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1.  Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility – Reykjavik Study 
Brain  2011;134(11):3398-3407.
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid–femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility – Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69–93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta–carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta–carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid–femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62–1.71 per standard deviation, P<0.002). Carotid–femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid–femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
doi:10.1093/brain/awr253
PMCID: PMC3212721  PMID: 22075523
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
2.  Distal Shift of Arterial Pressure Wave Reflection Sites with Aging 
Hypertension  2010;56(5):920-925.
An early return of reflected waves, the backward propagation of the arterial pressure wave from the periphery to the heart, is associated with the augmentation of central pulse pressure and cardiovascular risks. The location of arterial pressure wave reflection, along with arterial stiffening, have a major influence on the timing of the reflected wave. To determine the influence of aging on the location of a major reflection site, arterial length (via three-dimensional artery tracing of magnetic resonance imaging) and central (carotid-femoral) and peripheral (femoral-ankle) pulse wave velocity were measured in 208 adults varying in age. The major reflection site was detected by carotid-femoral pulse wave velocity and the reflected wave transit time (via carotid arterial pressure wave analysis). The length from the aortic valve to the major reflection site (e.g., effective reflecting length) significantly increased with aging. The effective reflecting length normalized by the arterial length demonstrated that the major reflection sites located between the aortic bifurcation and femoral site in most of the subjects. The normalized effective reflecting length did not alter with aging until 65-year-old and increased remarkably thereafter in men and women. The effective reflecting length was significantly and positively associated with the difference between central and peripheral pulse wave velocity (r=0.76). This correlation remained significant even when the influence of aortic pulse wave velocity was partial out (r=0.35). These results suggest that the major reflection site shifts distally with aging partly due to the closer matching of impedance provided by central and peripheral arterial stiffness.
doi:10.1161/HYPERTENSIONAHA.110.160549
PMCID: PMC3018759  PMID: 20876449
arterial stiffness; arterial wave reflection; magnetic resonance image
3.  Cardiovascular outcome associations among cardiovascular magnetic resonance measures of arterial stiffness: the Dallas heart study 
Background
Cardiovascular magnetic resonance (CMR) has been validated for the noninvasive assessment of total arterial compliance and aortic stiffness, but their associations with cardiovascular outcomes is unknown. The purpose of this study was to evaluate associations of CMR measures of total arterial compliance and two CMR measures of aortic stiffness with respect to future cardiovascular events.
Methods
The study consisted of 2122 Dallas Heart Study participants without cardiovascular disease who underwent CMR at 1.5 Tesla. Aortic stiffness was measured by CMR-derived ascending aortic distensibility and aortic arch pulse wave velocity. Total arterial compliance was calculated by dividing left ventricular stroke volume by pulse pressure. Participants were monitored for cardiovascular death, non-fatal cardiac events, and non-fatal extra-cardiac vascular events over 7.8 ± 1.5 years. Cox proportional hazards regression was used to assess for associations between CMR measures and cardiovascular events.
Results
Age, systolic blood pressure, and resting heart rate were independently associated with changes in ascending aortic distensibility, arch pulse wave velocity, and total arterial compliance (all p < .0001). A total of 153 participants (6.9%) experienced a cardiovascular event. After adjusting for traditional risk factors, total arterial compliance was modestly associated with increased risk for composite events (HR 1.07 per 1SD, p = 0.03) while the association between ascending aortic distensibility and composite events trended towards significance (HR 1.18 per 1SD, p = 0.08). Total arterial compliance and aortic distensibility were independently associated with nonfatal cardiac events (HR 1.11 per 1SD, p = 0.001 and HR 1.45 per 1SD, p = 0.0005, respectively), but not with cardiovascular death or nonfatal extra-cardiac vascular events. Arch pulse wave velocity was independently associated with nonfatal extra-cardiac vascular events (HR 1.18 per 1SD, p = 0.04) but not with cardiovascular death or nonfatal cardiac events.
Conclusions
In a multiethnic population free of cardiovascular disease, CMR measures of arterial stiffness are associated with future cardiovascular events. Total arterial compliance and aortic distensibility may be stronger predictors of nonfatal cardiac events, while pulse wave velocity may be a stronger predictor of nonfatal extra-cardiac vascular events.
doi:10.1186/1532-429X-16-33
PMCID: PMC4031496  PMID: 24886531
Arterial stiffness; Pulse wave velocity; Aortic distensibility; Total arterial compliance; Cardiovascular magnetic resonance
4.  Bramwell-Hill modeling for local aortic pulse wave velocity estimation: a validation study with velocity-encoded cardiovascular magnetic resonance and invasive pressure assessment 
Background
The Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV), which is the propagation speed of the systolic pressure wave through the aorta. The main objective of this study was to test the validity of this model locally in the aorta by using PWV-assessments based on in-plane velocity-encoded cardiovascular magnetic resonance (CMR), with invasive pressure measurements serving as the gold standard.
Methods
Seventeen patients (14 male, 3 female, mean age ± standard deviation = 57 ± 9 years) awaiting cardiac catheterization were prospectively included. During catheterization, intra-arterial pressure measurements were obtained in the aorta at multiple locations 5.8 cm apart. PWV was determined regionally over the aortic arch and locally in the proximal descending aorta. Subsequently, patients underwent a CMR examination to measure aortic PWV and aortic distention. Distensibility was determined locally from the aortic distension at the proximal descending aorta and the pulse pressure measured invasively during catheterization and non-invasively from brachial cuff-assessment. PWV was determined regionally in the aortic arch using through-plane and in-plane velocity-encoded CMR, and locally at the proximal descending aorta using in-plane velocity-encoded CMR. Validity of the Bramwell-Hill model was tested by evaluating associations between distensibility and PWV. Also, theoretical PWV was calculated from distensibility measurements and compared with pressure-assessed PWV.
