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1.  A Novel SNP Associated with Nighttime Pulse Pressure in Young-Onset Hypertension Patients Could Be a Genetic Prognostic Factor for Cardiovascular Events in a General Cohort in Taiwan 
PLoS ONE  2014;9(6):e97919.
Background
Pulse pressure (PP) is a risk factor for cardiovascular disease. It has been reported that ambulatory blood pressure (BP) and nighttime BP parameters are heritable traits. However, the genetic association of pulse pressure and its clinical impact remain undetermined.
Method and Results
We conducted a genome-wide association study of PP using ambulatory BP monitoring in young-onset hypertensive patients and found a significant association between nighttime PP and SNP rs897876 (p = 0.009) at chromosome 2p14, which contains the predicted gene FLJ16124. Young-onset hypertension patients carrying TT genotypes at rs897876 had higher nighttime PP than those with CT and CC genotypes (TT, 41.6±7.3 mm Hg; CT, 39.1±6.0 mm Hg; CC, 38.9±6.3 mm Hg; p<0.05,). The T risk allele resulted in a cumulative increase in nighttime PP (β = 1.036 mm Hg, se. = 0.298, p<0.001 per T allele). An independent community-based cohort containing 3325 Taiwanese individuals (mean age, 50.2 years) was studied to investigate the genetic impact of rs897876 polymorphisms in determining future cardiovascular events. After an average 7.79±0.28 years of follow-up, the TT genotype of rs897876 was independently associated with an increased risk (in a recessive model) of coronary artery disease (HR, 2.20; 95% CI, 1.20–4.03; p = 0.01) and total cardiovascular events (HR, 1.99; 95% CI, 1.29–3.06; p = 0.002), suggesting that the TT genotype of rs897876C, which is associated with nighttime pulse pressure in young-onset hypertension patients, could be a genetic prognostic factor of cardiovascular events in the general cohort.
Conclusion
The TT genotype of rs897876C at 2p14 identified in young-onset hypertensive had higher nighttime PP and could be a genetic prognostic factor of cardiovascular events in the general cohort in Taiwan.
doi:10.1371/journal.pone.0097919
PMCID: PMC4043733  PMID: 24892410
2.  Cardiovascular Events in Patients with Atherothrombotic Disease: A Population-Based Longitudinal Study in Taiwan 
PLoS ONE  2014;9(3):e92577.
Background
Atherothrombotic diseases including cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral arterial disease (PAD), contribute to the major causes of death in the world. Although several studies showed the association between polyvascular disease and poor cardiovascular (CV) outcomes in Asian population, there was no large-scale study to validate this relationship in this population.
Methods and Results
This retrospective cohort study included patients with a diagnosis of CVD, CAD, or PAD from the database contained in the Taiwan National Health Insurance Bureau during 2001–2004. A total of 19954 patients were enrolled in this study. The atherothrombotic disease score was defined according to the number of atherothrombotic disease. The study endpoints included acute coronary syndrome (ACS), all strokes, vascular procedures, in hospital mortality, and so on. The event rate of ischemic stroke (18.2%) was higher than that of acute myocardial infarction (5.7%) in our patients (P = 0.0006). In the multivariate Cox regression analyses, the adjusted hazard ratios (HRs) of each increment of atherothrombotic disease score in predicting ACS, all strokes, vascular procedures, and in hospital mortality were 1.41, 1.66, 1.30, and 1.14, respectively (P≦0.0169).
Conclusions
This large population-based longitudinal study in patients with atherothrombotic disease demonstrated the risk of subsequent ischemic stroke was higher than that of subsequent AMI. In addition, the subsequent adverse CV events including ACS, all stroke, vascular procedures, and in hospital mortality were progressively increased as the increase of atherothrombotic disease score.
doi:10.1371/journal.pone.0092577
PMCID: PMC3960266  PMID: 24647769
3.  Association of Bilateral Brachial-Ankle Pulse Wave Velocity Difference with Peripheral Vascular Disease and Left Ventricular Mass Index 
PLoS ONE  2014;9(2):e88331.
