Repetition of Paclitaxel-Coated Devices for the Treatment of Lower Extremity Artery Disease: Mortality Outcomes and Predictors.

Background: A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives: To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods: We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results: The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions: Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

Malnutrition is Associated with Increased Morbidity and Death in Dialysis Patients Undergoing Endovascular Therapy for Peripheral Artery Disease.

OBJECTIVE: Revascularisation for peripheral artery disease (PAD) is increasingly common in dialysis patients. Patients with PAD who have undergone revascularisation are at high risk of subsequent complications. Malnutrition is an important modifiable risk factor for dialysis patients, yet few data exist on the prognostic impact of malnutrition on post-procedure long term outcomes. The objective was to assess the prevalence and prognostic association of malnutrition using the Controlling Nutritional Status (CONUT) score in a prospective cohort of dialysis patients undergoing endovascular therapy (EVT) for PAD. METHODS: A total of 395 consecutive dialysis patients undergoing endovascular revascularisation for lower extremity PAD between 2005 and 2019 were examined for the primary outcome of all cause death. Secondary outcomes included major adverse limb events (MALEs), defined as acute limb ischaemia, major amputation, and clinically driven revascularisation; and major adverse cardiovascular events (MACEs). Nutritional status was assessed by CONUT score, a screening tool for malnutrition, incorporating albumin, cholesterol, and total lymphocyte count. RESULTS: According to the CONUT score, 40.8% of patients were moderately or severely malnourished. During a median follow up of 2.2 years, 218 (55.2%) patients died; 211 (53.4%) patients had MALEs, and MACEs occurred in 135 (34.2%) patients. Compared with normal nutritional status, severe malnutrition was associated with a significantly increased risk of all cause death (adjusted hazard ration [aHR] 4.83, 95% confidence interval [CI] 2.56 - 9.12) and MALEs (aHR 2.42, 95% CI 1.23 - 4.74) but not MACEs (aHR 1.81, 95% CI 0.74 - 4.40). Similar results were observed when the CONUT score was analysed as a continuous variable. CONCLUSION: Malnutrition is common in dialysis patients with PAD requiring endovascular therapy and is strongly associated with increased death and MALEs. Clinical trials are needed to evaluate whether nutritional interventions improve outcomes for dialysis patients after peripheral revascularisation.

Differential Genetic and Epigenetic Effects of the KLF14 Gene on Body Shape Indices and Metabolic Traits.

The KLF14 gene is a key metabolic transcriptional transregulator with monoallelic maternal expression. KLF14 variants are only associated with adipose tissue gene expression, and KLF14 promoter methylation is strongly associated with age. This study investigated whether age, sex, and obesity mediate the effects of KLF14 variants and DNA methylation status on body shape indices and metabolic traits. In total, the data of 78,742 and 1636 participants from the Taiwan Biobank were included in the regional plot association analysis for KLF14 variants and KLF14 methylation, respectively. Regional plot association studies revealed that the KLF14 rs4731702 variant and the nearby strong linkage disequilibrium polymorphisms were the lead variants for lipid profiles, blood pressure status, insulin resistance surrogate markers, and metabolic syndrome mainly in female participants and for body shape indices mainly in obese women. Significant age-dependent associations between KLF14 promoter methylation levels and body shape indices, and metabolic traits were also noted predominantly in female participants. KLF14 variants and KLF14 hypermethylation status were associated with metabolically healthy and unhealthy phenotypes, respectively, in obese individuals, and only the KLF14 variants demonstrated a significant association with both higher adiposity and lower cardiometabolic risk in the same allele, revealing uncoupled excessive adiposity from its cardiometabolic comorbidities, especially in obese women. Variations of KLF14 are associated with body shape indices, metabolic traits, insulin resistance, and metabolically healthy status. Differential genetic and epigenetic effects of KLF14 are age-, sex- and obesity-dependent. These results provided a personalized reference for the management of cardiometabolic diseases in precision medicine.

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study.

PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM (p = 0.0098 and 5.02 × 10-7, respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.

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.

