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Background: An increased interarm systolic blood pressure difference is an easily determined physical examination finding. The relationship between interarm systolic blood pressure difference and risk of future cardiovascular disease is uncertain. We described the prevalence and risk factor correlates of interarm systolic blood pressure difference in the Framingham Heart Study (FHS) original and offspring cohorts and examined the association between interarm systolic blood pressure difference and incident cardiovascular disease and all-cause mortality., Methods: An increased interarm systolic blood pressure difference was defined as ≥ 10 mm Hg using the average of initial and repeat blood pressure measurements obtained in both arms. Participants were followed through 2010 for incident cardiovascular disease events. Multivariable Cox proportional hazards regression analyses were performed to investigate the effect of interarm systolic blood pressure difference on incident cardiovascular disease., Results: We examined 3390 (56.3% female) participants aged 40 years and older, free of cardiovascular disease at baseline, mean age of 61.1 years, who attended a FHS examination between 1991 and 1994 (original cohort) and from 1995 to 1998 (offspring cohort). The mean absolute interarm systolic blood pressure difference was 4.6 mm Hg (range 0-78). Increased interarm systolic blood pressure difference was present in 317 (9.4%) participants. The median follow-up time was 13.3 years, during which time 598 participants (17.6%) experienced a first cardiovascular event, including 83 (26.2%) participants with interarm systolic blood pressure difference ≥ 10 mm Hg. Compared with those with normal interarm systolic blood pressure difference, participants with an elevated interarm systolic blood pressure difference were older (63.0 years vs 60.9 years), had a greater prevalence of diabetes mellitus (13.3% vs 7.5%,), higher systolic blood pressure (136.3 mm Hg vs 129.3 mm Hg), and a higher total cholesterol level (212.1 mg/dL vs 206.5 mg/dL). Interarm systolic blood pressure difference was associated with a significantly increased hazard of incident cardiovascular events in the multivariable adjusted model (hazard ratio 1.38; 95% CI, 1.09-1.75). For each 1-SD-unit increase in absolute interarm systolic blood pressure difference, the hazard ratio for incident cardiovascular events was 1.07 (95% CI, 1.00-1.14) in the fully adjusted model. There was no such association with mortality (hazard ratio 1.02; 95% CI 0.76-1.38)., Conclusions: In this community-based cohort, an interarm systolic blood pressure difference is common and associated with a significant increased risk for future cardiovascular events, even when the absolute difference in arm systolic blood pressure is modest. These findings support research to expand clinical use of this simple measurement., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Higher left ventricular (LV) mass, wall thickness, and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates and types of HF incidence is unclear. In this study, 4,768 Framingham Heart Study participants (mean age 50 years, 56% women) were classified into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy) using American Society of Echocardiography-recommended thresholds of echocardiographic LV mass indexed to body surface area and relative wall thickness, and these groups were related to HF incidence. Whether risk for HF types (HF with reduced ejection fraction [<45%] vs preserved ejection fraction [≥45%]) varied by hypertrophy pattern was then evaluated. On follow-up (mean 21 years), 458 participants (9.6%, 250 women) developed new-onset HF. The age- and gender-adjusted 20-year HF incidence increased from 6.96% in the normal left ventricle group to 8.67%, 13.38%, and 15.27% in the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to the normal left ventricle group (p = 0.0002); eccentric hypertrophy carried the greatest risk (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.41 to 2.54), followed by concentric hypertrophy (HR 1.40, 95% CI 1.04 to 1.87). Participants with eccentric hypertrophy had a higher propensity for HF with reduced ejection fraction (HR 2.23, 95% CI 1.48 to 3.37), whereas those with concentric hypertrophy were more prone to HF with preserved ejection fraction (HR 1.66, 95% CI 1.09 to 2.51). In conclusion, in this large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HF with reduced and preserved ejection fraction, respectively., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We sought to determine whether depressed myocardial contraction fraction (MCF; ratio of left ventricular [LV] stroke volume to myocardial volume) predicts cardiovascular disease (CVD) events in initially healthy adults. A subset (n = 318, 60 ± 9 years old, 158 men) of the Framingham Heart Study Offspring cohort free of clinical CVD underwent volumetric cardiovascular magnetic resonance imaging in 1998 through 1999. LV ejection fraction (EF), mass, and MCF were determined. "Hard" CVD events consisted of cardiovascular death, myocardial infarction, stroke, or new heart failure. A Cox proportional hazards model adjusting for Framingham Coronary Risk Score was used to estimate hazard ratios for incident hard CVD events for gender-specific quartiles of MCF, LV mass, and LVEF. The lowest quartile of LV mass and highest quartiles of MCF and EF served as referents. Kaplan-Meier survival plots and log-rank test were used to compare event-free survival. MCF was greater in women (0.58 ± 0.13) than in men (0.52 ± 0.11, p <0.01). Nearly all participants (99%) had EF ≥0.55. During an up to 9-year follow-up (median 5.2), 31 participants (10%) developed an incident hard CVD event. Lowest-quartile MCF was 7 times more likely to develop a hard CVD (hazard ratio 7.11, p = 0.010) compared to the remaining quartiles, and increased hazards persisted even