Routine stress testing in diabetic patients after percutaneous coronary intervention: the POST-PCI trial.

BACKGROUND AND AIMS: The optimal follow-up surveillance strategy for high-risk diabetic patients with had undergone percutaneous coronary intervention (PCI) remains unknown. METHODS: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) study was a randomized trial comparing a follow-up strategy of routine functional testing at 1 year vs. standard care alone after high-risk PCI. Randomization was stratified according to diabetes status. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. RESULTS: Among 1706 randomized patients, participants with diabetes (n = 660, 38.7%) had more frequent comorbidities and a higher prevalence of complex anatomical or procedural characteristics than those without diabetes (n = 1046, 61.3%). Patients with diabetes had a 52% greater risk of primary composite events [hazard ratio (HR) 1.52; 95% confidence interval (CI) 1.02-2.27; P = .039]. The 2-year incidences of the primary composite outcome were similar between strategies of routine functional testing or standard care alone in diabetic patients (7.1% vs. 7.5%; HR 0.94; 95% CI 0.53-1.66; P = .82) and non-diabetic patients (4.6% vs. 5.1%; HR 0.89; 95% CI 0.51-1.55; P = .68) (interaction term for diabetes: P = .91). The incidences of invasive coronary angiography and repeat revascularization after 1 year were higher in the routine functional-testing group than the standard-care group irrespective of diabetes status. CONCLUSIONS: Despite being at higher risk for adverse clinical events, patients with diabetes who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing compared with standard care alone during follow-up.

Optical Coherence Tomography-Guided or Intravascular Ultrasound-Guided Percutaneous Coronary Intervention: The OCTIVUS Randomized Clinical Trial.

BACKGROUND: Intravascular imaging-guided percutaneous coronary intervention (PCI) with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) showed superior clinical outcomes compared with angiography-guided PCI. However, the comparative effectiveness of OCT-guided and IVUS-guided PCI regarding clinical outcomes is unknown. METHODS: In this prospective, multicenter, open-label, pragmatic trial, we randomly assigned 2008 patients with significant coronary artery lesions undergoing PCI in a 1:1 ratio to undergo either an OCT-guided or IVUS-guided PCI. The primary end point was a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at 1 year, which was powered for noninferiority of the OCT group compared with the IVUS group. Safety outcomes were also assessed. RESULTS: At 1 year, primary end point events occurred in 25 of 1005 patients (Kaplan-Meier estimate, 2.5%) in the OCT group and in 31 of 1003 patients (Kaplan-Meier estimate, 3.1%) in the IVUS group (absolute difference, -0.6 percentage points; upper boundary of one-sided 97.5% CI, 0.97 percentage points; P<0.001 for noninferiority). The incidence of contrast-induced nephropathy was similar (14 patients [1.4%] in the OCT group versus 15 patients [1.5%] in the IVUS group; P=0.85). The incidence of major procedural complications was lower in the OCT group than in the IVUS group (22 [2.2%] versus 37 [3.7%]; P=0.047), although imaging procedure-related complications were not observed. CONCLUSIONS: In patients with significant coronary artery lesions, OCT-guided PCI was noninferior to IVUS-guided PCI with respect to the incidence of a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at 1 year. The selected study population and lower-than-expected event rates should be considered in interpreting the trial. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique number: NCT03394079.

Low- or standard-dose edoxaban versus antiplatelet therapy for leaflet thrombus and cerebral thromboembolism after TAVR: A prespecified analysis of randomized ADAPT-TAVR trial.

BACKGROUND: The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. METHODS: In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. RESULTS: Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P = .03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P = .58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. CONCLUSIONS: In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction.

T7 phage display reveals NOLC1 as a GM3 binding partner in human breast cancer MCF-7 cells.

