Menopause, hormones, and cardiovascular vulnerability in women.
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Cardiovascular Diseases↗
Biomedical subjects
Daniel Levy
Publications and source records attributed to Daniel Levy.
Relations of serum aldosterone to cardiac structure: gender-related differences in the Framingham Heart Study.
Aldosterone is associated with myocardial fibrosis in experimental studies and with left ventricular remodeling in heart failure patients. We hypothesized that aldosterone influences ventricular remodeling in people without congestive heart failure in the community. We examined the relations between serum aldosterone and echocardiographic left ventricular measurements in 2820 Framingham Study subjects (mean age 57 years, 58% women, 88% white) free of myocardial infarction and overt heart failure. Serum aldosterone levels were higher in women compared with men. In linear regression models (adjusted for age, systolic blood pressure, weight, height, diabetes, heart rate, hypertension treatment, and ethnicity), left ventricular wall thickness and relative wall thickness were positively related, and left ventricular diastolic dimensions were inversely related to serum aldosterone in women (P<0.05 for all), but not in men (P>0.20 for all). There was no effect modification of the relations observed in women by menopausal status. The gender-related differences in relations of serum aldosterone to relative wall thickness were consistent across subgroups defined on the basis of sex-specific median values of systolic blood pressure and body mass index. Fractional shortening, left ventricular mass, and left atrial dimensions were not related to serum aldosterone in either sex. In conclusion, in our community-based sample of individuals free of myocardial infarction and heart failure, serum aldosterone was positively associated with a left ventricular geometric pattern suggestive of concentric remodeling (increased left ventricular wall thickness and relative wall thickness but decreased internal dimensions) in women but not in men. Additional investigations are warranted to confirm these findings.
Aged↗
Postoperative atrial fibrillation and mortality: do the risks merit changes in clinical practice?
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Atrial Fibrillation↗
Regulation of human microsomal epoxide hydrolase gene (EPHX1) expression by the transcription factor GATA-4.
Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a crucial role in the metabolism of numerous xenobiotics as well as in mediating the hepatic sodium-dependent uptake of bile acids that are involved in numerous physiological processes including the regulation of cholesterol metabolism. The transcription factors and nuclear receptors that control the constitutive and inducible expression of the mEH gene (EPHX1), however, have not been described. To characterize these factors, a series of 5'-deletion constructs have been transfected into human liver-derived HepG2 cells as well as non-hepatic HeLa cells. Promoter activity analysis indicated the presence of a positive regulatory element in the -80/-70 bp region. Sequence analysis revealed a putative GATA site at -79/-74 bp as well as an additional site at -31/-26 bp. Electrophoretic mobility shift assays with an anti-GATA-4 antibody confirmed that GATA-4 bound to these two sites with a dissociation constant of 1.56 nM (-79 site) and 0.65 nM (-31 site). Coexpression of GATA-4 stimulated EPHX1 promoter activity up to 7.5-fold in a dose-dependent manner. Endogenous EPHX1 message in HepG2 cells was also significantly increased by overexpression of GATA-4. Mutating the -79 element resulted in a 65% loss of promoter activity, while mutating the -31 element had no effect on basal activity but greatly reduced the response to additional GATA-4. In HeLa cells, which do not express GATA-4, EPHX1 activity was negligible; however, activity could be reconstituted by the addition of exogenous GATA-4. These results demonstrate that GATA-4 plays a critical role in regulating EPHX1 expression.
Binding Sites↗
Predictors of new-onset kidney disease in a community-based population.
CONTEXT: Kidney disease is associated with an increased risk for the development of cardiovascular disease and end-stage renal disease; however, risk factors for kidney disease have not been well studied. OBJECTIVE: To identify predictors of the development of new-onset kidney disease. DESIGN, SETTING, AND PARTICIPANTS: A community-based, longitudinal cohort study of 2585 participants who attended both a baseline examination in 1978-1982 and a follow-up examination in 1998-2001, and who were free of kidney disease at baseline. MAIN OUTCOME MEASURES: Kidney disease was assessed by the Modification of Diet in Renal Disease Study equation and defined by a glomerular filtration rate (GFR) in the fifth or lower percentile (< or =59.25 mL/min per 1.73 m2 in women, < or =64.25 mL/min per 1.73 m2 in men). Stepwise logistic regression was used to determine the impact of risk factors on the occurrence of new-onset kidney disease. Baseline and long-term, 12-year, averaged risk factor models were explored. RESULTS: At baseline, there were 1223 men and 1362 women, with a mean age of 43 years, who were free of preexisting kidney disease. After a mean follow-up of 18.5 years, 244 participants (9.4%) had developed kidney disease. In multivariable models, baseline age (odds ratio [OR], 2.36 per 10-year increment; 95% confidence interval [CI], 2.00-2.78), GFR (<90 mL/min per 1.73 m2: OR, 3.01; 95% CI, 1.98-4.58; 90-119 mL/min per 1.73 m2: OR, 1.84; 95% CI, 1.16-2.93), body mass index (OR, 1.23 per 1 SD; 95% CI, 1.08-1.41), diabetes (OR, 2.60; 95% CI, 1.44-4.70), and smoking (OR, 1.42; 95% CI, 1.06-1.91) were related to the development of kidney disease. In addition to baseline age and GFR, the long-term, averaged risk factors that were predictive of kidney disease included hypertension (OR, 1.57; 95% CI, 1.17-2.12), high-density lipoprotein cholesterol level (OR, 0.80 per 1 SD; 95% CI, 0.69-0.92), and diabetes (OR, 2.38; 95% CI, 1.45-3.92). Compared with a normal GFR (> or =120 mL/min per 1.73 m2), a mildly reduced GFR (<90 mL/min per 1.73 m2) predicted a 3-fold odds of progression to kidney disease (OR, 2.95; 95% CI, 1.94-4.49). CONCLUSIONS: Established cardiovascular disease risk factors are associated with the development of new-onset kidney disease. Patients with a mildly reduced GFR should be monitored for progression to kidney disease.
Adult↗
Association of aortic valve calcium detected by electron beam computed tomography with echocardiographic aortic valve disease and with calcium deposits in the coronary arteries and thoracic aorta.
We conducted electron beam computed tomographic (EBCT) testing in a representative sample of 327 Framingham Heart Study subjects without clinical cardiovascular disease. EBCT was compared with 2-dimensional echocardiography for the detection of degenerative aortic valve (AV) disease. We determined the association between EBCT measures of AV calcium and calcium deposits in the coronary arteries and thoracic aorta. Of 327 subjects (mean age 60 +/- 9 years; 51% men), 14% had EBCT AV calcium (median Agatston score 0, range 0 to 1,592). The prevalence of AV calcium increased predictably across decades of age. Compared with echocardiography, the sensitivity and specificity of EBCT for the detection of degenerative AV disease were 24% and 94%, respectively. In unadjusted logistic regression models, the prevalence of EBCT AV calcium increased across tertiles of coronary artery calcium (for trend across tertiles, odds ratio [OR] 2.2, 95% confidence interval [CI] 1.4 to 3.5) and thoracic aorta calcium (for trend OR 2.8, 95% CI 1.7 to 4.4). After adjustment for age and gender, the associations of AV calcium with coronary calcium and thoracic aorta calcium were attenuated and no longer statistically significant. Thus, compared with echocardiography, EBCT was specific but insensitive for the detection of degenerative AV disease. EBCT AV calcium was associated with calcium deposits in the coronary arteries and the thoracic aorta, but these associations were confounded by age and risk factors.
Aged↗
Plasma natriuretic peptide levels and the risk of cardiovascular events and death.
BACKGROUND: The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established. METHODS: We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. RESULTS: During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro-atrial natriuretic peptide. CONCLUSIONS: In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.
Atrial Natriuretic Factor↗
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 (> or =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.
Atrial Natriuretic Factor↗
Cross-sectional relations of urinary sodium excretion to cardiac structure and hypertrophy. The Framingham Heart Study.
