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Abstract Background Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. Methods From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3–5) and gastrointestinal (GI) bleeding (BARC types 3–5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. Results Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18–8.78). The incidence of major bleeding and GI bleeding (BARC types 3–5) was comparable between PPI users and non-users in the PS-matched cohort. Conclusions In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.

BackgroundData on the clinical impact of beta-blockers (BBs) in patients with myocardial infarction (MI) who had non-reduced left ventricular ejection fraction (LVEF) after percutaneous coronary intervention are limited.MethodsFrom 2016 to 2020, we evaluated a cohort of 12,101 myocardial infarction patients with a non-reduced LVEF (≥40%) from the Korean Acute Myocardial Infarction Registry V. Patients were divided into two groups based on their BB (carvedilol, bisoprolol, or nebivolol) treatment at discharge: with beta-blocker treatment (BB, n = 9,468) and without beta-blocker treatment (non-BB, n = 2,633). The primary endpoint after discharge was the occurrence of patient-oriented composite endpoints (POCEs), including all-cause mortality, any MI, or any revascularization at 1-year follow-up.ResultsThe median follow-up period was 353 days (interquartile range, 198–378 days). At 1-year follow-up, no significant differences were observed in the primary endpoint between the BB group and the non-BB group. Before propensity score (PS) matching, the POCE incidence was 3.1% in the BB group vs. 3.4% in the non-BB group [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.68–1.09, p = 0.225]. After PS matching, the POCE incidence remained similar between the two groups (3.7% vs. 3.4%, HR 1.01, 95% CI 0.76–1.35, p = 0.931). Individual outcomes, including all-cause mortality, myocardial infarction, and revascularization, also showed no significant differences between the two groups. Independent predictors of 1-year POCEs after discharge were age, chronic kidney disease, reduced LVEF, and multivessel disease.ConclusionBB treatment in patients with acute MI and non-reduced LVEF was not associated with a significant reduction in cardiovascular outcomes at 1-year follow-up.

Aims: Calcium channel blockers (CCBs) are frequently co-administered with clopidogrel in cardiovascular disease. Although an inhibitory drug interaction exists between them, comprehensive large-scale studies for its validation are lacking. We investigated interactions between CCBs and clopidogrel using a large-scale national registry of patients who underwent percutaneous coronary intervention (PCI). Methods and Results: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test consortium investigates the association between platelet function test and long-term prognosis during dual antiplatelet therapy including clopidogrel in patients using drug-eluting stents. We compared the ex vivo platelet reactivity using the VerifyNow P2Y12 test and clinical outcomes between CCB users and non-users. Between 2003 and 2018, 11 714 patients were enrolled and categorized into two groups according to CCB usage. A composite endpoint encompassing all-cause mortality, myocardial infarction, stent thrombosis, or stroke was defined as a major adverse cardiac and cerebrovascular event (MACCE). During the 5-year follow-up period, no significant differences were observed in P2Y12 reaction units (215.8 ± 84.7 vs 218.4 ± 76.7, P = .156), MACCEs, major bleeding, or high platelet reactivity rates, even after adjusting for propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). When limited to the high platelet reactivity cohort (≥252 PRU), the results remained consistent for MACCE [PSM-adjusted, HR: 0.923 (0.644-1.323), P -value .663; IPTW-adjusted, HR: 1.300 (0.822-2.056), P -value .262]. Conclusions: CCB and clopidogrel co-administration does not appear to significantly impact clopidogrel responsiveness or clinical outcomes. Despite these promising results, further investigation may be warranted. Clinical trial registration: Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028

Abstract Background Risks of recurrence and major bleeding with extended anticoagulation in Asian patients with venous thromboembolism (VTE) are similar to those in non-Asian patients but risks according to baseline risk factor profiles is not well documented. Methods Subgroup analysis of two randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with placebo or aspirin (100 mg) for extended treatment in Asian patients with VTE who had completed 6–12 months of anticoagulation. Index events were classified as unprovoked, provoked by major persistent risk factors, minor persistent risk factors, minor transient risk factors, or major transient risk factors. One-year cumulative risks of recurrent VTE were calculated for these risk factor profiles. Results 367 patients received rivaroxaban, 159 aspirin, and 48 placebo. For patients with unprovoked VTE, one-year cumulative incidences of recurrence in the 202 patients given rivaroxaban, the 89 given aspirin and the 28 given placebo were 1.6%, 5.8%, and 14.8%, respectively. For patients with VTE provoked by minor persistent risk factors, these incidences were 0% in the 74 patients given rivaroxaban, 9.3% in the 36 given aspirin, and 0% in the 12 given placebo. No recurrent VTE occurred in patients with VTE provoked by major persistent or transient risk factors or minor transient risk factors. Rivaroxaban was not associated with a significant increase in major bleeding. Conclusions Rivaroxaban seems to be an effective and safe option for extended treatment in Asian patients, especially those presenting with unprovoked VTE. Subgroups of patients with provoked risk factors were too small to draw meaningful conclusions. Trial registration NCT00439725 and NCT02064439.

Abstract This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96–0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96–1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P

Background Clopidogrel monotherapy improved clinical outcomes compared with aspirin monotherapy during a chronic maintenance period in patients who underwent coronary stenting in the HOST‐EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) trial. However, it is uncertain whether the beneficial effect of clopidogrel over aspirin is different according to the renal function. Methods and Results We conducted a post hoc analysis of the HOST‐EXAM trial. Chronic kidney disease (CKD) was defined as baseline estimated glomerular filtration rate

Introduction: Low-density lipoprotein (LDL) cholesterol-lowering treatment is beneficial for the secondary or primary prevention of high-risk atherosclerotic cardiovascular disease (ASCVD). However, the prognostic implications of low LDL cholesterol levels in patients without previous ASCVD and without statin use remain elusive. Methods: From a nationwide cohort, 2,432,471 participants without previous ASCVD or statin use were included. For myocardial infarction (MI) and ischemic stroke (IS), participants were followed-up from 2009 to 2018. They were stratified according to 10-year ASCVD risk (

Abstract Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

Abstract Body mass index (BMI), as an important risk factor related to metabolic disease. However, in some studies higher BMI was emphasized as a beneficial factor in the clinical course of patients after acute myocardial infarction (AMI) in a concept known as the “BMI paradox.” The purpose of this study was to investigate how clinical outcomes of patients treated for AMI differed according to BMI levels. A total of 10,566 patients in the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) from May 2010 to June 2015 were divided into three BMI groups (group 1: BMI

