Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.

BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

Requirement of ß subunit for the reduced voltage-gated Na+ current of a Brugada syndrome patient having novel double missense mutation (p.A385T/R504T) of SCN5A.

Mutations within the SCN5A gene, which encodes the α-subunit 5 (NaV1.5) of the voltage-gated Na+ channel, have been linked to three distinct cardiac arrhythmia disorders: long QT syndrome type 3, Brugada syndrome (BrS), and cardiac conduction disorder. In this study, we have identified novel missense mutations (p.A385T/R504T) within SCN5A in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of SCN5A mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the NaV1.5 current (INa) in HEK293 cells transfected with the wild-type and mutant SCN5A with or without SCN1B co-expression. The amplitude of INa was not altered in mutant SCN5A (p.A385T/R504T) alone. Furthermore, a rightward shift of the voltage-dependent inactivation and faster recovery from inactivation was observed, suggesting a gain-of-function state. Intriguingly, the coexpression of SCN1B with p.A385T/R504T revealed significant reduction of INa and slower recovery from inactivation, consistent with the loss-of-function in Na+ channels. The SCN1B dependent reduction of INa was also observed in a single mutation p.R504T, but p.A385T co-expressed with SCN1B showed no reduction. In contrast, the slower recovery from inactivation with SCN1B was observed in A385T while not in R504T. The expression of SCN1B is indispensable for the electrophysiological phenotype of BrS with the novel double mutations; p.A385T and p.R504T contributed to the slower recovery from inactivation and reduced current density of NaV1.5, respectively.

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial.

BACKGROUND: Long-term comparative outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stents and coronary artery bypass grafting (CABG) are limited in patients with multivessel coronary artery disease. METHODS: This prospective, multicenter, randomized controlled trial was conducted in 27 international heart centers and was designed to randomly assign 1776 patients with angiographic multivessel coronary artery disease to receive PCI with everolimus-eluting stents or CABG. After inclusion of 880 patients (438 in the PCI group and 442 in the CABG group) between July 2008 and September 2013, the study was terminated early because of slow enrollment. The primary end point was the composite of death from any cause, myocardial infarction, or target vessel revascularization. RESULTS: During a median follow-up of 11.8 years (interquartile range, 10.6-12.5 years; maximum, 13.7 years), the primary end point occurred in 151 patients (34.5%) in the PCI group and 134 patients (30.3%) in the CABG group (hazard ratio [HR], 1.18 [95% CI, 0.88-1.56]; P=0.26). No significant differences were seen in the occurrence of a safety composite of death, myocardial infarction, or stroke between groups (28.8% and 27.1%; HR, 1.07 [95% CI, 0.75-1.53]; P=0.70), as well as the occurrence of death from any cause (20.5% and 19.9%; HR, 1.04 [95% CI, 0.65-1.67]; P=0.86). However, spontaneous myocardial infarction (7.1% and 3.8%; HR, 1.86 [95% CI, 1.06-3.27]; P=0.031) and any repeat revascularization (22.6% and 12.7%; HR, 1.92 [95% CI, 1.58-2.32]; P<0.001) were more frequent after PCI than after CABG. CONCLUSIONS: In patients with multivessel coronary artery disease, there were no significant differences between PCI and CABG in the incidence of major adverse cardiac events, the safety composite end point, and all-cause mortality during the extended follow-up. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT05125367 and NCT00997828.

In Situ Preconditioning of Human Mesenchymal Stem Cells Elicits Comprehensive Cardiac Repair Following Myocardial Infarction.

