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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.

Introduction Association between arterial vascular dysfunction and risk of venous thromboembolism (VTE) is uncertain. We determined the associations between comprehensive measures of arterial vascular function and risk of incident VTE in a community-based cohort study with robust longitudinal follow-up. Materials and methods In the Framingham Heart Study Original, Offspring, Third Generation, and Omni cohorts, we measured carotid-femoral pulse wave velocity and central pulse pressure (n = 8261, age 51.5 ± 15.5 years, 54% women), flow-mediated dilation and hyperemic velocity (n = 6540, age 47.9 ± 14.1 years, 54% women), and peripheral arterial tonometry ratio (n = 4998, age 54.3 ± 16.0 years, 52% women). Deep venous thrombosis and pulmonary embolism were diagnosed with imaging studies and adjudicated by three Framingham Heart Study physicians. Results and conclusions The rate of incident VTE was 1.6–2.1 per 1000 person-years during mean follow-up of 8.5–11.2 years. In age- and sex-adjusted Cox proportional hazards regression models, carotid-femoral pulse wave velocity was associated with increased risk of VTE (HR 1.32, 95% CI 1.05–1.66, p = 0.02), however the association was no longer statistically significant after multivariable adjustment (HR 1.24, 95% CI 0.96–1.61, p = 0.10). None of the other vascular variables were associated with the risk of VTE in any of the models. In our comprehensive examination of arterial vascular function and risk of VTE, we did not observe any association between select arterial function measures and risk of VTE after multivariable adjustment.

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.

Rationale & Objective The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. Study Design Cross-sectional cohort analysis of data from the Jackson Heart Study. Settings & Patients 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. Predictors Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. Outcomes Prevalent albuminuria, urinary albumin-creatinine ratio. Analytical Approach 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. Results Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). Limitations Cross-sectional analyses cannot inform causality. Conclusions Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans., Graphical abstract

Higher central pulse pressure is associated with higher carotid-femoral pulse wave velocity (CFPWV) and an increased risk of cardiovascular disease (CVD). A smaller aortic root diameter (AoR) is associated with higher central pulse pressure. We hypothesized that the combination of a smaller AoR and higher CFPWV is associated with increased CVD risk (relative to a larger AoR and lower CFPWV). We tested this hypothesis in the community-based Framingham Study (N=1970, mean age 60 years, 57% women). We created sex-specific longitudinal echocardiographic AoR trajectories over 2 decades, categorizing participants into smaller versus larger AoR groups. We cross-classified participants based on their AoR trajectory and CFPWV (dichotomized at the sex-specific median). We used Cox regression to relate the cross-classified groups to CVD incidence on follow-up (median 17 years): lower CFPWV, larger AoR (referent group; 6.4/1000 person-years); lower CFPWV, smaller AoR (6.9/1000 person-years); higher CFPWV, larger AoR (23.1/1000 person-years); and higher CFPWV, smaller AoR (21.9/1000 person-years). In sex-pooled analyses, groups with higher CFPWV were associated with a multivariable-adjusted 1.8-fold risk of CVD ( P P for sex×AoR-CFPWV group interaction 0.04). In men, the group with smaller AoR and higher CFPWV was associated with a 2.5- to 2.8-fold risk of CVD ( P

Community-based studies have evaluated cross-sectional age relations of aortic stiffness measures, which are not often recapitulated in longitudinal studies. We examined baseline and longitudinal change in aortic stiffness in 5491 participants (mean age, 49.5±14.5 years; 54% women) who attended 2 sequential examinations (6.0±0.6 years apart) of the Framingham Heart Study. Cross-sectional relations of central hemodynamics (mean arterial pressure, central pulse pressure, carotid-femoral pulse wave velocity, and characteristic impedance) with age and risk factors were assessed at visits 1 and 2 (models 1 and 2). We used model 1 coefficients (M 1 ), visit 1 risk factor levels (R 1 ), and age at each visit (A 1 , A 2 ) to estimate values at visits 1 (M 1 R 1 A 1 ) and 2 (M 1 R 1 A 2 ). While using model 1 coefficients, we accounted for age and risk factor level (R 2 ) changes to predict values at visit 2 (M 1 R 2 A 2 ). Using model 2 coefficients (M 2 ) and visit 2 age and risk factor levels, we predicted visit 2 values (M 2 R 2 A 2 ). We calculated predicted change 3 ways: delta1=M 1 R 1 A 2 −M 1 R 1 A 1 , delta2=M 1 R 2 A 2 −M 1 R 1 A 1 , and delta3=M 2 R 2 A 2 −M 1 R 1 A 1 . Delta1 values were biased and correlated poorly with actual changes ( r =−0.02–0.14). For mean arterial pressure, delta1=1.9±0.8 mm Hg ( r =0.14), observed change=−3.3±10.3 mm Hg, and discrepancy=5.2±10.2 mm Hg ( P 5 ( r =0.07), observed change=20.5±68.2 dyne×sec/cm 5 , and discrepancy=−13.3±68.7 dyne×sec/cm 5 ( P r =0.17–0.54) but remained biased whereas delta3 values were moderately correlated with change with no bias. Projected change in hemodynamic measures extrapolated from cross-sectional age relations may differ substantially from actual change, particularly for variables with nonlinear age relations.

