Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction.

Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory ß subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern. OBJECTIVE: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. METHODS: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. RESULTS: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). CONCLUSION: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.

Impact of post-implantation time on bioresorbable vascular scaffold outcomes for type C versus non-type C coronary lesions: A longer-term study.

BACKGROUND: We have demonstrated that bioresorbable vascular scaffold (BVS) for ACC/AHA type C lesions was associated with higher risks of long-term target lesion revascularization (TLR) and target lesion failure (TLF). We determined the specific time after which higher risks of BVS for type C lesions are reduced in a longer-term follow-up. METHODS: We analyzed data of 457 patients (59 ± 12 years, 87% male) with 714 BVS implanted for 529 lesions and a median follow-up of 56.4 (48.6-62.6) months. Patients with BVS for at least one type C lesion (N = 177) at index intervention and all non-type C lesions (N = 280) were compared for TLF (cardiac death, target vessel myocardial infarction, TLR). We specified the interactions between the non-type C versus type C group and the event-free survival times dichotomized at 24, 30, 32, 33, 36, and 39 months respectively. RESULTS: The type C group had more multivessel disease (86% versus 65%, p < 0.001), left anterior descending artery treated (68% versus 53%, p = 0.002), intravascular imaging used (48% vs. 25%, p < 0.001), and BVS (2.3 ± 0.9 vs. 1.1 ± 0.3, p < 0.001) implanted with a longer total length (57 ± 21 vs. 29 ± 8 mm, p < 0.001). The TLR or TLF was higher (both log-rank p < 0.05) in the type C than in the non-type C group. However, the risks of TLR (hazard ratio: 3.6, 95% CI = 1.1-11.6) and TLF (hazard ratio: 3.8, 95% CI = 1.2-12.1) for type C lesions only remained higher until 24 months post-BVS implantation. CONCLUSION: BVS provides a longer-term advantage, particularly for type C lesions with the majority requiring long stenting.

Lesion impacts on long-term outcomes in patients implanted with bioresorbable vascular scaffold.

BACKGROUND: Bioresorbable vascular scaffold (BVS) had been implanted to several kinds of complex coronary lesions in real-world practice. We tested if long-term outcomes of BVS for complex lesions would be worse than that for relatively simple lesions. METHODS: We analyzed 457 patients (59 ± 12 years, 87% male) with 714 BVS implanted for their 529 lesions and median follow-up of 32.7 (26.8-39.3) months. Complex group (N = 284) was defined as those with BVS for acute coronary syndrome, chronic total occlusion, bifurcation/ostial lesions, instent restenosis/hybrid with metallic stents, diffuse lesions (overlapped by 2 BVS with each â‰§ 18 mm), venous graft/left main lesions, or lesions after rotablation. We compared their outcomes with the remaining 173 patients as non-complex group. RESULTS: The complex group had more chronic kidney disease (7% vs. 2%), multivessel disease (78% vs. 65%), use of intravascular imaging (40% vs. 23%), and more BVS (1.8 ± 0.9 vs. 1.1 ± 0.3) with longer total lengths (47 ± 22 vs. 29 ± 8 mm) implanted than non-complex group (all p < 0.05). However, the long-term target lesion revascularization (TLR) or target lesion failure (TLF) was similar (log rank p > 0.05) between the two groups. Multivariate Cox regression analyses showed BVS for ACC/AHA type C lesions was independently associated with higher risks of TLR (hazard ratio: 2.7, 95% CI = 1.1-6.6) and TLF (hazard ratio: 2.6, 95% CI = 1.1-6.3). CONCLUSION: Comparable outcomes were found between BVS for complex and non-complex lesion category. However, higher risks of TLR and TLF for type C lesions still suggested the prognostic impact of lesion complexity on long-term outcomes of BVS.

Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

Combined corrected QT interval and growth differentiation factor-15 level has synergistic predictive value for long-term outcome of angiographically confirmed coronary artery disease.

