Lian-Yu Lin

Association among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis and Metabolic Syndrome in Adolescents and Adults

OBJECTIVE Perfluoroalkyl chemicals (PFCs) have been used worldwide in a variety of consumer products. The effect of PFCs on glucose homeostasis is not known. RESEARCH DESIGN AND METHODS We examined 474 adolescents and 969 adults with reliable serum measures of metabolic syndrome profile from the National Health and Nutrition Examination Survey 1999–2000 and 2003–2004. RESULTS In adolescents, increased serum perfluorononanoic acid (PFNA) concentrations were associated with hyperglycemia (odds ratio [OR] 3.16 [95% CI 1.39–7.16], P < 0.05). Increased serum PFNA concentrations also have favorable associations with serum HDL cholesterol (0.67 [0.45–0.99], P < 0.05). Overall, increased serum PFNA concentrations were inversely correlated with the prevalence of the metabolic syndrome (0.37 [0.21–0.64], P < 0.005). In adults, increased serum perfluorooctanoic acid concentrations were significantly associated with increased β-cell function (β coefficient 0.07 ± 0.03, P < 0.05). Increased serum perfluorooctane sulfate (PFOS) concentrations were associated with increased blood insulin (0.14 ± 0.05, P < 0.01), homeostasis model assessment of insulin resistance (0.14 ± 0.05, P < 0.01), and β-cell function (0.15 ± 0.05, P < 0.01). Serum PFOS concentrations were also unfavorably correlated with serum HDL cholesterol (OR 1.61 [95% CI 1.15–2.26], P < 0.05). CONCLUSIONS Serum PFCs were associated with glucose homeostasis and indicators of metabolic syndrome. Further clinical and animal studies are warranted to clarify putative causal relationships.

The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients

BACKGROUND A growing body of evidence links macrophage activation and fibrosis to the pathogenesis of heart failure (HF). Galectin-3 is one of the most likely mediators between macrophage activation and myocardial fibrosis. However, the exact relationship is unknown in humans. We assessed the impact of galectin-3 on serum markers of cardiac extracellular matrix (ECM) turnover in HF patients. METHODS Patients with HF manifestations and a left ventricular ejection fraction (LVEF) <or=50% were enrolled in this study. Gender, age, medications, serum biochemical data, and outcomes of heart failure were recorded. Serum galectin-3, extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. RESULTS A total of 106 (83 males and 23 females) patients were enrolled. The age was 61+/-16 y and LVEF was 35+/-9%. Their mean NYHA functional class was 2.2. Log galectin-3 was significantly correlated with log PIIINP (p=0.006), log TIMP-1 (p=0.025), log MMP-2 (p=0.016), and NYHA functional class (p=0.034); but not age, sex or LVEF. After adjusting for age, sex, smoking status and LVEF, the relationship between galectin-3 and ECM turnover biomarkers (including PIIINP, TIMP, and MMP-2) remained significant. After adjusting for age, sex, smoking status and NYHA functional class, the relationship between galectin-3 and PIIINP or MMP-2 remained significant. CONCLUSIONS Galectin-3 is significantly correlated with serum markers of cardiac ECM turnover in HF patients. This implies a relationship between macrophage activation and ECM turnover in patients with HF.

Personal exposure to submicrometer particles and heart rate variability in human subjects

We conducted a study on two panels of human subjects—9 young adults and 10 elderly patients with lung function impairments—to evaluate whether submicrometer particulate air pollution was associated with heart rate variability (HRV). We measured these subjects’ electrocardiography and personal exposure to number concentrations of submicrometer particles with a size range of 0.02–1 μm (NC0.02–1) continuously during daytime periods. We used linear mixed-effects models to estimate the relationship between NC0.02–1 and log10-transformed HRV, including standard deviation of all normal-to-normal intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent NN intervals (r-MSSD), low frequency (LF, 0.04–0.15 Hz), and high frequency (HF, 0.15–0.40 Hz), adjusted for age, sex, body mass index, tobacco exposure, and temperature. For the young panel, a 10,000-particle/cm3 increase in NC0.02–1 with 1–4 hr moving average exposure was associated with 0.68–1.35% decreases in SDNN, 1.85–2.58% decreases in r-MSSD, 1.32–1.61% decreases in LF, and 1.57–2.60% decreases in HF. For the elderly panel, a 10,000-particle/cm3 increase in NC0.02–1 with 1–3 hr moving average exposure was associated with 1.72–3.00% decreases in SDNN, 2.72–4.65% decreases in r-MSSD, 3.34–5.04% decreases in LF, and 3.61–5.61% decreases in HF. In conclusion, exposure to NC0.02–1 was associated with decreases in both time-domain and frequency-domain HRV indices in human subjects.

Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents.