An Innovative Customized Biomimetic Hydrogel for Drug Screening Application Potential: Biocompatibility and Cell Invasion Ability.

The ability of Pluronic F127 (PF127) conjugated with tetrapeptide Gly-Arg-Gly-Asp (GRGD) as a sequence of Arg-Gly-Asp (RGD) peptide to form the investigated potential hydrogel (hereafter referred to as 3DG bioformer (3BE)) to produce spheroid, biocompatibility, and cell invasion ability, was assessed in this study. The fibroblast cell line (NIH 3T3), osteoblast cell line (MG-63), and human breast cancer cell line (MCF-7) were cultured in the 3BE hydrogel and commercial product (Matrigel) for comparison. The morphology of spheroid formation was evaluated via optical microscopy. The cell viability was observed through cell counting Kit-8 assay, and cell invasion was investigated via Boyden chamber assay. Analytical results indicated that 3BE exhibited lower spheroid formation than Matrigel. However, the 3BE appeared biocompatible to NIH 3T3, MG-63, and MCF-7 cells. Moreover, cell invasion ability and cell survival rate after invasion through the 3BE was displayed to be comparable to Matrigel. Thus, these findings demonstrate that the 3BE hydrogel has a great potential as an alternative to a three-dimensional cell culture for drug screening applications.

Circulating chemerin level is associated with metabolic, biochemical and haematological parameters-A population-based study.

OBJECTIVE: This study aims to analyse the association of chemerin levels with several metabolic, biochemical and haematological parameters in a large Taiwanese population with relative healthy status. DESIGN: Cross-sectional study. METHODS: Data of 4101 healthy participants without history of hypertension, diabetes, dyslipidaemia and renal insufficiency from Taiwan Biobank were analysed. The demographic, biochemical and haematologic parameters were retrieved from the database. Chemerin levels were measured using commercially available enzyme-linked immunosorbent assay. Univariate and multivariate analysis was performed to test the independent correlates of chemerin. RESULTS: In the univariate analysis, circulating chemerin levels were positively associated with body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), systolic (SBP) and diastolic blood pressure (DBP), haemoglobin A1C (HbA1C), total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), creatinine, uric acid, alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT), leucocyte and platelet counts both in men and women and negatively associated with high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR) and total bilirubin. In the multivariate analysis, BMI, HbA1C, triglyceride, uric acid, γ-GT and platelet counts predicted chemerin levels independently both in men and in women with positive correlation, while eGFR, total bilirubin and HDL-C predicted circulating chemerin levels independently with negative correlation. CONCLUSIONS: Chemerin level is independently associated with multiple metabolic, biochemical and haematological parameters. This study provides further evidence on the molecular basis linking obesity with several human diseases.

Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population.

MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46-MUC1-THBS3-MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46-MUC1-THBS3-MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.

Association Rule Mining and Prognostic Stratification of 2-Year Longevity in Octogenarians Undergoing Endovascular Therapy for Lower Extremity Arterial Disease: Observational Cohort Study.

BACKGROUND: Two-year longevity is a crucial consideration in revascularization strategies for patients with symptomatic lower extremity arterial disease (LEAD). However, factors associated with 2-year longevity and risk stratification in octogenarians or nonagenarians have been underreported. OBJECTIVE: This paper aims to investigate the associated variables and stratify the 2-year prognosis in older patients with LEAD. METHODS: We performed logistic regression and association rule mining based on the Apriori algorithm to discover independent variables and validate their associations with 2-year longevity. Malnutrition, inflammation, and stroke factors were identified. C statistics and Kaplan-Meier analysis were used to assess the impact of different numbers of malnutrition, inflammation, and stroke factors on 2-year longevity. RESULTS: We recruited a total of 232 octogenarians or nonagenarians (mean age 85 years, SD 4.2 years) treated with endovascular therapy. During the study period, 81 patients died, and 27 of those (33%) died from a cardiac origin within 2 years. Association rules analysis showed the interrelationships between 2-year longevity and the neutrophil-lymphocyte ratio (NLR) and nutritional status as determined by the Controlling Nutritional Status (CONUT) score or Geriatric Nutritional Risk Index (GNRI). The cut-off values of NLR, GNRI, and CONUT were ≥3.89, ≤90.3, and >3, respectively. The C statistics for the predictive power for 2-year longevity were similar between the CONUT score and the GNRI-based models (0.773 vs 0.760; P=.57). The Kaplan-Meier analysis showed that 2-year longevity was worse as the number of malnutrition, inflammation, and stroke factors increased from 0 to 3 in both the GNRI-based model (92% vs 68% vs 46% vs 12%, respectively; P<.001) and the CONUT score model (87% vs 75% vs 49% vs 10%, respectively; P<.001). The hazard ratio between those with 3 factors and those without was 18.2 (95% CI 7.0-47.2; P<.001) in the GNRI and 13.6 (95% CI 5.9-31.5; P<.001) in the CONUT score model. CONCLUSIONS: This study demonstrated the association and crucial role of malnutrition, inflammation, and stroke factors in assessing 2-year longevity in older patients with LEAD. Using this simple risk score might assist clinicians in selecting the appropriate treatment.

Contemporary cardiovascular outcomes in Taiwanese patients undergoing endovascular therapy for symptomatic lower extremity peripheral arterial disease.

BACKGROUND/PURPOSE: To investigate contemporary cardiovascular (CV) outcomes in Taiwanese patients with symptomatic low extremity peripheral artery disease treated with endovascular therapy. METHODS: An observational cohort study with up to 155 months of follow-up was conducted using a single-center registry database between July 2005 and June 2017. Long-term outcomes and predictors of future CV events were analyzed in 936 patients with 1246 affected legs. RESULTS: This study cohort comprised 21% claudicants and 79% critical limb ischemia (CLI) patients. Compared with claudicants, CLI patients had higher rates of medical comorbidities, tissue inflammation, and lesion complexities. During the study period, 349 patients died (130 CV deaths and 219 non-CV deaths), 306 had non-fatal CV events. The rates of 5-year freedom from all-cause mortality, major CV events (MACEs), and non-fatal CV events were 54.9%, 67.1%, and 56.6% respectively. For CLI patients, independent factors for all-cause mortality were age (odds ratio [OR] 1.03), atrial fibrillation (OR 1.79), albumin (OR 0.62), hematocrit (OR 0.96), body mass index (OR 0.94), C-reactive protein (OR 1.18), dialysis (OR 2.16), and non-ambulance (OR 2.05). Congestive heart failure, dialysis, and non-ambulance independently predicted the MACEs (OR 2.04, 1.93, and 1.67, respectively). For claudicants, coronary artery disease (CAD) was the essential factor for all-cause mortality (OR 2.24), MACE (OR 2.76) and non-fatal CV events (OR 1.82). CONCLUSION: Long-term survival and MACE-free rates were significantly worse in CLI patients than in claudicants. Malnutrition and inflammation were associated with long-term survival. CAD, low hematocrit, dialysis, CHF, and ambulatory status predicted future CV events.

Pleiotropic association of LIPC variants with lipid and urinary 8-hydroxy deoxyguanosine levels in a Taiwanese population.

BACKGROUND: Hepatic lipase (HL, encoded by LIPC) is a glycoprotein primarily synthesized and secreted by hepatocytes. Previous studies had demonstrated that HL is crucial for reverse cholesterol transport and affects the metabolism, composition, and level of several lipoproteins. In current study, we investigated the association of LIPC (Lipase C, Hepatic Type) variants with circulating and urinary biomarker levels by using subgroup and mediation analyses. METHODS: A total of 572 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs) by using TaqMan assay. Fasting levels of glucose, lipid profile, inflammation markers, urine creatinine and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The chi-square test, 2-sample t test and Analysis of variance (ANOVA) were used to examine differences among variables and genotype frequencies. RESULTS: SNPs rs2043085 and rs1532085 were significantly associated with urinary 8-OHdG levels, whereas all three SNPs were more significantly associated with Triglycerides (TG) or HDL-cholesterol (HDL-C) levels after additional adjustment for HDL-C or TG levels, respectively. Subgroup analyses revealed that the association of the LIPC SNPs with the levels of serum TG, HDL-C, and urinary 8-OHdG were predominantly observed in the men but not in the women. Differential associations of the LIPC SNPs with various lipid levels were observed in participants with different adiposity statuses. Mediation analyses indicated that TG levels acted as a suppressor masking the association of the LIPC genotypes with HDL-C levels, particularly in the men (Sobel test, all P < 0.01). CONCLUSION: Our data revealed that interaction and suppression effects mediated the pleiotropic association of the LIPC variants. The effects of the LIPC SNPs depended on sex, adiposity status, and TG levels. Thus, our findings can provide a method for identifying high-risk populations of cardiovascular diseases for clinical diagnosis.

Feasibility and Mid-Term Outcomes of Drug-Coated Balloon Angioplasty Between Intermittent Claudication and Critical Limb Ischemia in Patients with Femoropopliteal Disease.

BACKGROUND: The efficacy of drug-coated balloons (DCBs) in critical limb ischemia (CLI) is unclear. To investigate the clinical characteristics and outcomes of DCBs in symptomatic femoropopliteal disease between patients with intermittent claudication (IC) and CLI. METHODS: Data were retrospectively collected from three centers in Taiwan on patients who received DCBs for femoropopliteal lesions between March 2013 and June 2017. We compared the clinical characteristics and outcomes regarding binary restenosis, amputation-free survival (AFS), and major adverse limb events (MALEs) between groups. Cox proportional hazards analysis was used to identify predictors of outcome endpoints. RESULTS: We enrolled a total of 200 affected limbs in 174 patients, including 83 limbs in 71 patients with IC and 117 limbs in 103 patients with CLI. Compared to the patients with claudication, those with CLI were older and had higher proportions of medical comorbidities, tissue inflammation, poor runoff, and vessel calcification. The 3-year rates of freedom from binary restenosis (57% vs. 59%, p = 0.781), and MALEs (77% vs. 67%, p = 0.507) were similar between the two groups. However, the 3-year AFS was significantly higher in the IC group compared to the CLI group (91% vs. 73%, p = 0.001). Lesion length and severe calcification independently predicted binary restenosis, and restenotic lesion predicted MALEs. Age, congestive heart failure, and dialysis were independently associated with AFS. CONCLUSIONS: Despite advanced limb ischemia and comorbidities, the mid-term outcomes in surviving CLI patients were similar to those in the IC patients after treatment with DCBs for femoropopliteal disease.

2019 Focused Update of the Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure.

Heart failure is a growing epidemic, especially in Taiwan because of the aging population. The 2016 Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry showed that the guideline-recommended therapies were prescribed suboptimally both at the time of hospital discharge and during follow-up. We, therefore, conducted this 2019 focused update of the guidelines of the Taiwan Society of Cardiology for the diagnosis and treatment of heart failure to reinforce the importance of new diagnostic and therapeutic modalities of heart failure. The 2019 focused update discusses new diagnostic criteria, pharmacotherapy, non-pharmacological management, and certain co-morbidities of heart failure. Angiotensin receptor neprilysin inhibitor and If channel inhibitor is introduced as new and recommended medical therapies. Latest criteria of cardiac resynchronization therapy, implantable cardioverter-defibrillator, heart transplantation, and ventricular assist device therapy are reviewed in the non-pharmacological management chapter. Co-morbidities in heart failure are discussed including chronic kidney disease, diabetes, chronic obstructive pulmonary disease, and sleep-disordered breathing. We also explain the adequate use of oxygen therapy and non-invasive ventilation in heart failure management. A particular chapter for chemotherapy-induced cardiac toxicity is incorporated in the focused update to emphasize the importance of its recognition and management. Lastly, implications from the TSOC-HFrEF registry and post-acute care of heart failure are discussed to highlight the importance of guideline-directed medical therapy and the benefits of multidisciplinary disease management programs. With guideline recommendations, we hope that the management of heart failure can be improved in our society.

Drug-Coated Balloon vs. Conventional Balloon Angioplasty in Dialysis Patients With Symptomatic Femoropopliteal Disease　- A Matched Comparison.

BACKGROUND: Recent randomized trials have shown the treatment benefits of use of a drug-coated balloon (DCB) over conventional percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. However, the effectiveness and safety of DCB for dialysis patients remain unclear.Methods and Results:Consecutive dialysis patients, who underwent PTA or DCB for femoropopliteal disease, were assessed retrospectively via 2:1 propensity score matching. Effectiveness and safety endpoints, including binary restenosis, clinically driven target lesion revascularization (CD-TLR), amputations, major adverse cardiac events (MACE), and deaths, were compared between groups. A total of 278 dialysis patients with 339 limbs were eligible for matching: 84 limbs from 77 patients treated with PTA and 46 limbs from 37 patients treated with DCB were compared after matching. Baseline patient and lesion characteristics were not different between groups. Patients treated with DCB had significantly higher rates of freedom from binary restenosis (52.4% vs. 18.6%, P<0.001) and CD-TLR (56.4% vs. 25.9%, P=0.001) at 2 years compared with patients treated with PTA. Both groups had similar outcomes for amputation, MACE, and death. Cox proportional analysis showed that treatment with DCB was independently associated with a reduction of binary restenosis (hazard ratio [HR] 0.368, P=0.001) and CD-TLR (HR 0.390, P=0.004). CONCLUSIONS: This study suggested superior 2-year outcomes using DCB compared with PTA and similar safety profiles in dialysis patients with femoropopliteal disease.

Clinical Outcomes of Repetition of Drug-Coated Balloon for Femoropopliteal Restenosis After Drug-Coated Balloon Treatment.

BACKGROUND: To compare the clinical outcomes of patients undergoing repeated drug-coated balloon (DCB) treatment for femoropopliteal (FP) DCB restenosis with those of patients without repetition-DCB.Methods and Results:From March 2013 to September 2014, 102 patients (118 affected legs) underwent DCB for symptomatic FP disease; 47 patients had restenosis, and 37 underwent reintervention over a 45-month follow-up. We compared the outcomes of repetition-DCB for DCB restenosis with those of patients without repetition. The baseline patient and lesion characteristics were similar between groups. The mean lesion length was 200.8±113.1 and 195.2±134.6 mm, P=0.894, respectively. In addition, the procedural and follow-up outcomes were not different. The rates of freedom from binary restenosis (70% vs. 14%, P=0.001) and clinically driven target lesion revascularization (CD-TLR) (78% vs. 38%, P=0.026) at 1 year were statistically different between groups. Cox regression analysis showed that repetition of DCB was the only predictor for freedom from binary restenosis (hazard ratio [HR]: 6.15, 95% confidence interval (CI) 1.60 to 23.6, P=0.008) and CD-TLR (HR: 5.37, 95% CI 1.32-22.0, P=0.019). CONCLUSIONS: For FP DCB restenosis, repetition of DCB can potentially improve vessel patency and significantly reduce the need for reintervention compared with conventional treatment. However, these observations require further confirmation in larger scale studies.

Outcomes of Endovascular Therapy With the Controlled Antegrade Retrograde Subintimal Tracking (CART) or Reverse CART Technique for Long Infrainguinal Occlusions.

PURPOSE: To compare the safety, efficacy, and clinical outcomes associated with the controlled antegrade retrograde subintimal tracking (CART) or reverse CART (r-CART) technique to the conventional retrograde approach in the treatment of patients with long infrainguinal occlusions. METHODS: From May 2008 to April 2014, 121 patients failed antegrade recanalization and underwent a retrograde approach to recanalize long infrainguinal occlusions. Patients who underwent successful endovascular therapy (EVT) by the conventional retrograde approach (CRA group) were compared to patients who had successful EVT using the CART/r-CART technique (CART group) after failure of a bidirectional approach. The efficacy, safety, vessel patency, and other clinical outcomes were compared between the groups. RESULTS: Fifty-eight patients (mean age 71.6 ± 12.2 years; 32 men) underwent successful EVT (47.9%, 58/121) using the conventional retrograde approach (CRA group), while 44 patients (mean age 70.8 ± 11.1 years; 31 men) among the 50 patients who underwent the CART/r-CART technique were successfully treated (88.0%, 44/50). Both groups had similar average occlusion lengths and gained 100% immediate hemodynamic success after EVT. There was no significant difference between the groups regarding procedure-related complications. During follow-up, 28 patients died (p=0.380), but there were no differences in the rates of major (p=0.279) or minor amputation (p=0.417) between the groups. There was no difference in the 2-year primary patency (31% vs 24%, p=0.686), assisted primary patency (66% vs 76%, p=0.251), target vessel revascularization (65% vs 54%, p=0.845), or sustained clinical success (52% vs 46%, p=0.995) rates between the CRA and CART groups, respectively. CONCLUSION: Based on acceptable safety, efficacy, and follow-up results in this study, the CART/r-CART technique can salvage patients with long peripheral occlusions after failure of the conventional antegrade or retrograde approach.

Interactive effects of C-reactive protein levels on the association between APOE variants and triglyceride levels in a Taiwanese population.

BACKGROUND: Apolipoprotein E (APOE) plays a major role in lipid metabolism and inflammation. However, the association between APOE gene polymorphisms and serum triglyceride levels remains controversial. We tested the effects of APOE variants on triglyceride levels and their interactions with the inflammatory marker C-reactive protein (CRP) in a Taiwanese population. METHODS: Two APOE single nucleotide polymorphisms (SNPs) rs429358 and rs7412 were genotyped by TaqMan Assay using real time PCR in 595 healthy subjects attending the clinic for routine visits. RESULTS: After adjustment for clinical covariates, subjects carrying the rs429358-TT genotype and non-ε4 alleles were found to have higher CRP levels, whereas those with rs7412-CC genotype and non-ε2 alleles had significantly higher total and low-density lipoprotein cholesterol levels (all P < 0.01). Using subgroup and interaction analyses, we observed significantly lower triglyceride levels in subjects carrying the rs429358-TT genotype and non-ε4 alleles in the low CRP group (P = 2.71 × 10(-4) and P = 4.32 × 10(-4), respectively), but not in those in the high CRP group (interaction P = 0.013 and 0.045, respectively). In addition, multivariate stepwise linear regression analysis showed that subjects carrying the rs429358-TT genotype and non-ε4 alleles with low CRP levels had significantly lower triglyceride levels (P < 0.001 and P < 0.001, respectively). In addition, when combined with the risk alleles of GCKR, APOA5 and LPL gene variants, we observed that triglyceride levels increased significantly with the number of risk alleles (P = 2.9 × 10(-12)). CONCLUSIONS: The combination of SNPs and ε alleles at the APOE locus is involved in managing lipid and CRP levels in the Taiwanese population. APOE polymorphisms interact with CRP to regulate triglyceride levels, thus triglyceride concentration is influenced by both the genetic background of the APOE locus and the inflammatory status of a subject.

CRP and SAA1 Haplotypes Are Associated with Both C-Reactive Protein and Serum Amyloid A Levels: Role of Suppression Effects.

To test the statistical association of the CRP and SAA1 locus variants with their corresponding circulating levels and metabolic and inflammatory biomarker levels by using mediation analysis, a sample population of 599 Taiwanese subjects was enrolled and five CRP and four SAA1 variants were genotyped. Correlation analysis revealed that C-reactive protein (CRP) and serum amyloid A (SAA) levels were significantly associated with multiple metabolic phenotypes and inflammatory marker levels. Our data further revealed a significant association of CRP and SAA1 variants with both CRP and SAA levels. Mediation analysis revealed that SAA levels suppressed the association between SAA1 genotypes/haplotypes and CRP levels and that CRP levels suppressed the association between CRP haplotypes and SAA levels. In conclusion, genetic variants at the CRP and SAA1 loci independently affect both CRP and SAA levels, and their respective circulating levels act as suppressors. These results provided further evidence of the role of the suppression effect in biological science and may partially explain the missing heritability in genetic association studies.