AbstractRheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342–0.385; P = 6.40 × 10–241) and RF levels (β [change in RF level per sRAGE increment] = − 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA.
Annie Doubleday, Catherine J. Knott, Marnie F. Hazlehurst
et al.
Abstract Background Neighborhood greenspaces provide opportunities for increased physical activity and social interaction, and thus may reduce the risk of Type 2 diabetes. However, there is little robust research on greenspace and diabetes. In this study, we examine the longitudinal association between neighborhood greenspace and incident diabetes in the Multi-Ethnic Study of Atherosclerosis. Methods A prospective cohort study (N = 6814; 2000-2018) was conducted to examine the association between greenspace, measured as annual and high vegetation season median greenness determined by satellite (Normalized Difference Vegetation Index) within 1000 m of participant homes, and incident diabetes assessed at clinician visits, defined as a fasting glucose level of at least 126 mg/dL, use of insulin or use of hypoglycemic medication, controlling for covariates in stages. Five thousand five hundred seventy-four participants free of prevalent diabetes at baseline were included in our analysis. Results Over the study period, 886 (15.9%) participants developed diabetes. Adjusting for individual characteristics, individual and neighborhood-scale SES, additional neighborhood factors, and diabetes risk factors, we found a 21% decrease in the risk of developing diabetes per IQR increase in greenspace (HR: 0.79; 95% CI: 0.63, 0.99). Conclusions Overall, neighborhood greenspace provides a protective influence in the development of diabetes, suggesting that neighborhood-level urban planning that supports access to greenspace--along with healthy behaviors--may aid in diabetes prevention. Additional research is needed to better understand how an area’s greenness influences diabetes risk, how to better characterize greenspace exposure and usage, and future studies should focus on robust adjustment for neighborhood-level confounders.
Oluseye Ogunmoroti, Olatokunbo Osibogun, Di Zhao
et al.
Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30–46) vs 38 (31–47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.
Oluseye Ogunmoroti, Olatokunbo Osibogun, Richard A Ferraro
et al.
Background Hepatocyte growth factor (HGF) is a biomarker with potential for use in the diagnosis, treatment and prognostication of cardiovascular disease (CVD). Elevated HGF is associated with calcification in the coronary arteries. However, knowledge is limited on the role HGF may play in extracoronary calcification (ECC). This study examined whether HGF is associated with ECC in the aortic valve (AVC), mitral annulus (MAC), ascending thoracic aorta and descending thoracic aortic (DTAC). Methods At baseline, adults aged 45–84 years, free of CVD, in the Multi-Ethnic Study of Atherosclerosis had HGF and ECC measured by ELISA and cardiac CT scan, respectively. ECC measurements were repeated after an average of 2.4 years of follow-up. Prevalent ECC was defined as Agatston score >0 at baseline. Incident ECC was defined as Agatston score >0 at follow-up among participants with Agatston score=0 at baseline. We used Poisson and linear mixed-effects regression models to estimate the association between HGF and ECC, adjusted for sociodemographic and CVD risk factors. Results Of 6648 participants, 53% were women. Mean (SD) age was 62 (10) years. Median (IQR) of HGF was 905 (757-1087) pg/mL. After adjustment for CVD risk factors, the highest HGF levels (tertile 3) were associated with greater prevalence and extent of AVC, MAC and DTAC at baseline compared with the lowest tertile (tertile 1). Additionally, the risk of incident AVC and MAC increased by 62% and 45%, respectively, in demographic-adjusted models. However, the associations were not statistically significant in fully adjusted models. The highest HGF levels were also associated with 10% and 13% increase in MAC and DTAC progression, respectively, even after adjustment for CVD risk factors. Conclusion Higher HGF levels were significantly associated with a greater risk of calcification at some extracoronary sites, suggesting an alternate biological pathway that could be targeted to reduce CVD risk.
Mahsima Shabani, Hooman Bakhshi, Mohammad R. Ostovaneh
et al.
Abstract Aims Little is known about the association of temporal changes in inflammatory biomarkers and the risk of death and cardiovascular diseases. We aimed to evaluate the association between temporal changes in C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and risk of heart failure (HF), cardiovascular disease (CVD), and all-cause mortality in individuals without a history of prior CVD. Methods and results Participants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort with repeated measures of inflammatory biomarkers and no CVD event prior to the second measure were included. Quantitative measures, annual change, and biomarker change categories were used as main predictors in Cox proportional hazard models stratified based on sex and statin use. A total of 2258 subjects (50.6% female, mean age of 62 years) were studied over an average of 8.1 years of follow-up. The median annual decrease in CRP levels was 0.08 mg/L. Fibrinogen and IL-6 levels increased by a median of 30 mg/dL and 0.24 pg/mL annually. Temporal changes in CRP were positively associated with HF risk among females (HR: 1.18 per each standard deviation increase, P < 0.001) and other CVD in both female (HR: 1.12, P = 0.004) and male participants (HR: 1.24, P = 0.003). The association of CRP change with HF and other CVD was consistently observed in statin users (HR: 1.23 per SD increase, P = 0.001 for HF and HR: 1.19 per SD increase, P < 0.001 for other CVD). There were no significant associations between temporal changes of fibrinogen or IL-6 with HF or other CVD. Men with sustained high values of IL-6 had a 2.3-fold higher risk of all-cause mortality (P < 0.001) compared with those with sustained low values. Conclusions Temporal change in CRP is associated with HF only in women and statin users, and other CVD in both women and men, and statin users. Annual changes in fibrinogen and IL-6 were not predictive of cardiovascular outcomes in either sex.
