Search

Background Stiffness of the proximal aorta may play a critical role in adverse left ventricular (LV)–vascular interactions and associated LV diastolic dysfunction. In a community‐based sample, we sought to determine the association between proximal aortic stiffness measured by cardiovascular magnetic resonance (CMR) and several clinical measures of LV diastolic mechanics. Methods and Results Framingham Heart Study Offspring adults (n=1502 participants, mean 67±9 years, 54% women) with available 1.5T CMR and transthoracic echocardiographic measures were included. Measures included proximal descending aortic strain and aortic arch pulse wave velocity by CMR (2002–2006) and diastolic function (mitral Doppler E and A wave velocity, E wave area, and LV tissue Doppler e' velocity) by echocardiography (2005–2008). Multivariable linear regression analysis was used to relate CMR aortic stiffness measures to measures of echocardiographic LV diastolic function. All continuous variables were standardized. In multivariable‐adjusted regression analyses, aortic strain was inversely associated with E wave deceleration time (estimated β=−0.10±0.032, P =0.001), whereas aortic arch pulse wave velocity was inversely associated with E/A ratio (estimated β=−0.094±0.027, P =0.0006), E wave area (estimated β=−0.070±0.027, P =0.010), and e' (estimated β=−0.061±0.027, P =0.022), all indicating associations of higher aortic stiffness by CMR with less favorable LV diastolic function. Compared with men, women had a larger inverse relationship between pulse wave velocity and E/A ratio (interaction β=−0.085±0.031, P =0.0064). There was no significant effect modification by age or a U‐shaped (quadratic) relation between aortic stiffness and LV diastolic function measures. Conclusions Higher proximal aortic stiffness is associated with less favorable LV diastolic function. Future studies may clarify temporal relations of aortic stiffness with varying patterns and progression of LV diastolic dysfunction.

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 Waveform parameters derived from pressure‐only Windkessel models are related to cardiovascular disease risk and could be useful for understanding arterial system function. However, prior reports varied in their adjustment for potential confounders. Methods and Results Carotid tonometry waveform data from 2539 participants (mean age 63±11 years, 58% women) of the Framingham Heart Study were used to derive Windkessel measures using pressure and assuming a linear model with fixed diastolic time constant (τ dias ) and variable asymptotic pressure (P inf , median 54.5; 25th, 75th percentiles: 38.4, 64.9 mm Hg) or nonlinear model with inverse pressure‐dependent τ dias and fixed P inf (20 mm Hg). During follow‐up (median 15.1 years), 459 (18%) participants had a first cardiovascular disease event. In proportional hazards models adjusted for age, sex, total cholesterol, high‐density lipoprotein cholesterol, smoking, antihypertensive medication use, diabetes mellitus, and physician‐acquired systolic blood pressure, only the systolic time constant (τ sys ) derived from the nonlinear model was related to risk for cardiovascular disease events (hazard ratio=0.91 per 1 SD, 95% CI=0.84–0.99, P =0.04). When heart rate was added to the model, τ sys (hazard ratio=0.92, CI=0.84–1.00, P =0.04) and reservoir pressure amplitude (hazard ratio=1.14, CI=1.01–1.28, P =0.04) were related to events. In contrast, measures derived from the linear model were not related to events in models that adjusted for risk factors including systolic blood pressure ( P >0.31) and heart rate ( P >0.19). Conclusions Our results suggest that pressure‐only Windkessel measures derived by using a nonlinear model may provide incremental risk stratification, although associations were modest and further validation is required.

Background Black individuals have greater risk for cardiovascular disease ( CVD ) than whites. Identifying CVD risk factors associated with abnormal aortic hemodynamics in blacks may optimize CVD prevention and treatment strategies. Methods and Results Jackson Heart Study participants underwent applanation tonometry (2011–2016) with assessment of carotid‐femoral pulse wave velocity ( CFPWV ) and forward wave amplitude ( FWA ). CVD risk factors were assessed during examination 3 (2009–2012). We examined the association of risk factors with binary and continuous CFPWV and FWA in multivariable stepwise models. We evaluated for effect modification by sex to determine differential associations of risk factors with aortic hemodynamics in men and women. We examined 1322 individuals (mean age 66±11 years, 66% women). Age was strongly associated with elevated CFPWV (odds ratio, 4.76; 95% confidence interval, 3.84–5.89 [ P FWA (odds ratio, 2.30; 95% CI , 1.98–2.69 [ P CFPWV compared with women (odds ratio, 1.54; 95% confidence interval, 1.11–2.13 [ P =0.009]). Heart rate, mean arterial pressure, and use of antihypertensive medications were associated with elevated CFPWV and FWA (all P ≤0.02). Additionally, total/high‐density lipoprotein cholesterol and fasting glucose were associated with elevated CFPWV (both P ≤0.002) and use of diabetes mellitus medications was associated with elevated FWA ( P ≤0.0001). We observed a steeper association of age and mean arterial pressure with unfavorable aortic hemodynamics in women than men. Conclusions In blacks in the community, differential CVD risk factors are associated with aortic stiffness and FWA. Future work may determine the impact of risk factor modification on abnormal central aortic hemodynamics and CVD outcomes.

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 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 Fibroblast growth factor 23 ( FGF 23) is emerging as a novel biomarker of bone metabolism, chronic kidney disease, and cardiovascular disease ( CVD ). However, its clinical correlates and potential predictive role in a community‐based setting are incompletely understood. Methods and Results We evaluated participants of the Framingham Heart Study (seventh examination cycle of the Offspring cohort plus second examination cycle of the multiethnic Omni cohort) to identify clinical correlates of plasma FGF 23 (N=3236) and examine its cross‐sectional association with vascular function (N=2209), and longitudinal association with 10‐year incidence of CVD (N=2823), and all‐cause mortality (N=3223). Circulating FGF 23 concentrations were positively related to African‐American and Asian ethnicity, waist circumference, current smoking, serum glucose, history of CVD , and antihypertensive medication use; and negatively related to male sex, hormone replacement therapy, and estimated glomerular filtration rate. Multivariable‐adjusted cross‐sectional analyses showed no consistent association of FGF 23 with vascular function measures. During a median follow‐up time of 10.8 years, 347 incident CVD events and 412 deaths occurred. Multivariable‐adjusted Cox regression models revealed a positive association of FGF 23 with all‐cause mortality (hazard ratio [ HR ] per SD increase, 1.31; 95% CI, 1.20–1.42), but not with incident CVD ( HR per SD increase, 1.05; 95% CI, 0.94–1.17). Conclusions In our large, community‐based sample, FGF 23 was associated with mortality risk, but not with vascular function or incident CVD .

Background The differing relations of steady and pulsatile components of central hemodynamics and aortic stiffness with cardiac dimensions and function have not been fully elucidated. Methods and Results Central hemodynamics and carotid‐femoral pulse wave velocity ( CFPWV , a measure of aortic stiffness) were measured by arterial tonometry in 5799 participants of the Framingham Heart Study (mean age 51 years, 54% women) and related to echocardiographic left ventricular ( LV ) dimensions and systolic and diastolic function using multivariable‐adjusted partial Pearson correlations. Mean arterial pressure ( MAP , steady component of central blood pressure) was associated positively with LV wall thickness ( r =0.168; P LV diastolic dimension ( r =0.035, P =0.006). Central pulse pressure (pulsatile component of central blood pressure) showed a direct correlation with both LV diastolic dimension and LV wall thickness ( r =0.08 and 0.044, both P MAP ). CFPWV was not associated with LV structure (all P ≥0.27) in MAP ‐adjusted models). Both MAP and CFPWV were associated inversely with LV diastolic function (E′; r =−0.140 and −0.153, respectively; both P LV mass and central pulse pressure ( r =−0.142 and −0.108, both P MAP and CFPWV were not associated with LV fractional shortening ( P ≥0.10), whereas central pulse pressure was positively related ( r =0.064, P Conclusions Pulsatile and steady components of central pressure are conjointly yet variably related to LV structure. CFPWV is related to LV diastolic function but not to systolic function. Additional studies are warranted to confirm these observations.

Background Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated. Measures and Results We related objective measures of moderate‐ to vigorous‐intensity physical activity ( MVPA , assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P =0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P =0.03) but were not associated with augmentation index (estimate 0.13%; P =0.25). MVPA was associated positively with log e left ventricular mass (estimate 0.006 log e [g/m 2 ]; P =0.0003), left ventricular wall thickness (estimate 0.07 mm; P =0.0001), and left atrial dimension (estimate 0.10 mm; P =0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P =0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting Conclusions In our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.

Background Somatic growth in childhood is accompanied by substantial remodeling of the aorta. Obesity is associated with increased aortic stiffness and flow and may interfere with aortic remodeling during growth. Wide pulse pressure ( PP ) indicates mismatch between aortic impedance and pulsatile flow and increases risk for future systolic hypertension and cardiovascular disease ( CVD ). We hypothesized that the rise of pediatric obesity would be associated with a temporal trend to higher PP . Methods and Results We analyzed demographic, anthropometric, and blood pressure ( BP ) data for 8‐ to 17‐year‐old children (N=16 457) from the cross‐sectional National Health and Nutrition Examination Surveys ( NHANES ) for 1976 through 2008. Multivariable adjusted survey regression was used to examine temporal trends in PP and mean arterial pressure ( MAP ) and the relation to obesity. Across this period, unadjusted PP was higher (0.29 mm Hg/y, 95% CI 0.26 to 0.33 mm Hg/y; P MAP was lower (−0.24 mm Hg/y, 95% CI −0.27 to −0.20 mm Hg/y; P PP by 32% ( P 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 Conclusions PP has increased during the rise of pediatric obesity. Higher PP may indicate mismatch between aortic diameter, wall stiffness, and flow in obese children during a period of rapid somatic growth when the aorta is already under considerable remodeling stress.