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1.  Assessment of the Cost-Effectiveness and Clinical Outcomes of a Fourth-Generation Synchronous Telehealth Program for the Management of Chronic Cardiovascular Disease 
Background
Telehealth programs are a growing field in the care of patients. The evolution of information technology has resulted in telehealth becoming a fourth-generation synchronous program. However, long-term outcomes and cost-effectiveness analysis of fourth-generation telehealth programs have not been reported in patients with chronic cardiovascular diseases.
Objective
We conducted this study to assess the clinical outcomes and cost-effectiveness of a fourth-generation synchronous telehealth program for patients with chronic cardiovascular diseases.
Methods
We retrospectively analyzed 575 patients who had joined a telehealth program and compared them with 1178 patients matched for sex, age, and Charlson comorbidity index. The program included: (1) instant transmission of biometric data, (2) daily telephone interview, and (3) continuous decision-making support. Data on hospitalization, emergency department (ED) visits, and medical costs were collected from the hospital’s database and were adjusted to the follow-up months.
Results
The mean age was 64.5 years (SD 16.0). The mean number of monthly ED visits (mean 0.06 SD 0.13 vs mean 0.09 SD 0.23, P<.001), hospitalizations (mean 0.05 SD 0.12 vs mean 0.11 SD 0.21, P<.001), length of hospitalization (mean 0.77 days SD 2.78 vs mean 1.4 SD 3.6, P<.001), and intensive care unit admissions (mean 0.01 SD 0.07 vs mean 0.036 SD 0.14, P<.001) were lower in the telehealth group. The monthly mean costs of ED visits (mean US$20.90 SD 66.60 vs mean US$37.30 SD 126.20, P<.001), hospitalizations (mean US$386.30 SD 1424.30 vs mean US$878.20 SD 2697.20, P<.001), and all medical costs (mean US$587.60 SD 1497.80 vs mean US$1163.60 SD 3036.60, P<.001) were lower in the telehealth group. The intervention costs per patient were US$224.80 per month. Multivariate analyses revealed that age, telehealth care, and Charlson index were the independent factors for ED visits, hospitalizations, and length of hospitalization. A bootstrap method revealed the dominant cost-effectiveness of telehealth care over usual care.
Conclusions
Better cost-effectiveness and clinical outcomes were noted with the use of a fourth-generation synchronous telehealth program in patients with chronic cardiovascular diseases. The intervention costs of this new generation of telehealth program do not increase the total costs for patient care.
doi:10.2196/jmir.3346
PMCID: PMC4071228  PMID: 24915187
cardiovascular disease; cost-benefit analysis; telehealth
2.  Postprandial Glucose Improves the Risk Prediction of Cardiovascular Death Beyond the Metabolic Syndrome in the Nondiabetic Population 
Diabetes Care  2009;32(9):1721-1726.
OBJECTIVE
With increasing evidence about the cardiovascular risk associated with postprandial nonfasting glucose and lipid dysmetabolism, it remains uncertain whether the postprandial glucose concentration increases the ability of metabolic syndrome to predict cardiovascular events.
RESEARCH DESIGN AND METHODS
This was an observational study of 15,145 individuals aged 35–75 years without diabetes or cardiovascular diseases. Postprandial glucose was obtained 2 h after a lunch meal. Metabolic syndrome was diagnosed using the criteria of the U.S. National Cholesterol Education Program Adult Treatment Panel III. Cardiovascular and all-cause deaths were primary outcomes.
RESULTS
During a median follow-up of 6.7 years, 410 individuals died, including 82 deaths from cardiovascular causes. In a Cox model adjusting for metabolic syndrome status as well as age, sex, smoking, systolic blood pressure, LDL, and HDL cholesterol levels, elevated 2-h postprandial glucose increased the risk of cardiovascular and all-cause death (per millimole per liter increase, hazard ratio 1.26 [95% CI 1.11–1.42] and 1.10 [1.04–1.16], respectively), with significant trends across the postprandial glucose quintiles. Including 2-h postprandial glucose into a metabolic syndrome–included multivariate risk prediction model conferred a discernible improvement of the model in discriminating between those who died of cardiovascular causes and who did not (integrated discrimination improvement 0.4, P = 0.005; net reclassification improvement 13.4%, P = 0.03); however, the improvement was only marginal for all-cause death.
CONCLUSIONS
Given the risk prediction based on metabolic syndrome and established cardiovascular risk factors, 2-h postprandial glucose improves the predictive ability to identity nondiabetic individuals at increased risk of cardiovascular death.
doi:10.2337/dc08-2337
PMCID: PMC2732157  PMID: 19502543
3.  N-3 polyunsaturated fatty acids decrease levels of doxorubicin-induced reactive oxygen species in cardiomyocytes -- involvement of uncoupling protein UCP2 
Background
Use of the chemotherapeutic drug doxorubicin (DOX) is associated with serious cardiotoxicity, as it increases levels of reactive oxygen species (ROS). N-3 polyunsaturated fatty acid dietary supplements can be of benefit to patients undergoing cancer therapy. The aims of this study were to determine whether DOX-induced cardiotoxicity is related to mitochondrial uncoupling proteins and whether eicosapentaenoic acid (EPA, C20:5 n-3) or docosahexaenoic acid (DHA, C22:6 n-3) affects DOX-induced cardiomyocyte toxicity.
