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1.  The Efficiency of First-Trimester Uterine Artery Doppler, ADAM12, PAPP-A and Maternal Characteristics in the Prediction of Pre-Eclampsia 
To estimate the efficiency of first-trimester uterine artery Doppler, A-disintegrin and metalloprotease 12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A) and maternal characteristics in the prediction of pre-eclampsia.
This is a prospective cohort study of patients presenting for first-trimester aneuploidy screening between 11-14 weeks’ gestation. Maternal serum ADAM12 and PAPP-A levels were measured by immunoassay, and mean uterine artery Doppler pulsatility indices (PI) were calculated. Outcomes of interest included pre-eclampsia, early pre-eclampsia, defined as requiring delivery at <34 weeks’ gestation, and gestational hypertension. Logistic regression analysis was used to model the prediction of pre-eclampsia using ADAM12 multiples of the median (MoM), PAPP-A MoM, and uterine artery Doppler PI MoM, either individually or in combination. Sensitivity, specificity, and area under the receiver-operating characteristic curves (AUC) were used to compare the screening efficiency of the models using non-parametric U-statistics.
Of 578 patients with complete outcome data, there were 54 (9.3%) cases of preeclampsia and 13 (2.2%) cases of early pre-eclampsia. Median ADAM12 levels were significantly lower in patients who developed pre-eclampsia compared to those who did not. (0.81 v. 1.01 MoMs; p<0.04) For a fixed false positive rate (FPR) of 10%, ADAM12, PAPP-A, and uterine artery Doppler in combination with maternal characteristics identified 50%, 48%, and 52% of patients who developed pre-eclampsia, respectively. Combining these first-trimester parameters did not improve the predictive efficiency of the models.
First-trimester ADAM12, PAPP-A, and uterine artery Doppler are not sufficiently predictive of pre-eclampsia. Combinations of these parameters do not further improve their screening efficiency.
PMCID: PMC3929514  PMID: 23980220
ADAM12; PAPP-A; placental dysfunction; pre-eclampsia; uterine artery Doppler
2.  Experimental exposure to diesel exhaust increases arterial stiffness in man 
Exposure to air pollution is associated with increased cardiovascular morbidity, although the underlying mechanisms are unclear. Vascular dysfunction reduces arterial compliance and increases central arterial pressure and left ventricular after-load. We determined the effect of diesel exhaust exposure on arterial compliance using a validated non-invasive measure of arterial stiffness.
In a double-blind randomized fashion, 12 healthy volunteers were exposed to diesel exhaust (approximately 350 μg/m3) or filtered air for one hour during moderate exercise. Arterial stiffness was measured using applanation tonometry at the radial artery for pulse wave analysis (PWA), as well as at the femoral and carotid arteries for pulse wave velocity (PWV). PWA was performed 10, 20 and 30 min, and carotid-femoral PWV 40 min, post-exposure. Augmentation pressure (AP), augmentation index (AIx) and time to wave reflection (Tr) were calculated.
Blood pressure, AP and AIx were generally low reflecting compliant arteries. In comparison to filtered air, diesel exhaust exposure induced an increase in AP of 2.5 mmHg (p = 0.02) and in AIx of 7.8% (p = 0.01), along with a 16 ms reduction in Tr (p = 0.03), 10 minutes post-exposure.
Acute exposure to diesel exhaust is associated with an immediate and transient increase in arterial stiffness. This may, in part, explain the increased risk for cardiovascular disease associated with air pollution exposure. If our findings are confirmed in larger cohorts of susceptible populations, this simple non-invasive method of assessing arterial stiffness may become a useful technique in measuring the impact of real world exposures to combustion derived-air pollution.
PMCID: PMC2660278  PMID: 19284640
3.  Pulse Wave Velocity in Korean American Men and Women 
Arterial stiffness is an important clinical marker of cardiovascular diseases. Although many studies have been conducted on different racial groups, less is known about arterial stiffness in Asian Americans. Korean Americans constitute the fifth largest subgroup in the Asian American population and reportedly have a noticeably high prevalence of hypertension. The aims of this study were to assess arterial stiffness and blood pressure and to examine the effect of age and gender on arterial stiffness and blood pressure in 102 Korean American men and women aged 21 to 60 years. The values of arterial stiffness for Korean Americans in this study were compared to published reference values for other racial and ethnic groups. Arterial stiffness was measured by carotid-femoral pulse wave velocity, which is the gold standard for determining arterial stiffness. Findings indicated that aging was an important determinant of arterial stiffness, which increased linearly with age. Although there was no gender difference observed in arterial stiffness, the effect of age on arterial stiffness was greater in women than in men. After adjusting for covariates including age, body mass index, and smoking, multiple regression models showed that arterial stiffness and gender were significant predictors of systolic and diastolic blood pressure. The comparisons of these findings to those from several other studies that used the same method to measure arterial stiffness showed that Korean Americans may have levels of arterial stiffness that are similar to or slightly higher than those of other racial groups. Considering that arterial stiffness is an independent predictor of future development of hypertension, more studies are required to examine cardiovascular risk of this understudied group.
