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1.  Mortality Benefit of a Fourth-Generation Synchronous Telehealth Program for the Management of Chronic Cardiovascular Disease: A Longitudinal Study 
We have shown that a fourth-generation telehealth program that analyzes and responds synchronously to data transferred from patients is associated with fewer hospitalizations and lower medical costs. Whether a fourth-generation telehealth program can reduce all-cause mortality has not yet been reported for patients with chronic cardiovascular disease.
We conducted a clinical epidemiology study retrospectively to determine whether a fourth-generation telehealth program can reduce all-cause mortality for patients with chronic cardiovascular disease.
We enrolled 576 patients who had joined a telehealth program and compared them with 1178 control patients. A Cox proportional hazards model was fitted to analyze the impact of risk predictors on all-cause mortality. The model adjusted for age, sex, and chronic comorbidities.
There were 53 (9.3%) deaths in the telehealth group and 136 (11.54%) deaths in the control group. We found that the telehealth program violated the proportional hazards assumption by the Schoenfeld residual test. Thus, we fitted a Cox regression model with time-varying covariates. The results showed an estimated hazard ratio (HR) of 0.866 (95% CI 0.837-0.896, P<.001; number needed to treat at 1 year=55.6, 95% CI 43.2-75.7 based on HR of telehealth program) for the telehealth program on all-cause mortality after adjusting for age, sex, and comorbidities. The time-varying interaction term in this analysis showed that the beneficial effect of telehealth would increase over time.
The results suggest that our fourth-generation telehealth program is associated with less all-cause mortality compared with usual care after adjusting for chronic comorbidities.
PMCID: PMC4909389  PMID: 27177497
cardiovascular diseases; telemedicine; all-cause mortality; outcome assessment (health care)
2.  Nonalcoholic Fatty Liver Disease Is Associated With QT Prolongation in the General Population 
Nonalcoholic fatty liver disease (NAFLD) is independently associated with QT prolongation among patients with diabetes. It has not yet been determined whether this association remains valid in the general population. We designed an observational study to explore this association.
Methods and Results
We conducted a cross-sectional analysis of 31 116 consecutive participants in our health management program. Heart rate–corrected QT (QTc) interval was derived from 12-lead electrocardiography and by Bazett’s formula. NAFLD was diagnosed by abdominal ultrasonography and classified as none, mild, moderate, or severe, according to the ultrasonographic criteria. A multivariable linear regression model was fitted for the association between QTc interval and potential predictors (including demographic, anthropometric, biochemical factors, and comorbidities). Multivariable logistic regression analyses were fitted to assess the association between the severity of NAFLD and QTc prolongation, with the adjustment of significant predictors derived from multivariable linear regression. The mean QTc interval was 421.3 ms (SD 45.4 ms). In the multivariable linear regression analyses, mild, moderate, and severe NAFLD were associated with increases of 2.55, 6.59, and 12.13 ms, respectively, in QTc interval compared with no NAFLD (all P<0.001). In the multivariable logistic regression analyses, mild, moderate, and severe NAFLD were associated with an increased risk for QTc prolongation, with odds ratios of 1.11 (95% CI: 1.01 to 1.21, P<0.05), 1.61 (95% CI: 1.36 to 1.9, P<0.001), and 1.31 (95% CI: 1.16 to 2.24, P<0.01), respectively, in women, and 1.11 (95% CI: 1.01 to 1.21, P<0.05), 1.39 (95% CI: 1.22 to 1.59, P<0.001), and 1.87 (95% CI: 1.16 to 2.24, P<0.001), respectively, in men, after adjusting for predictors known to be associated with the QTc interval. The association remained significant among subgroups with or without diabetes.
The severity of NAFLD was associated with a higher risk for QTc prolongation in the general population with and without diabetes.
PMCID: PMC4608068  PMID: 26199227
diabetes; general population; nonalcoholic fatty liver disease; QT prolongation
3.  Assessment of the Cost-Effectiveness and Clinical Outcomes of a Fourth-Generation Synchronous Telehealth Program for the Management of Chronic Cardiovascular Disease 
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.
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.
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.
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.
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.
