Insulin resistance (IR) and pancreatic β-cell dysfunction lead to type 2 diabetes mellitus (DM). We tested whether risk factors would differ for DM that was preceded predominantly by IR, β-cell dysfunction, or both among 4,384 older adults (mean age, 72.7 (standard deviation, 5.6) years) in the Cardiovascular Health Study, which was conducted in North Carolina, California, Maryland, and Pennsylvania (1989–2007). When evaluating established risk factors, we found older age, greater adiposity, higher systolic blood pressure, a lower high-density lipoprotein cholesterol level, a higher triglyceride level, and a lower alcohol intake to be independently associated with greater IR but, conversely, with better β-cell function (P < 0.001). The prospective associations between some risk factors and incident DM varied significantly depending on whether DM was preceded predominantly by IR, β-cell dysfunction, or both. For example, obesity and lower high-density lipoprotein cholesterol levels were positively associated with DM preceded predominantly by IR (hazard ratio (HR) = 5.02, 95% confidence interval (CI): 2.81, 9.00; and HR = 1.97, 95% CI: 1.32, 2.93, respectively), with a significant association with and an insignificant trend toward a lower risk of DM preceded predominantly by β-cell dysfunction (HR = 0.33, 95% CI: 0.14, 0.80; and HR = 0.78, 95% CI: 0.43, 1.39, respectively). In conclusion, among older adults, DM risk factors were differentially associated with DM preceded predominantly by IR or β-cell dysfunction. Biologic and clinical implications of putative subtypes of DM require further investigation.
aging; diabetes mellitus; incidence; insulin resistance; insulin-secreting cells; risk factors
Studies relating adiposity to cognition in the elderly show
conflicting results, which may be explained by the choice of adiposity
measures. Thus, we studied the longitudinal associations of different
adiposity measures, fat mass by bioelectrical impedance analysis (BIA), body
mass index (BMI) and waist circumference (WC), with cognitive performance in
the Cardiovascular Health Study.
Cognitive performance was assessed with the modified Mini Mental
State Examination (3MS), the Digit Symbol Substitution Test (DSST), and a
composite of both. We used linear mixed models to estimate rates of change
in cognitive function scores associated with adiposity measured at
The final sample was comprised of 2,681 women (57.9%) and
1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6
years. Adiposity was associated with slower cognitive decline in most
analyses. Results were similar for fat mass, BMI and WC. Higher fat-free
mass was also related to slower cognitive decline. Results were similar in
analyses excluding persons with cancer, smokers, and persons with short
follow-up, poor self-reported health, or persons with cardiovascular
Higher adiposity and higher fat-free mass in the elderly was related
to better cognitive performance. This finding was not explained by
confounding by pre-existing conditions.
adiposity; fat mass; bioelectrical impedance; body mass index; waist circumference; cognition
Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits.
We conducted two targeted analyses. First, we examined whether known single nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5 × 10-4 (0.05/325 tests).
Setting & Participants
Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395) and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium.
We used 19 kidney SNPs and 64 vascular SNPs.
Outcomes & Measurements
Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria.
In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were non-significant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (p=9.3E-10) and diastolic (p=1.6E-14) blood pressure and coronary artery disease (p=2.2E-6), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were non-significant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (p=1.06E-07 and p=7.05E-08).
Combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations.
Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
We investigated associations of early pregnancy maternal vitamin D concentrations with differential gene expression and post transcription regulation.
Plasma 25-hydroxyvitamin D (25[OH]D) was measured among participants of a nested case-control study. Participants with low (<25.5 ng/ml) and high (≥31.7 ng/ml) 25[OH]D were identified among controls. Peripheral blood messenger RNA (mRNA) (N=21) and microRNA (miRNA) (N=13) expression studies were conducted among participants with low and high 25[OH]D concentrations. Differential expression between low/high groups were evaluated using Student’s T-test, fold change and SAM comparisons. We further investigated functions and functional relationships of differentially expressed mRNAs and targets of differentially expressed miRNAs.
305 genes (299 up-regulated and 6 down-regulated) and 11 miRNAs (10 down-regulated and 1 up-regulated) were differentially expressed among participants with low 25[OH]D compared with those who had high 25[OH]D. Genes that participate in a wide range of cellular functions, including organ and system development (e.g. angiogenesis), inflammation and metabolic processes (e.g. carbohydrate/lipid metabolism), as well as miRNAs that target these genes were differentially expressed among women with low 25[OH]D compared with those with high 25[OH]D.
Early pregnancy plasma 25[OH]D concentrations are associated with maternal peripheral blood gene expression and post-transcription regulation.
vitamin D; transcription; post-transcription regulation; microarray; early pregnancy; whole blood
Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.
RESEARCH DESIGN AND METHODS
This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.
Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88–0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93–1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85–0.97) and 0.87 (0.79–0.95), respectively].
The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial / ethnic groups on lipoprotein profile.