BACKGROUND: Increased sodium intake has been positively associated with high blood pressure (BP) and hypertensive target organ damage, but associations with cardiac structure in nonhypertensive individuals have yielded inconsistent results. We tested the hypothesis that sodium intake is associated with left ventricular (LV) mass and left ventricular hypertrophy (LVH), independent of BP, in the community. METHODS: We analyzed the cross-sectional relationships between urinary sodium excretion and LV measurements in a community-based sample of 2660 Framingham Offspring Study participants (mean age 58 years, 56% women and 44% men). Participants with known coronary artery disease, congestive heart failure, or renal failure as well as those using diuretics were excluded. Urinary sodium excretion was measured on a spot urine sample and was indexed to urinary creatinine. RESULTS: In sex-specific, multivariable linear regression models adjusting for covariates known to influence LV measurements, log urinary sodium was not associated with LV mass, wall thickness, end-diastolic dimensions, or left atrial size in either sex. Urinary sodium was not related to LVH defined as LV mass >/= sex-specific 80th percentile value. In analyses restricted to hypertensive individuals (n = 983, 470 women), urinary sodium was not associated with LV mass or LVH. CONCLUSIONS: In our large community-based sample, urinary sodium excretion was not related to LV mass, function, or hypertrophy.
Aged↗
Mitral annular calcification is a predictor for incident atrial fibrillation.
BACKGROUND: Mitral annular calcification (MAC) has been associated with adverse cardiovascular disease outcomes and stroke in longitudinal and community-based cohorts. Prospective data are limited on its association with atrial fibrillation (AF). METHODS: We examined the association between MAC and the long-term risk of AF over 16 years of follow-up in participants in the original cohort of the Framingham Heart Study who attended a routine examination between 1979 and 1981. MAC was assessed by M-mode echocardiography. cox proportional-hazards models were used to estimate hazard ratios (hr) for incident af. RESULTS: Of 1126 subjects who had adequate echocardiographic assessment and were AF-free at baseline, 149 (13%) had MAC. There were 217 cases of incident AF (42 in subjects with MAC). The age- and sex-adjusted incidence rate was 362 per 10,000 person-years in subjects with MAC compared with 185 per 10,000 person-years in those without MAC. In multivariable-adjusted analyses, MAC was associated with an increased risk of AF (HR 1.6, 95% CI 1.1-2.2). This association was attenuated upon further adjustment for left atrial size (HR 1.4, 95% CI 0.9-2.0). CONCLUSIONS: The association between MAC and incident AF may be mediated partially through left atrial enlargement. These data suggest the importance of better understanding the mechanisms involved in cardiac valvular calcification.
Age Distribution↗
Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study.
AIMS: Hyperhomocysteinaemia is a risk factor for congestive heart failure, especially in women. We investigated if homocysteine promotes left ventricular (LV) remodelling. METHODS AND RESULTS: We examined cross-sectional relations of plasma total homocysteine to echocardiographic LV structure and function in 2697 Framingham Heart Study participants (mean age 58 years, 58% women) free of heart failure and previous myocardial infarction. Adjusting for age and height, plasma homocysteine was positively related to LV mass, wall thickness, and relative wall thickness in women (p=0.0004-0.04), but not in men (p=0.28-0.68). Adjusting additionally for other clinical covariates, the relations of plasma homocysteine to LV mass and wall thickness in women remained statistically significant, but the relation to relative wall thickness became of borderline significance (1.92 g, 0.01 cm, and 0.29% increase, respectively, for a 1-SD increase in ln[homocysteine], p=0.01-0.08). LV mass and wall thickness were higher in the fourth quartile of plasma homocysteine compared to the lower three in all models in women (p=0.0003-0.02), but not in men (p=0.25-0.78). Plasma homocysteine was not related to left atrial size or LV fractional shortening in either sex. CONCLUSION: In our community-based sample, plasma homocysteine was directly related to LV mass and wall thickness in women but not in men.
Cardiac Volume↗
Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: the Framingham heart study.
AIMS: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key regulator of extracellular matrix degradation. We examined relations of plasma total TIMP-1 to cardiovascular risk factors and echocardiographic left ventricular (LV) structure and function in a community-based sample. METHODS AND RESULTS: We studied 1069 Framingham Heart Study participants (mean age 56 years, 58% women) free of heart failure and previous myocardial infarction. Plasma TIMP-1 was higher in men compared with women, and increased with age, body mass index and total/HDL-cholesterol ratio, but decreased with alcohol intake. Plasma TIMP-1 was also directly related to smoking, diabetes and use of anti-hypertensive treatment. Adjusting for age, sex and height, plasma TIMP-1 was positively associated with LV mass, wall thickness, relative wall thickness, end-systolic diameter, and left atrial diameter and the risk of having increased LV end-diastolic diameter or increased wall thickness, and negatively correlated with fractional shortening. Additional adjustment for clinical covariates attenuated the relations of plasma TIMP-1 to most echocardiographic measures. CONCLUSIONS: In our cross-sectional investigation, plasma total TIMP-1 was related to major cardiovascular risk factors and to indices of LV hypertrophy and systolic dysfunction. This raises the possibility that cardiovascular risk factors may influence cardiovascular remodelling via extracellular matrix degradation, which may be reflected in plasma TIMP-1 levels.
Cardiovascular Diseases↗
Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study.
Kidney disease is a risk factor for the development of cardiovascular disease, all-cause mortality, and ESRD. It is not known to what extent genetic factors play a role in the development of kidney disease in the general population. Multipoint variance components linkage analysis was performed using Genehunter on 330 families from the Framingham Heart Study offspring cohort, using a 10-cM genomewide scan for serum creatinine, GFR, and creatinine clearance (CRCL) measured from 1998 to 2001. GFR was estimated using the simplified Modification of Diet in Renal Disease Study equation, and CRCL was estimated using the Cockcroft-Gault equation. Covariates in the adjustment included age, gender, body mass index, diabetes, systolic BP, hypertension treatment, tobacco use, and HDL cholesterol. Overall, 1224 subjects (52% women), mean age 59, were available for analysis. Mean creatinine was 0.87 mg/dl, mean GFR was 87 ml/min per 1.73 m(2), and mean creatinine clearance was 100 ml/min. The multivariable-adjusted heritability estimates for creatinine, GFR, and CRCL were 0.29, 0.33, and 0.46, respectively. The peak log of the odds ratio (LOD) scores for serum creatinine, GFR, and CRCL were 2.28 at 176 cM on chromosome 4, 2.19 at 78 cM on chromosome 4, and 1.91 at 103 cM on chromosome 3, respectively. In a community-based sample, measures of serum creatinine, GFR, and CRCL are heritable, suggesting an underlying genetic component. These results also provide suggestive evidence for linkage to measures of kidney function. Further research is necessary to identify the genes involved in the development of kidney disease and to understand their roles in this complex process.
Adult↗
Monocyte cytokine production, systemic inflammation and cardiovascular disease in very elderly men and women: the Framingham Heart Study.
In very elderly participants of the Framingham Heart Study (mean age 79 years, 276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP) levels. Interleukin-6, tumour necrosis factor alpha and interleukin-1 production, and CRP were not associated with prevalent cardiovascular disease, and nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels. Further studies are warranted to examine the prognostic implications of CRP and related cytokines for CVD in the elderly.
Aged↗
Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular disease: the Framingham Heart Study.
BACKGROUND: Among patients with end-stage renal disease (ESRD), the risk of cardiovascular disease is 10 to 20 times higher than the general population. Adults with ESRD have increased coronary-artery calcification (CAC) detected by electron-beam computed tomography (EBCT). Because the risk of coronary heart disease is increased even at moderate declines in kidney function, we sought to test whether high CAC scores are seen among those with mild reductions in kidney function. METHODS: Men and women free of symptomatic cardiovascular disease underwent EBCT. Coronary calcium was quantified using the method described by Agatston. Renal function was estimated by glomerular filtration rate (GFR). Spearman correlation coefficients were used to test the association between GFR and CAC. RESULTS: Three hundred nineteen subjects (162 men/157 women), mean age 60, were included. Mean GFR was 86 +/- 23 mL/min/1.73 m2 (range 31-169; 10% with GFR <60 mL/min/1.73 m2). The median CAC scores by quartile of GFR were 85.9, 48.1, 7.9, and 2.7. Overall, the unadjusted correlation of GFR and CAC was -0.28 (P < 0.0001). This remained significant after adjustment for age and sex (-0.11, P < 0.05), and additionally after adjustment for body mass index (-0.11, P < 0.05), hypertension (-0.11, P < 0.05), or total cholesterol (-0.12, P= 0.04). A similar correlation was noted after multivariable adjustment (-0.10, P < 0.08). CONCLUSION: Mild declines in kidney function are associated with subclinical coronary artery calcification in a sample of subjects free of clinically apparent cardiovascular disease. This might help explain the increased risk of cardiovascular disease among individuals with renal dysfunction. Larger ongoing studies are needed to better quantify this finding.
