end-diastolic volume (M/V) ratios, T2 and pre-/post-contrast T1 relaxation times, synthetic extracellular volume, and myocardial fibrosis (MF) were measured. 3D shape modelling was implemented to delineate ventricular geometry. LV and RV mass (indexed to body-surface-area) and M/V ratio were significantly greater in Afr-a than Eu-a hypertensives (67.1 ± 21.7 vs. 58.3 ± 16.7 g/m2, 12.6 ± 3.48 vs. 10.7 ± 2.71 g/m2, 0.79 ± 0.21 vs. 0.70 ± 0.14 g/mL, and 0.16 ± 0.04 vs. 0.13 ± 0.03 g/mL, respectively; P < 0.03). Afr-a patients showed greater basal interventricular septum thickness than Eu-a patients, influencing LV hypertrophy and RV cavity changes. This biventricular remodelling was associated with prolonged T2 relaxation time (47.0 ± 2.2 vs. 45.7 ± 2.2 ms, P = 0.005) and higher prevalence (23% vs. 4%, P = 0.001) and extent of MF [2.3 (0.6-14.3) vs. 1.6 (0.9-2.5) % LV mass, P = 0.008] in Afr-a patients. Multivariable linear regression showed that modifiable cardiovascular risk factors and greater end-diastolic volume, but not ethnicity, were independently associated with greater LV mass. CONCLUSION: Afr-a hypertensives had distinctive biventricular remodelling, including increased RV mass, septal thickening and myocardial tissue abnormalities compared with Eu-a hypertensives. From this study, modifiable cardiovascular risk factors and ventricular geometry, but not ethnicity, were independently associated with greater LV myocardial mass.

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.

An artificial intelligence tool for automated analysis of large-scale unstructured clinical cine cardiac magnetic resonance databases.

Aims: Artificial intelligence (AI) techniques have been proposed for automating analysis of short-axis (SAX) cine cardiac magnetic resonance (CMR), but no CMR analysis tool exists to automatically analyse large (unstructured) clinical CMR datasets. We develop and validate a robust AI tool for start-to-end automatic quantification of cardiac function from SAX cine CMR in large clinical databases. Methods and results: Our pipeline for processing and analysing CMR databases includes automated steps to identify the correct data, robust image pre-processing, an AI algorithm for biventricular segmentation of SAX CMR and estimation of functional biomarkers, and automated post-analysis quality control to detect and correct errors. The segmentation algorithm was trained on 2793 CMR scans from two NHS hospitals and validated on additional cases from this dataset (n = 414) and five external datasets (n = 6888), including scans of patients with a range of diseases acquired at 12 different centres using CMR scanners from all major vendors. Median absolute errors in cardiac biomarkers were within the range of inter-observer variability: <8.4 mL (left ventricle volume), <9.2 mL (right ventricle volume), <13.3 g (left ventricular mass), and <5.9% (ejection fraction) across all datasets. Stratification of cases according to phenotypes of cardiac disease and scanner vendors showed good performance across all groups. Conclusion: We show that our proposed tool, which combines image pre-processing steps, a domain-generalizable AI algorithm trained on a large-scale multi-domain CMR dataset and quality control steps, allows robust analysis of (clinical or research) databases from multiple centres, vendors, and cardiac diseases. This enables translation of our tool for use in fully automated processing of large multi-centre databases.

Reproducibility of sequential ambulatory blood pressure and pulse wave velocity measurements in normotensive and hypertensive individuals.

OBJECTIVE: Errors in blood pressure (BP) measurement account for a large proportion of misclassified hypertension diagnoses. Ambulatory blood pressure monitoring (ABPM) is often considered to be the gold standard for measurement of BP, but uncertainty remains regarding the degree of measurement error. The aim of this study was to determine reproducibility of sequential ABPM in a population of normotensive and well controlled hypertensive individuals. METHODS: Individual participant data from three randomized controlled trials, which had recorded ABPM and carotid-femoral pulse wave velocity (PWV) at least twice were combined ( n  = 501). We calculated within-individual variability of daytime and night-time BP and compared the variability between normotensive ( n  = 324) and hypertensive ( n  = 177) individuals. As a secondary analysis, variability of PWV measurements was also calculated, and multivariable linear regression was used to assess characteristics associated with blood pressure variability (BPV). RESULTS: Within-individual coefficient of variation (CoV) for systolic BP was 5.4% (day) and 7.0% (night). Equivalent values for diastolic BP were 6.1% and 8.4%, respectively. No statistically significant difference in CoV was demonstrated between measurements for normotensive and hypertensive individuals. Within-individual CoV for PWV exceeded that of BP measurements (10.7%). BPV was associated with mean pressures, and BMI for night-time measurements. PWV was not independently associated with BPV. CONCLUSION: The variability of single ABPM measurements will still yield considerable uncertainty regarding true average pressures, potentially resulting in misclassification of hypertensive status and incorrect treatment regimes. Repeated ABPM may be necessary to refine antihypertensive therapy.

