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Background: Guidelines emphasize screening people with elevated BP for the presence of end-organ damage. Methods: We characterized the prevalence, correlates, and prognosis of hypertension-mediated organ damage (HMOD) in the community-based Framingham Study. 7898 participants (mean age 51.6 years, 54% women) underwent assessment for the following HMOD: electrocardiographic and echocardiographic left ventricular hypertrophy, abnormal brain imaging findings consistent with vascular injury, increased carotid intima-media thickness, elevated carotid-femoral pulse wave velocity, reduced kidney function, microalbuminuria, and low ankle-brachial index. We characterized HMOD prevalence according to blood pressure (BP) categories defined by four international BP guidelines. Participants were followed up for incidence of cardiovascular disease. Results: The prevalence of HMOD varied positively with systolic BP and pulse pressure but negatively with diastolic BP; it increased with age, was similar in both sexes, and varied across BP guidelines based on their thresholds defining hypertension. Among participants with hypertension, elevated carotid-femoral pulse wave velocity was the most prevalent HMOD (40%–60%), whereas low ankle-brachial index was the least prevalent ( Conclusions: The prevalence of HMOD varies across international BP guidelines based on their different thresholds for defining hypertension. The presence of HMOD confers incremental prognostic information regarding cardiovascular disease risk at every BP category.

Background: We investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression with the risk of dysglycemia, insulin resistance, and dyslipidemia. Methods: We included 3862, 17.7-year-old, participants from the Avon Longitudinal Study of Parents and Children, followed up for 7 years. cfPWV, cIMT, and fasting plasma samples were repeatedly measured. We computed homeostatic model assessment (HOMA) of insulin resistance and percent pancreatic beta-cell function. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models. Results: A higher cfPWV at 17.7 years was associated with higher insulin at age 24.5 years (odds ratio, 1.25 [CI, 1.08–1.44]; P =0.003), which slightly attenuated after covariates adjustment. Higher cIMT at 17.7 years was associated with lower insulin (odds ratio, 0.06 [0.01–0.95]; P =0.046) at 24.5 years, after covariate adjustments. In mixed-effect models, the 7-year progression in cfPWV (predictor) was directly associated with the increase in triglyceride (outcome). cIMT progression was associated with the 7-year increase in LDL (low-density lipoprotein), triglyceride, and glucose. In cross-lagged models, higher cfPWV at 17.7 years was associated with higher insulin ( β =0.06, SE, 0.12, P =0.014), HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years. However, insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 17.7 years were not associated with cfPWV at 24.5 years. Higher cIMT at 17.7 years was associated with reduced insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years, but not vice versa. Higher glucose at 17.7 years was associated with higher cfPWV and cIMT at 24.5 years only. Conclusions: Arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and insulin resistance in young adulthood.

Background: Low-normal serum potassium (K) and low dietary K intake are more prevalent in Black than White individuals and are potentially modifiable risk factors for cardiovascular disease (CVD), hypertension, and diabetes, conditions that disproportionately affect Black adults. Arterial stiffness predicts the development of CVD. We sought to determine the associations of K measures with arterial stiffness and incident CVD. Methods: We used data from participants of the Jackson Heart Study who were free of CVD at baseline. We used multivariable linear regression to assess the associations of serum K and dietary K intake with two measures of arterial stiffness: peripheral pulse pressure (PP) and carotid-femoral PWV (CFPWV) - the gold standard. Additionally, we analyzed associations of K measures with incident CVD using multivariable Cox proportional hazard models. Results: Of 4467 participants included in our analyses, 1218 had low-normal serum K (K ≤ 4.0 mmol/L) at baseline, and 407 participants had a CVD event over a median of 13.7 years of follow-up. In minimally-adjusted models, there were significant inverse associations of serum K with PP and CFPWV. The association between serum K and CFPWV persisted after multivariable adjustment (Table). In multivariable models with serum K categorized into quintiles, those with serum K > 4.4 mmol/L had significantly lower CFPWV. There were no significant associations between dietary K and outcomes of arterial stiffness. There were no significant associations between either measure of K and incident CVD. Conclusions: In this cohort of Black adults, higher serum K was significantly associated with reduced arterial stiffness.

Introduction: Spherical remodeling of atria and ventricles is associated with cardiovascular disease (CVD) and mortality. We hypothesized that volumetric left atrial (LA) and left ventricular (LV) sphericity index (SI) are associated with adverse measures of LV structure and function in older adults free of CVD. Methods: Framingham Heart Study 2nd generation participants without prevalent CVD with echocardiography at exam 8 were studied (n=1701). Volumetric LA SI was calculated as the ratio of biplane LA volume to the volume of a sphere [4/3*pi*(r^3)] calculated using the radius of LA length (r=½ average length of the atria in 4- and 2-chamber views in diastole). Volumetric LV SI was calculated as the ratio of LV end-diastolic volume (LVEDV) to the volume of a sphere calculated using the radius of LV length (r= ½ length of LV in 4-chamber view in diastole). LVEDV was measured by biplane area-length method. In multivariable models adjusting for CV risk factors including age, sex, BMI, hypertension, dyslipidemia, diabetes, and smoking, we evaluated the relations of LA and LV SI with echocardiographic LV structure and function: wall thickness (septal and posterior wall average), mass, global longitudinal strain, ejection fraction (EF), and log-transformed mitral Doppler E/A. β coefficients are presented as standard deviation (SD) change in outcome per SD change in predictor variable. Results: Descriptives are presented in the Table . There was no association of LA or LV SI with sex (p=0.48, p=0.61, respectively). LA SI was associated with worse (positive) LV global longitudinal strain (std β±SE: 0.08±0.03, p=0.016). LV SI was associated with LV wall thickness (std β±SE: 0.24±0.03, p Conclusions: In a large community sample without prevalent CVD, spherical remodeling of the heart was associated with unfavorable LV structure and both systolic and diastolic dysfunction.

