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
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
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
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
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
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
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.
angiotensin-converting enzyme; coronary artery disease; randomized clinical trial; arterial stiffness; pulse wave velocity
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.
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.
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.
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.
arterial stiffness; arterial wave reflection; blood pressure; cardiac performance; hypertension.
Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits.
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.
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.
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).
Combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations.
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.
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).
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.
blood pressure; child; NHANES; pulse pressure
The aim of this study was to investigate the association between aortic root remodeling and incident heart failure (HF).
Age-associated increases in aortic root diameter (AoD) might be associated with arterial stiffening, afterload changes, cardiac remodeling, and the development of HF.
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).
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.
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.
aortic root; general community; heart failure; remodeling; risk
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.
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).
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.
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
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.
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.
aging; cardiovascular disease; endothelial dysfunction; nitric oxide synthase; vasodilation
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
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
Numerous genetic loci influence systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans 1-3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N=74,064) and follow-up studies (N=48,607), we identified at genome-wide significance (P= 2.7×10-8 to P=2.3×10-13) four novel PP loci (at 4q12 near CHIC2/PDGFRAI, 7q22.3 near PIK3CG, 8q24.12 in NOV, 11q24.3 near ADAMTS-8), two novel MAP loci (3p21.31 in MAP4, 10q25.3 near ADRB1) and one locus associated with both traits (2q24.3 near FIGN) which has recently been associated with SBP in east Asians. For three of the novel PP signals, the estimated effect for SBP was opposite to that for DBP, in contrast to the majority of common SBP- and DBP-associated variants which show concordant effects on both traits. These findings indicate novel genetic mechanisms underlying blood pressure variation, including pathways that may differentially influence SBP and DBP.
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
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
Blood pressure (BP) is a major cardiovascular disease risk factor. To date, few variants associated with inter-individual BP variation have been identified. A genome-wide association study of systolic (SBP), diastolic BP (DBP), and hypertension in the CHARGE Consortium (n=29,136) identified 13 SNPs for SBP, 20 for DBP, and 10 for hypertension at p <4×10-7. The top 10 loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to number of risk alleles carried. When 10 CHARGE SNPs for each trait were meta-analyzed jointly with the Global BPgen Consortium (n=34,433), four CHARGE loci attained genome-wide significance (p<5×10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK/ULK3, SH2B3, TBX3/TBX5, ULK4), and one for hypertension (ATP2B1). Identifying novel BP genes advances our understanding of BP regulation and highlights potential drug targets for the prevention or treatment of hypertension.