Human bone marrow-derived mesenchymal stem cells (BM-MSCs), represented as a population of adult stem cells, have long been considered as one of the most promising sources for cell-based cardiac regenerative therapy. However, their clinical use has been significantly hampered by low survival and poor retention following administration into failing hearts. Here, to improve the therapeutic effectiveness of BM-MSCs, we examined a novel therapeutic platform named in situ preconditioning in a rat myocardial infarction (MI) model. In situ preconditioning was induced by a combinatory treatment of BM-MSCs with genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) and heart-derived extracellular matrix (hdECM) hydrogel. Subsequently, our results demonstrated that in situ preconditioning with cell mixture substantially improved the survival/retention of BM-MSCs in the MI-induced rat hearts. Enhanced retention of BM-MSCs ultimately led to a significant cardiac function improvement, which was derived from the protection of myocardium and enhancement of vessel formation in the MI hearts. The results provide compelling evidence that in situ preconditioning devised to improve the therapeutic potential of BM-MSCs can be an effective strategy to achieve cardiac repair of MI hearts.

An Adult Mouse Model of Dilated Cardiomyopathy Caused by Inducible Cardiac-Specific Bis Deletion.

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians.

PURPOSE: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. METHODS: We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. RESULTS: A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). CONCLUSIONS: In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors.Genet Med 18 8, 833-841.

Cardiovascular autonomic dysfunctions in elderly patients with essential tremor: comparison with healthy controls.

Questionnaire-based analyses show that patients with essential tremor (ET) may have several autonomic dysfunctions, especially in the cardiovascular and genitourinary domains; yet the laboratory correlates of autonomic dysfunction in ET are unknown and have not been studied. Herein, we explored whether sympathetic and parasympathetic functions differed between control subjects and patients with ET. Seventy-five elderly patients with ET were enrolled in this study, along with 25 age-matched controls. Orthostatic vital signs, ambulatory 24-h blood pressure monitoring and 24-h Holter monitoring values were recorded and metaiodobenzylguanidine (MIBG) uptake was assessed using the heart-to-mediastinum ratio (H/M ratio). The frequencies of orthostatic hypotension, supine hypertension, nocturnal hypertension and non-dipping were not different between the ET patients and the controls, although ET patients had more episodes of orthostatic intolerance. The ET group also had similar heart rate variations as the control group for all the time-domains. The mean H/M ratios for the ET group were not statistically different from that of the control group. This result proves that the autonomic control of the cardiovascular system is normal in ET.

Purification of cardiomyocytes from differentiating pluripotent stem cells using molecular beacons that target cardiomyocyte-specific mRNA.

BACKGROUND: Although methods for generating cardiomyocytes from pluripotent stem cells have been reported, current methods produce heterogeneous mixtures of cardiomyocytes and noncardiomyocyte cells. Here, we report an entirely novel system in which pluripotent stem cell-derived cardiomyocytes are purified by cardiomyocyte-specific molecular beacons (MBs). MBs are nanoscale probes that emit a fluorescence signal when hybridized to target mRNAs. METHOD AND RESULTS: Five MBs targeting mRNAs of either cardiac troponin T or myosin heavy chain 6/7 were generated. Among 5 MBs, an MB that targeted myosin heavy chain 6/7 mRNA (MHC1-MB) identified up to 99% of HL-1 cardiomyocytes, a mouse cardiomyocyte cell line, but <3% of 4 noncardiomyocyte cell types in flow cytometry analysis, which indicates that MHC1-MB is specific for identifying cardiomyocytes. We delivered MHC1-MB into cardiomyogenically differentiated pluripotent stem cells through nucleofection. The detection rate of cardiomyocytes was similar to the percentages of cardiac troponin T- or cardiac troponin I-positive cardiomyocytes, which supports the specificity of MBs. Finally, MHC1-MB-positive cells were sorted by fluorescence-activated cell sorter from mouse and human pluripotent stem cell differentiating cultures, and ≈97% cells expressed cardiac troponin T or cardiac troponin I as determined by flow cytometry. These MB-based sorted cells maintained their cardiomyocyte characteristics, which was verified by spontaneous beating, electrophysiological studies, and expression of cardiac proteins. When transplanted in a myocardial infarction model, MB-based purified cardiomyocytes improved cardiac function and demonstrated significant engraftment for 4 weeks without forming tumors. CONCLUSIONS: We developed a novel cardiomyocyte selection system that allows production of highly purified cardiomyocytes. These purified cardiomyocytes and this system can be valuable for cell therapy and drug discovery.