Methods and results
Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P<1.97 * 10−05 (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N=2430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N=1594), Chinese (N=758) and Hispanic (N=1422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only.
Our findings suggest the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race / ethnicity.
Lipoprotein size; race / ethnicity; ApoB; Hepatic Lipase; NMR
To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.
Methods and results
In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25–1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01–1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.
An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
Epidemiology; Adiposity; Heart failure; Fatty acid-binding protein 4
Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease.
Methods and Results
Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8).
Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
epidemiology; fatty acids; genome-wide association study
Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cells membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain under-studied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, were independently associated with HRV in two independent cohorts in the US and Portugal.
Methods and Results
In two independent cohorts of older US adults (Cardiovascular Health Study ([CHS], age=72±5yrs, 1989/1995) and young Portuguese adults (Porto, age=19±2yrs, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2, but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (N=1,076) and repeated short-term (5-min) ECGs in Porto (N=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour standard-deviation-of-all-normal-to-normal-intervals (SDNN) both cross-sectionally (−12%, 95%CI=6–19%, p=0.001) and longitudinally (−15%, 95%CI=4–25 %, p= 0.009), and lower 24-hour SDANN and SDNN-index (p<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV, in particular time-domain indices (SDNN, SDANN, SDNN-index; p<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-min SDNN (95%CI=1–8%, p=0.04), and 7% lower 5-min rMSSD (95%CI=1–13%, p=0.04).
Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV related mechanisms whereby trans-18:2 may increase arrhythmic risk.
Electrophysiology; trans-fatty acids; heart rate variability; nutrition
Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk), and cohorts with prevalent cardiovascular disease (CVD), heart failure (HF) or advanced age (higher risk).
Methods and Results
In a population-based study of older adults, we examined the relationships of total and high-molecular-weight (HMW) adiponectin with mortality among subgroups defined by baseline cardiovascular status: no CVD, HF or atrial fibrillation (AF) (Group 1); CVD but no HF/AF (Group 2); and HF/AF (Group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in Group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (HR=0.81 per 1-SD [0.65–0.95]), but above this cutpoint, higher levels conferred greater risk (HR=1.19 [1.12–1.27]). Further adjustment for diabetes or insulin resistance, protection against which has been proposed to mediate adiponectin’s beneficial relationships with outcome, attenuated the association in the lower range. There was no significant association in Group 2, but in Group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for Group 2, and magnified the one for Group 3 (HR=1.31 [1.15–1.50]). Results were similar for HMW adiponectin, and for cardiovascular mortality.
Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction, but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as relates to older adults.
Adiponectin; Aging; Mortality
Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown.
In 1249 mother-offspring pairs recruited from the Jerusalem Perinatal Study, we used archival data to characterize ppBMI and GWG and follow-up data from offspring to assess CMR, including body mass index (BMI), waist circumference, glucose, insulin, blood pressure, and lipid levels, at an average age of 32. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk. We fit linear regression models to examine the associations of ppBMI and GWG with CMR traits with and without adjustment for GRS. Compared to unadjusted models, the coefficient for the association of a one-standard-deviation (SD) difference in GWG and offspring BMI decreased by 41% (95%CI −81%, −11%) from 0.847 to 0.503 and the coefficient for a 1SD difference in GWG and WC decreased by 63% (95%CI −318%, −11%) from 1.196 to 0.443. For other traits, there were no statistically significant changes in the coefficients for GWG with adjustment for GRS. None of the associations of ppBMI with CMR traits were significantly altered by adjustment for GRS.
Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults.
Objective. We use a case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new home address. Methods. We conducted an ambidirectional case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new address using data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults from four U.S. sites beginning in 1989. Relocation was assessed twice a year during follow-up. Event occurrences were classified as present or absent for the period preceding the first reported move, as compared with an equal length of time immediately prior to and following this period. Results. Older adults (65+) that experience incident cardiovascular disease had an increased probability of reporting a change of residence during the following year (OR 1.6, 95% confidence interval (CI) = 1.2–2.1). Clinical conditions associated with relocation included stroke (OR: 2.0, 95% CI: 1.2–3.3), angina (OR: 1.6, 95% CI: 1.0–2.6), and congestive heart failure (OR: 1.5, 95% CI: 1.0–2.1). Conclusions. Major incident cardiovascular disease may increase the probability of residential relocation in older adults. Case-crossover analyses represent an opportunity to investigate triggering events, but finer temporal resolution would be crucial for future research on residential relocations.
To determine if the associations among established risk factors and reduced kidney function vary by age.
