Left ventricular hypertrophy patterns and incidence of heart failure with preserved versus reduced ejection fraction.

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.

Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study.

AIMS: Reduced physical activity is associated with increased risk of heart failure (HF) in middle-aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF). METHODS AND RESULTS: We evaluated 1142 elderly participants (mean age 76 years) from the Framingham Study without prior myocardial infarction and who attended a routine examination when daily physical activity was assessed systematically with a questionnaire. A composite score, the physical activity index (PAI), was calculated and modelled as tertiles, and related to incidence of HF, HFPEF, and HFREF on follow-up using proportional hazards regression models adjusting for age and sex, and then additionally for standard HF risk factors. Participants with HF and EF <45% vs. ≥45% were categorized as HFREF and HFPEF, respectively. On follow-up (mean 10 years), 250 participants developed HF (108 with HFPEF, 106 with HFREF, 36 with unavailable EF). In age- and sex-adjusted models, the middle and highest PAI tertiles were associated with a 15-56% lower risk of any HF, of HFREF, and of HFPEF, with a graded response across tertiles. In multivariable models, the association of higher PAI with lower risk of any HF and with HFPEF was maintained, whereas the association with HFREF was attenuated. CONCLUSIONS: Our study of an older community-based sample extends to the elderly and to HFPEF previous findings of a protective effect of physical activity on HF risk.

Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction.

BACKGROUND: About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF. METHODS AND RESULTS: We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus ≤45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60±12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF (P≤0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF. CONCLUSIONS: Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes.

Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community.

AIMS: Heart failure (HF) is a major public health burden worldwide. Of patients presenting with HF, 30-55% have a preserved ejection fraction (HFPEF) rather than a reduced ejection fraction (HFREF). Our objective was to examine discriminating clinical features in new-onset HFPEF vs. HFREF. METHODS AND RESULTS: Of 712 participants in the Framingham Heart Study (FHS) hospitalized for new-onset HF between 1981 and 2008 (median age 81 years, 53% female), 46% had HFPEF (EF >45%) and 54% had HFREF (EF ≤45%). In multivariable logistic regression, coronary heart disease (CHD), higher heart rate, higher potassium, left bundle branch block, and ischaemic electrocardiographic changes increased the odds of HFREF; female sex and atrial fibrillation increased the odds of HFPEF. In aggregate, these clinical features predicted HF subtype with good discrimination (c-statistic 0.78). Predictors were examined in the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study. Of 4436 HF patients (median age 75 years, 47% female), 32% had HFPEF and 68% had HFREF. Distinguishing clinical features were consistent between FHS and EFFECT, with comparable discrimination in EFFECT (c-statistic 0.75). In exploratory analyses examining the traits of the intermediate EF group (EF 35-55%), CHD predisposed to a decrease in EF, whereas other clinical traits showed an overlapping spectrum between HFPEF and HFREF. CONCLUSION: Multiple clinical characteristics at the time of initial HF presentation differed in participants with HFPEF vs. HFREF. While CHD was clearly associated with a lower EF, overlapping characteristics were observed in the middle of the left ventricular EF range spectrum.

Higher aldosterone and lower N-terminal proatrial natriuretic peptide as biomarkers of salt sensitivity in the community.

BACKGROUND: Salt sensitivity, a trait characterized by a pressor blood pressure response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity. DESIGN: Prospective cohort study. METHODS: We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55 ± 9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially 'salt sensitive' if their serum aldosterone was >sex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic blood pressure on follow-up (median four years). RESULTS: Participants who were 'salt sensitive' (N = 437) experienced significantly greater increases in blood pressure (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and -0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and -0.2 mmHg; on higher versus lower sodium diet, respectively; P = 0.033 and P = 0.0127 for differences between groups in Δ systolic and Δ diastolic blood pressure, respectively). CONCLUSIONS: Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.

A systematic assessment of causes of death after heart failure onset in the community: impact of age at death, time period, and left ventricular systolic dysfunction.