BACKGROUND: The corrected QT interval (QTc) predicts prognosis for the general population and patients with coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is a biomarker of myocardial fibrosis and left ventricular (LV) remodelling. The interaction between these two parameters is unknown. SUBJECTS AND METHODS: This study included 487 patients with angiographically confirmed CAD. QTc was calculated using the Bazett formula. Multiple biochemistries and GDF-15 levels were measured. The primary endpoint was total mortality, and the secondary endpoints comprised the combination of total mortality, myocardial infarction and hospitalisation for heart failure and stroke. RESULTS: The mean follow-up period was 1029 ± 343 days (5-1692 days), during which 21 patients died and 47 had secondary endpoints. ROC curve analysis for the optimal cut-off value of primary endpoint is 1.12 ng/mL for GDF-15 (AUC = 0.787, P = 9.0 × 10-6 ) and 438.5 msec for QTc (AUC = 0.698, P = .002). Utilising linear regression, QTc has a positive correlation with Log-GDF-15 (r = .216, P = 1.0 × 10-6 ). Utilising Kaplan-Meier analysis, both QTc interval and GDF-15 level are significant predictors for primary end point (P = .000194, P = 2.0 × 10-6 , respectively) and secondary endpoint (P = .00028, P = 6.15 × 10-8 , respectively). When combined these two parameters together, a significant synergistic predictive power was noted for primary and secondary endpoint (P = 2.31 × 10-7 , P = 1.26 × 10-8 , respectively). This combined strategy also showed significant correlation with the severity of CAD (P < .001). CONCLUSION: In Chinese patient with angiographically confirmed CAD, a combined strategy utilising an ECG parameter (QTc) and a circulating biomarker (GDF-15) has good correlation with the severity of CAD, and improves the predictive power for total mortality.

Small chemical compounds Y16 and Rhosin can inhibit calcium sensitization pathway in vascular smooth muscle cells of spontaneously hypertensive rats.

BACKGROUND/PURPOSE: The small-molecule compounds Y16 and Rhosin can inhibit the activation of leukemia-associated Rho guanine nucleotide exchange factor (LARG) and small G-protein RhoA, respectively, in breast cancer cells and inhibit their growth and migration. However, it remains unclear whether they have inhibitory effects on the vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs). METHODS: Primary cultured VSMCs from SHRs were treated with different concentrations of Y16 or Y16 plus Rhosin for 24 h, followed by 10-min stimulation with 10-7 M angiotensin II (Ang II). The cells were then harvested, and the total protein was extracted. The co-immunoprecipitation method, Western blot analysis, and MTT assay were performed to determine the LARG-RhoA interaction, the protein levels of RhoA and MYPT1, and cell viability, respectively. RESULTS: Y16 dose-dependently inhibited the LARG-RhoA complex formation induced by Ang II. With 50 µM of Y16, the effect of inhibition was statistically significant. Y16 also reduced the formation of phospho-MYPT1 stimulated by Ang II. With 5 µM of Y16, the inhibitory effect was statistically significant. When 25 µM of Y16 and 25 µM of Rhosin were combined, the inhibitory effect on LARG-RhoA interaction was statistically significant. When Y16 and Rhosin were combined, a significantly reduced concentration could effectively inhibit MYPT1 phosphorylation (2.5 µM compared with 5 µM for Y16 alone). CONCLUSION: Treating SHR VSMCs with Y16 can suppress the activation of LARG, prevent LARG binding to RhoA, and decrease the phosphorylation of MYPT1, thus weakening the activation of the calcium (Ca2+) sensitization pathway in SHR VSMCs.

Sex, racial differences and healthy aging in normative reference ranges on diastolic function in Ethnic Asians: 2016 ASE guideline revisited.

BACKGROUND: Diastolic dysfunction (DD) has shown to be a hallmark pathological intermediate in the development of heart failure with preserved ejection fraction (HFpEF). We aim to establish age- and sex-stratified normal reference values of diastolic indices and to explore racial-differences. METHODS: We explored age- and sex-related structural/functional alterations from 6023 healthy ethnic Asians (47.1 ± 10.9 years, 61.3% men) according to 2016 American Society of Echocardiography (ASE) diastolic dysfunction (DD) criteria. Racial comparisons were made using data from London Life Sciences Prospective Population (LOLIPOP) study. RESULTS: Age- and sex-based normative ranges (including mean, median, 10% and 90% lower and upper reference values) were extracted from our large healthy population. In fully adjusted models, advanced age was independently associated with cardiac structural remodeling and worsened diastolic parameters including larger indexed LA volume (LAVi), lower e', higher E/e', and higher TR velocity; all p < 0.001), which were more prominent in women (P interaction: <0.05). Broadly, markedly lower e', higher E/e' and smaller LAVi were observed in ethnic Asians compared to Whites. DD defined by 2016 ASE criteria, despite at low prevalence (0.42%) in current healthy population, increased drastically with advanced age and performed perfectly in excluding abnormal NT-proBNP (≥125 pg/mL) (Specificity: 99.8%, NPV: 97.6%). CONCLUSION: This is to date the largest cohort exploring the normative reference values using guideline-centered diastolic parameters from healthy Asians, with aging played as central role in diastolic dysfunction. Our observed sex and ethnic differences in defining healthy diastolic cut-offs likely impact future clinical definition for DD in Asians.