Aging is associated with an increased prevalence of subclinical atherosclerosis and stiffening of the arterial walls (arteriosclerosis). These 2 coexisting conditions are mitigated by the presence of ideal cardiovascular health (optimal levels of fasting blood glucose, cholesterol, resting blood pressure, body mass index, no smoking, good dietary quality, and regular physical activity). We hypothesized that the concomitant presence of subclinical atherosclerosis (coronary artery calcification), arteriosclerosis (higher carotid-femoral pulse wave velocity), and suboptimal cardiovascular health is associated with increased risk of cardiovascular disease relative to the absence of these 3 conditions. We tested our hypothesis in the community-based Framingham Heart Study cohort (N=2580, mean age 52 years, 49% women). We classified participants based on (1) the presence versus absence of coronary artery calcium; (2) higher (>sex-specific median) carotid-femoral pulse wave velocity; (3) poor cardiovascular health (score 0–7). Thus, participants could have no abnormalities (referent group), 1, 2, or 3 suboptimal measures. We used Cox regression to relate the number of suboptimal measures (0–3) to the incidence of cardiovascular disease during follow-up (median 14 years). Cardiovascular disease incidence rates/1000 person-years in groups with 0 to 3 suboptimal measures were 1.93 (95% CI, 1.28–2.90), 4.68 (95% CI, 3.48–6.29), 8.93 (95% CI, 6.99–11.41), and 18.26 (95% CI, 14.65–22.77), respectively. Compared with the group with no abnormalities, corresponding multivariable-adjusted hazards ratios for cardiovascular disease were 1.81, 2.18, and 3.71, respectively ( P

Background and Purpose: Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants. Methods: Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events. Results: During follow-up (median, 9.2 years; range, 0.04–10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90–1.21]; P =0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84–1.08]; P =0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61–0.94]; P =0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89–1.49]; P =0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53–0.86]; P =0.001). Conclusions: Novel digital PAT measures may represent a marker of stroke risk in the community.

Background: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. Methods: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). Results: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03–1.76]; P =0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08–1.48]; P =0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00–1.35]; P =0.049). Conclusions: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.

As far back as the ancient Egyptians and Greeks, physicians have observed and interpreted the arterial pulse to diagnose disease. In the last 20 years, advances in modern engineering have rendered quantitative pulse wave analysis widely available, reliable, and reproducible. To date, measurement of arterial stiffness has remained almost exclusively a research activity. However, ongoing technological improvements coupled with already strong and growing evidence of clinical value should facilitate integration of arterial stiffness measures into clinical practice in the near future. This brief review will highlight clinical areas where arterial stiffness measures are likely to be the most informative in clinical practice.

Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp +/− mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp +/− mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. Conclusions: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Introduction: Poor quality neighborhoods are independent risk factors for cardiovascular disease (CVD) but are understudied in Blacks, who face large CVD health disparities. Arterial stiffness (AS) precedes development of hypertension and adverse CVD events but the effect of neighborhood on AS among Blacks remain unknown. Objective: We compared the association between neighborhood environment and AS among Blacks in Jackson, MS and Atlanta, GA. Methods: We studied 1592 Blacks (age 58 ± 10, 38% male) living in Jackson, MS from the Jackson Heart Study (JHS) and 451 Blacks (age 53 ± 10, 39% male) living in Atlanta, GA from the Morehouse/Emory Center for Health Equity (MECA) study, without known CVD. Neighborhood problems (includes measures of aesthetic quality, walking environment, food access), social cohesion (includes activity with neighbors), and violence/safety were assessed using validated questionnaires. AS was measured as pulse wave velocity (PWV) using MRI in JHS and as PWV and augmentation index (AIx) using applanation tonometry (Sphygmocor Inc) in MECA. Multivariable linear regression models were used to examine the association between neighborhood characteristics and AS, adjusting for potential confounders. Results: Improved social characteristics, measured as social cohesion in JHS (β = -0.32 [-0.63, - 0.02], p=0.04) and activity with neighbors (β = -0.23 [-0.40, - 0.05] p=0.01) in MECA, were associated with lower PWV in both cohorts and lower AIx (β = -1.74 [-2.92, - 0.56], p=0.004) in MECA, after adjustment for CVD risk factors and income. Additionally, in MECA better food access (β = -1.18 [-2.35, - 0.01], p=0.05) was associated with lower AIx, and in JHS, lower neighborhood problems (β = -0.33 [-0.64, - 0.02], p=0.04) and lower violence (β = -0.30 [-0.61, 0.002], p=0.05) were associated with lower PWV (Fig). Conclusion: Neighborhood social characteristics show an independent association with vascular health of Blacks, findings that were reproducible in two distinct American cities.

Introduction: Using magnetic resonance (MR) diffusion tensor imaging (DTI), we previously showed a cross-sectional association between carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness, and subtle white-matter injury in clinically asymptomatic middle-age adults. Although coronary artery calcification (CAC) predicted cerebral small vessel diseases evident in conventional MR technique in some studies, it remains unclear whether CAC predicts DTI-based subtle white matter injuries. Hypothesis: CAC and CFPWV are associated with global measures of subtle white-matter injury in middle-aged adults free of clinical brain diseases. Methods: We studied third-generation participants of the Framingham Heart Study who were assessed for CAC (2002-2005), CFPWV, and brain DTI (2009-2013). After excluding prevalent stroke, dementia, other neurological conditions, or those with missing data, 1052 participants (women, 45.4%, mean age: 45.4 years) were analyzed. Two DTI-based outcomes were examined (average within voxels from the white matter mask): free water (FW) and FW-corrected fractional anisotropy (FA). Using linear regression, we calculated slopes of the outcomes per 20-80 th percentiles higher CAC (log-transformed Agatston score) or CFPWV (negative inverse) after adjustment for age and age squared at CAC or CFPWV, time between at CAC/CFPWV and DTI exam, systolic blood pressure, diabetes, total cholesterol, medication(s) for hypertension or dyslipidemia, smoking, and total cranial volume. Results: After multivariable adjustment, in men, CAC was associated only with FA (p=0.033), whereas CFPWV was associated only with FW (p=0.030) ( Figure ). No associations were observed in women. Conclusions: In men, CAC assessed at >7.5 years earlier was associated with worse FA, while CFPWV assessed at 1.7 years earlier was associated with worse FW. CAC may be a sensitive maker to predict subtle white-matter injury in asymptomatic middle-aged men.

