Association Between Adequate Serum 25(OH)D Levels and Atherogenic Dyslipidemia in Young Adults.

AIM: This study aimed to investigate the association between vitamin D deficiency and novel biomarkers of atherogenic dyslipidemia among young adults. METHOD: A total of 976 young adults were recruited between 2011 and 2019. Their serum 25(OH)D levels were measured, and lipid profile markers, including low-density lipoprotein cholesterol (LDL-C), low-density lipoprotein triglyceride (LDL-TG), and small-dense low-density lipoprotein cholesterol (sdLDL-C), were assessed as novel biomarkers of atherogenic dyslipidemia. Multivariable linear regression was used to analyze the association between vitamin D levels and lipid profile markers. Odds ratios were calculated to assess the risk of atherogenic dyslipidemia in individuals with serum 25(OH)D levels below 30 ng/mL compared to those with levels above 30 ng/mL. Structural equation modeling (SEM) was employed to explore potential mediation pathways. RESULTS: The study found a significant association between vitamin D levels and lower levels of LDL-C, LDL-TG, sdLDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and total cholesterol. Individuals with serum 25(OH)D levels below 30 ng/mL exhibited significantly higher odds ratios for developing atherogenic dyslipidemia in a dose-response pattern compared to those with vitamin D levels above 30 ng/mL. Notably, structural equation modeling (SEM) analysis revealed that vitamin D did not affect atherogenic lipid markers through the mediation of insulin resistance markers or high-sensitivity C-reactive protein. CONCLUSION: This study provides evidence of an association between vitamin D deficiency and atherogenic dyslipidemia in young adults. It further highlights that individuals with serum 25(OH)D levels below 30 ng/mL are at a significantly higher risk of developing atherogenic dyslipidemia in a dose-response manner compared to those with higher vitamin D levels. These findings underscore the potential role of vitamin D in dyslipidemia management and emphasize the importance of maintaining sufficient vitamin D levels for cardiovascular health in young adults.

The Association between 4-Tertiary-Octylphenol, Apoptotic Microparticles, and Carotid Intima-Media Thickness in a Young Taiwanese Population.

As one of the most common alkylphenols, 4-tertiary-octylphenol (4-tOP) is commonly used in many consumer products. Our previous epidemiological study revealed a negative correlation between serum 4-tOP levels and carotid intima-media thickness (CIMT), which serves as a biomarker of arteriosclerosis. We aimed to explore the role of apoptotic microparticles, markers of vascular endothelial cell function, in the 4-tOP and CIMT connection. To investigate this, we enrolled 886 Taiwanese adolescents and young adults (aged 12-30 years) and examined the relationships among serum 4-tOP levels, apoptotic microparticles (CD31+/CD42a-, CD31+/CD42a+), and CIMT. Our results showed negative associations among serum 4-tOP levels, both apoptotic microparticles, and CIMT in multiple linear regression analysis. The odds ratios for CIMT (≥75th percentile) and the natural logarithm of 4-tOP were highest when both CD31+/CD42a- and CD31+/CD42a+ were greater than the 50th percentile. Conversely, the odds ratios were lowest when both CD31+/CD42a- and CD31+/CD42a+ were less than the 50th percentile. In the structural equation model, we demonstrated that serum 4-tOP levels were negatively correlated with CIMT and indirectly and negatively correlated with CIMT through both apoptotic microparticles. In conclusion, our study reported the inverse association between 4-tOP apoptotic microparticles and CIMT in a young Taiwanese population. Further experimental studies are needed to clarify these associations.

The role of angiotensin I-converting enzyme gene polymorphism and global DNA methylation in the negative associations between urine di-(2-ethylhexyl) phthalate metabolites and serum adiponectin in a young Taiwanese population.

BACKGROUND: Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the phthalate compounds used as a plasticizer, has been shown to decrease adiponectin levels in vitro and in vivo studies. However, the role of angiotensin I-converting enzyme (ACE) gene polymorphism and epigenetic changes in the relationship between DEHP exposure and adiponectin levels is not well understood. METHODS: This study examined the correlation between urine levels of DEHP metabolite, epigenetic marker 5mdC/dG, ACE gene phenotypes, and adiponectin levels in a sample of 699 individuals aged 12-30 from Taiwan. RESULTS: Results showed a positive relationship between mono-2-ethylhexyl phthalate (MEHP) and 5mdC/dG, and a negative association between both MEHP and 5mdC/dG with adiponectin. The study found that the inverse relationship between MEHP and adiponectin was stronger when levels of 5mdC/dG were above the median. This was supported by differential unstandardized regression coefficients (- 0.095 vs. - 0.049, P value for interaction = 0.038)). Subgroup analysis also showed a negative correlation between MEHP and adiponectin in individuals with the I/I ACE genotype, but not in those with other genotypes, although the P value for interaction was borderline significant (0.06). The structural equation model analysis indicated that MEHP has a direct inverse effect on adiponectin and an indirect effect via 5mdC/dG. CONCLUSIONS: In this young Taiwanese population, our findings suggest that urine MEHP levels are negatively correlated with serum adiponectin levels, and epigenetic modifications may play a role in this association. Further study is needed to validate these results and determine causality.

