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Background: The prevalence of hypertension and uncontrolled hypertension may differ by age and sex., Methods: We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models., Results: The prevalence of hypertension increased with age from 40% (ages, 43-46 years) to 93% (ages, 91-94 years). Within hypertensive individuals, the prevalence of uncontrolled hypertension was higher in men (33%) than women (23%) at ages 43 to 46 years but became higher in women than men starting at ages 61 to 64, with 56% of women and 40% men having uncontrolled hypertension at ages 91 to 94. This sex difference was not explained by differences in coronary heart disease, diabetes, body mass index, estimated glomerular filtration rate, number of antihypertension medications, classes of medications, or adherence to medications. In both sexes, uncontrolled hypertension was associated with a higher risk for chronic kidney disease progression (hazard ratio, 1.5 [1.2-1.9]; P =4.5×10 -4 ), heart failure (hazard ratio, 1.6 [1.4-2.0]; P =8.1×10 -7 ), stroke (hazard ratio, 2.1 [1.6-2.8]; P =1.8×10 -8 ), and mortality (hazard ratio, 1.5 [1.3-1.6]; P =6.2×10 -19 )., Conclusions: Sex differences in the prevalence of hypertension and uncontrolled hypertension vary by age, with the latter having implications for health throughout the life course., Competing Interests: The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. USRDS data were used for Table 3. The opinions presented do not necessarily represent those of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, or the US Government. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government.

Importance: Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension., Objective: To identify protein markers associated with EBP and test their association with incident hypertension., Design, Setting, and Participants: This study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024., Exposures: Plasma proteins., Main Outcomes and Measures: EBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication., Results: Among the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor β receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, β estimate, -3.39; 95% CI, -4.79 to -2.00; P = 2.33 × 10-6; PTGDS: exercise DBP β estimate, -2.50; 95% CI, -3.29 to -1.70; P = 1.18 × 10-9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10-5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: β, -0.38; 95% CI, -0.64 to -0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P < .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10-5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10-7)., Conclusions and Relevance: Plasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=-0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; P <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Purpose: The aim of this study was to understand the serum metabolomic signatures of moderate-to-vigorous physical activity (MVPA) and sedentary behavior, and further associate their metabolomic signatures with incident cardiometabolic diseases., Methods: This analysis included 2711 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 yr (2008-2011). An untargeted, liquid chromatography-mass spectrometry was used to profile the serum metabolome. The associations of metabolites with accelerometer-measured MVPA and sedentary time were examined using survey linear regressions adjusting for covariates. The weighted correlation network analysis identified modules of correlated metabolites in relation to sedentary time, and the modules were associated with incident diabetes, dyslipidemia, and hypertension over the 6-yr follow-up., Results: Of 624 metabolites, 5 and 102 were associated with MVPA and sedentary behavior at false discovery rate (FDR) <0.05, respectively, after adjusting for socioeconomic and lifestyle factors. The weighted correlation network analysis identified 8 modules from 102 metabolites associated with sedentary time. Four modules (branched-chain amino acids, erythritol, polyunsaturated fatty acid, creatine) were positively, and the other four (acyl choline, plasmalogen glycerol phosphatidyl choline, plasmalogen glycerol phosphatidyl ethanolamine, urea cycle) were negatively correlated with sedentary time. Among these modules, a higher branched-chain amino acid score and a lower plasmalogen glycerol phosphatidyl choline score were associated with increased risks of diabetes and dyslipidemia. A higher erythritol score was associated with an increased risk of diabetes, and a lower acyl choline score was linked to an increased risk of hypertension., Conclusions: In this study of US Hispanics/Latinos, we identified multiple serum metabolomic signatures of sedentary behavior and their associations with risk of incident diabetes, hypertension, and dyslipidemia. These findings suggest a potential role of circulating metabolites in the links between sedentary behavior and cardiometabolic diseases., (Copyright © 2023 by the American College of Sports Medicine.)

Background Systolic blood pressure increases with age after midlife, particularly in women, and contributes to development of wide pulse pressure hypertension in middle-aged and older adults. Relative contributions of aortic stiffness and premature wave reflection to increases in pulse pressure remain controversial. Methods and Results We evaluated visit-specific values and change in key correlates of pulse pressure, aortic characteristic impedance, forward and backward wave amplitude, and global reflection coefficient, at 3 sequential examinations of the Framingham Generation 3 (N=4082), Omni-2 (N=410), and New Offspring Spouse (N=103) cohorts (53% women). Data were analyzed using repeated-measures linear mixed models adjusted for age, sex, and risk factor exposures. Pulse pressure increased markedly with age after midlife (age and age-squared terms, P <0.0001), particularly in women (age slope 3.1±0.2 mm Hg/decade higher in women, P <0.0001). In sex-specific models, change in pulse pressure was closely related (all P <0.0001) to baseline (6.7±0.2 and 7.3±0.2 mm Hg/SD in men and women, respectively) and change (11.8±0.1 and 11.7±0.1 mm Hg/SD) in forward wave amplitude, whereas relations with baseline (2.1±0.15 and 2.0±0.14 mm Hg/SD) and change (4.0±0.13 and 3.4±0.11 mm Hg/SD) in global reflection coefficient were weaker. Global reflection coefficient fell as aortic characteristic impedance increased ( P <0.0001), consistent with the hypothesis that impedance matching reduces relative wave reflection in the arterial system. Conclusions Proximal aortic stiffening, as assessed by higher aortic characteristic impedance and larger forward wave amplitude, is strongly associated with longitudinal increase in pulse pressure, especially in women, whereas wave reflection has more modest relations.

