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1.  Arterial Stiffness and Wave Reflection: Biomarkers of Cardiovascular Risk 
Artery research  2009;3(2):56-64.
Arterial stiffness and excessive pressure pulsatility have emerged as important risk factors for cardiovascular disease. Arterial stiffness increases with age and in the presence of traditional cardiovascular disease risk factors, such as hypertension, diabetes and lipid disorders. Pathologic stiffening of large arteries with advancing age and risk factor exposure predominantly involves the elastic aorta and carotid arteries, whereas stiffness changes are relatively limited in muscular arteries. Aortic stiffening is associated with increased pulse wave velocity and pulse pressure, which are related but distinct measures of the pulsatile energy content of the pressure waveform. A dramatic increase in pulsatile energy content of pressure and flow waves in the arterial system places considerable pulsatile stress on the heart, large arteries and distal circulation. Large artery stiffening is associated with abnormalities in microvascular structure and function that may contribute to tissue damage, particularly in susceptible high flow organs such as the brain and kidneys. This brief review summarizes results of recent research on risk factors for and adverse effects of large artery stiffening.
PMCID: PMC2705910  PMID: 20161241
Arterial stiffness; aorta; pulse pressure; pulse wave velocity; wave reflection
2.  Central Pulse Pressure and Its Hemodynamic Determinants in Middle-Aged Adults With Impaired Fasting Glucose and Diabetes 
Diabetes Care  2013;36(8):2359-2365.
Pulse pressure (PP), a strong predictor of cardiovascular events in type 2 diabetes, is a composite measure affected by several hemodynamic factors. Little is known about the hemodynamic determinants of central PP in type 2 diabetes or whether abnormalities in central pulsatile hemodynamics are already present in individuals with impaired fasting glucose (IFG). In a population-based study, we aimed to compare central PP and its hemodynamic determinants among adults with normal fasting glucose (n = 1654), IFG (n = 240), and type 2 diabetes (n = 33).
We measured carotid pressure, left ventricular outflow, aortic root diameter, carotid artery flow, and distension in order to measure various structural and hemodynamic arterial parameters.
IFG was associated with a greater mean arterial pressure (MAP) but was not associated with intrinsic aortic stiffening or abnormal aortic pulsatile indices after adjustment for MAP. After adjustment for age, sex, and MAP, type 2 diabetes was associated with a higher aortic root characteristic impedance (Zc), aortic root elastance-thickness product (Eh), and aortic root pulse wave velocity (but not aortic root diameter), a greater carotid-femoral pulse wave velocity, and lower total arterial compliance and wave reflection magnitude. Carotid size, Zc, distensibility, or Eh did not significantly differ between the groups.
Type 2 diabetes, but not IFG, is associated with greater large artery stiffness, without abnormalities in aortic root diameter or carotid stiffness. Subjects with type 2 diabetes demonstrate a decreased reflection magnitude, which may indicate an increased penetration of pulsatile energy to distal vascular beds.
PMCID: PMC3714490  PMID: 23610081
3.  Relations of arterial stiffness and endothelial function to brain aging in the community 
Neurology  2013;81(11):984-991.
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
PMCID: PMC3888200  PMID: 23935179
4.  Effect of acute resistance exercise on carotid artery stiffness and cerebral blood flow pulsatility 
Arterial stiffness is associated with cerebral flow pulsatility. Arterial stiffness increases following acute resistance exercise (RE). Whether this acute RE-induced vascular stiffening affects cerebral pulsatility remains unknown. Purpose: To investigate the effects of acute RE on common carotid artery (CCA) stiffness and cerebral blood flow velocity (CBFv) pulsatility. Methods: Eighteen healthy men (22 ± 1 yr; 23.7 ± 0.5 kg·m−2) underwent acute RE (5 sets, 5-RM bench press, 5 sets 10-RM bicep curls with 90 s rest intervals) or a time control condition (seated rest) in a randomized order. CCA stiffness (β-stiffness, Elastic Modulus (Ep)) and hemodynamics (pulsatility index, forward wave intensity, and reflected wave intensity) were assessed using a combination of Doppler ultrasound, wave intensity analysis and applanation tonometry at baseline and 3 times post-RE. CBFv pulsatility index was measured with transcranial Doppler at the middle cerebral artery (MCA). Results: CCA β-stiffness, Ep and CCA pulse pressure significantly increased post-RE and remained elevated throughout post-testing (p < 0.05). No changes in MCA or CCA pulsatility index were observed (p > 0.05). There were significant increases in forward wave intensity post-RE (p < 0.05) but not reflected wave intensity (p > 0.05). Conclusion: Although acute RE increases CCA stiffness and pressure pulsatility, it does not affect CCA or MCA flow pulsatility. Increases in pressure pulsatility may be due to increased forward wave intensity and not pressure from wave reflections.
