The effects of estrogen replacement therapy on prognosis in women with established coronary disease remain uncertain. The authors conducted a retrospective cohort study of 726 women (mean age, 66.2 years) who survived first myocardial infarction to hospital discharge from 1980 through 1991, while enrolled at Group Health Cooperative of Puget Sound in western Washington State. Estrogen replacement therapy after myocardial infarction (122 women) was ascertained from computerized pharmacy records. Reinfarctions (n = 135) and deaths (n = 183) through 1993 were identified, and relative risks were calculated. The relative risk for reinfarction associated with current estrogen replacement therapy after myocardial infarction, adjusting for age and time since infarction, was 0.64 (95% confidence interval (CI) 0.32-1.30), and that for past estrogen replacement therapy was 0.90 (95% CI 0.62-1.31). The relative risk for all-cause mortality associated with current estrogen replacement therapy was 0.50 (95% CI 0.25-1.00), and that for past estrogen replacement therapy was 0.79 (95% CI 0.56-1.09). While estrogen users were less likely than nonusers to have a history of diabetes or congestive heart failure, adjustment for these and additional prognostic factors altered risk estimates only slightly. Estrogen replacement therapy after first myocardial infarction was not associated with increased risk of reinfarction or mortality. This study provides reassurance regarding the safety of estrogen replacement therapy after myocardial infarction in women.

Objective

High circulating concentrations of parathyroid hormone (PTH) have been associated with increased risks of hypertension, left ventricular hypertrophy, congestive heart failure and cardiovascular mortality. Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function.

Design

Cross-sectional study.

Participants

A total of 6545 persons without clinical cardiovascular disease participating in the community-based Multi-Ethnic Study of Atherosclerosis.

Measurements

Brachial artery flow-mediated dilation (FMD) as well as aortic pulse pressure and arterial pulse parameters derived from Windkessel modelling of the radial pressure waveform.

Results

Higher serum PTH concentration was associated with lower brachial artery FMD (mean difference -0·09% per 10 pg/ml PTH), higher aortic pulse pressure (0·53 mmHg per 10 pg/ml) and reduced Windkessel capacitive index C1 (large artery elasticity, -0·12 ml/mmHg × 10 per 10 pg/ml), adjusting for potential confounding variables (all P-values ≤ 0·001). These relationships were independent of serum calcium concentration, serum 25-hydroxyvitamin D concentration and estimated glomerular filtration rate and were consistent across relevant participant subgroups. Associations of PTH with aortic pulse pressure and capacitive index C1 were attenuated after adjustment for blood pressure. Serum PTH concentration was not associated with the oscillatory index C2 (small artery elasticity).

Conclusions

Higher serum PTH concentration was associated with impaired endothelial function, increased aortic pulse pressure and decreased capacitive index C1 in a large, diverse, community-based population. These relationships may help explain previously observed associations of elevated PTH with cardiovascular disease.

Background

Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.

Methods

We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.

Results

Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (-0.19, -0.08, P < 0.001) and 0.15-ml/min/year faster decline (-0.21, -0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, -0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.

Conclusions

Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.

Objectives

This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.

Background

FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.

Methods

Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.

Results

Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45).

Conclusions

FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

Objective

Prospective studies reporting a positive association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis.

Methods

Lp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score > 0 or carotid intima-media thickness value > 80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death).

Results

516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01-1.26) for Lp-PLA2 activity and 1.10 (1.01-1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis.

Conclusion

In this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media.

Background

Identifying potentially modifiable risk factors is critically important for reducing the burden of chronic kidney disease. We sought to examine the association of body mass index (BMI) with kidney function decline in a cohort of young adults with preserved glomerular filtration at baseline.

Study design

Longitudinal cohort.

Setting & participants

2,839 black and white young adults with cystatin C-based estimated glomerular filtration rate (eGFRcys)>90mL/min/1.73m(2) taking part in the year-10 examination (in 1995-1996) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Predictor

BMI, categorized as 18.5-24.9 (reference), 25.0-29.9, 30.0-39.9, and ≥40.0kg/m(2).

Outcomes

Trajectory of kidney function decline, rapid decline (>3% per year), and incident eGFRcys <60mL/min/1.73m(2) over 10 years of follow-up.

Measurements

GFRcys estimated from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation for calibrated cystatin C at CARDIA years 10, 15, and 20.

Results

At year 10, participants had a mean age of 35.1 years, median eGFRcys of 114mL/min/1.73m(2), and 24.5% had BMI≥30.0kg/m(2). After age 30 years, average eGFRcys was progressively lower with each increment in BMI after adjustment for baseline age, race, sex, hyperlipidemia, smoking status, and physical activity. Higher BMI category was associated with successively higher odds of rapid decline (for 25.0-29.9, 30.0-39.9, and ≥40.0kg/m(2), adjusted ORs were 1.50 [95% CI, 1.21-1.87], 2.01 [95% CI, 1.57-2.87], and 2.57 [95% CI, 1.67-3.94], respectively). 18 participants (0.6%) had incident eGFRcys<60mL/min/1.73m(2). In unadjusted analysis, higher BMI category was associated with incident eGFRcys<60mL/min/1.73m(2) (for 25.0-29.9, 30.0-39.9, and ≥40.0kg/m(2), ORs were 5.17 [95% CI, 1.10-25.38], 7.44 [95% CI, 1.54-35.95], and 5.55 [95% CI, 0.50-61.81], respectively); adjusted associations were no longer significant.

Limitations

Inability to describe kidney function before differences by BMI category were already evident. Absence of data for measured GFR or GFR estimated from serum creatinine level.

Conclusions

Higher BMI categories are associated with greater declines in kidney function in a cohort of young adults with preserved GFR at baseline. Clinicians should vigilantly monitor overweight and obese patients for evidence of early kidney function decline.

Background

Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.

Objective

To investigate whether PAC count improves model performance for AF risk.

Design

Prospective cohort study.

Setting

4 U.S. communities.

Patients

A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.

Measurements

The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.

Results

In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.

Limitation

This study does not establish a causal link between PACs and AF.

Conclusion

The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.

Primary funding source

American Heart Association, Joseph Drown Foundation, and National Institutes of Health.

Background

Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C level with incidence of either low or high ABI are unknown.

Study design

Prospective longitudinal cohort study.

Setting & participants

MESA (Multi-Ethnic Study of Atherosclerosis) enrolled community-dwelling adults (N=6,814) aged 45-84 years who were free of clinical cardiovascular disease at baseline.

Predictors

Baseline albumin-creatinine ratio (ACR) and serum cystatin C level.

Outcomes

Development of low (<0.90), and high (>1.40) ABI using multinomial regression among persons with ABI of 0.90-1.40 at baseline.

Results

During 9.8 years of follow-up, 221 and 89 participants progressed to low and high ABIs, respectively. Baseline ACR and cystatin C level were higher among progressors compared with nonprogressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99-1.20) and high (OR, 1.16; 95% CI, 1.01-1.32) ABIs. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03-3.12) and high (OR, 2.76; 95% CI, 1.32-5.77) ABIs. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00-1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81-1.25) ABI, but the highest quintile of cystatin C was not associated independently with either outcome.

Limitations

Single measure of albuminuria and low number of progressors to high ABI.

Conclusions

In adults free of clinical cardiovascular disease, albuminuria was a strong independent risk factor for the development of both high and low ABIs, important and different measures of peripheral artery disease.

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

Background

Fatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.

Methods and results

Subjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge.

Conclusions

Our findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population.