Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRß.

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction. Vascular smooth muscle cells (VSMCs), the main components of atherosclerotic plaque, switch from contractile to synthetic phenotypes during atherogenesis. Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis, and it can be reversely regulated by deubiquitinases. However, the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated. In this study, RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases, which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch. Further in vivo studies using Apoe-/- mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype. Moreover, VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro. Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation, adhesion, and proliferation. Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated. Mechanistically, we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRß with its catalytic triad, thereby reducing the K48-linked ubiquitylation of PDGFRß. Inhibiting OTUB1 in VSMCs could promote PDGFRß degradation via the ubiquitin-proteasome pathway, so it was beneficial in preventing VSMCs' phenotype switch. These findings revealed that knocking down OTUB1 ameliorated VSMCs' phenotype switch and atherosclerosis progression, indicating that OTUB1 could be a valuable translational therapeutic target in the future.

Coronary slow flow and angiography-derived index of microcirculatory resistance as prognostic predictors in patients with angina and normal coronary arteries: a retrospective cohort study.

BACKGROUND: This study aims to investigate prognostic implications of coronary slow flow (CSF) and angiography-derived index of microcirculatory resistance (caIMR) in patients with angina and normal coronary arteries. METHODS: A total of 582 patients were enrolled with angiographically normal coronary arteries. caIMR was calculated using a commercial software. Patients were followed up for a median of 45 months. The primary endpoint was defined as major adverse cardiovascular events (MACEs) comprising death, myocardial infarction and readmission for angina or heart failure. RESULTS: CSF was diagnosed when TIMI grade 2 flow presented in at least one coronary artery. Multivariate analysis indicated TIMI-flow-based determination of CSF was not significantly associated with MACEs [hazard ratio (HR): 2.14; 95% confidence interval (CI): 0.87-5.31; p = 0.099), while caIMR >42 (HR: 2.53; 95% CI: 1.02-6.32; p = 0.047) were independent predictors of MACEs. Incorporation of caIMR improved the area under the curve from 0.587 to 0.642. CONCLUSIONS: caIMR was an independent prognostic factor of long-term cardiovascular events in patients with CSF. Evaluation of caIMR improved the risk stratification of patients with angiographically-normal coronary arteries.

Real-world performance of indobufen versus aspirin after percutaneous coronary intervention: insights from the ASPIRATION registry.

BACKGROUND: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. METHODS: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. RESULTS: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. CONCLUSIONS: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. TRIAL REGISTRATION: Chinese Clinical Trial Register ( https://www.chictr.org.cn ); Number: ChiCTR2300067274.

Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Sex Differences in Coronary Inflammation and Atherosclerosis Phenotypes in Response to Imaging Marker of Stress-Related Neural Activity.

BACKGROUND: Sex-specific differences in coronary phenotypes in response to stress have not been elucidated. This study investigated the sex-specific differences in the coronary computed tomography angiography-assessed coronary response to mental stress. METHODS: This retrospective study included patients with coronary artery disease and without cancer who underwent resting 18F-fluorodexoyglucose positron emission tomography/computed tomography and coronary computed tomography angiography within 3 months. 18F-flourodeoxyglucose resting amygdalar uptake, an imaging biomarker of stress-related neural activity, coronary inflammation (fat attenuation index), and high-risk plaque characteristics were assessed by coronary computed tomography angiography. Their correlation and prognostic values were assessed according to sex. RESULTS: A total of 364 participants (27.7% women and 72.3% men) were enrolled. Among those with heightened stress-related neural activity, women were more likely to have a higher fat attenuation index (43.0% versus 24.0%; P=0.004), while men had a higher frequency of high-risk plaques (53.7% versus 39.3%; P=0.036). High amygdalar 18F-flourodeoxyglucose uptake (B-coefficient [SE], 3.62 [0.21]; P<0.001) was selected as the strongest predictor of fat attenuation index in a fully adjusted linear regression model in women, and the first-order interaction term consisting of sex and stress-related neural activity was significant (P<0.001). Those with enhanced imaging biomarkers of stress-related neural activity showed increased risk of major adverse cardiovascular event both in women (24.5% versus 5.1%; adjusted hazard ratio, 3.62 [95% CI, 1.14-17.14]; P=0.039) and men (17.2% versus 6.9%; adjusted hazard ratio, 2.72 [95% CI, 1.10-6.69]; P=0.030). CONCLUSIONS: Imaging-assessed stress-related neural activity carried prognostic values irrespective of sex; however, a sex-specific mechanism linking psychological stress to coronary plaque phenotypes existed in the current hypothesis-generating study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05545618.