Background:Heart failure (HF) may arise from alterations in metabolic, structural, and signaling pathways, but its genetic architecture is incompletely understood. To elucidate potential genetic contributors to cardiac remodeling and HF, we integrated genome-wide single-nucleotide polymorphisms, gene expression, and DNA methylation using a transomics analytical approach.Methods:We used robust rank aggregation (where the position of a certain gene in a rank order list [based on statistical significance level] is tested against a randomly shuffled rank order list) to derive an integrative transomic score for each annotated gene associated with a HF trait.Results:We evaluated ≤8372 FHS (Framingham Heart Study) participants (54% women; mean age, 55±17 years). Of these, 62 (0.7%) and 35 (0.4%) had prevalent HF with reduced ejection fraction and HF with preserved left ventricular ejection fraction, respectively. During a mean follow-up of 8.5 years (minimum–maximum, 0.005–18.6 years), 223 (2.7%) and 234 (2.8%) individuals developed incident HF with reduced ejection fraction and HF with reduced ejection fraction, respectively. Top genes includedMMP20andMTSS1(promotes actin assembly at intercellular junctions) for left ventricular systolic function;ITGA9(receptor forVCAM1[vascular cell protein 1]) andC5for left ventricular remodeling;NUP210(expressed during myogenic differentiation) andANK1(cytoskeletal protein) for diastolic function;TSPAN16andRAB11FIP3(involved in regulation of actin cytoskeleton) for prevalent HF with reduced ejection fraction;ANKRD13DandTRIM69for incident HF with reduced ejection fraction;HPCAL1andPTTG1IPfor prevalent HF with reduced ejection fraction; andZNF146(close to theCOX7A1enzyme) andZFP3(close toSLC52A1—the riboflavin transporter) for incident HF with reduced ejection fraction. We tested the HF-related top single-nucleotide polymorphisms in the UK biobank, wherers77059055inTPM1(minor allele frequency, 0.023; odds ratio, 0.83;P=0.002) remained statistically significant upon Bonferroni correction.Conclusions:Our integrative transomics approach offers insights into potential molecular and genetic contributors to HF and its precursors. Although several of our candidate genes have been implicated in HF in animal models, independent replication is warranted.

Vascular function varies with age because of physiological and pathological factors. We examined relations of longitudinal change in vascular function with change in metabolic traits. Longitudinal changes in vascular function and metabolic traits were examined in 5779 participants (mean age, 49.8±14.5 years; 54% women) who attended sequential examinations of the Framingham Offspring, Third Generation, and Omni-1 and Omni-2 cohorts. Multivariable regression analysis related changes in vascular measures (dependent variables), including carotid-femoral pulse wave velocity (CFPWV), forward pressure wave amplitude, characteristic impedance, central pulse pressure, and mean arterial pressure (MAP), with change in body mass index, fasting total:high-density lipoprotein cholesterol ratio, serum triglycerides, and blood glucose. Analyses accounted for baseline value of each vascular and metabolic measure, MAP change, and multiple comparisons. On follow-up (mean, 5.9±0.6 years), aortic stiffness (CFPWV, 0.2±1.6 m/s), and pressure pulsatility (forward pressure wave, 1.2±12.4 mm Hg; characteristic impedance, 23±73 dyne×sec/cm 5 ; central pulse pressure, 2.6±14.7 mm Hg; all P P P

Hypertension and increased vascular stiffness are viewed as inevitable parts of aging. To elucidate whether the age-related decrease in vascular function is avoidable, we assessed the prevalence, correlates, and prognosis of healthy vascular aging (HVA) in 3196 Framingham Study participants aged ≥50 years. We defined HVA as absence of hypertension and pulse wave velocity P

The aim of this study was to assess characteristic impedance (Z c ) of the proximal aorta in young and middle-aged individuals with isolated systolic hypertension (ISH). Z c is an index of aortic stiffness relative to aortic size. In the Dallas Heart Study, 2001 untreated participants 18 to 64 years of age (mean age: 42.3 years; 44% black race) were divided into the following groups based on office blood pressure (BP) measurements: (1) optimal BP (systolic BP [SBP] c , aortic arch pulse wave velocity, and minimum ascending aortic size were quantified using cardiovascular magnetic resonance. In multivariable-adjusted linear models, Z c was highest in the ISH group compared with the optimal BP, isolated diastolic hypertension, or systolic–diastolic hypertension groups (103.2±4.0 versus 68.3±2.1, 75.4±6.0, and 88.9±4.8 dyne*seconds/cm 5 , respectively; all P c –ISH association did not differ by race. Aortic pulse wave velocity was highest in the ISH group compared with the optimal BP, isolated diastolic hypertension, or systolic–diastolic hypertension groups (6.3±0.3 versus 4.3±0.1, 4.4±0.4 and 5.5±0.3 m/s, respectively; all P P >0.2). Results were similar in a subgroup of 1551 participants 18 to 49 years of age. In a multiracial population-based sample, we found evidence of a mismatch between proximal aortic stiffness and diameter in young and middle-aged adults with ISH.