Pulse pressure has been frequently used as a surrogate marker of arterial compliance. However, the prevalence and prognostic significance of mismatch between pulse pressure and arterial stiffness remains unclear. We measured carotid-femoral pulse wave velocity (CFPWV) and central pulse pressure (CPP) in 2119 Framingham Offspring Cohort participants (mean age, 60 years; 57% women). The participants were divided into 4 groups according to CPP and CFPWV status (categorized as high/low based on ≥age- and sex-specific median values) and followed up for cardiovascular disease (CVD) events. At baseline, 832 of 2119 (39%) participants had discordant CPP and CFPWV status, 417 with low CPP and high CFPWV, and 415 with high CPP and low CFPWV. The multivariable-adjusted risk for CVD events (n=246; median follow-up, 12.6 years) in individuals with a CPP-CFPWV mismatch (hazard ratio for low CPP with high CFPWV, 1.21; 95% CI, 0.83–1.76; hazard ratio for high CPP with low CFPWV, 0.76; 95% CI, 0.49–1.19) was comparable with the CVD risk observed in the low CPP with low CFPWV (referent group). In contrast, participants with a high CPP with high CFPWV (hazard ratio, 1.52; 95% CI, 1.10–2.11) experienced significantly increased CVD risk. The interaction term between CPP and CFPWV status on CVD risk was borderline significant in the multivariable model ( P =0.08). Our results demonstrate that pulse pressure-arterial stiffness mismatch is common in the community. CFPWV may modify the association of CPP with CVD risk, with the greatest risk being observed in those with elevated CPP and CFPWV.

Background: Studies of air pollution exposure and arterial stiffness have reported inconsistent results and large studies employing the reference standard of arterial stiffness, carotid-femoral pulse-wave velocity (CFPWV), have not been conducted. Aim: To study long-term exposure to ambient fine particles (PM2.5), proximity to roadway, and short-term air pollution exposures in relation to multiple measures of arterial stiffness in the Framingham Heart Study. Methods: We assessed central arterial stiffness using CFPWV, forward pressure wave amplitude, mean arterial pressure and augmentation index. We investigated long-and short-term air pollution exposure associations with arterial stiffness with linear regressions using long-term residential PM2.5 (2003 average from a spatiotemporal model using satellite data) and proximity to roadway in addition to short-term averages of PM2.5, black carbon, particle number, sulfate, nitrogen oxides, and ozone from stationary monitors. Results: We examined 5842 participants (mean age 51 ± 16, 54% women). Living closer to a major roadway was associated with higher arterial stiffness (0.11 m/s higher CFPWV [95% CI: 0.01, 0.22] living

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.

Background: Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction. Methods: EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Z c ) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12. Results: In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, −3.0±0.8 mm Hg, P P c were greater in the sacubitril-valsartan group (−16±6 dyne×second/cm 5 , P =0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction P =0.036). With LVEFc were greater in the sacubitril-valsartan group (trough, −3±8 dyne×second/cm 5 versus post-dose, −17±8 dyne×second/cm 5 ; interaction P =0.024) with no sex difference (treatment×sex interaction, P =0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Z c in women (women, −80±21 dyne×second/cm 5 versus men, −20±13 dyne×second/cm 5 ; interaction P =0.019). Conclusions: In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Z c . In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Z c in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02874794.

Background Aortic stiffening begins in youth and antedates future hypertension. In adults, excess weight, systemic inflammation, dyslipidemia, insulin resistance, neurohormonal activation, and altered adipokines are implicated in the pathogenesis of increased aortic stiffness. In adolescents, we assessed the relations of comprehensive measures of aortic stiffness with body mass index (BMI) and related but distinct circulating biomarkers. Methods and Results A convenience sample of 246 adolescents (mean age, 16±2 years; 45% female, 24% Black, and 43% Hispanic) attending primary care or preventive cardiology clinics at 2 tertiary hospitals was grouped as normal weight (N=98) or excess weight (N=148, defined as BMI ≥age‐ and sex‐referenced 85th percentile). After an overnight fast, participants underwent anthropometry, noninvasive arterial tonometry, and assays for serum lipids, CRP (C‐reactive protein), glucose, insulin, renin, aldosterone, and leptin. We used multivariable linear regression to relate arterial stiffness markers (including carotid‐femoral pulse wave velocity) to BMI z score and a biomarker panel. Carotid‐femoral pulse wave velocity was higher in excess weight compared with normal weight group (5.0±0.7 versus 4.6±0.6 m/s; P z score (0.09 [95% CI, 0.01–0.18]; P =0.04) and with low‐density lipoprotein cholesterol (0.26 [95% CI, 0.03–0.50]; P =0.03). Conclusions Higher BMI and low‐density lipoprotein cholesterol were associated with greater aortic stiffness in adolescents. Maintaining optimal BMI and lipid levels may mitigate aortic stiffness.

Rationale: BCL11B (B-cell leukemia 11b) is a transcription factor known as an essential regulator of T lymphocytes and neuronal development during embryogenesis. A genome-wide association study showed that a gene desert region downstream of BCL11B , known to function as a BCL11B enhancer, harbors single nucleotide polymorphisms associated with increased arterial stiffness. However, a role for BCL11B in the adult cardiovascular system is unknown. Objective: Based on these human findings, we sought to examine the relation between BCL11B and arterial function. Methods and Results: Here we report that BCL11B is expressed in the vascular smooth muscle where it regulates vascular stiffness. RNA sequencing of aortas from wild-type and Bcl11b null mice (BSMKO) identified the cGMP (cyclic guanosine monophosphate)-cGMP-dependent protein kinase G (PKG) as the most significant differentially regulated signaling pathway in BSMKO compared with wild-type mice. BSMKO aortas showed decreased levels of PKG1, increased levels of Ca ++ -calmodulin-dependent serine/threonine phosphatase calcineurin (PP2B) and decreased levels of their common phosphorylation target, phosphorylated vasodilator-stimulated phosphoprotein (pVASP S239 ), a regulator of cytoskelatal actin rearrangements. Decreased pVASP S239 in BSMKO aortas was associated with increased actin polymerization (filamentous/globular actin ratio). Functionally, aortic force, stress, wall tension, and stiffness, measured ex vivo in organ baths, were increased in BSMKO aortas, and BSMKO mice had increased pulse wave velocity, the in vivo index of arterial stiffness. Despite having no effect on blood pressure or microalbuminuria, increased arterial stiffness in BSMKO mice was associated with increased incidence of cerebral microbleeds compared with age-matched wild-type littermates. Conclusions: We have identified vascular smooth muscle BCL11B as a crucial regulator of aortic smooth muscle function and a potential therapeutic target for vascular stiffness.

Aortic stiffness increases markedly with age and is associated with excess risk for various adverse clinical outcomes, including heart disease, dementia, and kidney disease. Although evidence for adverse effects of aortic stiffening is overwhelming, integration of direct and indirect measures of aortic stiffness into routine clinical assessment has lagged behind the science. This brief review will examine recent evidence supporting the value of stiffness as an important new risk factor for hypertension and cardiovascular disease and will offer suggestions for incorporating stiffness measures into routine clinical practice.