Results
Treatment of H9C2 cells with DOX resulted in decreased cell viability and UCP2 expression. Treatment with 100 μM EPA or 50 μM DHA for 24 h resulted in a maximal mitochondria concentration of these fatty acids and increased UCP2 expression. Pretreatment with 100 μM EPA or 50 μM DHA prevented the DOX-induced decrease in UCP2 mRNA and protein levels, but these effects were not seen with EPA or DHA and DOX cotreatment. In addition, the DOX-induced increase in ROS production and subsequent mitochondrial membrane potential change (∆ψ) were significantly attenuated by pretreatment with EPA or DHA.
Conclusion
EPA or DHA pre-treatment inhibits the DOX-induced decrease in UCP2 expression, increase in ROS production, and subsequent mitochondrial membrane potential change that contribute to the cardiotoxicity of DOX.
Electronic supplementary material
The online version of this article (doi:10.1186/s12929-014-0101-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12929-014-0101-3
PMCID: PMC4237738  PMID: 25407516
EPA; DHA; Doxorubicin; ROS; UCP2
4.  Measurement of Visceral Fat: Should We Include Retroperitoneal Fat? 
PLoS ONE  2014;9(11):e112355.
Objective
Whether retroperitoneal fat should be included in the measurement of visceral fat remains controversial. We compared the relationships of fat areas in peritoneal, retroperitoneal, and subcutaneous compartments to metabolic syndrome, adipokines, and incident hypertension and diabetes.
Methods
We enrolled 432 adult participants (153 men and 279 women) in a community-based cohort study. Computed tomography at the umbilicus level was used to measure the fat areas.
Results
Retroperitoneal fat correlated significantly with metabolic syndrome (adjusted odds ratio (OR), 5.651, p<0.05) and the number of metabolic abnormalities (p<0.05). Retroperitoneal fat area was significantly associated with blood pressure, plasma glycemic indices, lipid profile, C-reactive protein, adiponectin (r = −0.244, P<0.05), and leptin (r = 0.323, p<0.05), but not plasma renin or aldosterone concentrations. During the 2.94±0.84 years of follow-up, 32 participants developed incident hypertension. Retroperitoneal fat area (hazard ration (HR) 1.62, p = 0.003) and peritoneal fat area (HR 1.62, p = 0.009), but not subcutaneous fat area (p = 0.14) were associated with incident hypertension. Neither retroperitoneal fat area, peritoneal fat area, nor subcutaneous fat areas was associated with incident diabetes after adjustment.
Conclusions
Retroperitoneal fat is similar to peritoneal fat, but differs from subcutaneous fat, in terms of its relationship with metabolic syndrome and incident hypertension. Retroperitoneal fat area should be included in the measurement of visceral fat for cardio-metabolic studies in human.
doi:10.1371/journal.pone.0112355
PMCID: PMC4234414  PMID: 25401949
5.  Multi-scale symbolic entropy analysis provides prognostic prediction in patients receiving extracorporeal life support 
Critical Care  2014;18(5):548.
Introduction
Extracorporeal life support (ECLS) can temporarily support cardiopulmonary function, and is occasionally used in resuscitation. Multi-scale entropy (MSE) derived from heart rate variability (HRV) is a powerful tool in outcome prediction of patients with cardiovascular diseases. Multi-scale symbolic entropy analysis (MSsE), a new method derived from MSE, mitigates the effect of arrhythmia on analysis. The objective is to evaluate the prognostic value of MSsE in patients receiving ECLS. The primary outcome is death or urgent transplantation during the index admission.
Methods
Fifty-seven patients receiving ECLS less than 24 hours and 23 control subjects were enrolled. Digital 24-hour Holter electrocardiograms were recorded and three MSsE parameters (slope 5, Area 6–20, Area 6–40) associated with the multiscale correlation and complexity of heart beat fluctuation were calculated.
Results
Patients receiving ECLS had significantly lower value of slope 5, area 6 to 20, and area 6 to 40 than control subjects. During the follow-up period, 29 patients met primary outcome. Age, slope 5, Area 6 to 20, Area 6 to 40, acute physiology and chronic health evaluation II score, multiple organ dysfunction score (MODS), logistic organ dysfunction score (LODS), and myocardial infarction history were significantly associated with primary outcome. Slope 5 showed the greatest discriminatory power. In a net reclassification improvement model, slope 5 significantly improved the predictive power of LODS; Area 6 to 20 and Area 6 to 40 significantly improved the predictive power in MODS. In an integrated discrimination improvement model, slope 5 added significantly to the prediction power of each clinical parameter. Area 6 to 20 and Area 6 to 40 significantly improved the predictive power in sequential organ failure assessment.
Conclusions
MSsE provides additional prognostic information in patients receiving ECLS.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0548-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0548-3
PMCID: PMC4221713  PMID: 25341381
6.  Evaluation of Circulating Adipokines and Abdominal Obesity as Predictors of Significant Myocardial Ischemia Using Gated Single-Photon Emission Computed Tomography 
PLoS ONE  2014;9(5):e97710.
Objective
Coronary artery disease (CAD) is associated with abdominal obesity and metabolic syndrome. Adipocytes secrete adipokines, including the newly discovered adipocyte fatty acid binding protein (A-FABP) and chemerin. Adipokines contribute to the pathogenesis of CAD. In patients with CAD, the presence of significant ischemia predicts adverse outcomes. It is unknown whether adipokines can be better predictors of the presence of significant myocardial ischemia than conventional risk factors. This study aimed to compare adipokines with clinical risk factors and abdominal obesity as predictive factors for significant myocardial ischemia.
Methods
One hundred and ninety-six adults with suspected, but unproven, CAD were consecutively enrolled. The main measures were clinical and biochemical parameters and stress myocardial perfusion imaging with gated myocardial perfusion single-photon emission computed tomography (SPECT), with computed tomography (CT) attenuation correction. The abdominal visceral fat area was examined using a hybrid SPECT/CT scanner. Serum levels of high-sensitivity C-reactive protein (hs-CRP) and adipokines (adiponectin, A-FABP, and chemerin) were evaluated.