Background A parental history of cardiovascular disease (CVD) confers greater risk of future CVD among offspring. Whether the presence of parental modifiable risk factors contribute to or modify CVD risk in offspring is unclear. Methods and Results We studied 6278 parent-child trios in the multigenerational longitudinal Framingham Heart Study. We assessed parental history of CVD and modifiable risk factors (smoking, hypertension, diabetes, obesity, and hyperlipidemia). Multivariable Cox models were used to evaluate the association of parental history and future CVD among offspring. Among 6278 individuals (mean age 45±11 years), 44% had at least 1 parent with history of CVD. Over a median follow-up of 15 years, 353 major CVD events occurred among offspring. Parental history of CVD conferred 1.7-fold increased hazard of future CVD (hazard ratio [HR], 1.71 [95% CI, 1.33-2.21]). Parental obesity and smoking status were associated with higher hazard of future CVD (obesity: HR, 1.32 [95% CI, 1.06-1.64]; smoking: HR, 1.34 [95% CI, 1.07-1.68], attenuated after adjusting for offspring smoking status). By contrast, parental history of hypertension, diabetes, and hypercholesterolemia were not associated with future CVD in offspring ( P >0.05 for all). Furthermore, parental risk factors did not modify the association of parental CVD history on future offspring CVD risk. Conclusions Parental history of obesity and smoking were associated with a higher hazard of future CVD in offspring. By contrast, other parental modifiable risk factors did not alter offspring CVD risk. In addition to parental CVD, the presence of parental obesity should prompt a focus on disease prevention.

Background: Abnormal blood pressure (BP) responses to exercise can predict adverse cardiovascular outcomes, but their optimal measurement and definitions are poorly understood. We combined frequently sampled BP during cardiopulmonary exercise testing with vascular stiffness assessment to parse cardiac and vascular components of exercise BP., Methods: Cardiopulmonary exercise testing with BP measured every two minutes and resting vascular tonometry were performed in 2858 Framingham Heart Study participants. Linear regression was used to analyze sex-specific exercise BP patterns as a function of arterial stiffness (carotid-femoral pulse wave velocity) and cardiac-peripheral performance (defined by peak O 2 pulse)., Results: Our sample was balanced by sex (52% women) with mean age 54±9 years and 47% with hypertension. We observed variability in carotid-femoral pulse wave velocity and peak O 2 pulse across individuals with clinically defined exercise hypertension (peak systolic BP [SBP] in men ≥210 mm Hg; in women ≥190 mm Hg). Despite similar resting SBP and cardiometabolic profiles, individuals with higher peak O 2 pulse displayed higher peak SBP ( P ≤0.017) alongside higher fitness levels ( P <0.001), suggesting that high peak exercise SBP in the context of high peak O 2 pulse may in fact be favorable. Although both higher (favorable) O 2 pulse and higher (adverse) arterial stiffness were associated with greater peak SBP ( P <0.0001 for both), the magnitude of association of carotid-femoral pulse wave velocity with peak SBP was higher in women (sex-carotid-femoral pulse wave velocity interaction P <0.0001). In sex-specific models, exercise SBP measures accounting for workload (eg, SBP during unloaded exercise, SBP at 75 watts, and SBP/workload slope) were directly associated with the adverse features of greater arterial stiffness and lower peak O 2 pulse., Conclusions: Higher peak exercise SBP reflects a complex trade-off between arterial stiffness and cardiac-peripheral performance that differs by sex. Studies of BP responses to exercise accounting for vascular and cardiac physiology may illuminate mechanisms of hypertension and clarify clinical interpretation of exercise BP.

Background: Non-genetic factors contribute to differences in diabetes risk across race/ethnic and socioeconomic groups, which raises the question of whether effects of predictors of diabetes are similar across populations. We studied diabetes incidence in the primarily non-Hispanic White Framingham Heart Study (FHS, N = 4066) and the urban, largely immigrant Hispanic Community Health Study/Study of Latinos (HCHS/SOL, N = 6891) Please check if the affiliations are captured and presented correctly., Methods: Clinical, behavioral, and socioeconomic characteristics were collected at in-person examinations followed by seven-day accelerometry. Among individuals without diabetes, Cox proportional hazards regression models (both age- and sex-adjusted, and then multivariable-adjusted for all candidate predictors) identified predictors of incident diabetes over a decade of follow-up, defined using clinical history or laboratory assessments., Results: Four independent predictors were shared between FHS and HCHS/SOL. In each cohort, the multivariable-adjusted hazard of diabetes increased by approximately 50% for every ten-year increment of age and every five-unit increment of body mass index (BMI), and was 50-70% higher among hypertensive than among non-hypertensive individuals (all P < 0.01). Compared with full-time employment status, the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for part-time employment was 0.61 (0.37,1.00) in FHS and 0.62 (0.41,0.95) in HCHS/SOL. Moderate-to-vigorous physical activity (MVPA) was an additional predictor in common observed in age- and sex-adjusted models, which did not persist after adjustment for other covariates (compared with MVPA ≤ 5 min/day, HR for MVPA level ≥ 30 min/day was 0.48 [0.31,0.74] in FHS and 0.74 [0.56,0.97] in HCHS/SOL). Additional predictors found in sex- and age-adjusted analyses among the FHS participants included male gender and lower education, but these predictors were not found to be independent of others in multivariable adjusted models, nor were they associated with diabetes risk among HCHS/SOL adults., Conclusions: The same four independent predictors - age, body mass index, hypertension and employment status - were associated with diabetes risk across two disparate US populations. While the reason for elevated diabetes risk in full-time workers is unclear, the findings suggest that diabetes may be part of the work-related burden of disease. Our findings also support prior evidence that differences by gender and socioeconomic position in diabetes risk are not universally present across populations., (© 2022. The Author(s).)