Adult↗
Is baseline autonomic tone associated with new onset atrial fibrillation?: Insights from the framingham heart study.
BACKGROUND: Recent reports have indicated that autonomic tone fluctuations measured by heart rate variability (HRV) precede episodes of paroxysmal atrial fibrillation (AF). Little is known about the impact of baseline autonomic tone and the development of new onset AF in a population-based cohort. The purpose of this study was to assess the role of HRV as a predictor of new onset AF. METHOD: Ambulatory ECG recordings obtained from the Framingham Heart Study subjects attending a routine examination were processed for HRV. The HRV variables analyzed included standard deviation of normal R-R intervals (SDNN), low frequency power (LF), high frequency power (HF), and LF/HF ratio. There were 1434 women and 1142 men (54 +/- 14.1 years) eligible for the study. RESULTS: In 12 years of follow-up, 65 women and 67 men had new onset AF. The study had 80% power to detect a hazard ratio (HR) of 1.3 per standard deviation (SD) decrement in HRV. A one SD decrement in log LF/HF was associated with increased risk of developing AF (HR = 1.23; 95% confidence intervals (CI) = 1.06-1.44) in age- and sex-adjusted models; the association was no longer significant (HR = 1.15; 95% CI = 0.98-1.35) after adjusting for potential confounders. CONCLUSION: Autonomic dysregulation at baseline, as reflected by an altered HRV is associated with risk of AF; however, this association does not persist after adjusting for potential confounders. Much of the apparent association between HRV and AF is mediated by traditional risk factors.
Adult↗
Association between obesity and a prothrombotic state: the Framingham Offspring Study.
Although obesity is associated with increased cardiovascular risk, the mechanism has not been fully explained. Since thrombosis is a critical component of cardiovascular disease, we examined the relationship between obesity and hemostatic factors. We studied 3230 subjects (55% females, mean age 54 years) without a history of cardiovascular disease in cycle 5 of the Framingham Offspring Study. Obesity was assessed by body mass index and waist-to-hip ratio. Fasting blood samples were obtained for fibrinogen, plasminogen activator inhibitor (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, factor VII antigen, von Willebrand factor (VWF), and plasma viscosity. Body mass index was directly associated with fibrinogen, factor VII, PAI-1 and tPA antigen in both men and women (p>0.001) and with VWF and viscosity in women. Similar associations were present between waist-to-hip ratio and the hemostatic factors. With minor exceptions for VWF and viscosity, all associations persisted after controlling for age, smoking, total and HDL cholesterol, triglycerides, glucose level, blood pressure, and use of antihypertensive medication. The association between increased body mass index and waist-to-hip ratio and prothrombotic factors and impaired fibrinolysis suggests that obesity is a risk factor whose effect is mediated in part by a prothrombotic state.
Adult↗
Genome-wide linkage to chromosome 6 for waist circumference in the Framingham Heart Study.
While several loci for BMI have been identified, it is not known whether genes underlie the process of regional fat deposition. We sought to test whether waist circumference, a measure of central adiposity, contains a genetic component. Variance components linkage analysis was performed on 330 families from the Framingham Heart Study original and offspring cohorts, using a 10-cM genome-wide linkage analysis. Overall, 2,086 subjects (51% women), mean age 48 years, were available for analysis. The overall heritability of waist circumference was 0.41. The maximum logarithm of odds (LOD) score in the full dataset was 3.3 on chromosome 6 at marker D6S1009; when subjects were limited to those aged <60 years, the peak LOD score was 3.7 at the same location. Substantial evidence exists for linkage to waist circumference, a measure of central adiposity. Potential candidate genes include ESR1, OPRM1, and NMBR. Further research is necessary to understand the genes involved in central adiposity.
Abdomen↗