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OBJECTIVE - Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated dilation (FMD), in individuals with metabolic syndrome.
METHODS - A total of 18 participants with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours or placebo for 7 days in a randomized, double-blind, crossover trial.
RESULTS - Acipimox reduced FFA concentrations among individuals with metabolic syndrome to near normal levels (P = 0.01), but there was no change among healthy controls (P = 0.17). Acipimox did not improve endothelial-dependent FMD in either group (metabolic syndrome: P = 0.42; healthy controls: P = 0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P = 0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in FMD and baseline measures of BMI ( ρ = -0.09) or waist circumference ( ρ = -0.15).
CONCLUSIONS - In groups with normal or elevated baseline FFA, short-term reductions do not improve endothelial function assessed by FMD.
© 2019 The Obesity Society.
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
RATIONALE - Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied.
OBJECTIVE - To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults.
METHODS - This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants.
MEASUREMENTS - In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome.
RESULTS - Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised β 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement.
CONCLUSIONS - Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
BACKGROUND - One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability.
METHODS AND RESULTS - We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]).
CONCLUSIONS - The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
© 2017 American Heart Association, Inc.
BACKGROUND - The determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle-aged, biracial community-based cohort.
METHODS AND RESULTS - At the CARDIA year-25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (β 0.94, 95% CI 0.24-1.64; =0.009), but this association was no longer significant after further adjustment for lung volume (β 0.42, 95% CI -0.68 to 0.96; =0.74). Insulin resistance, inflammation (C-reactive protein and interleukin-6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e'] and left atrial volume index).
CONCLUSIONS - In a large biracial cohort of middle-aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
BACKGROUND - Despite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease.
METHODS AND RESULTS - In 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a "metabolic" risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time-dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low-stable, low-worsening, high-stable, intermediate-worsening, intermediate-stable, and high-worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher-risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories.
CONCLUSIONS - Transitions in metabolic risk occur early in life. Obesity-related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
BACKGROUND - Metabolic syndrome (MetS) is diagnosed by the presence of at least 3 of the following: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein. Individuals with MetS also typically have elevated plasma levels of the antifibrinolytic factor, plasminogen activator inhibitor-1 (PAI-1), but the relationships between PAI-1 and MetS diagnostic criteria are not clear. Understanding these relationships can elucidate the relevance of MetS to cardiovascular disease risk, because PAI-1 is associated with ischemic events and directly involved in thrombosis.
METHODS AND RESULTS - In a cross-sectional analysis of 2220 Ghanaian men and women from urban and rural locales, we found the age-standardized prevalence of MetS to be as high as 21.4% (urban women). PAI-1 level increased exponentially as the number of diagnostic criteria increased linearly (P<10), supporting the conclusion that MetS components have a joint effect that is stronger than their additive contributions. Body mass index, triglycerides, and fasting glucose were more strongly correlated with PAI-1 than with canonical MetS criteria, and this pattern did not change when pair-wise correlations were conditioned on all other risk factors, supporting an independent role for PAI-1 in MetS. Finally, whereas the correlations between conventional risk factors did not vary significantly by sex or across urban and rural environments, correlations with PAI-1 were generally stronger among urban participants.
CONCLUSIONS - MetS prevalence in the West African population we studied was comparable to that of the industrialized West. PAI-1 may serve as a key link between MetS, as currently defined, and the endpoints with which it is associated. Whether this association is generalizable will require follow-up.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
OBJECTIVE - Metabolic syndrome is associated with insulin resistance and increased future risk of type 2 diabetes. This study investigates the relationship between insulin secretion, insulin resistance and individual metabolic syndrome components in subjects without a prior diagnosis of diabetes.
RESEARCH DESIGN AND METHODS - We assessed insulin secretion during hyperglycemic clamps by infusing dextrose to maintain hyperglycemia (200mg/dL), followed by L-arginine administration. Studies in 98 individuals (mean age 45.3±1.2years, 56% female, 22% African-American, 49% with metabolic syndrome) were analyzed. We tested the association between the number of metabolic syndrome components and individual outcome variables using linear mixed-effects models to adjust for potential confounding effects of age, sex, and race.
RESULTS - Insulin sensitivity index was reduced in the presence of 1 or more metabolic syndrome components. Insulin sensitivity was independently associated with age, waist circumference, male gender and decreased HDL cholesterol. The acute insulin response was greater with two or more metabolic syndrome components, and late glucose-stimulated and L-arginine-stimulated insulin responses exhibited a similar trend. In contrast, the disposition index, a measure of beta cell compensation for insulin resistance, was linearly lower with the number of metabolic syndrome components, and was negatively associated with age, Caucasian race, waist circumference, fasting glucose, and decreased HDL cholesterol.
CONCLUSIONS - The insulin secretory response in metabolic syndrome is inadequate for the worsening insulin sensitivity, as demonstrated by a decline in disposition index. A dysfunctional insulin secretory response is evident in non-diabetic individuals and worsens with accumulation of metabolic syndrome components.
Copyright © 2016 Elsevier Inc. All rights reserved.
CONTEXT - The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction.
OBJECTIVE - To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil.
DESIGN - IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2).
SETTING - Two-center study.
PARTICIPANTS - Obese AA women.
INTERVENTION - A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks.
MAIN OUTCOME - IS, FMD.
RESULTS - G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04).
CONCLUSIONS - The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.
CONTEXT AND OBJECTIVE - We examined whether a prevalent caveolin-1 gene (CAV1) variant, previously related to insulin resistance, is associated with metabolic syndrome (MetS).
PATIENTS AND METHODS - We included subjects genotyped for the CAV1 variant rs926198 from two cohorts: 735 Caucasians from the HyperPATH multicenter study, and 810 Hispanic participants from the HTN-IR cohort.
RESULTS - Minor allele carriers from HyperPATH cohort (57% of subjects) had higher Framingham risk scores, higher odds of diabetes (10.7% vs 5.7%, p=0.016), insulin resistance (44.3% vs 35.1%, p=0.022), low HDL (49.3% vs 39.6%, p=0.018) and MetS (33% vs 20.5%, p<0.001) but similar BMI. Consistently, minor allele carriers exhibited higher odds of MetS, even when adjusted for confounders and relatedness (OR 2.83 (1.73-4.63), p<0.001). The association with MetS was replicated in the Hispanic cohort HTN-IR (OR 1.61, [1.06-2.44], p=0.025). Exploratory analyses suggest that MetS risk is modified by a CAV1 variant-BMI status interaction, whereby the minor allele carrier status strongly predicted MetS (OR 3.86 [2.05-7.27], p<0.001) and diabetes (OR 2.27 [1.07-4.78], p=0.03) in non-obese, but not in obese subjects. In addition, we observed a familial aggregation for MetS diagnosis in minor allele carriers.
CONCLUSION - The prevalent CAV1 gene variant rs926198 is associated with MetS in separate Caucasian and Hispanic cohorts. These findings appear to be driven by an interaction between the genetic marker and obesity status, suggesting that the CAV1 variant may improve risk profiling in non-obese subjects. Additional studies are needed to confirm the clinical implications of our results.
Copyright © 2015 Elsevier Inc. All rights reserved.