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.

Importance: Orthostatic hypotension (OH) and hypertension (OHT) are aberrant blood pressure (BP) regulation conditions associated with higher cardiovascular disease risk. The relations of OH and OHT with heart failure (HF) risk in the community are unclear and there remains a paucity of data on the relations with HF subtypes [HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)]., Objective: Relate OH and OHT with HF risk and its subtypes., Design: Prospective observational cohort., Setting: Community-based individuals in the Framingham Heart Study Original Cohort., Participants: 1,914 participants (mean age 72 years; 1159 women) attending examination cycle 17 (1981-1984) followed until December 31, 2017 for incident HF or death., Exposures: OH or OHT, defined as a decrease or increase, respectively, of ≥20/10 mmHg in systolic/diastolic BP upon standing from supine position., Outcomes and Measures: At baseline, 1,241 participants had a normal BP response (749 women), 274 had OH (181 women), and 399 had OHT (229 women). Using Cox proportional hazards regression models, we related OH and OHT to risk of HF, HFrEF, and HFpEF compared to the absence of OH and OHT (reference), adjusting for age, sex, body mass index, systolic and diastolic BP, hypertension treatment, smoking, diabetes, and total cholesterol/high-density lipoprotein., Results: On follow-up (median 13 years) we observed 492 HF events (292 in women; 134 HFrEF, 116 HFpEF, 242 HF indeterminate EF). Compared to the referent, participants with OH [n = 84/274 (31%) HF events] had a higher HF risk (Hazards Ratio [HR] 1.47, 95% CI 1.13-1.91). Moreover, OH was associated with a higher HFrEF risk (HR 2.21, 95% CI 1.34-3.67). OHT was not associated with HF risk., Conclusions and Relevance: Orthostatic BP response may serve as an early marker of HF risk. Findings suggest shared pathophysiology of BP regulation and HF, including HFrEF., Competing Interests: The authors have declared that no competing interests exist.

Background The epidemiology of hypertension subtypes has not been well characterized in the recent era. Methods and Results We delineated the prevalence, predictors, progression, and prognostic significance of hypertension subtypes in 8198 Framingham Heart Study participants (mean age, 46.5 years; 54% women). The prevalence of hypertension subtypes was as follows: nonhypertensive (systolic blood pressure [SBP] <140 mm Hg and diastolic blood pressure [DBP] <90 mm Hg), 79%; isolated systolic hypertension (ISH; SBP ≥140 mm Hg and DBP <90 mm Hg), 8%; isolated diastolic hypertension (SBP <140 mm Hg and DBP ≥90 mm Hg), 4%; and systolic-diastolic hypertension (SDH; SBP ≥140 mm Hg and DBP ≥90 mm Hg), 9%. The prevalence of ISH and SDH increased with age. Analysis of a subsample of nonhypertensive participants demonstrated that increasing age, female sex, higher heart rate, left ventricular mass, and greater left ventricular concentricity were predictors of incident ISH and SDH. Higher baseline DBP was associated with the risk of developing isolated diastolic hypertension and SDH, whereas higher SBP was associated with all 3 hypertension subtypes. On follow-up (median, 5.5 years), isolated diastolic hypertension often reverted to nonhypertensive BP (in 42% of participants) and ISH progressed to SDH (in 26% of participants), whereas SDH frequently transitioned to ISH (in 20% of participants). During follow-up (median, 14.6 years), 889 participants developed cardiovascular disease. Compared with the nonhypertensive group (referent), ISH (adjusted hazard ratio [HR], 1.57; 95% CI, 1.30-1.90) and SDH (HR, 1.66; 95% CI, 1.36-2.01) were associated with increased cardiovascular disease risk, whereas isolated diastolic hypertension was not (HR, 1.03; 95% CI, 0.68-1.57). Conclusions Hypertension subtypes vary in prevalence with age, are dynamic during short-term follow-up, and exhibit distinctive prognoses, underscoring the importance of blood pressure subphenotyping.

Background: Guidelines emphasize screening people with elevated BP for the presence of end-organ damage., Methods: We characterized the prevalence, correlates, and prognosis of hypertension-mediated organ damage (HMOD) in the community-based Framingham Study. 7898 participants (mean age 51.6 years, 54% women) underwent assessment for the following HMOD: electrocardiographic and echocardiographic left ventricular hypertrophy, abnormal brain imaging findings consistent with vascular injury, increased carotid intima-media thickness, elevated carotid-femoral pulse wave velocity, reduced kidney function, microalbuminuria, and low ankle-brachial index. We characterized HMOD prevalence according to blood pressure (BP) categories defined by four international BP guidelines. Participants were followed up for incidence of cardiovascular disease., Results: The prevalence of HMOD varied positively with systolic BP and pulse pressure but negatively with diastolic BP; it increased with age, was similar in both sexes, and varied across BP guidelines based on their thresholds defining hypertension. Among participants with hypertension, elevated carotid-femoral pulse wave velocity was the most prevalent HMOD (40%-60%), whereas low ankle-brachial index was the least prevalent (<5%). Left ventricular hypertrophy, reduced kidney function, microalbuminuria, increased carotid intima-media thickness, and abnormal brain imaging findings had an intermediate prevalence (20%-40%). HMOD frequently clustered within individuals. On follow-up (median, 14.1 years), there were 384 cardiovascular disease events among 5865 participants with concurrent assessment of left ventricular mass, carotid-femoral pulse wave velocity, kidney function, and microalbuminuria. For every BP category above optimal (referent group), the presence of HMOD increased cardiovascular disease risk compared with its absence., Conclusions: The prevalence of HMOD varies across international BP guidelines based on their different thresholds for defining hypertension. The presence of HMOD confers incremental prognostic information regarding cardiovascular disease risk at every BP category.