PMCID: PMC3958641  PMID: 24678301
arterial stiffness; blood pressure; exercise; wave reflection
5.  Aortic Stiffness, Blood Pressure Progression, and Incident Hypertension 
Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. Vascular stiffness and blood pressure pulsatility are related; however, temporal relationships between vascular stiffening and blood pressure elevation have not been fully delineated.
To examine temporal relationships among vascular stiffness, central hemodynamics, microvascular function, and blood pressure progression.
Design, Setting, and Participants
Longitudinal community-based cohort study conducted in Framingham, Massachusetts. The present investigation is based on the 2 latest examination cycles (cycle 7: 1998–2001; cycle 8: 2005–2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971–1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1759 participants (mean [SD] age: 60 [9] years; 974 women).
Main Outcome Measures
The primary outcomes were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPWV, FWA, and augmentation index during examination cycle 8.
In a multivariable-adjusted regression model, higher FWA (β, 1.3 [95% CI, 0.5–2.1] mm Hg per 1 SD; P=.002) and higher CFPWV (β, 1.5 [95% CI, 0.5–2.6] mm Hg per 1 SD; P=.006) during examination cycle 7 were jointly associated with systolic blood pressure during examination cycle 8. Similarly, in a model that included systolic and diastolic blood pressure and additional risk factors during examination cycle 7, higher FWA (odds ratio [OR], 1.6 [95% CI, 1.3–2.0] per 1 SD; P < .001), augmentation index (OR, 1.7 [95% CI, 1.4–2.0] per 1 SD; P < .001), and CFPWV (OR, 1.3 [95% CI, 1.0–1.6] per 1 SD; P=.04) were associated with incident hypertension during examination cycle 8 (338 cases [32%] in 1048 participants without hypertension during examination cycle 7). Conversely, blood pressure during examination cycle 7 was not associated with CFPWV during examination cycle 8. Higher resting brachial artery flow (OR, 1.23 [95% CI, 1.04–1.46]) and lower flow-mediated dilation (OR, 0.80 [95% CI, 0.67–0.96]) during examination cycle 7 were associated with incident hypertension (in models that included blood pressure and tonometry measures collected during examination cycle 7).
In this cohort, higher aortic stiffness, FWA, and augmentation index were associated with higher risk of incident hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening.
PMCID: PMC3594687  PMID: 22948697
6.  Association of Ultrasonographic Parameters with Subclinical White-Matter Hyperintensities in Hypertensive Patients 
Background and Purpose. Cerebral white matter hyperintensities (WMHs) are regarded as typical MRI expressions of small-vessel disease (SVD) and are common in hypertensive patients. Hypertension induces pathologic changes in macrocirculation and in microcirculation. Changes in microcirculation may lead to SVD of brain and consequently to hypertensive end-organ damage. This damage is regarded the result of interactions between the macrovascular and microvascular levels. We sought to investigate the association of cerebral WMHs with ultrasonographic parameters of cerebral macrocirculation evaluated by carotid duplex ultrasound (CDU) and transcranial doppler (TCD). Subjects and Methods. The study was prospective, cross-sectional and consecutive and included hypertensive patients with brain MRI with WMHs. Patients underwent CDU and TCD. The clinical variables recorded were demographic characteristics (age, gender, race) and vascular risk factors (hypertension, diabetic mellitus, hypercholesterolemia, current smoking, and body mass index). Excluded from the study were patients with history of clinical stroke (including lacunar stroke and hemorrhagic) or transient ischemic attack (either hemispheric or ocular), hemodynamically significant (>50%) extra- or intracranial stenosis, potential sources of cardioembolism, and absent transtemporal windows. WMHs were quantified with the use of a semiquantitative visual rating method. Ultrasound parameters investigated were (1) common carotid artery (CCA) diameter and intima-media thickness, (2) blood flow velocity in the CCA and internal carotid artery (ICA), and (3) blood flow velocity and pulsatility index of middle cerebral artery (MCA). Results. A total of 52 patients fulfilled the study inclusion criteria (mean age 71.4 ± 4.5 years, 54% men, median WMH-score: 20). The only two ultrasound parameters that were independently associated with WMH score in multivariate linear regression models adjusting for demographic characteristics and vascular risk factors were increased mean common carotid artery (CCA) diameter (beta = 0.784, SE = 0.272, P = 0.006, R2 = 23.9%) and increased middle cerebral artery pulsatility index (MCA-PI; beta = 0.262, SE = 0.110, P = 0.025, R2 = 9.0%). Among all ultrasound parameters the highest AUC (areas under the receiver operating characteristic curve) were documented for MCA-PI (AUC = 0.82, 95% CI = 0.68−0.95, P < 0.001) and mean CCA diameter (AUC = 0.80, 95% CI = 0.67−0.92, P < 0.001). Conclusions. Our study showed that in hypertensive individuals with brain SVD the extent of structural changes in cerebral microcirculation as reflected by WMHs burden is associated with the following ultrasound parameters of cerebral macrocirculation: CCA diameter and MCA-PI.