Clinical significance of chronic kidney disease and atrial fibrillation on morbidity and mortality in patients with acute myocardial infarction.

BACKGROUND/AIMS: Atrial fibrillation (AF) often coexists with acute myocardial infarction (AMI), and chronic kidney disease (CKD) is a major risk for AMI. However, the combined impact of CKD and AF on the mortality and morbidity in AMI population has not been determined. METHODS: Between January 2004 and December 2009, a total of 4,738 AMI patients were enrolled prospectively. Patients were divided into four groups according to the combined status of CKD and AF. The primary endpoint was a combination of 5-year major adverse cardiac and cerebrovascular events (MACCE). RESULTS: The prevalence of AF was significantly higher in CKD patients than in non-CKD patients (6.76 vs. 3.31%, p < 0.001). The highest cumulative event rate of MACCE and death was observed in patients with both CKD and AF (68.5 and 64.0%), respectively. In multivariable analyses, compared with patients with neither AF nor CKD, hazard ratios (HR) for composite of MACCE were 1.66 (95% CI, 1.14-2.41), 1.24 (95% CI, 1.06-1.46), and 2.10 (95% CI, 1.42-3.13) for patients with AF only, those with CKD only, and those with both CKD and AF, respectively (p for interaction = 0.935). Patients with both CKD and AF had a greatest risk for all-cause mortality (HR 2.54; 95% CI, 1.60-4.53), and the significant synergistic interaction was observed between CKD and AF (p for interaction = 0.015). CONCLUSION: The combined effect of AF and CKD on the risk of MACCE after an AMI is stronger than any separate condition, and it confers a synergistic effect on the all-cause mortality risk.

Clinical outcomes and predictors of unprotected left main stem culprit lesions in patients with acute ST segment elevation myocardial infarction.

OBJECTIVES: We aimed at comparing the clinical outcomes of the patients who underwent percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI) due to left main coronary arteries (LMCA) and non-LMCA determining the predictors of mortality in the patients. BACKGROUND: There are few data regarding the midterm prognosis of STEMI due to LMCA as compared with them due to non-LMCA. METHODS: A total of 4,697 patients with STEMI (61 patients with LMCA and 4,636 patients with non-LMCA) were enrolled in a nationwide Korea Acute Myocardial Infarction (MI) Registry between November 2005 and September 2009. The primary endpoints was a composite of cardiac death, nonfatal MI, and target lesion and vessel revascularization (TLR/TVR) during a 12-month clinical follow-up. RESULTS: The LMCA group had a higher incidence of total major adverse cardiac events (MACEs) (26.2% vs. 7.8%; P < 0.001) at 12 months, which was largely attributable to cardiac deaths at 1 month (21.3% vs. 3.8%; P < 0.001). Therefore, there was no statistical difference in cardiac deaths, nonfatal MI, TLR/TVR, and MACEs after 1 month between the two groups. Presenting in cardiogenic shock (HR, 4.25; 95% CI, 1.01-17.97; P = 0.049) and heart rate ≥100 bpm (HR, 4.97; 95% CI, 1.18-21.00; P = 0.029) were independent predictors of cardiac death due to LMCA. CONCLUSION: Patients with STEMI and a LMCA had poor clinical outcomes, which is attributable to hemodynamic deterioration during the periprocedural period. However, after that time, midterm MACEs of the survivors following the periprocedural period may not be different between STEMI due to LMCA and non-LMCA.

Impact of occluded culprit arteries on long-term clinical outcome in patients with non-ST-elevation myocardial infarction: 48-month follow-up results in the COREA-AMI Registry.