Results
In-plane velocity-encoded CMR provides stronger correlation (p = 0.02) between CMR and pressure-assessed PWV than through-plane velocity-encoded CMR (r = 0.69 versus r = 0.26), with a non-significant mean error of 0.2 ± 1.6 m/s for in-plane versus a significant (p = 0.006) error of 1.3 ± 1.7 m/s for through-plane velocity-encoded CMR. The Bramwell-Hill model shows a significantly (p = 0.01) stronger association between distensibility and PWV for local assessment (r = 0.8) than for regional assessment (r = 0.7), both for CMR and for pressure-assessed PWV. Theoretical PWV is strongly correlated (r = 0.8) with pressure-assessed PWV, with a statistically significant (p = 0.04) mean underestimation of 0.6 ± 1.1 m/s. This theoretical PWV-estimation is more accurate when invasively-assessed pulse pressure is used instead of brachial cuff-assessment (p = 0.03).
Conclusions
CMR with in-plane velocity-encoding is the optimal approach for studying Bramwell-Hill associations between local PWV and aortic distensibility. This approach enables non-invasive estimation of local pulse pressure and distensibility.
doi:10.1186/1532-429X-14-2
PMCID: PMC3312851  PMID: 22230116
5.  Site-specific association between distal aortic pulse wave velocity and peripheral arterial stenosis severity: a prospective cardiovascular magnetic resonance study 
Background
Vascular disease expression in one location may not be representative for disease severity in other vascular territories, however, strong correlation between disease expression and severity within the same vascular segment may be expected. Therefore, we hypothesized that aortic stiffening is more strongly associated with disease expression in a vascular territory directly linked to that aortic segment rather than in a more remote segment. We prospectively compared the association between aortic wall stiffness, expressed by pulse wave velocity (PWV), sampled in the distal aorta, with the severity of peripheral arterial occlusive disease (PAOD) as compared to atherosclerotic markers sampled in remote vascular territories such as PWV in the proximal aorta and the normalized wall index (NWI), representing the vessel wall thickness, of the left common carotid artery.
Methods
Forty-two patients (23 men; mean age 64±10 years) underwent velocity-encoded cardiovascular magnetic resonance (CMR) in the proximal and distal aorta, whole-body contrast-enhanced MR angiography (CE-MRA) and carotid vessel wall imaging with black-blood CMR in the work-up for PAOD. Strength of associations between aortic stiffness, carotid NWI and peripheral vascular stenosis grade were assessed and evaluated with multiple linear regression.
Results
Stenosis severity correlated well with PWV in the distal aorta (Pearson rP=0.64, p<0.001, Spearman rS=0.65, p<0.001) but to a lesser extent with PWV in the proximal aorta (rP=0.48, p=0.002, rS=0.22, p=0.18). Carotid NWI was not associated with peripheral stenosis severity (rP=0.17, p=0.28, rS=0.14, p=0.37) nor with PWV in the proximal aorta (rP=0.22, p=0.17) nor in the distal aorta (rP=0.21, p=0.18). Correlation between stenosis severity and distal aortic PWV remained statistically significant after correction for age and gender.
Conclusions
Distal aortic wall stiffness is more directly related to peripheral arterial stenosis severity than markers from more remote vascular territories such as proximal aortic wall stiffness or carotid arterial wall thickness. Site-specific evaluation of vascular disease may be required for full vascular risk estimation.
doi:10.1186/s12968-014-0095-8
PMCID: PMC4298121  PMID: 25600313
Cardiovascular magnetic resonance; Atherosclerosis; Peripheral arterial occlusive disease; Pulse wave velocity; Carotid vessel wall
6.  Aortic stiffness is associated with cardiac function and cerebral small vessel disease in patients with type 1 diabetes mellitus: assessment by magnetic resonance imaging 
European Radiology  2009;20(5):1132-1138.
Objective
To evaluate, with the use of magnetic resonance imaging (MRI), whether aortic pulse wave velocity (PWV) is associated with cardiac left ventricular (LV) function and mass as well as with cerebral small vessel disease in patients with type 1 diabetes mellitus (DM).
Materials and methods
We included 86 consecutive type 1 DM patients (49 male, mean age 46.9 ± 11.7 years) in a prospective, cross-sectional study. Exclusion criteria included aortic/heart disease and general MRI contra-indications. MRI of the aorta, heart and brain was performed for assessment of aortic PWV, as a marker of aortic stiffness, systolic LV function and mass, as well as for the presence of cerebral white matter hyperintensities (WMHs), microbleeds and lacunar infarcts. Multivariate linear or logistic regression was performed to analyse the association between aortic PWV and outcome parameters, with covariates defined as age, gender, mean arterial pressure, heart rate, BMI, smoking, DM duration and hypertension.
Results
Mean aortic PWV was 7.1 ± 2.5 m/s. Aortic PWV was independently associated with LV ejection fraction (ß = -0.406, P = 0.006), LV stroke volume (ß = -0.407, P = 0.001), LV cardiac output (ß = -0.458, P = 0.001), and with cerebral WMHs (P < 0.05). There were no independent associations between aortic stiffness and LV mass, cerebral microbleeds or lacunar infarcts.
