PCSK9 inhibitor added to high-intensity statin therapy to prevent cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention: a randomized, double- blind, placebo-controlled, multicenter SHAWN study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1,212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at 1-year follow-up between 2 groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Comparison of intravascular ultrasound-guided with angiography-guided double kissing crush stenting for patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DKCRUSH VIII trial.

BACKGROUND: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion. TRIAL DESIGN: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure. CONCLUSIONS: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.

Platelet Surface CD62p and Serum Vitamin D Levels are Associated with Clopidogrel Resistance in Chinese Patients with Ischemic Stroke.

BACKGROUND: To explore the association of platelet activation markers, vitamin D, and antiplatelet drugs resistance in ischemic stroke patients. METHODS: A total of 230 patients with ischemic stroke were enrolled in this study. Platelet aggregation, platelet activation marker (CD62p), and vitamin D were measured after 7-14 days of dual antiplatelet treatment (aspirin + clopidogrel). All individuals were divided into a drug resistance group and a drug sensitive group according to the platelet maximum aggregation rate induced by antagonist adenosine diphosphate or arachidonic acid. RESULTS: In this study, the prevalence of aspirin resistance was low (1.2%), while the prevalence of clopidogrel resistance (CR) was 24.8%, so we focused on CR. The percentage of CD62p on activated platelet [(25.74 ± 4.61) versus (12.41 ± 3.93), P < .001] and the prevalence of hypertension [93.0% (53) versus 79.8% (138), P = .021] in CR group were significantly higher than those in clopidogrel sensitive (CS) group, while the vitamin D concentration [(8.96 ± 4.41) versus (13.9 ± 4.84) ng/mL, P = .003] in CR group was significantly lower compared with the CS group. No significant difference was found in soluble P-selectin between these 2 groups [(56.2 ± 16.13) versus (54.2 ± 14.87) ng/mL, P = .258], neither in calcium [(2.29 ± .12) versus (2.33 ± .13) mmol/L, P = .821]. Logistic regression analysis showed that hypertension (odds ratio [OR] = 5.348, 95% confidence intervals [CI] 1.184-23.350, P = .026), expression of platelet CD62p (OR = 1.095, 95% CI 1.052-1.201, P = .018) and vitamin D level (OR = .832, 95% CI .763-.934, P = .005) were associated with CR in ischemic stroke patients. CONCLUSIONS: CR in ischemic stroke patients is associated with several independent predictors, including increased platelet activation marker CD62p, decreased vitamin D level, and hypertension.

Association between the MTHFR A1298C polymorphism and risk of cancer: evidence from 265 case-control studies.

Many molecular, epidemiological studies have been performed to explore the association between MTHFR A1298C polymorphism and cancer risk. However, the results were inconsistent or even contradictory. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR A1298C (81,040 cases and 114,975 controls from 265 studies) polymorphism. Overall, significant association was observed between MTHFR A1298C polymorphism and cancer risk when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly increased cervical cancer (dominant model: OR 1.46, 95 % CI 1.13-1.90; AC vs. AA: OR 1.48, 95 % CI 1.13-1.92) and lymphoma (dominant model: OR 1.22, 95 % CI 1.04-1.44; recessive model: OR 1.66, 95 % CI 1.15-2.39; CC vs. AA: OR 1.75, 95 % CI 1.21-2.53) risk were observed in Asians, and significantly decreased colorectal cancer risk was found in Asians (recessive model: OR 0.75, 95 % CI 0.59-0.96; CC vs. AA: OR 0.77, 95 % CI 0.60-1.00). In summary, this meta-analysis suggests that MTHFR A1298C polymorphism is associated with increased cervical cancer and lymphoma risk in Asians, and MTHFR A1298C polymorphism is associated with decreased colorectal cancer risk in Asians. Moreover, this meta-analysis also points out the importance of new studies, such as oral cancer and chronic myeloid leukemia, because they had high heterogeneity in this meta-analysis (I (2) > 75 %).

High platelet reactivity affects the clinical outcomes of patients undergoing percutaneous coronary intervention.

