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1.  Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study 
Hypertension  2014;64(2):259-265.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
doi:10.1161/HYPERTENSIONAHA.114.03371
PMCID: PMC4184952  PMID: 24866142
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
2.  Arterial Stiffness and Hypertension: Chicken or Egg? 
Hypertension  2014;64(2):210-214.
doi:10.1161/HYPERTENSIONAHA.114.03449
PMCID: PMC4185002  PMID: 24799614
3.  Recent Advances in Hypertension: Arterial Stiffness and Hypertension 
Hypertension  2014;64(1):13-18.
Over the past decade, increased aortic stiffness has emerged as an important risk factor for target organ damage and cardiovascular disease events. Aortic stiffness can be assessed as pulse wave velocity (PWV), which is a measure of aortic wall stiffness, and pulse pressure (PP), which is affected by wall stiffness and the interaction between flow and diameter. Because these stiffness measures have different sensitivities to geometry and other factors, they are only moderately correlated and play a complementary role in risk prediction. Arterial stiffness has long been viewed as a complication of hypertension that integrates long-term adverse effects of elevated blood pressure and other risk factors. However, PWV is only modestly correlated with risk factors other than age and blood pressure, which likely explains the ability of PWV to add to standard risk prediction models and reclassify risk in a clinically relevant manner. Recent studies have demonstrated that stiffness can antedate and contribute to the pathogenesis of hypertension, raising the possibility that early assessment of arterial stiffness may provide insight into complications including hypertension that develop years later. The role that stiffness plays in the pathogenesis of hypertension and cardiovascular disease has sparked considerable interest in defining basic mechanisms that stiffen the aortic wall, increase PP and contribute to target organ damage with a hope that elucidation of these mechanisms will allow for development of more effective treatments.
doi:10.1161/HYPERTENSIONAHA.114.00921
PMCID: PMC4063409  PMID: 24752432
4.  Longitudinal and Circumferential Strain of the Proximal Aorta 
Background
Accurate assessment of mechanical properties of the proximal aorta is a requisite first step for elucidating the pathophysiology of isolated systolic hypertension. During systole, substantial proximal aortic axial displacement produces longitudinal strain, which we hypothesize causes variable underestimation of ascending aortic circumferential strain compared to values in the longitudinally constrained descending aorta.
Methods and Results
To assess effects of longitudinal strain, we performed magnetic resonance imaging in 375 participants (72 to 94 years old, 204 women) in the Age, Gene/Environment Susceptibility‐Reykjavik Study and measured aortic circumferential and longitudinal strain. Circumferential ascending aortic area strain uncorrected for longitudinal strain was comparable in women and men (mean [95% CI], 8.3 [7.8, 8.9] versus 7.9 [7.4, 8.5]%, respectively, P=0.3). However, longitudinal strain was greater in women (8.5±2.5 versus 7.0±2.5%, P<0.001), resulting in greater longitudinally corrected circumferential ascending aortic strain (14.4 [13.6, 15.2] versus 13.0 [12.4, 13.7]%, P=0.010). Observed circumferential descending aortic strain, which did not require correction (women: 14.0 [13.2, 14.8], men: 12.4 [11.6, 13.2]%, P=0.005), was larger than uncorrected (P<0.001), but comparable to longitudinally corrected (P=0.12) circumferential ascending aortic strain. Carotid‐femoral pulse wave velocity did not correlate with uncorrected ascending aortic strain (R=−0.04, P=0.5), but was inversely related to longitudinally corrected ascending and observed descending aortic strain (R=−0.15, P=0.004; R=−0.36, P<0.001, respectively). Longitudinal strain was also inversely related to carotid‐femoral pulse wave velocity and other risk factors for higher aortic stiffness including treated hypertension.
Conclusions
Longitudinal strain creates substantial and variable errors in circumferential ascending aortic area strain measurements, particularly in women, and should be considered to avoid misclassification of ascending aortic stiffness.
doi:10.1161/JAHA.114.001536
PMCID: PMC4338743  PMID: 25523153
aortic stiffness; ascending aorta; carotid‐femoral pulse wave velocity; circumferential strain; longitudinal strain
5.  Aortic Stiffness, Blood Pressure Progression, and Incident Hypertension 
Context
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.