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Revascularization for Patients With Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease.

Coronary artery disease (CAD) is one of the main causes of heart failure (HF) with preserved ejection fraction (HFpEF). The efficacy of revascularization therapy in patients with HFpEF and CAD, however, remains unclear. Patients who underwent coronary angiography from January 2017 to December 2019 were included in this retrospective study if they further satisfied the diagnosis of HFpEF (left ventricular ejection fraction ≥50% plus plasma N-terminal pro-BNP ≥125 pg/ml) and CAD (patients had a history of confirmed myocardial infarction or ≥50% stenosis in at least 1 epicardial coronary vessel). Clinical data, way of revascularization, and outcome events (unplanned repeated revascularization, HF readmission, cardiovascular death, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and all-cause death) were recorded and analyzed. A total of 1,111 patients were enrolled for the present analysis. Based on whether the revascularization was complete or not, the patients were divided into the complete revascularization group (n = 780) and the incomplete/no revascularization group (n = 331). All patients were followed up with a median of 355 days. The overall rates of unplanned repeated revascularization, HF readmission, and cardiovascular death were 6.6%, 5.0%, and 0.4%, respectively. Compared with incompletely/not revascularized patients, completely revascularized patients had a lower rate of unplanned repeated revascularization (10.9% vs 4.7%, p <0.001) and cardiovascular death (0.9% vs 0.1%, p = 0.048). However, HF readmission, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and noncardiac death were comparable between the 2 groups. The regression analysis showed that hyperlipidemia, previous myocardial infarction, in-stent restenosis, and way of revascularization were associated with the composite events of unplanned repeated revascularization, HF readmission, and cardiovascular death during the follow-up. Complete revascularization may reduce unplanned repeated revascularization and cardiovascular death for patients with HFpEF and CAD.

Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway.

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.

Pinacidil ameliorates cardiac microvascular ischemia-reperfusion injury by inhibiting chaperone-mediated autophagy of calreticulin.

Calcium overload is the key trigger in cardiac microvascular ischemia-reperfusion (I/R) injury, and calreticulin (CRT) is a calcium buffering protein located in the endoplasmic reticulum (ER). Additionally, the role of pinacidil, an antihypertensive drug, in protecting cardiac microcirculation against I/R injury has not been investigated. Hence, this study aimed to explore the benefits of pinacidil on cardiac microvascular I/R injury with a focus on endothelial calcium homeostasis and CRT signaling. Cardiac vascular perfusion and no-reflow area were assessed using FITC-lectin perfusion assay and Thioflavin-S staining. Endothelial calcium homeostasis, CRT-IP3Rs-MCU signaling expression, and apoptosis were assessed by real-time calcium signal reporter GCaMP8, western blotting, and fluorescence staining. Drug affinity-responsive target stability (DARTS) assay was adopted to detect proteins that directly bind to pinacidil. The present study found pinacidil treatment improved capillary density and perfusion, reduced no-reflow and infraction areas, and improved cardiac function and hemodynamics after I/R injury. These benefits were attributed to the ability of pinacidil to alleviate calcium overload and mitochondria-dependent apoptosis in cardiac microvascular endothelial cells (CMECs). Moreover, the DARTS assay showed that pinacidil directly binds to HSP90, through which it inhibits chaperone-mediated autophagy (CMA) degradation of CRT. CRT overexpression inhibited IP3Rs and MCU expression, reduced mitochondrial calcium inflow and mitochondrial injury, and suppressed endothelial apoptosis. Importantly, endothelial-specific overexpression of CRT shared similar benefits with pinacidil on cardiovascular protection against I/R injury. In conclusion, our data indicate that pinacidil attenuated microvascular I/R injury potentially through improving CRT degradation and endothelial calcium overload.

