Marina Cecelja

Increased Wave Reflection Rather Than Central Arterial Stiffness Is the Main Determinant of Raised Pulse Pressure in Women and Relates to Mismatch in Arterial Dimensions A Twin Study

OBJECTIVES Our aim was to examine the relative contributions of the first systolic shoulder (P1) and augmentation pressure (DeltaP(aug)) to central pulse pressure (cPP), their relation to central arterial stiffness (pulse wave velocity [PWV]) and arterial diameters, and their respective heritability estimates. BACKGROUND cPP is augmented above P1 by DeltaP(aug) due to pressure waves reflected from the periphery of the circulation. METHODS Women (n = 496) from the Twins UK adult twin registry (112 monozygotic, 135 dizygotic pairs) age 21 to 81 years were studied. cPP, P1, and DeltaP(aug) were estimated using the SphygmoCor system (Atcor, West Ryde, Australia) from transformed radial waveforms. Carotid-femoral PWV was measured using the same system. Aortic and femoral artery diameters were measured by ultrasonography. Heritability was estimated using structural equation modeling. RESULTS P1 and DeltaP(aug) accounted for 22% and 76%, respectively, of the variance in cPP. After adjustment for mean arterial pressure and heart rate, P1 strongly independently positively correlated with PWV (standardized regression coefficient, beta = 0.4, p < 0.0001), whereas DeltaP(aug) did not independently correlate with PWV but independently negatively correlated with the ratio of the diameter of the femoral to that of the abdominal aorta (beta = -0.12, p < 0.001). Estimates of heritability (h(2)) of cPP, PWV, P1, and DeltaP(aug) were 0.43, 0.34, 0.31, and 0.62, respectively, after adjustment for mean arterial pressure and heart rate. CONCLUSIONS These results suggest that, in women, DeltaP(aug) is highly heritable, is associated with the ratio of distal to proximal arterial diameters, and, independent of PWV, is a major determinant of cPP.

The relationship between DXA-based and anthropometric measures of visceral fat and morbidity in women.

BackgroundExcess accumulation of visceral fat is a prominent risk factor for cardiovascular and metabolic morbidity. While computed tomography (CT) is the gold standard to measure visceral adiposity, this is often not possible for large studies - thus valid, but less expensive and intrusive proxy measures of visceral fat are required such as dual-energy X-ray absorptiometry (DXA). Study aims were to a) identify a valid DXA-based measure of visceral adipose tissue (VAT), b) estimate VAT heritability and c) assess visceral fat association with morbidity in relation to body fat distribution.MethodsA validation sample of 54 females measured for detailed body fat composition - assessed using CT, DXA and anthropometry – was used to evaluate previously published predictive models of CT-measured visceral fat. Based upon a validated model, we realised an out-of-sample estimate of abdominal VAT area for a study sample of 3457 female volunteer twins and estimated VAT area heritability using a classical twin study design. Regression and residuals analyses were used to assess the relationship between adiposity and morbidity.ResultsPublished models applied to the validation sample explained >80% of the variance in CT-measured visceral fat. While CT visceral fat was best estimated using a linear regression for waist circumference, CT body cavity area and total abdominal fat (R2 = 0.91), anthropometric measures alone predicted VAT almost equally well (CT body cavity area and waist circumference, R2 = 0.86). Narrow sense VAT area heritability for the study sample was estimated to be 58% (95% CI: 51-66%) with a shared familial component of 24% (17-30%). VAT area is strongly associated with type 2 diabetes (T2D), hypertension (HT), subclinical atherosclerosis and liver function tests. In particular, VAT area is associated with T2D, HT and liver function (alanine transaminase) independent of DXA total abdominal fat and body mass index (BMI).ConclusionsDXA and anthropometric measures can be utilised to derive estimates of visceral fat as a reliable alternative to CT. Visceral fat is heritable and appears to mediate the association between body adiposity and morbidity. This observation is consistent with hypotheses that suggest excess visceral adiposity is causally related to cardiovascular and metabolic disease.