Purpose of Review: This review aims to investigate the blood pressure (BP)-lowering effects of emerging drugs developed to treat diabetic kidney disease and heart failure (HF). We summarize the potential pathophysiological mechanisms responsible for mitigating hypertensive target organ damage and evaluating the available clinical data on these newer drugs., Recent Findings: Nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists (MRAs), dual angiotensin II receptor-neprilysin inhibitors (valsartan with sacubitril), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and soluble guanylate cyclase stimulators are new classes of chemical agents that have distinct mechanisms of action and have been shown to be effective for the treatment of cardiovascular (CV) disease (CVD), HF, and type 2 diabetes mellitus (T2D). These drugs can be used either alone or in combination with other antihypertensive and CV drugs. Among these, SGLT2i and valsartan with sacubitril offer new avenues to reduce CVD mortality. SGLT2i have a mild-to-moderate effect on BP lowering with a favorable effect on CV and renal hemodynamics and have been shown to produce a significant reduction in the incidence of major adverse CVD events (as monotherapy or add-on therapy) compared with controls (placebo or non-SGLT2i treatment). Most of the participants in these studies had hypertension (HTN) at baseline and were receiving antihypertensive therapy, including renin-angiotensin system blockers. The combination of valsartan with sacubitril also lowers BP in the short term and has demonstrated a striking reduction in CVD mortality and morbidity in HF patients with a reduced left ventricular ejection fraction. If widely adopted, these novel therapeutic agents hold significant promise for reducing the public health burden posed by HTN and CVD. Based on the results of several clinical trials and considering the high prevalence of HTN and T2D, these new classes of agents have emerged as powerful therapeutic tools in managing and lowering the BP of patients with diabetic kidney disease and HF., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

[Figure: see text].

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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 <0.01). After multivariable adjustment, carotid-femoral pulse wave velocity was associated with BMI 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.

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 <0.01). Overweight and obesity (compared to normal BMI), hypertension, and diabetes status were individually and conjointly associated with higher LVM and worse GLS (p<0.01 for all). We observed an increase of 34% for LVM and of 9% for GLS between individuals with a normal BMI and without hypertension or diabetes compared to obese individuals with hypertension and diabetes. Presence of hypertension was associated with higher LVEF, whereas people with diabetes had lower LVEF., 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., Competing Interests: Susan Cheng has received consulting fees from Zogenix for work unrelated to this manuscript. Gary F. Mitchell has the following disclosures: a) grants: NIH, Novartis (both significant); b) consulting: Novartis, Servier, Merck, Bayer (all significant); and c) ownership: Cardiovascular Engineering, Inc. (significant). These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose of Review: To highlight pharmacological and non-pharmacological approaches to reversing hypertensive left ventricular hypertrophy (LVH). We identify high-risk phenotypes that may benefit from aggressive blood pressure (BP) management to prevent incident outcomes such as the development of atherosclerotic cardiovascular disease, stroke, and heart failure., Recent Findings: LVH is a modifiable risk factor. Intensive BP lowering (systolic BP < 120 mmHg) induces greater regression of electrocardiographic LVH than standard BP targets. The optimal agents for inducing LVH regression include renin-angiotensinogen-aldosterone system inhibitors and calcium channel blockers, although recent meta-analyses have demonstrated superior efficacy of non-hydrochlorothiazide diuretics. Novel agents (such as sacubitril/valsartan) and non-pharmacological approaches (like bariatric surgery) hold promise but longitudinal studies assessing their impact on clinical outcomes are needed. LVH regression is achievable with appropriate therapy with first-line antihypertensive agents. Additional studies are warranted to assess if intensive BP lowering in high-risk groups (such as blacks, women, and malignant LVH) improves outcomes.

Background Few studies examined the associations of midlife blood pressure (BP) responses to submaximal exercise with the risk of cardiovascular outcomes and mortality in later life. Methods and Results We evaluated 1993 Framingham Offspring Study participants (mean age, 58 years; 53.2% women) attending examination cycle 7. We related BP responses to submaximal exercise with prevalent subclinical cardiovascular disease (CVD) using multivariable linear regression models. We also related BP responses to submaximal exercise to the incidence of hypertension, CVD, and all-cause mortality using Cox proportional hazards regression models. Each SD increment of exercise BP was associated with higher log-transformed left ventricular mass (systolic blood pressure [SBP], β=0.02, P =<0.001; diastolic blood pressure [DBP], β=0.01, P =0.004) and carotid intima-media thickness (SBP, β=0.08, P =<0.001). Rapid BP recovery (per 1 SD increment) was associated with lower log left ventricular mass (SBP recovery ; β=-0.03, P =<0.001) and carotid intima-media thickness (SBP recovery , β=-0.07, P =0.003; DBP recovery , β=-0.09, P =0.003). Additionally, Each SD increment of exercise BP was associated with a higher risk of incident hypertension (SBP, hazard ratio [HR], 1.40; 95% CI, 1.20-1.62; DBP, HR, 1.24; 95% CI, 1.11-1.40) and CVD (DBP, HR, 1.15; 95% CI, 1.02-1.30). Finally, the multivariable-adjusted HR for each 1-SD increment of BP recovery was 0.46 (SBP recovery , 95% CI, 0.38-0.54) and 0.55 (DBP recovery , 95% CI, 0.45-0.67) for hypertension; 0.80 (SBP recovery , 95% CI, 0.69-0.93) for CVD; and 0.76 (SBP recovery , 95% CI, 0.65-0.88) for all-cause mortality. Conclusions Higher submaximal exercise BP and impaired BP recovery after submaximal exercise in midlife may be markers of subclinical and clinical CVD and mortality in later life.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10 -8 ) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Purpose of Review: Given that the life expectancy and the burden of hypertension are projected to increase over the next decade, hypertensive heart disease (HHD) may be expected to play an even more central role in the pathophysiology of cardiovascular disease (CVD). A broader understanding of the features and underlying mechanisms that constitute HHD therefore is of paramount importance., Recent Findings: HHD is a condition that arises as a result of elevated blood pressure and constitutes a key underlying mechanism for cardiovascular morbidity and mortality. Historically, studies investigating HHD have primarily focused on left ventricular (LV) hypertrophy (LVH), but it is increasingly apparent that HHD encompasses a range of target-organ damage beyond LVH, including other cardiovascular structural and functional adaptations that may occur separately or concomitantly. HHD is characterized by micro- and macroscopic myocardial alterations, structural phenotypic adaptations, and functional changes that include cardiac fibrosis, and the remodeling of the atria and ventricles and the arterial system. In this review, we summarize the structural and functional alterations in the cardiac and vascular system that constitute HHD and underscore their underlying pathophysiology.