The effect and molecular mechanism of statins on the expression of human anti-coagulation genes.

Statins are potent lipid-lowering drugs. Large prospective clinical trials have shown the anti-thrombotic effect of statins, e.g., preventing deep vein thrombosis. However, the mechanism underlying the beneficial effect of statins in reducing thrombus formation remains to be established. We, thus, conduct this study to investigate the potential molecular mechanisms. The cultured human hepatoma cells (HepG2) were used as the in vitro model. The human protein C gene promoter was cloned into the luciferase reporter to study the transcriptional regulation of human protein C gene. Wistar rats fed with simvastatin (5 mg/kg day) were used as the in vivo model. We found that simvastatin increased the expression of protein C in hepatocytes (361 ± 64% and 313 ± 59% after 2 h and 6 h of stimulation, respectively, both p < 0.01). In the animal study, the serum protein C levels were increased in the simvastatin-treated group (7 ± 2.2 unit/ml vs 23.4 ± 19.3 unit/ml and 23.4 ± 18.2 unit/ml and 1 and 2 weeks of treatment, respectively, both p < 0.05). Regarding the possible molecular mechanism, we found that the level of hepatocyte nuclear factor 1α (HNF1α) was also increased in both the in vivo and in vitro models. We found that the protein C promoter activity was increased by simvastatin, and this effect was inhibited by HNF1α knockdown and constitutively active Rac1. Therefore, stains may modulate protein C expression through small GTPase Rac 1 and HNF1α.

Reduction of blood pressure elevation by losartan in spontaneously hypertensive rats through suppression of LARG expression in vascular smooth muscle cells.

BACKGROUND/PURPOSE: This study sought to elucidate the mechanism by which losartan inhibits blood pressure (BP) elevation in spontaneously hypertensive rats (SHRs). METHODS: Four-week-old Wistar-Kyoto (WKY) rats and SHRs were either treated with losartan (20 mg/kg/day) for 8 weeks or served as untreated controls. BP was measured by the tail-cuff method. At 12 weeks, isometric contraction of the aortic rings of the rats was evaluated with a force transducer and recorder. The mRNA and protein levels of the target Rho guanine nucleotide exchange factors (RhoGEFs), and the extent of myosin phosphatase target subunit 1 (MYPT-1) phosphorylation in the aorta, were determined using quantitative real-time polymerase chain reaction (qPCR) assay and Western blot analysis. RESULTS: The BP of the four-week-old SHRs did not differ from that of the age-matched WKY rats, whereas the BP of the twelve-week-old control group SHRs was higher than that of the control group WKY rats. Losartan treatment, however, inhibited BP elevation in both rat strains, doing so to a greater extent in the treatment group SHRs. The contractile force in response to angiotensin II of the aortic rings from the SHRs treated with losartan was significantly lower than that of the aortic rings from the non-treated SHRs. The protein expression of leukemia-associated RhoGEF (LARG) was significantly higher in the non-treated SHRs compared to the non-treated WKY rats. CONCLUSION: The study results showed that the reduction of BP elevation by losartan in SHRs occurs through the suppression of LARG expression and MYPT-1 phosphorylation in vascular smooth muscle cells.

Duration of Clopidogrel-Based Dual Antiplatelet Therapy and Clinical Outcomes in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention　- A Real-World Observation in Taiwan From 2012 to 2015.

BACKGROUND: Little information is available in Asia about the real-world practice of dual antiplatelet therapy (DAPT) duration for acute coronary syndrome (ACS) and its influence on clinical outcomes.Methods and Results:The Taiwan ACS STENT Registry was a prospective, multicenter study to observe ACS patients using clopidogrel-based DAPT after percutaneous coronary intervention (PCI). The primary outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Overall, 2,221 ACS patients (62 years, 83% men) were included. DAPT duration was ≤9 months in 935 (42.1%). The incidence of primary outcome was higher in patients receiving DAPT ≤9 months compared with those receiving DAPT >9 months at 1 year (3.5% vs. 1.6%, P=0.0026). The incidence of stent thrombosis (overall 0.5%) was similar between groups. Multivariable analysis showed that DAPT >9 months was associated with a significantly lower risk of primary outcome (odds ratio 0.725, 95% confidence interval 0.545-0.965). CONCLUSIONS: Our data showed that short duration of DAPT (≤9 months) was common (42.1%) in Taiwan for ACS patients undergoing PCI. DAPT ≤9 months increased the risk of the primary outcome.

Comparison of Home and Ambulatory Blood Pressure Measurements in Association With Preclinical Hypertensive Cardiovascular Damage.

OBJECTIVE: To evaluate whether home or ambulatory blood pressure (BP) monitoring was associated with preclinical hypertensive cardiovascular target organ damage (TOD). METHODS: We enrolled participants with prehypertension and stage 1 hypertension from 11 medical centers within the Taiwan hypertension-associated cardiac disease consortium. Recordings of clinical BP measurement, ambulatory BP monitoring for 24 hours, and home BP monitoring during morning and evening were made. The measured parameters of target organ damage included left ventricular mass index (LVMI), left atrial volume index (LAVI), and carotid-femoral pulse wave velocity (PWV). RESULTS: Data were collected from 561 study participants (mean age, 65.0 ± 10.8 years; men, 61.3%). Morning and evening home BP values were slightly higher than the daytime and nighttime ABP values (difference for systolic morning-daytime/evening-nighttime, 7.3 ± 14.2/11.3 ± 18.5 mm Hg, P < .001; for diastolic, 5.4 ± 9.4/7.3 ± 12.1, P < .001). Daytime ambulatory (r = 0.114), nighttime ambulatory (r = 0.130), morning home (r = 0.310), and evening home (r = 0.220) systolic BPs (SBPs) were all associated with LVMI (all P < .05). The correlation coefficient was significantly greater for the relationship between daytime home SBP and LVMI than for the relationship between ambulatory SBP and LVMI (P < .01). The goodness of fit of the association between SBP and LVMI improved by adding home daytime SBP to the other SBPs (P < .001). Similar findings were observed for LAVI, but not for PWV. CONCLUSION: These findings indicate that morning SBP assessed by home monitoring appears to be a better predictor than other BP measures to determine preclinical hypertensive cardiovascular damage in patients with early-stage hypertension.

Circulating Chemerin Levels, but not the RARRES2 Polymorphisms, Predict the Long-Term Outcome of Angiographically Confirmed Coronary Artery Disease.

Chemerin, a novel adipokine, has been associated with metabolic, inflammatory, and atherosclerotic diseases. We aimed to determine the genetic basis of chemerin levels by conducting a genome-wide association study (GWAS) and to investigate the role of RARRES2 polymorphisms and circulating chemerin levels in the long-term outcome of coronary artery disease (CAD). A total of 2197 participants from the Taiwan Biobank (TWB) were recruited for the GWAS analysis, and 481 patients with angiographically confirmed CAD were enrolled for long-term outcome analysis. One locus of genome-wide significance with a single independent association signal was identified in the GWAS for chemerin levels with the peak association at the RARRES2 gene promoter region polymorphism rs3735167 (p = 2.35 × 10-21). In the CAD population, borderline significance was noted between RARRES2 polymorphisms and chemerin levels, whereas high chemerin levels were associated with obesity, female sex, diabetes mellitus, hypertension, current smoking, high platelet and leukocyte counts, anemia, impaired renal function, high C-reactive protein (CRP) levels, and multi-vessel disease. Kaplan⁻Meier survival curves indicated that the patients with high chemerin and CRP levels, but not those with RARRES2 polymorphisms, had a lower survival rate and higher combined cerebral and cardiovascular event rates. Combined chemerin and CRP levels further revealed a stepwise increase in poor clinical outcomes from low- to high-risk subgroups. In conclusion, rs3735167 is the lead RARRES2 polymorphism for chemerin levels in Taiwanese. Chemerin levels, but not the rs3735167 genotypes, predicted the long-term outcome of CAD, especially when combined with CRP levels.

Changing Practice Pattern of Acute Coronary Syndromes in Taiwan from 2008 to 2015.

BACKGROUND: Patients with acute coronary syndrome (ACS), including ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation (NSTE)-ACS have a significant risk of morbidity and mortality. This study evaluated the practice patterns of ACS care in Taiwan from 2005 to 2018. METHODS: Data from two nationwide ACS registries (2008-2010 and 2012-2015) were used. ACS patients who received percutaneous coronary interventions (PCIs) during admission were compared between the two registries. RESULTS: In STEMI, the door-to-balloon time for primary PCI decreased by 25 min from a median of 96 to 71 min (p < 0.0001) from the first to second registry. More complex PCI procedures and drug-eluting stents were used for ACS. However, the onset-to-door time was still long for both STEMI and NSTE-ACS. The D2B time for NSTE-ACS was long, especially in the elderly and female patients. Although the prescription rate of secondary preventive medications for ACS increased, it was still relatively low compared with Western data, especially in NSTE-ACS. CONCLUSIONS: The registry data showed that ACS care quality has improved in Taiwan. However, areas including onset-to-door time and use of secondary preventive medications still need further improvements.

Single allele Lmbrd1 knockout results in cardiac hypertrophy.

BACKGROUND/PURPOSE: LMBD1 protein, a type IV-B plasma membrane protein possessing nine putative trans-membrane domains, was previously demonstrated at cellular level to play a critical part in the signaling cascade of insulin receptor through its involvement in regulating clathrin-mediated endocytosis. However, at physiological level, the significance of LMBD1 protein in cardiac development remains unclear. METHODS: To understand the role of Lmbrd1 gene involved in the cardiac function, heterozygous knockout mice were used as an animal model system. The pathological outcomes were analyzed by micro-positron emission tomography, ECG acquisition, cardiac ultrasound, and immunohistochemistry. RESULTS: By studying the heterozygous knockout of Lmbrd1 (Lmbrd1+/-), we discovered that lack of Lmbrd1 not only resulted in the increase of cardiac-glucose uptake, pathological consequences were also observed. Here, we have distinguished that Lmbrd1+/- is sufficient in causing cardiac diseases through a pathway independent of the recessive vitamin B12 cblF cobalamin transport defect. Lmbrd1+/- mice exhibited an increase in myocardial glucose uptake and insulin receptor signaling that is insensitive to the administration of additional insulin. Pathological symptoms such as cardiac hypertrophy, ventricular tissue fibrosis, along with the increase of heart rate and cardiac muscle contractility were observed. As Lmbrd1+/- mice aged, the decrease in ejection fraction and fraction shortening showed signs of ventricular function deterioration. CONCLUSION: The results suggested that Lmbrd1 gene not only plays a significant role in mediating the energy homeostasis in cardiac tissue, it may also be a key factor in the regulation of cardiac function in mice.

Growth Differentiation Factor 15 May Predict Mortality of Peripheral and Coronary Artery Diseases and Correlate with Their Risk Factors.

Plasma GDF15 concentrations were measured in 612 Taiwanese individuals without overt systemic disease. Clinical parameters, GDF15 genetic variants, and 22 biomarker levels were analyzed. We further enrolled 86 patients with PAD and 481 patients with CAD, who received endovascular intervention and coronary angiography, respectively, to examine the role of GDF15 level in predicting all-cause mortality. Significant associations were found between GDF15 genotypes/haplotypes and GDF15 levels. The circulating GDF15 level was positively associated with age, smoking, hypertension, and diabetes mellitus as well as circulating levels of lipocalin 2 and various biomarkers of inflammation and oxidative stress. Kaplan-Meier survival analysis showed that baseline GDF15 levels of above 3096 pg/mL and 1123 pg/mL were strong predictors of death for patients with PAD and CAD, respectively (P = 0.011 and P < 0.001). GDF15 more accurately reclassified 17.3% and 29.2% of patients with PAD and CAD, respectively (P = 0.0046 and P = 0.0197), compared to C-reactive protein. Both genetic and nongenetic factors, including cardiometabolic and inflammatory markers and adipokines, were significantly associated with GDF15 level. A high level of GDF15 was significantly associated with an increase of all-cause mortality in patients with high-risk PAD and in patients with angiographically documented CAD.