Arterial stiffness is increased with increasing age, and pulse pressure (PP), a marker of arterial stiffness, is a predictor of incident cardiovascular disease and mortality. However, the prognostic relevance of PP in heart failure (HF) with preserved ejection fraction has not been fully understood. We studied 4796 patients with HF with preserved ejection fraction from the PARAGON-HF trial. All patients underwent sequential run-in phases of valsartan and sacubitril/valsartan before randomization. We categorized patients by PP quartile and evaluated the influence of baseline PP on the PARAGON-HF primary end point (total HF hospitalizations and cardiovascular death). At screening, the median PP was 58 mm Hg (interquartile range, 50–69 mm Hg). There was a nonlinear, J-shaped association between PP and outcomes. Multivariable Cox proportional hazards models showed that patients in the highest PP quartile had a higher risk of the primary end point (adjusted hazard ratio, 1.39 [95% CI, 1.14–1.69]; P =0.001), total HF hospitalizations (adjusted hazard ratio, 1.43 [95% CI, 1.15–1.79]; P =0.001), and myocardial infarction (adjusted hazard ratio, 1.54 [95% CI, 1.06–2.23]; P =0.022) compared with those in the second (lowest risk) PP quartile. Reductions in PP during sacubitril/valsartan run-in were associated with a decreased risk of the primary end point and total HF hospitalizations. One year after randomization, PP was significantly lower in the sacubitril/valsartan group compared with the valsartan group (3.0 mm Hg decrease [95% CI, 2.4–3.5]; P

Introduction Obesity, hypertension, and diabetes are independently associated with cardiac remodeling and frequently co-cluster. The conjoint and separate influences of these conditions on cardiac remodeling have not been investigated. Materials and methods We evaluated 5,741 Framingham Study participants (mean age 50 years, 55% women) who underwent echocardiographic measurements of left ventricular (LV) mass (LVM), LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral E/e’, left atrial end-systolic (peak) dimension (LASD) and emptying fraction (LAEF). We used multivariable generalized linear models to estimate the adjusted-least square means of these measures according to cross-classified categories of body mass index (BMI; normal, overweight and obese), hypertension (yes/no), and diabetes (yes/no). Results We observed statistically significant interactions of BMI category, hypertension, and diabetes with LVM, LVEF, GLS, and LAEF (p for all 3-way interactions Conclusions Obesity, hypertension, and diabetes interact synergistically to influence cardiac remodeling. These findings may explain the markedly heightened risk of heart failure and cardiovascular disease when these factors co-cluster.

BackgroundIt is well established that coronary artery disease progresses along with myocardial disease. However, data on the association between coronary artery calcium (CAC) and echocardiographic variables are lacking.Methods and resultsAmong 2,650 Framingham Study participants (mean age 51 yrs, 48% women; 40% with CAC>0), we related CT-based CAC score to left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e', global longitudinal strain (GLS), left atrial emptying fraction (LAEF), and aortic root diameter (AoR), using multivariable-adjusted generalized linear models. CAC score (independent variable) was used as log-transformed continuous [ln(CAC+1)] and as a categorical (0, 1-100, and ≥101) variable. Adjusting for standard risk factors, higher CAC score was associated with higher LVMi and AoR (βLVMI per 1-SD increase 0.012, βAoR 0.008; P58 years; βAoR0.0042;PConclusionsWe observed that subclinical atherosclerosis was associated with ventricular and aortic remodeling. The prognostic significance of these associations warrants evaluation in additional mechanistic studies.

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.

Objectives This study sought to evaluate the course, correlates, and prognosis of longitudinal changes in left ventricular (LV) diastolic dysfunction (DD) in the community-based Framingham Heart Study. Background Relationships of clinical risk factors to longitudinal progression of DD are incompletely understood. Methods Diastolic function was assessed by echocardiography performed at consecutive examinations (visits 1 and 2, mean interval 5.6 years) in 1,740 participants (64 ± 8 years of age at visit 1, 59% women) with normal LV systolic function and no atrial fibrillation. Results Of 1,615 individuals with normal-to-mild DD at visit 1, 198 (12%) progressed to ≥ moderate DD at visit 2. Progression was more likely in women and with advancing age (p Conclusions In a community-based cohort of middle-aged to older adults, cardiometabolic risk factors and noncardiac comorbidities were associated with DD progression. Moderate or worse DD was associated with higher risk of CVD or death.

Key Points Question Is estimated cardiorespiratory fitness (eCRF) in midlife associated with subclinical atherosclerosis, vascular stiffness, and risk of cardiometabolic disease and mortality? Findings In this cohort study of 2962 Framingham Offspring Study participants, higher midlife eCRF was associated with lower burdens of subclinical atherosclerosis and vascular stiffness, and with a lower risk of hypertension, diabetes, chronic kidney disease, cardiovascular disease, and mortality over a mean follow-up of 15 years. Meaning These findings suggest that prognostic ability of midlife eCRF may extend to a wide range of cardiometabolic diseases., This cohort study examines the association of estimated cardiorespiratory fitness in midlife with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality among participants in the Framingham Offspring Study., Importance The associations of estimated cardiorespiratory fitness (eCRF) during midlife with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality are not well understood. Objective To examine associations of midlife eCRF with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality. Design, Setting, and Participants This cohort study included 2962 participants in the Framingham Study Second Generation (conducted between 1979 and 2001). Data were analyzed from January 2020 to June 2020. Exposures eCRF was calculated using sex-specific algorithms (including age, body mass index, waist circumference, physical activity, resting heart rate, and smoking) and was categorized as: (1) tertiles of standardized eCRF at examination cycle 7 (1998 to 2001); (2) tertiles of standardized average eCRF between examination cycles 2 and 7 (1979 to 2001); and (3) eCRF trajectories between examination cycles 2 and 7, with the lowest tertile or trajectory (ie, low eCRF) as referent group. Main Outcomes and Measures Subclinical atherosclerosis (carotid intima-media thickness [CIMT], coronary artery calcium [CAC] score); arterial stiffness (carotid-femoral pulse wave velocity [−1000/CFPWV]); incident hypertension, diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), and mortality after examination cycle 7. Results A total of 2962 participants were included in this cohort study (mean [SD] age, 61.5 [9.2] years; 1562 [52.7%] women). The number of events or participants at risk after examination cycle 7 (at a mean follow-up of 15 years) was 728 of 1506 for hypertension, 214 of 2268 for diabetes, 439 of 2343 for CKD, 500 of 2608 for CVD, and 770 of 2962 for mortality. Compared with the low eCRF reference value, high single examination eCRF was associated with lower CFPWV (β [SE], −11.13 [1.33] ms/m) and CIMT (β [SE], −0.12 [0.05] mm), and lower risk of hypertension (hazard ratio [HR], 0.63; 95% CI, 0.46-0.85), diabetes (HR, 0.38; 95% CI, 0.23-0.62), and CVD (HR, 0.71; 95% CI, 0.53-0.95), although it was not associated with CKD or mortality. Similarly, compared with the low eCRF reference, high eCRF trajectories and mean eCRF were associated with lower CFPWV (β [SE], −11.85 [1.89] ms/m and −10.36 [1.54] ms/m), CIMT (β [SE], −0.19 [0.06] mm and −0.15 [0.05] mm), CAC scores (β [SE], −0.67 [0.25] AU and −0.63 [0.20] AU), and lower risk of hypertension (HR, 0.54; 95% CI, 0.34-0.87 and HR, 0.48; 95% CI, 0.34-0.68), diabetes (HR, 0.27; 95% CI, 0.15-0.48 and HR, 0.31; 95% CI, 0.18-0.54), CKD (HR, 0.63; 95% CI, 0.40-0.97 and HR, 0.64; 95% CI, 0.44-0.94), and CVD (HR, 0.46; 95% CI, 0.31-0.68 and HR, 0.43; 95% CI, 0.30-0.60). Compared with the reference value, a high eCRF trajectory was associated with lower risk of mortality (HR, 0.69; 95% CI, 0.50-0.95). Conclusions and Relevance In this cohort study, higher midlife eCRF was associated with lower burdens of subclinical atherosclerosis and vascular stiffness, and with a lower risk of hypertension, diabetes, chronic kidney disease, cardiovascular disease, and mortality. These findings suggest that midlife eCRF may serve as a prognostic marker for subclinical atherosclerosis, arterial stiffness, cardiometabolic health, and mortality in later life.

Background Studies in chronic kidney disease populations suggest that the non–glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β 2 -microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine. Study Design Cross-sectional study. Setting & Participants Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m 2 ) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m 2 ). Predictors Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers. Outcomes Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR cr, eGFR cys , eGFR B2M , and eGFR BTP , respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest. Results eGFR cys , eGFR B2M , and eGFR BTP had significantly less strong residual associations with age and sex than eGFR cr in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR cys and eGFR B2M , but not eGFR BTP , had significant residual associations with C-reactive protein levels in both studies. Limitations Small sample size may limit power to detect associations. Participants may be healthier than the general population. Conclusions Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs.