Deubiquitinase OTUB1 regulates doxorubicin-induced cardiotoxicity via deubiquitinating c-MYC.

BACKGROUND: Doxorubicin (DOX), an anthracycline drug widely used in antitumor therapies, has dose-dependent toxicity that can cause cardiomyocyte apoptosis and oxidative stress, thus limiting its clinical application. OTUB1 (ovarian tumor associated proteinase B1) is an OTU superfamily deubiquitinase that effectively regulates cell proliferation, inflammatory responses, apoptosis, and oxidative stress by specifically removing K48- and K63-linked ubiquitination; however, its role in DOX-induced cardiotoxicity remains unknown. MATERIALS AND METHODS: A DOX-induced subacute cardiotoxicity mouse model was established by intraperitoneal injection, and cardiac injury was assessed by echocardiography, serum cardiac markers, and histopathological staining. Western blotting, qRT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) immunohistochemistry were used to analyze cell apoptosis, tissue oxidative stress was assessed by superoxide dismutase (SOD) activity, malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) activity. Cell counting kit-8 (CCK-8) assay, TUNEL staining, Western blotting, qRT-PCR, and reactive oxygen species (ROS) flow cytometry were applied on isolated neonatal mice cardiomyocytes to assess apoptosis and oxidative stress. Differentially expressed genes were analyzed using RNA sequencing and clustering analyses. c-MYC inhibitor 10,058-F4 and siRNA targeting c-Myc were used to investigate the roles of c-MYC in OTUB1's regulations of DOX-induced cardiotoxicity. Immunoprecipitation and Western blotting were performed to reveal the deubiquitinating effects of OTUB1 on c-MYC expression. RESULTS: We found that global Otub1-knockdown in vivo alleviated the subacute DOX treatment-induced cardiac dysfunction, fibrosis, and cardiomyocyte atrophy. Mechanistically, unbiased RNA sequencing and molecular biology experiments revealed that cardiomyocyte apoptosis, inflammation, and oxidative stress in DOX-induced cardiotoxicity were significantly compromised in the Otub1-knockdown group. Further in vitro studies have shown that c-MYC, a critical regulator of apoptosis, is indispensable in OTUB1's regulations of DOX-induced cardiotoxicity. Deubiquitinating effects of OTUB1 on K48- and K63-linked ubiquitination of c-MYC protein are essential for promoting cardiomyocyte apoptosis and oxidative responses. CONCLUSIONS: OTUB1-c-MYC inhibition protected cardiomyocytes against DOX-induced apoptosis and oxidative stress, suggesting that OTUB1 is a potential translational therapeutic target for preventing DOX-induced cardiotoxicity.

Hippo pathway-manipulating neutrophil-mimic hybrid nanoparticles for cardiac ischemic injury via modulation of local immunity and cardiac regeneration.

The promise of regeneration therapy for restoration of damaged myocardium after cardiac ischemic injury relies on targeted delivery of proliferative molecules into cardiomyocytes whose healing benefits are still limited owing to severe immune microenvironment due to local high concentration of proinflammatory cytokines. Optimal therapeutic strategies are therefore in urgent need to both modulate local immunity and deliver proliferative molecules. Here, we addressed this unmet need by developing neutrophil-mimic nanoparticles NM@miR, fabricated by coating hybrid neutrophil membranes with artificial lipids onto mesoporous silica nanoparticles (MSNs) loaded with microRNA-10b. The hybrid membrane could endow nanoparticles with strong capacity to migrate into inflammatory sites and neutralize proinflammatory cytokines and increase the delivery efficiency of microRNA-10b into adult mammalian cardiomyocytes (CMs) by fusing with cell membranes and leading to the release of MSNs-miR into cytosol. Upon NM@miR administration, this nanoparticle could home to the injured myocardium, restore the local immunity, and efficiently deliver microRNA-10b to cardiomyocytes, which could reduce the activation of Hippo-YAP pathway mediated by excessive cytokines and exert the best proliferative effect of miR-10b. This combination therapy could finally improve cardiac function and mitigate ventricular remodeling. Consequently, this work offers a combination strategy of immunity modulation and proliferative molecule delivery to boost cardiac regeneration after injury.