Everolimus-Eluting Bioresorbable Vascular Scaffold in Real World Practice - A Single Center Experience.

BACKGROUND: Drug-eluting stents are widely used in coronary artery intervention. However, vessel caging and very late thrombotic events are of persistent and substantial concern. Bioresorbable vascular scaffolds (BVS) were developed to deliver vascular reparative therapy, by eliminating permanent mechanical restraint. However, data regarding its clinical performance is lacking. METHODS: After the BVS implantation procedure received national approval in May 2014, patients receiving BVS implantation until November 2014 in National Taiwan University Hospital (NTUH) were enrolled. Clinical variables, angiographic data, procedural details, and follow-up information were collected and compared with those receiving BVS at NTUH as part of the global ABSORB EXTEND trial. RESULTS: A total of 35 patients (38 target vessels) with 48 BVS implanted after approval were enrolled, as the "real-world practice" group. Data of the 34 patients (34 target vessels) with 37 BVS implanted in the ABSORB EXTEND trial were also obtained. Differences in lesion complexity (0% type B2/C lesion in ABSORB EXTEND, versus 23.7% in real-world, p = 0.007) and lesion length (20.9 ± 6.1 mm in ABSORB EXTEND, versus 29.5 ± 15.9 mm in real-world, p = 0.008) were noted. The ischemia-driven target vessel revascularization after an average of 732 days follow-up was 11.8% in the ABSORB EXTEND trial. However, there was no ischemia-driven target lesion revascularization (TLR), no scaffold thrombosis, no myocardial infarction (MI), and no patients passed during the follow-up period. In real-world patients, there is 5.3% of MI, 2.6% ischemia-driven TLR, and 2.6% of non-fatal probable scaffold thrombosis. CONCLUSIONS: The use of BVS in real-world practice is feasible, with clinical outcomes comparable to those in the ABSORB EXTEND trial.

The 2017 Focused Update of the Guidelines of the Taiwan Society of Cardiology (TSOC) and the Taiwan Hypertension Society (THS) for the Management of Hypertension.

Hypertension (HT) is the most important risk factor for cardiovascular diseases. Over the past 25 years, the number of individuals with hypertension and the estimated associated deaths has increased substantially. There have been great debates in the past few years on the blood pressure (BP) targets. The 2013 European Society of Hypertension and European Society of Cardiology HT guidelines suggested a unified systolic BP target of 140 mmHg for both high-risk and low-risk patients. The 2014 Joint National Committee report further raised the systolic BP targets to 150 mmHg for those aged ≥ 60 years, including patients with stroke or coronary heart disease, and raised the systolic BP target to 140 mmHg for diabetes. Instead, the 2015 Hypertension Guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society suggested more aggressive BP targets of < 130/80 mmHg for patients with diabetes, coronary heart disease, chronic kidney disease with proteinuria, and atrial fibrillation patients on antithrombotic therapy. Based on the main findings from the Systolic Blood Pressure Intervention Trial (SPRINT) and several recent meta-analyses, the HT committee members of the Taiwan Society of Cardiology and the Taiwan Hypertension Society convened and finalized the revised BP targets for management of HT. We suggested a new systolic BP target to < 120 mmHg for patients with coronary heart disease, chronic kidney disease with an eGFR of 20-60 ml/min/1.73 m2, and elderly patients aged ≥ 75 years, using unattended automated office BP measurement. When traditional office BP measurement is applied, we suggested BP target of < 140/90 mmHg for elderly patients with an age ≥ 75 years. Other BP targets with traditional office BP measurement remain unchanged. With these more aggressive BP targets, it is foreseeable that the cardiovascular events will decrease substantially in Taiwan.

Next-generation sequencing of nine atrial fibrillation candidate genes identified novel de novo mutations in patients with extreme trait of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. METHODS: We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. RESULTS: We identified a novel mutation in the 5' untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10(-4)). Functional study showed that the mutation in the 5' untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. CONCLUSIONS: The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause.

Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study.

BACKGROUND: The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. METHODS: Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet Mapping(TM) (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. RESULTS: Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. CONCLUSIONS: Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. KEY WORDS: Clopidogrel • CYP2C19 polymorphism • Platelet aggregation • Proton pump inhibitors • TEG • VASP.