Barbara N. Harding, Kerri L. Wiggins, Paul N. Jensen
et al.
AbstractPurposeOpioids, gabapentinoids, and nonsteroidal anti‐inflammatory drugs (NSAIDs) may have adverse cardiovascular effects. We evaluated whether these medications were associated with incident clinically detected atrial fibrillation (AF) or monitor‐detected supraventricular ectopy (SVE), including premature atrial contractions (PACs) and supraventricular tachycardia (SVT).MethodsWe used data from the Multi‐Ethnic Study of Atherosclerosis (MESA), a cohort study that enrolled 6814 Americans without clinically detected cardiovascular disease in 2000 to 2002. At the 2016 to 2018 examination, 1557 individuals received ambulatory electrocardiographic (ECG) monitoring. Longitudinal analyses investigated time‐varying medication exposures at the first five exams (through 2011) in relation to incident clinically detected AF through 2015 using Cox proportional hazards regression models. Cross‐sectional analyses investigated medication exposures at 2016 to 2018 examination and the risk of monitor‐detected SVE using linear regression models.ResultsThe longitudinal cohort included 6652 participants. During 12.4 years of mean follow‐up, 982 participants (14.7%) experienced incident clinically detected AF. Use of opioids, gabapentinoids, and NSAIDs were not associated with incident AF. The cross‐sectional analysis included 1435 participants with ECG monitoring. Gabapentinoid use was associated with an 84% greater average frequency of PACs/hour (95% CI, 25%‐171%) and a 44% greater average number of runs of SVT/day (95% CI, 3%‐100%). No associations were found with use of opioids or NSAIDs in cross‐sectional analyses.ConclusionsIn this study, gabapentinoid use was associated with SVE. Given the rapid increase in gabapentinoid use, additional studies are needed to clarify whether these medications cause cardiovascular complications.
Amanda Sammut, Steven Shea, Roger S. Blumenthal
et al.
ObjectiveAlbuminuria is a marker for subclinical cardiovascular disease (CVD) in the general population. It is uncertain whether this association is present in patients with rheumatoid arthritis (RA), a population with increased atherosclerosis and CVD events.MethodsUrine albumin from a spot morning collection was measured, and the urine albumin‐to‐creatinine ratio (uACR) was calculated for RA patients and a population‐based sample of demographically matched non‐RA controls. Associations of elevated uACR (≥25 mg/gm for women and ≥17 mg/gm for men) with CVD risk factors and measures of atherosclerosis (coronary artery calcification, ultrasound‐determined maximal intima‐media thickness of the common carotid artery and internal carotid artery [ICA], and the presence of focal plaque in the ICA) were compared cross‐sectionally according to RA status.ResultsWe compared 196 RA patients with 271 non‐RA controls. Elevated uACR was found in 18% of the RA patients compared with 17% of the controls (P = 0.89). After adjustment, RA was associated with 57% lower odds of elevated uACR (P = 0.016). Higher serum creatinine levels and hypertension were both strongly and significantly associated with elevated uACR in the control group but not in the RA group (both P for interaction < 0.05). Among RA characteristics, the adjusted prevalence of elevated uACR among those treated with tumor necrosis factor inhibitors was less than half that among those not so treated (9% versus 20%, respectively; P = 0.047).ConclusionThere was no association in the RA group of elevated uACR with measures of atherosclerosis or with several key cardiometabolic risk factors, which suggests a lower usefulness of elevated uACR as an indicator of subclinical CVD in RA.
Yuanjie Pang, Miranda Jones, Maria Tellez-Plaza
et al.
We investigated the associations of urinary concentrations of antimony, cadmium, tungsten and uranium with geographic locations and with ambient air pollution in 304 adults in the Multi-Ethnic Study of Atherosclerosis from six US cities. After adjustment for sociodemographics, body mass index, and smoking status, urinary cadmium was the highest in Winston-Salem among all study sites (the geometric mean [GM] in Winston-Salem was 0.84 µg/L [95% confidence interval (CI) 0.57–1.22]). The adjusted GMs of urinary tungsten and uranium were highest in Los Angeles (0.11 µg/L [95% CI 0.08–0.16] and 0.019 µg/L [95% CI 0.016–0.023], respectively). The adjusted GM ratio comparing fine particulate matter (PM2.5) tertiles 2 and 3 with the lowest tertile were 1.64 (95% CI 1.05–2.56) and 3.55 (95% CI 2.24–5.63) for tungsten, and 1.18 (95% CI 0.94–1.48) and 1.70 (95% CI 1.34–2.14) for uranium. The results for tungsten remained similar after adjustment for study site. Urinary cadmium, tungsten and uranium concentrations differed by geographic locations in MESA (Multi-Ethnic Study of Atherosclerosis) communities. PM2.5 levels could contribute to geographic differences in tungsten exposure. These findings highlight the need to implement preventive strategies to decrease toxic metal exposure and to evaluate the health effects of chronic exposure to those metals.