after adjustment for LV mass (hazard ratio 6.09, p = 0.020). The highest-quartile LV mass/height 2.7 had a nearly fivefold risk (hazard ratio 4.68, p = 0.016). Event-free survival was shorter in lowest-quartile MCF (p = 0.0006) but not in lowest-quartile LVEF. In conclusion, in a cohort of adults initially without clinical CVD, lowest-quartile MCF conferred an increased hazard for hard CVD events after adjustment for traditional CVD risk factors and LV mass., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Little is known about the familial aggregation of intermittent claudication (IC). Our objective was to examine whether parental IC increased the risk of IC in adult offspring, independent of the established cardiovascular risk factors. We evaluated the Offspring Cohort Participants of the Framingham Heart Study who were ≥30 years old, cardiovascular disease free, and had both parents enrolled in the Framingham Heart Study (n = 2,970 unique participants, 53% women). Pooled proportional hazards regression analysis was used to examine whether the 12-year risk of incident IC in offspring participants was associated with parental IC, adjusting for age, gender, diabetes, smoking, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive and lipid treatment. Of the 909 person-examinations in the parental IC history group and 5,397 person-examinations in the no-parental IC history group, there were 101 incident IC events (29 with parental IC history and 72 without a parental IC history) during follow-up. The age- and gender-adjusted 12-year cumulative incidence rate per 1,000 person-years was 5.08 (95% confidence interval [CI] 2.74 to 7.33) and 2.34 (95% CI 1.46 to 3.19) in participants with and without a parental IC history. A parental history of IC significantly increased the risk of incident IC in the offspring (multivariable adjusted hazard ratio 1.81, 95% CI 1.14 to 2.88). The hazard ratio was unchanged, with an adjustment for the occurrence of cardiovascular disease (hazard ratio 1.83, 95% CI 1.15 to 2.91). In conclusion, IC in parents increases the risk of IC in adult offspring, independent of the established risk factors. These data suggest a genetic component of peripheral artery disease and support future research into genetic causes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The prevalence and clinical correlates of left ventricular (LV) wall motion abnormalities (WMAs), associated with morbidity and mortality, have not been well-characterized in the population. Framingham Heart Study Offspring Cohort participants (n = 1,794, 844 men, age 65 ± 9 years) underwent cine cardiovascular magnetic resonance for evaluation of LV function. A subset (n = 1,009, 460 men) underwent cardiac multidetector computed tomography for analysis of coronary artery calcium. The presence of coronary heart disease and heart failure (CHD-HF) were assessed in relation to the presence of WMAs. WMAs were present in 117 participants (6.5%) and were associated with male gender, elevated hemoglobin A1c, LV mass, LV end-diastolic volume, and lower LV ejection fraction. Of the 1,637 participants without CHD-HF, 68 (4.2%) had WMAs. In this group, WMAs were associated with obesity, hypertension, and Framingham coronary heart disease risk score in the age- and gender-adjusted analyses and were associated with male gender and hypertension on multivariate analysis. Most subjects with WMAs were in the greatest coronary artery calcium groups. The presence of coronary artery calcium greater than the seventy-fifth percentile and Agatston score >100 were associated with a greater than twofold risk of WMAs in the age- and gender-adjusted analysis but were no longer significant when additionally adjusted for CHD-HF. Previous Q-wave myocardial infarction was present in 29% of the 117 participants with WMAs. In conclusion, in the present longitudinally followed free-living population, 4.2% of the participants without CHD-HF had WMAs. WMAs were associated with the clinical parameters associated with cardiovascular disease risk. Aggressive risk factor modification may be prudent for subjects with WMAs, particularly those free of clinical CHD-HF., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: This analysis was undertaken to determine the long-term intraindividual variability, determinants of change, and capacity of the inflammatory marker C-reactive protein (CRP) to predict metabolic traits and diabetes in a large community-based population., Methods: Intraindividual CRP variability, predictors of CRP change, and metabolic events were evaluated in the Framingham Heart Study Offspring cohort using data from the same 2409 participants with CRP measured by the same methodology at each of 3 examination cycles, spanning 20 years., Results: Between the first and second examinations (averaging 16 years apart), 23% to 47% of men and 27% to 49% of women remained within the same quintile of CRP values. An additional 24% to 51% of men and 24% to 50% of women occupied an adjacent quintile. Intermediate-term CRP variability (over 4 years) was similar to long-term variability. Both long- and intermediate-term variability of CRP were significantly less than that of plasma cholesterol measured in these same groups. Linear regression models for CRP at the intermediate examination demonstrated that CRP at the initial examination contributed the largest proportion of the variability (partial R-square = 0.27) seen in the overall model after adjustment for other covariates known to affect CRP concentrations. Although logistic regression models demonstrated that CRP over the intermediate term did not predict new-onset metabolic syndrome at the final examination, CRP did predict an increase in glucose and new-onset diabetes., Conclusion: The results of this longitudinal analysis suggest the intraindividual, long-term variability of CRP concentrations is relatively small and predictive of new diabetes over an intermediate-term of 4 years.