BACKGROUND: The high mortality rate in patients with heart failure (HF) is influenced by presence of multiple comorbidities. Data are limited on the relative contributions of cardiovascular versus noncardiovascular diseases to death in individuals with HF in the community. METHODS AND RESULTS: We examined the incidence and predictors of cardiovascular versus noncardiovascular death in participants with HF in the Framingham Heart Study. Underlying, immediate, and contributing causes of death (3 key elements of the World Health Organization classification) were adjudicated by a 3-physician review panel. During 1971 to 2004, 1025 participants with HF died (499 men, mean [SD] age at death 79 [11] years), including 463 participants with left ventricular ejection fraction (LVEF) data. Cardiovascular disease was the cause of death in 66.1% overall. Stratified by LVEF, cardiovascular deaths occurred in 44.5% and 69.9% of those with preserved and reduced LVEF, respectively. Presence of reduced LVEF increased the risk of cardiovascular death, with odds ratios of 3.16 (95% confidence interval [CI], 1.73 to 5.78) in men and 2.39 (95% CI, 1.39 to 4.08) in women. Prior myocardial infarction was associated with increased cardiovascular death in women with HF (odds ratio, 1.87; 95% CI, 1.10 to 3.16) but not in men. The risk of cardiovascular disease death decreased in women (odds ratio after 1980, 0.41; 95% CI, 0.24 to 0.69) and men (odds ratio, 0.66; 95% CI, 0.41 to 1.07, P=0.095) with HF over time. Infections and kidney disease emerged as key immediate and contributing causes of death, respectively. CONCLUSIONS: Individuals with HF in the community often experience cardiovascular death, but noncardiovascular disease also contributes significantly especially among those with preserved LVEF.

Validation of an atrial fibrillation risk algorithm in whites and African Americans.

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups. METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure. RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk. CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community.

AIMS: To evaluate the association of serum phosphorus with cardiac structure/function and incident heart failure. METHODS AND RESULTS: We related serum phosphorus to echocardiographic left ventricular (LV) measurements cross-sectionally, and to incident heart failure prospectively in 3300 participants (mean age 44 years, 51% women) free of heart failure, myocardial infarction, and chronic kidney disease (estimated glomerular filtration rate [eGFR]<60 mL/min/1.73 m(2)). Cross-sectionally, serum phosphorus was related positively to LV mass, internal dimensions, and systolic dysfunction. On follow-up (mean 17.4 years), 157 individuals developed heart failure. In models adjusting for established risk factors as time-varying covariates, each mg/dL increment in serum phosphorus was associated with a 1.74-fold risk of heart failure [95% confidence intervals (CI) 1.17-2.59]. Individuals in the highest serum phosphorus quartile experienced a two-fold (95% CI 1.28-3.40) risk of heart failure compared with participants in the lowest quartile. These relations were maintained upon additional adjustment for LV mass/dimensions and systolic dysfunction. In analyses restricted to individuals with eGFR >90 mL/min/1.73 m(2), no proteinuria and serum phosphorus <4.5 mg/dL, the association of serum phosphorus with heart failure remained robust. CONCLUSION: In our community-based sample, higher serum phosphorus was associated with greater LV mass cross-sectionally, and with an increased risk of heart failure prospectively.

Relations of lipid concentrations to heart failure incidence: the Framingham Heart Study.

BACKGROUND: The relations of lipid concentrations to heart failure (HF) risk have not been elucidated comprehensively. METHODS AND RESULTS: In 6860 Framingham Heart Study participants (mean age, 44 years; 54% women) free of baseline coronary heart disease, we related high-density lipoprotein cholesterol (HDL-C) and non-HDL-C to HF incidence during long-term follow-up, adjusting for clinical covariates and myocardial infarction at baseline and updating these at follow-up examinations. We evaluated dyslipidemia-specific population burden of HF by calculating population attributable risks. During follow-up (mean of 26 years), 680 participants (49% women) developed HF. Unadjusted HF incidence in the low (<160 mg/dL) versus high (> or =190 mg/dL) non-HDL-C groups was 7.9% and 13.8%, respectively, whereas incidence in the high (> or =55 [men], > or =65 [women] mg/dL) versus low (<40 [men], <50 [women] mg/dL) HDL-C groups was 6.1% and 12.8%, respectively. In multivariable models, baseline non-HDL-C and HDL-C, modeled as continuous measures, carried HF hazards (confidence intervals) of 1.19 (1.11 to 1.27) and 0.82 (0.75 to 0.90), respectively, per SD increment. In models updating lipid concentrations every 8 years, the corresponding hazards (confidence intervals) were 1.23 (1.16 to 1.31) and 0.77 (0.70 to 0.85). Participants with high baseline non-HDL-C and those with low HDL-C experienced a 29% and 40% higher HF risk, respectively, compared with those in the desirable categories; the population attributable risks for high non-HDL-C and low HDL-C were 7.5% and 15%, respectively. Hazards associated with non-HDL-C and HDL-C remained statistically significant after additional adjustment for interim myocardial infarction. CONCLUSIONS: Dyslipidemia carries HF risk independent of its association with myocardial infarction, suggesting that lipid modification may be a means for reducing HF risk.