Background: Heart failure (HF) is a heterogeneous clinical syndrome with varying prognosis. Subphenotyping of HF is a research priority to advance our understanding of the syndrome. We formulated a subphenotyping schema and compared long-term mortality risk among the HF subphenotypes in the community-based Framingham Study., Methods and Results: In hierarchical order, we grouped participants with new-onset HF (stratified by HF with reduced [HFrEF] vs. preserved ejection fraction [HFpEF]) according to the presence of: (1) coronary heart disease (CHD), (2) metabolic syndrome (MetS), (3) hypertension, and (4) 'other' causes. Age at HF onset was lowest in people with the MetS (mean 76 vs. 77 years for HFrEF and HFpEF, respectively) and highest in those with hypertension only (mean 82 and 85 years for HFrEF and HFpEF, respectively). For HFrEF, 10-year cumulative mortality and hazards ratios [HR] were 87% for CHD (n = 219; referent group), 88% for MetS (n = 105; HR 0.95 [95% CI 0.73-1.23]), 82% for hypertension (n = 104; HR 0.71 [0.55-0.91]), and 78% for other (n = 37; HR 0.81 [0.55-1.19]). Corresponding 10-year cumulative mortality and HR data for HFpEF were: 85% for CHD (n = 84; referent), 83% for MetS (n = 118; HR 0.98 [0.72-1.33]), 81% for hypertension (n = 127; HR 0.71 [0.52-0.95]), and 76% for other (n = 43; HR 0.76 [0.50-1.14]). In a sample without overt heart failure (n = 5536), several echocardiographic and vascular indices showed graded worsening of age- and sex adjusted-values among those having CHD, MetS, hypertension, or obesity, compared with individuals not having these risk factors., Conclusions: HF subphenotypes characterized by the presence of CHD or metabolic syndrome present at a younger age and are marked by greater mortality risk. The clinical utility of the proposed subphenotyping schema warrants further research., Competing Interests: Dr. Mitchell is the owner and president of Cardiovascular Engineering, Inc., a company that designs and manufactures devices that measure vascular stiffness, serves as a consultant to and receives honoraria and grant support from Novartis, Servier and the National Institutes of Health. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the other authors have any conflicts of interest to disclose.

Objectives: Prior studies suggest that hypertensive target organ damage (TOD) is a heritable trait. However, the risk that parental TOD confers on propensity for TOD in their offspring, and how hypertensive TOD clusters in the context of parental versus offspring hypertension status remain unclear., Methods: We studied 3238 Framingham Heart Study participants (mean age 39 ± 8 years, 53% women) with available parental data on TOD. Parents and offspring underwent measurements for left ventricular hypertrophy, increased relative wall thickness, albuminuria and conventional risk factors., Results: Prevalence of any TOD (left ventricular hypertrophy or albuminuria) in participants with zero and at least one parents with any TOD was 7 and 13%, respectively (P < 0.001 for difference). Having at least one parent with TOD was associated with greater odds of TOD in offspring than individuals without parental TOD [multivariable-adjusted odds ratio (OR), 1.65; 95% confidence interval (95% CI), 1.27-2.14]. Similarly, parental left ventricular hypertrophy was associated with offspring left ventricular hypertrophy (OR, 2.73; 95% CI 1.92-3.89), parental increased relative wall thickness conferred increased odds of increased relative wall thickness in the offspring (OR, 1.54; 95% CI 1.16-2.04) and parental albuminuria was related to offspring albuminuria (OR, 1.49; 95% CI 1.03-2.16). These associations remained significant upon adjustment for other risk factors, including blood pressure, and in analyses of subgroups defined according to parental or offspring hypertension status., Conclusion: Overall, our data suggest that familial clustering of TOD in the community is independent of blood pressure. Additional studies are warranted to confirm our observations.