PMCID: PMC3463900  PMID: 23056917
7.  Blood Pressure, Internal Carotid Atery Flow Parameters and Age-Related White Matter Hyperintensities 
Hypertension  2014;63(5):1011-1018.
White matter hyperintensities (WMH) are associated with hypertension. We examined interactions between blood pressure (BP), internal carotid artery (ICA) flow velocity parameters and WMH. We obtained BP measurements from 694 community-dwelling subjects at mean ages 69.6 (±0.8) and again at 72.6 (±0.7) years, plus brain MRI and ICA ultrasound at age 73±1 years. Diastolic and mean BP decreased and pulse pressure increased but systolic BP did not change between 70 and 73 years. Multiple linear regression, corrected for vascular disease and risk factors, showed that WMH at age 73 were associated with history of hypertension (β=0.13, p<0.001) and with BP at age 70 (systolic β=0.08, mean β=0.09, diastolic β=0.08, all p<0.05); similar but attenuated associations were seen for BP at age 73. Lower diastolic BP and higher pulse pressure were associated with higher ICA pulsatility index at age 73 (diastolic BP: standardized β, age 70=−0.24, p<0.001; pulse pressure age 70 β=0.19, p<0.001). WMH were associated with higher ICA pulsatility index (β=0.13, p=0.002) after adjusting for BP and correction for multiple testing. Therefore falling diastolic BP and increased pulse pressure are associated with increased ICA pulsatility index, which in turn is associated with WMH. This suggests that hypertension and WMH may either associate indirectly because hypertension increases arterial stiffness which leads to WMH over time, or co-associate through advancing age and stiffer vessels, or both. Reducing vascular stiffness may reduce WMH progression and should be tested in randomised trials, in addition to testing antihypertensive therapy.
PMCID: PMC3984108  PMID: 24470459
blood flow velocity; blood pressure; pulse pressure; white matter hyperintensities; ageing; magnetic resonance imaging
8.  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
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.  Site-specific association between distal aortic pulse wave velocity and peripheral arterial stenosis severity: a prospective cardiovascular magnetic resonance study 
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.
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.
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.
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.
PMCID: PMC4298121  PMID: 25600313
Cardiovascular magnetic resonance; Atherosclerosis; Peripheral arterial occlusive disease; Pulse wave velocity; Carotid vessel wall
11.  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.
PMCID: PMC3018759  PMID: 20876449
arterial stiffness; arterial wave reflection; magnetic resonance image
12.  Circulating endothelial progenitor cells and large artery structure and function in young subjects with uncomplicated Type 1 Diabetes 
Carotid intima-media thickness (IMT), indices of large artery stiffness and measures of endothelium function may be used as markers of early atherosclerosis in type 1 diabetes mellitus (T1DM). The aim of the present study was to compare the indices of large artery structure and function as well as endothelial function and regenerating capacity between adolescents with T1DM and healthy control of similar age. In addition, the associations of different vascular measures with endothelial progenitor cells (EPCs), glyco-metabolic control and serum levels of advanced glycation endproducts (AGEs), soluble receptors for AGEs (sRAGE) and adiponectin were evaluated.