Conclusion
Aortic stiffness is independently associated with systolic LV function and cerebral WMHs in patients with type 1 DM.
doi:10.1007/s00330-009-1655-4
PMCID: PMC2850521  PMID: 19915847
Aorta; Magnetic resonance imaging; Type 1 diabetes mellitus; Heart; Brain
7.  Chasing the reflected wave back into the heart: a new hypothesis while the jury is still out 
Background:
Arterial stiffness directly influences cardiac function and is independently associated with cardiovascular risk. However, the influence of the aortic reflected pulse pressure wave on left ventricular function has not been well characterized. The aim of this study was to obtain detailed information on regional ventricular wall motion patterns corresponding to the propagation of the reflected aortic wave on ventricular segments.
Methods:
Left ventricular wall motion was investigated in a group of healthy volunteers (n = 14, age 23 ± 3 years), using cardiac magnetic resonance navigator-gated tissue phase mapping. The left ventricle was divided into 16 segments and regional wall motion was studied in high temporal detail.
Results:
Corresponding to the expected timing of the reflected aortic wave reaching the left ventricle, a characteristic “notch” of regional myocardial motion was seen in all radial, circumferential, and longitudinal velocity graphs. This notch was particularly prominent in septal segments adjacent to the left ventricular outflow tract on radial velocity graphs and in anterior and posterior left ventricular segments on circumferential velocity graphs. Similarly, longitudinal velocity graphs demonstrated a brief deceleration in the upward recoil motion of the entire ventricle at the beginning of diastole.
Conclusion:
These results provide new insights into the possible influence of the reflected aortic waves on ventricular segments. Although the association with the reflected wave appears to us to be unambiguous, it represents a novel research concept, and further studies enabling the actual recording of the pulse wave are required.
doi:10.2147/VHRM.S20845
PMCID: PMC3119594  PMID: 21731888
arterial pressure wave; reflected wave; ventricular wall motion; cardiovascular magnetic resonance imaging; tissue phase mapping
8.  The effect of hypertension on aortic pulse wave velocity in type-1 diabetes mellitus patients: assessment with MRI 
To investigate in type-1 diabetes mellitus (DM1) patients the role of hypertension and of DM1 itself on aortic stiffness by using magnetic resonance imaging (MRI). Consecutive patients from the diabetes and hypertension outpatient clinic and healthy volunteers were included in our study. Subjects were divided into four groups: 32 healthy volunteers (mean age: 54.5 ± 6.8 years), 20 DM1 patients (mean age: 48.3 ± 5.9 years), 31 hypertensive patients (mean age: 59.9 ± 7.2 years) and 28 patients with both DM1 and hypertension (mean age: 50.1 ± 6.2 years). Aortic stiffness was measured by means of pulse wave velocity (PWV) using velocity-encoded MRI. Analysis of variance (ANOVA), uni- and multivariable regression models and the Bonferroni-test for multiple testing, were used for statistical analyses. Mean aortic PWV was 5.7 ± 1.2 m/s in healthy volunteers, 5.9 ± 1.2 m/s in DM1 patients without hypertension, 7.3 ± 1.2 m/s in hypertensive patients and 7.3 ± 1.3 m/s in patients with both DM1 and hypertension. Compared to healthy control subjects, aortic PWV was significantly higher in patients with hypertension (P < 0.001) and in patients with both DM1 and hypertension (P < 0.001), whereas aortic PWV was not increased in patients having DM1 alone. Furthermore, aortic PWV was significantly higher in DM1 patients with hypertension than in patients with DM1 alone (P = 0.002). These findings remained after adjustment for confounding factors. Hypertension has a predominant contributive effect on aortic stiffness in DM1 patients whereas the direct diabetic effect on aortic stiffness is small.
doi:10.1007/s10554-011-9841-2
PMCID: PMC3326366  PMID: 21394612
Aortic pulse wave velocity; MRI; Type-1 diabetes mellitus; Hypertension
9.  Aortic Stiffness Increases Upon Receipt of Anthracycline Chemotherapy 
Journal of Clinical Oncology  2009;28(1):166-172.
Purpose
Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events.
Patients and Methods
We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models.
Results
At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001).
Conclusion
A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.
doi:10.1200/JCO.2009.23.8527
PMCID: PMC2799231  PMID: 19901105
10.  Age-Related Changes in Aortic Arch Geometry: Relationship with Proximal Aortic Function and Left Ventricular Mass and Remodeling 
Objectives
To define age-related geometric changes of the aortic arch and determine their relationship to central aortic stiffness and left ventricular remodeling.
Background
The proximal aorta has been shown to thicken, enlarge in diameter and lengthen with aging in humans. However, no systematic study has described age-related longitudinal and transversal remodeling of the aortic arch and their relationship with left ventricular mass and remodeling.
Methods
We studied 100 subjects (55 women, 45 men, average age: 46±16 years) free of overt cardiovascular disease using magnetic resonance imaging to determine aortic arch geometry (length, diameters, height, width and curvature), aortic arch function (local aortic distensibility and arch pulse wave velocity PWV) and left ventricular volumes and mass. Radial tonometry was used to calculate central blood pressure.
Results
Aortic diameters and arch length increased significantly with age. The ascending aorta increased most with age leading to aortic arch widening and decreased curvature. These geometric changes of the aortic arch were significantly related to decreased ascending aortic distensibility, increased aortic arch PWV (p<0.001) and to increased central blood pressures (p<0.001). Increased ascending aortic diameter, lengthening and decreased curvature of the aortic arch (unfolding) were all significantly associated with increased LV mass and concentric remodeling independently of age, gender, body size and central blood pressure (p<0.01).