A recent study reported that the aortic–brachial arterial stiffness gradient, defined as carotid–radial/carotid–femoral pulse wave velocity (PWV ratio), predicts all-cause mortality better than carotid–femoral pulse wave velocity (CFPWV) alone in dialysis patients. However, the prognostic significance of PWV ratio for cardiovascular disease (CVD) in the community remains unclear. Accordingly, we assessed the correlates and prognostic value of the PWV ratio in 2114 Framingham Heart Study participants (60±10 years; 56% women) free of overt CVD. Mean PWV ratio decreased from 1.36±0.19 in participants aged P

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography–tandem mass spectrometry–based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate C16:0/C24:0 (independent variable) to the following echocardiographic measures (dependent variables; separate models for each): left ventricular mass, left ventricular ejection fraction, left atrial emptying fraction, left atrial end‐systolic volume, E/e′ (a measure of left ventricular diastolic function), and left ventricular global circumferential and longitudinal strain by speckle‐tracking echocardiography. In multivariable‐adjusted analyses, higher C16:0/C24:0 per standard deviation increment was associated with lower left ventricular ejection fraction (0.991‐fold change in left ventricular ejection fraction; P =0.0004), worse global circumferential strain (β=0.34, P =0.004), higher left atrial end‐systolic volume (β=2.48, pP Conclusions Our cross‐sectional observations in a large community‐based sample are consistent with a potential detrimental impact of higher ceramide ratio (C16:0/24:0) on cardiac remodeling traits, which may partly explain the associations of these molecular species with clinical heart failure.

Background Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD] ) and, in turn, elevate risk for cardiovascular disease ( CVD ) events. Methods and Results We related arterial stiffness measures (carotid‐femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50±15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross‐sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P SD 1.28, 95% CI, 1.02–1.61; P SD 1.37 and 1.45, respectively; P CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI , 0–77%; P Conclusions Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD . Our observations in a large community‐based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD .

Background and Purpose— Aortic stiffening increases the transfers of high pressure and flow pulsatility to small cerebral vessels potentially causing the accumulation of vascular brain injury. Our aim was to investigate the prospective association of aortic stiffness with the risks of incident mild cognitive impairment and dementia. Methods— We studied 1101 dementia-free Framingham Offspring study participants (mean age, 69±6 years; 54% women). Aortic stiffness was measured as carotid–femoral pulse wave velocity using applanation tonometry and modeled as a linear variable and the top 2 quintiles (>11.4 m/s). Outcomes were the 10-year risk of incident mild cognitive impairment and dementia, including clinically characterized Alzheimer disease. We observed 106, 77, and 59 events of mild cognitive impairment, all-cause dementia, and clinical Alzheimer disease, respectively. Results— After adjustment for age and sex, higher continuous aortic stiffness predicted an increased risk of mild cognitive impairment (hazard ratio, 1.40 [95% confidence interval, 1.13–1.73]), all-cause dementia (hazard ratio, 1.45 [95% confidence interval, 1.13–1.87]), and Alzheimer disease (hazard ratio, 1.41 [95% confidence interval, 1.06–1.87]). In risk factor–adjusted statistical models, aortic stiffness remained a significant predictor of mild cognitive impairment but not incident dementia. In nondiabetic patients, the top 2 quintiles of aortic stiffness were associated with a higher risk of incident all-cause dementia across all statistical models. Conclusions— Aortic stiffness was an independent predictor of incident mild cognitive impairment in the whole sample and with incident dementia in nondiabetic patients. Our findings suggest aortic stiffness as a potentially modifiable risk factor for clinical cognitive impairment and dementia.

High arterial stiffness seems to be causally involved in the pathogenesis of hypertension. We tested the hypothesis that offspring of parents with hypertension may display higher arterial stiffness before clinically manifest hypertension, given that hypertension is a heritable condition. We compared arterial tonometry measures in a sample of 1564 nonhypertensive Framingham Heart Study third-generation cohort participants (mean age: 38 years; 55% women) whose parents were enrolled in the Framingham Offspring Study. A total of 468, 715, and 381 participants had 0 (referent), 1, and 2 parents with hypertension. Parental hypertension was associated with greater offspring mean arterial pressure (multivariable-adjusted estimate=2.9 mm Hg; 95% confidence interval, 1.9–3.9, and 4.2 mm Hg; 95% confidence interval, 2.9–5.5, for 1 and 2 parents with hypertension, respectively; P P =0.003 for both). Carotid–femoral pulse wave velocity and augmentation index displayed similar dose-dependent relations with parental hypertension in sex-, age-, and height-adjusted models, but associations were attenuated on further adjustment. Offspring with at least 1 parent in the upper quartile of augmentation index and carotid–femoral pulse wave velocity had significantly higher values themselves ( P ≤0.02). In conclusion, in this community-based sample of young, nonhypertensive adults, we observed greater arterial stiffness in offspring of parents with hypertension. These observations are consistent with higher vascular stiffness at an early stage in the pathogenesis of hypertension.

Background:Relations between central pulse pressure (PP) or pressure amplification and major cardiovascular disease (CVD) events are controversial. Estimates of central aortic pressure derived using radial artery tonometry and a generalized transfer function may better predict CVD risk beyond the pr

Aortic stiffness is associated with cognitive decline and cerebrovascular disease late in life, although these associations have not been examined in young adults. Understanding the effects of aortic stiffness on the brain at a young age is important both from a pathophysiological and public health perspective. The aim of this study was to examine the cross-sectional associations of aortic stiffness with cognitive function and brain aging in the Framingham Heart Study Third Generation cohort (47% men; mean age, 46 years). Participants completed the assessment of aortic stiffness (carotid–femoral pulse wave velocity), a neuropsychological test battery assessing multiple domains of cognitive performance and magnetic resonance imaging to examine subclinical markers of brain injury. In adjusted regression models, higher aortic stiffness was associated with poorer processing speed and executive function (Trail Making B–A; β±SE, −0.08±0.03; P P P

Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid–binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C-reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid–binding protein 4, and leptin concentrations (all P P =0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels ( P P =0.02), but inversely with leptin and leptin receptor levels ( P ≤0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension.

Background Blacks have more severe endothelial dysfunction and aortic stiffening as compared with whites. We aimed to investigate the association between aortic stiffness and microvascular function in the black community. Methods and Results We assessed the association between forearm vascular reactive hyperemia (an indicator of microvascular function) and aortic stiffness in 1458 black participants (N=965 [66% women]; mean age: 66±11 years) in the Jackson Heart Study. We evaluated 2 measures of aortic stiffness: brachial pulse pressure and carotid‐femoral pulse wave velocity. Using high‐resolution ultrasound and Doppler, we evaluated brachial blood flow at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. Multiple cardiovascular risk factors were significantly related to baseline and hyperemic brachial flow velocity. Women had lower baseline flow across the entire age spectrum. During hyperemia, we observed a significant age‐sex interaction for flow velocity ( P =0.02). Female sex was protective against microvascular dysfunction among younger participants, but older women exhibited a greater attenuation of the hyperemic flow reserve. In multivariable models that adjusted for cardiovascular disease risk factors and mean arterial pressure, higher carotid‐femoral pulse wave velocity (β=−0.106±0.033; P =0.001 was related to lower baseline flow. However, during reactive hyperemia, elevated brachial pulse pressure (β=−0.070±0.031; P =0.03) and carotid‐femoral pulse wave velocity (β=−0.128±0.030; P Conclusions In a sample of blacks, higher aortic stiffness and pressure pulsatility were associated with lower flow reserve during reactive hyperemia, beyond changes attributable to traditional cardiovascular disease risk factors alone.

Background Adipokines mediate cardiometabolic risk associated with obesity but their role in the pathogenesis of obesity‐associated heart failure remains uncertain. We investigated the associations between circulating adipokine concentrations and echocardiographic measures in a community‐based sample. Methods and Results We evaluated 3514 Framingham Heart Study participants (mean age 40 years, 53.8% women) who underwent routine echocardiography and had select circulating adipokines measured, ie, leptin, soluble leptin receptor, fatty acid–binding protein 4, retinol‐binding protein 4, fetuin‐A, and adiponectin. We used multivariable linear regression, adjusting for known correlates (including weight), to relate adipokine concentrations (independent variables) to the following echocardiographic measures (dependent variables): left ventricular mass index, left atrial diameter in end systole, fractional shortening, and E/e′. In multivariable‐adjusted analysis, left ventricular mass index was inversely related to circulating leptin and fatty acid–binding protein 4 concentrations but positively related to retinol‐binding protein 4 and leptin receptor levels ( P ≤0.002 for all). Left atrial end‐systolic dimension was inversely related to leptin but positively related to retinol‐binding protein 4 concentrations ( P ≤0.0001). E/e′ was inversely related to leptin receptor levels ( P =0.0002). We observed effect modification by body weight for select associations (leptin receptor and fatty acid–binding protein 4 with left ventricular mass index, and leptin with left atrial diameter in end systole; P Conclusions In our cross‐sectional study of a large, young to middle‐aged, relatively healthy community‐based sample, key indices of subclinical cardiac remodeling were associated with higher or lower circulating concentrations of prohypertrophic and antihypertrophic adipokines in a context‐specific manner. These observations may offer insights into the pathogenesis of the cardiomyopathy of obesity.

Background Left ventricular diastolic dysfunction ( DD ) is common, particularly in women and older individuals, and it is associated with adverse cardiovascular outcomes. We evaluated the impact of age‐ and sex‐specific diagnostic criteria on the assessment of DD in the community‐based Framingham Heart Study. Methods and Results We estimated age‐ and sex‐specific reference limits for echocardiographic measures of DD in a healthy reference subsample (N=2355, mean age 44 years, 66% women). The prevalence, correlates, and association with future cardiovascular disease were compared for DD using age‐ and sex‐specific versus single cut point reference limits in a broad sample (N=6102, mean age 50 years, 56% women). Using age‐ and sex‐specific criteria, DD was present in ≈25% to 30% of individuals across age groups, and it was directly associated with a number of modifiable risk factors. In contrast, with single cut point criteria, age was the primary determinant of DD . During follow‐up (mean 7.9±2.2 years), incident cardiovascular disease occurred in 213 of 5770 individuals. Using age‐ and sex‐specific criteria, mild and moderate‐severe DD were associated with 50% (95% confidence interval, 1.09–2.05) and 65% (95% confidence interval, 1.14–2.38) higher incidences of cardiovascular disease, respectively, in age‐ and sex‐adjusted analyses. With single cut point criteria, moderate‐severe DD (hazard ratio, 1.66; 95% confidence interval, 1.05–2.61), but not mild DD (hazard ratio, 0.94; 95% confidence interval, 0.63–1.40), was associated with incident cardiovascular disease. Conclusions Age‐ and sex‐specific reference limits may result in DD assessments that are less dependent on age, more robustly related to modifiable risk factors, and are more closely associated with incident cardiovascular disease.

Background: B-cell leukemia 11b (Bcl11b) is a zinc-finger transcription factor known as master regulator of T lymphocytes and neuronal development during embryogenesis. However, a role for Bcl11b in the cardiovascular system has never been described. Based on human findings from a genome-wide association study (GWAS) that a gene desert region downstream of BCL11B , known to function as BCL11B enhancer, harbors single nucleotide polymorphisms (SNPs) associated with increased arterial stiffness, we sought to examine relations between Bcl11b and arterial function. Methods and Results: We found for the first time that Bcl11b is expressed in the vascular smooth muscle (VSM) of human and murine vasculature and transcriptionally regulates the expression of VSM contractile proteins smooth muscle myosin and smooth muscle α-actin. Lack of Bcl11b in VSM-specific Bcl11b null mice (BSMKO) resulted in an increased expression of Ca ++ -calmodulin-dependent serine/threonine phosphatase calcineurin in BSMKO VSM cells and aortas, which were inversely correlated with levels of phosphorylated VASP S239 , a calcineurin de-phosphorylation target. Decreased pVASP S239 in BSMKO aortas was associated with increased actin polymerization (F/G actin ratio), consistent with pVASP S239 ’s function as regulator of cytoskeletal actin rearrangements, and was normalized by treatment with calcineurin inhibitor cyclosporine A. Functionally, Bcl11b deletion in VSM cells translated in increased aortic force, stress and wall tension, measured ex vivo in BSMKO aortas in organ baths, and increased pulse wave velocity, the in vivo index of arterial stiffness, in BSMKO mice compared to WT littermates. Moreover, Bcl11b and pVASP S239 expression were decreased in aortas of obese and aged mice, two models of arterial stiffness. Bcl11b deletion in VSM had no effect on baseline blood pressure or angiotensin II-induced hypertension, measured in conscious WT and BSMKO mice by radiotelemetry, but dramatically increased the incidence of angII-induced aortic aneurysms in BSMKO mice. Conclusions: Taken together, our results identify VSM Bcl11b as a novel and crucial regulator of VSM cell phenotype and vascular structural and functional integrity

Current guidelines recommend reporting eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFRcr-cys) as more accurate than either eGFRcr or eGFRcys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR (mGFR) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFRcr and eGFRcys with eGFRcr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR was 64 (52, 73) ml/min per 1.73 m(2), and the prevalence of decreased GFR was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr in four metrics, better than eGFRcys in two metrics, and similar to eGFRcys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr or eGFRcys.

Objective— Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease; however, it is not known whether NAFLD contributes to cardiovascular disease independent of established risk factors. We examined the association between NAFLD and vascular function. Approach and Results— We conducted a cross-sectional study of 2284 Framingham Heart Study participants without overt cardiovascular disease who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes mellitus, hyperlipidemia, hypertension, body mass index, and visceral adipose tissue. The prevalence of NAFLD in our sample (mean age, 52±12 years; 51.4% women) was 15.3%. In age-, sex-, and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation ( r =−0.05; P =0.02), lower peripheral arterial tonometry ratio ( r =−0.20; P r =0.13; P r =0.11; P r =0.06; P =0.005) and lower peripheral arterial tonometry ratio ( r =−0.12; P Conclusions— For multiple measures of vascular function, the relationship with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relationship with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction.

Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular–microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72–92 years) participating in the Age, Gene/Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=−2.28±0.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, −1.35 to −0.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, −2.22 to −0.40; 95% confidence interval of indirect effect including renal vascular resistance, −2.51 to −0.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss.

Background— Elevated blood pressure is the leading modifiable risk factor for cardiovascular disease (CVD) and premature death. The blood pressure waveform consists of discrete hemodynamic components, derived from measured central pressure and flow, which may contribute separately to risk for an adverse outcome. However, pressure-flow measures have not been studied in a large, community-based sample. Methods and Results— We used proportional hazards models to examine the association of incident CVD with forward pressure wave amplitude, mean arterial pressure, and global reflection coefficient derived from wave separation analysis and echocardiography in 2492 participants (mean age 66±9 years, 56% women) in the Framingham Heart Study. During follow-up (0.04–6.8 years), 149 participants (6%) had a CVD event. In multivariable models adjusting for age, sex, antihypertensive therapy, body mass index, heart rate, total and high-density lipoprotein cholesterol concentrations, smoking, and the presence of diabetes mellitus, forward pressure wave amplitude (hazard ratio, 1.40; 95% confidence interval, 1.16–1.67; P =0.0003) was associated with incident CVD, whereas mean arterial pressure (hazard ratio, 1.10; 95% confidence interval, 0.94–1.29; P =0.25) and global wave reflection (hazard ratio, 0.93; 95% confidence interval, 0.78–1.12; P =0.58) were not. After adding systolic blood pressure and carotid-femoral pulse wave velocity to the model, forward pressure wave amplitude persisted as a correlate of events (hazard ratio, 1.33; 95% confidence interval, 1.05–1.68; P =0.02). Conclusions— Higher forward pressure wave amplitude (a measure of proximal aortic geometry and stiffness) was associated with increased risk for incident CVD, whereas mean arterial pressure and relative wave reflection (correlates of resistance vessel structure and function) were not associated with increased risk for incident CVD.

To examine the putative measures of arterial stiffness and the mechanisms of adverse effects of stiffness on blood pressure and target organ damage using data from comprehensive hemodynamic profiles obtained in the Framingham Heart Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.Once thought to be a consequence of longstanding hypertension, recent evidence suggests that aortic stiffness antedates and contributes to the pathogenesis of hypertension and target organ damage in the heart, brain, and kidneys. Carotid-femoral pulse-wave velocity (CFPWV) has emerged as the reference standard measure of aortic stiffness and a powerful predictor of cardiovascular disease risk. Augmentation index, a putative measure of arterial stiffness and wave reflection, has complex relations with stiffness and risk. Recent evidence suggests that wave reflection, which is a normal consequence of impedance mismatch between compliant aorta and stiff muscular arteries, is protective and limits the exposure of target organs to potentially harmful pulsatile energy. Aortic stiffening produces impedance matching that reduces wave reflection and exposes the microcirculation to excessive pulsatile stress, resulting in microvascular target organ damage and dysfunction.CFPWV provides a powerful new tool for risk stratification and elucidation of the pathogenesis of target organ damage in hypertension.