Association of Urinary Lead and Cadmium Levels, and Serum Lipids with Subclinical Arteriosclerosis: Evidence from Taiwan.

BACKGROUND: Exposure to lead and cadmium has been linked to changes in lipid metabolism and the development of arteriosclerosis, but the role of lipoprotein profiles in this relationship is not well understood, including the potential role of novel lipid biomarkers. METHODS: In this study, we enrolled 736 young Taiwanese subjects aged 12 to 30 years to assess the correlation between urine levels of lead and cadmium, lipoprotein profiles, and carotid intima-media thickness (CIMT). RESULTS: Higher levels of lead and cadmium were significantly associated with higher levels of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), and CIMT. Participants with higher levels of lead and cadmium had the highest mean values of CIMT, LDL-C, sdLDL-C, and LDL-TG. In a structural equation model, lead had a direct and indirect association with CIMT through LDL-C and sdLDL-C, whereas cadmium had a direct association with CIMT and an indirect association through LDL-C. CONCLUSION: Our results suggest higher levels of lead and cadmium are associated with abnormal lipid profiles and increased CIMT. These heavy metals could have additive effects on lipids and CIMT, and the relationship between them may be mediated by lipoprotein levels. Further research is needed to determine the causal relationship.

Global DNA methylation mediates the association between serum perfluorooctane sulfonate and carotid intima-media thickness in young and middle-aged Taiwanese populations.

PURPOSE: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals used in the manufacture of many everyday products. Previous reports have shown PFAS exposure may contribute to cardiovascular diseases (CVD). Recent studies have also identified a critical role for DNA methylation, a model of epigenetic regulation, in the pathogenesis of CVD. Additionally, PFAS has been shown to affect DNA methylation. Our previous study reported the positive association between serum perfluorooctane sulfonate (PFOS) levels and mean carotid intima-media thickness (CIMT), a biomarker of arteriosclerosis, in a cohort composed of adolescent and young adult Taiwanese. However, the contribution of DNA methylation in the mechanism of PFOS-induced arteriosclerosis has never been explored in previous literature. APPROACH AND RESULTS: In this cross-sectional study, we included 1425 young and middle-aged Taiwanese individuals (12-63 years) to investigate the correlation between serum PFOS levels, 5mdC/dG (a global DNA methylation marker) and the mean CIMT. We showed that the positive association between serum PFOS levels, 5mdC/dG, and mean CIMT. The regression coefficients of mean CIMT with a one-unit increase in ln-PFOS concentration were higher when the levels of 5mdC/dG were above the 50th percentile in the multiple regression analysis. In the structural equation model (SEM), the results showed that serum PFOS levels were directly correlated with mean CIMT and indirectly correlated with CIMT through 5mdC/dG. CONCLUSIONS: Our results showed that PFOS exposure has direct associations on arteriosclerosis and indirect direct associations on arteriosclerosis through DNA methylation. The results suggest that DNA methylation might regulate the relationship between PFOS and arteriosclerosis in the study subjects. Additional works are required to understand the causal inference between PFOS, DNA methylation, and arteriosclerosis.

Global DNA methylation mediates the association between urine mono-2-ethylhexyl phthalate and serum apoptotic microparticles in a young Taiwanese population.

Di-(2-ethylhexyl) phthalate (DEHP) has been used as a plasticizer for decades. Recent research evidence has revealed that environmental factors can alter vascular endothelial cell function through DNA methylation. However, no previous in vitro/vivo study has explored the role of DNA methylation in DEHP exposure and vascular endothelial cell function. In the present study, we enrolled 793 subjects aged 12 to 30 years from a young Taiwanese cohort to investigate the association between mono-2-ethylhexyl phthalate (MEHP) (urine DEHP metabolite), 5mdC/dG (global DNA methylation marker), CD31+/CD42a-, CD31+/CD42a+, and CD14 (apoptotic microparticles of vascular cells). In multiple regression analyses, the levels of mono-2-ethylhexyl phthalate (MEHP) were positively associated with 5mdC/dG and all three apoptotic microparticles. In addition, the regression coefficients between MEHP and the three types of apoptotic microparticles were higher when the 5mdC/dG levels were higher than the 50th percentile. In the structural equation model (SEM), we found that MEHP had a direct correlation with CD31+/CD42a- and an indirect association with CD31+/CD42a- through the effect of 5mdC/dG. Moreover, MEHP only had a direct association with CD31+/CD42a+ and an indirect association with CD14. In conclusion, the results show that global DNA methylation mediates the relationship between MEHP and apoptotic microparticles. These findings indicate that DNA methylation may play a role in the pathogenesis of DEHP-induced endothelial cell apoptosis in humans. Further studies are needed to clarify the causal inference.

Association between Levels of Urine Di-(2-ethylhexyl)phthalate Metabolites and Heart Rate Variability in Young Adults.

Phthalate exposure is associated with cardiovascular risk. Among the various phthalates, di-(2-ethylhexyl) phthalate (DEHP) is a deleterious plasticizer in our daily lives. This study investigated the association between DEHP exposure and the alteration of heart rate variability (HRV). During 2017-2019, we recruited 974 young adults to investigate the effects of living environments and dietary habits on cardiometabolic disorders in Taiwan. We quantitatively analyzed urinary metabolites of DHEP. A continuous electrocardiogram was recorded to obtain a 5-min ECG. Time-domain and frequency-domain HRV analyses were performed. Multiple linear regression showed that urinary oxidized DEHP metabolites MEHHP and MEOHP were associated with decreased HRV after controlling for associated cardiovascular risk factors. A higher MEHHP level was associated with a lower triangular interpolation of NN interval histogram (TINN), very low frequency (VLF), and low frequency/high frequency (LF/HF) ratio. A higher MEOHP level was associated with a decreased LF/HF ratio. In addition, trend analysis showed that higher MEHHP and MEOHP quantiles were significantly associated with a decreased LF/HF ratio. DEHP is a potentially harmful and invisible chemical. The urinary DEHP metabolites MEHHP and MEOHP are associated with decreased HRV, indicating an adverse effect on autonomic balance in young adults in Taiwan.

Comparison of cystatin C-based and creatinine-based glomerular filtration rate in the prediction of postoperative residual hypertension in aldosterone-producing adenoma patients after adrenalectomy.

Renal function is associated with postoperative residual hypertension in aldosterone-producing adenoma(APA) patients. Cystatin C-based glomerular filtration rate (GFR) can more accurately estimate renal function than creatinine-based methods. However, which renal function estimation method can more accurately predict postoperative hypertension in APA patients is still unknown. We recruited 180 APA patients who underwent adrenalectomy. Preoperative creatinine and cystatin C-based GFRs were calculated. Residual hypertension was defined as persistent hypertension > 140/90 mmHg or requiring anti-hypertensive medications 1 year after surgery. Sixty-five(36.1%) of the 180 APA patients had residual hypertension. Multivariate logistic regression and receiver operating characteristic (ROC) curve analysis showed a combination of creatinine and cystatin method CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine-cystatin GFR was significantly associated with residual postoperative hypertension and had the largest area under the ROC curve, which was statistically larger than that of Cockcroft-Gault creatinine-based GFR. In both net reclassification index and integrated discrimination index models, CKD-EPI creatinine-cystatin GFR significantly improved the discriminatory power of CG-GFR. Among these renal function estimations used in the presented study, creatinine-cystatin combined GFR was a precise method to predict residual postoperative hypertension in APA patients received adrenalectomy. These finding may help identify those patients with higher risk of residual hypertension after operation.

Left Ventricular Dysfunction in Patients With Primary Aldosteronism: A Propensity Score-Matching Follow-Up Study With Tissue Doppler Imaging.