Importance: Given that hypertension remains a leading risk factor for chronic disease globally, there are substantial ongoing efforts to define the optimal range of blood pressure (BP)., Objective: To identify a common threshold level above which BP rise tends to accelerate in progression toward hypertension., Design, Setting, and Participants: This longitudinal, community-based epidemiological cohort study of adults enrolled in Framingham, Massachusetts, included 1252 participants (mean [SD] age, 35.3 [2.7] years) from the Framingham Original Cohort, of whom 790 (63.1%) were women. Each participant contributed up to 28 serial examinations of standardized resting BP measurements between 1948 and 2005., Exposures: Age and systolic BP., Main Outcomes and Measures: Via a segmented mixed model, we identified significant change points in the association between advancing age and increasing systolic BP among individuals categorized by their age at hypertension onset., Results: Individuals maintained a relatively stable resting systolic BP level prior to hypertension onset. Systolic BP level began to rise at a more rapid rate after reaching a level of 123.2 mm Hg (95% CI, 122.7-130.1 mm Hg) in people with onset at 40 to 49 years; 122.0 mm Hg (95% CI, 120.3-123.9 mm Hg) in those with onset between 50 and 59 years, 124.9 mm Hg (95% CI, 120.2-127.9 mm Hg) in those with onset between 60 and 69 years, and 120.5 mm Hg (95% CI, 118.0-123.2 mm Hg) in those with onset between 70 and 79 years (P = .29 for between-group heterogeneity)., Conclusions and Relevance: We observed that individuals in the community generally maintained a systolic BP of less than 120 to 125 mm Hg, above which systolic BP increased at a relatively rapid rate toward overt hypertension. This trend was consistent whether the hypertension manifested earlier or later in life. Thus, a resting systolic BP that chronically exceeds the range of approximately 120 to 125 mm Hg may represent an important threshold of underlying vascular remodeling and signal incipient hypertension irrespective of age. Further investigations are needed to unravel the sequence of hemodynamic and vascular changes occurring prior to hypertension onset.

Objective: To determine the association between blood pressure during midlife (40-64 years) to late life (≥65 years) and risk of incident dementia., Methods: This study included 1,440 (758 women, mean age 69 ± 6 years) Framingham Offspring participants who were free of dementia and attended 5 consecutive examinations at 4-year intervals starting at midlife (1983-1987, mean age 55 years) until late life (1998-2001, mean 69 years) and subsequently were followed up for incident dementia (mean 8 years). We determined the effect of midlife hypertension (≥140/90 mm Hg), late life hypertension, lower late life blood pressure (<100/70 mm Hg), persistence of hypertension during mid- to late life, and steep decline in blood pressure from mid- to late life over an 18-year exposure period., Results: During the follow-up period, 107 participants (71 women) developed dementia. Using multivariable Cox proportional hazards models, we found that midlife systolic hypertension (hazard ratio [HR] 1.57, 95% confidence interval [CI] 1.05-2.35) and persistence of systolic hypertension into late life (HR 1.96, 95% CI 1.25-3.09) were associated with an elevated risk of incident dementia. However, in individuals with low to normal blood pressure (≤140/90 mm Hg) at midlife, a steep decline in systolic blood pressure during mid- to late life was also associated with a >2-fold increase in dementia risk (HR 2.40, 95% CI 1.39-4.15)., Conclusions: Elevated blood pressure during midlife, persistence of elevated blood pressure into late life, and, among nonhypertensives, a steep decline in blood pressure during mid- to late life were associated with an increased dementia risk in a community-based cohort. Our data highlight the potential sustained cognitive benefits of lower blood pressures in midlife but also suggest that declining blood pressure in older adults with prehypertension or normotension, but not in those with hypertension, may be a risk marker for dementia., (© 2017 American Academy of Neurology.)

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., (© 2017 American Heart Association, Inc.)

Aims: Parental hypertension is known to predict high blood pressure (BP) in children. However, the extent to which risk for hypertension is conferred across multiple generations, notwithstanding the impact of environmental factors, is unclear. Our objective was therefore to evaluate the degree to which risk for hypertension extends across multiple generations of individuals in the community., Methods and Results: We studied three generations of Framingham Heart Study participants with standardized blood pressure measurements performed at serial examinations spanning 5 decades (1948 through 2005): First Generation (n = 1809), Second Generation (n = 2631), and Third Generation (n = 3608, mean age 39 years, 53% women). To capture a more precise estimate of conferrable risk, we defined early-onset hypertension (age <55 years) as the primary exposure. In multinomial logistic regression models adjusting for standard risk factors as well as physical activity and daily intake of dietary sodium, risk for hypertension in the Third Generation was conferred simultaneously by presence of early-onset hypertension in parents [OR 2.10 (95% CI, 1.66-2.67), P < 0.001] as well as in grandparents [OR 1.33 (95% CI, 1.12-1.58), P < 0.01]., Conclusion: Early-onset hypertension in grandparents raises the risk for hypertension in grandchildren, even after adjusting for early-onset hypertension in parents and lifestyle factors. These results suggest that a substantial familial predisposition for hypertension exists, and this predisposition is not identical when assessed from one generation to the next. Additional studies are needed to elucidate the mechanisms underlying transgenerational risk for hypertension and its clinical implications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Pregnancy characteristics are associated with risk of cardiovascular diseases, but their independent associations with hypertension or blood pressure (BP) levels remain uncertain. We linked the Swedish Medical Birth Register with Västerbotten Intervention Program data (Northern Sweden). Using linear and logistic regression, we related pregnancy factors in any prior pregnancy with BP and hypertension at 40 years of age in 15 896 parous women free of prepregnancy hypertension. Pregnancy factors included parity, age at first delivery, preeclampsia, gestational diabetes mellitus, placental abruption, shortest gestational age small for gestational age baby (

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention., Competing Interests: Conflict of interests N. P. has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. S. K. has received Research Grant-Merck, Bayer, Aegerion; SAB-Catabasis, Regeneron Genetics Center, Merck, Celera; Equity-San Therapeutics, Catabasis; Consulting-Novartis, Aegerion, Bristol Myers-Squibb, Sanofi, AstraZeneca, Alnylam. P. Sever has received research awards from Pfizer Inc. A. Malarstig and M. Uria-Nickelsen are full time employees of Pfizer. D. Reily and M. Hoek are full time employees of Merck and co Inc. M.J. Caulfield is Chief Scientist for Genomics England a UK Government company. The authors declare no competing financial interest.

