Daniel Levy

Prognostic Implications of Echocardiographically Determined Left Ventricular Mass in the Framingham Heart Study

A pattern of left ventricular hypertrophy evident on the electrocardiogram is a harbinger of morbidity and mortality from cardiovascular disease. Echocardiography permits the noninvasive determination of left ventricular mass and the examination of its role as a precursor of morbidity and mortality. We examined the relation of left ventricular mass to the incidence of cardiovascular disease, mortality from cardiovascular disease, and mortality from all causes in 3220 subjects enrolled in the Framingham Heart Study who were 40 years of age or older and free of clinically apparent cardiovascular disease, in whom left ventricular mass was determined echocardiographically. During a four-year follow-up period, there were 208 incident cardiovascular events, 37 deaths from cardiovascular disease, and 124 deaths from all causes. Left ventricular mass, determined echocardiographically, was associated with all outcome events. This relation persisted after we adjusted for age, diastolic blood pressure, pulse pressure, treatment for hypertension, cigarette smoking, diabetes, obesity, the ratio of total cholesterol to high-density lipoprotein cholesterol, and electrocardiographic evidence of left ventricular hypertrophy. In men, the risk factor-adjusted relative risk of cardiovascular disease was 1.49 for each increment of 50 g per meter in left ventricular mass corrected for the subjects height (95 percent confidence interval, 1.20 to 1.85); in women, it was 1.57 (95 percent confidence interval, 1.20 to 2.04). Left ventricular mass (corrected for height) was also associated with the incidence of death from cardiovascular disease (relative risk, 1.73 [95 percent confidence interval, 1.19 to 2.52] in men and 2.12 [95 percent confidence interval, 1.28 to 3.49] in women). Left ventricular mass (corrected for height) was associated with death from all causes (relative risk, 1.49 [95 percent confidence interval, 1.14 to 1.94] in men and 2.01 [95 percent confidence interval, 1.44 to 2.81] in women). We conclude that the estimation of left ventricular mass by echocardiography offers prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors. An increase in left ventricular mass predicts a higher incidence of clinical events, including death, attributable to cardiovascular disease.

Lifetime Risk for Development of Atrial Fibrillation The Framingham Heart Study

Background—Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated. Methods and Results—We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%. Conclusions—Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.

Temporal Relations of Atrial Fibrillation and Congestive Heart Failure and Their Joint Influence on Mortality: The Framingham Heart Study

Background Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality. Methods and Results We studied participants in the Framingham Study with new‐onset AF or CHF. Multivariable Cox proportional hazards models with time‐dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person‐years, and the incidence of AF among CHF subjects was 54 per 1000 person‐years. In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Preexisting CHF adversely affected survival in individuals with AF, but preexisting AF was not associated with adverse survival in those with CHF. Conclusions Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis. Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted. (Circulation. 2003;107:2920‐2925.)

Impact of Obesity on Plasma Natriuretic Peptide Levels

Background—The mechanisms linking obesity to hypertension have not been established, but sodium retention and excessive sympathetic tone are key contributors. The natriuretic peptides are important regulators of sodium homeostasis and neurohormonal activation, raising the possibility that obese individuals have an impaired natriuretic peptide response. Methods and Results—We examined the relations of plasma B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide (N-ANP) to body mass index in 3389 Framingham Study participants (1803 women) without heart failure. Multivariable regression analyses were performed, adjusting for clinical and echocardiographic covariates. BNP levels below the assay detection limit and N-ANP levels in the lowest sex-specific quartile were categorized as low. Multivariable-adjusted mean plasma BNP levels in lean (<25 kg/m2), overweight (25 to 29.9 kg/m2), and obese (≥30 kg/m2) men were 21.4, 15.5, and 12.7 pg/mL, respectively (trend P <0.0001). Corresponding values in women were 21.1, 16.3, and 13.1 pg/mL (trend P <0.001). A similar pattern was noted for plasma N-ANP. Obese individuals had higher odds of having low plasma BNP (multivariable-adjusted odds ratios: men, 2.51; 95% CI, 1.71 to 3.68; women, 1.84; 95% CI, 1.32 to 2.58) and low plasma N-ANP (odds ratios: men, 4.81; 95% CI, 2.98 to 7.76; women, 2.85; 95% CI, 2.01 to 4.04) compared with lean individuals. Diabetes also was associated with low plasma natriuretic peptide levels, and the negative effects of obesity and diabetes on natriuretic peptide levels were additive. Conclusions—Obese individuals have low circulating natriuretic peptide levels, which may contribute to their susceptibility to hypertension and hypertension-related disorders.

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

BACKGROUNDnAtrial 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.nnnMETHODSnWe 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.nnnFINDINGSn457 (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).nnnINTERPRETATIONnFrom 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.

Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death

OBJECTIVESnThis study examined the relations of echocardiographically determined left ventricular (LV) mass and hypertrophy to the risk of sudden death.nnnBACKGROUNDnEchocardiographic LV hypertrophy is associated with increased risk for all-cause mortality and cardiovascular disease morbidity and mortality. However, little is known about the association of echocardiographic LV hypertrophy with sudden death.nnnMETHODSnWe examined the relations of LV mass and hypertrophy to the incidence of sudden death in 3,661 subjects enrolled in the Framingham Heart Study who were > or =40 years of age. The baseline examination was performed from 1979 to 1983 and LV hypertrophy was defined as LV mass (adjusted for height) > 143 g/m in men and > 102 g/m in women. During up to 14 years of follow-up there were 60 sudden deaths. Cox models examined the relations of LV mass and LV hypertrophy to sudden death risk after adjusting for known risk factors.nnnRESULTSnThe prevalence of LV hypertrophy was 21.5%. The risk factor-adjusted hazard ratio (HR) for sudden death was 1.45 (95% confidence interval [CI] 1.10 to 1.92, p=0.008) for each 50-g/m increment in LV mass. For LV hypertrophy, the risk factor-adjusted HR for sudden death was 2.16 (95% CI 1.22 to 3.81, p=0.008). After excluding the first 4 years of follow-up, both increased LV mass and LV hypertrophy conferred long-term risk of sudden death (HR 1.53, 95% CI 1.01 to 2.28, p=0.047 and HR 3.28, 95% CI 1.58 to 6.83, p=0.002, respectively).nnnCONCLUSIONSnIncreased LV mass and hypertrophy are associated with increased risk for sudden death after accounting for known risk factors.

Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study.

OBJECTIVEnTo examine the association of echocardiographically determined left ventricular mass with incidence of coronary heart disease in an elderly cohort.nnnDESIGNnCohort study with a follow-up period of 4 years.nnnSETTINGnPopulation-based.nnnSUBJECTSnElderly original volunteer subjects of the Framingham Heart Study who were free of clinically apparent coronary heart disease. This group included 406 men (mean age, 68 years: range, 60 to 90) and 735 women (mean age, 69 years: range, 59 to 90).nnnMEASUREMENTS AND MAIN RESULTSnDuring 4 years of follow-up, coronary heart disease events occurred in 37 men and 33 women. Baseline echocardiographically determined left ventricular mass was associated with incidence of coronary disease in both sexes (P less than 0.01). After adjusting for age, systolic blood pressure, smoking, and the ratio of total/high density lipoprotein cholesterol, the relative risk for a coronary event, per 50 g/m increment in left ventricular mass/height, was 1.67 in men (95% CI, 1.24 to 2.23) and 1.60 in women (95% CI, 1.10 to 2.32).nnnCONCLUSIONSnEchocardiographic assessment of left ventricular mass offers prognostic information beyond that provided by traditional risk factors, which can improve our ability to identify individuals at high risk for coronary heart disease. These findings may have widespread implications regarding the applications of echocardiography in clinical practice.

Inflammatory Markers and Risk of Heart Failure in Elderly Subjects Without Prior Myocardial Infarction

Background—Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with worse functional status and adverse prognosis. It is unclear whether cytokine levels can predict the incidence of CHF in asymptomatic individuals. Methods and Results—We investigated the relations of serum interleukin-6 (IL-6), C-reactive protein (CRP), and spontaneous production of tumor necrosis factor-&agr; (TNF&agr;) by peripheral blood mononuclear cell (PBMC) to CHF incidence among 732 elderly Framingham Study subjects (mean age 78 years, 67% women) free of prior myocardial infarction and CHF. On follow-up (mean 5.2 years), 56 subjects (35 women) developed CHF. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60 (PBMC TNF&agr;) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration (P =0.04, and 0.03, respectively, for trend). A serum CRP level ≥5 mg/dL was associated with a 2.8-fold increased risk of CHF (P =0.02). Subjects with elevated levels of all 3 biomarkers (serum IL-6 and PBMC TNF&agr; >median values, CRP≥5 mg/dL) had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34 to 12.37], P =0.01) compared with the other subjects. Conclusions—In our elderly, community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, was associated with increased risk of CHF in people without prior myocardial infarction. Additional epidemiological investigations are warranted to confirm the contribution of inflammation to the pathogenesis of CHF in the general population.

Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction Insights From the Framingham Heart Study of the National Heart, Lung, and Blood Institute

Background— The contributions of risk factors and disease pathogenesis to heart failure with preserved ejection fraction (HFPEF) versus heart failure with reduced ejection fraction (HFREF) have not been fully explored. Methods and Results— We examined clinical characteristics and risk factors at time of heart failure onset and long-term survival in Framingham Heart Study participants according to left ventricular ejection fraction ≤45% (n=314; 59%) versus >45% (n=220; 41%) and hierarchical causal classification. Heart failure was attributed to coronary heart disease in 278 participants (52%), valvular heart disease in 42 (8%), hypertension in 140 (26%), or other/unknown causes in 74 (14%). Multivariable predictors of HFPEF (versus HFREF) included elevated systolic blood pressure (odds ratio [OR]=1.13 per 10 mm Hg; 95% confidence interval [CI], 1.04 to 1.22), atrial fibrillation (OR=4.23; 95% CI, 2.38 to 7.52), and female sex (OR=2.29; 95% CI, 1.35 to 3.90). Conversely, prior myocardial infarction (OR=0.32; 95% CI, 0.19 to 0.53) and left bundle-branch block QRS morphology (OR=0.21; 95% CI, 0.10 to 0.46) reduced the odds of HFPEF. Long-term prognosis was grim, with a median survival of 2.1 years (5-year mortality rate, 74%), and was equally poor in men and women with HFREF or HFPEF. Conclusions— Among community patients with new-onset heart failure, there are differences in causes and time-of-onset clinical characteristics between those with HFPEF versus HFREF. In people with HFREF, mortality is increased when coronary heart disease is the underlying cause. These findings suggest that heart failure with reduced left ventricular systolic function and heart failure with preserved left ventricular systolic function are partially distinct entities, with potentially different approaches to early detection and prevention.

Natural History of Asymptomatic Left Ventricular Systolic Dysfunction in the Community

Background—Information is limited regarding the rates of progression to congestive heart failure (CHF) and death in individuals with asymptomatic left ventricular systolic dysfunction (ALVD). We sought to characterize the natural history of ALVD, by studying unselected individuals with this condition in the community. Methods and Results—We studied 4257 participants (1860 men) from the Framingham Study who underwent routine echocardiography. The prevalence of ALVD (visually estimated ejection fraction [EF]≤50% without a history of CHF) was 6.0% in men and 0.8% in women. During up to 12 years of follow-up, rates of CHF among subjects with normal left ventricular systolic function (EF >50%, n=4128) and ALVD (n=129) were 0.7 and 5.8 per 100 person-years, respectively. After adjustment for cardiovascular disease risk factors, ALVD was associated with a hazards ratio (HR) for CHF of 4.7 (95% CI 2.7 to 8.1), compared with individuals without ALVD. An elevated risk of CHF after ALVD was observed even in individuals without prior myocardial infarction or valvular disease, with an adjusted HR of 6.5 (CI 3.1 to 13.5). Mild ALVD (EF 40% to 50%, n=78) and moderate-to-severe ALVD (EF <40%, n=51) were associated with adjusted HRs for CHF of 3.3 (CI 1.7 to 6.6) and 7.8 (CI 3.9 to 15.6), respectively. ALVD was also associated with an increased mortality risk (adjusted HR 1.6, CI 1.1 to 2.4). The median survival of ALVD subjects was 7.1 years. Conclusion—Individuals with ALVD in the community are at high risk of CHF and death, even when only mild impairment of EF is present. Additional studies are needed to define optimal therapy for mild ALVD.