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BACKGROUND: Aortic stiffness, assessed as carotid-femoral pulse wave velocity, provides a measure of vascular age and risk for adverse cardiovascular disease outcomes, but it is difficult to measure. The shape of arterial pressure waveforms conveys information regarding aortic stiffness; however, the best methods to extract and interpret waveform features remain controversial. METHODS: We trained a convolutional neural network with fixed-scale (time and amplitude) brachial, radial, and carotid tonometry waveforms as input and negative inverse carotid-femoral pulse wave velocity as label. Models were trained with data from 2 community-based Icelandic samples (N=10 452 participants with 31 126 waveforms) and validated in the community-based Framingham Heart Study (N=7208 participants, 21 624 waveforms). Linear regression rescaled predicted negative inverse carotid-femoral pulse wave velocity to equivalent artificial intelligence vascular age (AI-VA). RESULTS: The AI-VascularAge model predicted negative inverse carotid-femoral pulse wave velocity with R2=0.64 in a randomly reserved Icelandic test group (n=5061, 16%) and R2=0.60 in the Framingham Heart Study. In the Framingham Heart Study (up to 18 years of follow-up; 479 cardiovascular disease, 200 coronary heart disease, and 213 heart failure events), brachial AI-VA was associated with incident cardiovascular disease adjusted for age and sex (model 1; hazard ratio, 1.79 [95% CI, 1.50-2.40] per SD; P<0.0001) or adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent diabetes, hypertension treatment, and current smoking (model 2; hazard ratio, 1.50 [95% CI, 1.24-1.82] per SD; P<0.0001). Similar hazard ratios were demonstrated for incident coronary heart disease and heart failure events and for AI-VA values estimated from carotid or radial waveforms. CONCLUSIONS: Our results demonstrate that convolutional neural network--derived AI-VA is a powerful indicator of vascular health and cardiovascular disease risk in a broad community-based sample. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness increases with age and is associated with an increased risk of adverse outcomes on short-term follow-up (typically <10 years). Data regarding associations of arterial stiffness with health outcomes on longer-term follow-up are lacking.Methods: We evaluated 7283 Framingham Study participants (mean age 50 years, 53% women) who underwent assessment of carotid-femoral pulse wave velocity (a marker of arterial stiffness) via applanation tonometry at one or more routine examinations. We used time-dependent Cox proportional hazards regression models to relate carotid-femoral pulse wave velocity to the incidence of health outcomes (updating carotid-femoral pulse wave velocity and all covariates at serial examinations).Results: On long-term follow-up (median 15 years; minimum-maximum, 0-20), participants developed cardiometabolic disease (hypertension [1255 events]; diabetes [381 events]), chronic kidney disease (529 events), dementia (235 events), cardiovascular disease (684 events) and its components (coronary heart disease [314 events], heart failure [191 events], transient ischemic attacks or stroke [250 events]), and death (1086 events). In multivariable-adjusted models, each SD increment in carotid-femoral pulse wave velocity was associated with increased risk of hypertension (hazard ratio [HR], 1.32 [95% CI, 1.21-1.44]), diabetes (HR, 1.32 [95% CI, 1.11-1.58]), chronic kidney disease (1.19 [95% CI, 1.05-1.34]), dementia (HR 1.27 [95% CI, 1.06-1.53]), cardiovascular disease (HR, 1.20 [95% CI, 1.06-1.36]) and its components (coronary heart disease, HR 1.37 [95% CI, 1.13-1.65]; transient ischemic attack/stroke, HR, 1.24 [95% CI, 1.00-1.53]), and death (HR, 1.29 [95% CI, 1.17-1.43]). The association with heart failure was borderline nonsignificant (HR, 1.21 [95% CI, 0.98-1.51], P=0.08).Conclusions: Our prospective observations of a large community-based sample establish the long-term prognostic importance of arterial stiffness for multiple health outcomes. [ABSTRACT FROM AUTHOR]

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Intrinsic frequencies (IFs) derived from arterial waveforms are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures is unknown. We hypothesized that IFs are associated with incident CVD risk. Our sample was drawn from the Framingham Heart Study Original, Offspring, and Third Generation Cohorts and included participants free of CVD at baseline (N=4700; mean age 52 years, 55% women). We extracted 2 dominant frequencies directly from a series of carotid pressure waves: the IF of the coupled heart and vascular system during systole (ω1) and the IF of the decoupled vasculature during diastole (ω2). Total frequency variation (Δω) was defined as the difference between ω1 and ω2. We used Cox proportional hazards regression models to relate IFs to incident CVD events during a mean follow-up of 10.6 years. In multivariable models adjusted for CVD risk factors, higher ω1 (hazard ratio [HR], 1.14 [95% CI], 1.03-1.26]; P=0.01) and Δω (HR, 1.16 [95% CI, 1.03-1.30]; P=0.02) but lower ω2 (HR, 0.87 [95% CI, 0.77-0.99]; P=0.03) were associated with higher risk for incident composite CVD events. In similarly adjusted models, higher ω1 (HR, 1.23 [95% CI, 1.07-1.42]; P=0.004) and Δω (HR, 1.26 [95% CI, 1.05-1.50]; P=0.01) but lower ω2 (HR, 0.81 [95% CI, 0.66-0.99]; P=0.04) were associated with higher risk for incident heart failure. IFs were not significantly associated with incident myocardial infarction or stroke. Novel IFs may represent valuable markers of heart failure risk in the community. [ABSTRACT FROM AUTHOR]

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/cm5; central pulse pressure, 2.6±14.7 mm Hg; all P<0.0001) increased, whereas MAP fell (-3±10 mm Hg; P<0.0001). Worsening of each metabolic trait was associated with increases in CFPWV and MAP (P<0.0001 for all associations) and an increase in MAP was associated with an increase in CFPWV. Overall, worsening metabolic traits were associated with worsening aortic stiffness and MAP. Opposite net change in aortic stiffness and MAP suggests that factors other than distending pressure contributed to the observed increase in aortic stiffness. Change in metabolic traits explained a greater proportion of the change in CFPWV and MAP than baseline metabolic values. [ABSTRACT FROM AUTHOR]

BACKGROUND: Deep neural networks have been used to estimate age from ECGs, the electrocardiographic age (ECG-age), which predicts adverse outcomes. However, this prediction ability has been restricted to clinical settings or relatively short periods. We hypothesized that ECG-age is associated with death and cardiovascular outcomes in the long-standing community-based FHS (Framingham Heart Study). METHODS: We tested the association of ECG-age with chronological age in the FHS cohorts in ECGs from 1986 to 2021. We calculated the gap between chronological and ECG-age (Δage) and classified individuals as having normal, accelerated, or decelerated aging, if Δage was within, higher, or lower than the mean absolute error of the model, respectively. We assessed the associations of Δage, accelerated and decelerated aging with death or cardiovascular outcomes (atrial fibrillation, myocardial infarction, and heart failure) using Cox proportional hazards models adjusted for age, sex, and clinical factors. RESULTS: The study population included 9877 FHS participants (mean age, 55±13 years; 54.9% women) with 34 948 ECGs. ECG-age was correlated to chronological age (r=0.81; mean absolute error, 9±7 years). After 17±8 years of follow-up, every 10-year increase of Δage was associated with 18% increase in all-cause mortality (hazard ratio [HR], 1.18 [95% CI, 1.12–1.23]), 23% increase in atrial fibrillation risk (HR, 1.23 [95% CI, 1.17–1.29]), 14% increase in myocardial infarction risk (HR, 1.14 [95% CI, 1.05–1.23]), and 40% increase in heart failure risk (HR, 1.40 [95% CI, 1.30–1.52]), in multivariable models. In addition, accelerated aging was associated with a 28% increase in all-cause mortality (HR, 1.28 [95% CI, 1.14–1.45]), whereas decelerated aging was associated with a 16% decrease (HR, 0.84 [95% CI, 0.74–0.95]). CONCLUSIONS: ECG-age was highly correlated with chronological age in FHS. The difference between ECG-age and chronological age was associated with death, myocardial infarction, atrial fibrillation, and heart failure. Given the wide availability and low cost of ECG, ECG-age could be a scalable biomarker of cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background--Cigarette smoking increases risk for multiple diseases. MicroRNAs regulate gene expression and may play a role in smoking-induced target organ damage. We sought to describe a microRNA signature of cigarette smoking and relate it to smoking-associated clinical phenotypes, gene expression, and lung inflammatory signaling. Methods and Results--Expression profiling of 283 microRNAs was conducted on whole blood-derived RNA from 5023 Framingham Heart Study participants (54.0% women; mean age, 55±13 years) using TaqMan assays and high-throughput reverse transcription quantitative polymerase chain reaction. Associations of microRNA expression with smoking status and associations of smoking-related microRNAs with inflammatory biomarkers and pulmonary function were tested with linear mixed effects models. We identified a 6-microRNA signature of smoking. Five of the 6 smoking-related microRNAs were associated with serum levels of C-reactive protein or interleukin-6; miR-1180 was associated with pulmonary function measures at a marginally significant level. Bioinformatic evaluation of smoking-associated genes coexpressed with the microRNA signature of cigarette smoking revealed enrichment for immune-related pathways. Smoking-associated microRNAs altered expression of selected inflammatory mediators in cell culture gain-of-function assays. Conclusions--We characterized a novel microRNA signature of cigarette smoking. The top microRNAs were associated with systemic inflammatory markers and reduced pulmonary function, correlated with expression of genes involved in immune function, and were sufficient to modulate inflammatory signaling. Our results highlight smoking-associated microRNAs and are consistent with the hypothesis that smoking-associated microRNAs serve as mediators of smoking-induced inflammation and target organ damage. These findings call for further mechanistic studies to explore the diagnostic and therapeutic use of smoking-related microRNAs. [ABSTRACT FROM AUTHOR]

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 <7.6 m/s (mean+2 SD of a reference sample aged <30 years). Overall, 566 (17.7%) individuals had HVA, with prevalence decreasing from 30.3% in people aged 50 to 59 to 1% in those aged ≥70 years. In regression models adjusted for physical activity, caloric intake, and traditional cardiovascular disease (CVD) risk factors, we observed that lower age, female sex, lower body mass index, use of lipid-lowering drugs, and absence of diabetes mellitus were cross-sectionally associated with HVA (P<0.001 for all). A unit increase in a cardiovascular health score (Life's Simple 7) was associated with 1.55-fold (95% confidence interval, 1.38-1.74) age- and sex-adjusted odds of HVA. During a follow-up of 9.6 years, 391 CVD events occurred. In Cox regression models adjusted for traditional CVD risk factors, including blood pressure, HVA was associated with a hazard ratio of 0.45 (95% confidence interval, 0.26-0.77) for CVD relative to absence of HVA. Although HVA is achievable in individuals acculturated to a Western lifestyle, maintaining normal vascular function beyond 70 years of age is challenging. Although our data are observational, our findings support prevention strategies targeting modifiable factors and behaviors and obesity, in particular, to prevent or delay vascular aging and the associated risk of CVD. [ABSTRACT FROM AUTHOR]