Objectives Limited information is available concerning the epidemiology of stroke and acute myocardial infarction (AMI) in the Republic of Korea. This study aimed to develop a national surveillance system to monitor the incidence of stroke and AMI using national claims data. Methods We developed and validated identification algorithms for stroke and AMI using claims data. This validation involved a 2-stage stratified sampling method with a review of medical records for sampled cases. The weighted positive predictive value (PPV) and negative predictive value (NPV) were calculated based on the sampling structure and the corresponding sampling rates. Incident cases and the incidence rates of stroke and AMI in the Republic of Korea were estimated by applying the algorithms and weighted PPV and NPV to the 2018 National Health Insurance Service claims data. Results In total, 2,200 cases (1,086 stroke cases and 1,114 AMI cases) were sampled from the 2018 claims database. The sensitivity and specificity of the algorithms were 94.3% and 88.6% for stroke and 97.9% and 90.1% for AMI, respectively. The estimated number of cases, including recurrent events, was 150,837 for stroke and 40,529 for AMI in 2018. The age- and sex-standardized incidence rate for stroke and AMI was 180.2 and 46.1 cases per 100,000 person-years, respectively, in 2018. Conclusion This study demonstrates the feasibility of developing a national surveillance system based on claims data and identification algorithms for stroke and AMI to monitor their incidence rates.

Abstract Aims Evidence for the effectiveness of left ventricular (LV) unloading in patients who received venoaterial extracorporeal membrane oxygenation (VA‐ECMO) for acute myocardial infarction (AMI) or non‐AMI induced cardiogenic shock (CS) is limited. The aim of the present study was to compare the effect of LV unloading in AMI‐induced and non‐AMI‐induced CS. Methods and results This is a single‐centre retrospective observational study of patients with CS undergoing VA‐ECMO from January 2011 to March 2019. Patients were classified as AMI‐induced and non‐AMI‐induced CS. The association of LV unloading with 90‐day mortality in both groups was analysed using Cox proportional hazard regression analysis. Results Of the 128 CS patients, 71 (55.5%) patients received VA‐ECMO due to AMI‐induced CS, and the remaining 57 (44.5%) received VA‐ECMO due to non‐AMI‐induced CS. The modality of LV unloading was predominantly with IABP (94.5%). In the AMI‐induced CS group, LV unloading did not reduce 90‐day mortality (adjusted hazard ratio 1.96, 95% confidence interval 0.90–4.27, P = 0.089). However, in the non‐AMI‐induced CS group, LV unloading combined with VA‐ECMO significantly reduced 90‐day mortality (adjusted hazard ratio 0.37, 95% confidence interval 0.14–0.96, P = 0.041; P for interaction = 0.029) as compared with those who received VA‐ECMO alone. Conclusions LV unloading with VA‐ECMO may reduce 90‐day mortality compared with VA‐ECMO alone in patients with non‐AMI‐induced CS, but not in AMI‐induced CS.

Background Carriers of CYP2C19 loss‐of‐function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. Methods and Results The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel‐based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3‐year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all‐cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3‐year clinical outcomes. Conclusions In older patients, the presence of any CYP2C19 loss‐of‐function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. Registration URL: https://clinicaltrials.gov. Identifier: NCT04734028.

Background Although age and body mass index (BMI) significantly affect platelet reactivity units and clinical outcomes after percutaneous coronary intervention, there are limited data on the relationship between high on‐treatment platelet reactivity (HPR) and clinical outcomes on age and BMI differences. Thus, we investigated the association of HPR with clinical outcomes according to age and BMI. Methods and Results The study analyzed 11 714 patients who underwent platelet function tests after percutaneous coronary intervention. The primary end point was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), whereas the secondary end point was major bleeding. HPR was defined as platelet reactivity units ≥252. Patients were categorized by age (22.6 kg/m2). Patients 22.6 kg/m2 had increases in MACCEs (adjusted HR, 1.387 [95% CI, 1.140–1.688]; P=0.001). No differences were shown in major bleeding. Conclusions HPR was linked to an increase in MACCEs or a decrease in major bleeding in patients after percutaneous coronary intervention, depending on age and BMI. This study is the first to observe that clinical outcomes in patients with HPR after percutaneous coronary intervention may vary based on age and BMI. Because the study is observational, the results should be viewed as hypothesis generating and emphasize the need for randomized clinical trials.

Abstract Stent thrombosis (ST) is a fatal complication after percutaneous coronary intervention (PCI). The association between P2Y12 reaction unit (PRU) level and stent thrombosis occurrence remains unclear. Based on the multicenter, observational PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry of patients with drug-eluting stents (DES) implantation, a total of 11,714 patients with PRU values were analyzed. We sought to identify the predictors of early stent thrombosis (EST) and compared the primary outcome, a composite of cardiac death, myocardial infarction, and revascularization, between EST and non-EST groups. EST, defined as definite ST within 1 month after index PCI, occurred in 51 patients. PRU values were significantly higher in the EST group (263.5 ± 70.8 vs. 217.5 ± 78.7, p

Abstract The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double‐blind, active‐controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p

Abstract Background Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients. Methods The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke. Results Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P

Abstract Lysophosphatidic acid receptor 4 (LPAR4) exhibits transient expression at the cardiac progenitor stage during pluripotent stem cell (PSC)-derived cardiac differentiation. Using RNA sequencing, promoter analyses, and a loss-of-function study in human PSCs, we discovered that SRY-box transcription factor 17 (SOX17) is an essential upstream factor of LPAR4 during cardiac differentiation. We conducted mouse embryo analyses to further verify our human PSC in vitro findings and confirmed the transient and sequential expression of SOX17 and LPAR4 during in vivo cardiac development. In an adult bone marrow transplantation model using LPAR4 promoter-driven GFP cells, we observed two LPAR4+ cell types in the heart following myocardial infarction (MI). Cardiac differentiation potential was shown in heart-resident LPAR4+ cells, which are SOX17+, but not bone marrow-derived infiltrated LPAR4+ cells. Furthermore, we tested various strategies to enhance cardiac repair through the regulation of downstream signals of LPAR4. During the early stages following MI, the downstream inhibition of LPAR4 by a p38 mitogen-activated protein kinase (p38 MAPK) blocker improved cardiac function and reduced fibrotic scarring compared to that observed following LPAR4 stimulation. These findings improve our understanding of heart development and suggest novel therapeutic strategies that enhance repair and regeneration after injury by modulating LPAR4 signaling.