PMCID: PMC4071228  PMID: 24915187
cardiovascular disease; cost-benefit analysis; telehealth
4.  Risk of hip/femur fractures during the initiation period of α-adrenoceptor blocker therapy among elderly males: a self-controlled case series study 
This study aimed to evaluate the risk of hip/femur fractures during the initiation period of α-adrenoceptor blocker therapy using the National Health Insurance claims database, Taiwan, with a self-controlled case series design.
All male beneficiaries aged over 50 years as of 2007, who were incident users of α-adrenoceptor blockers and also had a diagnosis of hip/femur fracture within the 2007–2009 study period were identified. The first day when the α-adrenoceptor blocker was prescribed was set as the index date. We partitioned the initial 21 day period following the index date as the post-exposure risk period 1, days 22–60 after the index date as the post-exposure risk period 2, the 21 day period prior to the index date as the pre-exposure risk period 1 and days 22–60 prior to the index date as the pre-exposure risk period 2. The remainder of the study period was defined as the unexposed period. The incidence rate ratio (IRR) of hip/femur fractures within each risk period compared with the unexposed period was estimated using a conditional Poisson regression model.
A total of 5875 men were included. Compared with the unexposed period, the IRR of hip/femur fractures was 1.36 (95% confidence interval 1.06, 1.74, P = 0.017) within the post-exposure risk period 1 for patients without concomitant prescriptions of anti-hypertensive agents.
Use of α-adrenoceptor blockers was associated with a small but significant increase in the risk of hip/femur fractures during the early initiation period in patients without concomitant prescriptions of anti-hypertensive agents.
PMCID: PMC4631193  PMID: 25924025
adrenergic α1-receptor antagonists; femoral fractures; hip fractures; self-controlled case series design
5.  Postprandial Glucose Improves the Risk Prediction of Cardiovascular Death Beyond the Metabolic Syndrome in the Nondiabetic Population 
Diabetes Care  2009;32(9):1721-1726.
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.
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.
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.
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.
PMCID: PMC2732157  PMID: 19502543
6.  Increased risk of ischemic heart disease among subjects with cataracts 
Medicine  2016;95(28):e4119.
Association between cataract and the risk of ischemic heart disease (IHD) development is not completely clear.
The primary aim of the study was to evaluate the association between cataract and the risk of incident IHD. The secondary aim was to investigate the subsequent IHD risk of patients with cataracts undergoing cataract surgery.
Retrospective data from the Longitudinal Health Insurance Database 2000 (LHID2000) was analyzed. Study participants were composed of patients with cataracts (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 366) (n = 32,456), and a comparison cohort without the cataracts (n = 32,456) from 2000 to 2010. Cox proportional hazards regression was used to address the hazard ratio (HR) of IHD associated with cataract.
Within 12 years of follow up, the overall incidence rates of IHD were 24.2 per 1000 person-years in the cataract cohort and 18.2 per 1000 person-years in the noncataract cohort with an adjusted hazard ratio (aHR) of 1.35 (95% CI = 1.29–1.41; P < 0.001). Furthermore, the cataract patients undergoing cataract surgery were associated with a higher risk of IHD compared with those cataract patients without surgery (aHR = 1.07, 95% CI: 1.01–1.14; P < 0.05).
Our finding suggested that patients with cataracts are at an increased risk of subsequent IHD development.
PMCID: PMC4956792  PMID: 27428198
cataract; cataract surgery; cohort study; incidence; ischemic heart disease
7.  Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease 
We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA 2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA 2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.
Methods and Results
Plasma Lp‐PLA 2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA 2 activity levels and outcomes. At baseline, the median Lp‐PLA 2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA 2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA 2 activity. There were no associations between on‐treatment Lp‐PLA 2 activity or changes of Lp‐PLA 2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA 2 activity or changes in Lp‐PLA 2 activity levels and the effects of darapladib on outcomes.
Although high Lp‐PLA 2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA 2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA 2 activity.
Clinical Trial Registration
URL: Unique identifier: NCT00799903.
PMCID: PMC4937279  PMID: 27329448
atherosclerosis; coronary disease; inflammation; lipoprotein; myocardial infarction; Biomarkers; Coronary Artery Disease; Pharmacology; Treatment; Risk Factors
8.  Risk of ischemic stroke during the initiation period of α-blocker therapy among older men 
Alpha-blockers are notorious for their first-dose effect of acute hypotension during the early initiation period. Because acute cerebral hypoperfusion may precipitate an episode of ischemic stroke, we aimed to provide a quantitative estimate of the risk of ischemic stroke during the early initiation period of α-blocker therapy, using a self-controlled case series design.
We identified all men aged 50 years or more as of 2007 who were incident users of α-blockers and had a diagnosis of ischemic stroke during the 2007–2009 study period using claims data from Taiwan’s National Health Insurance claims database. The first day on which the α-blocker was prescribed was the index date. We partitioned different risk periods according to their relationship to the index date (pre-exposure risk periods 1 and 2 = ≤ 21 d and 22–60 d before index date, respectively; post-exposure risk periods 1 and 2 = ≤ 21 d and 22–60 d after index date, respectively); the remainder of the study period was defined as the unexposed period. We estimated the incidence rate ratio (IRR) of ischemic stroke in each risk period relative to the unexposed period using a conditional Poisson regression model.
A total of 7502 men were included. Compared with the risk in the unexposed period, the risk of ischemic stroke was increased in post-exposure risk period 1 among all patients in the study population (adjusted IRR 1.40, 95% confidence interval [CI], 1.22–1.61) and among patients without concomitant prescriptions for other antihypertensive agents (adjusted IRR 2.11, 95% CI 1.73–2.57).
Alpha-blocker therapy was associated with an increased risk of ischemic stroke during the early initiation period, especially among patients who were not taking other antihypertensive agents.
PMCID: PMC4771534  PMID: 26644502
9.  Clinical Outcomes in Low Risk Coronary Artery Disease Patients Treated with Different Limus-Based Drug-Eluting Stents - A Nationwide Retrospective Cohort Study Using Insurance Claims Database 
PLoS ONE  2015;10(4):e0122860.
The clinical outcomes of different limus-based drug-eluting stents (DES) in a real-world setting have not been well defined. The aim of this study was to investigate the clinical outcomes of three different limus-based DES, namely sirolimus-eluting stent (SES), Endeavor zotarolimus-eluting stent (E-ZES) and everolimus-eluting stent (EES), using a national insurance claims database. We identified all patients who received implantation of single SES, E-ZES or EES between January 1, 2007 and December 31, 2009 from the National Health Insurance claims database, Taiwan. Follow-up was through December 31, 2011 for all selected clinical outcomes. The primary end-point was all-cause mortality. Secondary end-points included acute coronary events, heart failure needing hospitalization, and cerebrovascular disease. Cox regression model adjusting for baseline characteristics was used to compare the relative risks of different outcomes among the three different limus-based DES. Totally, 6584 patients were evaluated (n=2142 for SES, n=3445 for E-ZES, and n=997 for EES). After adjusting for baseline characteristics, we found no statistically significant difference in the risk of all-cause mortality in three DES groups (adjusted hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 0.94-1.38, p=0.20 in E-ZES group compared with SES group; adjusted HR: 0.77, 95% CI: 0.54-1.10, p=0.15 in EES group compared with SES group). Similarly, we found no difference in the three stent groups in risks of acute coronary events, heart failure needing hospitalization, and cerebrovascular disease. In conclusion, we observed no difference in all-cause mortality, acute coronary events, heart failure needing hospitalization, and cerebrovascular disease in patients treated with SES, E-ZES, and EES in a real-world population-based setting in Taiwan.
PMCID: PMC4388589  PMID: 25848942
10.  Total 25-Hydroxyvitamin D Concentration as a Predictor for All-Cause Death and Cardiovascular Event Risk among Ethnic Chinese Adults: A Cohort Study in a Taiwan Community 
PLoS ONE  2015;10(3):e0123097.
Evidence of an inverse association between serum 25-hydoroxyvitamin D [25(OH)D] and the risk of all-cause death and cardiovascular disease from prospective studies is inconsistent. We tested the relationship between 25(OH)D and the risk among adult ethnic Chinese in Taiwan.
We conducted a community-based cohort study of 1816 participants (age 60.2±10.2 yrs, 45.0% women) in the Chin-Shan Community Cardiovascular Cohort Study who were free of cardiovascular diseases at baseline and provided 25(OH)D measurements.
During a median 9.6 (interquartile range, 8.8- 10.5) years’ follow-up period, totally 263 cases developed cardiovascular death events and 559 participants were documented to death from any cause. As 25(OH)D concentration increased, the incidence rates of cardiovascular events and all-cause death decreased progressively. 25(OH)D was inversely associated with all-cause death: the adjusted hazard ratio was 0.49 (95% confidence interval [CI], 0.25-0.97) for the third quartile and a significant J-shape relationship was found. The performance measures by integrated discriminative improvement showed significant improvement after adding 25(OH)D information (0.14%, 95% CI, 0.03-0.31, P=0.050, for all-cause death and 0.32%, 95% CI, 0.02-0.62, P=0.018 for cardiovascular events).
These findings suggested a modest inverse association between 25(OH)D and the risk of all-cause death among diabetic participants and a good predictive factor in the community. Further studies to investigate the mechanism of vitamin D role on health effect are warranted.
PMCID: PMC4373875  PMID: 25807387
11.  N-3 polyunsaturated fatty acids decrease levels of doxorubicin-induced reactive oxygen species in cardiomyocytes -- involvement of uncoupling protein UCP2 
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.
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.
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.
PMCID: PMC4237738  PMID: 25407516
EPA; DHA; Doxorubicin; ROS; UCP2
12.  Measurement of Visceral Fat: Should We Include Retroperitoneal Fat? 
PLoS ONE  2014;9(11):e112355.
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.
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.
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.
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.
PMCID: PMC4234414  PMID: 25401949
13.  Multi-scale symbolic entropy analysis provides prognostic prediction in patients receiving extracorporeal life support 
Critical Care  2014;18(5):548.
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.
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.
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.
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.
PMCID: PMC4221713  PMID: 25341381
14.  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.
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.
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.
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).
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.
PMCID: PMC4026442  PMID: 24842767
15.  Enigmatic Ectopic Fat: Prevalence of Nonalcoholic Fatty Pancreas Disease and Its Associated Factors in a Chinese Population 
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.
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.
PMCID: PMC3959709  PMID: 24572250
diabetes; nonalcoholic fatty liver disease; nonalcoholic fatty pancreas disease; obesity
16.  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.
PMCID: PMC4147635  PMID: 25170292
Gal-3; heart failure; MMP-2
17.  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.
PMCID: PMC3891226  PMID: 24459427
18.  The Association between Nonalcoholic Fatty Pancreas Disease and Diabetes 
PLoS ONE  2013;8(5):e62561.
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.
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.
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.
PMCID: PMC3643962  PMID: 23671610
19.  A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers 
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.
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.
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).
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.
PMCID: PMC3598308  PMID: 23414574
N-3 fatty acid; Biomarker; Food frequency questionnaire
20.  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.
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.
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.
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.
WBC and neutrophil count had a similar ability to predict the long-term ischemic stroke events among Taiwanese.
PMCID: PMC3641985  PMID: 23317415
White blood cell count; Neutrophil count; Ischemic stroke event
21.  Common sequence variants in CD36 gene and the levels of triglyceride and high-density lipoprotein cholesterol among ethnic Chinese in Taiwan 
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).
The CD36 gene variants were significantly associated with triglycerides and HDL-cholesterol concentrations among ethnic Chinese in Taiwan.
PMCID: PMC3575328  PMID: 23249574
Metabolic syndrome; CD 36 gene polymorphism
22.  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 
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.
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).
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).
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.
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)
23.  Relationship between Bone Mineral Density and Serum Osteoprotegerin in Patients with Chronic Heart Failure 
PLoS ONE  2012;7(8):e44242.
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.
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).
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.
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.
PMCID: PMC3431321  PMID: 22957004
24.  Differential effects of the changes of LDL cholesterol and systolic blood pressure on the risk of carotid artery atherosclerosis 
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.
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.
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).
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.
PMCID: PMC3445849  PMID: 22900906
Latent growth curve modeling; Carotid intima media thickness; Blood pressure; LDL cholesterol
25.  Lipid-related residual risk and renal function for occurrence and prognosis among patients with first-event acute coronary syndrome and normal LDL cholesterol 
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.
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).
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.
PMCID: PMC3235983  PMID: 22099211
acute coronary syndrome; residual risk; dyslipidemia

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