PMCID: PMC3553793  PMID: 22222176
arterial stiffness; hypertension; Korean Americans
4.  Dehydroepiandrosterone replacement therapy in older adults improves indices of arterial stiffness 
Aging cell  2012;11(5):876-884.
Serum dehydroepiandrosterone (DHEA) concentrations decrease ~80% between ages 25 and 75 yr. Aging also results in an increase in arterial stiffness, which is an independent predictor of cardiovascular disease (CVD) risk and mortality. Therefore, it is conceivable that DHEA replacement in older adults could reduce arterial stiffness. We sought to determine if DHEA replacement therapy in older adults reduces carotid augmentation index (AI) and carotid-femoral pulse wave velocity (PWV) as indices of arterial stiffness.
A randomized, double-blind trial was conducted to study the effects of 50 mg/d DHEA replacement on AI (n=92) and PWV (n=51) in women and men aged 65–75 yr. Inflammatory cytokines and sex hormones were measured in fasting serum.
AI decreased in the DHEA group but not in the placebo group (difference between groups, −6±2 AI units, p=0.002). PWV also decreased (difference between groups, −3.5±1.0 m/sec, p=0.001); however, after adjusting for baseline values, the between-group comparison became non-significant (p=0.20). The reductions in AI and PWV were accompanied by decreases in inflammatory cytokines (TNFα and IL-6, p<0.05) and correlated with increases in serum DHEAS (r = −0.31 and −0.37, respectively, p<0.05). The reductions in AI also correlated with free testosterone index (r = −0.23, p=0.03).
DHEA replacement in elderly men and women improves indices of arterial stiffness. Arterial stiffness increases with age and is an independent risk factor for CVD. Therefore the improvements observed in the present study suggest that DHEA replacement might partly reverse arterial aging and reduce CVD risk.
PMCID: PMC3444670  PMID: 22712469
vasculature; augmentation index; aging
5.  The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus 
Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.
Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).
In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.
Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.
Trial registration
Clinical trial registration: NCT01392560
PMCID: PMC3915232  PMID: 24475922
Diabetes mellitus; Systemic blood pressure; SGLT2 inhibition; Empagliflozin; Hyperglycaemia; Arterial stiffness; Heart rate variability
6.  Association of glomerular filtration rate with arterial stiffness in Chinese women with normal to mildly impaired renal function 
Both decreased glomerular filtration rate (GFR) and arterial stiffness were considered as risk factors for atherosclerosis. Previous studies have suggested the association between central arterial stiffness and the degree of GFR loss. Whether decreased GFR contributes to peripheral artery stiffness remains controversial. Moreover, data analyzed from a cohort of Chinese women are rare. Our aim was to explore the relationship between GFR and regional arterial stiffness in Chinese women.
In this cross-sectional study, we randomly recruited 1131 adult women residents with GFR ≥ 60 mL/min per 1.73 m2 estimated by the Chinese Modification of Diet in Renal Disease equation from three large communities. Central and peripheral arterial stiffness were estimated simultaneously by measuring carotid-femoral pulse wave velocity (PWVcf) and carotid-radial PWV (PWVcr) using a validated automatic device. Augmentation Index at heart rate 75 beats/minutes (AIx-75) was measured by pulse wave analysis as a composite parameter reflecting both large and distal arterial properties.
The mean estimated GFR (eGFR) of the study group was 100.05 ± 23.26 mL/minute per 1.73 m2. Subjects were grouped by tertiles of eGFR level. PWVcf and AIx-75 increased ongoing from the top to the bottom eGFR tertile, while the values of PWVcr were comparable. Both univariate Pearson correlations and multiple stepwise regression analyses showed that eGFR significantly correlated to PWVcf, but not to PWVcr and AIx-75.
In Chinese women with normal to mildly impaired renal function, decreased eGFR affected carotid-to-femoral rather than carotid-to-radial stiffening. This provides rational to conduct future prospective studies to investigate predictors of atherosclerosis in this population.
PMCID: PMC3418906  PMID: 22916063
Arterial stiffness; Augmentation index; Pulse wave velocity; Glomerular filtration rate; Chinese women
7.  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.
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.
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.
PMCID: PMC3270043  PMID: 21862461
Hypertensive disorder of pregnancy; Endothelial function; Arterial stiffness; Blood pressure; Lipids; ALSPAC
8.  In vivo assessment of arterial stiffness in the isoflurane anesthetized spontaneously hypertensive rat 
Cardiovascular Ultrasound  2014;12(1):37.