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
Vitamin D and parathyroid hormone (PTH) may impact cardiovascular health among individuals with kidney disease and in the general population. We investigated associations of serum 25-hydroxyvitamin D (25OHD) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25OHD and intact PTH concentrations were measured using mass-spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9±4.9 years, 69.7% were female and 21% had chronic kidney disease (CKD; glomerular filtration rate <60ml/min). Mean (SD) 25OHD was 25.2 (10.2) ng/ml and median PTH was 51 pg/ml (range 39–65 pg/ml). After adjustment, 25OHD was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels ≥ 65 pg/ml were associated with greater NT-proBNP, cardiac troponin T and left ventricular mass in subjects with CKD. The regression coefficients were: 120 (36.1, 204 pg/ml), 5.2 (3.0, 7.4 pg/ml) and 17 (6.2, 27.8 g) (p-value <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. Among older adults with CKD, PTH excess is associated with higher NT-pro-BNP, cardiac troponin T, and left ventricular mass. In conclusion, these findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.
Vitamin D; parathyroid hormone; cardiac biomarkers; left ventricular mass; epi-demiology
After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions.
To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated.
Population-based inception cohort study.
Enrollees in Group Health, an integrated health care system, aged 30–84 with newly diagnosed AF in 2001–2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385).
Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6–36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs).
Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5–24.9 kg/m2), BMI levels of 25.0–29.9 (overweight), 30.0–34.9 (obese 1), 35.0–39.9 (obese 2), and ≥ 40.0 kg/m2 (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF.
For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2220-4) contains supplementary material, which is available to authorized users.
cohort study; anthropometry; electrocardiogram; atrial fibrillation
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
octogenarians; kidney function; mortality
It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.
In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15439 participants (baseline 45–64 years, 55% women, and 27% black) from baseline (1987–1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline ≥65 years, 58% women, and 15% black) from baseline (first cohort, 1989–1990; second cohort, 1992–1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD): coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.
In ARIC, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89/1000 person-years (with AF) and 1.30/1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CI) of AF for SCD and NSCD were 3.26 (2.17–4.91) and 2.43 (1.60–3.71), respectively. In CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00/1000 person-years (with AF) and 3.82/1000 person-years (without AF). The multivariable HRs (95% CI) of AF for SCD and NSCD were 2.14 (1.60–2.87) and 3.10 (2.58–3.72), respectively. The meta-analyzed HRs (95% CI) of AF for SCD and NSCD were 2.47 (1.95–3.13) and 2.98 (2.52–3.53), respectively.
Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in AF patients is warranted.
Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
heart failure; insulin; epidemiology
QT is a risk factor for sudden cardiac death (SCD). A genome wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used MESA to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African-Americans (AFA), Hispanics (HIS) and Chinese (CHN)), age 45–84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates.
More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9msec, p= 7.20×10-7). Significant associations in CAU and HIS were located at the 5′ end, while associations in CHN were located at the 3′ end.
NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3′ end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. Further investigations are needed across ethnically diverse population cohorts.
Genetics; Electrocardiography; Arrhythmia; Electrophysiology
Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).
Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.
Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.
The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
apolipoprotein E; chronic kidney disease; kidney function; elderly
Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.
The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults.
Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified.
NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25% increment from baseline to ≥190 pg/ml and for cTnT as a >50% increment from baseline in participants with detectable levels (≥3 pg/ml).
A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk.
These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.
aging; exercise; heart failure; natriuretic peptides
Whether elevations of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1)) are associated with future risk of kidney disease has not been investigated.
1:1 nested case-control study
Setting & Participants
686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
NGAL and KIM-1 were measured at baseline and expressed as log-transformed continuous variables and categorized into deciles.
Kidney function was estimated by cystatin C using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD Stage 3 was defined as eGFR <60 ml/min/1.73m2 and a eGFR decline >1 ml/min/1.73m2 per year, and rapid kidney function decline (RKFD) was defined as decline of ≥3 ml/min/1.73m2 per year.
Cases were defined as persons with eGFR >60 ml/min/1.73m2 who subsequently developed incident CKD Stage 3 and/or had RKFD by MESA year 5 visit. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g).
Of the 343 cases, 145 had incident CKD Stage 3, 141 had RKFD and 57 had both. Mean eGFR for controls was 81 (±10) ml/min/1.73m2 at baseline and 80 (±10) at follow-up, compared with 82 (±13) and 58 (±10) for cases. Each doubling of KIM-1 (pg/ml) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD Stage 3 and/or RKFD. Compared to the lowest 90%, the highest decile of KIM-1 was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (ng/ml) were not associated with incident CKD Stage 3 and/or RKFD (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL were standardized for urine creatinine.
The case-control design limits ability to account for persons who died or were not available for follow-up.
Urinary KIM-1 is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.
KIM-1; NGAL; kidney function decline
Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality, as well as sudden death in women.
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
The risk of SCD associated with baseline NT-proBNP was examined in 5447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP
Over a median follow-up of 12.5 years (maximum of 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% CI: 2.9, 6.1, p<0.001) in the highest quintile compared to the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk-factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the 5th versus the 1st quintile of 2.5 (95% CI: 1.6, 3.8, p<0.001).
NT-proBNP provides information regarding the risk of sudden cardiac death in a community based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP