Sex differences in heart failure development following myocardial infarction (MI) are not fully understood. We hypothesized that differential MI signaling could explain variations in outcomes. ...Analysis of the mouse heart attack research tool 1.0 (422 mice; young = 5.4 ± 0.1; old = 23.3 ± 0.1 months of age) was used to dissect MI signaling pathways, which was validated in a new cohort of mice (4.8 ± 0.2 months of age); and substantiated in humans. Plasma collected at visit 2 from the MI subset of the Jackson Heart Study (JHS; a community-based study consisting of middle aged and older adults of African ancestry) underwent glycoproteomics grouped by outcome: (1) heart failure hospitalization after visit 2 (
n
= 3 men/12 women) and (2) without hospitalization through 2012 (
n
= 24 men/21 women). Compared to young male mice, the infarct region of young females had fewer, but more efficient tissue clearing neutrophils with reduced pro-inflammatory gene expression. Apolipoprotein (Apo) F, which acts upstream of the liver X receptors/retinoid X receptor (LXR/RXR) pathway, was elevated in the day 7 infarcts of old mice compared to young controls and was increased in both men and women with heart failure. In vitro, Apo F stimulated CD36 and peroxisome proliferator-activated receptor (PPAR)γ activation in male neutrophils to turn off NF-κB activation and stimulate LXR/RXR signaling to initiate resolution. Female neutrophils were desensitized to Apo F and instead relied on thrombospondin-1 stimulation of CD36 to upregulate AMP-activated protein kinase, resulting in an overall better wound healing strategy. With age, female mice were desensitized to LXR/RXR signaling, resulting in enhanced interleukin-6 activation, a finding replicated in the JHS community cohort. This is the first report to uncover sex differences in post-MI neutrophil signaling that yielded better outcomes in young females and worse outcomes with age.
Background Metabolic dyslipidemia (high triglyceride) and low high-density lipoprotein cholesterol (HDL-C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes ...mellitus-related abnormalities in the triglyceride-HDL-C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL-C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL-C at baseline (2001-2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow-up of 9.5 years (interquartile range, 8.7-10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL-C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12-1.64
=0.002) and coronary artery disease events (HR, 1.46; 95% CI, 1.18-1.81
=0.001) but not stroke (HR, 1.38; 95% CI, 0.90-2.11
=0.140). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03-1.63
=0.025) and coronary artery disease events (HR, 1.48; 95% CI, 1.14-1.93
=0.003) but not stroke (HR, 1.23; 95% CI, 0.74-2.05
=0.420). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.
...this sex- and race-specific score, unlike ATP-III MetS classification, did not exhibit differences in CHD prediction by sex or race and thus may provide similar risk information across ...sub-populations.
Background/Aims: The metabolic syndrome (MetS), as assessed using dichotomous criteria, is associated with increased risk of future chronic kidney disease (CKD), though this relationship is unclear ...among African Americans, who have lower risk for MetS but higher risk for CKD. Methods: We performed logistic regression using a sex- and race-specific MetS-severity z-score to assess risk of incident CKD among 2,627 African-American participants of the Jackson Heart Study, assessed at baseline and 8 years later. Based on quartile of baseline MetS severity, we further assessed prevalence of being in the lowest quartile of baseline GFR, the lowest quartile of relative GFR at follow-up, microalbuminuria and incident CKD. Results: Higher MetS-severity was associated with higher prevalence of GFR in the lowest quartile at baseline among males and females. Among African-American females but not males, higher baseline MetS-severity was associated with a higher prevalence of baseline elevations in microabuminuria (p<0.01), steep decline in GFR (p<0.001) and a higher incidence of CKD (p<0.0001). Women in increasing quartiles of baseline MetS-severity exhibited a linear trend toward higher odds of future CKD (p<0.05), with those in the 4th quartile of MetS-severity (compared to the 1st) having an odds ratio of 2.47 (95% confidence interval 1.13, 5.37); no such relationship was seen among men (p value for trend 0.49). Conclusion: MetS-severity exhibited sex-based interactions regarding risk for future GFR deterioration and CKD, with increasing risk in women but not men. These data may have implications for triggering CKD screening among African-American women with higher degrees of MetS-severity.
Aims/hypothesis
The study aimed to assess for an association between the degree of severity of the metabolic syndrome and risk of type 2 diabetes beyond that conferred by the individual components of ...the metabolic syndrome.
Methods
We assessed HRs for an Adult Treatment Panel III (ATP-III) metabolic syndrome score (ATP-III MetS) and a sex- and race-specific continuous metabolic syndrome severity
z
score related to incident diabetes over a median of 7.8 years of follow-up among participants of two observational cohorts, the Atherosclerosis Risk in Communities study (
n
= 10,957) and the Jackson Heart Study (
n
= 2137).
Results
The ATP-III MetS had an HR for incident diabetes of 4.36 (95% CI 3.83, 4.97), which was attenuated in models that included the individual metabolic syndrome components. By contrast, participants in the fourth quartile of metabolic syndrome severity (compared with the first quartile) had an HR of 17.4 (95% CI 12.6, 24.1) for future diabetes; in models that also included the individual metabolic syndrome components, this remained significant, with an HR of 3.69 (95% CI 2.42, 5.64). There was a race × metabolic syndrome interaction in these models such that HR was greater for black participants (5.30) than white participants (2.24). When the change in metabolic syndrome severity score was included in the hazard models, this conferred a further association, with changes in metabolic syndrome severity score of ≥0.5 having a HR of 2.66 compared with changes in metabolic syndrome severity score of ≤0.
Conclusions/interpretation
Use of a continuous sex- and race-specific metabolic syndrome severity
z
score provided an additional prediction of risk of diabetes beyond that of the individual metabolic syndrome components, suggesting an added risk conferred by the processes underlying the metabolic syndrome. Increases in this score over time were associated with further risk, supporting the potential clinical utility of following metabolic syndrome severity over time.
Nonalcoholic fatty liver disease (NAFLD) is an obesity‐related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease ...worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African‐ and/or Hispanic‐Americans and fine‐mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta‐analyzed. Fine‐mapping across African American cohorts was conducted using meta‐analysis. African‐ and Hispanic‐American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m2, respectively. Hepatic steatosis was 0.20‐0.34 heritable in African‐ and Hispanic‐American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine‐mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Conclusion: Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African‐ and Hispanic‐Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries. (Hepatology 2013;53:966–975)
Melatonin is a hormone that is secreted at night by the pineal gland. It exerts its function by binding to the MT
and MT
receptors, which are encoded by the MTNR1A and MTNR1B genes, respectively. ...Previous studies reveal that MTNR1B variants are associated with insulin secretion impairments and an increased body mass index (BMI) in individuals of European and Asian ancestries. Obesity is highly prevalent in the US and disproportionately affects African Americans. Here, we hypothesized that common single nucleotide polymorphisms (SNPs) imputed in 1000 Genomes in the MTNR1B gene are associated with adiposity in African American adult men and women and that the association is modified by insomnia.
We used an additive genetic model to describe the association between the adiposity traits (BMI and waist circumference) and selected MTNR1B variants in 3,029 Jackson Heart Study participants, with an average age of 55.13 ± 12.84 years, and 62% were women. We regressed the adiposity measures on the estimated allelic or genotypic dosage at every selected SNP and adjusted for age, sex, population stratification, and insomnia. Thirty common SNPs, spanning the MTNR1B gene, with a minor allele frequency ≥ 5%, a call rate ≥ 90%, a Hardy-Weinberg equilibrium p value > 10
, were available for the analysis.
The allele T of rs76371840 was associated with adiposity (OR = 1.47 1.13-1.82; P
= 0.0499), and the allele A of rs8192552 showed a significant association with waist circumference (β = 0.023 ± 0.007; P
= 0.0077) after correcting for multiple testing. When insomnia was included in the adiposity analysis model, the following four variants became significantly associated with adiposity: rs6483208; rs4388843; rs4601728; and rs12804291.
Our data indicate that polymorphisms in the MTNR1B gene are associated with obesity traits in African Americans. To the best of our knowledge, this is the first study to explore the effect of insomnia on the association between the circadian MTNR1B genetic variants and metabolic traits in an African American sample population. We observed that insomnia affected the association between the MTNR1B variants and adiposity.
Estimates of adiposity in evaluating the metabolic syndrome (MetS) have traditionally utilized measures of waist circumference (WC), whereas body mass index (BMI) is more commonly used clinically. ...Our objective was to determine if a MetS severity Z-score employing BMI as its measure of adiposity (MetS-Z-BMI) would perform similarly to a WC-based score (MetS-Z-WC) in predicting future disease.
To formulate the MetS-Z-BMI, we performed confirmatory factor analysis on a sex- and race/ethnicity-specific basis on MetS-related data for 6870 adult participants of the National Health and Nutrition Survey 1999–2010. We then validated this score and compared it to MetS-Z-WC in assessing correlations with future coronary heart disease (CHD) and Type 2 diabetes mellitus (T2DM) using Cox proportional hazard analysis of 13,094 participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study.
Loading factors, which represent the relative contribution of each component to the latent MetS factor, were lower for BMI than for WC in formulating the two respective scores (MetS-Z-BMI and MetS-Z-WC). Nevertheless, MetS-Z-BMI and MetS-Z-WC exhibited similar hazard ratios (HR) toward future disease. For each one standard-deviation-unit increase in MetS-Z-BMI, HR for CHD was 1.76 (95% confidence interval CI: 1.65, 1.88) and HR for T2DM was 3.39 (CI 3.16, 3.63) (both p < 0.0001). There were no meaningful differences between the MetS-Z-WC and MetS-Z-BMI scores in their associations with future CHD and T2DM.
A MetS severity Z-score utilizing BMI as its measure of adiposity operated similarly to a WC-based score in predicting future CHD and T2DM, suggesting overall similarity in MetS-based risk as estimated by both measures of adiposity. This indicates potential clinical usefulness of MetS-Z-BMI in assessing and following MetS-related risk over time.
•Waist circumference is often used to classify metabolic syndrome (MetS), but BMI is often collected in clinical settings.•We developed a measure of MetS severity that uses BMI instead of WC.•We show that MetS severity using BMI predicts future disease as well as the measure that uses WC.•MetS severity using BMI has much greater clinical potential than the measure using WC.
Purpose
Several mechanisms have been described through which dietary intake of choline and its derivative betaine may be associated in both directions with subclinical atherosclerosis. We assessed ...the association of dietary intake of choline and betaine with cardiovascular risk and markers of subclinical cardiovascular disease.
Methods
Data from 3924 Jackson Heart Study (JHS) African-American participants with complete food frequency questionnaire at baseline and follow-up measurements of heart disease measures were used. Multivariable linear regression models were employed to assess associations between choline and betaine intake with carotid intima-media thickness, coronary artery calcium, abdominal aortic calcium and left ventricular mass. Cox proportional hazards regression models were used to estimate associations with time to incident coronary heart disease (CHD), ischemic stroke and cardiovascular disease (CVD).
Results
During an average nine years of follow-up, 124 incident CHD events, 75 incident stroke events and 153 incident CVD events were documented. In women, greater choline intake was associated with lower left ventricular mass (
p
= 0.0006 for trend across choline quartiles) and with abdominal aortic calcium score. Among all JHS participants, there was a statistically significant inverse association between dietary choline intake and incident stroke,
β
= −0.33 (
p
= 0.04). Betaine intake was associated with greater risk of incident CHD when comparing the third quartile of intake with the lowest quartile of intake (HR 1.89, 95 % CI 1.14, 3.15).
Conclusions
Among our African-American participants, higher dietary choline intake was associated with a lower risk of incident ischemic stroke, and thus putative dietary benefits. Higher dietary betaine intake was associated with a nonlinear higher risk of incident CHD.
PDF