Resistin plays an important role in the pathophysiology of obesity-mediated insulin resistance in mice. However, the biology of resistin in humans is quite different from that in rodents. Therefore, the association between resistin and insulin resistance remains unclear in humans. Here, we tested whether and how the endocannabinoid system (ECS) control circulating peripheral blood mononuclear cells (PBMCs) that produce resistin and infiltrate into the adipose tissue, heart, skeletal muscle, and liver, resulting in inflammation and insulin resistance. Using human PBMCs, we investigate whether the ECS is connected to human resistin. To test whether the ECS regulates inflammation and insulin resistance in vivo, we used 2 animal models such as “humanized” nonobese diabetic/Shi-severe combined immunodeficient interleukin-2Rγ (null) (NOG) mice and “humanized” resistin mouse models, which mimic human body. In human atheromatous plaques, cannabinoid 1 receptor (CB1R)-positive macrophage was colocalized with the resistin expression. In addition, resistin was exclusively expressed in the sorted CB1R-positive cells from human PBMCs. In CB1R-positive cells, endocannabinoid ligands induced resistin expression via the p38–Sp1 pathway. In both mouse models, a high-fat diet increased the accumulation of endocannabinoid ligands in adipose tissue, which recruited the CB1R-positive cells that secrete resistin, leading to adipose tissue inflammation and insulin resistance. This phenomenon was suppressed by CB1R blockade or in resistin knockout mice. Interestingly, this process was accompanied by mitochondrial change that was induced by resistin treatment. These results provide important insights into the ECS–resistin axis, leading to the development of metabolic diseases. Therefore, the regulation of resistin via the CB1R could be a potential therapeutic strategy for cardiometabolic diseases.

ABSTRACT: Background: Hypertension and dyslipidemia significantly contribute to cardiovascular disease development. Their coexistence poses challenges in managing multiple medications, influencing treatment adherence. Objective: This study aimed to assess the efficacy and safety of a combined treatment approach using a fixed-dose combination therapy. Methods: This multicenter, 8-week, randomized, double-blind, Phase IV trial was named Telmisartan/Amlodipine/Rosuvastatin from Samjin Pharmaceuticals and evaluated the efficacy and safety of fixed-dose combination treatment in patients with essential hypertension and dyslipidemia. They were randomly assigned to 2 fixed-dose combination therapy groups, telmisartan 40 mg/amlodipine 5 mg/rosuvastatin 10 mg (TEL/ALD/RSV) or amlodipine 5 mg/atorvastatin 10 mg (ALD/ATV) after washout/run-in period. The primary outcomes were the change in mean sitting systolic blood pressure and the percentage change of LDL-C after 8 weeks of medical treatment. Adverse drug reactions and events were assessed. Results: Of a total of 304 patients who underwent screening, 252 were randomized to the TEL/ALD/RSV group (125 patients) and the ALD/ATV group (127 patients). The mean (SD) ages of the TEL/ALD/RSV group and the ALD/ATV group were 67.4 (11.3) and 68.2 (10.6) years, respectively (P = 0.563). The least-squares mean (SE) in mean sitting systolic blood pressure changes between the 2 groups were –16.27 (0.93) mm Hg in the TEL/ALD/RSV group, –6.85 (0.92) mm Hg in the ALD/ATV group (LSM difference = –9.42 mm Hg; 95% CI, –11.99 to –6.84; P < .001). For LDL-C level changes, a significant difference was noted between the 2 groups: –50.03% (1.18%) in the TEL/ALD/RSV group, –39.60% (1.17%) in the ALD/ATV group (LSM difference = –10.43%; 95% CI, –13.70 to –7.16; P < .001). No severe adverse events were observed. Conclusions: TEL/ALD/RSV proved to be more efficient than ALD/ATV in lowering blood pressure and reducing LDL-C levels among patients with hypertension and dyslipidemia, with no notable safety concerns. (Curr Ther Res Clin Exp. 2024; XX:XXX–XXX). ClinicalTrials.gov identifier: NCT03860220.

Abstract Prognostic effect of discontinuing renin–angiotensin–aldosterone-system-inhibitor (RAASi) for patients with heart failure (HF) after acute myocardial infarction (AMI) whose left ventricular (LV) systolic function was restored during follow-up is unknown. To investigate the outcome after discontinuing RAASi in post-AMI HF patients with restored LV ejection fraction (EF). Of 13,104 consecutive patients from the nationwide, multicenter, and prospective Korea Acute Myocardial Infarction-National Institutes of Health (KAMIR-NIH) registry, HF patients with baseline LVEF

Abstract Background Although vasospastic angina (VSA) is known to be caused by coronary artery spasm, no study has fully elucidated the exact underlying mechanism. Moreover, in order to confirm VSA, patients should undergo invasive coronary angiography with spasm provocation test. Herein, we investigated the pathophysiology of VSA using peripheral blood-derived induced pluripotent stem cells (iPSCs) and developed an ex vivo diagnostic method for VSA. Methods and results With 10 mL of peripheral blood from patients with VSA, we generated iPSCs and differentiated these iPSCs into target cells. As compared with vascular smooth muscle cells (VSMCs) differentiated from iPSCs of normal subjects with negative provocation test, VSA patient-specific iPSCs-derived VSMCs showed very strong contraction in response to stimulants. Moreover, VSA patient-specific VSMCs exhibited a significant increase in stimulation-induced intracellular calcium efflux (Changes in the relative fluorescence unit [ΔF/F]; Control group vs. VSA group, 2.89 ± 0.34 vs. 10.32 ± 0.51, p

Abstract Background Potent P2Y12 inhibitors are recommended for up to 12 months after percutaneous coronary intervention (PCI) in patients diagnosed with acute coronary syndrome (ACS). However, the prescription pattern is diverse in real world practice, which includes various switching between antiplatelet regimens. In this study, we analyzed the prescription patterns of prasugrel, and assessed the safety and effectiveness of P2Y12 inhibitors switching patterns in a real world registry of patients subjected to PCI after ACS. Methods The EFF-K study included 3077 ACS patients receiving prasugrel-based dual antiplatelet therapy. The cohort was divided into those who were administered with prasugrel as the primary antiplatelet treatment (naïve cohort) or as a substitute agent after clopidogrel or ticagrelor pre-treatment (switch cohort). The primary endpoint was a net adverse clinical event (NACE; a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or TIMI major bleeding unrelated to coronary-artery bypass grafting). Results A total of 3077 patients diagnosed with ACS were included in the analysis. Among the total population, 726 patients (23.6%) were classed as the naïve cohort and 2351 patients (76.4%) as the switch cohort. Baseline characteristics showed that the switch cohort had more comorbidities, such as hypertension, diabetes mellitus, heart failure and previous PCI. The major cause of switching to prasugrel in the switch cohort was the necessity for a more potent antiplatelet agent (56.3%). During a 12-month follow-up period, 51 patients (1.7%) experienced at least one NACE. The incidence of NACE did not differ between the naïve and switch cohort (1.5% vs. 1.7%, Hazard ratio 1.17, 95% Confidence interval 0.56–2.43, P = 0.677). In subgroup analysis, no significant interaction was observed between the treatment strategy and the incidence of NACE across various subgroups. Conclusions Dual antiplatelet therapy with prasugrel seems to be safe and effective both as a primary treatment and as a substitute for other P2Y12 inhibitors in a real world registry of Asian ACS patients receiving PCI. Trial registration: KCT0002356, registered June 13, 2017.

Background: This study aimed to evaluate the impact of the treatment modality on post-procedural acute kidney injury (AKI) and other clinical outcomes in patients with advanced chronic kidney disease who underwent surgical or transcatheter aortic valve replacement (AVR). Methods: A total of 147 patients with advanced chronic kidney disease (stage 3 to 5) who underwent isolated surgical AVR (SAVR group; n=70) or transcatheter AVR (TAVR group; n=77) were retrospectively studied. Postprocedural AKI was defined according to the RIFLE definition (an acronym corresponding to the risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease). Factors associated with postoperative complications and mortality were analyzed using multivariable logistic regression models and Cox proportional hazard models. Results: Postprocedural AKI occurred in 17 (24.3%) and 6 (7.8%) patients in the SAVR and TAVR groups, respectively (p=0.006). Multivariable analyses demonstrated that the SAVR group had higher risks of AKI (odds ratio [OR], 5.63; 95% confidence interval [CI], 1.85–17.73; p=0.002) and atrial fibrillation (OR, 16.65; 95% CI, 4.44–62.50; p

Background Data on the incidence, relevant patient factors, and clinical outcomes of the misdiagnosis of ST‐segment–elevation myocardial infarction (STEMI) in the modern era of percutaneous coronary intervention are limited. Methods and Results Data from KAMIR (Korea Acute Myocardial Infarction Registry) between November 2011 and June 2020 were analyzed. Out of 28 470 patients with acute myocardial infarction, 11 796 were eventually diagnosed with STEMI following a coronary angiogram. They were classified into 2 groups: patients with an initial working diagnosis of STEMI before starting the initial treatment and patients with an initial working diagnosis of non‐STEMI (misdiagnosed group). Out of 11 796 patients with a final diagnosis of STEMI, 165 (1.4%) were misdiagnosed. The door‐to‐angiography time in the misdiagnosed group was 5 times longer than that in the timely diagnosed group (median 220 [interquartile range {IQR}, 66–1177] versus 43 [IQR, 31–58] minutes; P

Background Although high platelet reactivity (HPR) on clopidogrel is associated with higher ischemic events and lower bleeding events in patients who have undergone percutaneous coronary intervention with drug‐eluting stents, the differential risk of HPR in East Asian women versus men is unknown. Methods and Results We compared 11 714 patients enrolled in the PTRG‐DES (Platelet Function and Genotype‐Related Long‐Term Prognosis in Drug‐Eluting Stent–Treated Patients With Coronary Artery Disease) Consortium according to sex and the presence/absence of HPR on clopidogrel (defined as ≥252 P2Y12 reactivity units). The primary study end point was major adverse cardiac and cerebrovascular events (MACCEs; comprising all‐cause mortality, myocardial infarction, cerebrovascular accident, and stent thrombosis). HPR was more common in women (46.7%) than in men (28.1%). In propensity‐adjusted models, HPR was an independent predictor of MACCEs (men with HPR: hazard ratio [HR], 1.60 [95% CI, 1.20–2.12]; women with HPR: HR, 0.99 [95% CI, 0.69–1.42]) and all‐cause mortality (men with HPR: HR, 1.61 [95% CI, 1.07–2.44]; women with HPR: HR, 0.92 [95% CI, 0.57–1.50]) in men, although those associations were insignificant among women. In addition, a significant interaction between sex was noted in the associations between HPR and MACCE (Pinteraction=0.013) or all‐cause mortality (Pinteraction=0.025). Conclusions In this study, HPR was a differential risk factor for 1‐year MACCEs and all‐cause mortality in women and men. And it was an independent predictor of 1‐year MACCEs and all‐cause mortality in men but not in women. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04734028. Registered July 9, 2003, https://clinicaltrials.gov/ct2/show/NCT04734028

Abstract Background Considering the nature of diabetes mellitus (DM) in coronary artery disease, it is unclear whether complete revascularization is beneficial or not in patients with DM. We investigated the clinical impact of angiographic complete revascularization in patients with DM. Methods A total of 5516 consecutive patients (2003 patients with DM) who underwent coronary stenting with 2nd generation drug-eluting stent were analyzed. Angiographic complete revascularization was defined as a residual SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score of 0. The patient-oriented composite outcome (POCO, including all-cause death, any myocardial infarction, and any revascularization) and target lesion failure (TLF) at three years were analyzed. Results Complete revascularization was associated with a reduced risk of POCO in DM population [adjusted hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.52–0.93, p = 0.016], but not in non-DM population (adjusted HR 0.90, 95% CI 0.69–1.17, p = 0.423). The risk of TLF was comparable between the complete and incomplete revascularization groups in both DM (adjusted HR 0.75, 95% CI 0.49–1.16, p = 0.195) and non-DM populations (adjusted HR 1.11, 95% CI 0.75–1.63, p = 0.611). The independent predictors of POCO were incomplete revascularization, multivessel disease, left main disease and low ejection fraction in the DM population, and old age, peripheral vessel disease, and low ejection fraction in the non-DM population. Conclusions The clinical benefit of angiographic complete revascularization is more prominent in patients with DM than those without DM after three years of follow-up. Relieving residual disease might be more critical in the DM population than the non-DM population. Trial registration The Grand Drug-Eluting Stent registry NCT03507205.

Abstract Background This study evaluated the circadian efficacy of a telmisartan 40 mg/S-amlodipine 2.5 mg fixed-dose combination (Telmisartan40/S-Amlodipine2.5) compared to telmisartan 80 mg (Telmisartan80) in patients with essential hypertension who did not respond to 2–4 weeks’ treatment with telmisartan 40 mg. Methods Eligible patients with essential hypertension (clinic mean sitting systolic blood pressure [MSSBP] ≥140 mmHg, or ≥ 130 mmHg in those with diabetes mellitus or chronic kidney disease) were randomly assigned to Telmisartan40/S-Amlodipine2.5 or Telmisartan80 for 8 weeks. All patients underwent ambulatory BP monitoring (ABPM) at baseline and 8 weeks later. Primary endpoints were changes in mean 24-h SBP and DBP on 24-h ABPM from baseline after 8 weeks. Secondary endpoints were changes in daytime, nighttime, and morning SBP and DBP, and clinic MSSBP and MSDBP. Results A total of 316 Korean patients were enrolled, 217 patients were randomized to treatment, and 192 patients completed the study. Compared to Telmisartan80, Telmisartan40/S-Amlodipine2.5 showed significantly better reductions in 24-h mean SBP and DBP after 8 weeks. Telmisartan40/S-Amlodipine2.5 also significantly reduced secondary endpoints compared to Telmisartan80. Among 15 adverse events (7 [Telmisartan40/S-Amlodipine2.5] and 8 [Telmisartan80]), there were five adverse drug reactions; 14 events were mild, and none were identified with significant between-group differences. Conclusions Telmisartan40/S-Amlodipine2.5 was tolerable and more effective than Telmisartan80 in lowering 24-h mean ambulatory BP in patients with essential hypertension not responding adequately to Telmisartan40. Our findings support the fact that the combination of S-amlodipine with telmisartan is more appropriate than increasing the dose of telmisartan monotherapy. Trial registration ClinicalTrials.gov , NCT02231788 . Registered 4 September 2014.

Background/Aims While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown. Methods Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared. Results Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD. Conclusions In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.

Background Clopidogrel monotherapy was more effective in reducing the risk of adverse clinical events than aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) with drug‐eluting stent (DES), according to the HOST‐EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) trial. However, it remains unknown whether these effects differ based on sex. Methods and Results This was a prespecified secondary analysis of HOST‐EXAM in South Korea. Patients who maintained dual antiplatelet therapy without adverse clinical events for 6 to 18 months after PCI with DES were included. The primary end point was a composite of all‐cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, or Bleeding Academic Research Consortium (BARC) bleeding type ≥3 at 24 months after randomization. The bleeding end point was BARC types 2 to 5. The primary end point was comparable between the sexes (adjusted hazard ratio [HR], 0.79 [95% CI, 0.62–1.02]; P=0.067), and the bleeding end point (adjusted HR, 0.79 [95% CI, 0.54–1.17]; P=0.240) was also similar. Compared with aspirin, clopidogrel was associated with lower risk of primary composite end point (adjusted HR, 0.70 [95% CI, 0.55–0.89]; P=0.004) and bleeding end point (adjusted HR, 0.65 [95% CI, 0.44–0.96]; P=0.031) in men but not in women. Conclusions The primary composite end point and bleeding events were comparable between the sexes during chronic maintenance antiplatelet monotherapy after PCI with DES. Clopidogrel monotherapy, compared with aspirin, significantly reduced the risk of the primary composite end point and bleeding events in men. However, the beneficial effect of clopidogrel on the primary end point and bleeding events was mitigated in women. Registration Information clinicaltrials.gov. Identifier: NCT02044250.

BackgroundOlder patients who treated by percutaneous coronary intervention (PCI) are at a higher risk of adverse cardiac outcomes. We sought to investigate the clinical impact of bifurcation PCI in older patients from Korea and Italy.MethodsWe selected 5,537 patients who underwent bifurcation PCI from the BIFURCAT (comBined Insights from the Unified RAIN and COBIS bifurcAtion regisTries) database. The primary outcome was a composite of target vessel myocardial infarction, clinically driven target lesion revascularization, and stent thrombosis at two years.ResultsIn patients aged ≥75 years, the mean age was 80.1 ± 4.0 years, 65.2% were men, and 33.7% had diabetes. Older patients more frequently presented with chronic kidney disease (CKD), severe coronary calcification, and left main coronary artery disease (LMCA). During a median follow-up of 2.1 years, older patients showed similar adverse clinical outcomes compared to younger patients (the primary outcome, 5.7% vs. 4.5%; p = 0.21). Advanced age was not an independent predictor of the primary outcome (p = 0.93) in overall patients. Both CKD and LMCA were independent predictors regardless of age group.ConclusionsOlder patients (≥75 years) showed similar clinical outcomes to those of younger patients after bifurcation PCI. Advanced age alone should not deter physicians from performing complex PCIs for bifurcation disease.

BackgroundOxygen therapy is used in various clinical situation, but its clinical outcomes are inconsistent. The relationship between the fraction of inspired oxygen (FIO2) during transcatheter aortic valve implantation (TAVI) and clinical outcomes has not been well studied. We investigated the association of FIO2 (low vs. high) and myocardial injury in patients undergoing TAVI.MethodsAdults undergoing transfemoral TAVI under general anesthesia were randomly assigned to receive FIO2 0.3 or 0.8 during procedure. The primary outcome was the area under the curve (AUC) for high-sensitivity cardiac troponin I (hs-cTnI) during the first 72 h following TAVI. Secondary outcomes included the AUC for postprocedural creatine kinase-myocardial band (CK-MB), acute kidney injury and recovery, conduction abnormalities, pacemaker implantation, stroke, myocardial infarction, and in-hospital mortality.ResultsBetween October 2017 and April 2022, 72 patients were randomized and 62 were included in the final analysis (n = 31 per group). The median (IQR) AUC for hs-cTnI in the first 72 h was 42.66 (24.82-65.44) and 71.96 (35.38-116.34) h·ng/mL in the FIO2 0.3 and 0.8 groups, respectively (p = 0.066). The AUC for CK-MB in the first 72 h was 257.6 (155.6-322.0) and 342.2 (195.4-485.2) h·ng/mL in the FIO2 0.3 and 0.8 groups, respectively (p = 0.132). Acute kidney recovery, defined as an increase in the estimated glomerular filtration rate ≥ 25% of baseline in 48 h, was more common in the FIO2 0.3 group (65% vs. 39%, p = 0.042). Other clinical outcomes were comparable between the groups.ConclusionsThe FIO2 level did not have a significant effect on periprocedural myocardial injury following TAVI. However, considering the marginal results, a benefit of low FIO2 during TAVI could not be ruled out.

BackgroundDiabetes mellitus (DM) is a critical risk factor for the pathogenesis and progression of coronary artery disease, with a higher prevalence of complex coronary artery disease, including bifurcation lesions. This study aimed to elucidate the optimal stenting strategy for coronary bifurcation lesions in patients with DM.MethodsA total of 905 patients with DM and bifurcation lesions treated with second-generation drug-eluting stents (DES) from a multicenter retrospective patient cohort were analyzed. The primary outcome was the 5-year incidence of target lesion failure (TLF), which was defined as a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization.ResultsAmong all patients with DM with significant bifurcation lesions, 729 (80.6%) and 176 (19.4%) were treated with one- and two-stent strategies, respectively. TLF incidence differed according to the stenting strategy during the mean follow-up of 42 ± 20 months. Among the stent strategies, T- and V-stents were associated with a higher TLF incidence than one-stent strategy (24.0 vs. 7.3%, p < 0.001), whereas no difference was observed in TLF between the one-stent strategy and crush or culotte technique (7.3 vs. 5.9%, p = 0.645). The T- or V-stent technique was an independent predictor of TLF in multivariate analysis (hazard ratio, 3.592; 95% confidence interval, 2.117–6.095; p < 0.001). Chronic kidney disease, reduced left ventricular ejection fraction, and left main bifurcation were independent predictors of TLF in patients with DM.ConclusionT- or V-stenting in patients with DM resulted in increased cardiovascular events after second-generation DES implantation.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03068494?term=03068494&draw=2&rank=1, identifier: NCT03068494.

Abstract Background Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance. Methods Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo. Results KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo. Conclusions KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.

IntroductionRenin-angiotensin-system inhibitors (RASi) have shown survival benefits after acute myocardial infarction (MI), but the role of routine long-term use of RASi remains unclear. Thereby, we explored the therapeutic effects of RASi medication at 1-year follow-up from acute MI.MethodsUsing the nationwide Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) registry, we included and analyzed 10,822 subjects. Patients were stratified into those taking RASi at 1-year follow-up (n = 7,696) and those not taking RASi at 1-year follow-up (n = 3,126). Patients were followed up for 2-years from the 1-year follow-up; 2-year all-cause mortality and cardiac mortality were analyzed as primary and secondary outcomes, respectively.ResultsThe use of RASi at 1-year follow-up was not associated with decreased all-cause mortality (log-rank P = 0.195) or cardiac mortality (log-rank P = 0.337). In multivariate analyses, RASi medication at 1-year follow-up did not reduce all-cause mortality (P = 0.758) or cardiac mortality (P = 0.923), while RASi medication at discharge substantially reduced 1-year all-cause and cardiac mortality. Treatment with either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker at 1-year follow-up did not show survival benefits from 1-year follow-up, respectively. The use of RASi at 1-year follow-up did not show a prognostic interaction between previous history of chronic kidney disease, post-MI acute heart failure, concomitant use of beta-blockers at 1-year follow-up, or 1-year LVEF.ConclusionAcute MI patients taking RASi at 1-year follow-up were not associated with improved 2-year all-cause mortality or cardiac mortality from the 1-year follow-up. This study provides valuable information regarding tailored medication strategy after acute MI.Clinical trial registration[www.ClinicalTrials.gov], identifier [KCT0000863].

Abstract Background The homing capacity of human mesenchymal stem cells (hMSCs) to the injured sites enables systemic administration of hMSCs in clinical practice. In reality, only a small proportion of MSCs are detected in the target tissue, which is a major bottleneck for MSC-based therapies. We still don’t know the mechanism how MSCs are chemo-attracted to certain target organ and engrafted through trans-endothelial migration. In this study, we aimed to determine the mechanism how the circulating hMSCs home to the injured liver. Methods and results When we compare the cytokine array between normal and injured mouse liver at 1-day thioacetamide (TAA)-treatment, we found that chemerin, CXCL2, and CXCL10 were higher in the injured liver than normal one. Among three, only chemerin was the chemoattractant of hMSCs in 2D- and 3D-migration assay. Analysis of the signal transduction pathways in hMSCs showed that chemerin activated the phosphorylation of JNK1/2, ERK1/2 and p38, and finally upregulated CD44, ITGA4, and MMP-2 that are involved in the transendothelial migration and extravasation of MSCs. Upstream transcription regulators of CD44, ITGA4, and MMP-2 after chemerin treatment were MZF1, GATA3, STAT3, and STAT5A. To develop chemerin as a chemoattractant tool, we cloned gene encoding the active chemerin under the CMV promoter (CMV-aChemerin). We analyzed the migration of hMSCs in the 3D model for space of the Disse, which mimics transmigration of hMSCs in the liver. CMV-aChemerin-transfected hepatocytes were more effective to attract hMSC than control hepatocytes, leading to the enhanced transendothelial migration and homing of hMSCs to liver. The homing efficiency of the intravascularly-delivered hMSCs to liver was evaluated after systemic introduction of the CMV-aChemerin plasmid packed in liposome-vitamin A conjugates which target liver. CMV-aChemerin plasmid targeting liver significantly enhanced homing efficiency of hMSCs to liver compared with control plasmid vector. Conclusions Chemerin is the newly found chemoattractant of hMSCs and may be a useful tool to manipulate the homing of the intravascularly-administered hMSC to the specific target organ.

Abstract Background The human skin-derived precursors (SKPs) are a good cell source for regeneration. However, the isolation of SKP from human skin is limited. To overcome this drawback, we hypothesized that the component of plant stem cells could convert human fibroblasts to SKPs. Methods Human dermal fibroblasts were treated with shikimic acid, a major component of Sequoiadendron giganteum callus extract. The characteristics of these reprogrammed cells were analyzed by qPCR, western blot, colony-forming assay, and immunofluorescence staining. Artificial human skin was used for CO2 laser-induced wound experiments. Human tissues were analyzed by immunohistochemistry. Results The reprogrammed cells expressed nestin (a neural precursor-specific protein), fibronectin, and vimentin and could differentiate into the ectodermal and mesodermal lineage. Nestin expression was induced by shikimic acid through the mannose receptor and subsequent MYD88 activation, leading to P38 phosphorylation and then CREB binding to the nestin gene promoter. Finally, we confirmed that shikimic acid facilitated the healing of cut injury and enhanced dermal reconstruction in a human artificial skin model. Moreover, in a clinical study with healthy volunteers, plant callus extracts increased the expression of stem cell markers in the basal layer of the epidermis and collagen deposit in the dermis. Conclusions These results indicate that shikimic acid is an effective agent for tissue regeneration.

Background: The optimal side branch (SB) treatment strategy after simple crossover stenting in bifurcation lesions is still controversial. Objectives: The purpose of this study was to compare the long-term outcomes of a 1-stent strategy with simple crossover alone versus with an additional SB–opening procedure in patients with left main (LM) and non-LM coronary bifurcation lesions. Methods: Patients who underwent percutaneous coronary intervention with a 1-stent strategy for bifurcation lesions including LM were selected from the COBIS (Coronary Bifurcation Stenting) III registry and divided into the simple crossover–alone group and SB-opening group. Clinical outcomes were assessed by the 5-year rate of target lesion failure (a composite of cardiac death, target vessel myocardial infarction, and target lesion repeat revascularization). Results: Among 2,194 patients who underwent the 1-stent strategy, 1,685 (76.8%) patients were treated with simple crossover alone, and 509 (23.2%) patients were treated with an additional SB-opening procedure. Although the baseline SB angiographic disease was more severe in the SB-opening group, the final lumen diameter of the SB was larger. The 5-year observed target lesion failure rate was similar between the 2 groups (7.0% in the simple crossover vs. 6.7% in SB-opening group; hazard ratio: 0.99; 95% confidence interval: 0.66 to 1.48; p = 0.947), even in the subgroup analyses including LM (9.5% vs. 11.3%; p = 0.442) and true bifurcation (5.3% vs. 7.8%; p = 0.362). The results were not changed after an inverse probability of treatment weighting adjustment. There was no difference in the overall and SB-related target lesion revascularization rate in both groups. Conclusions: The long-term clinical outcome of the 1-stent strategy with simple crossover alone for coronary bifurcation lesions was acceptable compared to those of additional SB-opening procedures. (Korean Coronary Bifurcation Stenting [COBIS] Registry III [COBIS III]; NCT03068494)

Background: There is a paucity of data regarding the long-term clinical outcomes of first- versus second-generation drug-eluting stent (DES), especially when used to treat complex lesions such as bifurcation lesions. Objectives: The current study compares the efficacy and safety of first- versus second-generation DES at the 5-year follow-up in patients who underwent bifurcation percutaneous coronary intervention (PCI). Methods: A total of 5,498 patients with a bifurcation lesion who underwent PCI were pooled at a single patient level from COBIS (Coronary Bifurcation Stenting) registries II and III. Five-year target lesion failure (TLF) (the composite of cardiac death, myocardial infarction [MI], and target lesion revascularization [TLR]) and cardiac death or MI were compared between the use of first-generation DES (n = 2,436) and second-generation DES (n = 3,062) during PCI. Propensity score matching was performed to reduce selection bias. Results: After a 1:1 propensity score matching procedure was conducted, the cohort consisted of 1,702 matched pairs. Patients treated with second-generation DES had a significantly lower risk of TLF at 5 years than those treated with first-generation DES in both overall and propensity-matched populations (matched hazard ratio [HRmatched]: 0.576; 95% confidence interval [CI]: 0.456 to 0.727; p

Background/Aims We evaluated changes in the ascending aorta dimension post-transcatheter aortic valve replacement (TAVR) in bicuspid aortic valve (BiAV) and tricuspid aortic valve (TAV) patients. Methods Patients with severe aortic stenosis undergoing TAVR at Seoul National University Hospital were consecutively recruited. Patients with less than 12 months’ follow-up and/or with an ascending aorta size larger than 50 mm were excluded. The ascending aorta size was measured on a parasternal long axis view using transthoracic echocardiography. Results Among the 67 patients who were included (age: 76.5 ± 6.5 years; male: 52.2%; AV area: 0.67 ± 0.15 cm2), 19 (28.4%) had BiAV; 48 (71.6%) had TAV. The median (interquartile ranges) follow-up duration was 398 days (361 to 451). BiAV patients were younger (73.2 ± 7.2 vs. 77.8 ± 5.8, p = 0.008), and had lower incidences of chronic renal disease (5.3% vs. 35.4%, p = 0.014) and history of coronary intervention (15.8% vs. 50.0%, p = 0.013), than TAV patients. On pre-procedural echocardiography, the ascending aorta dimensions in BiAV patients were larger than those in TAV patients (40.5 ± 3.8 mm vs. 35.9 ± 4.2 mm, p < 0.005). The ascending aorta dimension changed minimally during follow-up; post-TAVR, the ascending aorta’s growth rate was –0.11 ± 1.9 and 0.26 ± 1.8 mm/yr in patients with BiAV and TAV, respectively (p = 0.50). Progression of the ascending aorta’s dimension postTAVR was not clinically significant in BiAV patients. Conclusions The concern about the progression of aortopathy in BiAV patients post-TAVR may not be a clinical issue. This should be confirmed in studies with a larger population and with a longer follow-up duration.

Abstract Background Dust storms affect human health by impairing visibility and promoting interactions with microscopic organisms, such as bacteria and fungi. Although ST-elevation MI (STEMI) and non-ST-elevation MI (NSTEMI) differ mechanistically, few studies have investigated the incidence of cardiovascular diseases according to infarction type; these studies have yielded inconsistent findings. This study aimed to examine whether PM size (

Abstract Background Hepatic stellate cells (HSCs) are activated in response to liver injury with TIF1γ-suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1γ in HSCs induces damage on hepatocytes and liver fibrosis. Method Lrat:Cas9-ERT2:sgTif1γ mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1γ. HepG2 were treated retinol with/without siRNA for Stimulated by retinoic acid 6 (STRA6) or Retinoic acid receptor(RAR)-antagonist, and LX2 were treated siTIF1γ and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis. Results When we blocked the Tif1γ in HSCs using Lrat:Cas9-ERT2:sgTif1γ mice, retinol is distributed into hepatocytes. Retinol influx was confirmed using HepG2, and the increased intracellular retinol led to the upregulation of lipogenesis-related-genes and triglyceride. This effect was inhibited by a RAR-antagonist or knock-down of STRA6. In the LX2, TIF1γ-suppression resulted in upregulation of STRA6 and retinol release, which was inhibited by STRA6 knock-down. The role of STRA6-mediated retinol transfer from HSCs to hepatocytes in liver fibrosis was demonstrated by in vivo experiments where blocking of STRA6 reduced fibrosis. Conclusions Retinol from HSCs via STRA6 in response to injury with TIF1γ-reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis.

Background/Aims We evaluated the contemporary use of lipid-lowering therapy (LLT) in Korean patients with atherosclerotic cardiovascular disease (ASCVD), and identified factors associated with statin non-prescription. Methods Using the Korean Health Insurance Review and Assessment data, we identified LLT-naïve subjects newly diagnosed with ASCVD between 2011 and 2012, and followed up until 2015. LLT-naïve status was defined as no LLT prescription for 1 year before ASCVD diagnosis. ASCVD was defined as first hospitalization or emergency room visit for coronary artery disease (CAD), acute cerebrovascular disease (CVD), or peripheral artery disease (PAD). Statin intensity was defined per the 2013 American College of Cardiology/American Heart Association guideline for cholesterol treatment. Results The study enrolled 80,884 subjects newly diagnosed with ASCVD, of whom only 48,725 (60.2%) received LLT during the follow-up period. Statin, combination of statin and non-statin, and non-statin LLT were administered in 50.5%, 9.7%, and 0.1% of all subjects, respectively. Statins were prescribed to 80.4% of CAD patients but only to 50.2% and 46.8% of CVD and PAD patients. Statin-based LLT usually had moderate- (77.2%) or high-intensity (18.5%). Subjects not prescribed statins were younger or older (< 40 or ≥ 70 years), more commonly female, and more likely to have comorbidities. Statins were prescribed at the time of ASCVD diagnosis in 45.5% of all subjects, and in 53.0% within 90 days of diagnosis. Conclusions Only 60% of LLT-naïve Korean patients newly diagnosed with ASCVD received statins. Statins were often prescribed in subjects with CAD but less commonly in those with CVD or PAD. Moderate-intensity statins were most frequently used.

BackgroundSystemic inflammatory response syndrome (SIRS) is a systemic insult that has been described with many interventional cardiac procedures. The outcomes of patients undergoing transcatheter aortic valve implantation (TAVI) are thought to be influenced by this syndrome not only on short-term, but also on long-term.ObjectiveWe assessed the association of SIRS to different clinical, echocardiographic, and computed tomographic (CT) outcomes after TAVI.MethodsTwo hundred and twenty-four consecutive patients undergoing TAVI were enrolled in this study. They were assessed for the occurrence of SIRS within the first 48 h after TAVI. Patients were followed-up for short- and long-term clinical outcomes. Serial echocardiographic follow-ups were conducted at 1-week, 6-months, and 1-year. CT follow-up at 1 year was recorded.ResultsEighty patients (36%) developed SIRS. Among different parameters, only pre-TAVI total leucocytic count (TLC), pre-TAVI heart rate, and post-TAVI systolic blood pressure independently predicted the occurrence of SIRS. The incidence of HALT was not significantly different between both groups, albeit higher among SIRS patients (p = 0.1) at 1-year CT follow-up. Both groups had similar patterns of LV recovery on serial echocardiography. Long-term follow-up showed that all-cause death, cardiac death, and re-admission for heart failure (HF) or acute coronary syndrome (ACS) were significantly more frequent among SIRS patients. Early safety and clinical efficacy outcomes were more frequently encountered in the SIRS group, while device-related events and time-related valve safety were comparable.ConclusionAlthough SIRS implies an early acute inflammatory status post-TAVI, yet its clinical sequelae seem to extend to long-term clinical outcomes.

Тhe most pressing issue in generating induced pluripotent stem cells (iPSCs) in clinical practice is the cell source. Compared to human dermal fibroblasts (HDFs), which have been widely used, human peripheral blood could be a more easily obtainable alternative. However, iPSCs generated from fresh peripheral blood require inconvenient specific methods including isolation. Recently, we succeeded in isolating and culturing human heart-derived circulating cells called circulating multipotent stem (CiMS) cells. Here, we investigated the generation efficiency of CiMS-derived iPSCs (CiMS-iPSCs) and tested their differentiation potential into mesodermal lineages and cardiovascular cells. We isolated and cultured CiMS cells from peripheral mononuclear cells with a high efficiency. Moreover, our method succeeded in reprogramming the CiMS cells and generating iPSCs with higher efficiency compared to when HDFs were used. Compared to HDF-iPSCs or human embryonic stem cells (hESCs), CiMS-iPSCs showed high differentiation potential into mesodermal lineage cells and subsequently into endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Further, we checked the epigenetic status of each cell type. While methylation of the CpG site of the brachyury T promoter did not differ between cell types, the histone H3 lysine 4 trimethylation level in the brachyury T promoter region was enhanced in CiMS-iPSCs, compared to that in other cell types. In contrast, histone H3 lysine 9 acetylation was downregulated during the differentiation process of the CiMS-iPSCs. In the myocardial infarction model, the CiMS-iPSCs group showed more therapeutic potential in regenerating the myocardium than other cell types. Our study showed a new method to isolate human heart-derived stem cells from human peripheral blood and to generate iPSCs efficiently. Due to epigenetic memory, these CiMS-iPSCs easily differentiated into cardiovascular lineage cells, resulting in improved efficiency in vivo. These results suggest that our new method using CiMS cells has therapeutic potential in regenerative medicine using cell therapy.

Background Despite advances in devices and techniques, coronary bifurcation lesion remains a challenging lesion subset in the field of percutaneous coronary intervention (PCI). We evaluate 10‐year trends in bifurcation PCI and their effects on patient outcomes. Methods and Results We analyzed 10‐year trends in patient/lesion characteristics, devices, PCI strategy, stent optimization techniques, and clinical outcomes using data from 5498 patients who underwent bifurcation PCI from 2004 to 2015. Clinical outcomes 2 years after the index procedure were evaluated in terms of target vessel failure (a composite of cardiac death, myocardial infarction, and target vessel revascularization) and a patient‐oriented composite outcome (a composite of all‐cause death, myocardial infarction, and any revascularization). During the 10‐year study period, patient and lesion complexity, such as multivessel disease, diabetes mellitus, chronic kidney disease, and left main bifurcation, increased continuously (all P

We developed and assessed whether a novel neutrophil-to-hemoglobin and lymphocyte (NHL) score would improve the ability to predict clinical outcome compared with neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) in acute myocardial infarction (AMI). We examined 13,072 AMI patients from the Korean AMI Registry–National Institute of Health database. NHL score was calculated as follows: NHL score (U) = N/(Hb × L), where N, Hb, and L are baseline blood neutrophil, hemoglobin, and lymphocyte count. The primary outcome was the occurrence of major adverse cerebrocardiovascular events (MACCEs) at 2 years. The NLR, SII, and NHL score were independent predictors of 2-year MACCEs. The area under the curve of the NHL score (0.637) for predicting 2-year MACCEs was significantly higher compared with those of SII (0.589) and NLR (0.607). The NHL score significantly improved the reclassification and integrated discrimination compared with NLR ( p < 0.0001) and SII ( p < 0.0001). A high NHL score (≥ 0.35 U) was an independent predictor of 2-year MACCEs (adjusted hazard ratio, 1.41; 95% confidence interval, 1.29–1.55; p < 0.001). The NHL score could be a novel model for predicting long-term MACCEs in patients with AMI.

Background/Aims Minimising total ischemic time (TIT) is important for improving clinical outcomes in patients with ST-segment elevation myocardial infarction who have undergone percutaneous coronary intervention (PCI). TIT has not shown a significant improvement due to persistent pre-hospital delay. This study aimed to investigate the risk factors associated with pre-hospital delay. Methods Individuals enrolled in the Korea Acute Myocardial Infarction Registry-National Institutes of Health between 2011 and 2015 were included in this study. The study population was analyzed according to the symptom-to-door time (STDT; within 60 or > 60 minutes), and according to the type of hospital visit (emergency medical services [EMS], non-PCI center, or PCI center). Results A total of 4,874 patients were included in the analysis, of whom 28.4% arrived at the hospital within 60 minutes of symptom-onset. Old age (> 65 years), female gender, and renewed ischemia were independent predictors of delayed STDT. Utilising EMS was the only factor shown to reduce STDT within 60 minutes, even when cardiogenic shock was evident. The overall frequency of EMS utilisation was low (21.7%). Female gender was associated with not utilising EMS, whereas cardiogenic shock, previous myocardial infarction, familial history of ischemic heart disease, and off-hour visits were associated with utilising EMS. Conclusions Factors associated with delayed STDT and not utilising EMS could be targets for preventive intervention to improve STDT and TIT.