Triglycerides as vascular risk factors: new epidemiologic insights.

PURPOSE OF REVIEW: Targeting triglycerides as a vascular risk factor is justified because of the role of triglyceride-rich lipoproteins in atherogenesis. This review examines recent evidence connecting triglycerides with cardiovascular disease (CVD) in the context of advances in insights concerning the pathophysiology, population burden and prognostic impact of fasting versus nonfasting values. RECENT FINDINGS: Cross-sectional surveys indicate that mean triglyceride levels in the United States have increased in recent decades. Although elevated fasting triglycerides are consistently associated with increased CVD risk, adjustment for other risk factors (especially high-density lipoprotein cholesterol (HDL-C)) substantially attenuates this relationship. A recent meta-analysis of 27 prospective studies of western populations reported a triglyceride impact on CVD in both sexes, for both fasting and nonfasting values. Nonfasting triglycerides maintained an independent graded relationship with CVD in fully adjusted analyses, with elevated 4 h postprandial triglyceride imposing a 4.5-fold increment relative to lower levels. SUMMARY: Evidence supports a potential role for both fasting and nonfasting triglycerides as vascular risk factors, owing in part to the accompanying burden of atherogenic remnant particles, small dense low-density lipoprotein, reduced HDL-C and a high frequency of accompanying insulin resistance. Triglyceride-associated CVD risk occurs even in patients with low low-density lipoprotein cholesterol (LDL-C), and lowering both lipids provides more benefit than reducing LDL-C alone.

Hypertension: reflections on risks and prognostication.

Framingham Heart Study cardiovascular disease prospective population epidemiologic research has played an important role in the evolution of modern cohort study design and the advancement of preventive cardiology. To date no single essential factor has been identified; multiple interrelated factors are promoting increased risk for development of CHD. Elevated blood pressure has emerged as a prominent member of cardiovascular risk factors. The study's documentation of a strong link of blood pressure to development of cardiovascular events stimulated the pharmaceutical industry to develop medications for controlling blood pressure and, in turn, national campaigns to combat hypertension and its adverse vascular outlook.

Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.

BACKGROUND: Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers. METHODS: We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45-95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. FINDINGS: 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0.05, except body-mass index p=0.08), clinical model C statistic 0.78 (95% CI 0.76-0.80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0.78 (95% CI 0.75-0.80) to 0.79 (0.77-0.82), p=0.005. Echocardiographic measurements did not improve risk reclassification (p=0.18). INTERPRETATION: From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community, assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures.

Adverse consequences of the 50% misconception.

It is often claimed that only 50% of the incidence of coronary artery disease in the population can be attributed to the standard major risk factors. A careful review of published research demonstrates that 75% to 90% of coronary artery disease incidence in a variety of populations is explained by the standard modifiable risk factors. In conclusion, these data suggest that a more rigorous focus on these conventional risk factors and the lifestyle behaviors that promote them has great potential to reduce the burden of coronary artery disease worldwide.

Current perceptions of the epidemiology of atrial fibrillation.

Atrial fibrillation (AF), an escalating dysrhythmia, is accountable for extensive population morbidity and mortality. In the United States, approximately 2.3 million people are presently diagnosed with AF and it is estimated that this prevalence may increase to 5.6 million by 2050. Foremost predisposing risk factors for this dysrhythmia include advanced age and cardiovascular disease and its risk factors. The chief hazard of AF is embolic stroke, which is increased four- to fivefold, and in advanced age, it becomes a dominant stroke risk factor. AF also carries a doubled mortality rate.

Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals.

OBJECTIVE: Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS: We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS: Leptin levels were higher in women and strongly correlated with BMI (P < 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CHF) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% CI 1.03-1.55] and 1.28 [1.09-1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75-1.24]) but only modestly attenuated the relation to CVD incidence (1.23 [1.00-1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS: In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality.