The Efficacy and Safety of Short-Term Tolvaptan Usage in Patients with Acute Decompensated Heart Failure.

Background: Patients admitted with acute decompensated heart failure (ADHF) have a poor prognosis and poor quality of life due to dyspnea and edema. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective water diuretic. This study aimed to evaluate the efficacy and safety of a short course of tolvaptan to treat volume overload in patients with ADHF. Methods: We conducted a phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a short course of tolvaptan (15 mg/day for 4 days) in hospitalized ADHF patients with volume overload despite the use of conventional diuretics. The primary end-point was the change in body weight after 4 days of treatment. The secondary end-points were the change in intake/output balance, change in serum sodium/potassium concentrations, physician/patient assessed signs and symptoms of heart failure after 4 days of treatment, and all-cause mortality in 1 month. Results: A total of 110 patients were screened, and 91 were randomized to receive 15 mg/day of tolvaptan for 4 days (n = 46) or matching placebo (n = 45). Compared to the placebo-treated patients, tolvaptan significantly reduced body weight (-1.36 ± 2.13 kg in the tolvaptan group vs. -0.59 ± 1.27 kg in the placebo group, p = 0.0394). The tolvaptan group also had a negative intake/urine volume balance compared to the placebo group (-509.3 ± 2788.2 ml vs. 975.5 ± 1903.1 ml, p = 0.0059). The safety profile of tolvaptan was acceptable. Conclusions: Tolvaptan significantly reduced volume overload in hospitalized ADHF patients with volume overload despite the use of conventional diuretics.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Ethyl-Ester Omega-3 Fatty Acid in Taiwanese Hypertriglyceridemic Patients.

AIM: Information regarding the effects of omega-3 fatty acid on hypertriglyceridemic patients in Chinese is still limited. This study aimed to investigate the efficacy and safety of Omacor®, a prescription ethyl-ester omega-3 fatty acid for the treatment of hypertriglyceridemia, administered at doses of 2 g/day and 4 g/day to Taiwanese hypertriglyceridemic patients. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel study in adults with hypertriglyceridemia was conducted. After a five-week diet lead in period patients with triglycerides =200-1000 mg/dL were randomized to receive Omacor®, a concentrated preparation of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in a dose of 1 g twice daily (2 g Omacor®), 2 g twice daily (4 g Omacor®) or placebo, for eight weeks. The primary endpoint was the percentage change in triglyceride serum levels from baseline to the end of treatment. RESULTS: A total of 253 Taiwanese patients were randomized, of which 65.6% (166) were men. At the end of the treatment, the percentage change in triglyceride serum levels in both the Omacor® 4 g/day (－32.1%) and 2 g/day (－29.7%) groups was larger than in the placebo group (－5.4%) (p＜0.001). The incidence of drug-related adverse events was as follows: 0.0%, 1.2%, and 0.0% in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Omacor® may be a feasible option to treat hypertriglyceridemia in Taiwanese patients.

A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of STA-2 (Green Tea Polyphenols) in Patients with Chronic Stable Angina.

BACKGROUND: Green tea intake has been shown to improve endurance capacity in animal studies, but whether it has a similar effect on humans remains unclear. A randomized, double-blinded, parallel-controlled study was conducted to evaluate the short-term effect of STA-2, a pharmaceutical preparation of green tea polyphenols, in patients with effort-induced angina and documented positive exercise tolerance test. METHODS: A total of 79 patients recruited from three medical centers were randomly assigned to receive 2 STA-2 250 mg capsules, each containing 100 mg green tea polyphenols, three times daily, or placebo for six weeks after two consecutive symptom-limited treadmill exercise tests to ascertain the reproducibility of exercise tolerance. RESULTS: There was no difference in total exercise tolerance time from baseline to Week 6 between two groups (p = 0.639). There were also no observed improvements in subgroup analyses stratified by age, gender, and BMI categories. However, a significant reduction in low-density lipoprotein levels was shown in patients in the STA-2 group (-8.99 ± 19.18 mg/dL) versus the placebo group (0.57 ± 19.77 mg/dL), p = 0.037, with greater benefits in patients not taking antihyperlipidemic drugs (STA-2: -9.10 ± 19.96 mg/dL vs. placebo: 4.42 ± 15.08 mg/dL, p = 0.037). CONCLUSIONS: STA-2 treatment for 6 weeks did not increase exercise time as measured on a treadmill. However, this study also indicated that STA-2 treatment could have potential beneficial effects on LDL-cholesterol concentrations.

Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10(-24)). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway.

Unique clinical characteristics and SCN5A mutations in patients with Brugada syndrome in Taiwan.

BACKGROUND/PURPOSE: Brugada syndrome (BrS) is a hereditable sudden cardiac death (SCD). Mutations in the SCN5A gene (the most common BrS-causing gene) are responsible for 20-25% of this disease in Caucasian populations. However, the prevalence of SCN5A mutations in patients with BrS in the Chinese Han population in Taiwan remains unknown. Therefore, in this study, we investigated the prevalence of the SCN5A mutation in the largest BrS cohort in Taiwan. METHODS: We consecutively enrolled 47 unrelated patients with BrS from medical centers and hospitals in Taiwan between 2000 and 2010. Mutations within all the 27 translated exons, and exon-intron boundaries of the SCN5A-encoded cardiac sodium channel were screened in all patients with BrS using direct sequencing. A total of 500 unrelated healthy volunteers with a normal electrocardiogram were genotyped as a control group. RESULTS: SCN5A genetic variants were identified in 14 of the 47 patients with BrS and four of the 14 patients with BrS had missense mutations (1651 G>A, 1776 C>G, 3578 G>A). The prevalence rate of SCN5A mutations was approximately 8% (4/47), which was significantly lower than that reported in Caucasian populations (20-25%; p = 0.0007). The average age of these 14 BrS patients with SCN5A variants at diagnosis (12 men and 2 women) was 40 ± 13 years. Four patients experienced SCD, and six presented with seizure or syncope. Only three patients (3/14, 21.4%) had a family history of SCD. CONCLUSION: The prevalence of SCN5A mutations in the Chinese Han population in Taiwan may be lower than that reported in the Caucasian populations. In addition, most patients with BrS did not have a family history of SCD.

Proteinuria and Reduced Estimated Glomerular Filtration Rate Independently Predict Risk for Acute Myocardial Infarction: Findings from a Population-Based Study in Keelung, Taiwan.

BACKGROUND: The aim of this study was to evaluate the independent roles of proteinuria and reduced estimated glomerular filtration rate (GFR) in the development of acute myocardial infarction in a northern Taiwanese population. METHODS: We conducted a community-based prospective cohort study in Keelung, the northernmost county of Taiwan. A total of 63,129 subjects (63% women) ≥ 20 years of age who had no history of coronary heart disease were recruited and followed-up. Univariate and multivariate proportional hazards regression analysis was performed to assess the association between proteinuria and estimated GFR and the risk of acute myocardial infarction. RESULTS: There were 305 new cases of acute myocardial infarction (114 women and 191 men) documented during a four-year follow-up period. After adjustment of potential confounding covariates, heavier proteinuria (dipstick urinalysis reading 3+) and estimated GFR of less than 60 ml/min/1.73 m(2) independently predicted increased risk of developing acute myocardial infarction. The adjusted hazard ratio (aHR) of heavier proteinuria for occurrence of acute myocardial infarction was 1.85 [95% confidence intervals (CI), 1.17-2.91, p < 0.01] (vs. the reference group: negative dipstick proteinuria). The aHR of estimated GFR of 30-59 ml/min/1.73 m(2) for occurrence of acute myocardial infarction was 2.4 (95% CI, 1.31-4.38, p < 0.01) (vs. the reference group: estimated GFR ≥ 90 ml/ min/1.73 m(2)), and that of estimated GFR of 15-29 ml/min/1.73 m(2) was 5.26 (95% CI, 2.26-12.26, p < 0.01). CONCLUSIONS: We demonstrated that both heavier proteinuria and lower estimated GFR are significant independent predictors of developing future acute myocardial infarction in a northern Taiwanese population. KEY WORDS: Acute myocardial infarction; Estimated glomerular filtration rate; Proteinuria.

Renin-angiotensin system gene polymorphisms predict the risk of stroke in patients with atrial fibrillation: a 10-year prospective follow-up study.

BACKGROUND: Little evidence is available regarding the impact of genetic polymorphisms on the risk of stroke in patients with atrial fibrillation (AF). Angiotensin II plays a pathophysiologic role in prothrombotic atrial endocardial remodeling. OBJECTIVE: The purpose of this study was to investigate the effect of polymorphisms of renin-angiotensin system genes on the incidence of stroke in a prospective cohort of patients with AF. METHODS: A total of 712 AF patients were longitudinally followed-up for 10.3 ± 2.7 years. Eight polymorphisms of renin-angiotensin system genes were genotyped. RESULTS: Patients carrying the G-6 allele in the promoter of the angiotensinogen gene, which was associated with higher promoter activity, were more likely to develop stroke than were noncarriers (hazard ratio 2.54, 95% confidence interval [1.26-5.12], P = .009 after adjustment for CHADS2 score). G-6A polymorphism provides information additional to CHADS2 on stroke risk prediction (C-statistic 0.672 vs. 0.724, P = .039). In haplotype analysis, angiotensinogen gene promoter haplotypes containing -217G/-6G, which was associated with the highest promoter activity, were associated with an increased risk of stroke (P = .004). G-217/G-6 haplotype carriers were even more likely to develop stroke than were noncarriers (hazard ratio 2.78, 95% confidence interval 1.37-5.64, P = .003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (P = .012 for interaction). CONCLUSION: In addition to the CHADS2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke in patients with AF. Genotyping of the angiotensinogen gene is helpful to determine which AF patients may benefit from treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.

Prognostic factors of heart failure with preserved ejection fraction: a 12-year prospective cohort follow-up study.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) is a clinically important issue, the factors that affect its prognosis are still unclear. The aim of this study was to establish prognostic factors and develop a severity scale for the disease based on a long-term follow-up cohort of HFpEF patients. METHODS: The study included 438 HFpEF patients, as confirmed via echocardiography. Baseline characteristics, including echocardiographic findings and genetic polymorphisms, were determined. Patients were followed-up for up to 12 years. Kaplan-Meier curves and Cox regression models were used to determine the risk factors for mortality and major cardiovascular events (MACE). A severity scale was established using the significant risk factors. The receiver operating characteristics (ROC) curves for the scale were plotted. RESULTS: The prescription of angiotensin-converting enzyme (ACE) inhibitors [hazard ratio (HR) 0.28; 95% confidence interval (CI): 0.13-0.58 for mortality] and calcium channel blockers (CCB) was associated with a significant decrease in overall mortality and MACE. Echocardiographic E/Em ratio and ACE gene D polymorphisms were powerful factors associated with both mortality and MACE [(E/Em; HR 1.66; 95% CI: 1.32-2.29 for mortality) and (ACE gene D allele, HR 1.99; 95% CI: 1.26-3.16 for mortality)]. The ROC curves indicated a good diagnostic efficiency for severity scores (area under the curve 0.72). CONCLUSIONS: In a long-term follow-up cohort of HFpEF patients, simple clinical, echocardiographic, medication, and even genetic variables were associated with MACE or mortality, and the developed composite severity scale identified patients with a higher probability of experiencing the events.

Additive effect of the metabolic syndrome score to the conventional CHADS2 score for the thromboembolic risk stratification of patients with atrial fibrillation.

BACKGROUND: The CHA2DS2-VASC scoring scheme may not be better than the CHADS2 scoring scheme in predicting thromboembolic risk for patients with atrial fibrillation (AF) in Asians. Metabolic syndrome is associated with an increased risk of thrombosis. OBJECTIVE: To evaluate whether metabolic syndrome offers incremental information over the CHADS2 scheme in predicting thromboembolic risk for patients with AF in the Taiwanese population. METHODS: The study population consisted of 721 consecutive patients with AF who had been followed up for a median of 10.8 years. Thromboembolic end points were defined as ischemic stroke/transient ischemic accident and peripheral embolisms. Clinical factors associated with thromboembolic end points were identified by Cox regression analysis. Different scoring systems were compared by receiver operating characteristic (ROC) analysis. RESULTS: We found that components in the CHADS2 scheme were associated with an increased risk of thromboembolism. The CHA2DS2-VASC scheme did not provide information additional to that provided by the CHADS2 scheme on thromboembolism risk (ROC area: 0.670 vs 0.665; P > .05). Metabolic syndrome components were also associated with increased risk of thromboembolism. The incident thromboembolic rate increased incrementally when metabolic syndrome score increased. Additional metabolic syndrome components provide additional information to the CHADS2 scheme on thromboembolism risk (ROC area: 0.670 vs 0.729; P = .034). We therefore proposed a new scoring scheme called CHADS2-MS scoring scheme. In patients with low to intermediate CHADS2 scores (0-1), the use of the CHADS2-MS score may additionally identify patients with high-risk AF for future thromboembolism. CONCLUSIONS: We, for the first time, demonstrated that metabolic syndrome components were associated with thromboembolic risk in Taiwanese patients with AF. In addition to the conventional CHADS2 scheme, the calculation of the CHADS2-MS score provides additional information on stroke risk assessment.

Association of Small-Conductance Calcium-Activated Potassium Channels and Atrial Fibrillation - How Far Have We Gone?

UNLABELLED: Atrial fibrillation (AF) is the most common sustained and most important arrhythmia in clinical practice. The mechanisms underlying AF initiation and maintenance are known to be complex and heterogeneous. The general understanding of the detailed molecular basis of AF is still incomplete. Recently, these is increasing evidence that small conductance calcium-activated potassium (SK) channels are associated with atrial action potential repolarization and the pathogenesis of AF. Although the functional role of SK channels in the genesis of AF is not entirely clear, new insights into the basic pathophysiological mechanism of AF have been provided. Besides, genome-wide association studies also implicate that genes coding for SK channels are related to the risk of developing AF. This article reviews recent work on the association of SK channels and AF, genetic studies of SK channels, and discuss future investigation and developments regarding this field. KEY WORDS: Atrial fibrillation; Genetics; Small conductance calcium-activated potassium channels.

Conductive channels identified with contrast-enhanced MR imaging predict ventricular tachycardia in systolic heart failure.

OBJECTIVES: This study evaluated whether the conductive channel (CC) identified by late gadolinium enhanced-cardiac magnetic resonance (LGE-CMR) is associated with ventricular tachycardia (VT) in patients with systolic heart failure (HF). BACKGROUND: One recent study demonstrated that the CC formed by heterogeneous tissue within the core scar could be detected by LGE-CMR and that the CC is responsible for clinical VT. We hypothesized that the CC could help identify HF patients at risk for VT. METHODS: A total of 63 patients from a CMR database with left ventricular ejection fraction (LVEF) below 50% and with hyperenhancement on LGE-CMR were included. The cine and LGE images were analyzed to derive the LV function and scar characteristics, and to identify the CC. The outcomes, including VT, ventricular fibrillation (VF), and total mortality, were obtained by reviewing medical records. RESULTS: After a median 1,379 (interquartile range: 271 to 1,896) days of follow-up, 8 patients had VT/VF attacks and 14 patients died. Among the CMR-measured parameters, only the probability of identifying the CC by LGE-CMR was higher in patients with VT/VF than those without VT/VF (75.0% vs. 16.4%, p < 0.001). The probability of identifying the CC was also higher in the total mortality group than the survival group (50.0% vs. 16.3%, p = 0.004). The other LGE-CMR variables were not significantly different between the 2 groups. A univariate Cox regression model showed that CC identification was positively associated with VT/VF attacks (hazard ratio [HR]: 27.032, 95% confidence interval [CI]: 3.291 to 222.054, p = 0.002) and excess total mortality (HR: 4.766, 95% CI: 1.643 to 13.824, p = 0.004). The LVEF was inversely associated with VT/VF attacks (HR: 0.119, 95% CI: 0.015 to 0.977, p = 0.048) and excess total mortality (HR: 0.491, 95% CI: 0.261 to 0.925, p = 0.028) during follow-up. CONCLUSIONS: We demonstrated that CC identification using LGE-CMR can help identify HF patients at risk for VT/VF.

Genetic variation-optimized treatment benefit of angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease: a 12-year follow-up study.

OBJECTIVES: The objective of this study was to examine the relationship between renin-angiotensin system genotypes and the pharmacogenetics of angiotensin-converting enzyme (ACE) inhibitors in Chinese patients with coronary artery disease (CAD). METHODS: Patients with angiographic CAD were recruited from 1995 to 2003. The baseline characteristics and genetic polymorphisms [ACE gene insertion/deletion (I/D) polymorphisms, six polymorphisms of the angiotensinogen (AGT) gene, and A-1166C polymorphisms of the angiotensin-II type I receptor gene (AGT1R)] were established. Patients were divided into two groups (ACE inhibitor or no ACE inhibitor) and followed for up to 12 years. Kaplan-Meier curves and Cox regression models were used to determine the survival and major cardiovascular events (MACE) event-free survival trends. Pharmacogenetic effects were determined by several Cox regression models. RESULTS: Of the 784 patients, 432 were treated with ACE inhibitors and 352 were not. ACE inhibitors were associated with a lower MACE rate at 4000 days. In addition, the ACE I/D gene D and AGT1R gene C alleles were associated with a higher MACE rate on the basis of a multivariate regression analysis. This effect was attenuated by the pharmacogenetic interaction of ACE inhibitors and the ACE gene (ACE inhibitors* ACE gene, hazard ratio: 0.8, 95% confidence interval: 0.62-0.94, P=0.03). CONCLUSIONS: ACE inhibitors were associated with a significant decrease in MACE in Chinese patients diagnosed with CAD. Genetic variants were also associated with event-free survival, but their effects were modified by the use of ACE inhibitors.

Renin-Angiotensin System Genes Polymorphisms and Long-Term Prognosis in Taiwanese Patients with Hypertension and Coronary Artery Disease.

OBJECTIVES: The objective of this study was to evaluate the renin-angiotensin system genetic effects and pharmacogenetic interactions for angiotensin-converting enzyme (ACE) inhibitors in hypertensive coronary artery disease (CAD) patients. METHODS: Subjects with hypertension and angiographic CAD were recruited from 1995 to 2003. Baseline characteristics and genetic polymorphisms [ACE gene insertion/deletion (I/D) polymorphism, six polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphisms of the angiotensin II type I receptor gene (AGT1R)] were collected. Patients were assigned to 2 groups (ACE inhibitor or No-ACE inhibitor) and followed-for up to 12 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival and major cardiovascular events (MACE) event-free survival trends. Pharmacogenetic effects were determined by several Cox regression models. RESULTS: Of the 518 patients in our study, 290 were treated with ACE inhibitors and 228 were not. Prescription of ACE inhibitors was associated with a lower rate of MACE at 4000 days. In addition, ACE I/D gene D was associated with a higher rate of MACE in a multivariate regression analysis [hazard ration (HR): 1.64, 95% confidence interval (CI): 1.27-1.98, p < 0.001]. This effect could be attenuated by the pharmacogenetic interaction of ACE inhibitors and the ACE gene (ACE in hibitors*ACE D gene, HR: 0.68, 95% CI: 0.52-0.84, p = 0.014). CONCLUSIONS: The use of ACE inhibitors was associated with a significant decrease in MACE in hypertensive patients diagnosed with CAD. Genetic variants were also associated with event-free survival, but their effects were modified by the use of ACE inhibitors. KEY WORDS: Angiotensin-converting enzyme inhibitors; Coronary artery disease; Hypertension; Pharmacogenetic.

Contrast-Induced Encephalopathy after Percutaneous Coronary Intervention.

UNLABELLED: Contrast-induced encephalopathy (CIE) is a rare complication that presents with transient neurologic deficits and is caused by neurotoxicity of intravascular contrast media. The prognosis can be extremely favorable even in comatose patients. We reported a 76-year-old woman admitted for scheduled coronary angiography. The total amount of Optiray contrast media used was 150 mL. Immediately after the procedure, the patient developed consciousness disturbance, global aphasia, cortical blindness and right-sided weakness. CIE was diagnosed by computed tomography and subsequent magnetic resonance imaging. The patient recovered completely within 48 hours without any neurological deficits. KEY WORDS: Angioplasty; Contrast-induced encephalopathy; Percutaneous coronary intervention.

Next-Generation Sequencing in the Genetics of Human Atrial Fibrillation.

UNLABELLED: The International Human Genome Sequencing Consortium published the first draft of the human genome in the journal Nature in February 2001, providing the sequence of the entire genome's three billion base pairs. The Human Genome Project involves a concerted effort to better understand the human DNA sequence through identification of all the genes. The knowledge that can be derived from the genome could result in the development of novel diagnostic assays, targeted therapies and the improved ability to predict the onset, severity and progression of diseases. This has been made possible by many parallelized, high-throughput technologies such as next-generation sequencing. In this review, we discuss the possible application of next-generation sequencing in finding the susceptibility gene(s) or disease mechanism of an important human arrhythmia called atrial fibrillation. KEY WORDS: Arrhythmia; Atrial fibrillation; Genetics, Next-generation sequencing.

Differential baseline expression and angiotensin II-stimulation of leukemia-associated RhoGEF in vascular smooth muscle cells of spontaneously hypertensive rats.

PURPOSE: Studies to explore angiotensin II (Ang II) and its downstream signaling pathways via Rho guanine nucleotide exchange factors (RhoGEFs) and RhoA signaling are crucial to understanding the mechanisms of smooth muscle contraction leading to hypertension. This study aimed to investigate the Ang II-induced expression of RhoGEFs in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) and to identify the possible regulator associated with hypertension. METHODS: Cultured VSMCs of the aorta from SHRs and Wistar-Kyoto (WKY) rats were treated with or without Ang II or Ang II plus Ang II type 2 receptor antagonists. The expression levels of RhoGEF messenger RNA (mRNA) and protein were determined. To evaluate the changes of aortic ring contractile force in response to Ang II, a nonviral carrier system was adopted to deliver the leukemia-associated RhoGEF (LARG) small interfering RNA via nanoparticles into aortic rings. RESULTS: The baseline mRNA levels of three RhoGEFs in cultured VSMCs of WKY rats did not increase with age, but they were significantly higher in 12-week-old SHRs than in 5-week-old SHRs. Expression levels of LARG mRNA were higher in SHRs than in age-matched WKY rats. The baseline LAGR protein of 12-week-old SHRs was about four times higher than that of WKY rats of the same age. After Ang II-stimulation, LAGR protein expression was significantly increased in 12-week-old WKY rats but remained unchanged in 12-week-old SHRs. LARG small interfering RNA was successfully delivered into aortic rings using nanoparticles. LARG knockdown resulted in 12-week-old SHRs showing the greatest reduction in aortic ring contraction. CONCLUSION: There were differences in age-related RhoGEF expression at baseline and in response to Ang II-stimulation between SHRs and WKY rats in this study. Nanotechnology can assist in studying the silencing of LARG in tissue culture. The findings of this study indicate that LARG gene expression may be associated with the genesis of hypertension in SHRs.

Angiotensin-converting enzyme inhibitors enhance the effect of cyclooxygenase inhibitors on breast cancer: a nationwide case-control study.

OBJECTIVES: Angiotensin-converting enzyme (ACE) inhibitors are first-line antihypertensive and potential cancer preventive agents. Interest in breast cancer prevention is growing, and more clinical evidence is needed regarding the effects of preventive therapy, alone or in combination. METHODS: This was a nationwide case-control analysis from the Taiwan National health Insurance Research Database. We analyzed 16,847 female breast cancer patients (diagnosed between 1 January 2002 and 31 December 2008) and 50,541 matched individuals. Longitudinal exposure to ACE inhibitors and cyclooxygenase inhibitors was compared. RESULTS: The risk of developing breast cancer among patients taking both aspirin and an ACE inhibitor decreased as the ACE inhibitor dose increased. Among patients receiving between 28 and 364 cumulative defined daily doses (cDDDs) of aspirin, the adjusted odds ratios (ORs) were 0.97 (0.90-1.06), 0.91 (0.82-1.03), and 0.79 (0.68-0.92) for women taking ACE inhibitors for 0-27, 28-364, and more than 365 cDDD, respectively. Among women receiving more than 365 cDDD of aspirin, the adjusted ORs were 0.91 (0.80-1.03), 0.81 (0.70-0.94), and 0.81 (0.71-0.92) as the ACE inhibitor dose increased, respectively. Women taking nonaspirin NSAIDs along with an ACE inhibitor had the same finding. Among women taking 28-364 cDDD of NSAIDs, the adjusted ORs were 0.85 (0.81-0.89), 0.87 (0.81-0.94), and 0.80 (0.73-0.88); for women receiving more than 365 cDDD of NSAIDs, the adjusted ORs were 0.68 (0.62-0.74), 0.61 (0.53-0.70), and 0.60 (0.52-0.70) as the ACE inhibitor dose increased, respectively. CONCLUSION: The findings of this nationwide analysis support the hypothesis that ACE inhibitors enhance the antitumor effect of cyclooxygenase inhibitors on breast cancer.

Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.

BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Cardiac myosin binding protein C and MAP-kinase activating death domain-containing gene polymorphisms and diastolic heart failure.

OBJECTIVE: Myosin binding protein C (MYBPC3) plays a role in ventricular relaxation. The aim of the study was to investigate the association between cardiac myosin binding protein C (MYBPC3) gene polymorphisms and diastolic heart failure (DHF) in a human case-control study. METHODS: A total of 352 participants of 1752 consecutive patients from the National Taiwan University Hospital and its affiliated hospital were enrolled. 176 patients diagnosed with DHF confirmed by echocardiography were recruited. Controls were matched 1-to-1 by age, sex, hypertension, diabetes, renal function and medication use. We genotyped 12 single nucleotide polymorphisms (SNPs) according to HapMap Han Chinese Beijing databank across a 40 kb genetic region containing the MYBPC3 gene and the neighboring DNA sequences to capture 100% of haplotype variance in all SNPs with minor allele frequencies ≥ 5%. We also analyzed associations of these tagging SNPs and haplotypes with DHF and linkage disequilibrium (LD) structure of the MYBPC3 gene. RESULTS: In a single locus analysis, SNP rs2290149 was associated with DHF (allele-specific p = 0.004; permuted p = 0.031). The SNP with a minor allele frequency of 9.4%, had an odds ratio 2.14 (95% CI 1.25-3.66; p = 0.004) for the additive model and 2.06 for the autosomal dominant model (GG+GA : AA, 95% CI 1.17-3.63; p = 0.013), corresponding to a population attributable risk fraction of 12.02%. The haplotypes in a LD block of rs2290149 (C-C-G-C) was also significantly associated with DHF (odds ratio 2.10 (1.53-2.89); permuted p = 0.029). CONCLUSIONS: We identified a SNP (rs2290149) among the tagging SNP set that was significantly associated with early DHF in a Chinese population.

A predictive model for risk of prehypertension and hypertension and expected benefit after population-based life-style modification (KCIS No. 24).

BACKGROUND: Few reports have identified and quantified significant risk factors responsible for multistate natural course of progression to hypertension and also regression of prehypertension to normal, which provides baseline risks to estimate the size of expected benefit derived from population-based life-style modification. METHODS: Data used for estimating clinical parameters governing temporal natural course of hypertension are derived from 42,027 participants attending screening annually between 1999 and 2002. Information on transition history between normal, prehypertension, stage 1 and stage 2 hypertension between screens was therefore collected to compute multistep composite risk scores without intervention program. The expected benefits of risk reduction in prehypertension and hypertension under different intervention programs by modifying the related risk factors from abnormal to normal ranges were estimated. RESULTS: The majority of risk factors play a more remarkable role in prehypertension and stage 1 hypertension but less in stage 2 hypertension. The greater the number of risk factors included in the intervention programs becomes, the lower the mean risk score is expected to achieve. The 5-year predicted cumulative risk for stage 2 hypertension decreased from 23.6% in the absence of intervention program to 14% with the provision of "six-component intervention" in men. The results were similar for women. CONCLUSIONS: Multiple risk factors responsible for multistep transitions between prehypertension and hypertension were identified by using population-based screening data to derive multistep composite risk scores, which are useful for the expected benefit of reducing risk of hypertension by providing population-based life-style modification.