Rodent models are increasingly used to study the development and progression of arterial stiffness. Both the non-invasive Doppler derived Pulse Wave Velocity (PWV) and the invasively determined arterial elastance index (EaI) have been used to assess arterial stiffness in rats and mice, but the need for anesthetic agents to make these in vivo estimates may limit their utility. Thus, we sought to determine: 1) if known differences in arterial stiffness in spontaneously hypertensive rats (SHR) are detectable by PWV and EaI measurements when made under isoflurane anesthesia, and 2) if these two uniquely acquired assessments of arterial elasticity correlate.
We obtained PWV and EaI measurements in isoflurane anesthetized young and old SHRs, which are known to have significant differences in arterial stiffness. Doppler pulse waves were recorded from carotid and iliac arteries and the distance (D) between probe applantation sites was recorded. Simultaneously, an EKG was obtained, and the time intervals between the R-wave of the EKG to the foot of the Doppler waveforms were measured and averaged over three cardiac cycles. Pulse-transit time (T) of the carotid to iliac artery was determined, and PWV was calculated as Distance (D)/Time (T), where D = the distance from the carotid to the iliac notch and T = (R to iliac foot) - (R to carotid foot). EaI was subsequently determined from pressure volumes loops obtained via left ventricle catheterization.
PWV and EaI were found to be significantly faster in the older rats (13.2 ± 2.0 vs. 8.0 ± 0.8 m/sec, p < 0.001; 120 ± 20 vs. 97 ± 16 mmHg/μl/g, p <0.05). Bland-Altman analyses of intra- and inter-observer measures demonstrate a statistically significant relationship between readings (p < 0.0001). PWV and EaI measurements were found to be significantly and positively correlated with a correlation coefficient of 0.53 (p < 0.05).
Our study suggests that isoflurane administration does not limit Doppler PWV or EaI measures in their ability to provide accurate, in vivo assessments of relative arterial stiffness in isoflurane anesthetised SHR rats. Furthermore, PWV data obtained in these rats correlate well with invasively determined EaI.
PMCID: PMC4245200  PMID: 25227282
Blood pressure; Arterial stiffness; Pulse wave velocity; Arterial elasticity index; Doppler; Ultrasound; Isoflurane; Anesthesia; SHR; Rat
9.  Long-Term Trandolapril Treatment Is Associated With Reduced Aortic Stiffness 
Hypertension  2007;49(6):1271-1277.
The Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial evaluated angiotensin-converting enzyme inhibition with trandolapril versus placebo added to conventional therapy in patients with stable coronary disease and preserved left ventricular function. The PEACE hemodynamic substudy evaluated effects of trandolapril on pulsatile hemodynamics. Hemodynamic studies were performed in 300 participants from 5 PEACE centers a median of 52 months (range, 25 to 80 months) after random assignment to trandolapril at a target dose of 4 mg per day or placebo. Central pulsatile hemodynamics and carotid–femoral pulse wave velocity were assessed by using echocardiography, tonometry of the carotid and femoral arteries, and body surface transit distances. Patients randomly assigned to trandolapril tended to be older (mean±SD: 64.2±7.9 versus 62.9±7.7 years; P=0.14), with a higher body mass index (28.5±4.0 versus 27.8±3.9 kg/m2; P=0.09) and lower ejection fraction (57.1±8.1% versus 58.7±8.4%; P<0.01). At the time of the hemodynamic substudy, the trandolapril group had lower mean arterial pressure (93.1±10.2 versus 96.3±11.3 mm Hg; P<0.01) and lower carotid-femoral pulse wave velocity (geometric mean [95% CI]: 10.4 m/s [10.0 to 10.9 m/s] versus 11.2 m/s [10.7 to 11.8 m/s]; P=0.02). The difference in carotid–femoral pulse wave velocity persisted (P<0.01) in an analysis that adjusted for baseline characteristics and follow-up mean pressure. In contrast, there was no difference in aortic compliance, characteristic impedance, augmentation index, or total arterial compliance. Angiotensin-converting enzyme inhibition with trandolapril produced a modest reduction in carotid–femoral pulse wave velocity, a measure of aortic wall stiffness, beyond what would be expected from blood pressure lowering or differences in baseline characteristics alone.
PMCID: PMC2553625  PMID: 17452505
angiotensin-converting enzyme; coronary artery disease; randomized clinical trial; arterial stiffness; pulse wave velocity
10.  Increased aortic stiffness and blood pressure in non-classic Pompe disease 
Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p < 0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20 %), more Pompe patients had a history of hypertension (36 %, p = 0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p < 0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly.
PMCID: PMC4013448  PMID: 24407465
11.  Circulating Angiogenic Cell Populations, Vascular Function, and Arterial Stiffness 
Atherosclerosis  2011;220(1):145-150.
Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.
We studied 1,948 Framingham Heart Study participants (mean age, 66±9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.