Sixteen uncomplicated young T1DM patients (mean age 18 ± 2 years, history of disease 11 ± 5 years, HbA1c 7.7 ± 1.1%) and 26 controls (mean age 19 ± 2 years) were studied. A radiofrequency-based ultrasound system (Esaote MyLab 70) was used to measure carotid IMT and wave speed (WS, index of local stiffness), applanation tonometry (PulsePen) was applied to obtain central pulse pressure (PP) and augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV, Complior) was used as index of aortic stiffness. Peripheral endothelium-dependent vasodilation was determined as reactive hyperemia index (RHI, EndoPAT). Circulating EPCs, glycometabolic profile, AGEs (autofluorescence method), sRAGE and adiponectin were also measured.
After adjusting for age, sex and blood pressure, T1DM adolescents had significantly higher carotid IMT (456 ± 7 vs. 395 ± 63 μm, p < 0.005), carotid WS (p < 0.005), PWV (p = 0.01), AIx (p < 0.0001) and central PP (p < 0.01) and lower EPCs (p = 0.02) as compared to controls. RHI was reduced only in diabetic patients with HbA1c ≥7.5% (p < 0.05). In the overall population, EPCs were an independent determinant of carotid IMT (together with adiponectin), while fasting plasma glucose was an independent determinant of carotid WS, AIx and central PP.
Our findings suggest that young subjects with relatively long-lasting T1DM have a generalized preclinical involvement of large artery structure and function, as well as a blunted endothelium regenerating capacity. Hyperglycemia and suboptimal chronic glycemic control seem to deteriorate the functional arterial characteristics, such as large arteries stiffness, wave reflection and peripheral endothelium-dependent vasodilation, whereas an impaired endothelium regenerating capacity and adiponectin levels seem to influence arterial structure.
PMCID: PMC3198903  PMID: 21981808
Type 1 diabetes; Endothelial progenitor cells; Endothelium-dependent vasodilation; Radiofrequency based ultrasound; Carotid intima-media thickness; Carotid stiffness; Aortic stiffness; Arterial wave reflection; Advanced glycation end-products; Adiponectin
13.  Augmentation index and aortic stiffness in bicuspid aortic valve patients with non-dilated proximal aortas 
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.
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.
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).
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.
PMCID: PMC3602003  PMID: 23496804
Bicuspid aortic valve; Arterial stiffness; Augmentation index; Pulse wave velocity
14.  The KCNMB1 E65K Variant is Associated with Reduced Central Pulse Pressure in the Community-Based Framingham Offspring Cohort 
Journal of hypertension  2009;27(1):55-60.
Genetic variants that influence large conductance calcium-activated potassium channel (BKCa) function may alter arterial function and contribute to the known heritability of arterial stiffness and blood pressure. The β1-subunit (KCNMB1) of the BKCa channel includes two coding region polymorphisms. E65K, a gain-of-function polymorphism, is predicted to enhance BKCa channel opening and vasorelaxation, whereas V110L has no known effect. We and others have reported that E65K carriers have reduced blood pressure.
To test our hypothesis that E65K has a favorable effect on arterial function, we related arterial tonometry and brachial artery phenotypes to genotypes in 1,100 Framingham Offspring Study participants with available genotypes and phenotypes (53% women; mean age 61.5±9.4 years).
The minor allele frequency was 0.10 for E65K and 0.09 for V110L; both were in Hardy-Weinberg equilibrium (χ2 p > 0.05), and haplotype analysis found R2=0.01. E65K was associated with lower augmented pressure (7.4±3.3 vs. 9.0±3.8 mm Hg, p=0.01) and central pulse pressure (47.1±7.3 vs. 50.7±7.8 mm Hg, p=0.01) in multivariable analyses. No association was noted between E65K and mean arterial pressure, carotid-femoral pulse wave velocity or brachial artery diameter, flow velocity or volume flow. V110L was not associated with tonometry or brachial measures.
A diminished augmented pressure in K-carriers suggests a reduced or delayed wave reflection and supports the hypothesis that E65K reduces arterial impedance mismatch in the arterial tree. Our findings in a middle-aged community-based cohort, if replicated, would support that E65K has a favorable effect on arterial function and pulsatile hemodynamic load.
PMCID: PMC2637763  PMID: 19050450
KCNMB1; Single Nucleotide Polymorphism; Genetics; Vascular Tonometry
Journal of hypertension  2009;27(10):2010-2021.