OBJECTIVE Bilirubin is a potent antioxidant and a cyroprotectant. Low serum bilirubin is associated with atherosclerosis. Little is known about its role in metabolic syndrome (MS) among children and adolescents. METHODS We examined 4723 children and adolescents aged 12-17 years with reliable measures of various serum hepatic profiles and metabolic risks from Health and Nutrition Examination Survey 1999-2004. RESULTS The results showed that the prevalence of the MS was from 6.6+/-1.2% in the lowest quartile to 2.1+/-1.9% in the highest quartile of the concentration of total bilirubin. The graded association remained significant after the adjustment of other co-variates. The odds ratios for the MS were around 0.29 (0.08-0.99) and 0.23 (0.08-0.65) for the upper two quartiles when using the lowest quartile as reference for the concentration of total bilirubin. The quartiles of the serum total bilirubin levels were inversely correlated with the homeostasis model assessment (HOMA-IR) and insulin while not associated with the serum C-reactive protein (CRP) levels. CONCLUSIONS The serum total bilirubin levels are inversely correlated with the prevalence of the MS. The mechanism of the association between MS and total bilirubin may be related to the insulin resistance status.

Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation-- a nation wide database analysis.

BACKGROUND Atrial fibrillation (AF) is a risk factor for ischemic stroke. Stroke-prevention strategies based on risk schemes have been developed but most of the data are from western people. Our goal is to investigate the risk factors of ischemic stroke in Taiwanese with AF in a nation-wide database. METHODS A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. By using ambulatory and inpatient claim data, we included subjects with AF and were above 20 years old. We excluded those who had ever taken warfarin or aspirin or had valvular heart diseases. RESULT A total of 7920 patients (3633 women, 4287 men) were included in the final analyses. Cox regression analysis showed that the risk factors for ischemic stroke were age (OR=1.338 for age 65-74 years vs. age 20-64 years, P=0.014; OR=1.652 for age over 75 years vs. age 20-64 years, P<0.001), hypertension (HTN) (OR=2.656, P<0.001), diabetes mellitus (DM) (OR=1.341, P=0.005), heart failure (OR=1.611, P<0.001), previous ischemic stroke or transient ischemic accident (TIA) (OR=2.752, P<0.001) and peripheral arterial disease (PAD) (OR=1.814, P=0.006). The gender, coronary artery disease, history of myocardial infarction and chronic renal insufficiency were not associated with ischemic stroke. The rate of ischemic stroke was much lower in current cohort as compared with that in whites. Frequent used risk schemes including CHADS₂ and CHA₂DS₂-VASC had comparable but only limited ability to predict ischemic stroke in subjects with AF. CONCLUSION Compare with western people, hypertension plays a more important role in ischemic stroke in Taiwanese with AF and the incidence is lower. A substantial number of ischemic strokes cannot be accurately predicted by current risk schemes.

Effects of Particle Size Fractions on Reducing Heart Rate Variability in Cardiac and Hypertensive Patients

It is still unknown whether the associations between particulate matter (PM) and heart rate variability (HRV) differ by particle sizes with aerodynamic diameters between 0.3 μm and 1.0 μm (PM0.3–1.0), between 1.0 μm and 2.5 μm (PM1.0–2.5), and between 2.5 μm and 10 μm (PM2.5–10). We measured electrocardiographics and PM exposures in 10 patients with coronary heart disease and 16 patients with either prehypertension or hypertension. The outcome variables were standard deviation of all normal-to-normal (NN) intervals (SDNN), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (r-MSSD), low frequency (LF; 0.04–0.15 Hz), high frequency (HF; 0.15–0.40 Hz), and LF:HF ratio for HRV. The pollution variables were mass concentrations of PM0.3–1.0, PM1.0–2.5, and PM2.5–10. We used linear mixed-effects models to examine the association between PM exposures and log10-transformed HRV indices, adjusting for key personal and environmental attributes. We found that PM0.3–1.0 exposures at 1- to 4-hr moving averages were associated with SDNN and r-MSSD in both cardiac and hypertensive patients. For an interquartile increase in PM0.3–1.0, there were 1.49–4.88% decreases in SDNN and 2.73–8.25% decreases in r-MSSD. PM0.3–1.0 exposures were also associated with decreases in LF and HF for hypertensive patients at 1- to 3-hr moving averages except for cardiac patients at moving averages of 2 or 3 hr. By contrast, we found that HRV was not associated with either PM1.0–2.5 or PM2.5–10. HRV reduction in susceptible population was associated with PM0.3–1.0 but was not associated with either PM1.0–2.5 or PM2.5–10.