BACKGROUND: The prognostic impact of occluded culprit arteries in non-ST-elevation myocardial infarction (NSTEMI) patients beyond 12 months has not been investigated. OBJECTIVES: The impact of occluded culprit arteries on a composite of cardiac death (CD), recurrent nonfatal MI (RMI), and target vessel revascularization (TVR) in patients who presented with NSTEMI was investigated during a 48-month follow-up using propensity-score (PS) matching. METHODS: A total of 2,878 NSTEMI patients in the COREA-AMI (COnvergent REgistry of cAtholic and chonnAm university for Acute MI) Registry were classified according to the angiographic flow of culprit arteries (occlusion [OC], n = 1,070; nonocclusion, n = 1,808). After PS matching, the incidence of the primary end-point, a composite of CD, RMI, and TVR was compared. RESULTS: The median follow-up duration was 47.3 months (IQR 32.7-66.2). In the PS-matched population, the 48-month cumulative rates of the primary end-point (27.5% vs. 17.9%, P < 0.001) and each event were higher in the OC group (CD: 9.0% vs. 5.4%, RMI: 16.3% vs. 9.4%, TVR: 10.5% vs. 5.6%, respectively, P < 0.05). In multivariate Cox regression analysis, occluded culprit arteries showed the significant statistical impact on the primary end-point (HR 1.689 [1.385-2.059], P < 0.001) and each event (CD: 1.736 [1.218-2.475], RMI: 1.918 [1.468-2.505], TVR: 2.042 [1.453-2.869], respectively, P < 0.05). Furthermore, in the 12-month landmark analysis, occluded culprit arteries were still associated with higher risk of primary end-point beyond 12 months (P < 0.001). CONCLUSIONS: Occluded culprit arteries were independently associated with the higher risk of CD, RMI, and TVR in NSTEMI patients during the 48-month follow-up.

Revolutionizing biomedical research: The imperative need for heart-kidney-connected organoids.

Organoids significantly advanced our comprehension of organ development, function, and disease modeling. This Perspective underscores the potential of heart-kidney-connected organoids in understanding the intricate relationship between these vital organs, notably the cardiorenal syndrome, where dysfunction in one organ can negatively impact the other. Conventional models fall short in replicating this complexity, necessitating an integrated approach. By co-culturing heart and kidney organoids, combined with microfluidic and 3D bioprinting technologies, a more accurate representation of in vivo conditions can be achieved. Such interconnected systems could revolutionize our grasp of multi-organ diseases, drive drug discovery by evaluating therapeutic agents on both organs simultaneously, and reduce the need for animal models. In essence, heart-kidney-connected organoids present a promising avenue to delve deeper into the pathophysiology underlying cardiorenal disorders, bridging existing knowledge gaps, and advancing biomedical research.

Daily oral administration of probiotics engineered to constantly secrete short-chain fatty acids effectively prevents myocardial injury from subsequent ischemic heart disease.

AIM: Given the extremely limited regeneration potential of the heart, one of the most effective strategies to reduce the prevalence and mortality of coronary artery disease is prevention. Short-chain fatty acids (SCFAs), which are by-products of beneficial probiotics, have been reported to possess cardioprotective effects. Despite their beneficial roles, delivering SCFAs and maintaining their effective concentration in plasma present major challenges. Therefore, in the present study, we aimed to devise a strategy to prevent coronary heart disease effectively by using engineered probiotics to continuously release SCFAs in vivo. METHODS AND RESULTS: We engineered a novel probiotic cocktail, EcN_TL, from the commercially available Escherichia coli Nissle 1917 strain to continuously secrete SCFAs by introducing the propionate and butyrate biosynthetic pathways. Oral administration of EcN_TL enhanced and maintained an effective concentration of SCFAs in the plasma. As a preventative strategy, we observed that daily intake of EcN_TL for 14 days prior to ischemia-reperfusion injury significantly reduced myocardial injury and improved cardiac performance compared to EcN administration. We uncovered that EcN_TL's protective mechanisms included reducing neutrophil infiltration into the infarct site and promoting the polarization of wound-healing macrophages. We further revealed that SCFAs at plasma concentration protected cardiomyocytes from inflammation by suppressing the NF-κB activation pathway. CONCLUSIONS: These data provide strong evidence to support the use of SCFA-secreting probiotics to prevent coronary heart disease. Since SCFAs also play a key role in other metabolic diseases, EcN_TL can potentially be used to treat a variety of other diseases.

Versatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications.

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.

Artificial Intelligence-Enabled Quantitative Coronary Plaque and Hemodynamic Analysis for Predicting Acute Coronary Syndrome.

BACKGROUND: A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization. OBJECTIVES: This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA). METHODS: Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort. RESULTS: Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA. CONCLUSIONS: AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328).

Impact of the CYP2C19*17 polymorphism on the clinical outcome of clopidogrel therapy in Asian patients undergoing percutaneous coronary intervention.

The impact of the CYP2C19*17 polymorphism on the clinical outcome in Asians undergoing percutaneous coronary intervention (PCI) is unknown. We sought to assess the long-term impact of CYP2C19*17 on the risk for adverse clinical events in 2188 Korean patients taking clopidogrel after PCI. The prevalence of the CYP2C19*17 allele [*wt/*17: 2.4% (n = 53), *17/*17: 0%] was very low. The 2-year cumulative event rates for bleeding [*wt/*17 vs. *wt/*wt: 2 vs. 2.3%; adjusted hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.16-9.45], stent thrombosis (2 vs. 1.1%; HR, 3.98; 95% CI, 0.49-31.6) or composite of any death, and myocardial infarction or stroke (5.4 vs. 7.1%; HR, 1.37; 95% CI, 0.32-5.73) did not differ on the basis of the presence of CYP2C19*17. In conclusion, in our study population of Asian patients, the CYP2C19*17 polymorphism was not associated with adverse clinical outcomes after PCI because of its low prevalence, the rarity of homozygotes, and the relatively low rate of adverse clinical events.

Long-term clinical outcomes of the one-stent technique versus the two-stent technique for non-left main true coronary bifurcation disease in the era of drug-eluting stents.

BACKGROUND: Few studies have compared the long-term major adverse cardiac events (MACEs) between the one-stent technique (stenting only the main branch) and the two-stent technique (stenting of both the main and side branches) for the treatment of true coronary bifurcation lesions in the drug-eluting stent era. Therefore, we investigated this issue using the large nationwide coronary bifurcation registry. METHODS: The 1,147 patients with non-left main coronary true bifurcation lesions underwent percutaneous coronary intervention in the Korea Coronary Bifurcation Stent (COBIS) registry. All patients were stratified based on the stent placement technique: one stent (n = 898) versus two stents (n = 249). MACE, including death, nonfatal myocardial infarction (MI), and repeat vessel and lesion revascularization (TVR and TLR), were evaluated. RESULTS: The median follow-up duration was 20 months. The MACEs did not differ between the 2 groups. Findings from the one-stent group were similar to those of the two-stent group in composite of death, MI, or TVR, based on analysis by crude, multivariate Cox hazard regression model, inverse-probability-of-treatment weighting (hazard ratio [HR] 0.911, 95% confidence interval (CI) 0.614-1.351; HR 0.685 95% CI 0.381-1.232; HR 1.235, 95% CI 0.331-4.605, respectively). In further analysis with propensity score matching, the overall findings were consistent. CONCLUSIONS: The findings of the present study indicate that the one-stent technique was not inferior to the two-stent technique for the treatment of non-left main true coronary bifurcation lesions in terms of long-term MACEs.

Predictors of early and late target lesion revascularization after drug-eluting stent implantation.

INTRODUCTION: Recent studies have suggested the existence of a late catch-up phenomenon after drug-eluting stent (DES) implantation. The aim of this study is to identify predictors of early (≤1 year) and late (>1 year) target lesion revascularization (TLR) in DESs. METHODS: The COACT (CathOlic medical center percutAneous Coronary inTervention) registry was designed to evaluate the clinical outcomes after DES implantation. Data from 9,127 consecutive patients were reviewed, all of whom underwent percutaneous coronary intervention (PCI) with DES between January 2004 and December 2009, including 8,126 patients who received PCI with homogenous DES. RESULTS: During a median follow-up period of 24 months (interquartile range, 11-41), the cumulative incidences of early and late TLR were 4.7% (95% confidence interval [CI], 4.2-5.1) and 3.3% (95% CI, 2.9-3.7). Independent predictors of early TLR were multivessel disease (odds ratio [OR] 1.637; 95% CI 1.241-2.158, P < 0.001) and stent diameter (OR 0.614; 95% CI 0.437-0.862, P = 0.005). Independent predictors of late TLR were stent diameter (OR 0.567; 95% CI 0.367-0.875, P = 0.010), insulin-dependent diabetes mellitus (OR 2.235; 95% CI 1.314-3.802, P = 0.003), first-generation DES (OR 5.104; 95% CI 2.744-9.492, P < 0.001), and elevated levels of high-sensitivity C-reactive protein at follow-up coronary angiography >2 mg/dL (OR 1.616; 95% CI 1.173-2.226, P = 0.003). CONCLUSIONS: Although multivessel disease and stent diameter were associated with early TLR, late TLR was more associated with clinical comorbidities including insulin-dependent diabetes and procedural factors like the generation of the stent used and stent diameter. The risk factors for TLR may be markedly different at different time points during TLR.

Persistent coronary artery spasm documented by follow-up coronary angiography in patients with symptomatic remission of variant angina.

For patients with variant angina it is very important to start medical therapy using calcium-channel blockers. However, the decision of physicians regarding whether to decrease the dose of the drug or discontinue it is controversial. We investigated whether the nature of spasm is remissive and whether the termination of medications is safe. The subjects studied were included in the Vasospastic Angina in Catholic Medical Center Registry from March 2001 to December 2009. We analyzed 37 patients (62 lesions) with variant angina, diagnosed using coronary angiography (CAG) and he acetylcholine provocation test, without any organic coronary stenosis, whose symptoms were well controlled after medication. The follow-up CAG with provocation test was performed at a median interval of 44 months. The characteristics of spasm were analyzed on each pair of CAGs. The study group consisted of 23 men (62.2 %) and 14 women (37.8 %) with a mean age of 59 ± 11.1 years. The follow-up CAG with provocation test showed that the characteristics of the spasmodic nature were consistent with the first test in all patients. Although the patients with variant angina had no chest pain after medical treatment, the spasmodic nature of coronary arteries still remained. We may decrease the drug dosage after carefully checking the patient's symptoms but recommend not discontinuing therapy, even if the patient is asymptomatic.

New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a).

Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). There are abundant and unequivocal data to indicate that low-density lipoproteins (LDL) are a cause of ASCVD. Reduction of plasma low-density lipoprotein cholesterol (LDL-C) by medical therapy such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have proven to significantly reduce the risk of cardiovascular events. However, for many reasons, many patients are not able to achieve LDL-C levels recommended by guidelines on currently available therapies. This has led to the development of new drugs lowering LDL-C, such as inclisiran, bempedoic acid, and evinacumab, in the hope of reducing cardiovascular (CV) risk. Drugs targeting lipoprotein (a) (Lp[a]) also have a role in the prevention of atherosclerosis, with genetic studies having established that 20%-30% of the human population inherits plasma Lp(a) levels in the atherogenic range. In this paper, we will review the recent progress made in the approaches to LDL-C and Lp(a) therapeutic modulation.