Arteries experience marked variations in blood pressure and flow during the cardiac cycle that can intensify during exercise, in disease, or with aging. Diverse observations increasingly suggest the importance of such pulsatility in arterial homeostasis and adaptations. We used a transverse aortic arch banding model to quantify chronic effects of increased pulsatile pressure and flow on wall morphology, composition, and biaxial mechanical properties in paired mouse arteries: the highly pulsatile right common carotid artery proximal to the band (RCCA-B) and the nearly normal left carotid artery distal to the band (LCCA-B). Increased pulsatile mechanical stimuli in RCCA-B increased wall thickness compared to LCCA-B, which correlated stronger with pulse (r*=0.632; p<0.01) than mean (r*=0.020; p=0.47) or systolic (r*=0.466; p<0.05) pressure. Similarly, inner diameter at mean pressure increased in RCCA-B and correlated slightly stronger with a normalized index of blood velocity pulsatility (r*=0.915; p≪0.001) than mean flow (r*=0.834; p<0.001). Increased wall thickness and luminal diameter in RCCA-B resulted from significant increases in cell number per cross-sectional area (p<0.001) and collagen to elastin ratio (p<0.05) as well as a moderate (1.7-fold) increase in glycosaminoglycan content, which appear to have contributed to the significant decrease (p<0.001) in the in vivo axial stretch in RCCA-B compared to LCCA-B. Changes in RCCA-B also associated with a signficant increase in monocyte chemoattractant protein-1 (p<0.05). Pulsatile pressure and flow are thus important stimuli in the observed three-dimensional arterial adaptations, and there is a need for increased attention to the roles of both axial wall stress and adventitial remodeling.
PMCID: PMC2783509  PMID: 19584753
16.  Consistency of aortic distensibility and pulse wave velocity estimates with respect to the Bramwell-Hill theoretical model: a cardiovascular magnetic resonance study 
Arterial stiffness is considered as an independent predictor of cardiovascular mortality, and is increasingly used in clinical practice. This study aimed at evaluating the consistency of the automated estimation of regional and local aortic stiffness indices from cardiovascular magnetic resonance (CMR) data.
Forty-six healthy subjects underwent carotid-femoral pulse wave velocity measurements (CF_PWV) by applanation tonometry and CMR with steady-state free-precession and phase contrast acquisitions at the level of the aortic arch. These data were used for the automated evaluation of the aortic arch pulse wave velocity (Arch_PWV), and the ascending aorta distensibility (AA_Distc, AA_Distb), which were estimated from ascending aorta strain (AA_Strain) combined with either carotid or brachial pulse pressure. The local ascending aorta pulse wave velocity AA_PWVc and AA_PWVb were estimated respectively from these carotid and brachial derived distensibility indices according to the Bramwell-Hill theoretical model, and were compared with the Arch_PWV. In addition, a reproducibility analysis of AA_PWV measurement and its comparison with the standard CF_PWV was performed. Characterization according to the Bramwell-Hill equation resulted in good correlations between Arch_PWV and both local distensibility indices AA_Distc (r = 0.71, p < 0.001) and AA_Distb (r = 0.60, p < 0.001); and between Arch_PWV and both theoretical local indices AA_PWVc (r = 0.78, p < 0.001) and AA_PWVb (r = 0.78, p < 0.001). Furthermore, the Arch_PWV was well related to CF_PWV (r = 0.69, p < 0.001) and its estimation was highly reproducible (inter-operator variability: 7.1%).
The present work confirmed the consistency and robustness of the regional index Arch_PWV and the local indices AA_Distc and AA_Distb according to the theoretical model, as well as to the well established measurement of CF_PWV, demonstrating the relevance of the regional and local CMR indices.
PMCID: PMC3038969  PMID: 21272312
17.  Circulating Vascular Growth Factors and Central Hemodynamic Load in the Community 
Hypertension  2012;59(4):773-779.
Mean and pulsatile components of hemodynamic load are related to cardiovascular disease. Vascular growth factors play a fundamental role in vascular remodeling. The links between growth factors and hemodynamic load components are not well described.
In 3496 participants from the Framingham Heart Study Third Generation cohort (mean age 40±9 years, 52% women) we related 4 tonometry derived measures of central arterial load (carotid femoral pulse wave velocity and forward pressure wave, mean arterial pressure, and the global reflection coefficient) to circulating concentrations of angiopoietin 2, its soluble receptor; vascular endothelial growth factor, its soluble receptor; hepatocyte growth factor; insulin-like growth factor-1, and its binding protein3. Using multivariable linear regression models, adjusted for standard cardiovascular risk factors, serum insulin-like growth factor-1concentrations were negatively associated with carotid femoral pulse wave velocity, mean arterial pressure, and reflection coefficient (p≤0.01 for all), whereas serum vascular endothelial growth factor levels were positively associated with carotid femoral pulse wave velocity and mean arterial pressure (p≤0.02). Serum insulin-like growth factor binding protein −3 and soluble angiopoietin-2 receptor levels were positively related to mean arterial pressure and to forward pressure wave, respectively (p<0.05).