Results
A-FABP levels correlated significantly with adiponectin, hs-CRP, body mass index, waist circumference, and visceral fat area. A-FABP was significantly associated with metabolic syndrome (OR 3.2, 95% CI 1.6–6.4, p = 0.001), significant myocardial ischemia (OR 1.9, 95% CI 1.0–3.4, p = 0.05), and stress lung-to-heart ratio (β = 0.03, p = 0.03) on SPECT. Chemerin was significantly associated with serum triglyceride levels but not with metabolic syndrome, significant ischemia, or stress lung-to-heart ratio on SPECT. A-FABP was better at detecting significant inducible ischemia than other biomarkers, although this was a modest improvement (area under ROC curve 0.579, 95% CI 0.46–0.69).
Conclusions
Serum A-FABP concentrations correlate significantly with visceral fat area, metabolic syndrome, and predicted significant myocardial ischemia on SPECT. This may help to more accurately assess CAD risk, especially in patients with metabolic syndrome.
doi:10.1371/journal.pone.0097710
PMCID: PMC4026442  PMID: 24842767
7.  Enigmatic Ectopic Fat: Prevalence of Nonalcoholic Fatty Pancreas Disease and Its Associated Factors in a Chinese Population 
Background
Fatty infiltration of the pancreas is an enigmatic manifestation of ectopic fat deposition in obesity. Studies have shown that pancreatic lipid accumulation interferes with insulin secretion in humans. However, the prevalence of fatty pancreas and its associated factors in the general population remain unclear. The aim of this study was to investigate the prevalence of fatty pancreas and its association with diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiometabolic risk factors in a Chinese population.
Methods and Results
This was a cross‐sectional study. A total of 8097 subjects with or without fatty pancreas (n=1297 and 6800, respectively) were recruited. Each subject was assessed by using abdominal sonography to diagnose NAFLD and fatty pancreas. Clinical and metabolic parameters were compared between groups, and their associations with fatty pancreas were examined. The prevalence of fatty pancreas was 16%. The fatty pancreas group had a significantly greater proportion of subjects with diabetes (12.6% versus 5.2%) and NAFLD (67.2% versus 35.1%) than did the non–fatty pancreas group (P<0.001). In the logistic regression analysis, age (P<0.001), general or central obesity (P<0.001), diabetes (P<0.001), and NAFLD (P<0.001) were independently associated with fatty pancreas after adjustment for sex, lipid profile, alanine transaminase/aspartate transaminase ratio, hypertension, smoking, alcohol drinking, and exercise.
Conclusions
The prevalence of fatty pancreas is high in the general population. Both diabetes and NAFLD are important associated factors of fatty pancreas, independent of age, sex, adiposity, and other cardiometabolic risk factors.
doi:10.1161/JAHA.113.000297
PMCID: PMC3959709  PMID: 24572250
diabetes; nonalcoholic fatty liver disease; nonalcoholic fatty pancreas disease; obesity
8.  Comparison the Prognostic Value of Galectin-3 and Serum Markers of Cardiac Extracellular Matrix Turnover in Patients with Chronic Systolic Heart Failure 
Background: Galectin-3 (Gal-3) shows the ability of survival prediction in heart failure (HF) patients. However, Gal-3 is strongly associated with serum markers of cardiac extracellular matrix (ECM) turnover. The aim of this study is to compare the impact of Gal-3 and serum markers of cardiac ECM turnover on prognostic prediction of chronic systolic HF patients. Methods: Serum Gal-3, brain natriuretic peptide (BNP), extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2, 9 (MMP-2, 9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. Cox regression analysis was used for survival analysis.
Results: A total of 105 (81 male) patients were enrolled. During 980±346 days follow-up, 17 patients died and 36 episodes of HF admission happened. Mortality of these patients was significantly associated with the log PIIINP (β= 15.380; P=0.042), log TIMP-1(β= 44.530; P=0.003), log MMP-2 (β= 554.336; P<0.001), log BNP (β= 28.273; P=0.034). Log Gal-3 (β= 7.484; P=0.066) is borderline associated with mortality. Mortality or first HF admission of these patients was significantly associated with the log TIMP-1(β= 16.496; P=0.006), log MMP-2 (β= 221.864; P<0.001), log BNP (β= 5.999; P=0.034). Log Gal-3 (β= 4.486; P=0.095) only showed borderline significance. In several models adjusting clinical parameters, log MMP-2 was significantly associated with clinical outcome. In contrast, log Gal-3 was not.
Conclusion: The prognostic strength of MMP-2 to clinical outcome prediction in HF patients is stronger than Gal-3.
doi:10.7150/ijms.8083
PMCID: PMC4147635  PMID: 25170292
Gal-3; heart failure; MMP-2
9.  Twenty-Four-Hour Urinary Aldosterone Predicts Inappropriate Left Ventricular Mass Index in Patients with Primary Aldosteronism 
The Scientific World Journal  2013;2013:294594.