Chronologic evolution and prognostic implications of impaired coronary flow after chronic total occlusion angioplasty.

Background: Although vessels have the potential to recover following successful recanalization of chronic total occlusion (CTO), evidence is limited about the clinical significance of slow flow (SF) phenomenon after recanalization. The aim of this study was to evaluate the determinants, development and prognostic impact of SF after percutaneous coronary intervention (PCI) for CTO. Methods: This was a retrospective cohort study, 500 patients were consecutively enrolled undergoing CTO PCI and consecutive follow-up angiography in Zhongshan Hospital, Fudan University, between 2015 and 2020. Coronary flow was assessed by corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC). The association between SF and outcomes of CTO PCI was evaluated by analyzing the clinical, angiographic, and procedural characteristics. Results: SF was observed in 29 (5.8%) patients immediately after CTO PCI. Prior myocardial infraction, right coronary artery (RCA) revascularization and lack of bilateral collaterals were independent predictors of SF. SF was associated with increased risks of periprocedural myocardial infarction (PMI) [adjusted odds ratio (adOR): 4.12; 95% confidence interval (CI): 1.68-10.07; P=0.002] and target lesion restenosis (adOR: 2.50; 95% CI: 1.10-5.72; P=0.030). In patients with baseline left ventricular ejection fraction (LVEF) ≤60%, systolic improvement was compromised in the SF group (LVEF: 55.4%±9.6% in follow up vs. 52.1%±9.4% before CTO PCI, P=0.147) compared with that of the normal group (LVEF: 55.7%±9.3% vs. 51.6%±8.5%, P<0.001). Conclusions: SF has a significant influence on the prognosis of patients undergoing CTO PCI. Achieving normal coronary flow is essential in CTO revascularization.

Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3ß signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.

Exploring indicators of success in chronic total occlusion percutaneous coronary intervention with Stingray system-based antegrade dissection re-entry: Insights from retrospective analysis.

BACKGROUND: The predictors of success of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) through antegrade dissection and re-entry (ADR) using the Stingray system (Stingray ADR) remain elusive, mainly owing to the lack of consecutive angiographic and procedural records of patients. OBJECTIVES: This study aimed to identify indicators that can determine the success of CTO PCI performed using the Stingray ADR technique. METHODS: The clinical data of 115 patients who underwent CTO PCI through Stingray ADR at the same cardiac center were retrospectively and consecutively collected. Multivariate logistic regression analysis was performed to investigate the indicators of the success of ADR attempts. RESULTS: The technical success rate of Stingray ADR in CTO PCI was 72.2%. The overall technical success rate of CTO recanalization was 78.3% in all CTO PCIs having used Stingray Low Profile balloon. Vessel calcification (odds ratio [OR]: 4.03; 95% confidence interval [CI]: 1.49-11.88; p = 0.008), and retrograde puncture indicator (OR: 4.89; 95% CI: 1.51-17.11; p = 0.009) were identified as independent positive predictors. Blunt/no stump proximal to the occlusion segment (OR: 0.22; 95% CI: 0.06-0.64; p = 0.009), decision time before Stingray ADR (per 1 h increase) (OR: 0.54; 95% CI: 0.31-0.92; p = 0.026), operation duration of Stingray ADR (per 10 min increase) (OR: 0.62; 95% CI: 0.40-0.94; p = 0.028), and puncture site at the intraplaque region (OR: 0.24; 95% CI: 0.06-0.84; p = 0.026) were identified as the four negative independent predictors. CONCLUSIONS: This study revealed independent predictors of the success of CTO PCI performed using the Stingray ADR technique. As for CTO characteristics, the presence of calcification in the CTO segment and a tapered stump proximal to the lesion site can facilitate successful Stingray ADR. As for the procedures, the success rate of Stingray ADR can be improved by initiating the technique decisively and promptly, operating the system quickly and accurately and creating a puncture in the distal cap region of CTO under retrograde guidance.