Conclusions
Age-related unfolding of the aortic arch is related to increased proximal aortic stiffness in individuals without cardiovascular disease and associated with increased LV mass and mass-to-volume ratio independent of age, body size, central pressure and cardiovascular risk factors.
doi:10.1016/j.jacc.2011.06.012
PMCID: PMC3508703  PMID: 21903061
magnetic resonance imaging; aortic geometry; aging; elasticity; left ventricular remodeling
11.  Age-dependent changes in elastic properties of thoracic aorta evaluated by magnetic resonance in normal subjects 
OBJECTIVES
Aortic stiffness is an independent cardiovascular risk factor. Cardiac magnetic resonance (CMR) allows evaluation of aortic elastic properties by different indexes such as distensibility, the maximum rate of systolic distension (MRSD) and pulse wave velocity (PWV). We sought to define age-dependent changes of indexes of elastic properties of the thoracic aorta in healthy subjects.
METHODS
We enrolled 85 healthy subjects (53 males) free of overt cardiovascular disease subdivided into 6 classes of age (from 15 to >60 years). Distensibility, MRSD and PWV were measured by the analysis of CMR images acquired using a 1.5 T clinical scanner.
RESULTS
MRSD and distensibility decreased progressively through the classes of age (P < 0.001) after an initial plateau between 20 and 30 years in males and 15 and 20 years in females. Pulse wave velocity increased progressively with the age (P < 0.001). Distensibility was related to body mass index (P = 0.002), surface area (P < 0.005), weight (P = 0.005) and to left ventricular parameters such as mass index (P < 0.001) and end-diastolic volume index (P = 0.002). MRSD was related to end-diastolic volume index (P < 0.001) but not to body parameters. PWV was not related to body and ventricular parameters.
CONCLUSIONS
This study confirmed that physiological ageing is associated with a progressive impairment of the elastic properties of the aortic wall. Results of this study may be useful for the early identification of subjects with impaired aortic wall properties providing referral values of elasticity indexes assessed by CMR in different classes of age.
doi:10.1093/icvts/ivt261
PMCID: PMC3781791  PMID: 23760356
Elastic properties of aorta; Magnetic resonance imaging; Aortic stiffness; Pulse wave propagation; Maximal rate of systolic distension
12.  Normal values of aortic dimensions, distensibility, and pulse wave velocity in children and young adults: a cross-sectional study 
Background
Aortic enlargement and impaired bioelasticity are of interest in several cardiac and non-cardiac diseases as they can lead to cardiovascular complications. Cardiovascular magnetic resonance (CMR) is increasingly accepted as a noninvasive tool in cardiovascular evaluation. Assessment of aortic anatomy and bioelasticity, namely aortic distensibility and pulse wave velocity (PWV), by CMR is accurate and reproducible and could help to identify anatomical and bioelastic abnormalities of the aorta. However, normal CMR values for healthy children and young adults are lacking.
Methods
Seventy-one heart-healthy subjects (age 16.4 ± 7.6 years, range 2.3 - 28.3 years) were examined using a 3.0 Tesla CMR scanner. Aortic cross-sectional areas and aortic distensibility were measured at four positions of the ascending and descending thoracic aorta. PWV was assessed from aortic blood flow velocity measurements in a aortic segment between the ascending aorta and the proximal descending aorta. The Lambda-Mu-Sigma (LMS) method was used to obtain percentile curves for aortic cross-sectional areas, aortic distensibility and PWV according to age.
Results
Aortic areas, PWV and aortic distensibility (aortic cross-sectional areas: r = 0.8 to 0.9, p < 0.001; PWV: r = 0.25 to 0.32, p = 0.047 to 0.009; aortic distensibility r = -0.43 to -0.62, p < 0.001) correlated with height, weight, body surface area, and age. There were no significant sex differences.
Conclusions
This study provides percentile curves for cross-sectional areas, distensibility and pulse wave velocity of the thoracic aorta in children and young adolescents between their 3rd and 29th year of life. These data may serve as a reference for the detection of pathological changes of the aorta in cardiovascular disease.
doi:10.1186/1532-429X-14-77
PMCID: PMC3514112  PMID: 23151055
13.  Relation of plasma adiponectin levels and aortic stiffness after acute ST-segment elevation myocardial infarction 
Background:
Pulse wave velocity is a measure of aortic stiffness and an independent predictor of cardiovascular morbidity and mortality. Adiponectin is involved in atherosclerosis and inflammation. In the present study we aimed to explore the association between plasma adiponectin concentrations and pulse wave velocity in the acute phase after ST-segment elevation myocardial infarction (STEMI).
Methods:
Forty-six consecutive STEMI patients (mean age 57±11 years) treated with primary percutaneous coronary intervention (PCI) were enrolled in this cross-sectional study. Plasma adiponectin was measured 2 days after index event by enzyme-linked immunosorbent assay. Aortic pulse wave velocity (PWV) was calculated by the transit-time method with the use of a velocity-encoded, phase-contrast cardiac magnetic resonance protocol.
Results:
Median plasma adiponectin concentration was 2385 ng/ml (interquartile range 1735–5403). Males had lower plasma adiponectin values than females and current smokers had lower values than non-smokers (all p<0.02). Adiponectin was significantly associated with PWV (r=0.505, p<0.001), age (r=0.437, p=0.002), and total cholesterol (r=0.468, p=0.001). Multiple linear regression analysis revealed adiponectin as a predictor of PWV independently of age, sex, smoking status, total cholesterol, and N-terminal pro-B-type natriuretic peptide (p=0.027).
Conclusions:
Plasma adiponectin concentrations are strongly associated with aortic stiffness in patients after acute STEMI treated with primary PCI. Our data support a possible role for adiponectin as an independent risk marker for increased aortic stiffness in STEMI patients.
doi:10.1177/2048872613516015
PMCID: PMC3932779  PMID: 24337918
Adiponectin; aortic stiffness; cardiac magnetic resonance; pulse wave velocity; ST-segment elevation myocardial infarction
14.  Quantification of Aortic Stiffness Using MR Elastography and its Comparison to MRI-Based Pulse Wave Velocity 
Purpose
To determine the correlation in abdominal aortic stiffness obtained using magnetic resonance elastography (MRE) (μMRE) and MRI-based pulse wave velocity (PWV) shear stiffness (μPWV) estimates in normal volunteers of varying age; and also to determine the correlation between μMRE and μPWV.