Unequal arterial stiffness had been associated with cardiovascular risks. We investigated whether an association existed between unequal arterial stiffness indicated by bilateral brachial-ankle pulse wave velocity (baPWV) difference and ankle-brachial index (ABI), baPWV, echocardiographic parameters and interarm and interankle systolic blood pressure (BP) differences. A total of 1111 patients referred for echocardiographic examination were included in this study. The BPs, ABI and baPWV were measured simultaneously by an ABI-form device. The ΔbaPWV was defined as absolute value of difference between bilateral baPWV. We performed three multivariate analyses for determining the factors associated with a ΔbaPWV ≧ 185 cm/s (90 percentile of ΔbaPWV) (model 1: significant variables in univariate analysis and ABI <0.9 and baPWV; model 2: significant variables in univariate analysis and left ventricular mass index [LVMI]; model 3: significant variables in univariate analysis and interankle systolic BP difference ≧ 15 mmHg). The ABI <0.9 and high baPWV (both P<0.001) in model 1, high LVMI (P = 0.021) in model 2 and an interankle systolic BP difference ≧ 15 mmHg (P = 0.026) in model 3 were associated with a ΔbaPWV ≧ 185 cm/s, but the interarm systolic BP difference ≧ 10 mmHg was not (P = NS). Our study demonstrated ABI <0.9, high baPWV, high LVMI and an interankle systolic BP difference ≧ 15 mmHg were associated with unequal arterial stiffness.
doi:10.1371/journal.pone.0088331
PMCID: PMC3923774  PMID: 24551090
4.  Mitral Tissue Inhibitor of Metalloproteinase 2 Is Associated with Mitral Valve Surgery Outcome 
PLoS ONE  2014;9(1):e86287.
Background
Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown.
Methods
This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0–2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission.
Results
Mean age was 50.4±13.7 years. After a mean follow-up period of 101±59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age (56.6±14.4 vs. 49.2±13.4 years, respectively; p = 0.013) and left ventricular end-systolic diameter (LVESD) (39.7±8.2 vs. 35.5±7.5 mm, p = 0.010) at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan–Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival (log-rank test; p = 0.004). Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.12–0.65; p = 0.003), age (HR 1.05; 95% CI 1.02–1.09; p = 0.003) and LVESD (HR 1.05; 95% CI 1.01–1.10; p = 0.020).
Conclusions
The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery.
doi:10.1371/journal.pone.0086287
PMCID: PMC3903512  PMID: 24475101
5.  Coronary Collateral Circulation in Patients of Coronary Ectasia with Significant Coronary Artery Disease 
PLoS ONE  2014;9(1):e87001.
Objectives
Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development.
Methods
We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.
Results
73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4±3.5 vs 26.7±4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96±0.84 vs 2.48±0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development.
Conclusion
The presence of CE was associated with poorer coronary collateral development in patients with SCAD.
doi:10.1371/journal.pone.0087001
PMCID: PMC3903606  PMID: 24475209
6.  The hOGG1 Ser326Cys Gene Polymorphism and the Risk of Coronary Ectasia in the Chinese Population 
Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04–2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE.
doi:10.3390/ijms15011671
PMCID: PMC3907892  PMID: 24451144
coronary ectasia; 8-oxoguanine DNA glycosylase; polymorphism
7.  Influence of high-density lipoprotein cholesterol on coronary collateral formation in a population with significant coronary artery disease 
BMC Research Notes  2013;6:105.
Background
Coronary collateral circulation plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. Low High-density lipoprotein cholesterol (HDL-C) level is a strong risk factor for coronary artery disease (CAD) and is associated with poor cardiovascular outcome. It was recently reported to be associated with poor coronary collateral development in Turkish population. Hence, we investigated the influence of HDL-C on coronary collateral formation in Chinese population.
Methods
We evaluated 970 consecutive patients undergoing coronary angiography, and 501 patients with significant coronary artery disease (SCAD) were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patient groups as those with poor or good collaterals.
Results
The patients with poor collaterals had fewer diseased vessels (1.97 ± 0.84 vs 2.47 ± 0.68, p < 0.001) and lower diffuse score (2.65 ± 1.63 vs 3.76 ± 1.78, p < 0.001). There was no significant difference in HDL-C and other variables between good and poor collaterals. Multivariate analysis showed only number of diseased vessels (odd ratio 0.411, p < 0.001) was a significant predictor of poor collateral development.
Conclusions
The extent of CAD severity but not HDL-C level was the most powerful predictor of coronary collateral formation in our Chinese population with SCAD.
doi:10.1186/1756-0500-6-105
PMCID: PMC3606844  PMID: 23510196
Coronary artery disease; Coronary collateral circulation; High-density lipoprotein cholesterol
8.  A Comparison between Brachial and Echocardiographic Systolic Time Intervals 
PLoS ONE  2013;8(2):e55840.
Systolic time interval (STI) is an established noninvasive technique for the assessment of cardiac function. Brachial STIs can be automatically determined by an ankle-brachial index (ABI)-form device. The aims of this study are to evaluate whether the STIs measured from ABI-form device can represent those measured from echocardiography and to compare the diagnostic values of brachial and echocardiographic STIs in the prediction of left ventricular ejection fraction (LVEF) <50%. A total of 849 patients were included in the study. Brachial pre-ejection period (bPEP) and brachial ejection time (bET) were measured using an ABI-form device and pre-ejection period (PEP) and ejection time (ET) were measured from echocardiography. Agreement was assessed by correlation coefficient and Bland-Altman plot. Brachial STIs had a significant correlation with echocardiographic STIs (r = 0.644, P<0.001 for bPEP and PEP; r  = 0.850, P<0.001 for bET and ET; r = 0.708, P<0.001 for bPEP/bET and PEP/ET). The disagreement between brachial and echocardiographic STIs (brachial STIs minus echocardiographic STIs) was 28.55 ms for bPEP and PEP, -4.15 ms for bET and ET and -0.11 for bPEP/bET and PEP/ET. The areas under the curve for bPEP/bET and PEP/ET in the prediction of LVEF <50% were 0.771 and 0.765, respectively. Brachial STIs were good alternatives to STIs obtained from echocardiography and also helpful in prediction of LVEF <50%. Brachial STIs automatically obtained from an ABI-form device may be helpful for evaluation of left ventricular systolic dysfunction.
doi:10.1371/journal.pone.0055840
PMCID: PMC3567004  PMID: 23409059
9.  Areca Nut Chewing and Risk of Atrial Fibrillation in Taiwanese Men: A Nationwide Ecological Study 
Background: Areca nut chewing is associated with the risk of obesity, metabolic syndrome, hypertension, and cardiovascular mortality. Although a few case reports or case series have suggested the link between areca nut chewing and cardiac arrhythmias, information about the relationship between areca nut chewing and atrial fibrillation (AF) is lacking. Thus, a nationwide ecological study was conducted to investigate this.
Methods: Two national datasets, the nationwide population-based 2005 Taiwan National Health Insurance Research dataset (NHIRD) and the 2005 National Health Interview Survey (NHIS), were used for analyses. The clinical characteristics, inhabited area and medical histories for 375,360 eligible males were retrieved from the 2005 NHIRD. Health related behaviors including areca nut chewing, cigarette smoking, infrequent vegetable eating, and exercise habit were collected from the 2005 NHIS. The prevalence of AF and the areca nut chewing rate were evaluated by multivariate analysis.
Results: Of the 375,360 males (mean age, 44 years old), 1,326 (0.35%) were diagnosed with AF. The higher areca nut chewing rate, the higher prevalence rate of AF in Taiwan (Spearman correlation coefficient r = 0.558, p = 0.007). After adjusting for other covariates, the current areca nut chewing rate was found to be independently associated with the prevalence of AF. The adjusted odd ratio for areca nut chewing was 1.02 (95% CI = 1.00-1.04) in risk of AF prevalence.
Conclusions: Areca nut chewing is independently associated with the prevalence of AF in Taiwanese men. However, further exploration of the underlying mechanisms is necessary.
doi:10.7150/ijms.5998
PMCID: PMC3689880  PMID: 23794944
atrial fibrillation; areca nut chewing.
10.  Heart Rate Significantly Influences the Relationship between Atrial Fibrillation and Arterial Stiffness 
Background. Atrial fibrillation (AF) and vascular disease share several risk factors and the two diseases often coexist. Heart rate (HR) is reported to be a major determinant of arterial stiffness. AF patients often have a transiently or persistently rapid HR. Hence, this study was to assess whether AF was significantly associated with arterial stiffness and HR could significantly influence the relationship between AF and arterial stiffness. Besides, we also determine the main correlates of arterial stiffness in AF patients and see whether HR was correlated with arterial stiffness in these patients.
Methods. We included 166 AF and 1336 non-AF patients from subjects arranged for echocardiographic examinations. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV).
Results. Compared to non-AF patients, AF patients had a higher baPWV (p <0.001). In a multivariate model, including covariates of age, sex, blood pressures and so on, the presence of AF was significantly associated with baPWV (β = 0.079, P = 0.001). However, further adjustment for HR made this association disappear (β = 0.005, P = 0.832). In addition to age and systolic blood pressure, increased HR (β = 0.309, p <0.001) was a major determinant of increased baPWV in our AF patients.
Conclusions. This study demonstrated the presence of AF was associated with increased baPWV, but this association became insignificant after further adjustment for HR, which suggested HR could significantly influence the relationship between AF and baPWV. Besides, HR was positively correlated with arterial stiffness in our AF patients.
doi:10.7150/ijms.6619
PMCID: PMC3753413  PMID: 23983588
atrial fibrillation; arterial stiffness; pulse wave velocity; heart rate
11.  Association of Increased Arterial Stiffness and P Wave Dispersion with Left Ventricular Diastolic Dysfunction 
Background: The association between increased arterial stiffness and left ventricular diastolic dysfunction (LVDD) may be influenced by left ventricular performance. P wave dispersion is not only a significant determinant of left ventricular performance, but is also correlated with LVDD. This study is designed to compare left ventricular diastolic function among patients divided by brachial-ankle pulse wave velocity (baPWV) and corrected P wave dispersion (PWDC) and assess whether the combination of baPWV and PWDC can predict LVDD more accurately.
Methods: This cross-sectional study enrolled 270 patients and classified them into four groups according to the median values of baPWV and PWDC. LVDD was defined as impaired relaxation and pseudonormal/restrictive mitral inflow patterns.
Results: The ratio of transmitral E wave velocity to early diastolic mitral annulus velocity (E/Ea) was higher in group with higher baPWV and PWDC than in the other groups (all p <0.001). The prevalence of LVDD was higher in group with higher baPWV and PWDC than in the two groups with lower baPWV (p ≤ 0.001). The baPWV and PWDC were correlated with E/Ea and LVDD in multivariate analysis (p ≤ 0.030). The addition of baPWV and PWDC to a clinical mode could significantly improve the R square in prediction of E/Ea and C statistic and integrated discrimination index in prediction of LVDD (p ≤ 0.010).
Conclusions: This study showed increased baPWV and PWDC were correlated with high E/Ea and LVDD. The addition of baPWV and PWDC to a clinical model improved the prediction of high E/Ea and LVDD. Screening patients by means of baPWV and PWDC might help identify the high risk group of elevated left ventricular filling pressure and LVDD.
doi:10.7150/ijms.5753
PMCID: PMC3775098  PMID: 24046515
brachial-ankle pulse wave velocity; P wave dispersion; left ventricular diastolic dysfunction.
12.  Association of Arterial Stiffness and Electrocardiography-Determined Left Ventricular Hypertrophy with Left Ventricular Diastolic Dysfunction 
PLoS ONE  2012;7(11):e49100.
Objectives
Increased arterial stiffness is associated with left ventricular diastolic dysfunction (LVDD), but this association may be influenced by left ventricular (LV) performance. Left ventricular hypertrophy (LVH) is not only a significant determinant of LV performance, but is also correlated with LVDD. This study is designed to compare LV diastolic function among patients divided by brachial-ankle pulse wave velocity (baPWV) and electrocardiography (ECG)-determined LVH and to assess whether increased baPWV and ECG-determined LVH are independently associated with LVDD.
Methods
This cross-sectional study enrolled 270 patients and classified them into four groups according to the median value of baPWV and with/without ECG-determined LVH. The baPWV was measured using an ABI-form device. ECG-determined LVH was defined by Sokolow-Lyon criterion. LVDD was defined as impaired relaxation, pseudonormal, and restrictive mitral inflow patterns. Groups 1, 2, 3, and 4 were patients with lower baPWV and without ECG-determined LVH, lower baPWV but with ECG-determined LVH, higher baPWV but without ECG-determined LVH, and higher baPWV and with ECG-determined LVH respectively.
Results
Early diastolic mitral velocity (Ea) was gradually decreased from group 1 to group 4 (p≦0.027). Patients in group 4 had the highest prevalence of LVDD (all p<0.001). After multivariate analysis, both baPWV and ECG-determined LVH were independent determinants of Ea (β = −0.02, P<0.001; β = −1.77, P<0.001 respectively) and LVDD (odds ratio = 1.02, P = 0.011 and odds ratio = 3.53, P = 0.013 respectively).
Conclusion
Our study showed the group with higher baPWV and ECG-determined LVH had the lowest Ea and highest prevalence of LVDD. In addition, both baPWV and ECG-determined LVH were independently associated with Ea and LVDD. Hence, assessment of arterial stiffness by baPWV and LVH by ECG may be useful in identifying the high risk group of LVDD.
doi:10.1371/journal.pone.0049100
PMCID: PMC3492305  PMID: 23145083
13.  Association of Chronic Kidney Disease and Peripheral Artery Disease with Inappropriate Left Ventricular Mass 
PLoS ONE  2012;7(10):e48422.
Inappropriate left ventricular mass index (LVM) may develop as a response to particular hemodynamic and metabolic alterations. Inappropriate LVM and peripheral artery disease (PAD) characterized by abnormally low or high ankle-brachial index (ABI) are common in chronic kidney disease (CKD) patients, in whom there may be a close and cause-effect relationship. The aim of this study is to assess whether CKD and abnormal ABI has an independent and additive association with inappropriate LVM. A total of 1110 patients were included in the study. Inappropriate LVM was defined as observed LVM more than 28% of the predicted value. The ABI was measured using an ABI-form device. PAD was defined as ABI <0.9 or >1.3 in either leg. Multivariate analysis showed that patients with estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2 (odds ratio [OR], 1.644; P = 0.011) and PAD (OR, 2.082; P = 0.002) were independently associated with inappropriate LVM. The interaction between eGFR <45 ml/min/1.73 m2 and PAD on inappropriate LVM was statistically significant (P = 0.044). Besides, eGFR<45 ml/min/1.73 m2 (change in observed/predicted LVM, 19.949; P<0.001) and PAD (change in observed/predicted LVM, 11.818; P = 0.003) were also significantly associated with observed/predicted LVM. Our findings show that eGFR <45 ml/min/1.73 m2 and PAD are independently and additively associated with inappropriate LVM and observed/predicted LVM. Assessments of eGFR and ABI may be useful in identifying patients with inappropriate LVM.
doi:10.1371/journal.pone.0048422
PMCID: PMC3485213  PMID: 23119010
14.  Nicorandil-Induced Hyperkalemia in a Uremic Patient 
Case Reports in Medicine  2012;2012:812178.
Nicorandil is an antianginal agent with nitrate-like and ATP-sensitive potassium channel activator properties. After activation of potassium channels, potassium ions are expelled out of the cells, which lead to membrane hyperpolarization, closure of voltage-gated calcium channels, and finally vasodilation. We present a uremic case suffering from repeated junctional bradycardia, especially before hemodialysis. After detailed evaluation, nicorandil was suspected to be the cause of hyperkalemia which induced bradycardia. This case reminds us that physicians should be aware of this potential complication in patients receiving ATP-sensitive potassium channel activator.
doi:10.1155/2012/812178
PMCID: PMC3483680  PMID: 23118767
15.  Abnormally Low and High Ankle-Brachial Indices Are Independently Associated with Increased Left Ventricular Mass Index in Chronic Kidney Disease 
PLoS ONE  2012;7(9):e44732.
Abnormally low and high ankle-brachial indices (ABIs) are associated with high cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), but the mechanisms responsible for the association are not fully known. This study is designed to assess whether there is a significant correlation between abnormal ABI and echocariographic parameters in patients with CKD stages 3–5. A total of 684 pre-dialysis CKD patients were included in the study. The ABI was measured using an ABI-form device. Patients were classified into ABI <0.9, ≥0.9 to <1.3, and ≥1.3. Clinical and echocariographic parameters were compared and analyzed. Compared with patients with ABI of ≥0.9 to <1.3, the values of left ventricular mass index (LVMI) were higher in patients with ABI <0.9 and ABI ≥1.3 (P≤0.004). After the multivariate analysis, patients with ABI <0.9 (β = 0.099, P = 0.004) and ABI ≥1.3 (β = 0.143, P<0.001) were independently associated with increased LVMI. Besides, increased LVMI (odds ratio, 1.017; 95% confidence interval, 1.002 to 1.033; P = 0.031) was also significantly associated with ABI <0.9 or ABI ≥1.3. Our study in patients of CKD stages 3–5 demonstrated abnormally low and high ABIs were positively associated with LVMI. Future studies are required to determine whether increased LVMI is a causal intermediary between abnormal ABI and adverse cardiovascular outcomes in CKD.
doi:10.1371/journal.pone.0044732
PMCID: PMC3434147  PMID: 22957102
16.  A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes 
Diabetes  2011;60(9):2417-2423.
OBJECTIVE
The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases.
RESEARCH DESIGN AND METHODS
We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350).
RESULTS
The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS.
CONCLUSIONS
These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.
doi:10.2337/db10-1321
PMCID: PMC3161336  PMID: 21771975
17.  Predictor of poor coronary collaterals in chronic kidney disease population with significant coronary artery disease 
BMC Nephrology  2012;13:98.
Background
Coronary collateral circulation plays an important role to protect myocardium from ischemia, preserve myocardial contractility and reduce cardiovascular events. Chronic kidney disease (CKD) is associated with poor coronary collateral development and cardiovascular outcome. However, limited research investigates the predictors for collateral development in the CKD population.
Methods
We evaluated 970 consecutive patients undergoing coronary angiography and 202 patients with CKD, defined as a glomerular filtration rate less than 60 ml/min/1.73 m2, were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.
Results
The patients with poor collateral (n = 122) had a higher incidence of hypertension (82% vs 63.8%, p = 0.005), fewer diseased vessels numbers (2.1 ± 0.9 vs 2.6 ± 0.6, p < 0.001) and a trend to be diabetic (56.6% vs. 43.8%, p = 0.085) or female sex (37.7% vs. 25.0%, p = 0.067). Multivariate analysis showed hypertension (odd ratio (OR) 2.672, p = 0.006), diabetes (OR 1.956, p = 0.039) and diseased vessels numbers (OR 0.402, p < 0.001) were significant predictors of poor coronary collaterals development. Furthermore, hypertension and diabetes have a negative synergistic effect on collateral development (p = 0.004 for interaction).
Conclusions
In the CKD population hypertension and diabetes might negatively influence the coronary collaterals development.
doi:10.1186/1471-2369-13-98
PMCID: PMC3457843  PMID: 22935602
Chronic kidney disease; Coronary artery disease; Coronary collateral circulation, Hypertension, Diabetes
18.  P Wave Dispersion and Maximum P Wave Duration Are Independently Associated with Rapid Renal Function Decline 
PLoS ONE  2012;7(8):e42815.
The P wave parameters measured by 12-lead electrocardiogram (ECG) are commonly used as noninvasive tools to assess for left atrial enlargement. There are limited studies to evaluate whether P wave parameters are independently associated with decline in renal function. Accordingly, the aim of this study is to assess whether P wave parameters are independently associated with progression to renal end point of ≥25% decline in estimated glomerular filtration rate (eGFR). This longitudinal study included 166 patients. The renal end point was defined as ≥25% decline in eGFR. We measured two ECG P wave parameters corrected by heart rate, i.e. corrected P wave dispersion (PWdisperC) and corrected P wave maximum duration (PWdurMaxC). Heart function and structure were measured from echocardiography. Clinical data, P wave parameters, and echocardiographic measurements were compared and analyzed. Forty-three patients (25.9%) reached renal end point. Kaplan-Meier curves for renal end point-free survival showed PWdisperC > median (63.0 ms) (log-rank P = 0.004) and PWdurMaxC > median (117.9 ms) (log-rank P<0.001) were associated with progression to renal end point. Multivariate forward Cox-regression analysis identified increased PWdisperC (hazard ratio [HR], 1.024; P = 0.001) and PWdurMaxC (HR, 1.029; P = 0.001) were independently associated with progression to renal end point. Our results demonstrate that increased PWdisperC and PWdurMaxC were independently associated with progression to renal end point. Screening patients by means of PWdisperC and PWdurMaxC on 12 lead ECG may help identify a high risk group of rapid renal function decline.
doi:10.1371/journal.pone.0042815
PMCID: PMC3428341  PMID: 22952614
19.  Association of Interarm Systolic Blood Pressure Difference with Atherosclerosis and Left Ventricular Hypertrophy 
PLoS ONE  2012;7(8):e41173.
An interarm systolic blood pressure (SBP) difference of 10 mmHg or more have been associated with peripheral artery disease and adverse cardiovascular outcomes. We investigated whether an association exists between this difference and ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), and echocardiographic parameters. A total of 1120 patients were included in the study. The bilateral arm blood pressures were measured simultaneously by an ABI-form device. The values of ABI and baPWV were also obtained from the same device. Clinical data, ABI<0.9, baPWV, echocariographic parameters, and an interarm SBP difference ≥10 mmHg were compared and analyzed. We performed two multivariate forward analyses for determining the factors associated with an interarm SBP difference ≥10 mmHg [model 1: significant variables in univariate analysis except left ventricular mass index (LVMI); model 2: significant variables in univariate analysis except ABI<0.9 and baPWV]. The ABI<0.9 and high baPWV in model 1 and high LVMI in model 2 were independently associated with an interarm SBP difference ≥10 mmHg. Female, hypertension, and high body mass index were also associated with an interarm SBP difference ≥10 mmHg. Our study demonstrated that ABI<0.9, high baPWV, and high LVMI were independently associated with an interarm SBP difference of 10 mmHg or more. Detection of an interarm SBP difference may provide a simple method of detecting patients at increased risk of atherosclerosis and left ventricular hypertrophy.
doi:10.1371/journal.pone.0041173
PMCID: PMC3426512  PMID: 22927905
20.  Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study 
PLoS ONE  2012;7(3):e32907.
Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.
doi:10.1371/journal.pone.0032907
PMCID: PMC3315540  PMID: 22479346
21.  Postchallenge responses of nitrotyrosine and TNF-alpha during 75-g oral glucose tolerance test are associated with the presence of coronary artery diseases in patients with prediabetes 
Background
Meta-analysis has demonstrated an exponential relationship between 2-hr postchallenge hyperglycemia and coronary artery disease (CAD). Pulsatile hyperglycemia can acutely increase proinflammatory cytokines by oxidative stress. We hypothesized that postchallenge proinflammatory and nitrosative responses after 75 g oral glucose tolerance tests (75 g-OGTT) might be associated with CAD in patients without previously recognized type 2 diabetes mellitus (T2DM).
Methods
Serial changes of plasma glucose (PG), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitrotyrosine levels were analyzed during 75 g-OGTT in 120 patients (81 male; age 62 ± 11 years) before coronary angiography. Patients were classified as normal (NGT; 42%), impaired (IGT; 34%) and diabetic (T2DM; 24%) glucose tolerance by 75 g-OGTT.
Results
Postchallenge hyperglycemia elicited TNF-α, IL-6 and nitrotyrosine levels time-dependently, and 2-hr median levels of TNF-α (7.1 versus 6.4 pg/ml; P < 0.05) and nitrotyrosine (1.01 versus 0.83 μmol/l; P < 0.05), but not IL-6 or PG, were significantly higher in patients with CAD in either IGT or T2DM groups. After adjusting risk factors and glucose tolerance status, 2-hr nitrotyrosine in highest quartiles (OR: 3.1, P < 0.05) remained an independent predictor of CAD by logistic regression analysis.
Conclusions
These results highlight postchallenge proinflammatory and nitrosative responses by 75 g-OGTT, rather than hyperglycemia per se, are associated with CAD in patients without previous recognized diabetes.
doi:10.1186/1475-2840-11-21
PMCID: PMC3316140  PMID: 22397368
Postchallenge hyperglycemia; Inflammation; Oxidative stress; Nitrotyrosine oral; Glucose tolerance test; Coronary artery disease
22.  Chewing areca nut increases the risk of coronary artery disease in taiwanese men: a case-control study 
BMC Public Health  2012;12:162.
Background
Areca nut chewing has been reported to be associated with obesity, metabolic syndrome, hypertension, and cardiovascular mortality in previous studies. The aim of this study was to examine whether chewing areca nut increases the risk of coronary artery disease (CAD) in Taiwanese men.
Methods
This study is a hospital-based case-control study. The case patients were male patients diagnosed in Taiwan between 1996 and 2009 as having a positive Treadmill exercise test or a positive finding on the Thallium-201 single-photon emission computed tomography myocardial perfusion imaging. The case patients were further evaluated by coronary angiography to confirm their CAD. Obstructive CAD was defined as a ≥ 50% decrease in the luminal diameter of one major coronary artery. The patients who did not fulfill the above criteria of obstructive CAD were excluded.
The potential controls were males who visited the same hospital for health check-ups and had a normal electrocardiogram but no history of ischemic heart disease or CAD during the time period that the case patients were diagnosed. The eligible controls were randomly selected and frequency-matched with the case patients based on age. Multiple logistic regression analyses were used to estimate the odds ratio of areca nut chewing and the risk of obstructive CAD.
Results
A total of 293 obstructive CAD patients and 720 healthy controls, all men, were analyzed. Subjects who chewed areca nut had a 3.5-fold increased risk (95% CI = 2.0-6.2) of having obstructive CAD than those without, after adjusting for other significant covariates. The dose-response relationship of chewing areca nut and the risk of obstructive CAD was also noted. After adjusting for other covariates, the 2-way additive interactions for obstructive CAD risk were also significant between areca nut use and cigarette smoking, hypertension and dyslipidemia.
Conclusions
Long-term areca nut chewing was an independent risk factor of obstructive CAD in Taiwanese men. Interactive effects between chewing areca nut and cigarette smoking, hypertension, and dyslipidemia were also observed for CAD risk. Further exploration of their underlying mechanisms is necessary.
doi:10.1186/1471-2458-12-162
PMCID: PMC3372426  PMID: 22397501
Areca nut; Coronary artery disease; Atherosclerosis
23.  BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis 
Molecular Medicine  2011;17(9-10):1065-1074.
The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.
doi:10.2119/molmed.2011.00043
PMCID: PMC3188876  PMID: 21670849
24.  Sex Differential Genetic Effect of Chromosome 9p21 on Subclinical Atherosclerosis 
PLoS ONE  2010;5(11):e15124.
Background
Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated.
Methodology/Principal Findings
Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p = 0.021) and internal carotid artery (ICA) IMT (p = 0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p = 0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p = 0.010) and the greater risk for the presence of carotid plaque (OR = 1.57 for heterozygous carriers; OR = 1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women.
Conclusions
Chromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.
doi:10.1371/journal.pone.0015124
PMCID: PMC2994883  PMID: 21152093
25.  Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan 
PLoS ONE  2009;4(5):e5459.
Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population.
doi:10.1371/journal.pone.0005459
PMCID: PMC2674219  PMID: 19421330

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