Triglyceride-glucose index is associated with severe obstructive coronary artery disease and atherosclerotic target lesion failure among young adults.

BACKGROUND: Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF). METHODS: We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC). RESULTS: Among the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23-1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03-0.17, p = 0.005). During a medium of 33 month (IQR: 31-34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07-5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01-1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722-0.734, p = 0.04) to predict TLF. CONCLUSIONS: TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.

Association between NLRP3 inflammasome and periprocedural myocardial injury following elective PCI.

Background: Periprocedural myocardial injury (PMI) is a common complication of percutaneous coronary intervention (PCI) associated with poor prognosis. Inflammation has been demonstrated to exert a crucial role in PMI. However, how the inflammation is initiated or sustained in PMI remains elusive. Methods: RNA-seq in peripheral blood mononuclear cells (PBMCs) from 3 Non-PMI and 6 PMI patients was performed with subsequent bioinformatics analysis. RNA-seq results were verified in a patient cohort. We also established the coronary microembolization (CME) mice model to mimic PMI. The activity of caspase-1 in PBMCs was detected by flow cytometry. The levels of interleukin (IL)-1ß, IL-18 and cardiac troponin in plasma were measured by enzyme-linked immunosorbent assay. Results: We identified a total of 901 differentially expressed genes (DEGs) between Non-PMI and PMI patients. These DEGs participated in several inflammation-related processes. NOD-like receptor signaling pathway was significantly enriched in pathway analysis. All the key genes composed in the NLRP3 inflammasome, including NLRP3, PYCARD, CASP1 and IL1B, were upregulated in PMI patients. The activation of NLRP3 inflammasome was then verified by increased activity of caspase-1 in PBMCs, and elevated levels of IL-1ß and IL-18 in plasma in PMI patients. Spearman analysis confirmed tight correlations between caspase-1 activity, IL-1ß, IL-18 levels and troponin T level. In addition, caspase-1 activity, IL-1ß and IL-18 levels were also enhanced in CME mice. Conclusions: We discovered that NLRP3 inflammasome was involved in PMI, thus providing evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in PMI.

A Novel Parallel Wire-based Antegrade Dissection Re-entry Technique for Failed Retrograde Attempt of Coronary Chronic Total Occlusions with Risk Nomogram Analysis.

BACKGROUND: Rapid development in coronary chronic total occlusion (CTO) interventional techniques and devices have achieved a greater success rate with favorable outcomes. Antegrade dissection re-entry (ADR) technique is an important CTO crossing strategy and a desirable approach for long CTOs with good distal landing zone. However, unsuccessful procedures in contemporary CTO-percutaneous coronary intervention (PCI) remain, especially in lesions with non-interventional collaterals. METHOD: Based on a single center experience, a hybrid interventional algorithm, parallel wire-based ADR (PW-ADR) combines the advantages of parallel wire technique (PWT) and device-based ADR to target CTO lesions with failed retrograde approach. A retrospective analysis of patients who underwent PW-ADR was performed. A risk nomogram was created to identify patients at high risk for technical failure. RESULTS: A total of 57 patients treated with PW-ADR were ultimately included in the present study. A total of 46 (80.7%) cases achieved technical success and procedural success, with low incidence of in-hospital complications or 1-year major adverse cardiac events (MACE). The risk nomogram identified 3 predictor variables associated with technical failure of PW-ADR, including tortuous vessel, J-CTO score, and times of antegrade coronary angiography (CAG) during ADR, with promising accuracy (AUROC 0.947). CONCLUSION: The novel hybrid CTO-PCI algorithm, PW-ADR, provided an alternative interventional approach for complex CTO lesions with a promising success rate. The risk nomogram served as a prompter for high-risk cases, which may warrant a change in treatment strategy.