In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β=−0.052±0.011, P<0.001 and β=−0.030±0.011, P=0.008, respectively) and with higher carotid-brachial pulse wave velocity (β=0.144±0.043, P=0.001 and β=0.112±0.043, P=0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β=−0.229±0.094, P=0.015) However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.
In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.
PMCID: PMC3277804  PMID: 22093724
angiogenesis; vascular function; risk factors; endothelium; epidemiology
12.  The effect of L-arginine on arterial stiffness and oxidative stress in chronic kidney disease 
Indian Journal of Nephrology  2012;22(5):340-346.
Chronic kidney disease (CKD) is a growing problem worldwide. The disproportionate increase in the burden of cardiovascular disease in patients with CKD may be significantly contributed by nontraditional risk factors. Increased arterial stiffness has been recognized as an important player in contributing to this morbidity and mortality. The aim of this study was to report the effect of L-arginine on arterial stiffness and oxidative stress in patients with CKD. Thirty patients with stage II to IV CKD were administered 9 g of L- arginine per day orally for a period of 12 weeks. The parameters evaluated at baseline, at 8 weeks, and at the end of 12 weeks were serum nitric oxide (NO), carotid.femoral pulse wave velocity (cf PWV), and radial artery pulse wave analysis which included aortic augmentation pressure (AP), aortic augmentation index (AIx), aortic augmentation index at heart rate of 75 bpm, subendocardial viability ratio, radial pressures, and central aortic pressure. Serum levels of NO and malondialdehyde (MDA) were estimated at baseline and at the end of 12 weeks. The control group was composed of age- and sex-matched healthy individuals. Twenty-five patients completed the study. Two patients were lost to follow.up; three patients developed adverse events and were excluded. Baseline NO levels were low (13.55 ± 7.49 μM/L) in all the subjects. Administration of L-arginine resulted in improvement in the carotid-radial PWV (m/s) (10.08 ± 1.72 at baseline to 8.56 ± 1.16 by 12 weeks; P < 0.001), cf PWV (m/s) (13.06 ± 2.65 at baseline to 10.62 ± 1.93 at 12 weeks; P < 0.001), Aortic Augmentation Index (%) (32 ± 10.34 at baseline to 17.84 ± 8.05 at 12 weeks; P < 0.001), aortic augmentation pressure (mm of Hg) (14.03 ± 6.53 at baseline to 7.12 ± 3.85 at 12 weeks; P < 0.001), and NO (μM/L) (13.55 ± 7.49 at baseline to 30.22 ± 9.8 at 12 weeks; P < 0.001). There was no significant change in the levels of MDA (nanomol/ml) (20.0 ± 10.14 at baseline and 19.16 ± 9.36 at 12 weeks; P = ns). In conclusion, PWV, an indicator of arterial stiffness, is greatly increased even in the early stages of CKD. Supplementation of L-arginine is a safe, well-tolerated, and effective way of improving endothelial dysfunction in patients with CKD.
PMCID: PMC3544054  PMID: 23326043
Arterial stiffness; chronic kidney disease; L-arginine; oxidative stress; pulse wave velocity
13.  A multi-marker approach to evaluate correlates of vascular stiffness: The Framingham Heart Study 
Circulation  2008;119(1):37-43.
Arterial stiffness increases with age and contributes to the pathogenesis of systolic hypertension and cardiovascular disease in the elderly. Knowledge about pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches.
Methods and Results
We related seven circulating biomarkers, representing distinct biological pathways (C-reactive protein [CRP], aldosterone-to-renin ratio [ARR], N-terminal pro–atrial natriuretic peptide and B-type natriuretic peptide, plasminogen activator inhibitor [PAI]-1, fibrinogen, homocysteine) to 5 vascular function measures (central pulse pressure, carotid-femoral pulse wave velocity, mean arterial pressure, forward pressure wave amplitude [all measures of conduit artery stiffness], and augmented pressure, an indicator of wave reflection) in 2,000 Framingham Offspring Study participants (mean age 61 years, 55% women). Tonometry measures were obtained on average three years after biomarkers were measured. In multivariable linear regression models adjusting for covariates, the biomarker panel was significantly associated with all 5 vascular measures (p<0.003 for all). Upon backwards elimination, the ARR was positively associated with each stiffness measure (p≤0.002 for all). In addition, CRP was positively related to augmented pressure (p=0.0003), whereas PAI-1 was positively associated with mean arterial pressure (p=0.003), central pulse pressure (p=0.001) and forward pressure wave (p=0.01).
Our cross-sectional data on a community-based sample suggest a distinctive pattern of positive associations of biomarkers of renin-angiotensin-aldosterone system activation with pan-arterial vascular stiffness, PAI-1 with central vascular stiffness indices, and of CRP with wave reflection. These observations support the notion of differential influences of biological pathways on vascular stiffness measures.