Exaggerated systolic blood pressure (BP) augmentation with exercise has been associated with impaired endothelial function and cardiovascular risk. However, previous studies were largely restricted to men, did not evaluate diastolic BP, and focused on peak exercise measures, which are influenced by effort and fitness level. The aim of this study was to determine the association of exercise BP responses with risk of incident cardiovascular disease (CVD). BP was assessed during stage 2 of the Bruce protocol and during recovery in 3,045 Framingham Study subjects (mean age 43 years; 53% women). The association between exercise BP and CVD events during 20 years of follow-up was examined using Cox proportional hazards models. In age- and sex-adjusted analyses, exercise systolic and diastolic BP were associated with incident CVD (adjusted hazard ratios [HRs] for top quintile 1.55, 95% confidence interval [CI] 1.18 to 2.04; and 1.77, 95% CI 1.35 to 2.31, respectively, relative to the lower 4 quintiles; p <0.005). After adjustment for BP at rest and conventional risk factors, exercise diastolic BP (HR 1.41, 95% CI 1.01 to 1.95, p = 0.04), but not exercise systolic BP (HR 0.97, 95% CI 0.68 to 1.38, p = 0.86), remained a significant predictor of CVD. Similarly, in recovery responses after exercise, only diastolic BP (HR 1.53, 95% CI 1.08 to 2.18, p = 0.02) predicted incident CVD in multivariable models. In conclusion, in middle-aged adults, diastolic BP during low-intensity exercise and recovery predicted incident CVD. Our findings support the concept that dynamic BP provides incremental information to BP at rest and suggest that exercise diastolic BP may be a better predictor than exercise systolic BP in this age group.

Background: It is uncertain to what extent high C-reactive protein (CRP) concentrations reflect the presence of inflammatory conditions in the community., Methods: We evaluated 3782 Framingham Offspring Study participants (mean age 55 years; 52% women) free of baseline cardiovascular disease. Logistic regression models examined the prevalence of common inflammatory conditions by CRP categories, while a separate matched case-referent analysis evaluated the prevalence of uncommon inflammatory conditions. Cox models were used to assess the influence of common inflammatory conditions on relations between CRP and incident cardiovascular disease., Results: Common inflammatory conditions were reported by nearly half of the participants; these individuals were more likely to have markedly high CRP concentrations (>10 mg/L, P for trend=.001). In multivariable models, there were increased odds of having at least one common inflammatory condition with CRP concentrations of 1-3.0, 3.01-10, and >10 mg/L, compared with the referent category (<1 mg/L); the respective odds ratios with 95% confidence intervals were 1.41 (1.07-1.86), 1.45 (1.07-1.98), and 1.64 (1.09-2.47) in men, and 1.08 (0.82-1.43), 1.07 (0.80-1.44), and 1.38 (0.97-1.96) in women. In case-referent analyses, uncommon inflammatory conditions were more common in individuals with CRP >10 mg/L compared with those with CRP <1 mg/L (12.1% vs 6.6%; P=.0001). In multivariable models, higher CRP categories were not associated with incident cardiovascular disease, and with additional adjustment for inflammatory conditions, results remained unchanged., Conclusion: There is high prevalence of common and uncommon inflammatory conditions in individuals with high CRP concentrations. Higher CRP concentrations should be interpreted with caution in cardiovascular disease risk assessment.