Background Primary aldosteronism is the most common cause of secondary hypertension and is associated with left ventricular hypertrophy. However, whether aldosterone excess is responsible for left ventricular (LV) diastolic dysfunction is unknown. Methods and Results We prospectively enrolled 129 patients with aldosterone-producing adenoma and 120 patients with essential hypertension, and analyzed their clinical, biochemical, and echocardiographic data, including tissue Doppler images. The patients with aldosterone-producing adenoma were reevaluated 1 year after adrenalectomy. After propensity score matching, there were 105 patients in each group. The patients with aldosterone-producing adenoma had worse diastolic function than the patients with essential hypertension, as reflected by lower e' (P<0.001) and higher E/e' (P=0.003). Multivariate analysis showed that LV diastolic function was significantly correlated with age (P<0.001), sex (P<0.001), body mass index (P=0.002), systolic blood pressure (P=0.004), creatinine (P=0.008), and log-transformed aldosterone-renin ratio (P=0.003). After adrenalectomy, the patients with aldosterone-producing adenoma had significant improvements in LV diastolic function as reflected by an increase in e' (P=0.003) and decrease in E/e' (P=0.002). The change in E/e' was independently correlated with baseline E/e' (P<0.001) and change in LV mass index (P=0.006). Conclusions The patients with primary aldosteronism had worse LV diastolic function than the patients with essential hypertension after propensity score matching, and this could be reversed after adrenalectomy, suggesting that aldosterone excess may induce LV diastolic dysfunction.

IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.

Aims: An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. Methods and results: In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kB pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion. Conclusions: IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.

Aldosterone induces left ventricular subclinical systolic dysfunction: a strain imaging study.

BACKGROUND: Primary aldosteronism is associated with a higher incidence of left ventricular (LV) hypertrophy and diastolic dysfunction than essential hypertension. However, systolic function via endocardial measurements is similar between patients with primary aldosteronism and essential hypertension. Speckle-tracking echocardiography is a sensitive tool which can detect subclinical impairments in systolic function. The aim of this study was to investigate aldosterone-induced subclinical impairments in systolic function. METHODS: We prospectively enrolled patients with primary aldosteronism and essential hypertension and analyzed their clinical data, biochemical data, and echocardiographic parameters, including myocardial strain [global longitudinal strain (GLS)]. RESULTS: Thirty-six patients with primary aldosteronism and 31 patients with essential hypertension were enrolled for analysis. The patients with primary aldosteronism had significantly lower serum potassium levels, lower plasma renin activity, higher aldosterone-to-renin ratio (ARR), and higher 24-h urinary aldosterone levels than patients with essential hypertension. With regards to echocardiographic parameters, the patients with primary aldosteronism had a thicker ventricular wall and higher LV mass index than those with essential hypertension. Most importantly, we found significant degradation of GLS in the patients with primary aldosteronism compared with those with essential hypertension (-17.84 ±â€Š2.36 vs. -20.13 ±â€Š2.32, P < 0.001). In correlation analysis, GLS was significantly correlated with serum potassium level, LV mass index, log-transformed plasma renin activity, log-transformed ARR, and log-transformed 24-h urinary aldosterone levels (all P < 0.05). Multivariate linear regression analysis further identified log-transformed ARR (ß = 0.771, 95% confidence interval: 0.011-1.530, P = 0.047), and log-transformed 24-h urinary aldosterone level (ß = 1.765, 95% confidence interval: 0.01-3.529, P = 0.050) as independent factors correlated with GLS. CONCLUSION: Patients with primary aldosteronism have a lower magnitude of GLS than patients with essential hypertension, suggesting that aldosterone induces a subclinical decline in LV systolic function.

The relationship among cardiac structure, dietary salt and aldosterone in patients with primary aldosteronism.

Salt intake is highly associated with cardiac structure in patients with primary aldosteronism (PA). We investigated the association among dietary salt intake, aldosterone and left ventricular mass in patients with PA. We enrolled 158 patients with PA and 158 patients with essential hypertension. We measured 24-hour urinary sodium (UNa) and aldosterone (UAldo) level and echocardiography parameters. In patients with PA, the UAldo level was positively correlated with left ventricular mass index (LVMI; r=0.231, p=0.007). The UNa level was not linearly correlated with left ventricular structural parameters in patients with PA. To test if UNa has a non-linear relationship with LVMI among patients with PA, we categorized the participants according to the tertile of UNa (low, median, and high tertile). PA patients with medium tertile of UNa had significant lower LVMI than the other two groups (LVMI: 144.1 ± 42.9, 121.1 ± 33.4, and 136.7 ± 32.8 g/m2, from the lowest to the highest tertile of Una; analysis of variance p=0.006, post-hoc p <0.05). Multifactor analysis of variance confirmed this finding after adjustment for clinical parameters. Post-hoc analyses revealed that the high UNa tertile was associated with higher left ventricular end-diastolic volume compared with medium UNa tertile; while the low UNa tertile was associated with higher mean wall thickness compared with medium UNa tertile. The findings imply the reasons for increased LVMI may be different in patients with the highest and lowest UNa tertile. In conclusion, the medium tertile of 24-hour UNa is associated with lowest LVMI in patients with PA.