PMCID: PMC2722113  PMID: 19103986
arterial stiffness; renin-angiontensin-aldosterone system; C-reactive protein; plasminogen activator inhibitor; biomarker
14.  Stiffness of the large arteries in individuals with and without Down syndrome 
Down syndrome is known to cause premature aging in several organ systems. However, it remains unclear whether this aging effect also affects the structure and function of the large arterial trunks. In this controlled study, the possibility of changes in the large arteries due to aging was evaluated in patients with Down syndrome.
Eighty-two subjects of both genders were selected. The Down syndrome group had 41 active subjects consisting of 19 males and 22 females (mean age 21 ± 1, range 13–42 years) without cardiovascular complications and who did not use vasoactive drugs. The control group consisted of 41 healthy individuals without trisomy 21 of the same gender and age as the Down syndrome group and who did not use vasoactive medication. Carotid–femoral pulse wave velocity was obtained as an index of aortic stiffness using an automatic noninvasive method.
Individuals with Down syndrome had significantly lower blood pressure than those in the control group. Systolic blood pressure for the Down syndrome group and control group was 106 ± 2 mmHg vs 117 ± 2 mmHg (P < 0.001), respectively; diastolic blood pressure was 66 ± 2 mmHg vs 77 ± 2 mmHg (P < 0.001); and mean arterial pressure was 80 ± 1 mmHg vs 90 ± 1 mmHg (P < 0.001). Only age and systolic blood pressure were shown to correlate significantly with pulse wave velocity, but the slopes of the linear regression curves of these two variables showed no significant difference between the two study groups. Pulse wave velocity, which was initially significantly lower in the Down syndrome group (7.51 ± 0.14 m/s vs 7.84 ± 0.12 m/s; P <0.05), was similar between the groups after systolic blood pressure adjustment (7.62 ± 0.13 m/s vs 7.73 ± 0.13 m/s).
Despite evidence in the literature that patients with Down syndrome undergo early aging, this process does not seem to affect the large arterial trunks, given that values of carotid-femoral pulse wave velocity were similar in individuals with or without trisomy 21. Considering that Down syndrome presents with chronic hypotension, it is reasonable to propose that the prolonged reduction of arterial distending pressure may contribute to functional preservation of the arteries in patients with Down syndrome.
PMCID: PMC3119595  PMID: 21731889
aging; Down syndrome; pulse wave velocity; arterial stiffness
15.  Structural and functional abnormalities of large arteries in the Turner syndrome 
Heart  2005;91(11):1442-1446.
Objective: To analyse the structural and functional abnormalities in the large arteries in women with the Turner syndrome.
Methods: Aortic stiffness (assessed by means of the carotid femoral pulse wave velocity), level of amplification of the carotid pressure wave (by applanation tonometry), and carotid remodelling (by high resolution ultrasound) were studied in women with the Turner syndrome. Clinical and ambulatory blood pressures were taken into account in the analysis. Thus, 24 patients with the Turner syndrome and 25 healthy female subjects matched for age were studied.
Results: Women with the Turner syndrome had a higher augmentation index than the controls (Turner, mean (SD) 0.04 (0.14) v controls, −0.14 (0.13), p < 0.001) but a lower peripheral pulse pressure (39 (8) mm Hg v 47 (11) mm Hg, p  =  0.010 in the clinic; 44 (5) mm Hg v 47 (6) mm Hg, p  =  0.036 during the 24 hour ambulatory recording). The luminal diameter of the common carotid artery and the carotid–femoral pulse wave velocity were similar in the two groups, whereas carotid intima–media thickness tended to be higher in women with the Turner syndrome (0.53 (0.06) mm v 0.50 (0.05) mm, p  =  0.06). After correction for body surface area, carotid intima–media thickness and pulse wave velocity were higher in women with the Turner syndrome.
Conclusions: Vascular abnormalities observed in the Turner syndrome are implicated in the origin of the cardiovascular complications that occur in this syndrome. These abnormalities are morphological but also functional. An increase in the augmentation index can be explained in part by the short height of these patients.
PMCID: PMC1769156  PMID: 15761044
Turner syndrome; large arteries; hypertension; augmentation index; arterial stiffness
16.  Maternal carotid remodeling and increased carotid arterial stiffness in normal late-gestational pregnancy as assessed by radio-frequency ultrasound technique 
The adaption of elastic arteries to transient increase in hemodynamic load in normal pregnancy (NP) remains controversial. The purpose of this study was to investigate the NP carotid remodeling and regional arterial stiffness before and after parturition.
Fifty-one NP women and 30 age-matched non-pregnant women were included. All women underwent right common carotid artery (RCCA) measurements with MylabTwice ultrasound instrument (Esaote, Italy). Carotid intima-medial thickness (IMT), pulse wave velocity (PWV, m/s), distensibility coefficient (DC, 1/KPa), α, β, augmentation index (AIx, %) and carotid arterial pressure were obtained by the newly developed ultrasound vascular wall tracking methods: automatic QAS (Quality Arterial Stiffness) and QIMT (Quality Intima-Medial Thickness) Follow up study was performed.