Background Relations of orthostatic change in blood pressure with brain structure and function have not been studied thoroughly, particularly in younger, healthier individuals. Elucidation of factors that contribute to early changes in brain integrity may lead to development of interventions that delay or prevent cognitive impairment. Methods and Results In a sample of the Framingham Heart Study Third Generation (N=2119; 53% women; mean age±SD, 47±8 years), we assessed orthostatic change in mean arterial pressure ( MAP ), aortic stiffness (carotid‐femoral pulse wave velocity), neuropsychological function, and markers of subclinical brain injury on magnetic resonance imaging. Multivariable regression analyses were used to assess relations between orthostatic change in MAP and brain structural and neuropsychological outcomes. Greater orthostatic increase in MAP on standing was related to better Trails B‐A performance among participants aged SE , 0.062±0.029; P =0.031) and among participants with carotid‐femoral pulse wave velocity SE , 0.063±0.026; P =0.016). This relation was not significant among participants who were older or had stiffer aortas. Conversely, greater orthostatic increase in MAP was related to larger total brain volume among older participants (β± SE , 0.065±0.029; P =0.023) and among participants with carotid‐femoral pulse wave velocity ≥6.9 m/s (β± SE , 0.078±0.031; P =0.011). Conclusions Blunted orthostatic increase in MAP was associated with smaller brain volume among participants who were older or had stiffer aortas and with poorer executive function among persons who were younger or who had more‐elastic aortas. Our findings suggest that the brain is sensitive to orthostatic change in MAP , with results dependent on age and aortic stiffness.

Background— Obesity and cardiometabolic dysfunction are associated with increased risk of heart failure and other cardiovascular diseases. We sought to examine the association of cardiometabolic traits with left ventricular (LV) cardiac mechanics. We hypothesized that specific obesity-related phenotypes are associated with distinct aspects of LV strain. Methods and Results— We evaluated the associations of obesity-related phenotypes, including central adiposity, diabetes mellitus, insulin resistance, and circulating adipokine concentrations with echocardiographic measures of LV mechanical function among participants of the Framingham Heart Study Offspring and Third Generation cohorts. Among 6231 participants, the mean age was 51±16 years, and 54% were women. Greater body mass index was associated with worse LV longitudinal strain, radial strain (apical view), and longitudinal synchrony (multivariable-adjusted P P ≤0.006). Measures of insulin resistance, dyslipidemia, and diabetes mellitus also were associated with distinct aspects of LV mechanical function. Circulating leptin concentrations were associated with global longitudinal and radial strain (apical view, P Conclusions— Our findings highlight the association of central obesity and related cardiometabolic phenotypes above and beyond body mass index with subclinical measures of LV mechanical function. Interestingly, obesity-related traits were associated with distinct aspects of LV mechanics, underscoring potential differential effects along specific LV planes of deformation. These findings may shed light onto obesity-related cardiac remodeling and heart failure.

Introduction: Although hypertension in the elderly is no longer considered harmless, increasing arterial stiffness and blood pressure (BP) are still widely seen as inevitable parts of the aging process. However, these phenomena may not be unavoidable as they are nearly absent in populations leading traditional hunter-gatherer lifestyles. Our study had 3 aims: 1) to define a new concept - healthy vascular aging (HVA); 2) to assess prevalence and correlates of HVA in a sample acculturated to a western life-style; and 3) to estimate the magnitude of cardiovascular (CVD) risk associated with HVA vs. absence of HVA. Methods: We studied 3197 Framingham Heart Study participants aged ≥50 years (62±9 years, 56% women) who underwent physical examination, interviews, and measurement of carotid-femoral pulse wave velocity (PWV) in 1999-2008. We defined HVA as no hypertension (BP Results: In our sample, only 566 (17.7%) had HVA. Lower age (OR per 1-SD increase 0.18, 95% confidence interval [CI] 0.14-0.23), female sex (OR 2.03; 95% CI 1.54-2.68), lower BMI (OR per 1-SD increase 0.54; 95% CI 0.47-0.63) and no diabetes (OR 0.09; 95% CI 0.02-0.36) were significantly associated with HVA. A 1-unit increase in the cardiovascular health score conferred 1.55-fold (95% CI 1.38-1.74) odds of HVA. During follow-up (median 9.6 years), 391 participants had CVD events. HVA was associated with an age- and sex-adjusted hazard ratio (HR) of 0.36 (95% CI, 0.22-0.60) and a multivariable-adjusted HR of 0.45 (95% CI, 0.26-0.77) for CVD relative to absence of HVA. Conclusions: One in 6 individuals experiences HVA in our sample. Individuals with HVA are at a considerably low risk of CVD. Prevention strategies targeting modifiable factors and behaviors included in Life’s Simple 7 are important for preventing or delaying vascular aging and the associated risk of CVD.

Objective— Arterial hemodynamics and vascular calcification are associated with increased risk for cardiovascular disease, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease. Approach and Results— Framingham Heart Study Third Generation and Offspring Cohort participants free of cardiovascular disease underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity, central pulse pressure, forward wave amplitude, and augmentation index. Participants in each cohort (n=1905, 45±6 years and n=1015, 65±9 years, respectively) underwent multidetector computed tomography to assess the presence and quantity of thoracic aortic calcification, abdominal aortic calcification, and coronary artery calcification. In multivariable-adjusted models, both higher carotid-femoral pulse wave velocity and central pulse pressure were associated with greater thoracic aortic calcification and abdominal aortic calcification, whereas higher augmentation index was associated with abdominal aortic calcification. Among the tonometry measures, carotid-femoral pulse wave velocity was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio per SD for thoracic aortic calcification, 2.69 [95% confidence interval, 2.17–3.35]; abdominal aortic calcification, 1.47 [95% confidence interval, 1.26–1.73]; and coronary artery calcification, 1.48 [95% confidence interval, 1.28–1.72]; all P Conclusions— In community-dwelling individuals without prevalent cardiovascular disease, abnormal central arterial hemodynamics were positively associated with vascular calcification and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study.

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.

Background—Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Inter-relations of aortic stiffness and vasodilator function with incident CVD remain incompletely studied.Methods and Results—We used proportional hazards models to relate individual measures of vascular function to incident CVD in 4547 participants (mean age, 51±11 years; 54% women) in 2 generations of Framingham Heart Study participants. During follow-up (0.02–13.83 years), 232 participants (5%) experienced new-onset CVD events. In multivariable models adjusted for cardiovascular risk factors, both higher carotid-femoral pulse wave velocity (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.07–1.63;P=0.01) and lower hyperemic mean flow velocity (HR, 0.84; 95% CI, 0.71–0.99;P=0.04) were associated significantly with incident CVD, whereas primary pressure wave amplitude (HR, 1.12; 95% CI, 0.99–1.27;P=0.06), baseline brachial diameter (HR, 1.09; 95% CI, 0.90–1.31;P=0.39), and flow-mediated vasodilation (HR, 0.85; 95% CI, 0.69–1.04;P=0.12) were not. In mediation analyses, 8% to 13% of the relation between aortic stiffness and CVD events was mediated by hyperemic mean flow velocity.Conclusions—Our results suggest that associations between aortic stiffness and CVD events are mediated by pathways that include microvascular damage and remodeling.

Stiffening of conduit arteries is a risk factor for cardiovascular morbidity. Aortic wall stiffening increases pulsatile hemodynamic forces that are detrimental to the microcirculation in highly perfused organs, such as the heart, brain, and kidney. Arterial stiffness is associated with hypertension but presumed to be due to an adaptive response to increased hemodynamic load. In contrast, a recent clinical study found that stiffness precedes and may contribute to the development of hypertension although the mechanisms underlying hypertension are unknown. Here, we report that in a diet-induced model of obesity, arterial stiffness, measured in vivo, develops within 1 month of the initiation of the diet and precedes the development of hypertension by 5 months. Diet-induced obese mice recapitulate the metabolic syndrome and are characterized by inflammation in visceral fat and aorta. Normalization of the metabolic state by weight loss resulted in return of arterial stiffness and blood pressure to normal. Our findings support the hypothesis that arterial stiffness is a cause rather than a consequence of hypertension.

To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p0.05).Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.

Introduction: The presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community-dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure. Methods: We measured carotid-femoral pulse wave velocity (PWV) and classical CVD risk factors in participants of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no), and PWV status (high/low based on age- and sex-specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Results: We studied 2127 community-dwelling individuals (60 years, 57% women). 60% (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable-adjusted risk for CVD events ( n =248, median follow-up 12.6 years; Figure) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio [HR] 1.33, 95% confidence interval [95% CI] 0.86-2.05) and from hypertension with low PWV (HR 1.53, 95% CI 1.00-2.34) to hypertension with high PWV (HR 2.31, 95% CI 1.58-3.36). Conclusions: A substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated in this group. High PWV is associated with a trend towards increasing CVD risk in both non-hypertensives and hypertensives supporting the use of arterial stiffness measurements in both populations.

Background: Despite the higher rates of hypertension and cardiovascular disease (CVD) sequela due to hypertension in African Americans (AA), literature on the hemodynamic factors contributing to vascular stiffness is sparse in this high risk population. Objective: We investigated the hemodynamics of vascular stiffness and its components in a middle-aged cohort of AA using arterial tonometry and compared findings to what has been seen in a healthy cohort of non-Hispanic whites from Framingham. Methods: Noninvasive hemodynamic factors were measured in 1,750 Jackson Heart Study participants (68±11 years, 65% female). A healthy reference group from published work in Framingham was used to determine the prevalence of abnormals in the Jackson Heart Study sample. Reference group was defined in Framingham as those with: age ( Results: The prevalence rates of abnormal hemodynamic variables in a middle-aged group of AA was compared to that seen in middle-aged non-Hispanic whites in Framingham using a published reference sample of normals in Framingham. Compared to non-Hispanic whites in Framingham, the prevalence of abnormals found in Jackson Heart Study AA was higher for diastolic BP (p=0.009), peripheral resistance (p Conclusion: Abnormalities in pulsatile hemodynamic variables are much more common (and severe) in AA than European Americans, which may contribute to higher CVD risk in AA.

Background: While bariatric surgery is known to induce hemodynamic and metabolic pathway alterations, lifestyle-driven weight loss in obese adolescents are not well characterized with respect to hemodynamic and metabolomic effects. We studied aortic function and urine metabolomics changes in obese adolescent volunteers attending weight loss summer camps. Methods: Adolescents (n=45, 71% girls, mean age 15±1 year) attending long-standing weight loss camps over 3 summers volunteered to have weight, long term diet and activity history, and vascular tonometry after overnight fast at camp entry and exit. A subset (n=32) also gave urine entry and exit urine samples for metabolomic analysis (Metabolon, Durham NC). Camp administrators followed pre-existing protocols encouraging campers toward 5 hours or more of structured activity and free play as well as nutritionist-designed meal plan restricted to age-sex specific calorie goals. Paired students T-tests were used to assess changes in anthropometrics and hemodynamics. Osmolality-adjusted metabolomic changes were analyzed using principal components analysis; paired T-test with multiple comparison adjustment by Storey-Tibshirani false discovery rate thresholding; and Random Forest decision tree ensembles with selection of the top 30 biochemicals in variable importance gleaned from the Mean Decrease Accuracy metric, which randomly permutes a given chemical and reassesses predictive accuracy throughout the tree ensembles, and then grouped into pathway categories. Results: Median camp length was 6 weeks (25%,75% IQR 5,7). Campers on average lost body 11±4% of body weight (99±20 to 88±17 kilograms, p Conclusions: Diet and activity driven weight loss in excess weight adolescents is associated with salutary hemodynamic improvement and specific metabolic alterations, paralleling findings after bariatric surgery. More investigation into the mechanisms of lifestyle driven weight loss is warranted.

Background— 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=14 628 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 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m 2 increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10-mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size. Conclusions— 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.

Background— 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 third-generation cohort participants of the Framingham Heart Study (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 were lower in women than in men. Ang-2 was positively related to age, smoking, systolic blood pressure, hypertension treatment, and diabetes ( P P P P P Conclusion— Circulating levels of Ang-2 and sTie-2 are heritable traits associated with cardiovascular disease risk factors, including the metabolic syndrome. These observations are consistent with the notion that angiogenesis and vascular remodeling are determined in part by genetic influences and associated with metabolic risk factors.