Objective. Primary aldosteronism (PA) is associated with inappropriate left ventricular hypertrophy (LVH) in relation to a given gender and body size. There is no ideal parameter to predict the presence of LVH or inappropriate LVH in patients with PA. We investigate the performance of 24-hour urinary aldosterone level, plasma renin activity and aldosterone-to-renin ratio on this task. Methods. We performed echocardiography in 106 patients with PA and 31 subjects with essential hypertension (EH) in a tertiary teaching hospital. Plasma renin activity, aldosterone concentration, and 24-hour urinary aldosterone level were measured. Results. Only 24-hour urinary aldosterone was correlated with left ventricular mass index (LVMI) and excess LVMI among these parameters. The multivariate analysis revealed the urinary aldosterone level as an independent predictor for LVMI and excess LVMI. Analyzing the ability of urinary aldosterone, plasma aldosterone concentration, and plasma aldosterone-to-renin ratio to identify the presence of LVH (ROC AUC = 0.701, 0.568, 0.656, resp.) and the presence of inappropriate LV mass index (defined as measured LVMI in predicting LVMI ratio >135%) (ROC area under curve = 0.61, 0.43, 0.493, resp.) revealed the better performance of 24-hour urinary aldosterone. Conclusions. In conclusion, 24-hour urinary aldosterone level performed better to predict the presence of LVH and inappropriate LVMI in patients with PA.
doi:10.1155/2013/294594
PMCID: PMC3891226  PMID: 24459427
10.  The Association between Nonalcoholic Fatty Pancreas Disease and Diabetes 
PLoS ONE  2013;8(5):e62561.
Background
Fatty infiltration of the pancreas has been shown to interfere with insulin secretion. Both insulin sensitivity and secretion are important in the pathogenesis of diabetes and prediabetes. However, the relationship between diabetes, prediabetes, and fatty pancreas remains unknown. We aim to investigate the relationships that fatty pancreas and nonalcoholic fatty liver disease (NAFLD) have with prediabetes and diabetes in a Chinese population.
Patients and Methods
This was a cross-sectional study. A total of 7,464 subjects were recruited. NAFLD and fatty pancreas were assessed by sonography. Clinico-metabolic parameters were compared among subjects with normoglycemia, prediabetes, and diabetes. Multinomial logistic regression was used to evaluate the relationship between fatty pancreas and NAFLD and diabetes or prediabetes with adjustment for cardiometabolic risk factors.
Results
With an increase in glycemia, a significantly greater proportion of subjects had NAFLD and fatty pancreas (test for trend p<0.05). Similar trends were also found for hypertension, general and central obesity, low-HDL cholesterol, and hypertriglyceridemia. In the logistic regression analysis, age, hypertension, male gender, hypertriglyceridemia, and central obesity were significantly associated with prediabetes and diabetes. Furthermore, the ORs of prediabetes and diabetes for NAFLD were 1.798 (95% CI 1.544–2.094) and 2.578 (95% CI 2.024–3.284), respectively. In addition, fatty pancreas was independently related to diabetes (OR, 1.379; 95% CI, 1.047–1.816) and prediabetes (OR, 1.222; 95% CI, 1.002–1.491) in male subjects.
Conclusions
Both NAFLD and fatty pancreas were associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Fatty pancreas was also related to prediabetes in males.
doi:10.1371/journal.pone.0062561
PMCID: PMC3643962  PMID: 23671610
11.  A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers 
Background
Little evidence is available for the validity of dietary fish and polyunsaturated fatty acid intake derived from interviewer-administered questionnaires and plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentration.
Methods
We estimated the correlation of DHA and EPA intake from both questionnaires and biochemical measurements. Ethnic Chinese adults with a mean (± SD) age of 59.8 (±12.8) years (n = 297) (47% women) who completed a 38-item semi-quantitative food-frequency questionnaire and provided a plasma sample were enrolled. Plasma fatty acids were analyzed by capillary gas chromatography.
Results
The Spearmen rank correlation coefficients between the intake of various types of fish and marine n-3 fatty acids as well as plasma DHA were significant, ranging from 0.20 to 0.33 (P < 0.001). In addition, dietary EPA, C22:5 n-3 and DHA were significantly correlated with the levels of marine n-3 fatty acids and DHA, with the Spearman rank correlation coefficients ranging from 0.26 to 0.35 (P < 0.001). Moreover, compared with those in the lowest fish intake quintile, participants in the highest quintile had a significantly higher DHA level (adjusted mean difference, 0.99 ± 0.10%, test for trend, P < 0.001). Similar patterns between dietary DHA intake and plasma DHA levels were found. However, the association between dietary fish intake and plasma EPA was not significant (test for trend, P = 0.69).
Conclusions
The dietary intakes of fish and of long chain n-3 fatty acids, as determined by the food frequency questionnaire, were correlated with the percentages of these fatty acids in plasma, and in particular with plasma DHA. Plasma DHA levels were correlated to dietary intake of long-chain n-3 fatty acids.
doi:10.1186/1471-2288-13-23
PMCID: PMC3598308  PMID: 23414574
N-3 fatty acid; Biomarker; Food frequency questionnaire
12.  Total white blood cell count or neutrophil count predict ischemic stroke events among adult Taiwanese: report from a community-based cohort study 
BMC Neurology  2013;13:7.
Background
Evidence about whether white blood cell (WBC) or its subtypes can act as a biomarker to predict the ischemic stroke events in the general population is scanty, particularly in Asian populations. The aim of this study is to establish the predictive ability of total WBC count or subtypes for long-term ischemic stroke events in the cohort population in Taiwan.
Methods
The Chin-Shan Community Cohort Study began from 1990 to 2007 by recruiting 1782 men and 1814 women of Chinese ethnicity. Following a total of 3416 participants free from ischemic stroke events at baseline for a median of 15.9 years; we documented 187 new incident cases.
Results
The multivariate relative risk for the comparison of the participants in the fifth and first WBC count quintiles was 1.67 (95% confidence interval [CI], 1.02–2.73; P for trend=0.03), and the corresponding relative risk for neutrophil count was 1.93 (95% CI, 1.13–3.29; P for trend=0.02). The discriminative ability by WBC and neutrophil counts were similar (area under the receiver operating characteristic curve, 0.600 for adding WBC, 0.610 for adding neutrophils, 0.595 for traditional risk factor model). In addition, the net reclassification improvement (NRI) values between the neutrophil and white blood cell count models were not significant (NRI, =-2.60%, P=0.35), indicating the similar discrimination performance for both WBC and neutrophil counts.
Conclusions
WBC and neutrophil count had a similar ability to predict the long-term ischemic stroke events among Taiwanese.
doi:10.1186/1471-2377-13-7
PMCID: PMC3641985  PMID: 23317415
White blood cell count; Neutrophil count; Ischemic stroke event
13.  Common sequence variants in CD36 gene and the levels of triglyceride and high-density lipoprotein cholesterol among ethnic Chinese in Taiwan 
Background
Evidence of the genetic association between CD36 candidate gene and the risk of metabolic syndrome and its components has been inconsistent. This case–control study assessed the haplotype-tagged SNPs from CD36 on the risk of metabolic syndrome and components.
Methods and results
We recruited 1,000 cases and age, gender-matched controls were randomly selected from the participants with metabolic syndrome defined by International Diabetes Federation. Overall, the haplotype tagged SNPs of CD36 gene were not related to the risk of metabolic syndrome. For individuals with normal lipid levels, several SNPs were significantly associated with the triglycerides and HDL-cholesterol levels: Subjects with rs3211848 homozygote had a higher triglyceride level (99.16 ± 2.61 mg/dL), compared with non-carriers (89.27 ± 1.45 mg/dL, P = 0.001). In addition, compared with non-carriers, individuals with rs1054516 heterozygous and homozygous genotypes had a significantly lower HDL-cholesterol (46.6 ± 0.46 mg/dL for non-carrier, 44.6 ± 0.36 mg/dL for heterozygous, and 44.3 ± 0.56 mg/dL for homozygous, P = 0.0008).
Conclusion
The CD36 gene variants were significantly associated with triglycerides and HDL-cholesterol concentrations among ethnic Chinese in Taiwan.
doi:10.1186/1476-511X-11-174
PMCID: PMC3575328  PMID: 23249574
Metabolic syndrome; CD 36 gene polymorphism
14.  Identification of the HDL-ApoCIII to VLDL-ApoCIII ratio as a predictor of coronary artery disease in the general population: The Chin-Shan Community Cardiovascular Cohort (CCCC) study in Taiwan 
Background
Apolipoprotein (Apo) levels are considered more reliable than plasma lipoprotein levels for predicting coronary artery disease (CAD). However, a unanimous Apo marker for CAD has not been identified. In the Chin-Shan Community Cardiovascular Cohort (CCCC), we sought to identify a common Apo marker for predicting CAD in the general population.
Methods
We examined the cross-sectional association between Apo markers and CAD in the CCCC from 1990 to 2001. Among 3,602 subjects, 90 had angiographically proven CAD (>50% stenosis in ≥1 vessel), and 200 did not have CAD. These subjects were divided into the following 4 groups for analysis: normolipidemic (total cholesterol [TC] <200 mg/dL, triglyceride [TG] <150 mg/dL), hypertriglyceridemic (TC <200 mg/dL, TG ≥150 mg/dL), hypercholesterolemic (TC ≥200 mg/dL, TG <150 mg/dL), and hyperlipidemic (TC ≥200 mg/dL, TG ≥150 mg/dL).
Results
Compatible with findings in other populations, our results showed that CAD patients in the CCCC had higher ApoB and lower high-density lipoprotein (HDL) cholesterol and ApoAI concentrations than non-CAD subjects, but the differences were not significant in all groups. Plasma concentrations of ApoE and lipoprotein (a) were not consistently correlated with CAD. In contrast, the ratio of HDL-ApoCIII to very-low-density lipoprotein (VLDL)-ApoCIII was the only universal determinant for CAD in the normolipidemic group (P=0.0018), the hypertriglyceridemic group (P=0.0001), the hypercholesterolemic group (P=0.0001), and the hyperlipidemic group (P=0.0001). Overall, a high HDL-ApoCIII/VLDL-ApoCIII ratio was observed in all CAD patients, including those with a normal lipid profile. In multivariate analyses, the HDL-ApoCIII/VLDL-ApoCIII ratio was the strongest predictor for CAD among all lipid factors investigated (odds ratio, 2.04; 95% confidence interval, 1.46–2.84; P<0.0001).
Conclusions
A high HDL-ApoCIII to VLDL-ApoCIII ratio is a better marker for predicting CAD than are the conventional lipid markers or ApoAI and ApoB. High HDL-ApoCIII and low VLDL-ApoCIII values in CAD, irrespective of lipid variations, suggest that ApoCIII is markedly transported from VLDL to HDL in this disease. Measurement of plasma ApoCIII may improve CAD prediction in the general population.
doi:10.1186/1476-511X-11-162
PMCID: PMC3543287  PMID: 23173569
Apolipoproteins; Coronary artery disease; Lipoproteins; Cardiovascular risk factors; Chin-Shan Community Cardiovascular Cohort (CCCC) Study; High-density lipoprotein (HDL); Very-low-density lipoprotein (VLDL); Apolipoprotein CIII (ApoCIII)
15.  Relationship between Bone Mineral Density and Serum Osteoprotegerin in Patients with Chronic Heart Failure 
PLoS ONE  2012;7(8):e44242.