Objective
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.
Results
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).
Conclusion
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.
doi:10.1001/2012.jama.10503
PMCID: PMC3594687  PMID: 22948697
6.  Common Genetic Variation in the 3-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium 
Mitchell, Gary F. | Verwoert, Germaine C. | Tarasov, Kirill V. | Isaacs, Aaron | Smith, Albert V. | Yasmin | Rietzschel, Ernst R. | Tanaka, Toshiko | Liu, Yongmei | Parsa, Afshin | Najjar, Samer S. | O’Shaughnessy, Kevin M. | Sigurdsson, Sigurdur | De Buyzere, Marc L. | Larson, Martin G. | Sie, Mark P.S. | Andrews, Jeanette S. | Post, Wendy S. | Mattace-Raso, Francesco U.S. | McEniery, Carmel M. | Eiriksdottir, Gudny | Segers, Patrick | Vasan, Ramachandran S. | van Rijn, Marie Josee E. | Howard, Timothy D. | McArdle, Patrick F. | Dehghan, Abbas | Jewell, Elizabeth | Newhouse, Stephen J. | Bekaert, Sofie | Hamburg, Naomi M. | Newman, Anne B. | Hofman, Albert | Scuteri, Angelo | De Bacquer, Dirk | Ikram, Mohammad Arfan | Psaty, Bruce | Fuchsberger, Christian | Olden, Matthias | Wain, Louise V. | Elliott, Paul | Smith, Nicholas L. | Felix, Janine F. | Erdmann, Jeanette | Vita, Joseph A. | Sutton-Tyrrell, Kim | Sijbrands, Eric J.G. | Sanna, Serena | Launer, Lenore J. | De Meyer, Tim | Johnson, Andrew D. | Schut, Anna F.C. | Herrington, David M. | Rivadeneira, Fernando | Uda, Manuela | Wilkinson, Ian B. | Aspelund, Thor | Gillebert, Thierry C. | Van Bortel, Luc | Benjamin, Emelia J. | Oostra, Ben A. | Ding, Jingzhong | Gibson, Quince | Uitterlinden, André G. | Abecasis, Gonçalo R. | Cockcroft, John R. | Gudnason, Vilmundur | De Backer, Guy G. | Ferrucci, Luigi | Harris, Tamara B. | Shuldiner, Alan R. | van Duijn, Cornelia M. | Levy, Daniel | Lakatta, Edward G. | Witteman, Jacqueline C.M.
Background
Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
Methods and Results
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20,634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5,306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, beta=−0.075±0.012 SD/allele, P = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). Combined results for rs7152623 from 11 cohorts gave beta=−0.076±0.010 SD/allele, P=3.1x10−15. The association persisted when adjusted for mean arterial pressure (beta=−0.060±0.009 SD/allele, P = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) and older (9 cohorts, N=12,026, beta=−0.061±0.014 SD/allele, P=9.4x10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004).
Conclusions
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
doi:10.1161/CIRCGENETICS.111.959817
PMCID: PMC3288392  PMID: 22068335
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
7.  Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility – Reykjavik Study 
Brain  2011;134(11):3398-3407.
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid–femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility – Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69–93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta–carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta–carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid–femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62–1.71 per standard deviation, P<0.002). Carotid–femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid–femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
doi:10.1093/brain/awr253
PMCID: PMC3212721  PMID: 22075523
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
8.  Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum: Noninvasive Evaluation in the Framingham Heart Study 
Circulation  2010;122(14):1379-1386.
Background
Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial.
Methods and Results
We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53% women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: in younger participants, pulse pressure was lower and wave reflection higher with advancing age whereas in older participants, pulse pressure was higher and wave reflection lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80% (central) and 66% (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90% and 84% in the older participants (≥50 years, all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered.