Ganglioside GM3 is a simple monosialoganglioside (NeuAc-Gal-Glc-ceramide) that modulates cell adhesion, proliferation, and differentiation. Previously, we reported isolation of GM3-binding vascular endothelial growth factor receptor and transforming growth factor-ß receptor by the T7 phage display method (Chung et al., 2009; Kim et al., 2013). To further identify novel proteins interacting with GM3, we extended the T7 phage display method in this study. After T7 phage display biopanning combined with immobilized biotin-labeled 3'-sialyllactose prepared on a streptavidin-coated microplate, we isolated 100 candidate sequences from the human lung cDNA library. The most frequently detected clones from the blast analysis were the human nucleolar and coiled-body phosphoprotein 1 (NOLC1) sequences. We initially identified NOLC1 as a molecule that possibly binds to GM3 and confirmed this binding ability using the glutathione S-transferase fusion protein. Herein, we report another GM3-interacting protein, NOLC1, that can be isolated by the T7 phage display method. These results are expected to be helpful for elucidating the functional roles of ganglioside GM3 with NOLC1. When human breast cancer MCF-7 cells were examined for subcellular localization of NOLC1, immunofluorescence of NOLC1 was observed in the intracellular region. In addition, NOLC1 expression was increased in the nucleolus after treatment with the anticancer drug doxorubicin. GM3 and NOLC1 levels in the doxorubicin-treated MCF-7 cells were correlated, indicating possible associations between GM3 and NOLC1. Therefore, direct interactions between carbohydrates and cellular proteins can pave the path for new signaling phenomena in biology.

Positional scanning of natural product hispidol's ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases.

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

Tailoring a Dynamic Metal-Polymer Interaction to Improve Catalyst Selectivity and Longevity in Hydrogenation.

Controlling metal-support interactions is important for tuning the catalytic properties of supported metal catalysts. Here, premade Pd particles are supported on stable polymers containing different ligating functionalities to control the metal-polymer interactions and their catalytic properties in industrially relevant acetylene partial hydrogenation. The polymers containing strongly ligating groups (e.g., Ar-SH and Ar-S-Ar) can form a polymer overlayer on the Pd surface, which enables selective acetylene adsorption and partial hydrogenation to ethylene without deactivation. In contrast, polymers with weakly ligating groups (e.g., Ar-O-Ar) do not form an overlayer, resulting in non-selective hydrogenation and fast deactivation, similar to Pd catalysts on conventional inorganic supports. The results imply that tuning the metal-polymer interactions via rational polymer design can provide an efficient way of synthesizing selective and stable catalysts for hydrogenation.

Prognostic Value of Poststenting Fractional Flow Reserve After Imaging-Guided Optimal Stenting.

BACKGROUND: Prognostic value of poststenting fractional flow reserve (FFR) remains uncertain in patients undergoing an imaging-guided optimal stenting strategy. OBJECTIVES: The authors evaluated the prognostic value of poststenting FFR according to the intracoronary imaging-guided lesion preparation, stent sizing, and postdilation (iPSP) strategy to optimize stent outcomes. METHODS: Poststenting FFR assessment was performed in 1,108 lesions in 1,005 patients from the IRIS-FFR registry. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization at 5 years. RESULTS: At the index procedure, 326 lesions (29.4%) were treated using all 3 parts of the iPSP strategy. In the overall population, poststenting FFR was significantly associated with the risk of TVF at 5 years (per 0.01 increase of FFR, adjusted HR [aHR]: 0.94; 95% CI: 0.90-0.98; P = 0.004). Significant interaction was detected between poststenting FFR and the iPSP strategy on the risk of TVF at 5 years (P = 0.045 for interaction). In the iPSP group, poststenting FFR was not associated with the risk of TVF at 5 years (per 0.01 increase of FFR, aHR: 1.00; 95% CI: 0.96-1.05; P = 0.95), whereas a significant association between poststenting FFR and TVF at 5 years was observed in the no iPSP group (per 0.01 increase of FFR, aHR: 0.94; 95% CI: 0.90-0.99; P = 0.009). CONCLUSIONS: Poststenting FFR showed a significant association with cardiac events. However, its prognostic value appeared to be limited after the application of an imaging-guided optimal stenting strategy.

Impact of Target Lesion Revascularization on Long-Term Mortality After Percutaneous Coronary Intervention for Left Main Disease.