Purpose
Heart failure (HF) had been reported with increased risk of hip fractures. However, the relationship between circulating biomarkers and bone mineral density (BMD) in chronic HF remained unclear.
Methods
This is a cross-sectional study which recruited stable chronic HF from registry of the Heart Failure Center of National Taiwan University Hospital. Patients underwent dual-energy x-ray absorptiometry (DEXA) measurements at hip and lumbar spines and biochemical assessments including B-type natriuretic peptide (BNP-32), myostatin, follistatin and osteoprotegerin (OPG).
Results
A total of 115 stable chronic HF individuals with left ventricular ejection fraction (EF) <45% (74% of male, mean age at 59) were recruited with 24 patients in NYHA class I, 73 patients in NYHA class II and 18 patients in NYHA class III. Results of BMD showed that Z scores of hip in NYHA III group (−0.12±1.15) was significantly lower than who were NYHA II (0.58±1.04). Serum OPG was significantly higher in subjects of NYHA III (9.3±4.6 pmol/l) than NYHA II (7.4±2.8 pmol/l) or NYHA I (6.8±3.6 pmol/l) groups. There’s a significant negative association between log transformed serum OPG and trochanteric BMD (R = −0.299, P = 0.001), which remained significant after multivariate analysis.
Conclusions
Our study demonstrated an inverse association between serum OPG and trochanteric BMD in patients with HF. OPG may be a predictor of BMD and an alternative to DEXA for identifying at risk HF patients for osteoporosis.
doi:10.1371/journal.pone.0044242
PMCID: PMC3431321  PMID: 22957004
16.  Differential effects of the changes of LDL cholesterol and systolic blood pressure on the risk of carotid artery atherosclerosis 
Background
The effects of baseline and changes in blood pressure and low density lipoprotein (LDL) cholesterol on the carotid intima media thickness (IMT) have not been well documented.
Methods
A total of 2572 adults (mean age 53.8 years, 54.6% women) in a Taiwanese community undertook three blood pressure and LDL cholesterol examinations over 6 years. Latent growth curve modeling was used to investigate the effects of baseline and change in blood pressure and LDL cholesterol on IMT.
Results
Greater baseline LDL and blood pressure were associated with an increase in IMT (0.005 ± 0.002 mm per 1 mg/dL [p = 0.006] and 0.041 ± 0.004 mm mmHg [p <0.0001], respectively. Change in blood pressure was associated with a significant increase in IMT (0.047±0.016, P = 0.004), whilst the association between change in LDL and change in IMT was not statistically significant (0.008±0.006, P = 0.20).
Conclusions
Carotid IMT was associated with baseline blood pressure and LDL cholesterol, yet only changes of blood pressure, not LDL cholesterol, were related to carotid IMT during the 6-year observation.
doi:10.1186/1471-2261-12-66
PMCID: PMC3445849  PMID: 22900906
Latent growth curve modeling; Carotid intima media thickness; Blood pressure; LDL cholesterol
17.  Lipid-related residual risk and renal function for occurrence and prognosis among patients with first-event acute coronary syndrome and normal LDL cholesterol 
Background
We investigated relationship of low levels of high density lipoprotein cholesterol (HDL-C), high levels of triglycerides, and renal function for the odds, prognosis and survival following acute coronary events among patients with a first event and normal low density lipoprotein cholesterol levels.
Results
A case-control study based on 557 patients and 1086 matched control subjects was conducted. Case patients were followed up for survival with a median of 1.9 years. Participants in the higher quintiles of HDL-C had lower odds to develop acute coronary events (the adjusted odds ratios were 0.24 for the second, 0.24 for the third, 0.10 for the fourth and 0.05 for the fifth quintile). Patients with normal glomerular filtration rate were at a lower risk for all-cause death. However, a reverse association between triglycerides and death risk was found: patients with higher triglycerides were at a lower risk for all-cause death (adjusted relative risk, 0.38 for triglycerides ranging from 82 to 132.9 mg/dL, and 0.14 for triglycerides > = 133 mg/dL).
Conclusions
Low HDL-C was significantly associated with acute coronary events, and triglyceride levels as well as renal function were inversely related to all-cause deaths after the coronary event.
doi:10.1186/1476-511X-10-215
PMCID: PMC3235983  PMID: 22099211
acute coronary syndrome; residual risk; dyslipidemia
18.  Arterial function of carotid and brachial arteries in postmenopausal vegetarians 
Background:
Vegetarianism is associated with a lower risk of cardiovascular disease. However, studies of arterial function in vegetarians are limited.
Methods:
This study investigated arterial function in vegetarianism by comparing 49 healthy postmenopausal vegetarians with 41 age-matched omnivores. The arterial function of the common carotid artery was assessed by carotid duplex, while the pulse dynamics method was used to measure brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR). Fasting blood levels of glucose, lipids, lipoprotein (a), high-sensitivity C-reactive protein, homocysteine, and vitamin B12 were also measured.
Results:
Vegetarians had significantly lower serum cholesterol, high-density and low-density lipoprotein, and glucose compared with omnivores. They also had lower vitamin B12 but higher homocysteine levels. Serum levels of lipoprotein (a) and high-sensitivity C-reactive protein were no different between the two groups. There were no significant differences in carotid beta stiffness index, BAC, and BAD between the two groups even after adjustment for associated covariates. However, BAR was significantly lower in vegetarians than in omnivores. Multiple linear regression analysis revealed that age and pulse pressure were two important determinants of carotid beta stiffness index and BAD. Vegetarianism is not associated with better arterial elasticity.