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

Objectives This study aims to compare ethnic difference in proximal aortic pulse wave velocity (PWV) and characteristic impedance (Zc). Background Increased aortic stiffness is an independent predictor of target organ damage, incident hypertension, and all-cause mortality. However, previous studies have not directly assessed proximal aortic function in Blacks, the ethnic population with disproportionately high risk for incident hypertension and target organ complications. Methods We evaluated the multiethnic, population-based DHS (Dallas Heart Study) participants (N = 2,544, 54.2% women, 49.7% Black) who underwent cardiac magnetic resonance at 1.5-T. Aortic stiffness and Zc were determined from aortic arch PWV and lumen area measurements. Linear regression was used to evaluate ethnic differences in proximal aortic wall stiffness using aortic arch PWV and Zc as dependent variables with and without adjustment for traditional cardiovascular risk factors. Because cardiac output was significantly higher in Blacks compared to Whites and Hispanics, additional comparisons of PWV and Zc were performed after adjustment for cardiac output and peripheral vascular resistance. Results Compared with Whites, both Blacks and Hispanics had higher levels of aortic arch PWV (4.25, 95% confidence interval [CI]: 4.15 to 4.35 m/s, vs. 4.72, 95% CI: 4.64 to 4.81 m/s, vs. 4.48, 95% CI: 4.33 to 4.63 m/s, respectively, both p 5 , vs. 75.6, 95% CI: 74.0 to 77.2 dyne·s/cm 5 , vs. 70.1, 95% CI: 67.6 to 72.8 dyne·s/cm 5 , respectively, both p Conclusions In a multiethnic population-based-sample, Blacks and Hispanics had higher proximal aortic stiffness compared with Whites independent of blood pressure and relevant risk factors.

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 In recent decades, novel echocardiographic measures have constantly emerged. It is still unclear which echocardiographic measures have the most significant prognostic value in the general population. Accordingly, the aim of this study was to compare the prognostic value of a large panel of echocardiographic measures to identify the most promising measures. Methods A total of 1,497 Framingham study participants (mean age, 65 years; 55.4% women) who underwent echocardiographic measurements of left ventricular ejection fraction, left ventricular mass index, global longitudinal strain, global circumferential strain, mitral annular plane systolic excursion, mitral E/e′ ratio, maximum and minimum left atrial (LA) volume index, LA emptying fraction, and left ventricular longitudinal synchrony were evaluated. These measures were related to the incidence of two composite outcomes: cardiovascular disease (CVD) or death and atrial fibrillation (AF) or congestive heart failure (CHF). Results On follow-up (mean, 8.3 years), there were 241 CVD events or deaths and 139 AF or CHF events. In multivariate-adjusted Cox models, higher LA emptying fraction was associated with a lower risk (hazard ratios per SD, 0.80 and 0.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) while higher minimum LA volume index (hazard ratios per SD, 1.32 and 1.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) and maximum LA volume index (hazard ratios per SD, 1.26 and 1.54 for CVD or death and AF or CHF, respectively; P ≤ .002 for both) were associated with a higher risk for both composite outcomes. Conclusions In this community-based sample, LA volumes and function were the best echocardiographic predictors of clinical outcomes. Therefore, these values should be considered for inclusion in standard echocardiographic assessments for the purpose of risk stratification.

Background Lung function abnormalities are ubiquitous in heart failure (HF). It is unclear, however, if abnormal lung diffusion capacity is associated with cardiac remodeling and antedates HF. We hypothesized that lower lung diffusion capacity for carbon monoxide (DLCO) is associated with worse left ventricular (LV) systolic and diastolic function cross-sectionally, and with higher risk of HF prospectively. Methods We evaluated 2423 Framingham Study participants (mean age 66 years, 55% women) free of HF who underwent routine echocardiography and pulmonary function tests. We used multivariable regression models to relate DLCO, forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) to left ventricular ejection fraction (LVEF), left atrial (LA) emptying fraction (LAEF), E/e’, E/A, LV mass, and LA diameter (LAD). Multivariable-adjusted Cox proportional hazards regression was used to relate DLCO, FEV1, and FVC to incident HF. Results In multivariable-adjusted cross-sectional analyses, DLCO, FEV1, and FVC (dependent variables) were associated positively with LVEF (βDLCO = 0.208, βFEV1 = 0.021, and βFVC = 0.025 per 5% increment in LVEF; pDLCO = 0.707, βFEV1 = 0.058 and βFVC = 0.058 per 5% increment in LAEF; pDLCO = -0.289, βFVC = -0.047 per SD increment in E/A; p Conclusions Our large community-based observations are consistent with the concept that lower lung diffusion capacity and expiratory flow rates are associated with cardiac remodeling and may antedate HF. Additional studies are needed to confirm our findings and to evaluate the prognostic utility of pulmonary function testing for predicting HF.

The purpose of this study was to describe the prevalence and prognosis of HF stages in the community; to evaluate if preclinical HF stages are characterized by elevation of pro-inflammatory (C-reactive protein), neurohormonal activation (B-type natriuretic peptide, renin and aldosterone), and cardiac stress biomarkers (high-sensitivity troponin I, ST-2, and growth differentiation factor-15).The American Heart Association/American College of Cardiology heart failure (HF) classification has 3 stages. Knowledge regarding the community burden of HF stages is limited, and data on the biomarker profile associated with HF stages are scarce, although higher concentrations of certain biomarkers are associated with preclinical HF.We evaluated 6,770 participants (mean age 51 years; 54% women) from the Framingham Study, defining 4 stages: 1) healthy: no risk factors; 2) stage A: presence of HF risk factors (hypertension, diabetes, obesity, coronary artery disease), no cardiac structural/functional abnormality; 3) stage B: presence of prior myocardial infarction, valvular disease, left ventricular (LV) systolic dysfunction, LV hypertrophy, regional wall motion abnormality, or LV enlargement; 4) stage C/D: prevalent HF.The prevalence of HF stages A and B were 36.5% and 24.2%, respectively, rising with age (odds ratio: 1.70 [95% confidence interval: 1.64 to 1.77] per decade increment). In age- and sex-adjusted models, we observed a gradient of increasing biomarker levels across HF stages (p 0.05; n = 3,416). Adjusting for age and sex, mortality rose across HF stages (232 deaths, mean follow-up 7 years), with 2- and 8-fold mortality risks for stages B and C/D, respectively, compared with healthy.Approximately 60% of our sample has preclinical HF, and those in stage B had higher concentrations of HF biomarkers and experienced a substantial mortality risk.

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: Aortic stiffness is associated with cardiovascular and cerebrovascular events and cognitive decline. This mini-review focuses on relations of aortic stiffness with microvascular dysfunction and discusses the contribution of abnormal pulsatile hemodynamics to cerebrovascular damage and cognitive decline. We also provide a rationale for considering aortic stiffness as a putative and important contributor to memory impairment in older individuals. Summary: Aging is associated with stiffening of the aorta but not the muscular arteries, which reduces wave reflection and increases the transmission of pulsatility into the periphery. Aortic stiffening thereby impairs a protective mechanism that shields the peripheral microcirculation from excessive pulsatility within downstream target organs. Beyond midlife, aortic stiffness increases rapidly and exposes the cerebral microcirculation to abnormal pulsatile mechanical forces that are associated with microvascular damage and remodeling in the brain. Aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain; however, a mechanistic link between aortic stiffness and memory has not been established. We showed that in a community-based sample of older individuals, cerebrovascular resistance and white matter hyperintensities - markers of cerebrovascular remodeling and damage - mediated the relation between higher aortic stiffness and lower performance on memory function tests. These data suggest that microvascular and white matter damage associated with excessive aortic stiffness contribute to impaired memory function with advancing age. Key Messages: Increasing evidence suggests that vascular etiologies - including aortic stiffness and microvascular damage - contribute to memory impairment and the pathogenesis of dementia, including Alzheimer's disease. Interventions that reduce aortic stiffness may delay memory decline among older individuals.

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 Frailty is a risk factor for cardiovascular disease (CVD). Underlying mechanisms to explain the connection between frailty and CVD are unclear. We sought to examine the association between frailty and arterial stiffness, a precursor of hypertension and CVD. Methods We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005–2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies nonfrail, prefrail, and frail individuals. Arterial stiffness was assessed using carotid–femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as −1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking. Results Of 2,171 participants (55% women, 91% white), 45% were prefrail and 7% were frail. Mean ages were 67, 70, and 73 years, and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9–10.1), 10.3 (10.2–10.5), and 10.5 m/s (10.1–11.0); p = .0002 for nonfrail, prefrail, and frail groups, respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes. Conclusions Prefrailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and CVD.