BACKGROUND: The association of platelet reactivity and clinical outcomes, especially stent thrombosis, was not so clear. We sought to investigate whether high platelet reactivity affects clinical outcomes of patients with drug eluting stents (DESs) implantation. METHODS: All enrolled individuals treated with DESs implantation were evaluated by PL-11, using sequentially platelet counting method. The primary end point was the occurrence of definite and probable stent thrombosis at 2 years. The secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all cause death, spontaneous myocardial infarction (MI), target vessel revascularization (TVR), and ischemic stroke. RESULTS: A total of 1331consecutive patients were enrolled at our center. There were 91 patients (6.8 %) identified with high platelet reactivity (HPR) on aspirin, and 437 patients (32.9 %) with HPR on clopidogrel. At 2-year follow-up, the incidence of stent thrombosis was significantly higher in patients with HPR on aspirin (9.9 % vs. 0.4 %, p < 0.001), and HPR on clopidogrel (3.0 % vs. 0.1 %, p < 0.001). There were increased MACCE in the HPR on aspirin group (16.5 % vs. 8.5 %, p = 0.021), mainly driven by the higher all cause death (7.7 % vs. 1.6 %, p = 0.002) and MI (9.9 % vs. 1.9 %, p < 0.001) in the HPR on aspirin group. Similarly, the rate of MACCE was higher in the HPR on clopidogrel group (12.4 % vs. 7.4 %, p = 0.004). No differences in all bleeding and hemorrhagic stroke were observed. CONCLUSIONS: The present study demonstrated that high platelet reactivity on both aspirin and clopidogrel were associated with incremental stent thrombosis following DESs implantation.

Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis.

The previous, published data on the association between CYP1B1 polymorphisms and cancer risk remained controversial. To derive a more precise estimation of the association between the CYP1B1 polymorphisms and cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP1B1 Leu432Val, Asn453Ser, Arg48Gly, and Ala119Ser polymorphisms. For Asn453Ser and Arg48Gly polymorphisms, significantly decreased endometrial cancer was observed among Caucasians. For Ala119Ser polymorphism, we found that individuals with the minor variant genotypes had a high risk of prostate cancer. For Leu432Val polymorphism, we found that individuals with the minor variant genotypes had a higher risk of endometrial cancer and lung cancer and had a lower risk of ovarian cancer. In summary, this meta-analysis suggests that Leu432Val polymorphism is associated with ovarian cancer, lung cancer, and endometrial cancer risk; Asn453Ser and Arg48Gly polymorphisms are associated with endometrial cancer risk among Caucasians, Ala119Ser polymorphism is associated with prostate cancer risk, and Ala119Ser polymorphism is associated with breast cancer risk in Caucasians. In addition, our work also points out the importance of new studies for Ala119Ser polymorphism in endometrial cancer, because high heterogeneity was observed (I (2) > 75 %).

Association between the STK15 polymorphisms and risk of cancer: a meta-analysis.

The previous published data on the association between STK15 F31I and V57I polymorphisms and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and STK15 F31I (42,315 cases and 50,542 controls from 62 studies) and V57I polymorphisms (12,891 cases and 17,391 controls from 18 studies) in different inheritance models. Overall, significant association was observed between F31I and cancer risk when all the eligible studies were pooled into the meta-analysis (recessive model: OR = 1.14, 95 % CI = 1.06-1.24; AA vs. TT: OR = 1.12, 95 % CI = 1.02-1.24; A vs. T: OR = 1.05, 95 % CI = 1.01-1.09). In the further stratified and sensitivity analyses, for STK15 F31I, significantly increased breast cancer (recessive model: OR = 1.16, 95 % CI = 1.02-1.33; AA vs. TT: OR = 1.16, 95 % CI = 1.01-1.33) and ovarian cancer (dominant model: OR = 1.20, 95 % CI = 1.07-1.34; TA vs. TT: OR = 1.19, 95 % CI = 1.06-1.34; A vs. T: OR = 1.15, 95 % CI = 1.05-1.26) risk was found among Caucasians, and significantly decreased lung cancer risk was found among Caucasians (recessive model: OR = 0.65, 95 % CI = 0.49-0.87; AA vs. TT: OR = 0.65, 95 % CI = 0.49-0.88). For V57I polymorphism, significant decreased breast cancer risk was found among Caucasians (recessive model: OR = 0.76, 95 % CI = 0.61-0.95; AA vs. GG: OR = 0.75, 95 % CI = 0.60-0.94; A vs. G: OR = 0.92, 95 % CI = 0.86-0.98). In summary, this meta-analysis suggests that STK15 F31I polymorphism is associated with increased breast cancer and ovarian cancer risk among Caucasians, F31I polymorphism is associated with decreased lung cancer risk among Caucasians, and V57I polymorphism is associated with decreased breast cancer risk among Caucasians.

Association between the CYP1A2 polymorphisms and risk of cancer: a meta-analysis.

The previously published data on the association between CYP1A2*1C (rs2069514) and CYP1A2*1F (rs762551) polymorphisms and cancer risk have remained controversial. Hence, we performed a meta-analysis to investigate the association between CYP1A2*1F and CYP1A2*1C polymorphisms and cancer risk under different inheritance models. Overall, significant association was observed between CYP1A2*1F and cancer risk when all the eligible studies were pooled into the meta-analysis (dominant model: OR 1.08, 95 % CI 1.02-1.15; heterozygous model: OR 1.06, 95 % CI 1.01-1.12; additive model: OR 1.07, 95 % CI 1.02-1.13). In the further stratified and sensitivity analyses, for CYP1A2*1F polymorphism, significantly increased lung cancer risk and significantly decreased bladder cancer risk were observed in Caucasians. For CYP1A2*1C polymorphism, no significant association was found in overall and all subgroup analyses. In summary, this meta-analysis suggests that CYP1A2*1F polymorphism is associated with lung cancer and bladder cancer risk in Caucasians.

Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies.

Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I(2) > 75%).

Association between the CYP3A4 and CYP3A5 polymorphisms and cancer risk: a meta-analysis and meta-regression.

Previously published data on the association between CYP3A4 A392G and CYP3A5 Met235Thr polymorphisms and the risk of cancer remained controversial. Thus, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP3A4 A392G (18,629 cases and 22,323 controls from 49 studies) and CYP3A5 Met235Thr polymorphisms (14,334 cases and 18,183 from 39 studies) in different inheritance models. We used odds ratios with 95 % confidence intervals to assess the strength of the association. Overall, significant association was found between CYP3A4 A392G polymorphism and cancer susceptibility (dominant model, odds ratio (OR) = 1.19; 95 % confidence interval (CI) = 1.03-1.38). In the further stratified and sensitivity analyses, significant increased prostate cancer risk was found among Caucasians (dominant model, OR = 1.88; 95 % CI = 1.20-2.95; recessive model, OR = 2.10; 95 % CI = 1.23-3.60; additive model, OR = 1.80, 95 % CI = 1.24-2.63; homozygous model, OR = 2.34, 95 % CI = 1.36-4.03; heterozygote model, OR = 1.79, 95 % CI = 1.11-2.89) for CYP3A4 A392G. For CYP3A5 Met235Thr polymorphism, no significant association was found among overall analysis and any subgroup analysis. In summary, this meta-analysis suggests that CYP3A4 A392G polymorphism is associated with increased prostate cancer risk among Caucasians and CYP3A5 Met235Thr polymorphism is not associated with the risk of cancer.

ATM-R: An Adaptive Tradeoff Model With Reference Points for Constrained Multiobjective Evolutionary Optimization.

The goal of constrained multiobjective evolutionary optimization is to obtain a set of well-converged and well-distributed feasible solutions. To achieve this goal, a delicate tradeoff must be struck among feasibility, diversity, and convergence. However, balancing these three elements simultaneously through a single tradeoff model is nontrivial, mainly because the significance of each element varies in different evolutionary phases. As an alternative approach, we adapt distinct tradeoff models in various phases and introduce a novel algorithm named adaptive tradeoff model with reference points (ATM-R). In the infeasible phase, ATM-R takes the tradeoff between diversity and feasibility into account, aiming to move the population toward feasible regions from diverse search directions. In the semi-feasible phase, ATM-R promotes the transition from "the tradeoff between feasibility and diversity" to "the tradeoff between diversity and convergence." This transition is instrumental in discovering an adequate number of feasible regions and accelerating the search for feasible Pareto optima in succession. In the feasible phase, ATM-R places an emphasis on balancing diversity and convergence to obtain a set of feasible solutions that are both well-converged and well-distributed. It is worth noting that the merits of reference points are leveraged in ATM-R to accomplish these tradeoff models. Also, in ATM-R, a multiphase mating selection strategy is developed to generate promising solutions beneficial to different evolutionary phases. Systemic experiments on a diverse set of benchmark test functions and real-world problems demonstrate that ATM-R is effective. When compared to eight state-of-the-art constrained multiobjective optimization evolutionary algorithms, ATM-R consistently demonstrates its competitive performance.

Intravascular ultrasound-guided systematic two-stent techniques for coronary bifurcation lesions and reduced late stent thrombosis.

BACKGROUND: The effects of intravascular ultrasound (IVUS)-guided complex approaches using drug-eluting stents (DES) for coronary bifurcation lesions on clinical outcomes has not yet been studied in detail. OBJECTIVE: Our objective was to analyze the difference in 1-year outcomes following two-stent techniques involving implantation of DES for coronary bifurcation lesions between IVUS-guided and angiography-guided groups. METHODS: From May 26, 2007 to March 24, 2010, 628 patients received two-stent techniques (324 in the IVUS-guided group and 304 angiography-guided) and were prospectively studied. We compared major adverse cardiac events (MACE, including cardiac death, stent thrombosis [ST], myocardial infarction [MI] and target lesion/vessel revascularization) at 12-months follow-up, before and after adjusting for propensity score matching. RESULTS: At 12-months after the indexed procedure, patients in the angiography-guided group had significantly increased in-stent restenosis. Compared to the angiography-guided group, the IVUS-guided group had a significantly lower overall unadjusted ST rate (1.2% vs. 6.9%, P < 0.001), definite ST (0.6% vs. 5.3%, P < 0.001), late ST (0.6% vs. 4.3%, P = 0.003), MI (4.6% vs. 8.9%, P = 0.038) and cardiac death (0.9% vs. 3.3%, P = 0.049). By propensity score matching, 123 paired patients were matched. The late ST at 12-months follow-up was 0% in the IVUS-guided group versus 4.9% in the angiography-guided group (P = 0.029), resulting in significant differences in ST-elevation MI between the two groups (2.4% vs. 9.8%, P = 0.030). CONCLUSIONS: The IVUS-guided two-stent technique was associated with significantly reduced late stent thrombosis, with a resultant reduction in ST-elevation MI. © 2012 Wiley Periodicals, Inc.

Association analysis of USF1 gene polymorphisms and total unstable carotid plaque area in atherosclerotic stroke patients.

Polymorphisms of the upstream stimulatory factor 1 (USF1) have been associated with carotid artery intima-media thickness and coronary atherosclerotic lesions. Unstable carotid plaque is an atherosclerotic change of vascular morphology that has been correlated with cerebrovascular ischemic symptoms. Associations of three single nucleotide polymorphisms of the USF1 gene with total unstable carotid plaque area (CPA) were investigated in Chinese atherosclerotic stroke patients. We recruited 668 atherosclerotic stroke patients and 602 controls. Total unstable CPA values were measured by ultrasound. Genotypes were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) or mismatched PCR-RFLP. A significant difference in total unstable CPA was found for rs2516838 and rs2516839 genotypes (P = 0.039 and 0.046, respectively) in atherosclerotic stroke patients with unstable carotid plaque. Furthermore, in multiple logistic regression analysis adjusted by age, sex, BMI, hypertension, smoking status, glucose, total cholesterol, triglycerides, high-density lipoprotein-cholesterols, low-density lipoprotein-cholesterols and high-sensitivity C-reactive protein, significant associations were seen between the total unstable CPA values and genotypes of the rs2516838 or the rs2516839 in these patients. The rare allele C of rs2516838 or rare allele A of rs2516839 could predict relative low total unstable CPA values. The rs2516838 and rs2516839 polymorphisms of USF1 influence total unstable CPA in atherosclerotic stroke patients, which might be new markers to predict the risk of recurrence for this disease.

[Risk factors and clinical outcome of coronary artery aneurysms developed after drug-eluting stent implantation].

OBJECTIVE: To evaluate risk factors and clinical outcome of coronary artery aneurysms (CAA) developed after drug-eluting stent implantation evidenced by coronary angiographic follow-up. METHODS: This study analyzed 4500 consecutive patient with de novo coronary artery stenosis receiving drug-eluting stent (DES) implantation from January 2004 to May 2009. Seven hundred and sixty patients with angiographic follow-ups at 6 - 8 months and 28 - 48 months after the index procedure were enrolled. CAA was defined as a localized dilatation exceeding 1.5 times the diameter of the adjacent artery. The independent risk factors and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target-vessel revascularization (TVR) and in-stent thrombosis were analyzed. RESULTS: CAA was detected in 70 patients with 70 lesions (9.2%, 70/760). Logistic analysis showed that lesion in an infarct-related artery (OR: 5.9, P < 0.01), lesion in the left anterior descending artery (OR: 4.5, P < 0.01), lesion with chronic total occlusion (OR: 3.4, P < 0.05), and lesion length > 33 mm (OR: 2.9, P < 0.05) were independent risk factors for CAA. Follow-up duration was (1131 ± 478) days. MACE was found in 19 patients and all received TVR. There were 11 patients with myocardial infarction and 8 patients with evidence of in-stent thrombosis. Mortality was zero during follow-up. CONCLUSIONS: The risk factors for the development of CAA after DES are lesions in an infarct-related artery, in the left anterior descending artery, with chronic total occlusion, and with lesion length > 33 mm. MACE is not uncommon in patients with CAA and long-ferm clinical follow-up is warranted for patients with CAA.

[Comparison of short- and long-term outcome after percutaneous transluminal interventional therapy in octogenarians with coronary artery disease from radial or femoral approach].

OBJECTIVE: To compare the short-term and long-term outcome after percutaneous coronary intervention (PCI) between transradial intervention (TRI) and transfemoral intervention (TFI) in elderly patients. METHODS: From January 2005 to December 2010, 488 consecutive elderly patients ( ≥ 80 years old) were enrolled in this retrospective study. Patients were divided into TRI group (n = 235, PCIs were performed trans-radial approach) and TFI group (n = 253, PCIs were performed trans-femoral approach). Efficacy and safety data were compared between the two groups. RESULTS: There were no differences in success rate of stenting, procedure time, contrast amount, rates of contrast-induced nephropathy, major adverse cardiovascular events during hospitalization, at one year follow up and at two years follow up. Lower vascular complications were associated with TRI approach[ 17.9% (42/253) vs. 26.9% (68/253) , P < 0.05], especially in TIMI major bleeding ratio [1.3% (3/235) vs. 4.7% (12/253) , P < 0.05], TIMI minor bleeding [5.1% (12/235) vs. 15.8% (40/253) , P < 0.01], and time lying in bed [3.6 (2.8-4.2)h vs. 24.4 (24.0-25.1)h, P < 0.01] and hospitalization [3.0 (3.0-4.0)d vs. 5.0 (5.0-6.0)d, P < 0.01], and higher rates of crossover approach were associated with TRI [11.5% (27/235) vs. 2.0(5/253) , P < 0.01]. CONCLUSION: TRI is as feasible, safe and effective as TFI in elderly patients during short-term and long-term follow up, and TRI is associated with higher rates of crossover approach.

Regulation of short-chain fatty acids in the immune system.

A growing body of research suggests that short-chain fatty acids (SCFAs), metabolites produced by intestinal symbiotic bacteria that ferment dietary fibers (DFs), play a crucial role in the health status of symbiotes. SCFAs act on a variety of cell types to regulate important biological processes, including host metabolism, intestinal function, and immune function. SCFAs also affect the function and fate of immune cells. This finding provides a new concept in immune metabolism and a better understanding of the regulatory role of SCFAs in the immune system, which impacts the prevention and treatment of disease. The mechanism by which SCFAs induce or regulate the immune response is becoming increasingly clear. This review summarizes the different mechanisms through which SCFAs act in cells. According to the latest research, the regulatory role of SCFAs in the innate immune system, including in NLRP3 inflammasomes, receptors of TLR family members, neutrophils, macrophages, natural killer cells, eosinophils, basophils and innate lymphocyte subsets, is emphasized. The regulatory role of SCFAs in the adaptive immune system, including in T-cell subsets, B cells, and plasma cells, is also highlighted. In addition, we discuss the role that SCFAs play in regulating allergic airway inflammation, colitis, and osteoporosis by influencing the immune system. These findings provide evidence for determining treatment options based on metabolic regulation.

Handling Constrained Multiobjective Optimization Problems via Bidirectional Coevolution.

Constrained multiobjective optimization problems (CMOPs) involve both conflicting objective functions and various constraints. Due to the presence of constraints, CMOPs' Pareto-optimal solutions are very likely lying on constraint boundaries. The experience from the constrained single-objective optimization has shown that to quickly obtain such an optimal solution, the search should surround the boundary of the feasible region from both the feasible and infeasible sides. In this article, we extend this idea to cope with CMOPs and, accordingly, we propose a novel constrained multiobjective evolutionary algorithm with bidirectional coevolution, called BiCo. BiCo maintains two populations, that is: 1) the main population and 2) the archive population. To update the main population, the constraint-domination principle is equipped with an NSGA-II variant to move the population into the feasible region and then to guide the population toward the Pareto front (PF) from the feasible side of the search space. While for updating the archive population, a nondominated sorting procedure and an angle-based selection scheme are conducted in sequence to drive the population toward the PF within the infeasible region while maintaining good diversity. As a result, BiCo can get close to the PF from two complementary directions. In addition, to coordinate the interaction between the main and archive populations, in BiCo, a restricted mating selection mechanism is developed to choose appropriate mating parents. Comprehensive experiments have been conducted on three sets of CMOP benchmark functions and six real-world CMOPs. The experimental results suggest that BiCo can obtain quite competitive performance in comparison to eight state-of-the-art-constrained multiobjective evolutionary optimizers.

Serial intravascular ultrasound analysis comparing double kissing and classical crush stenting for coronary bifurcation lesions.

BACKGROUND: Compared with the classical crush, double kissing (DK) crush improved outcomes in patients with coronary bifurcation lesions. However, there is no serial intravascular ultrasound (IVUS) comparisons between these two techniques. OBJECTIVES: This study aimed to analyze the mechanisms of the two crush stenting techniques using serial IVUS imaging. METHODS: A total of 54 patients with IVUS images at baseline, post-stenting and eight-month follow-up were classified into classical (n = 16) and DK (n = 38) groups. All patients underwent final kissing balloon inflation (FKBI). Unsatisfactory kissing (KUS) was defined as the presence of wrist or >20% stenosis during FKBI at the side branch (SB) ostium. The vessels at bifurcation lesions were divided into the proximal main vessel (MV) stent, the crushed segment, the distal MV stent, the SB ostium and the SB stent body. RESULTS: KUS and incomplete crushing were commonly observed in the classical group (62.5%, 81.3%), compared with DK group (18.0%, 39.5%, P < 0.001 and P = 0.004). The post-stenting stent symmetry in the classical group was 71.85 ± 7.69% relative to 85.93 ± 6.09% in DK group (P = 0.022), resulting in significant differences in neointimal hyperplasia (NIH, 1.60 ± 0.21 mm(2) vs. 0.85 ± 0.23 mm(2) , P = 0.005), late lumen loss (1.31 ± 0.81 mm(2) vs. 0.55 ± 0.70 mm(2) , P = 0.013), and minimal lumen area (MLA, 3.57 ± 1.52 mm(2) vs. 4.52 ± 1.40 mm(2,) P = 0.042) at the SB ostium between two groups. KUS was positively correlated with the incomplete crush and was the only predictor of in-stent-restenosis (ISR) at the SB ostium. CONCLUSION: DK crush was associated with improved quality of the FKBI and larger MLA. KUS predicted the occurrence of ISR.

Oxidized low-density lipoprotein and ß-glycerophosphate synergistically induce endothelial progenitor cell ossification.

AIM: To investigate the ability of ox-LDL to induce ossification of endothelial progenitor cells (EPCs) in vitro and explored whether oxidative stress, especially hypoxia inducible factor-1α (HIF-1α) and reactive oxygen species (ROS), participate in the ossific process. METHODS: Rat bone marrow-derived endothelial progenitor cells (BMEPCs) were cultured in endothelial growth medium supplemented with VEGF (40 ng/mL) and bFGF (10 ng/mL). The cells were treated with oxidized low-density lipoprotein (ox-LDL, 5 µg/mL) and/or ß-glycerophosphate (ß-GP, 10 mmol/L). Calcium content and Von Kossa staining were used as the measures of calcium deposition. Ossific gene expression was determined using RT-PCR. The expression of osteocalcin (OCN) was detected with immunofluorescence. Alkaline phosphatase (ALP) activity was analyzed using colorimetric assay. Intercellular reactive oxygen species (ROS) were measured with flow cytometry. RESULTS: BMEPCs exhibited a spindle-like shape. The percentage of cells that expressed the cell markers of EPCs CD34, CD133 and kinase insert domain-containing receptor (KDR) were 46.2%±5.8%, 23.5%±4.0% and 74.3%±8.8%, respectively. Among the total cells, 78.3%±4.2% were stained with endothelial-specific fluorescence. Treatment of BMEPCs with ox-LDL significantly promoted calcium deposition, which was further significantly enhanced by co-treatment with ß-GP. The same treatments significantly increased the gene expression of core-binding factor a-1 (cbfa-1) and OCN, while decreased the gene expression of osteoprotegerin (OPG). The treatments also significantly enhanced the activity of ALP, but did not affect the number of OCN(+) cells. Furthermore, the treatments significantly increased ROS and activated the hypoxia inducible factor-1α (HIF-1α). In all these effects, ox-LDL acted synergistically with ß-GP. CONCLUSION: Ox-LDL and ß-GP synergistically induce ossification of BMEPCs, in which an oxidizing mechanism is involved.