Conclusion:
Apparently healthy postmenopausal vegetarians are not significantly better in terms of carotid beta stiffness index, BAC, and BAD, but have significantly decreased BAR than omnivores. Prevention of vitamin B12 deficiency might be beneficial for cardiovascular health in vegetarians.
doi:10.2147/VHRM.S18881
PMCID: PMC3166191  PMID: 21915169
postmenopausal women; vegetarians; carotid stiffness; brachial arterial distensibility
19.  The relation of aminoterminal propeptide of type III procollagen and heart rate variability parameters in heart failure patients: A potential serum marker to evaluate cardiac autonomic control and sudden cardiac death 
Background
Cardiac extra-cellular matrix (ECM) fibrosis plays an important role in the pathophysiology of heart failure (HF). It may provide electrical heterogeneity and substrate for arrhythmogenicity, which may cause sudden cardiac death (SCD).
Methods
Twenty-one Patients with HF manifestations, and left ventricular ejection fraction (LVEF) ≤ 50% were enrolled. The median age was 62 years and median LVEF was 33 %. Time- and frequency-domain analysis of heart rate variability (HRV) on 24-hour ambulatory electrocardiography recording was assessed. Serum markers of ECM turnover including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were analyzed.
Results
The serum PIIINP level was significantly correlated with standard deviation of all normal RR intervals (SDNN) (r=−0.722, p=<0.001), percentage of adjacent NN interval differences >50 ms (pNN50) (r=−0.528, p=0.014), percentage of adjacent NN interval differences >20 ms (pNN20) (r=−0.545, p=0.002), very low frequency (VLF) (r=−0.490, p=0.024), low frequency (LF) (r=−0.491, p=0.024), high frequency (HF) (r=−0.513, p=0.018). PINP, MMP-2, 9, TIMP-1 were not correlated with time- and frequency-domain analysis of HRV.
Conclusions
PIIINP was significantly correlated with time- and frequency-domain analysis of HRV in HF patients. PIIINP is a potential serological marker to evaluate cardiac autonomic control and risk of SCD in HF patients.
doi:10.1515/CCLM.2010.348
PMCID: PMC3141296  PMID: 20846104
extra-cellular matrix; heart failure; collagen; HRV
20.  Plasma fatty acids and the risk of metabolic syndrome in ethnic Chinese adults in Taiwan 
Background
Evidence of predictive power of various fatty acids on the risk of metabolic syndrome was scanty. We evaluated the role of various fatty acids, including saturated fat, monounsaturated fat, transfat, n-6 fatty acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for the risk of the metabolic syndrome in Taiwan.
Results
A nested case-control study based on 1000 cases of metabolic syndrome and 1:1 matched control subjects. For saturated fat, monounsaturated fat and transfat, the higher the concentration the higher the risk for metabolic syndrome: participants in the highest quintile had a 2.22-fold (95% confidence interval [CI], 1.66 to 2.97) higher risk of metabolic syndrome. In addition, the participants in higher EPA quintiles were less likely to have the risk of metabolic syndrome (adjusted risk, 0.46 [0.34 to 0.61] for the fifth quintile). Participants in the highest risk group (low EPA and high transfat) had a 2.36-fold higher risk of metabolic syndrome (95% CI, 1.38 to 4.03), compared with those in the lowest risk group (high EPA and low transfat). For prediction power, the area under ROC curves increased from 0.926 in the baseline model to 0.928 after adding fatty acids. The net reclassification improvement for metabolic syndrome risk was substantial for saturated fat (2.1%, P = 0.05).
Conclusions
Plasma fatty acid components improved the prediction of the metabolic syndrome risk in Taiwan.
doi:10.1186/1476-511X-10-33
PMCID: PMC3056817  PMID: 21333029
21.  Prediction model for high glycated hemoglobin concentration among ethnic Chinese in Taiwan 
Background
This study aimed to construct a prediction model to identify subjects with high glycated hemoglobin (HbA1c) levels by incorporating anthropometric, lifestyle, clinical, and biochemical information in a large cross-sectional ethnic Chinese population in Taiwan from a health checkup center.
Methods
The prediction model was derived from multivariate logistic regression, and we evaluated the performance of the model in identifying the cases with high HbA1c levels (> = 7.0%). In total 17,773 participants (age > = 30 years) were recruited and 323 participants (1.8%) had high HbA1c levels. The study population was divided randomly into two parts, with 80% as the derivation data and 20% as the validation data.
Results
The point-based clinical model, including age (maximal 8 points), sex (1 point), family history (3 points), body mass index (2 points), waist circumference (4 points), and systolic blood pressure (3 points) reached an area under the receiver operating characteristic curve (AUC) of 0.723 (95% confidence interval, 0.677- 0.769) in the validation data. Adding biochemical measures such as triglycerides and HDL cholesterol improved the prediction power (AUC, 0.770 [0.723 - 0.817], P = < 0.001 compared with the clinical model). A cutoff point of 7 had a sensitivity of 0.76 to 0.96 and a specificity of 0.39 to 0.63 for the prediction model.
Conclusions
A prediction model was constructed for the prevalent risk of high HbA1c, which could be useful in identifying high risk subjects for diabetes among ethnic Chinese in Taiwan.
doi:10.1186/1475-2840-9-59
PMCID: PMC2955643  PMID: 20875098
22.  Cell therapy generates a favourable chemokine gradient for stem cell recruitment into the infarcted heart in rabbits 
European Journal of Heart Failure  2009;11(3):238-245.