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

Background Left atrial ( LA ) size, a marker of atrial structural remodeling, is associated with increased risk for atrial fibrillation ( AF ) and cardiovascular disease ( CVD ). LA function may also relate to AF and CVD , irrespective of LA structure. We tested the hypothesis that LA function index ( LAFI ), an echocardiographic index of LA structure and function, may better characterize adverse LA remodeling and predict incident AF and CVD than existing measures. Methods and Results In 1786 Framingham Offspring Study eighth examination participants (mean age, 66±9 years; 53% women), we related LA diameter and LAFI (derived from the LA emptying fraction, left ventricular outflow tract velocity time integral, and indexed maximal LA volume) to incidence of AF and CVD on follow‐up. Over a median follow‐up of 8.3 years (range, 7.5–9.1 years), 145 participants developed AF and 139 developed CVD . Mean LAFI was 34.5±12.7. In adjusted Cox regression models, lower LAFI was associated with higher risk of incident AF (hazard ratio=3.83, 95% confidence interval=2.23–6.59, lowest [Q1] compared with highest [Q4] LAFI quartile) and over 2‐fold higher risk of incident CVD (hazard ratio=2.20, 95% confidence interval=1.32–3.68, Q1 versus Q4). Addition of LAFI , indexed maximum LA volume, or LA diameter to prediction models for AF or CVD did not significantly improve model discrimination for either outcome. Conclusions In our prospective investigation of a moderate‐sized community‐based sample, LAFI , a composite measure of LA size and function, was associated with incident AF and CVD . Addition of LAFI to the risk prediction models for AF or CVD , however, did not significantly improve their performance.

Background: Higher intake of polyunsaturated fatty acids (PUFAs) and higher circulating PUFAs are associated with lower cardiovascular disease (CVD) risk. The positive influence of PUFAs might be via lowering arterial stiffness, resulting in a better CVD risk profile; however, studies investigating circulating PUFAs in relation to arterial stiffness in a general population are limited. Objective: We investigated the associations of plasma phospholipid n–3 (ω-3) and n–6 PUFAs and fish oil intake with arterial stiffness. Methods: We used data from a subgroup of the Age, Gene/Environment Susceptibility–Reykjavik (AGES-Reykjavik) Study (n = 501, 75.0 ± 4.96 y, 46% men), a population-based study of community-dwelling older adults. Plasma phospholipid PUFAs were measured by GC at baseline, and fish oil intake was assessed at 3 time points: early life (ages 14–19 y), midlife (ages 40–50 y), and late life (ages 66–96 y, AGES-Reykjavik baseline) with the use of a validated food-frequency questionnaire. Arterial stiffness was determined as carotid–femoral pulse wave velocity (cf-PWV) with the use of an electrocardiogram after a mean follow-up of 5.2 ± 0.3 y. Regression coefficients (95% CIs), adjusted for demographics, follow-up time, risk factors, cholesterol, triglycerides, and serum vitamin D, were calculated by linear regression per SD increment in PUFAs. Results: Plasma total n–3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid were associated with lower cf-PWV [β (95% CI): −0.036 (−0.064, −0.008); −0.031 (−0.059, −0.003); −0.036 (−0.064, −0.009), respectively]. In contrast, plasma total n–6 PUFAs and linoleic acid were associated with higher cf-PWV [0.035 (0.009, 0.061) and 0.034 (0.008, 0.059)]. Regular fish oil consumption at early-, mid-, and late-life was not associated with cf-PWV. Conclusions: Our results show a positive association between plasma n–6 PUFAs and arterial stiffness, and suggest that higher concentrations of plasma long-chain n–3 PUFAs are associated with less arterial stiffness and therein may be one of the mechanisms underlying the association between plasma n–3 PUFAs and lower CVD risk.

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.

Background Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease. Study Design Cross-sectional analysis of a substudy of a prospective cohort. Setting & Participants AGES (Age, Gene/Environment Susceptibility)−Reykjavik Study. Predictor Exposure to higher blood pressure in midlife. Outcomes & Measurements Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio. Results GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5mL/min/1.73m 2 and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment. Limitations This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit. Conclusions Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD.

Background/Objectives Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS’s independent contribution to macrovascular CVD risk measures in obese adolescents. Subjects/Methods This cross-sectional observational study was conducted at Children’s Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. 31 obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw, and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-à-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. Results The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. BMI associated positively with cIMTmax (r=0.52, p=0.006) and CFPWV (r=0.45, p=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=−0.63, p

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.