Methods
In-vivo aortic MRE and MRI were performed on 21 healthy volunteers with ages ranging from 18 to 65 years to obtain wave and velocity data along the long-axis of the abdominal aorta. The MRE wave images were analyzed to obtain mean stiffness, and the phase contrast images were analyzed to obtain PWV measurements and indirectly estimate stiffness values from Moens-Korteweg equation.
Results
Both μMRE and μPWV measurements increased with age, demonstrating linear correlations with R2 values of 0.81 and 0.67, respectively. Significant difference (p≤0.001) in mean μMRE and μPWV between young and old healthy volunteers was also observed. Furthermore, a poor linear correlation of R2 value of 0.43 was determined between μMRE and μPWV in initial pool of volunteers.
Conclusion
The results of this study indicate linear correlations between μMRE and μPWV with normal aging of the abdominal aorta. Significant differences in mean μMRE and μPWV between young and old healthy volunteers were observed.
doi:10.1002/jmri.24506
PMCID: PMC4318508  PMID: 24243654
Aortic Stiffness; Magnetic Resonance Elastography (MRE); PWV; aortic MRE
15.  Cerebral Perfusion and Aortic Stiffness Are Independent Predictors of White Matter Brain Atrophy in Type 1 Diabetic Patients Assessed With Magnetic Resonance Imaging 
Diabetes Care  2011;34(2):459-463.
OBJECTIVE
To identify vascular mechanisms of brain atrophy in type 1 diabetes mellitus (DM) patients by investigating the relationship between brain volumes and cerebral perfusion and aortic stiffness using magnetic resonance imaging (MRI).
RESEARCH DESIGN AND METHODS
Approval from the local institutional review board was obtained, and patients gave informed consent. Fifty-one type 1 DM patients (30 men; mean age 44 ± 11 years; mean DM duration 23 ± 12 years) and 34 age- and sex-matched healthy control subjects were prospectively enrolled. Exclusion criteria comprised hypertension, stroke, aortic disease, and standard MRI contraindications. White matter (WM) and gray matter (GM) brain volumes, total cerebral blood flow (tCBF), total brain perfusion, and aortic pulse wave velocity (PWV) were assessed using MRI. Multivariable linear regression analysis was used for statistics, with covariates age, sex, mean arterial pressure, BMI, smoking, heart rate, DM duration, and HbA1c.
RESULTS
Both WM and GM brain volumes were decreased in type 1 DM patients compared with control subjects (WM P = 0.04; respective GM P = 0.03). Total brain perfusion was increased in type 1 DM compared with control subjects (β = −0.219, P < 0.05). Total CBF and aortic PWV predicted WM brain volume (β = 0.352, P = 0.024 for tCBF; respective β = −0.458, P = 0.016 for aortic PWV) in type 1 DM. Age was the independent predictor of GM brain volume (β = −0.695, P < 0.001).
CONCLUSIONS
Type 1 DM patients without hypertension showed WM and GM volume loss compared with control subjects concomitant with a relative increased brain perfusion. Total CBF and stiffness of the aorta independently predicted WM brain atrophy in type 1 DM. Only age predicted GM brain atrophy.
doi:10.2337/dc10-1446
PMCID: PMC3024367  PMID: 21216862
16.  Gender specific patterns of age-related decline in aortic stiffness: a cardiovascular magnetic resonance study including normal ranges 
Background
Young females exhibit lower cardiovascular event rates that young men, a pattern which is lost, or even reversed with advancing age. As aortic stiffness is a powerful risk factor for cardiovascular events, a gender difference with advancing age could provide a plausible explanation for this pattern.
Methods
777 subjects (♀n = 408, ♂n = 369) across a wide range of age (21–85 years) underwent cardiovascular magnetic resonance to assess aortic pulse wave velocity (PWV) and, in addition, aortic distensibility at three levels; 1) ascending aorta (Ao) and 2) proximal descending aorta (PDA) at the level of the pulmonary artery and 3) the abdominal aorta (DDA).
Results
There was a strong negative correlation between increasing age and regional aortic distensibility (Ao♀R-0.84, ♂R-0.80, PDA♀R-0.82, ♂R-0.77, DDA♀R-0.80, ♂R-0.71 all p < 0.001) and a strong positive correlation with PWV, (♀R0.53, ♂R 0.63 both p < 0.001). Even after adjustment for mean arterial pressure, body mass index, heart rate, smoking and diabetes, females exhibited a steeper decrease in all distensibility measures in response to increasing age (Ao♀-1.3 vs ♂-1.1 mmHg-1, PDA ♀-1.2 vs ♂-1.0 mmHg, DDA ♀-1.8 vs ♂-1.4 mmHg-1 per 10 years increase in age all p < 0.001). No gender difference in PWV increase with age was observed (p = 0.11).
Conclusion
Although advancing age is accompanied by increased aortic stiffness in both males and females, a significant sex difference in the rate of change exists, with females showing a steeper decline in aortic elasticity. As aortic stiffness is strongly related to cardiovascular events our observations may explain the increase in cardiovascular event rates that accompanies the menopausal age in women.
doi:10.1186/s12968-015-0126-0
PMCID: PMC4332729
Aorta; Cardiovascular magnetic resonance; Age
17.  Measuring aortic pulse wave velocity using high-field cardiovascular magnetic resonance: comparison of techniques 
Background
The assessment of arterial stiffness is increasingly used for evaluating patients with different cardiovascular diseases as the mechanical properties of major arteries are often altered. Aortic stiffness can be noninvasively estimated by measuring pulse wave velocity (PWV). Several methods have been proposed for measuring PWV using velocity-encoded cardiovascular magnetic resonance (CMR), including transit-time (TT), flow-area (QA), and cross-correlation (XC) methods. However, assessment and comparison of these techniques at high field strength has not yet been performed. In this work, the TT, QA, and XC techniques were clinically tested at 3 Tesla and compared to each other.
Methods
Fifty cardiovascular patients and six volunteers were scanned to acquire the necessary images. The six volunteer scans were performed twice to test inter-scan reproducibility. Patient images were analyzed using the TT, XC, and QA methods to determine PWV. Two observers analyzed the images to determine inter-observer and intra-observer variabilities. The PWV measurements by the three methods were compared to each other to test inter-method variability. To illustrate the importance of PWV using CMR, the degree of aortic stiffness was assessed using PWV and related to LV dysfunction in five patients with diastolic heart failure patients and five matched volunteers.
Results
The inter-observer and intra-observer variability results showed no bias between the different techniques. The TT and XC results were more reproducible than the QA; the mean (SD) inter-observer/intra-observer PWV differences were -0.12(1.3)/-0.04(0.4) for TT, 0.2(1.3)/0.09(0.9) for XC, and 0.6(1.6)/0.2(1.4) m/s for QA methods, respectively. The correlation coefficients (r) for the inter-observer/intra-observer comparisons were 0.94/0.99, 0.88/0.94, and 0.83/0.92 for the TT, XC, and QA methods, respectively. The inter-scan reproducibility results showed low variability between the repeated scans (mean (SD) PWV difference = -0.02(0.4) m/s and r = 0.96). The inter-method variability results showed strong correlation between the TT and XC measurements, but less correlation with QA: r = 0.95, 0.87, and 0.89, and mean (SD) PWV differences = -0.12(1.0), 0.8(1.7), and 0.65(1.6) m/s for TT-XC, TT-QA, and XC-QA, respectively. Finally, in the group of diastolic heart failure patient, PWV was significantly higher (6.3 ± 1.9 m/s) than in volunteers (3.5 ± 1.4 m/s), and the degree of LV diastolic dysfunction showed good correlation with aortic PWV.
Conclusions
In conclusion, while each of the studied methods has its own advantages and disadvantages, at high field strength, the TT and XC methods result in closer and more reproducible aortic PWV measurements, and the associated image processing requires less user interaction, than in the QA method. The choice of the analysis technique depends on the vessel segment geometry and available image quality.
doi:10.1186/1532-429X-12-26
PMCID: PMC2874535  PMID: 20459799
18.  Pulse Wave Velocity Involving Proximal Portions of the Aorta Correlates with the Degree of Aortic Dilatation at the Sinuses of Valsalva in Ascending Thoracic Aortic Aneurysms 
Annals of Vascular Diseases  2014;7(4):404-409.
Objective: To determine the relationship between arterial stiffness measured in different aortic segments and the presence and extent of ascending thoracic aortic aneurysm (ATAA).
Methods: Patients at a Thoracic Aortic Diseases clinic at a University teaching hospital were compared to patients attending a Cardiology outpatient Clinic at the same institution. A non-invasive measure of vascular stiffness was performed using pulse wave velocity (PWV) measurement of several vascular segments—carotid-femoral pulse wave velocity (cfPWV), heart-femoral pulse wave velocity (hfPWV) and brachial-ankle pulse wave velocity (baPWV). Aortic dimensions were measured on echocardiogram.
Results: Patients with ATAA (N = 32) were 66 years and the same age as those without ATAA (N = 46). There was no significant difference between those with or without aortic aneurysm with respect to cfPWV, hfPWV or baPWV. In ATAA, there was a significant (p <0.05) inverse correlation between aortic diameter at the sinuses of Valsalva and cfPWV, as well as hfPWV, but not with baPWV. This relationship was not evident in persons without ATAA.
Conclusion: Reduced aortic stiffness (increased compliance), assessed by cfPWV or hfPWV, correlates with larger aortic size of ATAA at the level of the sinuses of Valsalva but not at the ascending aorta, suggesting cfPWV may be a useful method to assess the size of ATAA at the level of the sinuses of Valsalva. Overall aortic stiffness assessed by PWV did not differentiate persons with or without an ATAA, in individuals who do not have a genetic or inheritable cause of their ATAA.
doi:10.3400/avd.oa.14-00063
PMCID: PMC4293191  PMID: 25593626
Thoracic aortic aneurysm; aortic compliance; aortic stiffness
19.  Associations of Maternal Iron Intake and Hemoglobin in Pregnancy with Offspring Vascular Phenotypes and Adiposity at Age 10: Findings from the Avon Longitudinal Study of Parents and Children 
PLoS ONE  2014;9(1):e84684.
Background
Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.
Objective
To examine the relationship between maternal pregnancy dietary and supplement iron intake and hemoglobin, with offspring’s arterial stiffness (measured by carotid-radial pulse wave velocity), endothelial function (measured by brachial artery flow mediated dilatation), blood pressure, and adiposity (measured by body mass index), test for mediation by cord ferritin, birth weight, gestational age, and child dietary iron intake, and for effect modification by maternal vitamin C intake and offspring sex.
Design
Prospective data from 2958 mothers and children pairs at 10 years of age enrolled in an English birth cohort, the Avon Longitudinal Study for Parents and Children (ALSPAC), was analysed.
Results
2639 (89.2%) mothers reported dietary iron intake in pregnancy below the UK reference nutrient intake of 14.8 mg/day. 1328 (44.9%) reported taking iron supplements, and 129 (4.4%) were anemic by 18 weeks gestation. No associations were observed apart from maternal iron intake from supplements with offspring systolic blood pressure (−0.8 mmHg, 99% CI −1.7 to 0, P = 0.01 in the sample with all relevant data observed, and −0.7 mmHg, 99% CI −1.3 to 0, P = 0.008 in the sample with missing data imputed).
Conclusion
There was no evidence of association between maternal pregnancy dietary iron intake, or maternal hemoglobin concentration (which is less likely to be biased by subjective reporting) with offspring outcomes. There was a modest inverse association between maternal iron supplement intake during pregnancy with offspring systolic blood pressure at 10 years.
doi:10.1371/journal.pone.0084684
PMCID: PMC3882256  PMID: 24400110
20.  The association of maternal prenatal psychosocial stress with vascular function in the child at age 10–11 years: findings from the Avon longitudinal study of parents and children 
Objective
To investigate whether (1) maternal psychosocial stress (depression/anxiety) during pregnancy is associated with offspring vascular function and (2) whether any association differs depending on the gestational timing of exposure to stress. We also investigated whether any association is likely to be due to intrauterine mechanisms by (3) comparing with the association of paternal stress with offspring vascular function and (4) examining whether any prenatal association is explained by maternal postnatal stress.
Methods and results
Associations were examined in a UK birth cohort, with offspring outcomes (systolic and diastolic blood pressure, SBP and DBP, endothelial function assessed by brachial artery flow-mediated dilatation (FMD); arterial stiffness assessed by carotid to radial pulse wave velocity (PWV), brachial artery distensibility (DC), and brachial artery diameter (BD) assessed at age 10–11 years (n = 4318). Maternal depressive symptoms and anxiety were assessed at 18 and 32 weeks gestation and 8 months postnatally. Paternal symptoms were assessed at week 19. With the exception of DBP and BD, there were no associations of maternal depressive symptoms with any of the vascular outcomes. Maternal depressive and anxiety symptoms were associated with lower offspring DBP and wider BD, though the latter attenuated to the null with adjustment for confounding factors. Paternal symptoms were not associated with offspring outcomes. Maternal postnatal depressive symptoms were associated with lower offspring SBP.
Conclusions
We found no evidence to support the hypothesis that maternal stress during pregnancy adversely affects offspring vascular function at age 10–12 years via intrauterine mechanisms.
doi:10.1177/2047487313486039
PMCID: PMC4230381  PMID: 23559536
Arterial stiffness; blood pressure; child; developmental origins of health and disease; fetal development; pregnancy; psychological; stress
21.  Augmentation index and aortic stiffness in bicuspid aortic valve patients with non-dilated proximal aortas 
Background
We compared aortic stiffness, aortic impedance and pressure from wave reflections in the setting of bicuspid aortic valve (BAV) to the tricuspid aortic valve (TAV) in the absence of proximal aortic dilation. We hypothesized BAV is associated with abnormal arterial stiffness.
Methods
Ten BAV subjects (47 ± 4 years, 6 male) and 13 TAV subjects (46 ± 4 years, 10 male) without significant aortic valve disease were prospectively recruited. Characteristic impedance (Zc) was derived from echocardiographic images and pulse wave Doppler of the left ventricular outflow tract. Applanation tonometry was performed to obtain pulse wave velocity (PWV) at several sites as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflection.
Results
There were no significant differences between BAV and TAV subjects with regard to heart rate or blood pressure. Zc was similar between BAV and TAV subjects (p=0.25) as was carotid-femoral pulse wave velocity (cf-PWV) and carotid-radial PWV (cr-PWV) between BAV and TAV subjects (p=0.99). Carotid AIx was significantly higher in BAV patients compared with TAV patients (14.3 ± 4.18% versus -3.02 ± 3.96%, p=0.007).
Conclusions
Aortic stiffness and impedance is similar between subjects with BAV and TAV with normal aortic dimensions. The significantly higher carotid AIx in BAV, a proxy of increased pressure from wave reflections, may reflect abnormal vascular function distal to the aorta.
doi:10.1186/1471-2261-13-19
PMCID: PMC3602003  PMID: 23496804
Bicuspid aortic valve; Arterial stiffness; Augmentation index; Pulse wave velocity
22.  Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum: Noninvasive Evaluation in the Framingham Heart Study 
Circulation  2010;122(14):1379-1386.
Background
Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial.
Methods and Results
We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53% women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: in younger participants, pulse pressure was lower and wave reflection higher with advancing age whereas in older participants, pulse pressure was higher and wave reflection lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80% (central) and 66% (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90% and 84% in the older participants (≥50 years, all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered.
Conclusions
Higher pulse pressure at any age and higher pulse pressure with advancing age is predominantly associated with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.
doi:10.1161/CIRCULATIONAHA.109.914507
PMCID: PMC2981604  PMID: 20855656
aorta; arterial stiffness; pulse wave velocity; blood pressure; pulse pressure; cardiovascular disease
23.  Arterial Stiffness and Cognitive Decline in Well-Functioning Older Adults 
Background.
Stiffness of the central arteries in aging may contribute to cerebral microvascular disease independent of hypertension and other vascular risk factors. Few studies of older adults have evaluated the association of central arterial stiffness with longitudinal cognitive decline.
Methods.
We evaluated associations of aortic pulse wave velocity (centimeters per second), a measure of central arterial stiffness, with cognitive function and decline in 552 participants in the Health, Aging, and Body Composition (Health ABC) study Cognitive Vitality Substudy (mean age ± SD = 73.1 ± 2.7 years, 48% men and 42% black). Aortic pulse wave velocity was assessed at baseline via Doppler-recorded carotid and femoral pulse waveforms. Global cognitive function, verbal memory, psychomotor, and perceptual speed were evaluated over 6 years.
Results.
After adjustment for demographics, vascular risk factors, and chronic conditions, each 1 SD higher aortic pulse wave velocity (389 cm/s) was associated with poorer cognitive function: −0.11 SD for global function (SE = 0.04, p < .01), −0.09 SD for psychomotor speed (SE = 0.04, p = .03), and −0.12 SD for perceptual speed (SE = 0.04, p < .01). Higher aortic pulse wave velocity was also associated with greater decline in psychomotor speed, defined as greater than 1 SD more than the mean change (odds ratio = 1.42 [95% confidence interval = 1.06, 1.90]) but not with verbal memory or longitudinal decline in global function, verbal memory, or perceptual speed. Results were consistent with mixed models of decline in each cognitive test.
Conclusions.
In well-functioning older adults, central arterial stiffness may contribute to cognitive decline independent of hypertension and other vascular risk factors.
doi:10.1093/gerona/glr119
PMCID: PMC3210954  PMID: 21768503
Aging; Arterial stiffness; Cognitive decline
24.  Pulse Wave Imaging (PWI) in Normal, Hypertensive and Aneurysmal Human Aortas In Vivo: A Feasibility Study 
Physics in medicine and biology  2013;58(13):4549-4562.
Arterial stiffness is a well-established biomarker for cardiovascular risk, especially in the case of hypertension. The progressive stages of an abdominal aortic aneurysm (AAA) have also been associated with varying arterial stiffness. Pulse Wave Imaging (PWI) is a noninvasive, ultrasound imaging-based technique that uses the pulse wave-induced arterial wall motion to map the propagation of the pulse wave and measure the regional pulse wave velocity (PWV) as an index of arterial stiffness. In this study, the clinical feasibility of PWI was evaluated in normal, hypertensive, and aneurysmal human aortas. Radiofrequency-based speckle tracking was used to estimate the pulse wave-induced displacements in the abdominal aortic walls of normal (N = 15, mean age 32.5 years ± 10.2), hypertensive (N = 13, mean age 60.8 years ± 15.8), and aneurysmal (N = 5, mean age 71.6 years ± 11.8) human subjects. Linear regression of the spatio-temporal variation of the displacement waveform in the anterior aortic wall over a single cardiac cycle yielded the slope as the PWV and the coefficient of determination r2 as an approximate measure of the pulse wave propagation uniformity. The aortic PWV measurements in all normal, hypertensive, and AAA subjects were 6.03 ± 1.68, 6.69 ± 2.80, and 10.54 ± 6.52 m/s, respectively. There was no significant difference (p = 0.15) between the PWVs of the normal and hypertensive subjects while the PWVs of the AAA subjects were significantly higher (p < 0.001) compared to those of the other two groups. Also, the average r2 in the AAA subjects was significantly lower (p < 0.001) than that in the normal and hypertensive subjects. These preliminary results suggest that the regional PWV and the pulse wave propagation uniformity (r2) obtained using PWI, in addition to the PWI images and spatio-temporal maps that provide qualitative visualization of the pulse wave, may potentially provide valuable information for the clinical characterization of aneurysms and other vascular pathologies that regionally alter the arterial wall mechanics.
doi:10.1088/0031-9155/58/13/4549
PMCID: PMC4005727  PMID: 23770991
Abdominal aorta; abdominal aortic aneurysm; aortic stiffness; hypertension; pulse wave velocity (PWV); pulse wave imaging (PWI); speckle tracking
25.  Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children 
European Heart Journal  2011;33(3):335-345.
Aims
It is uncertain if the higher blood pressure (BP) observed in the offspring of hypertensive pregnancies is an isolated abnormality or one that is accompanied by impaired vascular function and alterations in lipid and inflammation markers that would be indicative of a more general cardiometabolic disturbance of the type observed in the mother during pre-eclampsia.
Methods and results
In a large UK cohort of maternal-offspring pairs (n = 3537–4654), assessed at age 9–12 years, we examined the associations of maternal gestational hypertension and pre-eclampsia with offspring BP, endothelial function assessed by brachial artery flow-mediated dilatation; arterial stiffness assessed by carotid to radial pulse wave velocity; brachial artery distensibility and BP (vascular outcomes); as well as markers of inflammation, lipids and apolipoproteins A1 and B. Offspring of women with pre-eclampsia or gestational hypertension had higher systolic blood pressure by 2.04 mmHg (95% CI: 1.33, 2.76) and 1.82 mmHg (95% CI: 0.03, 3.62), respectively, and higher diastolic blood pressure by 1.10 mmHg (95% CI: 0.47, 1.73) and 1.26 mmHg (95% CI: −0.32, 2.85), respectively, in analyses adjusted for maternal and offspring body mass index (BMI), offspring dietary sodium intake and other potential confounders. However, we found no associations of either hypertensive disorder of pregnancy with the other vascular outcomes or with inflammatory markers, lipids, and apolipoproteins.
Conclusion
Pre-eclampsia and gestational hypertension are associated with higher offspring BP in childhood in the absence of other vascular alterations or metabolic derangements. The findings support the existence of shared mother-offspring risk factors that are specific for higher BP, rather than the additional cardiometabolic abnormalities of hypertensive disorder of pregnancy having long-term consequences for offspring.
doi:10.1093/eurheartj/ehr300
PMCID: PMC3270043  PMID: 21862461
Hypertensive disorder of pregnancy; Endothelial function; Arterial stiffness; Blood pressure; Lipids; ALSPAC

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