BACKGROUND: Although target lesion revascularization (TLR) after percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) disease is not rare, its timing of occurrence and prognostic impact on long-term mortality is uncertain. OBJECTIVES: This study sought to investigate TLR incidence over time and its impact on mortality after PCI with drug-eluting stents (DES) for LMCA disease. METHODS: Using a pooled data from 4 multicenter observational registries (IRIS-DES [Interventional Cardiology Research Incorporation Society-Drug-Eluting Stents], IRIS-MAIN [Interventional Cardiology Research Incorporation Society-Left MAIN Revascularization], MAIN-COMPARE [Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization], and PRECOMBAT [PREmier of Randomized COMparison of Bypass Surgery versus AngioplasTy Using Drug-Eluting Stent in Patients with Left Main Coronary Artery Disease]), we evaluated 1,397 patients with LMCA disease treated with DES and available long-term mortality data. The association between TLR and the 10-year risk of mortality was examined by multivariable Cox proportional hazards regression, with TLR as a time-varying covariate. RESULTS: During maximum follow-up of 10 years (median 6.8 years), TLR occurred in 118 patients and its 10-year cumulative incidence was 10.8%. TLR mostly occurred within 2 years after initial PCI and decreased over time: early-stage TLR (within 2 years) in 73 (61.9%) patients and late-stage TLR (beyond 2 years) in 45 (38.1%) patients. Among all TLR patients, 23 patients underwent coronary artery bypass grafting and 95 underwent repeat PCI. In the time-varying multivariable Cox model, the presence of TLR was not significantly associated with an increased risk of mortality (adjusted HR: 0.90; 95% CI: 0.50-1.63; P = 0.73). CONCLUSIONS: Although the incidence of ischemia-driven TLR was mostly common within 2 years after left main PCI, TLR occurred steadily during the 10-year follow-up period. However, given that such patients were optimally revascularized, the prognostic impact of TLR on mortality was not substantial. (Evaluation of the First, Second, and New Drug-Eluting Stents in Routine Clinical Practice [IRIS-DES]; NCT01186133; Observational Study for Left Main Disease Treatment [IRIS-MAIN]; NCT01341327; Ten-Year Outcomes of Stents Versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease [MAIN COMPARE]; NCT02791412; Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease [PRECOMBAT]; NCT00422968).

Evaluation of Instantaneous Wave-Free Ratio and Fractional Flow Reserve in Severe Aortic Valve Stenosis.

BACKGROUND: The optimal functional evaluation of coronary artery stenosis in patients with severe aortic stenosis (AS) has not been established. The objective of the study was to evaluate the instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) in patients with and without severe AS. METHODS: We retrospectively investigated 395 lesions in 293 patients with severe AS and 2257 lesions in 1882 patients without severe AS between 2010 and 2022 from a subgroup of the Interventional Cardiology Research In-Cooperation Society FFR Registry. All patients had FFR values, and iFR was analyzed post hoc using dedicated software only in lesions with adequate resting pressure curves (311 lesions in patients with severe AS and 2257 lesions in patients with nonsevere AS). RESULTS: The incidence of iFR ≤0.89 was 66.6% and 31.8% (P<0.001), while the incidence of FFR ≤0.80 was 45.3% and 43.9% (P=0.60) in the severe AS group and the nonsevere AS group, respectively. In the severe AS group, most lesions (95.2%) with iFR >0.89 had FFR >0.80, while 36.2% of lesions with iFR ≤0.89 had FFR >0.80. During a median follow-up of 2 years, FFR ≤0.80 was significantly associated with deferred lesion failure (adjusted hazard ratio, 2.71 [95% CI, 1.08-6.80]; P=0.034), while iFR ≤0.89 showed no prognostic value (adjusted hazard ratio, 1.31 [95% CI, 0.47-3.60]; P=0.60) in the severe AS group. Lesions with iFR ≤0.89 and FFR >0.80, in particular, were not associated with a higher rate of deferred lesion failure at 3 years compared with lesions with iFR >0.89 (15.4% versus 17.0%; P=0.58). CONCLUSIONS: This study suggested that FFR appears to be less affected by the presence of severe AS and is more associated with prognosis. iFR may overestimate the functional severity of coronary artery disease without prognostic significance, yet it can be useful for excluding significant stenosis in patients with severe AS.

Optimal Minimal Stent Area and Impact of Stent Underexpansion in Left Main Up-Front 2-Stent Strategy.

BACKGROUND: We previously reported the use of minimal stent area to predict angiographic in-stent restenosis after drug-eluting stent implantation for unprotected left main (LM) disease. We aimed to evaluate the optimal minimal stent area criteria for up-front LM 2-stenting based on long-term clinical outcomes. METHODS: We identified 292 consecutive patients with LM bifurcation stenosis who were treated using the crush technique. The final minimal stent area was measured in the ostial left anterior descending artery (LAD), ostial left circumflex artery (LCX), and distal LM. The primary outcome was 5-year major adverse cardiac events, including all-cause death, myocardial infarction, and target lesion revascularization. RESULTS: The minimal stent area cutoff values that best predicted the 5-year major adverse cardiac events were 11.8 mm2 for distal LM (area under the curve, 0.57; P=0.15), 8.3 mm2 for LAD ostium (area under the curve, 0.62; P=0.02), and 5.7 mm2 for LCX ostium (area under the curve, 0.64; P=0.01). Using these criteria, the risk of 5-year major adverse cardiac events was significantly associated with stent underexpansion in the LAD ostium (hazard ratio, 3.14; [95% CI, 1.23-8.06]; P=0.02) and LCX ostium (hazard ratio, 2.60 [95% CI, 1.11-6.07]; P=0.03) but not in the distal LM (hazard ratio, 0.81 [95% CI, 0.34-1.91]; P=0.63). Patients with stent underexpansion in both ostial LAD and LCX had a significantly higher rate of 5-year major adverse cardiac events than those with no or 1 underexpanded stent of either ostium (P<0.01). CONCLUSIONS: Stent underexpansion in the LAD and LCX ostium was significantly associated with long-term outcomes in patients who underwent up-front 2-stenting for LM bifurcation stenosis.

Sex-Specific Disparities in Clinical Outcomes After Transcatheter Aortic Valve Replacement Among Different Racial Populations.

Background: Sex-related disparities in clinical outcomes following transcatheter aortic valve replacement (TAVR) and the impact of sex on clinical outcomes after TAVR among different racial groups are undetermined. Objectives: This study assessed whether sex-specific differences in baseline clinical and anatomical characteristics affect clinical outcomes after TAVR and investigated the impact of sex on clinical outcomes among different racial groups. Methods: The TP-TAVR (Trans-Pacific TAVR) registry is a multinational cohort study of patients with severe aortic stenosis who underwent TAVR at 2 major centers in the United States and 1 major center in South Korea. The primary outcome was a composite of death from any cause, stroke, or rehospitalization after 1 year. Results: The incidence of the primary composite outcome was not significantly different between sexes (27.9% in men vs 28% in women; adjusted HR: 0.97; 95% CI: 0.79-1.20). This pattern was consistent in Asian (23.5% vs 23.3%; adjusted HR: 0.99; 95% CI: 0.69-1.41) and non-Asian (30.8% vs 31.6%; adjusted HR: 0.95; 95% CI: 0.72-1.24) cohorts, without a significant interaction between sex and racial group (P for interaction = 0.74). The adjusted risk for all-cause mortality was similar between sexes, regardless of racial group. However, the adjusted risk of stroke was significantly lower in male patients than in female patients, which was more prominent in the non-Asian cohort. Conclusions: Despite significantly different baseline and procedural characteristics, there were no sex-specific differences in the adjusted 1-year rates of primary composite outcomes and all-cause mortality, regardless of different racial groups. (Transpacific TAVR registry [TP-TAVR]; NCT03826264).

Guiding Intervention for Complex Coronary Lesions by Optical Coherence Tomography or Intravascular Ultrasound.

BACKGROUND: Optical coherence tomography (OCT) and intravascular ultrasound (IVUS) have shown comparable outcomes in guiding percutaneous coronary intervention (PCI). However, their comparative effectiveness in complex coronary artery lesions remains unclear. OBJECTIVES: This study compared the effectiveness and safety of OCT-guided vs IVUS-guided PCI for complex coronary artery lesions. METHODS: This was a prespecified, main subgroup analysis of complex coronary artery lesions in the OCTIVUS (Optical Coherence Tomography Versus Intravascular Ultrasound Guided Percutaneous Coronary Intervention) trial, which included unprotected left main disease, bifurcation disease, an aorto-ostial lesion, a chronic total occlusion, a severely calcified lesion, an in-stent restenotic lesion, a diffuse long lesion, or multivessel PCI. The primary endpoint was a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target vessel revascularization. RESULTS: In 2,008 randomized patients, 1,475 (73.5%) underwent imaging-guided PCI for complex coronary artery lesions; 719 (48.7%) received OCT-guided and 756 (51.3%) IVUS-guided PCI. At a median follow-up of 2.0 years, primary endpoint event had occurred in 47 patients (6.5%) in the OCT-guided group and in 56 patients (7.4%) in the IVUS-guided group (HR: 0.87; 95% CI: 0.59-1.29; P = 0.50). These findings were consistent in adjusted analyses. The incidence of contrast-induced nephropathy was similar between the 2 groups (1.9% vs 1.5%; P = 0.46). The incidence of major procedural complications was lower in the OCT-guided group than in the IVUS-guided group (1.7% vs 3.4%; P = 0.03). CONCLUSIONS: Among patients with complex coronary artery lesions, OCT-guided PCI showed a similar risk of primary composite event of death from cardiac causes, target vessel-related myocardial infarction, or target vessel revascularization as compared with IVUS-guided PCI. (Optical Coherence Tomography Versus Intravascular Ultrasound Guided Percutaneous Coronary Intervention [OCTIVUS]; NCT03394079).

Surveillance Stress Testing After Percutaneous Intervention for Patients With Multivessel or Left Main Coronary Disease.

BACKGROUND: The optimal surveillance strategy after percutaneous coronary intervention (PCI) for high-risk patients with multivessel or left main coronary artery disease (CAD) remains uncertain. OBJECTIVES: This study aims to determine the prognostic role of routine functional testing in patients with multivessel or left main CAD who underwent PCI. METHODS: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented Versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) trial randomized high-risk PCI patients to routine functional testing at 1 year or standard care alone during follow-up. This analysis focused on participants with multivessel or left main CAD. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. RESULTS: Among 1,706 initially randomized patients, 1,192 patients with multivessel (n = 833) or left main (n = 359) were identified, with 589 in the functional testing group and 603 in the standard care group. Two-year incidences of primary outcome were similar between the functional testing group and the standard care group (6.2% vs 5.7%, respectively; HR: 1.09; 95% CI: 0.68-1.74; P = 0.73). This trend persisted in both groups of multivessel (6.2% vs 5.7%; HR: 1.09; 95% CI: 0.62-1.89; P = 0.78) and left main disease (6.2% vs 5.7%; HR: 1.09; 95% CI: 0.46-2.56; P = 0.85) (P for interaction = 0.90). Routine surveillance functional testing was associated with increased rates of invasive angiography and repeat revascularization beyond 1 year. CONCLUSIONS: In high-risk patients with multivessel or left main CAD who underwent PCI, there was no incremental clinical benefit from routine surveillance functional-testing compared with standard care alone during follow-up. (Pragmatic Trial Comparing Symptom-Oriented Versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention [POST-PCI]; NCT03217877).

Routine Stress Testing After PCI in Patients With and Without Acute Coronary Syndrome: A Secondary Analysis of the POST-PCI Randomized Clinical Trial.

Importance: The appropriate follow-up surveillance strategy for patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains unknown. Objective: To assess clinical outcomes in patients with and without ACS who have undergone high-risk PCI according to a follow-up strategy of routine stress testing at 12 months after PCI vs standard care alone. Design, Setting, and Participants: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented vs Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) trial was a randomized clinical trial that compared follow-up strategies of routine functional testing vs standard care alone 12 months after high-risk PCI. Patients were categorized as presenting with or without ACS. Patients were enrolled in the trial from November 2017 through September 2019, and patients were randomized from 11 sites in South Korea; data analysis was performed in 2022. Intervention: Patients categorized as presenting with or without ACS were randomized to either a routine functional testing or standard care alone follow-up strategy 12 months after high-risk PCI. Main Outcomes and Measures: The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years following randomization. Kaplan-Meier event rates through 2 years and Cox model hazard ratios (HRs) were generated, and interactions were tested. Results: Of 1706 included patients, 350 patients (20.5%) were female, and the mean (SD) patient age was 64.7 (10.3) years. In total, 526 patients (30.8%) presented with ACS. Compared with those without ACS, patients with ACS had a 55% greater risk of the primary outcome (HR, 1.55; 95% CI, 1.03-2.33; P = .03) due to higher event rates in the first year. The 2-year incidences of the primary outcome were similar between strategies of routine functional testing or standard care alone in patients with ACS (functional testing: 16 of 251 [6.6%]; standard care: 23 of 275 [8.5%]; HR, 0.76; 95% CI, 0.40-1.44; P = .39) and in patients without ACS (functional testing: 30 of 598 [5.1%]; standard care: 28 of 582 [4.9%]; HR, 1.04; 95% CI, 0.62-1.74; P = .88) (P for interaction for ACS = .45). Although a landmark analysis suggested that the rates of invasive angiography and repeat revascularization were higher after 1 year in the routine functional testing group, the formal interactions between ACS status and either invasive angiography or repeat revascularization were not significant. Conclusion and Relevance: Despite being at higher risk for adverse clinical events in the first year after PCI than patients without ACS, patients with ACS who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing at 12 months compared with standard care alone during follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT03217877.

Clinical outcomes after aortic valve replacement with severe stenosis of trileaflet aortic valve and low valve calcium score.

BACKGROUND: Some patients have severe aortic valve stenosis (AS) despite a lower degree of aortic valve calcification (AVC). This study compared the clinical features and prognosis of patients undergoing aortic valve replacement (AVR) for severe AS with a low AVC score compared with those with higher AVC scores. METHODS: This study included 1002 Korean patients with symptomatic severe degenerative AS who underwent AVR. We measured AVC score before AVR and defined low AVC as AVC score of <2000 units for male patients and <1300 units for female patients. Patients with bicuspid or rheumatic aortic valve disease were excluded. RESULTS: The mean age was 75.6±7.9 years and 487 patients (48.6%) were female. Mean left ventricular ejection fraction was 59.4%±10.4%, and concomitant coronary revascularisation was performed in 96 patients (9.6%). The median aortic valve calcium score was 3122 units (IQR 2249-4289 units) among male patients and 1756 units (IQR 1192-2572) among female patients. A total of 242 patients (24.2%) had low AVC; they were significantly younger (73.5±8.7 years vs 76.3±7.5 years, p<0.001) and were more likely to be female (59.5% vs 45.1%, p<0.001) and on haemodialysis (5.4% vs 1.8%, p=0.006) than those with high AVC. During a follow-up (median: 3.8 years), the patients with low AVC had significantly higher risk of death from any cause (adjusted HR 1.60, 95% CI 1.02 to 2.52, p=0.04), mostly non-cardiac cause. CONCLUSIONS: Patients with low AVC exhibit distinct clinical characteristics and a higher risk of long-term mortality compared with those with high AVC.

Design, synthesis, and repurposing of O6-aminoalkyl-sulfuretin analogs towards discovery of potential lead compounds as antileishmanial agents.

Up to date, there are still significantly unmet clinical needs for treatment of the fatal visceral leishmaniasis; a neglected tropical disease. Herein, a recently reported antileishmanial hit sulfuretin analog suffering from a low potency and a problematic aqueous solubility that hindered further development was used as a starting point. A mitigation rational via incorporation of O6-aminoalkyl moiety suggest structures analogous to literature-known compounds as cholinesterase inhibitors. Consequently, preparation and repurposing of a library of these compounds unveiled their potential activity against the parasite Leishmania donovani promastigotes. Further evaluation against intracellular form of the parasite and host cells suggested compounds 2a, 2c, and 2o derived from sulfuretin analogs bearing 2'-methoxy or 2',5'-dimethoxy substituents at ring-B as promising lead compounds with potential activity and acceptable safety window relative to the standard edelfosine. In silico simulation predicted plausible binding modes of these compounds to L. donovani fumarate reductase. Together this work presents compound 2o as a potential lead compound for further development.

Bestatin analogs-4-quinolinone hybrids as antileishmanial hits: Design, repurposing rational, synthesis, in vitro and in silico studies.

Amongst different forms of leishmaniasis, visceral leishmaniasis caused by L. donovani is highly mortal. Identification of new hit compounds might afford new starting points to develop novel therapeutics. In this lieu, a rationally designed small library of bestatin analogs-4-quinolone hybrids were prepared and evaluated. Analysis of SAR unveiled distinct profiles for hybrids type 1 and type 2, which might arise from their different molecular targets. Amongst type 1 bestatin analog-4-quinolone hybrids, hybrid 1e was identified as potential hit inhibiting growth of L. donovani promastigotes by 91 and 53% at 50 and 25 µM concentrations, respectively. Meanwhile, hybrid 2j was identified amongst type 2 bestatin analog-4-quinolone hybrids as potential hit compound inhibiting growth of L. donovani promastigotes by 50 and 38% at 50 and 25 µM concentrations, respectively. Preliminary safety evaluation of the promising hit compounds showed that they are 50-100 folds safer against human derived monocytic THP-1 cells relative to the drug erufosine. In silico study was conducted to predict the possible binding of hybrid 1e with methionine aminopeptidases 1 and 2 of L. donovani. Molecular dynamic simulations verified the predicted binding modes and provide more in depth understanding of the impact of hybrid 1e on LdMetAP-1 and LdMetAP-2.

Impact of Optimal Medical Therapy on Long-Term Outcomes After Myocardial Revascularization for Multivessel Coronary Disease.

Although optimal medical therapy (OMT) after coronary revascularization is advocated for intensive secondary prevention, its criteria and effect on long-term outcomes are uncertain. Using data from the ASAN-Multivessel (Asan Medical Center-Multivessel Revascularization) registry, we identified 8,311 patients who underwent coronary artery bypass grafting (CABG) (n = 3,115) or percutaneous coronary intervention (PCI) (n = 5,196). OMT was defined as the combination of minimum of 3 medications in 4 drug classes (antiplatelet drugs, statins, ß blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). Two primary outcomes were all-cause mortality and serious composite outcome of death, spontaneous myocardial infarction, or stroke at 10 years. Of 8,311 patients, 4,321 (52.0%) followed OMT. In the 3,397 propensity-score-matched cohort, OMT status compared with non-OMT status was significantly associated with a lower risk of all-cause mortality (10.7% vs 18.7%; hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.47 to 0.65) and serious composite outcome (14.5% vs 22.5%, HR 0.635, 95% CI 0.55 to 0.73) at 10 years. The association on 10-year mortality was more prominent in the PCI group (HR 0.45, 95% CI 0.36 to 0.56) than in the CABG group (HR 0.72, 95% CI 0.58 to 0.90) with a significant interaction (p = 0.001). Overall findings were consistent using different OMT criteria (all 4 types of medications). In conclusion, OMT significantly lowered the risks of mortality and major cardiovascular events at 10 years in patients with multivessel revascularization. The OMT impact on mortality was more remarkable in the PCI group than in the CABG group. This work was registered at http://ClinicalTrials.gov (Identifier: NCT02039752).

Synthesis and Biological Evaluation of O6-Aminoalkyl-Hispidol Analogs as Multifunctional Monoamine Oxidase-B Inhibitors towards Management of Neurodegenerative Diseases.

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells' death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE2 production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases.

Validation of Academic Research Consortium for High Bleeding Risk Definition in East-Asian Patients.

Background: Clinical applicability of the Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria in East-Asian patients receiving potent antiplatelet therapy for acute coronary syndromes (ACS) is still undetermined. Objectives: The purpose of this study was to validate the ARC definition for HBR in East-Asian patients with ACS for invasive management. Methods: We analyzed data from the TICAKOREA (Ticagrelor Versus Clopidogrel in Asian/Korean Patients With ACS Intended for Invasive Management) trial and randomly assigned 800 Korean ACS subjects to receive, in a 1:1 ratio, ticagrelor or clopidogrel. Patients were considered HBR if they met at least 1 major or 2 minor ARC-HBR criteria. The primary bleeding endpoint was Bleeding Academic Research Consortium 3 or 5 bleeding and the primary ischemic endpoint was a major adverse cardiovascular event (MACE) (a composite of cardiovascular death, myocardial infarction, or stroke) at 12 months. Results: Among 800 randomized patients, 129 (16.3%) were categorized HBR patients. HBR patients, compared with non-HBR patients, had a higher incidence of Bleeding Academic Research Consortium 3 or 5 bleeding (10.0% vs 3.7%; HR: 2.98; 95% CI: 1.52-5.86; P < 0.001) and MACE (14.3% vs 6.1%; HR: 2.35; 95% CI: 1.35-4.10; P = 0.002). The relative treatment effect of ticagrelor or clopidogrel on primary bleeding and ischemic outcomes were different between each group. Conclusions: This study validates the ARC-HBR definition in Korean ACS patients. Approximately 15% of patients qualified as HBR patients who were at increased risk not only for bleeding but also for thrombotic events. The clinical application of ARC-HBR to determine the relative effect of different antiplatelet regiments should be further investigated. (Safety and Efficacy of Ticagrelor Versus Clopidogrel in Asian/KOREAn Patients with Acute Coronary Syndromes Intended for Invasive Management [TICA KOREA]; NCT02094963).