CMR-Verified Diffuse Myocardial Fibrosis Is Associated With Diastolic Dysfunction in HFpEF

OBJECTIVES The purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV). BACKGROUND Increased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF. METHODS Forty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated. RESULTS Compared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% [interquartile range (IQR): 29.0% to 34.1%] vs. 27.9% [IQR: 26.2% to 29.4%], p < 0.001) and HFpEF (28.9% [IQR: 27.8% to 31.3%] vs. 27.9% [IQR: 26.2% to 29.4%], p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s(-1) [IQR: 0.79 to 1.49 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001) and HFpEF (2.89 s(-1) [IQR: 2.13 to 3.50 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = -0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = -0.238, p = 0.285, respectively). CONCLUSIONS In patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.

Reversal of deteriorated fractal behavior of heart rate variability by beta-blocker therapy in patients with advanced congestive heart failure

Beta‐Blocker Therapy and Heart Rate Variability. Introduction: The slope of the power spectrum in heart rate variability (HRV) reflects the fractal or scaling behavior in HR dynamics and recently was confirmed as an independent predictor of postmyocardial infarction survival. Whether or not the new measurement in HRV foresees the functional evolution in patients with advanced congestive heart failure treated by β blockers is unclear.

Association of Kidney Function With Residual Hypertension After Treatment of Aldosterone-Producing Adenoma

BACKGROUND Autonomous secretion of aldosterone in patients with primary aldosteronism increases glomerular filtration rate and causes kidney damage. The influence of a mild decrease in kidney function on residual hypertension after adrenalectomy is unexplored. STUDY DESIGN Nonconcurrent prospective study. SETTING & PARTICIPANTS The study was based on the Taiwan Primary Aldosteronism Investigation (TAIPAI) database. 150 patients (61 men; overall mean age, 47.2 +/- 11.6 years) with a diagnosis of aldosterone-producing adenoma had undergone unilateral adrenalectomy at National Taiwan University Hospital from July 1999 to January 2007. PREDICTOR Presurgery estimated glomerular filtration rate (eGFR). OUTCOMES & MEASUREMENTS Residual hypertension after adrenalectomy, defined either as less than 75% of recorded blood pressure measurements with systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg or requiring antihypertensive medications during the first year after surgery. RESULTS Before surgery, 27 (18%), 72 (48%), and 51 (34%) patients had moderately to severely decreased (<60 mL/min/1.73 m(2)), mildly decreased (60 <or= eGFR < 90 mL/min/1.73 m(2)), or nondecreased eGFR (>or=90 mL/min/1.73 m(2)), respectively. After surgery, 16 (59.3%), 29 (40.3%), and 10 (19.3%) patients in each category had postsurgery residual hypertension. Compared with patients without decreased eGFR before surgery, adjusted odds ratios for postsurgery residual hypertension were 2.7 (95% confidence interval, 1.03 to 7.0; P = 0.04) and 2.8 (95% confidence interval, 1.05 to 9.3) for mildly and moderately to severely decreased eGFR, respectively. LIMITATIONS Arbitrary definition for residual hypertension. CONCLUSIONS Two-thirds of patients with aldosterone-producing adenoma were cured of hypertension by means of unilateral adrenalectomy. Kidney function impairment, even mild, appears to be associated with a high incidence of postsurgery residual hypertension.

Kidney impairment in primary aldosteronism

BACKGROUND Kidney impairment is noted in primary aldosteronism (PA), and probably initiated by glomerular hyperfiltration. METHODS A prospectively defined survey was conducted on 602 patients who were suspected of PA in the multiple-center Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Estimated glomerular filtration rate (eGFR) was calculated and followed up at 1 yr after treatment. RESULTS The diagnosis of PA was confirmed in 330 patients. Among them 17% of these patients had kidney impairment (eGFR<60 ml/min/1.73 m²). Patients with PA had a higher prevalence of estimated hyperfiltration than those with essential hypertension (EH) (14.5% vs. 7.0%, p=0.005). The eGFR independently predicted PA (OR, 1.017) in the propensity-adjusted multivariate logistic model. In PA, plasma renin activity and lower serum potassium (p=0.018) was correlated with kidney impairment (p=0.001), while this relationship was not significant in patients with EH. Either unilateral adrenalectomy or treatment of spironolactone for PA patients caused a decrease of eGFR (p<0.001). Pre-operative hypokalemia (p=0.013) and the long latency of hypertension (p=0.016) could enhance the significant decrease of eGFR after adrenalectomy. CONCLUSIONS Patients with aldosteronism had relative estimated hyperfiltration than patients with EH. Calculation of eGFR may increase the specificity in identifying patients with PA. Our findings demonstrate the correlation of serum potassium and renin with estimated hyperfiltration in PA and their relationship to kidney damage. These results provide a high priority for future renal protective strategies and methods for the early diagnosis and prompt treatment of PA.