In our cross-sectional study of a large community-based sample, circulating vascular growth factor levels were related to measures of mean and pulsatile hemodynamic load in a pattern consistent with the known physiological effects of insulin-like growth factor-1 and vascular endothelial growth factor.
PMCID: PMC3336212  PMID: 22371357
Vasculature; Growth substances; angiogenesis; arteriosclerosis; elasticity
18.  Arterial stiffness 
JRSM Cardiovascular Disease  2012;1(6):cvd.2012.012024.
Measurements of biomechanical properties of arteries have become an important surrogate outcome used in epidemiological and interventional cardiovascular research. Structural and functional differences of vessels in the arterial tree result in a dampening of pulsatility and smoothing of blood flow as it progresses to capillary level. A loss of arterial elastic properties results a range of linked pathophysiological changes within the circulation including increased pulse pressure, left ventricular hypertrophy, subendocardial ischaemia, vessel endothelial dysfunction and cardiac fibrosis. With increased arterial stiffness, the microvasculature of brain and kidneys are exposed to wider pressure fluctuations and may lead to increased risk of stroke and renal failure. Stiffening of the aorta, as measured by the gold-standard technique of aortic Pulse Wave Velocity (aPWV), is independently associated with adverse cardiovascular outcomes across many different patient groups and in the general population. Therefore, use of aPWV has been proposed for early detection of vascular damage and individual cardiovascular risk evaluation and it seems certain that measurement of arterial stiffness will become increasingly important in future clinical care. In this review we will consider some of the pathophysiological processes that result from arterial stiffening, how it is measured and factors that may drive it as well as potential avenues for therapy. In the face of an ageing population where mortality from atheromatous cardiovascular disease is falling, pathology associated with arterial stiffening will assume ever greater importance. Therefore, understanding these concepts for all clinicians involved in care of patients with cardiovascular disease will become vital.
PMCID: PMC3738364  PMID: 24175072
19.  Relationship between carotid intima‐media thickness and arterial stiffness in children after Kawasaki disease 
Evidence of premature atherosclerosis and systemic arterial stiffening in patients after Kawasaki disease is accumulating.
To test the hypothesis that carotid intima‐media thickness (IMT), a surrogate marker of atherosclerosis, is associated with systemic arterial stiffness in children after Kawasaki disease.
A cohort of 72 patients was studied, comprising 26 patients with Kawasaki disease and coronary aneurysms (group I), 24 patients with Kawasaki disease and normal coronary arteries (group II) and 22 healthy age‐matched children (group III). The carotid IMT, carotid artery stiffness index, brachioradial pulse wave velocity (PWV), fasting total cholesterol, high‐density lipoprotein (HDL) cholesterol and low‐density lipoprotein (LDL) cholesterol were determined and compared among the three groups.
The carotid IMT was related to indices of arterial stiffness, and significant determinants of carotid IMT were identified by multivariate analysis. The mean (standard deviation (SD)) carotid IMT of both group I (0.41 (0.04) mm) and group II (0.39 (0.04) mm) was significantly greater than that of group III (0.36 (0.04) mm; p<0.001 and p = 0.008, respectively). For the entire cohort, carotid IMT correlated positively with LDL cholesterol (r = 0.31, p = 0.009), carotid artery stiffness index (r = 0.40, p = 0.001) and brachioradial PWV (r = 0.28, p = 0.016), but not with age, body mass index, systemic blood pressure, and HDL and total cholesterol. Multiple linear regression analysis identified carotid artery stiffness index (β = 0.25, p = 0.028) and subject grouping (β = −0.39, p = 0.001; model R2 = 0.29) as significant correlates of carotid IMT.
The increased carotid IMT in children after Kawasaki disease is associated with systemic arterial stiffening.
PMCID: PMC2083125  PMID: 16820386
20.  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.
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).
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.
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).
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.
PMCID: PMC3024367  PMID: 21216862
21.  High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells 
Annals of biomedical engineering  2009;37(6):1082-1092.