Comparison of central SBP in children estimated from a brachial cuff alone, brachial cuff-calibrated applanation radial tonometry and brachial cuff-calibrated carotid wall-tracking.

OBJECTIVES: We compared the agreement between different techniques to estimate central SBP (cSBP) in children and the relative impact of different methods of measuring peripheral blood pressure (BP). METHODS: A total of 135 children, aged 12.9 ±â€Š3.0 years including 67 boys, 85 with chronic kidney disease were studied. We measured cSBP using radiofrequency ultrasound carotid wall-tracking (Esaote ART.LAB system, a previously validated reference method), transformation of the radial artery pressure waveform obtained by tonometry (SphygmoCor) and a cuff-based system (cBP301; Centron Diagnostics) during a single visit. Carotid and radial tonometric-derived values were calibrated from mean and diastolic values of brachial BP obtained by aneroid sphygmomanometer. Brachial cuff only values were calibrated from the same aneroid sphygmomanometer values and from oscillometric values obtained from the brachial cuff. RESULTS: cSBP values estimated from radial tonometry were closely correlated with those obtained from the carotid (r = 0.959, mean difference -0.61 ±â€Š3.5 mmHg). cSBP values estimated by the brachial cuff only method agreed reasonably well with those obtained from the carotid (r = 0.847, mean difference 5 ±â€Š7.4 mmHg) when calibrated by the same method but when calibrated by oscillometric values from the brachial cuff, agreement was less good (r = 0.659, mean difference 8.7 ±â€Š11.4 mmHg). CONCLUSION: Radial tonometry with a radial-to-central transfer function can be used to estimate cSBP in children with acceptable accuracy when compared with the invasively validated carotid reference method. All methods are subject to errors introduced by calibration from peripheral BP.

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.

Decreased arterial elasticity in children with nondialysis chronic kidney disease is related to blood pressure and not to glomerular filtration rate.

We compared large artery mechanical properties in children with nondialysis stages of chronic kidney disease with those in children with normal renal function, examining the potential effect of blood pressure (BP) components and level of renal dysfunction. Common carotid artery mechanical properties, carotid-femoral pulse wave velocity, and carotid and peripheral BP were measured in children (n=226) with nondialysis chronic kidney disease (n=188; 11.9±3.7 years; 26%, 25%, 30%, 16%, and 3% in stages 1, 2, 3, 4 and 5, respectively) and healthy controls (n=38; 11.5±3.3 years). In children with nondialysis chronic kidney disease when compared with healthy controls, at similar levels of peripheral and carotid BP, carotid artery diastolic diameter and wall thickness were similar. In those with suboptimal BP (≥75th percentile), indices of arterial elasticity indicated greater stiffness than in healthy normotensive controls (distensibility: 92±31 versus 114±33 kPa(-1)×10(-3), P=0.03; compliance: 2.1±0.7 versus 2.6±0.7 m(2) kPa(-1)×10(-6), P=0.02; Young elastic modulus: 0.151±0.068 versus 0.109±0.049 kPa×10(3), P=0.02; and wall stress: 83.6±23.5 versus 68.7±14.9 kPa, P=0.02). In all children, mechanical properties were independently related to carotid and peripheral BP components but not to estimated glomerular filtration rate. In children with nondialysis chronic kidney disease, changes in elastic properties of the carotid artery are primarily related to BP and not to glomerular renal function.

Altered dependence of aortic pulse wave velocity on transmural pressure in hypertension revealing structural change in the aortic wall.

Aortic pulse wave velocity (aPWV), a major prognostic indicator of cardiovascular events, may be augmented in hypertension as a result of the aorta being stretched by a higher distending blood pressure or by a structural change. We used a novel technique to modulate intrathoracic pressure and thus aortic transmural pressure (TMP) to examine the variation of intrathoracic aPWV with TMP in hypertensive (n=20; mean±SD age, 52.1±15.3 years; blood pressure, 159.6±21.2/92.0±15.9 mm Hg) and normotensive (n=20; age, 55.5±11.1 years; blood pressure, 124.5±11.9/72.6±9.1 mm Hg) subjects. aPWV was measured using dual Doppler probes to insonate the right brachiocephalic artery and aorta at the level of the diaphragm. Resting aPWV was greater in hypertensive compared with normotensive subjects (897±50 cm/s versus 784±43 cm/s; P<0.05). aPWV was equal in hypertensive and normotensive subjects when measured at a TMP of 96 mm Hg. However, dependence of aPWV on TMP in normotensive subjects was greater than that in hypertensive subjects (9.6±1.6 versus 3.8±0.7 cm/s per mm Hg increase in TMP, respectively, means±SEM; P<0.01). This experimental behavior was best explained by a theoretical model incorporating strain-induced recruitment of stiffer fibers in normotensive subjects and fully recruited stiffer fibers in hypertensive subjects. These results explain previous contradictory findings with respect to isobaric aPWV in hypertensive compared with normotensive subjects. They suggest that hypertension is associated with a profound change in aortic wall mechanical properties possibly because of destruction of elastin leading to less strain-induced stiffening and predisposition to aortic dissection.

Central aortic blood pressure from ultrasound wall-tracking of the carotid artery in children: comparison with invasive measurements and radial tonometry.

Differences between central aortic root (c) and peripheral (p) systolic blood pressure (SBP) may be particularly marked in children, but noninvasive methods for assessing cSBP in children have not been validated. We compared estimates of cSBP obtained from radiofrequency ultrasound wall tracking of the carotid artery (ART.LAB system) with that measured directly by a catheter in the aortic root at the time of arterial cannulation. Carotid waveforms were calibrated from invasive measurements of mean and diastolic pressures. In 9 children aged 10.5 ± 5.0 years (mean ± SD), cSBP obtained from carotid wall tracking was highly correlated with invasive measures of cSBP (r=0.99) with mean (± SD) difference 3.9 ± 2.5 mm Hg. Second, we compared values of cSBP obtained from the carotid with those obtained using noninvasive applanation tonometry at the radial artery and a radial-to-aortic transfer function (SphygmoCor). Both carotid and radial tonometric measurements were calibrated from the same peripheral mean and diastolic measurements of blood pressure obtained by sphygmomanometry. In 84 children aged 13.2 ± 3.2 years, there was excellent agreement between the 2 methods (r=0.95; P<0.001) with mean difference 0.71 ± 3.7 mm Hg (95% confidence interval =-1.53 to 1.01). This invasive validation study confirms that cSBP as estimated by carotid wall tracking provides an acceptable measurement of true cSBP when calibration is from true mean and diastolic pressures. Close agreement of cSBP obtained by carotid wall tracking and radial tonometry suggests that these provide similar results when calibrated from the same peripheral blood pressure measurements.

Measurement of pulse wave velocity in children: comparison of volumetric and tonometric sensors, brachial-femoral and carotid-femoral pathways.

BACKGROUND: Pulse wave velocity (PWV), a measure of arterial stiffness strongly predictive of cardiovascular risk in adults, is usually measured by sequential ECG-referenced carotid and femoral tonometry. A simplified technique, more suitable for use in children, employs simultaneous volumetric recording from a sensor applied over the carotid artery and a cuff applied over the femoral artery or arm and thigh pressure cuffs applied over the brachial and femoral arteries. The purpose of this study was to compare PWV computed over the carotid-femoral path (PWVcf) with that over the brachial-femoral path (PWVbf) using a volumetric system (Vicorder) and to compare values of PWVcf obtained by the volumetric and a tonometric method (SphygmoCor) in children. METHOD: Vicorder PWVcf and PWVbf were compared in 156 children (3-18 years, 110 with chronic kidney disease), and PWVcf by Vicorder was compared to PWVcf by SphygmoCor in a subset of 122 patients. RESULTS: PWVcf by Vicorder was moderately correlated with PWVcf by SphygmoCor (R = 0.50, P < 0.000). PWVbf and PWVcf Vicorder were more closely correlated (R = 0.75, P < 0.0001), but with a significant systematic difference. Applying a correction factor to PWVbf measurements gave results similar to those obtained over the carotid-femoral path. Within-patient coefficients of variation for repeated measures were 5.9, 7.8, and 8.5% for PWVbf (Vicorder), PWVcf (Vicorder) and PWVcf (SphygmoCor), respectively. All PWV values showed a similar relation to age. CONCLUSION: Volumetric methods appear reproducible and are easy to use in children, but values obtained by Vicorder and SphygmoCor are not interchangeable even when measured over the same pathway.