Conclusions
Higher pulse pressure at any age and higher pulse pressure with advancing age is predominantly associated with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.
doi:10.1161/CIRCULATIONAHA.109.914507
PMCID: PMC2981604  PMID: 20855656
aorta; arterial stiffness; pulse wave velocity; blood pressure; pulse pressure; cardiovascular disease
9.  Relation of Long-term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia 
The American journal of cardiology  2014;113(12):2057-2063.
Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may in part explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function have not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow mediated dilation % and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 (53%) women, mean age 49±14 years). Spatially resolved average PM2.5 was associated with lower flow mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m3) was associated with −0.16% (95%CI: −0.27%, −0.05%) lower FMD% and −0.72 (95%CI: −1.38, −0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow mediated dilation %. Compared to living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% confidence interval (CI): −0.58%, −0.06%), but results for hyperemic flow velocity had wide confidence intervals −0.68 cm/s (95%CI: −2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults.
doi:10.1016/j.amjcard.2014.03.048
PMCID: PMC4066389  PMID: 24793676
Air Pollution; Brachial Artery; Microvessels; Endothelium; Vascular
10.  Arterial stiffness and cardiovascular events: The Framingham Heart Study 
Circulation  2010;121(4):505-511.
Background
Various measures of arterial stiffness and wave reflection have been proposed as cardiovascular risk markers. Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis in the community.
Methods and Results
We used proportional hazards models to analyze first-onset major cardiovascular disease (CVD) events (myocardial infarction, unstable angina, heart failure or stroke) in relation to arterial stiffness (pulse wave velocity, PWV), wave reflection (augmentation index, carotid-brachial pressure amplification) and central pulse pressure in 2232 participants (mean age 63 years, 58% women) in the Framingham Heart Study. During median follow-up of 7.8 (range 0.2 to 8.9) years, 151 of 2232 participants (6.8%) had an event. In multivariable models adjusting for age, sex, systolic blood pressure, use of antihypertensive therapy, total and HDL cholesterol concentrations, smoking and presence of diabetes, higher aortic PWV was associated with a 48% increase in CVD risk (95% CI, 1.16 to 1.91 per SD, P=0.002). After adding PWV to a standard risk factor model, integrated discrimination improvement was 0.7% (95% CI, 0.05 to 1.3%, P<0.05). In contrast, augmentation index, central pulse pressure and pulse pressure amplification were not related to CVD outcomes in multivariable models.
Conclusions
Higher aortic stiffness assessed by PWV is associated with increased risk for a first cardiovascular event. Aortic PWV improves risk prediction when added to standard risk factors and may represent a valuable biomarker of CVD risk in the community.
doi:10.1161/CIRCULATIONAHA.109.886655
PMCID: PMC2836717  PMID: 20083680
aorta; arterial stiffness; pulse wave velocity; cardiovascular disease; prognosis
11.  Central aortic pulsatile hemodynamics in obese premenopausal women 
Obesity is a known risk factor for cardiovascular disease (CVD) but the mechanism by which obesity contributes to cardiovascular risk is not well understood. Arterial stiffness is a CVD risk factor associated with obesity. We studied 16 obese body mass index (BMI > 30) and 10 lean (BMI < 25) healthy premenopausal women. We measured fasting glucose, insulin, and lipids, blood pressure, and arterial tonometry to assess arterial stiffness. Obese women had higher glucose, insulin, total cholesterol and triglyceride levels, blood pressures, cardiac output, and peak flow. Characteristic impedance was lower (146 ± 31 [(dyne · s) · cm−5] vs. 187 ± 48 [(dyne · s) · cm−5]; P = .01), aortic diameter was greater (2.54 ± 0.20 cm vs. 2.29 ± 0.21 cm; P < .01), and peripheral pulse pressure was similar in obese compared with lean women. Obesity in premenopausal women is associated with increased cardiac output and peak aortic flow. Increased aortic diameter in obese women was associated with reduced characteristic impedance, potentially preventing an increase in peripheral pulse pressure despite elevated flow, which suggests proximal aortic remodeling. When aortic remodeling and compensation for increased hemodynamic demands are limited by environmental or genetic interference, hypertension or CVD may result.
doi:10.1016/j.jash.2007.06.004
PMCID: PMC4428567  PMID: 20409864
Arterial stiffness; aortic compliance; tonometry; body mass index
12.  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.
doi:10.1016/j.artres.2009.02.002
PMCID: PMC2705910  PMID: 20161241
Arterial stiffness; aorta; pulse pressure; pulse wave velocity; wave reflection
13.  Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects 
Objectives
To determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular (CVD) events beyond conventional risk factors.
Background
Several studies have shown that aPWV may be a useful risk factor for predicting CVD but have been underpowered to examine whether this is true for different sub-groups.
Methods
We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with cardiovascular outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects.
Results
Of 17,635 participants, 1,785 (10%) had a cardiovascular (CVD) event. The pooled age- and sex-adjusted hazard ratio [95% CI] per SD change in loge aPWV was 1.35 [1.22, 1.50, p<0.001] for coronary heart disease (CHD), 1.54 [1.34, 1.78, p<0.001] for stroke, and 1.45 [1.30, 1.61, p<0.001) for CVD. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age (1.89, 1.77, 1.36 and 1.23 for ≤50, 51–60, 61–70 and >70 years respectively, pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor: CHD 1.23, [1.11, 1.35 p<0.001]; stroke 1.28, [1.16, 1.42 p<0.001]; cardiovascular events 1.30 [1.18, 1.43, p<0.001]. Reclassification indices showed the addition of aPWV improved risk prediction (13% for 10 year CVD risk for intermediate risk) for some sub-groups.
Conclusions
Consideration of aPWV improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors. aPWV may enable better identification of high-risk populations who may benefit from more aggressive cardiovascular risk factor management.
doi:10.1016/j.jacc.2013.09.063
PMCID: PMC4401072  PMID: 24239664
pulse wave velocity; meta-analysis; cardiovascular disease; prognostic factor
14.  A multi-marker approach to evaluate correlates of vascular stiffness: The Framingham Heart Study 
Circulation  2008;119(1):37-43.
Background
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).
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.108.816108
PMCID: PMC2722113  PMID: 19103986
arterial stiffness; renin-angiontensin-aldosterone system; C-reactive protein; plasminogen activator inhibitor; biomarker
15.  Physical Activity Measured by Accelerometry and its Associations With Cardiac Structure and Vascular Function in Young and Middle‐Aged Adults 
Background
Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated.
Measures and Results
We related objective measures of moderate‐ to vigorous‐intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P=0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m2]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes.
Conclusions
In our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.
doi:10.1161/JAHA.114.001528
PMCID: PMC4392434  PMID: 25792127
echocardiography; epidemiology; physical activity; vascular measures
16.  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.
doi:10.1161/HYPERTENSIONAHA.106.085738
PMCID: PMC2553625  PMID: 17452505
angiotensin-converting enzyme; coronary artery disease; randomized clinical trial; arterial stiffness; pulse wave velocity
17.  Left Ventricular Responses to Acute Changes in Late Systolic Pressure Augmentation in Older Adults 
American Journal of Hypertension  2013;26(7):866-871.
BACKGROUND
Changes in the cardiovascular system with age may predispose older persons to development of heart failure with preserved ejection fraction. Vascular stiffening, aortic pressure augmentation, and ventricular–vascular coupling have been implicated. We explored the potential for acute reductions in late systolic pressure augmentation to impact left ventricular relaxation in older persons without heart failure.
METHODS
Sixteen older persons free of known cardiovascular disease with the exception of hypertension had noninvasive tonometry and cardiac ultrasound to evaluate central augmentation index (AI) and diastolic function at baseline and after randomized, blinded administration of intravenous B-type natriuretic peptide (BNP) and hydralazine in a crossover design.
RESULTS
AI was significantly reduced after BNP (11.4±8.9 to −0.2±14.7%; P = 0.02) and nonsignificantly reduced after hydralazine (14.7±8.4% to 11.5±8.8%; P = 0.39). With decreased AI during BNP, a trend toward worsened myocardial relaxation by tissue Doppler imaging occurred (E’ velocity pre- and post-BNP: 10.0±2.5 and 8.8±2.0cm/s, respectively; P = 0.06). There was a significant fall in stroke volume with BNP (68.5±18.3 to 60.9±18.1ml; P = 0.02), suggesting that changes in preload overwhelmed effects of afterload reduction on ventricular performance. With hydralazine, neither relaxation nor stroke volume changed.
CONCLUSIONS
Acute changes in late systolic aortic pressure augmentation do not necessarily lead to improved systolic or diastolic function in older people. Preload may be a more important determinant of cardiac performance than afterload in older people with compensated ventricular function. The potential for changes in preload to impair rather than enhance left ventricular systolic and diastolic function in older people warrants further study.
CLINICAL TRIALS REGISTRATION
This study is registered at clinicaltrials.gov as NCT00204984.
doi:10.1093/ajh/hpt043
PMCID: PMC3731820  PMID: 23537892
arterial stiffness; arterial wave reflection; blood pressure; cardiac performance; hypertension.
18.  Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium 
Background
Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits.
Study Design
We conducted two targeted analyses. First, we examined whether known single nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5 × 10-4 (0.05/325 tests).
Setting & Participants
Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395) and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium.
Predictor
We used 19 kidney SNPs and 64 vascular SNPs.
Outcomes & Measurements
Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria.
Results
In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were non-significant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (p=9.3E-10) and diastolic (p=1.6E-14) blood pressure and coronary artery disease (p=2.2E-6), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were non-significant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (p=1.06E-07 and p=7.05E-08).
Limitations
Combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations.
Conclusions
Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
doi:10.1053/j.ajkd.2012.12.024
PMCID: PMC3660426  PMID: 23474010
19.  Temporal Trends in Pulse Pressure and Mean Arterial Pressure During the Rise of Pediatric Obesity in US Children 
Background
Somatic growth in childhood is accompanied by substantial remodeling of the aorta. Obesity is associated with increased aortic stiffness and flow and may interfere with aortic remodeling during growth. Wide pulse pressure (PP) indicates mismatch between aortic impedance and pulsatile flow and increases risk for future systolic hypertension and cardiovascular disease (CVD). We hypothesized that the rise of pediatric obesity would be associated with a temporal trend to higher PP.
Methods and Results
We analyzed demographic, anthropometric, and blood pressure (BP) data for 8‐ to 17‐year‐old children (N=16 457) from the cross‐sectional National Health and Nutrition Examination Surveys (NHANES) for 1976 through 2008. Multivariable adjusted survey regression was used to examine temporal trends in PP and mean arterial pressure (MAP) and the relation to obesity. Across this period, unadjusted PP was higher (0.29 mm Hg/y, 95% CI 0.26 to 0.33 mm Hg/y; P<0.0001), while MAP was lower (−0.24 mm Hg/y, 95% CI −0.27 to −0.20 mm Hg/y; P<0.0001) across examinations. Adjusting for body mass index partially attenuated the temporal trend for PP by 32% (P<0.0001). Obesity amplified the relation between taller height and higher PP (from 0.23 [95% CI 0.19 to 0.28] to 0.27 [95% CI 0.21 to 0.34] mm Hg/cm height in boys and from 0.08 [95% CI 0.04 to 0.13] to 0.22 [95% CI 0.13 to 0.31] mm Hg/cm height in girls; P<0.01 for both).
Conclusions
PP has increased during the rise of pediatric obesity. Higher PP may indicate mismatch between aortic diameter, wall stiffness, and flow in obese children during a period of rapid somatic growth when the aorta is already under considerable remodeling stress.
doi:10.1161/JAHA.113.000725
PMCID: PMC4309055  PMID: 24811611
blood pressure; child; NHANES; pulse pressure
20.  Aortic Root Remodeling and Risk of Heart Failure in the Framingham Heart Study 
JACC. Heart failure  2012;1(1):79-83.
Objectives
The aim of this study was to investigate the association between aortic root remodeling and incident heart failure (HF).
Background
Age-associated increases in aortic root diameter (AoD) might be associated with arterial stiffening, afterload changes, cardiac remodeling, and the development of HF.
Methods
The study sample consisted of participants of the Framingham Heart Study Original and Offspring cohorts who underwent serial echocardiographic measurements of AoD and continuous surveillance for new-onset HF. The AoD was measured at baseline, and the change in AoD between 8-year examination cycles was calculated. Pooled repeated observations (total 13,605 person-observations) in multivariable Cox regression analyses were used to relate baseline AoD and change in AoD to the incidence of HF on follow-up. Models were adjusted for known HF risk factors (age, sex, body mass index, blood pressure, hypertension treatment, diabetes, smoking, prior myocardial infarction, and valve disease).
Results
With adjustment for clinical risk factors, the risk of incident HF increased with greater AoD at baseline (hazard ratio: 1.19/1 SD; 95% confidence interval: 1.07 to 1.33) as well as increases in AoD over 8 years (hazard ratio: 1.20/1 SD; 95% confidence interval: 1.04 to 1.38). The AoD correlated with left ventricular mass (r = 0.50; p < 0.001). After adjustment for left ventricular mass in addition to clinical risk factors, the association of AoD with incident HF was rendered nonsignificant.
Conclusions
Aortic root remodeling is associated with future risk of HF among middle-aged and older adults in the community, potentially because it reflects parallel ventricular-vascular remodeling in those with an enlarged aortic root. Additional studies are warranted to confirm our findings.
doi:10.1016/j.jchf.2012.10.003
PMCID: PMC3755769  PMID: 23998002
aortic root; general community; heart failure; remodeling; risk
21.  Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function 
Obesity (Silver Spring, Md.)  2013;21(7):1496-1503.
Objective
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Results
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Conclusion
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
doi:10.1002/oby.20166
PMCID: PMC3742564  PMID: 23754461
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
22.  Nucleotide Excision DNA Repair is Associated with Age-Related Vascular Dysfunction 
Circulation  2012;126(4):468-478.
Background
Vascular dysfunction in atherosclerosis and diabetes, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction.
Methods and Results
In mice with genomic instability due to the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1d/− and XpdTTD mice), we explored age-dependent vascular function as compared to wild-type mice. Ercc1d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness and elevated blood pressure at very young age. The vasodilator dysfunction was due to decreased endothelial eNOS levels as well as impaired smooth muscle cell function, which involved phosphodiesterase (PDE) activity. Similar to Ercc1d/− mice, age-related endothelium-dependent vasodilator dysfunction in XpdTTD animals was increased. To investigate the implications for human vascular disease, we explored associations between single nucleotide polymorphisms (SNPs) of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium, and found a significant association of a SNP (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.
Conclusions
Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans, but with an accelerated progression, as compared to wild type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
doi:10.1161/CIRCULATIONAHA.112.104380
PMCID: PMC3430727  PMID: 22705887
aging; cardiovascular disease; endothelial dysfunction; nitric oxide synthase; vasodilation
23.  Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study 
Circulation  2012;125(23):2836-2843.
Background
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.
Methods and Results
Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry and brachial artery flow-mediated dilation (FMD) testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol (HDL) ratio (p≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (p=0.02), central pulse pressure (p<0.0001), mean arterial pressure (p=0.04) and baseline brachial flow (p=0.002) were positively associated with exercise systolic BP, whereas FMD was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (p<0.0001) whereas mean arterial pressure was positively related (p<0.0001).
Conclusions
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
doi:10.1161/CIRCULATIONAHA.111.063933
PMCID: PMC3636551  PMID: 22572915
blood pressure; endothelial function; exercise; vascular function; vascular stiffness
24.  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.
doi:10.1161/HYPERTENSIONAHA.111.179242
PMCID: PMC3336212  PMID: 22371357
Vasculature; Growth substances; angiogenesis; arteriosclerosis; elasticity
25.  Circulating Angiogenic Cell Populations, Vascular Function, and Arterial Stiffness 
Atherosclerosis  2011;220(1):145-150.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.atherosclerosis.2011.10.015
PMCID: PMC3277804  PMID: 22093724
angiogenesis; vascular function; risk factors; endothelium; epidemiology

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