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., (© 2016 American Heart Association, Inc.)

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., (© 2016 American Heart Association, Inc.)

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., (© 2015 American Heart Association, Inc.)

Background: Circulating Galectin-3 (Gal-3) concentrations are associated with an increased incidence of heart failure, atrial fibrillation, chronic kidney disease, and mortality. Recent evidence suggests that Gal-3 may also be an important modulator of cardiometabolic traits such as adiposity, insulin resistance, and hyperglycemia. We examined the associations of blood Gal-3 concentrations and cardiometabolic disease traits in the Framingham Heart Study., Methods and Results: In cross-sectional analyses of 2946 Framingham Heart Study participants (mean age 59 years, 55% women), higher Gal-3 concentrations were associated with higher body mass index, waist circumference, and triglycerides (P<0.0001 for all). Higher Gal-3 was associated with greater odds of obesity (multivariable-adjusted odds ratio 1.16 per 1-SD increase in log-Gal-3, 95% CI 1.06-1.28, P=0.002) and hypertension (odds ratio 1.18, 95% CI 1.07-1.29, P=0.0006). In prospective analyses, Gal-3 was associated with incident metabolic syndrome (hazard ratio 1.22, 95% CI 1.10-1.36, P=0.0002) and diabetes (hazard ratio 1.21, 95% CI 1.04-1.41, P=0.02), in age- and sex-adjusted, but not multivariable-adjusted models., Conclusions: In this large, community-based sample, circulating Gal-3 was associated with abdominal adiposity, dyslipidemia, and hypertension in cross-sectional analyses, but Gal-3 did not predict incident cardiometabolic disease after adjusting for cardiometabolic risk factors. Future investigations should focus on further elucidating mechanisms linking Gal-3 with cardiometabolic disease and on assessing whether modulation of the Gal-3 pathway might have positive cardiometabolic effects., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Hypertensive individuals on blood pressure (BP)-lowering treatment with BP in the normal or high-normal range have higher cardiovascular risk than untreated persons with usual BP in the same range. This residual risk (relative and absolute) is not well quantified and may be attributable in part to the higher burden of subclinical disease in treated individuals., Methods and Results: We assigned 3024 Framingham Offspring Cohort participants to 5 categories based on systolic BP (SBP) and diastolic BP (DBP) and use of BP-lowering treatment: (1) untreated SBP/DBP <120/80 mm Hg; (2) untreated SBP/DB ≥120/80 to <140/90 mm Hg; (3) treated SBP/DBP <140/90 mm Hg; (4) untreated SBP/DBP ≥140/90 mm Hg; and (5) treated SBP/DBP ≥140/90 mm Hg. A composite subclinical disease score was constructed, including information on left ventricular hypertrophy, systolic dysfunction, carotid ultrasound abnormality, peripheral artery disease, and microalbuminuria. The prevalence of subclinical disease rose across BP groups, as did the event rates for incident cardiovascular disease (449 events, median follow-up of 11 years; group 1, 0.65 event per 100 person-years; group 5, 3.20 events per 100 person-years; P<0.0001 for trend). On multivariable adjustment, treated hypertensives in groups 3 and 5 had 50% (95% CI 13% to 99%) and 28% (95% CI -6% to 73%) higher hazards, respectively, of developing cardiovascular disease compared with their untreated counterparts with similar levels of BP (groups 1 and 2 and group 4, respectively). The increased risk of cardiovascular disease in treated hypertensives was attributable in part to greater subclinical disease burden., Conclusions: Treated hypertensives have higher subclinical cardiovascular disease burden, which partly explains their higher cardiovascular disease risk compared with untreated persons with similar BP levels., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals., Methods: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases)., Results: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

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., (© 2014 American Heart Association, Inc.)

Background: In low-renin hypertension (LRH), serum aldosterone levels are higher in those subjects with primary aldosteronism and may be lower in those with non-aldosterone mineralocorticoid excess or primary renal sodium retention. We investigated the hypothesis that the frequency distribution of aldosterone in LRH is bimodal., Methods: Of the 3,532 attendees at the sixth examination cycle of the Framingham Offspring Study, 1,831 were included in this cross-sectional analysis after we excluded those with conditions or taking medications such as antihypertensive drugs that might affect renin or aldosterone., Results: Three hundred three subjects (17%) had untreated hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg). LRH, defined as plasma renin ≤5 mU/L, was present in 93 of those 303 hypertensive subjects (31%). Aldosterone values were adjusted statistically for age, sex, and the urinary sodium/creatinine ratio. In the subjects with LRH, the adjusted aldosterone distribution was bimodal (dip test for unimodality, P = 0.008). The adjusted aldosterone distribution was unimodal in the normal subjects (P = 0.98) and in the hypertensive subjects with normal plasma renin (P = 0.94)., Conclusions: In this community-based sample of white subjects, those with low-renin hypertension had a bimodal adjusted aldosterone distribution. Subjects with normal-renin hypertension and subjects with normal blood pressure had unimodal adjusted aldosterone distributions. These findings suggest 2 pathophysiological variants of LRH, one that is aldosterone-dependent and one that is non-aldosterone-dependent.

Background: Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension., Methods: Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes., Results: Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05-1.42, P=0.01]. Individuals in the upper sST2 quartile had a 2.6 mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8 mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P=0.27)., Conclusion: These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology.

Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

Aldosterone, the key hormone in the mineralocorticoid pathway, plays a fundamental role in salt and water homeostasis, blood pressure regulation, and cardiovascular remodeling. Both genomic and nongenomic mechanisms influence aldosterone-induced renal sodium reabsorption. Furthermore, the mineralocorticoid receptors in nonepithelial tissues, including the heart and vascular smooth muscle cells, have recently been discovered. Thus, aldosterone likely has pleiotropic effects that contribute to the modulation of blood pressure. Among patients with hypertension in general, and among those with more severe or resistant hypertension in particular, a higher-than-expected prevalence of primary hyperaldosteronism is noted. Among individuals with resistant hypertension, aldosterone antagonists have also been shown to be effective in lowering blood pressure. Most significantly, recent community-based studies among non-hypertensive individuals in the general population have demonstrated that both higher serum aldosterone concentrations and a higher aldosterone to renin ratio portend a greater risk of developing hypertension. The combination of the aforementioned observations underscores the importance of the mineralocorticoid pathway in the pathogenesis of hypertension.

Water and sodium retention precedes the development of high blood pressure (BP) and explains a compensatory rise in B-type natriuretic peptide (BNP) concentrations. It is unclear whether BNP concentrations antedate the BP progression. We hypothesized that higher BNP concentrations in our African American cohort will be associated with longitudinal increases in BP, progression of BP stage, and incident hypertension. Our study sample consisted of 888 normotensive (based on BP at examination 1 [2000-2004]) participants of the Jackson Heart Study (mean age, 47±12 years; 61% women). We examined the relation of BNP concentrations at the baseline examination to change in systolic and diastolic BPs, BP progression (an increase by 1 BP stage as defined by THE sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and incident hypertension by examination 2 (2005-2008) adjusting for baseline BP stages, systolic and diastolic BPS, traditional risk factors, and echocardiographic left ventricular mass. Over a median follow-up period of 5.0±0.8 years, 36.9% progressed to a higher BP stage and 19.3% developed hypertension. In multivariable regression models, higher log-BNP concentrations at examination 1 were significantly and positively associated with changes in systolic and diastolic BPs (P<0.05 for both). Baseline log-BNP was significantly associated with BP progression (P=0.046). Every SD increase in baseline log BNP was associated with a 12% increased risk of BP progression. Log-BNP was not significantly associated with incident hypertension (P=0.12). In our community-based sample of African Americans, higher BNP concentrations predicted a longitudinal increase in systolic and diastolic BPs and progression of BP stage.

The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21 732 person-observations obtained on Framingham Heart Study participants (mean age, 38 years, 52% women; 4993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) to age, sex, body mass index, smoking, diabetes mellitus, total/high-density lipoprotein cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater body mass index, and higher heart rate were positively associated with increase in all BP measures (P<0.0001). Notably, higher total/high-density lipoprotein cholesterol ratio was associated with greater mean arterial pressure (P<0.01). Conversely, diabetes mellitus and smoking were associated with higher pulse pressure (P<0.01). We also observed effect modification by sex: the increase in pulse pressure with age and body mass index was more pronounced in women compared with men (P<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations in a large community-based sample demonstrate a greater pulsatile load in women than in men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course.

Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA variation has become an additional target of investigation of the missing BP heritability. Analyses of common mitochondrial DNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of uncommon (frequency>5%) mitochon drial DNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study and genotyped 40 mitochondrial single nucleotide polymorphisms in 7219 Framingham Heart Study participants. The nonsynonymous mitochondrial single nucleotide polymorphism 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of respiratory complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7-mm Hg higher systolic BP at baseline (Pempirical=0.05) and 17-mg/dL higher mean FBG over 25 years of follow-up (Pempirical=0.009). Significant associations with FBG levels were also detected for nonsynonymous mitochondrial single nucleotide polymorphism 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of complex I. On average, individuals with rare allele 3316A had 17- and 25-mg/dL higher FBG at baseline (Pempirical=0.01) and over 25 years of follow-up (Pempirical=0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with systolic BP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.

Context: Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. Vascular stiffness and blood pressure pulsatility are related; however, temporal relationships between vascular stiffening and blood pressure elevation have not been fully delineated., Objective: To examine temporal relationships among vascular stiffness, central hemodynamics, microvascular function, and blood pressure progression., Design, Setting, and Participants: Longitudinal community-based cohort study conducted in Framingham, Massachusetts. The present investigation is based on the 2 latest examination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1759 participants (mean [SD] age: 60 [9] years; 974 women)., Main Outcome Measures: The primary outcomes were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPWV, FWA, and augmentation index during examination cycle 8., Results: In a multivariable-adjusted regression model, higher FWA (β, 1.3 [95% CI, 0.5-2.1] mm Hg per 1 SD; P = .002) and higher CFPWV (β, 1.5 [95% CI, 0.5-2.6] mm Hg per 1 SD; P = .006) during examination cycle 7 were jointly associated with systolic blood pressure during examination cycle 8. Similarly, in a model that included systolic and diastolic blood pressure and additional risk factors during examination cycle 7, higher FWA (odds ratio [OR], 1.6 [95% CI, 1.3-2.0] per 1 SD; P < .001), augmentation index (OR, 1.7 [95% CI, 1.4-2.0] per 1 SD; P < .001), and CFPWV (OR, 1.3 [95% CI, 1.0-1.6] per 1 SD; P = .04) were associated with incident hypertension during examination cycle 8 (338 cases [32%] in 1048 participants without hypertension during examination cycle 7). Conversely, blood pressure during examination cycle 7 was not associated with CFPWV during examination cycle 8. Higher resting brachial artery flow (OR, 1.23 [95% CI, 1.04-1.46]) and lower flow-mediated dilation (OR, 0.80 [95% CI, 0.67-0.96]) during examination cycle 7 were associated with incident hypertension (in models that included blood pressure and tonometry measures collected during examination cycle 7)., Conclusion: In this cohort, higher aortic stiffness, FWA, and augmentation index were associated with higher risk of incident hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening.