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).
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.
blood pressure; endothelial function; exercise; vascular function; vascular stiffness
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.
Vasculature; Growth substances; angiogenesis; arteriosclerosis; elasticity
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.
Arterial stiffness; aorta; pulse pressure; pulse wave velocity; wave reflection
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  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.
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).
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.
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.
We studied 1,948 Framingham Heart Study participants (mean age, 66±9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.
In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β=−0.052±0.011, P<0.001 and β=−0.030±0.011, P=0.008, respectively) and with higher carotid-brachial pulse wave velocity (β=0.144±0.043, P=0.001 and β=0.112±0.043, P=0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β=−0.229±0.094, P=0.015) However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.
In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.
angiogenesis; vascular function; risk factors; endothelium; epidemiology
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.
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed non-invasively in the brachial and digital arteries remains incompletely defined. In the Framingham Offspring, Third Generation and Omni cohorts, we measured flow-mediated dilation (FMD) (n=7031, age 48±13 years, 19-88 years, 54% women) and peripheral arterial tonometry (PAT) ratio (n=4352, 55±16 years, 19-90 years, 51% women). Abnormal vascular function for each measure was defined by the sex-specific 5th percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index (BMI) was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/HDL cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratio compared with men, using sex-specific reference values women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n=1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels.
vascular function; epidemiology; risk factors; cohort study; endothelium
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.
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.
aorta; arterial stiffness; pulse wave velocity; blood pressure; pulse pressure; cardiovascular disease
Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course.
Methods and Results
We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid-to-late adulthood, and to determine its short-term (4 years, n=6099 observations in 3506 individuals) and long-term (16 years, n=14628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P≤0.01). Aortic root diameter increased with age in both men and women, but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89mm in men; 0.68mm in women) adjusting for body size and blood pressure. A 5-kg/m2 increase in body mass index was associated with a larger aortic root (by 0.78mm in men; 0.51mm in women), adjusting for age and blood pressure. Each 10-mmHg increase in pulse pressure was related to a smaller aortic root (by 0.19mm in men; 0.08mm in women), adjusting for age and body size.
These longitudinal community-based data show that aortic root remodeling occurs over mid-to-late adulthood and is principally associated with age, sex, body size and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study.
Aorta; Epidemiology; Echocardiography; Remodeling; Risk factors
Experimental studies suggest that endothelial growth factors play an important role in angiogenesis and vascular remodeling. The clinical and genetic correlates of circulating angiopoietin-2 (Ang-2) and its soluble receptor/regulator Tie-2 (sTie-2) have not been determined in a community-based sample.
Methods and Results
Serum Ang-2 and sTie-2 were assayed in 3778 Framingham Third Generation cohort participants (mean age 40±9 years, 53% women). Clinical correlates and heritability of both biomarkers were assessed using generalized estimating equations and variance-component analyses. Ang-2 levels were higher and sTie-2 levels lower in women as compared to men. Ang-2 was positively related to age, smoking, systolic blood pressure (BP), hypertension treatment and diabetes (p<0.05 for all) but was inversely associated with total cholesterol and diastolic BP (p<0.0001 for both). Soluble Tie-2 was positively associated with body mass index, diabetes and triglycerides, but inversely related to age, alcohol consumption and glomerular filtration rate (p<0.05 for all). Both Ang-2 and sTie-2 were higher in participants with metabolic syndrome (p<0.005), with stronger associations of Ang-2 with BP traits and of sTie-2 with obesity-dyslipidemia components. Heritability estimates for Ang-2 and sTie-2 were 27% and 56%, respectively (p<0.0001). A region on chromosome 9 was significantly linked to circulating sTie-2 levels (LOD score 8.31).
Circulating levels of Ang-2 and sTie-2 are heritable traits that are associated with cardiovascular (CVD) risk factors including the metabolic syndrome. These observations are consistent with the notion that angiogenesis and vascular remodeling are in part determined by genetic influences, and associated with metabolic risk factors.
Angiopoietins; vascular remodeling; heritability; metabolic syndrome; CVD risk factors
Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous abdominal tissue (SAT) is more related to endothelium-dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n=3020, mean age 50 years, 47% women) We used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography-assessed VAT and SAT, body mass index (BMI) and waist circumference (WC), with brachial artery measures. In multivariable-adjusted models, BMI, WC, VAT and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all p<0.001), but not hyperemic mean flow velocity. In multivariable-adjusted models, BMI (p=0.002), WC (p=0.001) and VAT (p=0.01), but not SAT (p=0.24) were inversely associated with FMD%. However there was little incremental increase in the proportion of variability explained by VAT (R2=0.266) as compared to SAT (R2=0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.
Adiposity; obesity; endothelial dysfunction; visceral fat; subcutaneous fat; flow-mediated dilation; epidemiology; computed tomography
The utility of single versus combined blood pressure (BP) components in predicting cardiovascular disease (CVD) events is not established. We compared systolic BP (SBP) and diastolic BP (DBP) versus pulse pressure (PP) and mean arterial pressure (MAP) combined, and each of these four BP components alone in predicting CVD events.
Methods and Results
In participants in the original (n=4,760) and offspring (n=4,897) Framingham Heart Study who were free of CVD events and BP-lowering therapy, 1,439 CVD events occurred over serial 4-year intervals from 1952 to 2001. In pooled logistic regression using BP categories, combining SBP with DBP and PP with MAP improved model fit as compared to individual BP components (p<0.05 to p<0.0001). Significant interactions were noted between SBP and DBP (p=0.02) and between PP and MAP (p=0.01) in their respective multivariable models. Models with continuous variables for SBP + DBP and PP + MAP proved identical in predicting CVD events (AIC=10625 for both). Addition of a quadratic DBP2 term to DBP and SBP further improved fit (p=0.0016).
Combining PP with MAP and SBP with DBP produced models that were superior to single BP components for predicting CVD and the extent of CVD risk varied with the level of each BP component. PP + MAP (unlike SBP + DBP) have a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness vs. impaired peripheral resistance, but is not superior to SBP + DBP in predicting CVD events.
pulse pressure; mean arterial pressure; blood pressure; hypertension; cardiovascular diseases
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.
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.
aorta; arterial stiffness; pulse wave velocity; cardiovascular disease; prognosis
Clinic-based case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based cross-sectional observational study included 327 men and 355 women, age 42 to 83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. Polysomnographically derived apnea-hypopnea index and hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. Baseline brachial artery diameter was significantly associated with both apnea-hypopnea index and hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for apnea-hypopnea index. Age-, sex-, race-and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm, respectively, for those with apnea-hypopnea index <1.5, 1.5–4.9, 5–14.9, 15–29.9, ≥30; p=0.03. Baseline flow measures were associated with apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.
Sleep Apnea; Obstructive; Endothelium; Vascular; Remodeling; Vascular; Epidemiology
Inflammation causes vascular dysfunction and perpetuates proatherosclerotic processes. We hypothesized that a broad panel of inflammatory biomarkers and single nucleotide polymorphisms (SNPs) in inflammatory genes are associated with vascular stiffness.
We assessed 12 circulating inflammatory biomarkers [C-reactive protein (CRP), fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 (Lp-PLA2 mass and activity), monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, tumor necrosis factor receptor II (TNFRII)] in relation to tonometry variables [central pulse pressure (CPP), mean arterial pressure (MAP), forward pressure wave, reflected pressure wave (RPW), carotid-femoral pulse wave velocity (CFPWV), augmentation index] measured in 2409 Framingham Heart Study participants (mean age 60 years, 55% women, 13% ethnic/racial minorities). SNPs (n=2195) in 240 inflammatory candidate genes were related to tonometry measures in 1036 white individuals.
In multivariable analyses, biomarkers explained less than 1% of any tonometry measure's variance. Applying backwards elimination, markers related to tonometry (P<0.01) were: TNFRII (inversely) with MAP; CRP (positively) and Lp-PLA2 (inversely) with RPW; and interleukin-6 and osteoprotegerin (positively) with CFPWV. In genetic association analyses, lowest p-values (false discovery rate <0.50) were observed for rs10509561 (FAS), p=6.6×10−5 for CPP and rs11559271 (ITGB2), p=1.1×10−4 for MAP.
These data demonstrate that in a community-based sample, circulating inflammatory markers TNFRII (MAP), CRP, Lp-PLA2 activity (RPW), interleukin-6 and osteoprotegerin (CFPWV) were significantly but modestly associated with measures of arterial stiffness and wave reflection. Additional studies are needed to determine if variation in inflammatory marker genes are associated with tonometry measures.
tonometry; inflammation; epidemiology; polymorphism, single nucleotide; genetics
Growth factors play an important role in regulating vascular function. Data are limited regarding clinical and genetic correlates of endothelial growth factors and their associations with vascular function.
Methods and results
We evaluated clinical and genetic correlates of circulating vascular endothelial growth factor A (VEGF), its soluble receptor sFlt-1, and hepatocyte growth factor (HGF) in 3754 Framingham Study participants. We also related the growth factors to measures of brachial artery function. Serum VEGF and HGF were higher and sFLt-1 was lower in women and smokers. VEGF and HGF were associated positively with body mass index; both displayed strong positive associations with the metabolic syndrome (P < 0.001) and its components. The heritabilities of VEGF, sFlt-1, and HGF were 78, 13, and 38%, respectively. VEGF and HGF were related positively to baseline brachial diameter (P < 0.01) and to baseline mean flow velocity (P < 0.001) in age- and sex-adjusted models, but the multivariable models failed to reach significance. None of the growth factors were related to flow-mediated dilation.
In our community-based sample, circulating VEGF and HGF demonstrated high heritabilities and a sexual dimorphism. Increased angiogenesis and greater endothelial cell turnover may underlie associations of these growth factors with risk factors including smoking.
Vascular growth factors; VEGF; SFlt-1; HGF; Vascular function; Heritability; Metabolic syndrome
Proximal aortic diameter, including aortic root (AoR) diameter, has been inversely related to pulse pressure (PP) in cross-sectional studies. So, investigators have hypothesized that a smaller AoR diameter may increase risk of developing hypertension. Prospective studies are lacking to test this hypothesis.
We measured AoR diameter in 3195 Framingham Study participants (mean age 49 years, 57% women; 8460 person-examinations) free from hypertension and prior cardiovascular disease who underwent routine echocardiography. We related AoR to hypertension incidence and blood pressure (BP) progression (increment of ≥1 category, as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure).
On follow-up (median 4 years), 1267 individuals (15%, 661 women) developed hypertension and 2978 participants experienced BP progression (35%, 1588 women). In logistic regression models adjusted for age, sex, and height, AoR was positively associated with hypertension incidence (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08–1.23) and BP progression (OR, 1.09; 95% CI, 1.04–1.14) on follow-up. However, adjustment for other factors known to influence BP tracking (baseline systolic and diastolic blood pressure, smoking, diabetes, and weight) rendered these relations statistically non-significant (OR, 1.03; 95% CI, 0.96–1.11 for hypertension incidence; OR, 1.03; 95% CI, 0.97–1.08 for BP progression).
In our large community-based sample of non-hypertensive individuals, AoR diameter was not associated with hypertension incidence or BP progression prospectively after adjustment for potential confounders. Our prospective study does not support the notion that a smaller AoR predisposes to hypertension.
blood pressure; aorta; hypertension
Increased arterial stiffness and wave reflection have been identified as cardiovascular disease risk factors. In light of significant sex differences and the moderate heritability of vascular function measures, we hypothesized that variation in the genes coding for estrogen receptors alpha (ESR1) and beta (ESR2) and aromatase (CYP19A1) is associated with aortic stiffness and pressure wave reflection as measured by noninvasive arterial tonometry. 1261 unrelated Framingham Offspring Study participants who attended the 7th examination cycle (mean age 62±10 years, 52% women) and had arterial tonometry and genotyping data were included in the study. ANCOVA was used to assess the association of polymorphisms with forward wave amplitude, augmented pressure, augmentation index, carotid-femoral pulse wave velocity, and mean arterial pressure with adjustment for potential confounders. In the sex-pooled analysis, those homozygous for the minor allele at any of four ESR1 variants that were in strong linkage disequilibrium ((TA)n, rs2077647, rs2234693 and rs9340799) had on average 18% higher augmented pressure and 16% greater augmentation index compared to carriers of one or two major alleles (p=0.0002–0.01). A similar magnitude of association was detected in those homozygous for the common allele at two ESR2 SNPs (p=0.007–0.02). Our results are consistent with the hypothesis that variation in ESR1 and ESR2, but not CYP19A1, is associated with increased wave reflection, which may contribute to previously demonstrated associations between these variants and adverse clinical events. Our findings will need to be replicated in additional cohorts.
arterial stiffness; tonometry; estrogen receptor; polymorphism
Arterial stiffness increases with age and contributes to the pathogenesis of systolic hypertension and cardiovascular disease in the elderly. Knowledge about pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches.
Methods and Results
We related seven circulating biomarkers, representing distinct biological pathways (C-reactive protein [CRP], aldosterone-to-renin ratio [ARR], N-terminal pro–atrial natriuretic peptide and B-type natriuretic peptide, plasminogen activator inhibitor [PAI]-1, fibrinogen, homocysteine) to 5 vascular function measures (central pulse pressure, carotid-femoral pulse wave velocity, mean arterial pressure, forward pressure wave amplitude [all measures of conduit artery stiffness], and augmented pressure, an indicator of wave reflection) in 2,000 Framingham Offspring Study participants (mean age 61 years, 55% women). Tonometry measures were obtained on average three years after biomarkers were measured. In multivariable linear regression models adjusting for covariates, the biomarker panel was significantly associated with all 5 vascular measures (p<0.003 for all). Upon backwards elimination, the ARR was positively associated with each stiffness measure (p≤0.002 for all). In addition, CRP was positively related to augmented pressure (p=0.0003), whereas PAI-1 was positively associated with mean arterial pressure (p=0.003), central pulse pressure (p=0.001) and forward pressure wave (p=0.01).
Our cross-sectional data on a community-based sample suggest a distinctive pattern of positive associations of biomarkers of renin-angiotensin-aldosterone system activation with pan-arterial vascular stiffness, PAI-1 with central vascular stiffness indices, and of CRP with wave reflection. These observations support the notion of differential influences of biological pathways on vascular stiffness measures.
arterial stiffness; renin-angiontensin-aldosterone system; C-reactive protein; plasminogen activator inhibitor; biomarker
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.
KCNMB1; Single Nucleotide Polymorphism; Genetics; Vascular Tonometry
Endothelial dysfunction is prevalent among individuals with end-stage renal disease. Whether endothelial dysfunction is present in moderate chronic kidney disease (CKD) is uncertain.
Settings and Participants
Brachial reactivity measurements were obtained during the seventh examination cycle in 2818 (diameter measurements) and 2256 (flow measurements) Framingham Heart Study Offspring cohort participants (53% women, mean age 61±9 years).
Estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2, derived from creatinine- and cystatin-C based estimating equations; microalbuminuria status.
Brachial reactivity measurements (baseline brachial diameter, flow-mediated dilation, baseline and hyperemic mean flow).
Linear regression models were used to model brachial measures as a function of CKD status and microalbuminuria status.
Overall, 7.3% (n=206) of participants had CKD, and of 2301 with urinary measurements, 10.0% (n=230) had microalbuminuria. Brachial reactivity measures did not differ significantly by CKD status in either creatinine- or cystatin-C based equations, in either age- and sex-, or multivariable-adjusted models. In age- and sex-adjusted models, microalbuminuria was associated with decreased hyperemic mean flow (47.2±1.4 versus 51.4±0.5 mg/g, p=0.005), but the association was not significant after multivariable adjustment (p=0.09).
Predominantly white, ambulatory cohort; results may not be generalizable to other ethnic groups or to individuals with severe CKD.
Endothelial dysfunction was not a major correlate of CKD in our sample.
chronic kidney disease; brachial reactivity; cystatin C; Framingham Heart Study
Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that partially depends on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown.
Methods and Results
Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (n=1957, mean age 40±9 years, 49% women) at baseline and in 30 second intervals for 4-minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (termed PAT ratio) as the natural logarithm of the post-deflation to baseline pulse amplitude ratio in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of PAT ratio to cardiovascular risk factors was strongest in the 90-120 second post-deflation interval (overall model R2=0.159). In stepwise multivariable linear regression models, male sex, body mass index, total/HDL cholesterol, diabetes, smoking and lipid-lowering treatment were inversely related to PAT ratio; whereas increasing age was positively related to PAT ratio (all P<0.01).
Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further investigations to define the clinical utility and predictive value of digital pulse amplitude.
vascular; epidemiology; risk factors; cohort study
The metabolic syndrome (MS), a clustering of metabolic disturbances, is associated with increased cardiovascular risk. Limited information is available about the relations between MS, insulin resistance and vascular function. We measured brachial artery flow-mediated dilation (n=2123), and reactive hyperemia (n=1521) in Framingham Offspring participants without diabetes or clinical cardiovascular disease (mean age 59±9 years, 57% women). MS, determined by National Cholesterol Education Program criteria, was present in 36% of participants. Insulin resistance was determined using Homeostatic Model Assessment (HOMA-IR). In age- and sex-adjusted models, MS was associated with lower flow-mediated dilation and reactive hyperemia. There was progressively lower vasodilator function with increasing number of MS components (p for trend <0.0001). In multivariable models adjusting for the 5 MS components as continuous variables, MS (presence vs. absence) remained associated with lower flow-mediated dilation (2.84±0.12% vs. 3.17±0.08%, p=0.0496) and reactive hyperemia (50.8±1.0 cm/sec vs. 54.4±0.7cm/sec, p=0.009). Insulin resistance was inversely associated with flow-mediated dilation and reactive hyperemia in age- and sex-adjusted models, but these relations were no longer significant in models adjusting for the MS components. In conclusion, our observations are consistent with the hypothesis that MS and insulin resistance impair vascular function predominantly through the influence of the component metabolic abnormalities that comprise MS.
Metabolic Syndrome X; endothelium; epidemiology; risk factors