Compared to the non-pregnant controls, the arterial pressures were significantly increased and RCCA diameter was significantly enlarged in late gestational NP women. Twenty months after parturition, carotid diameter, DC, AIx, PWV and arterial wall tension were significantly decreased and had no significant difference with those in non-pregnant controls.
Carotid arterial remodeling and stiffening could be seen in the normal pregnant women, which seems to be a physiological adaption and could be recovered post partum. QIMT and QAS together could provide a comprehensive assessment of the maternal carotid arterial changes during pregnancy.
PMCID: PMC3669620  PMID: 23710816
Arterial stiffness; Intima-media thickness; Carotid artery; Normal pregnancy; Arterial remodeling
17.  Validity and reproducibility of arterial pulse wave velocity measurement using new device with oscillometric technique: A pilot study 
Availability of a range of techniques and devices allow measurement of many variables related to the stiffness of large or medium sized arteries. There is good evidence that, pulse wave velocity is a relatively simple measurement and is a good indicator of changes in arterial properties. The pulse wave velocity calculated from pulse wave recording by other methods like doppler or tonometry is tedious, time-consuming and above all their reproducibility depends on the operator skills. It requires intensive resource involvement. For epidemiological studies these methods are not suitable. The aim of our study was to clinically evaluate the validity and reproducibility of a new automatic device for measurement of pulse wave velocity that can be used in such studies.
In 44 subjects including normal healthy control and patients with coronary artery disease, heart brachial, heart ankle, brachial ankle and carotid femoral pulse wave velocities were recorded by using a new oscillometric device. Lead I and II electrocardiogram and pressure curves were simultaneously recorded. Two observers recorded the pulse wave velocity for validation and one observer recorded the velocity on two occasions for reproducibility.
Results and Discussion
Pulse wave velocity and arterial stiffness index were recorded in 24 control and 20 coronary artery disease patients. All the velocities were significantly high in coronary artery disease patients. There was highly significant correlation between the values noted by the two observers with low standard deviation. The Pearson's correlation coefficient for various velocities ranged from (r = 0.88–0.90) with (p < 0.0001). The reproducibility was also very good as shown by Bland-Altman plot; most of the values were lying within 2 SD. The interperiod measurements of pulse wave velocity were also significantly correlated (r = 0.71 – 0.98) (P < 0.0001). Carotid-femoral pulse wave velocity was found to correlate significantly with heart brachial, heart ankle, brachial ankle pulse wave velocity and arterial stiffness index values. Reproducibility of our method was good with very low variability in both interobserver and interperiod analysis.
The new device "PeriScope" based on oscillometric technique has been found to be a simple, non-invasive and reproducible device for the assessment of pulse wave velocity and can be used to determine arterial stiffness in large population based studies.
PMCID: PMC1224857  PMID: 16115324
Pulse wave velocity; Arterial stiffness index; Validity; Oscillometric device
18.  Vitamin D Status Is Associated With Arterial Stiffness and Vascular Dysfunction in Healthy Humans 
The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults.
Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function.
We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness.
Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (β = 0.1, p = 0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = −0.09, p = 0.04), augmentation index (β = −0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02).
Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.
PMCID: PMC3896949  PMID: 21718915
arterial stiffness; endothelial function; vitamin D
19.  Serum Uric Acid Level and Diverse Impacts on Regional Arterial Stiffness and Wave Reflection 
Both increased arterial stiffness and hyperuricaemia are associated with elevated cardiovascular risks. Little is known about the relations of serum uric acid (UA) level to regional arterial stiffness and wave reflection. The aim of the study was to investigate the gender-specific association of serum UA and indices of arterial function in a community-based investigation in China.
Cross-sectional data from 2374 adults (mean age 58.24 years) who underwent routine laboratory tests, regional pulse wave velocity (PWV) and pulse wave analysis measurements were analyzed in a gender-specific manner. None of the participants had atherosclerotic cardiovascular disease, chronic renal failure, systemic inflammatory disease, gout, or were under treatment which would affect serum UA level.
Men had higher serum UA level than women. Subjects with hyperuricaemia had significantly higher carotid-ankle PWV in both genders (P< 0.05), and the carotid-femoral PWV (PWVc-f) was higher in women (P< 0.001) while the augmentation index was marginally lower in men (P = 0.049). Multiple regression analysis showed that serum UA was an independent determinant only for PWVc-f in women (β = 0.104, P = 0.027) when adjusted for atherogenic confounders. No other independent relationship was found between UA level and other surrogates of arterial stiffness.
Serum UA levels are associated with alterations in systemic arterial stiffness that differ in men and women. Women might be more susceptible to large vascular damage associated with hyperuricaemia.
PMCID: PMC3469023  PMID: 23113222
Arterial stiffness; Gender; Public health; Pulse wave velocity; Uric acid; Wave reflection
20.  Association between serum homocysteine and arterial stiffness in elderly: a community-based study 
Arterial stiffness and homocysteine are both powerful predictors of cardiovascular disease, especially in older populations. Previous studies have investigated the association of homocysteine with arterial stiffness in human subjects, while the relationship between homocysteine and arterial stiffness in the elderly is still indefinite. The current study examined the association of homocysteine with arterial stiffness in Chinese community-based elderly persons.
We related serum levels of homocysteine to two measures of arterial stiffness (carotid-femoral pulse wave velocity (PWV) and carotid-radial PWV) in 780 participants (46.3% men, mean age 71.9 years (ranging 65–96 years old)) from two communities of Beijing, China. Arterial stiffness was measured within two days of the time of biomarker measurement.
In multiple-adjusted models, homocysteine levels were strongly associated with the carotid-femoral PWV (standardized β = 0.13, P < 0.001), even after adjustment for classical risk factors of cardiovascular disease. The association is also stronger when the carotid-femoral PWV is elevated above normal, whereas no significant association with homocysteine was observed for carotid-radial PWV.
In Chinese elderly persons, serum homocysteine levels are associated with alterations of aortic stiffness.
PMCID: PMC3981981  PMID: 24748879
The elderly; Homocysteine; Arterial stiffness; Pulse wave velocity
21.  Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness 
BMC Medical Genetics  2007;8(Suppl 1):S3.
About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions.
In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971–1975 (n = 1260), at a recent examination in 1998–2001 (n = 1233), and long-term averaged SBP and DBP from 1971–2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998–2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency ≥ 0.10, genotype call rate ≥ 0.80, and Hardy-Weinberg equilibrium p ≥ 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search.
In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10-5. The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 × 10-6) and rs1963982 (p = 3.3 × 10-6). For the five tonometry phenotypes, five SNPs had p values < 10-5; lowest p-values were for reflected wave (rs6063312, p = 2.1 × 10-6) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 × 10-6) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness.
These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.
PMCID: PMC1995621  PMID: 17903302
22.  Effect of beta-1-blocker, nebivolol, on central aortic pressure and arterial stiffness in patients with essential hypertension 
Indian Journal of Pharmacology  2012;44(3):407-411.
Blood pressure (BP) reduction is the major determinant of benefit provided by antihypertensive treatment. Although different drugs reduce peripheral BP to some extent, there may be a significant difference in their effect on central BP reduction. It has been shown that beta-blockers are efficient in reducing peripheral, but not central BP. This study was done to assess the effect of beta-1-blocker, nebivolol, in patients with essential hypertension on central aortic pressures and arterial stiffness.
Materials and Methods:
In this single arm, open-labeled study, 13 patients were given nebivolol, 5 mg orally once daily for 15 days. Primary outcome was change in central aortic pressure, and other measures of efficacy included changes in brachial BP, augmentation index (AIx%), AIx%@75 HR, augmentation pressure (AP), heart rate (HR), and carotid femoral pulse wave velocity (PWVcf).
Nebivolol 5 mg significantly reduced central aortic pressures [systolic BP, 131.5–111.6 mmHg; diastolic BP, 96.3–81.7 mmHg; Mean Arterial Pressure (MAP), 111.3–94.0 mmHg (all P<0.0001), and Pulse Pressure (PP), 35.2-29.7 mmHg (P<0.01)]. AIx%@75 HR reduced from 29 to 21.6 (P<0.001) and PWVcf reduced from 8.6 to 7.2 m/s (P<0.001). One subject was lost to followup.
Nebivolol 5 mg demonstrated antihypertensive efficacy in patients with essential hypertension by reducing not only peripheral brachial pressures, but also significantly reducing central aortic pressures, augmentation index, and carotid femoral pulse wave velocity, which is the marker of arterial stiffness.
PMCID: PMC3371470  PMID: 22701257
Nebivolol; central aortic pressures; arterial stiffness
23.  Effects of CPAP on “vascular” risk factors in patients with obstructive sleep apnea and arterial hypertension 
The aim of this study was to assess the effects of continuous positive airway pressure (CPAP) on arterial stiffness, central blood pressure, and reflected pulse wave characteristics in patients with severe obstructive sleep apnea (OSA) and stage 2–3 arterial hypertension.
Forty-four patients with hypertension and severe OSA (apnea/hypopnea index > 30) received stepped dose titration of antihypertensive treatment, consisting of valsartan 160 mg + amlodipine 5–10 mg + hydrochlorothiazide 25 mg. CPAP therapy was added after 3 weeks of continuous antihypertensive treatment with BP < 140/90 mmHg or after adjusting triple treatment in patients with resistant arterial hypertension. The patients were randomized to effective CPAP (4–15 mm H2O) or placebo CPAP (pressure 4 mm H2O) for three weeks, then crossed over to the alternative treatment in a single-blind manner. Office blood pressure (BP), ambulatory BP monitoring, ambulatory arterial stiffness index (AASI), aortic BP, carotid-femoral pulse wave velocity (cfPWV), and systolic wave augmentation index were measured using a Sphygmocor® device at baseline, after antihypertensive treatment, placebo CPAP, and effective CPAP.