Clinical ResearchVascular DiseaseProgression of Central Pulse Pressure Over 1 Decade of Aging and its Reversal by Nitroglycerin: A Twin Study

OBJECTIVES The goal of this study was to examine the progression of central arterial pulse pressure (cPP) in women and the degree to which this can be reversed by nitrovasodilation. BACKGROUND cPP can be partitioned into height of the first systolic shoulder (P1), generated by a forward pressure wave and related to arterial stiffness, and augmentation pressure (AP), thought to be influenced by pressure wave reflection from muscular arteries and/or aortic reservoir. METHODS Using a longitudinal cohort design, cPP, P1, and AP were estimated (using the SphygmoCor System [AtCor Medical Pty Ltd., West Ryde, Australia]) in 411 female twins over a mean follow-up of 10.8 years. In a subsample (n = 42), cPP, arterial stiffness (using pulse wave velocity [PWV]) and arterial diameters (using ultrasonography) were measured before and after nitroglycerin administration (400 μg s/l). RESULTS cPP increased more than peripheral pulse pressure (10.3 and 9.2 mm Hg, respectively; p < 0.0001). In women <60 years of age at follow-up, AP contributed more to the increase in cPP than did P1 (increases of 6.5 ± 6.4 mm Hg and 4.2 ± 7.8 mm Hg, respectively). P1 was significantly positively correlated to PWV (p < 0.0001); AP was correlated to aorto-femoral tapering (p < 0.0001) but not PWV. Nitroglycerin reduced cPP by 10.0 ± 6.0 mm Hg (p < 0.0001), equivalent to a decade of aging. The reduction in cPP was entirely explained by a decrease in AP, with no significant change in P1 or PWV but an increase in large artery diameters of 4% to 18% (p < 0.0001). CONCLUSIONS Age-related widening of cPP is driven in large part by an increase in AP, which can be reversed by selective dilation of muscular arteries, independent of 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 × 10−4). 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.

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 (&bgr;=0.19, P=0.008) and collagen type IV &agr; 1 (&bgr;=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 (&bgr;=–0.20, P=0.005), angiotensin-converting enzyme (&bgr;=–0.15, P=0.035), and B-cell CLL/lymphoma11B (&bgr;=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (&bgr;=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV &agr; 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.

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.

Central aortic stiffness, hypertension, and coronary allograft vasculopathy in children.

Purpose: The purpose of this study is to investigate whether central arterial stiffness in children is related to the extent of coronary allograft vasculopathy (CAV). Methods and Materials: 10 children (5 male) underwent Aortic MRI followed by X-ray angiography and intravascular ultrasound (IVUS). Published normal values were taken for age-matched controls. Pulse wave velocity (PWV) was measured using a VCG-gated gradient-echo pulse sequence with velocity encoding (temporal resolution 5 to 7ms). Magnitude images were used to give an image-based traditional assessment of central aortic stiffness ( index). Total peripheral vascular resistance (TPR) was calculated, using ascending aorta flux as the cardiac output. IVUS was performed in the left anterior descending coronary artery. Maximal and mean intimal thicknesses were recorded as measures of CAV burden. Results: PWV was significantly higher than normal volunteers (4.5 vs. 3.3 m/s; p 0.002). index was not raised significantly (3.2 vs. 2.5; p 0.17) and neither was TPR (1245 vs. 1144 dyn.sec.cm-5). PWV has significant positive correlation with CAV burden as measured by maximal intimal thickness (Pearson’s Coefficient 0.66; p 0.036) and mean intimal thickness (0.71; p 0.02). index also has significant positive correlations with these indices (0.74 and 0.78; p 0.014 and 0.008 respectively). TPR does not, however, correlate with these measures of CAV (Coefficients 0.015 and 0.001; p 0.9). BP parameters; age; time post-transplant; and PWV were added in a multivariate linear regression model for mean intimal thickness prediction in a forward stepwise manner. Only PWV remained in the model after stepwise exclusions (model R 0.51; p 0.02). Conclusions: In this study we demonstrate that central arterial stiffness, measured by pulse wave velocity correlates with coronary allograft vasculopathy independently of blood pressure. These findings warrant a larger study using PWV as a potential surrogate marker for adverse vascular modeling after heart transplantation.

[PP.03.08] THE HAEMODYNAMIC MECHANISM OF THE AGE-RELATED INCREASE IN PULSE PRESSURE IN WOMEN

Objective: An age-related increase in pulse pressure is the major cause of morbidity and mortality in the ageing population and is more marked in women than in men. The haemodynamic determinants of increased pulse pressure remain incompletely understood. The aim of this study is was to examine the contribution of ventricular dynamics, large artery stiffness, and pressure wave reflection to central pulse pressure. Design and method: A total of 2162 women aged 18 to 91 years (mean ± SD, age 57 ± 13 years) from the Twins UK cohort were studied. Non-invasive aortic flow velocity and blood pressure were measured by Doppler sonography and carotid tonometry system respectively. Carotid-femoral PWV was measured using the SphygmoCor system. Reflection index (the ratio of the peak of the backward pressure wave over that of the forward pressure wave) was computed from the pressure and flow waves. Results: Central pulse pressure increased with age, from 29.5 ± 0.46 mmHg for those aged below 40 years to 52.6 ± 0.85 mmHg for those over 70 years (means ± SE, P < 0.001). PWV increased approximately 13.2% per decade. Maximum flow velocity tended to increase (from 1.11 ± 0.01 to 1.16 ± 0.01 m/s over the 5 decades, P < 0.01), and ejection volume at the time of peak pulse pressure increased from 63.3 ± 1.41 to 72.3 ± 1.92 ml (P < 0.001) but reflection index decreased from 0.28 ± 0.01 to 0.25 ± 0.01 (P < 0.001). Conclusions: These results suggest that the age-related increase in central pulse pressure is driven mainly by an increase in arterial stiffening and increased ventricular ejection.

[OP.5B.05] CHARACTERISATION OF LONGITUDINAL CHANGES IN VASCULAR STRUCTURE AND FUNCTION OVER A 4 YEAR FOLLOW-UP PERIOD: AS ASSESSED BY MRI

Objective: Vascular aging is characterised by structural changes: wall thickening and change in lumen diameter, together with functional changes in aortic stiffness. We investigated the longitudinal structural and functional changes that occur in the aortic wall over a 4 year follow-up period. Design and method: Magnetic resonance imaging (MRI) was performed in 38 asymptomatic women aged between 53–73 years at baseline and 4 years later over from the aortic arch to aortic bifurcation. Phase-contrast MRI was performed at 2 levels to calculate aortic PWV. Aortic wall diameter and wall thickness were measured using a black-blood MRI sequence. Youngs incremental elastic modulus (E) was calculated from the simplified Moens-Korteweg equation: PWV = sqrt(Eh/D), where h is the average aortic wall thickness and D is average aortic diameter. Results: PWV did not differ significantly over the four year follow-up period (mean ± standard deviation for aortic PWV at visit one and two 7.74 ± 1.7 and 7.70 ± 1.5 m/sec respectively, P = 0.85). There was a significant increase in aortic wall thickness (0.16 ± 0.02 cm at baseline and 0.24 ± 0.06 cm at follow-up, P < 0.0001) and decrease in lumen diameter (2.23 ± 0.24 cm at baseline and 1.97 ± 0.14 cm at follow-up, P < 0.0001)). The calculated elastic modulus significantly decreased at follow-up (E at visit one and two 8.68 ± 4.2 and 5.41 ± 2.7 106 dynes/cm2, respectively, P < 0.0001). The dissociation between PWV and calculated E was explained by an increase in wall thickness/diameter ratio over the follow-up period (wall thickness/diameter ratio at visit one and two 0.07 ± 0.01 and 0.12 ± 0.03 respectively, P < 0.0001). Conclusions: In our cohort of older women, increase in aortic wall thickness was the most marked structural change and could potentially offset an increase in PWV produced by intrinsic stiffening of the aortic wall.

LA structural remodeling is predicted by arterial stiffening independently of conventional risk factors

Background Left atrium (LA) size and function are powerful biomarkers of cardiovascular outcomes in many diseases. We sought to determine if the expected age-associated increase in arterial stiffness (AS) and left ventricular (LV)-LA afterload leads to corresponding effects on LA function and this can be measured with cardiovascular magnetic resonance (CMR). Additionally, we investigated the significance of these markers in asymptomatic individuals with cardiovascular risk factors (CRF).