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 <40 years to 0.73±0.21 in those aged ≥80 years. In multivariable linear regression, older age, male sex, higher body mass index, diabetes mellitus, lower high-density lipoprotein cholesterol, higher mean arterial pressure, and higher heart rate were associated with lower PWV ratio (P<0.001 for all). During a median follow-up of 12.6 years, 248 first CVD events occurred. In Cox regression models adjusted for standard CVD risk factors, 1-SD changes in CFPWV (hazard ratio, 1.33; 95% confidence interval, 1.10-1.61) and PWV ratio (hazard ratio, 1.32; 95% confidence interval, 1.09-1.59) were associated with similar CVD risks. Models that included conventional CVD risk factors plus CFPWV or PWV ratio gave the same C statistics (C=0.783). Although PWV ratio has been reported to provide incremental predictive value over CFPWV in dialysis patients, we could not replicate these findings in our community-based sample. Our findings suggest that the prognostic significance of PWV ratio may vary based on baseline CVD risk, and CFPWV should remain the criterion standard for assessing vascular stiffness in the community. [ABSTRACT FROM AUTHOR]

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<0.0001). After accounting for body mass index, we found that central adiposity, as measured by waist circumference, was associated with worse global longitudinal strain and synchrony (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<0.0001), whereas no such association was found with leptin receptor, adiponectin, or C-reactive protein. 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. [ABSTRACT FROM AUTHOR]

Impaired regulation of blood pressure on standing can lead to adverse outcomes, including falls, syncope, and disorientation. Mean arterial pressure (MAP) typically increases on standing; however, an insufficient increase or a decline in MAP on standing may result in decreased cerebral perfusion. Orthostatic hypotension has been reported in older people with increased arterial stiffness, whereas the association between orthostatic change in MAP and arterial stiffness in young- to middle-aged individuals has not been examined. We analyzed orthostatic blood pressure response and comprehensive hemodynamic data in 3205 participants (1693 [53%] women) in the Framingham Heart Study Third Generation cohort. Participants were predominantly middle aged (mean age: 46±9 years). Arterial stiffness was assessed using carotid-femoral pulse wave velocity, forward pressure wave amplitude, and characteristic impedance of the aorta. Adjusting for standard cardiovascular disease risk factors, orthostatic change in MAP (6.9±7.7 mm Hg) was inversely associated with carotid-femoral pulse wave velocity (partial correlation, rp=-0.084; P<0.0001), forward wave amplitude (rp=-0.129; P<0.0001), and characteristic impedance (rp=-0.094; P<0.0001). The negative relation between forward wave amplitude and change in MAP on standing was accentuated in women (P=0.002 for sex interaction). Thus, higher aortic stiffness was associated with a blunted orthostatic increase in MAP, even in middle age. The clinical implications of these findings warrant further study. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct clinical entities, yet there is scant evidence for associations of proteomic signatures with future development of HFpEF versus HFrEF. Methods: We evaluated the association of 71 protein biomarkers with incident HFpEF versus HFrEF (left ventricular ejection fraction ≥ versus <50%) among Framingham Heart Study participants using multivariable Cox models. Results: Among 7038 participants (mean age 49 years; 54% women), 5 biomarkers were associated with increased risk of incident HFpEF (false discovery rate q<0.05): NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio [HR], 2.13; 95% CI, 1.52–2.99; P <0.001), growth differentiation factor-15 (HR, 1.67; 95% CI, 1.32–2.12; P <0.001), adrenomedullin (HR, 1.58; 95% CI, 1.23–2.04; P <0.001), uncarboxylated matrix Gla protein (HR, 1.55; 95% CI 1.23–1.95; P <0.001), and C-reactive protein (HR, 1.46; 95% CI, 1.17–1.83; P =0.001). Fourteen biomarkers were associated with incident HFrEF (multivariable P <0.001, q<0.05 for all). Of these, 3 biomarkers were associated with both HF subtypes (NT-proBNP, growth differentiation factor-15, and C-reactive protein). When compared directly, myeloperoxidase, resistin, and paraoxanase-1 were more strongly associated with HFrEF than HFpEF. Conclusions: We identified 5 protein biomarkers of new-onset HFpEF representing pathways of inflammation, cardiac stress, and vascular stiffness, which partly overlapped with HFrEF. We found 14 biomarkers associated with new-onset HFrEF, with some distinct associations including myeloperoxidase, resistin, and paraoxanase-1. Taken together, these findings provide insights into similarities and differences in the development of HF subtypes. Registration: URL: https://clinicaltrials.gov/ct2/show/NCT00005121; Unique identifier: NCT0005121. [ABSTRACT FROM AUTHOR]

Background-Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Interrelations 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. [ABSTRACT FROM AUTHOR]

The associations of long-term patterns of risk factors and the risk of incident atrial fibrillation (AF) are incompletely characterized. Among 4351 Framingham Study participants (mean age 50±11 years at baseline examination, 57% women) from the original and offspring cohorts, we defined longitudinal patterns, referred to as trajectories, of AF risk factors and a composite AF risk score using ≈16 years of data. We used Cox proportional hazards models to examine the association of trajectories to 15-year risk of AF. During follow-up, 719 participants developed AF. Five distinct trajectory groups were identified for systolic blood pressure (BP): groups 1 and 2 (normotensive throughout), group 3 (prehypertensive), group 4 (hypertensive initially with decreasing BP), and group 5 (hypertensive and increasing BP). In multivariable-adjusted analyses, compared with group 1, groups 4 (hazard ratio 2.05; 95% confidence interval 1.24-3.37) and 5 (hazard ratio 1.95; 95% confidence interval 1.08-3.49) were associated with incident AF. Three trajectory groups were identified for antihypertensive treatment. Compared with the group with no treatment throughout, the other 2 groups were associated with increased risk of incident AF. Distinct trajectories for diastolic BP, smoking, diabetes mellitus, and the composite risk score were not associated with increased 15-year risk of AF. Longitudinal trajectories may distinguish how exposures related to AF contribute toward prospective AF risk. Distinct trajectory groups with persistently elevated systolic BP and longer antihypertensive treatment are associated with increased risk of incident AF. [ABSTRACT FROM AUTHOR]

The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged ≥45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid-femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow-mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02-1.32; P=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43; P=0.04), and lower flow-mediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99; P=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF. [ABSTRACT FROM AUTHOR]

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<0.001 for both) and with greater forward pressure wave amplitude (1.6 mm Hg; 95% confidence interval, 0.6-2.7, and 1.9 mm Hg; 95% confidence interval, 0.6-3.2, for 1 and 2 parents with hypertension, respectively; 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. [ABSTRACT FROM AUTHOR]

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<0.01), larger lateral ventricular volumes (β±SE, 0.09±0.03; P<0.01) and a greater burden of white-matter hyperintensities (β±SE, 0.09±0.03; P<0.001). When stratifying by age, aortic stiffness was associated with lateral ventricular volume in young adults (30-45 years), whereas aortic stiffness was associated with white-matter injury and cognition in midlife (45-65 years). In conclusion, aortic stiffness was associated with cognitive function and markers of subclinical brain injury in young to middle-aged adults. Prospective studies are needed to examine whether aortic stiffening in young adulthood is associated with vascular cognitive impairment later in life. [ABSTRACT FROM AUTHOR]

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<0.001) and inversely with adiponectin (P=0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels (P<0.002 both). In fully adjusted models, aortic stiffness was positively associated with fatty acid-binding protein 4 concentrations (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. [ABSTRACT FROM AUTHOR]

The article discusses a research which examines the genetic variation influencing the biomarker levels of circulating endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor. It reveals the association of sTie-2 and hepatocyte growth factor concentrations with single-nucleotide polymorphisms It indicates that genetic variation contributes to the interindividual variation in biomarker levels.

Whether low diastolic blood pressure (DBP) is a risk factor for recurrent cardiovascular disease (CVD) events in persons with isolated systolic hypertension is controversial. We studied 791 individuals (mean age 75 years, 47% female, mean follow-up time: 8±6 years) with DBP <70 (n=225) versus 70 to 89 mm Hg (n=566) after initial CVD events in the original and offspring cohorts of the Framingham Heart Study. Recurrent CVD events occurred in 153 (68%) participants with lower DBP and 271 (48%) with higher DBP (P<0.0001). Risk of recurrent CVD events in risk factor-adjusted Cox regression was higher in those with DBP <70 mm Hg versus DBP 70 to 89 mm Hg in both treated (hazard ratio, 5.1 [95% confidence interval: 3.8-6.9] P<0.0001) and untreated individuals (hazard ratio, 11.7 [95% confidence interval: 6.5-21.1] P<0.0001; treatment interaction: P=0.71). Individually, coronary heart disease, heart failure, and stroke recurrent events were more likely with DBP <70 mm Hg versus 70 to 89 mm Hg (P<0.0001). To examine for an effect of wide pulse pressure on excess risk associated with low DBP, we defined 4 binary groupings of pulse pressure (≥68 versus <68 mm Hg) and DBP (<70 versus 70-89 mm Hg). CVD incidence rates were higher only in the group with pulse pressure ≥68 and DBP <70 mm Hg (76% versus 46%-54%; P<0.001). Persons with isolated systolic hypertension and prior CVD events have increased risk for recurrent CVD events in the presence of DBP <70 mm Hg versus DBP 70 to 89 mm Hg, whether treated or untreated, supporting wide pulse pressure as an important risk modifier for the adverse effect of low DBP. [ABSTRACT FROM AUTHOR]

The article discusses research which assessed the long-term risks related to early and late-onset prehypertension without progression to hypertension. Topics discussed include an investigation of the relation among blood pressure (BP) phenotypes and cause-specific mortality using a case-control design and the association of late and early-onset hypertension with increased odds of cardiovascular disease (CVD) and coronary heart disease (CHD) death versus other causes.

Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) aged from 19 to 90 years (mean age, 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width, and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated nonlinear relations with age (age: B=4.6±0.1%; P<0.001; age²: B=-4.2±0.1%; P<0.001) and higher augmentation in women (B=4.5±0.4%; P<0.001; model P²=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R²=0.62) and reduced the age coefficients: age (B=2.3±0.1%; P<0.001) and age² (B=-2.2±0.1%; P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke, and forward wave amplitude further improved model fit (R²=0.75) and attenuated the sex coefficient (B=1.9±0.2%; P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex difference in augmentation index may be explained by forward and backward wave morphology. [ABSTRACT FROM AUTHOR]

There is rapidly growing interest in applying measures of myocardial strain and synchrony in clinical investigations and in practice; data are limited regarding their reference ranges in healthy individuals.We performed speckle-tracking-based echocardiographic measures of left ventricular myocardial strain and synchrony in healthy adults (n=739, mean age 63 years, 64% women) without cardiovascular disease. Reference values were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were: -14.4% to -17.1% (women) and -14.4 to -15.2% (men) for longitudinal strain; -22.3% to -24.7% (women) and -17.9% to -23.7% (men) for circumferential strain; 121 to 165 ms (women) and 143 to 230 ms (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and 200 to 222 ms (women) and 216 to 303 ms (men) for transverse segmental synchrony. In multivariable analyses, women had ≈1.7% greater longitudinal strain, ≈2.2% greater transverse strain, and ≈3.2% greater circumferential strain (P<0.0001 for all) compared with men. Older age and higher diastolic blood pressure, even within the normal range, were associated with worse transverse segmental synchrony (P<0.001). Overall, covariates contributed to 12% of the variation in myocardial strain or synchrony in this healthy sample.We estimated age- and sex-specific reference limits for measures of left ventricular strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed to only a modest proportion of the variation. These data may facilitate the interpretation of left ventricular strain-based measures obtained in future clinical research and practice. [ABSTRACT FROM AUTHOR]