Baseline cfPWV was above the normal range in 94% of patients. After reaching target BP, the cfPWV decreased by 1.9 ± 1.0 msec (P = 0.007). Effective CPAP achieved a further cfPWV reduction of 0.7 msec (P = 0.03). Increased arterial stiffness (pulse wave velocity > 12 msec) persisted in 35% of patients on antihypertensive treatment and effective CPAP, in 56% of patients on antihypertensive treatment alone, and in 53% of patients on placebo CPAP. Only the combination of antihypertensive treatment with effective CPAP achieved a significant reduction in augmentation index and AASI, along with a further reduction in aortic and brachial BP.
Effective CPAP for 3 weeks resulted in a significant additional decrease in office BP, ambulatory BP monitoring, central BP, and augmentation index, together with an improvement in arterial stiffness parameters, ie, cfPWV and AASI, in a group of hypertensive patients with OSA.
PMCID: PMC3656895  PMID: 23690688
antihypertensive therapy; hypertension; obstructive sleep apnea; continuous positive airway pressure; blood pressure; arterial stiffness; ulse wave velocity
24.  Reduced Ascending Aortic Strain and Distensibility Earliest Manifestations of Vascular Aging in Humans 
Hypertension  2010;55(2):319-326.
Arterial stiffness predicts cardiovascular events beyond traditional risk factors. However, the relationship with aging of novel noninvasive measures of aortic function by MRI and their interrelationship with established markers of vascular stiffness remain unclear and currently limit their potential impact. Our aim was to compare age-related changes of central measures of aortic function with carotid distensibility, global carotid–femoral pulse wave velocity, and wave reflections. We determined aortic strain, distensibility, and aortic arch pulse wave velocity by MRI, carotid distensibility by ultrasound, and carotid–femoral pulse wave velocity by tonometry in 111 asymptomatic subjects (54 men, age range: 20 to 84 years). Central pressures were used to calculate aortic distensibility. Peripheral and central pulse pressure, augmentation index, and carotid–femoral pulse wave velocity increased with age, but aortic strain and aortic arch PWV were most closely and specifically related to aging. Ascending aortic (AA) strain and distensibility decreased, respectively, by 5.3±0.5% (R2 = 0.54, P<0.0001) and 13.6±1 kPa−1×10−3 (R2=0.62, P<0.0001), and aortic arch pulse wave velocity increased by 1.6±0.13 m/sec (R2=0.60, P<0.0001) for each decade of age after adjustment for gender, body size, and heart rate. We demonstrate in this study a dramatic decrease in AA distensibility before the fifth decade of life in individuals with diverse prevalence of risk factors free of overt cardiovascular disease. In particular, compared with other measures of aortic function, the best markers of subclinical large artery stiffening, were AA distensibility in younger and aortic arch pulse wave velocity in older individuals.
PMCID: PMC3035625  PMID: 20065154
MRI; aorta; aging; elasticity; pulse wave velocity
25.  Triglyceride to HDL-C Ratio and Increased Arterial Stiffness in Children, Adolescents, and Young Adults 
Pediatrics  2013;131(4):e1082-e1090.
Lipid levels are linked to early atherosclerosis. Risk stratification may be improved by using triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), which relates to arterial stiffness in adults. We tested whether TG/HDL-C was an independent predictor of arterial stiffness in youth.
Subjects 10 to 26 years old (mean 18.9 years, 39% male, 56% non-Caucasian, n = 893) had laboratory, anthropometric, blood pressure, and arterial stiffness data collected (brachial distensibility, augmentation index, carotid-femoral pulse-wave velocity). Subjects were stratified into tertiles of TG/HDL-C (low, n = 227; mid, n = 288; high, n = 379).
There was a progressive rise in cardiovascular (CV) risk factors and arterial stiffness across TG/HDL-C ratio. The high TG/HDL-C ratio group had the stiffest vessels (all P < .03 by analysis of variance). TG/HDL-C as a continuous variable was an independent determinant of brachial distensibility in CV risk factor adjusted model and for carotid-femoral pulse-wave velocity in obese subjects, with trend for higher augmentation index.
TG/HDL-C, an estimate of small, dense low-density lipoprotein cholesterol, is an independent determinant of arterial stiffness in adolescents and young adults, especially in obese youth. These data suggest that use of TG/HDL-C may be helpful in identifying young adults requiring aggressive intervention to prevent atherosclerotic CV diseases.
PMCID: PMC3608484  PMID: 23460684
arterial stiffness; dyslipidemia; pediatrics

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