Aims
Stem cell recruitment into the heart is determined by a concentration gradient of stromal-derived factor 1 (SDF-1) from bone marrow to peripheral blood and from blood to injured myocardium. However, this gradient is decreased in chronic myocardial infarction (MI). This study evaluated the effect of cell therapy using bone marrow stromal cells (BMSCs) on an SDF-1 gradient in post-infarction rabbits.
Methods and results
Myocardial infarction was induced in male New Zealand white rabbits (2.5–3 kg) by ligation of the left anterior descending coronary artery. Two months later, the rabbits were randomized to either saline or BMSC (2 × 106 autologous BMSCs injected into the left ventricular cavity) treatment. Four weeks after therapy, the SDF-1 gradients from bone marrow to blood and from blood to myocardium increased in the BMSC group compared with the saline group. This was accompanied by an increase in cells positive for CD34, CD117, and STRO-1 in the myocardium, resulting in more capillary density, better cardiac function, and a decrease in infarct size.
Conclusion
Generation of an SDF-1 gradient towards the heart is a novel effect of BMSC-based cell therapy. This effect facilitates stem cell recruitment into remodelled myocardium and supports improvement in cardiac function.
doi:10.1093/eurjhf/hfn035
PMCID: PMC2645052  PMID: 19147447
Stromal-derived factor 1; Bone marrow stromal cell; Myocardial infarction; Ventricular remodelling
23.  Carotid Artery Intima-Media Thickness, Carotid Plaque and Coronary Heart Disease and Stroke in Chinese 
PLoS ONE  2008;3(10):e3435.
Background
Our aim was to prospectively investigate the association between carotid artery intima-media thickness (IMT) as well as carotid plaque and incidence of coronary heart disease (CHD) and stroke in Chinese, among whom data are limited.
Methods and Findings
We conducted a community-based cohort study composed of 2190 participants free of cardiovascular disease at baseline in one community. During a median 10.5-year follow up, we documented 68 new cases of coronary heart disease and 94 cases of stroke. The multivariate relative risks (RRs) associated with a change of 1 standard deviation of maximal common carotid IMT were 1.38 (95% confidence interval [CI], 1.12–1.70) for CHD and 1.47 (95% CI, 1.28–1.69) for stroke. The corresponding RRs with internal carotid IMT were 1.47 (95% CI, 1.21–1.79) for CHD and 1.52 (95% CI, 1.31–1.76) for stroke. Carotid plaque measured by the degree of diameter stenosis was also significantly associated with increased risk of CHD (p for trend<0.0001) and stroke (p for trend<0.0001). However, these associations were largely attenuated when adjusting for IMT measurements.
Conclusions
This prospective study indicates a significant association between carotid IMT and incidence of CHD and stroke in Chinese adults. These measurements may be useful for cardiovascular risk assessment and stratification in Chinese.
doi:10.1371/journal.pone.0003435
PMCID: PMC2562458  PMID: 18927612
24.  Heritability and major gene effects on left ventricular mass in the Chinese population: a family study 
Background
Genetic components controlling for echocardiographically determined left ventricular (LV) mass are still unclear in the Chinese population.
Methods
We conducted a family study from the Chin-San community, Taiwan, and a total of 368 families, 1145 subjects, were recruited to undergo echocardiography to measure LV mass. Commingling analysis, familial correlation, and complex segregation analysis were applied to detect component distributions and the mode of inheritance.
Results
The two-component distribution model was the best-fitting model to describe the distribution of LV mass. The highest familial correlation coefficients were mother-son (0.379, P < .0001) and father-son (0.356, P < .0001). Genetic heritability (h2) of LV mass was estimated as 0.268 ± 0.061 (P < .0001); it decreased to 0.153 ± 0.052 (P = .0009) after systolic blood pressure adjustment. Major gene effects with polygenic components were the best-fitting model to explain the inheritance mode of LV mass. The estimated allele frequency of the gene was 0.089.
Conclusion
There were significant familial correlations, heritability and a major gene effect on LV mass in the population-based families.
doi:10.1186/1471-2261-6-37
PMCID: PMC1579230  PMID: 16945138
25.  Interaction of obesity, metabolic syndrome and Framingham risk on steatohepatitis among healthy Taiwanese: population-based nested case-control study 
Background
There have been scant reports on the cumulative effects of atherosclerotic risk factors on steatohepatitis.
Methods
We defined cases of steatohepatitis (n = 124) from one health examination center at National Taiwan University Hospital from January to December 2002. We selected controls, matched by age, gender and drinking status. Metabolic syndrome was defined by the modified ATP-III guidelines. High-dimensional interactions of risk factors for steatohepatitis were evaluated.
Results
Steatohepatitis cases had the highest C-reactive protein, lymphocytes, Framingham scores and predicted coronary risks. The odds ratio (OR) of metabolic syndrome for steatohepatitis was the highest (OR = 9.9), followed by high glucose status (OR = 4.5) and obesity (OR = 3.6). The highest area under the ROC curve was metabolic syndrome (area = 0.80), followed by obesity (0.75) and high glucose level (0.73). Metabolic syndrome was the highest population-attributable risk factor (0.59). Significant interaction was found with a three-factor model, including obesity, metabolic syndrome and Framingham risk status, with lesser average prediction error (22.6%), higher average cross-validation consistency (6.3) and lower average prediction error (24.3%). Compared with persons with no risk factors, OR increased as the number of risk factors increased (OR = 3.0 with one risk factor, 17.5 with two risk factors, 10.8 with three risk factors, respectively).
Conclusion
Metabolic syndrome, inflammation markers and atherosclerotic risk scores are significantly related to steatohepatitis status among the healthy examinee population in Taiwan.
doi:10.1186/1475-2840-5-12
PMCID: PMC1481540  PMID: 16707022

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