Arterial stiffening or reduced compliance of proximal pulmonary vessels has been shown to be an important predictor of outcomes in patients with pulmonary hypertension. Though current evidence indicates that arterial stiffening modulates flow pulsatility in downstream vessels and is likely related to microvascular damage in organs without extensive distributing arteries, the cellular mechanisms underlying this relationship in the pulmonary circulation are unexplored. Thus, this study was designed to examine the responses of the microvascular pulmonary endothelium to changes in flow pulsatility.
A flow system was developed to reproduce arterial-like pulse flow waves with the capability of modulating flow pulsatility through regulation of upstream compliance. Pulmonary microvascular endothelial cells (PMVECs) were exposed to steady flow and pulse flow waves of varied pulsatility with varied hemodynamic energy (low: pulsatility index or PI=1.0; medium: PI=1.7; high: PI=2.6) at flow frequency of 1Hz or 2Hz for different durations (1 and 6 hours). The mean flow rates in all the conditions were kept the same with shear stress at 14 dynes/cm2. Gene expression was evaluated by analyzing mRNA levels of adhesion molecules (ICAM-1, E-selectin), chemokine (MCP-1) and growth factor/receptor (VEGF, Flt-1) in PMVECs. Functional changes were observed with monocyte adhesion assay.
1) Compared to either steady flow or low pulsatility flow, increased flow pulsatility for 1hr induced significant increases in mRNA levels of ICAM-1, E-selectin and MCP-1. 2) Sustained high pulsatility flow perfusion induced increases in ICAM, E-selectin, MCP-1, VEGF and its receptor Flt-1 expression. 3) Flow pulsatility effects on PMVECs were frequency-dependent with greater responses at 2Hz and likely associated with the hemodynamic energy level. 4) Pulse flow waves with high flow pulsatility at 2Hz induced leukocyte adhesion and recruitment to PMVECs.
Increased upstream pulmonary arterial stiffness increases flow pulsatility in distal arteries and induces inflammatory gene expression, leukocyte adhesion and cell proliferation in the downstream PMVECs.
PMCID: PMC3057109  PMID: 19340571
22.  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
23.  Arterial stiffness, central hemodynamics, and cardiovascular risk in hypertension 
This review summarizes several scientific contributions at the recent Satellite Symposium of the European Society of Hypertension, held in Milan, Italy. Arterial stiffening and its hemodynamic consequences can be easily and reliably measured using a range of noninvasive techniques. However, like blood pressure (BP) measurements, arterial stiffness should be measured carefully under standardized patient conditions. Carotid-femoral pulse wave velocity has been proposed as the gold standard for arterial stiffness measurement and is a well recognized predictor of adverse cardiovascular outcome. Systolic BP and pulse pressure in the ascending aorta may be lower than pressures measured in the upper limb, especially in young individuals. A number of studies suggest closer correlation of end-organ damage with central BP than with peripheral BP, and central BP may provide additional prognostic information regarding cardiovascular risk. Moreover, BP-lowering drugs can have differential effects on central aortic pressures and hemodynamics compared with brachial BP. This may explain the greater beneficial effect provided by newer antihypertensive drugs beyond peripheral BP reduction. Although many methodological problems still hinder the wide clinical application of parameters of arterial stiffness, these will likely contribute to cardiovascular assessment and management in future clinical practice. Each of the abovementioned parameters reflects a different characteristic of the atherosclerotic process, involving functional and/or morphological changes in the vessel wall. Therefore, acquiring simultaneous measurements of different parameters of vascular function and structure could theoretically enhance the power to improve risk stratification. Continuous technological effort is necessary to refine our methods of investigation in order to detect early arterial abnormalities. Arterial stiffness and its consequences represent the great challenge of the twenty-first century for affluent countries, and “de-stiffening” will be the goal of the next decades.
PMCID: PMC3237102  PMID: 22174583
arterial elasticity; stiffness; compliance; central blood pressure; pulse wave velocity
24.  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
25.  Aortic stiffness and calcification in men in a population-based international study 
Atherosclerosis  2012;222(2):473-477.
Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men.
We examined the association in 906 men aged 40–49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography.
Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1–100 (n=411), 101–300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/second) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), p for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group.
The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40’s.
PMCID: PMC3361615  PMID: 22537531
aortic stiffness; aortic calcification; international multi-ethnic study

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