The present study reported a new hybrid-PCI strategy with a promising success rate for the treatment of CTO from a single center experience, over last 5 years. A retrospective analysis of patients who underwent PW-ADR was performed. A risk nomogram was created to identify patients at high risk for technical failure. 80.7% of patients treated with PW-ADR were achieved technical success and procedural success, with low incidence of in-hospital complications or 1-year MACE in the present study. A total of 3 predictor variables were identified to be associated with technical failure of PW-ADR, including tortuous vessel, J-CTO score, and times of antegrade CAG during ADR. This prediction tool may allow early identification of more complex and difficult CTO cases that require a timely switch in strategic approach or termination of the procedure to avoid unnecessary surgical risk.

Long-term clinical outcomes of drug-coated balloon for the management of chronic total occlusions.

OBJECTIVES: This study aims to compare the clinical outcomes of patients with de novo chronic total occlusion (CTO) lesions treated by hybrid strategy and drug-coated balloons (DCB)-only strategy. BACKGROUNDS: DCBs have been used as an alternative to or in combination with drug-eluting stents in CTO lesions. However, the clinical impact of DCB treatment on CTO lesion remains uncertain. METHODS: We retrospectively enrolled 154 patients with de novo CTO lesions treated by DCB, including 57 cases in hybrid group and 97 cases in DCB-only group. RESULTS: The lesions in hybrid group were more complicated than those in DCB-only group as shown by higher J-CTO score, and therefore higher percentage of retrograde approach, more IVUS guidance, more CTO guidewires, and longer procedural time were demonstrated. Although the percentage of non-flow-limiting dissection and residual stenosis of more than 30% were lower in hybrid group, TIMI flow grade, satisfactory and acceptable recanalization rate were not significantly different between two groups. During a median follow-up was 470 days, the incidence of target lesion revascularization (TLR), myocardial infarction and cardiac death was 11.0%, 1.3% and 1.9%, respectively. The long-term TLR-free survival was comparable between hybrid and DCB-only groups. By multivariate analysis, DCB length and age were predictors of TLR. CONCLUSION: DCB treatment appears effective and safe in selected de novo CTO lesions during long-term follow up. The recanalization results and long-term outcomes are comparable between hybrid and DCB-only group despite more complicated lesions in hybrid group.

Prognostic value and clinical usefulness of PIANO score in patients undergoing primary percutaneous coronary intervention.

BACKGROUND: In our previous study, the PIANO score was constructed to predict the occurrence of no-reflow phenomenon in patients undergoing primary percutaneous coronary intervention (PCI). In the current analysis, we sought to evaluate the prognostic value and clinical usefulness of the PIANO score in this population. METHODS: Patients with acute myocardial infarction (AMI) undergoing primary PCI were consecutively enrolled and followed up in this register. The endpoint of interest was all-cause mortality at 2 years after the procedure. The clinical benefits of thrombus aspiration (TA) during primary PCI in certain subgroups were also evaluated as exploratory analyses. RESULTS: A total of 2100 patients were identified, and 54.3% had high (≥8) PIANO score. After 2-year follow-up, patients with high PIANO score had higher risk of all-cause mortality after adjustment for propensity score (6.7% vs. 3.1%, adjusted hazard ratio = 2.11 [1.21-3.68], p = 0.008), especially in the first month (adjusted hazard ratio = 2.33 [1.17-4.65], p = 0.017). Restricted cubic spline analysis indicated the linear association between the PIANO score and 2-year all-cause mortality (nonlinear p = 0.556). Further analysis demonstrated that TA did not reduce all-cause mortality in the overall patients, as well as in those with visible thrombus, high thrombus burden, or occlusive lesions. However, the PIANO score defined "high-risk" (PIANO score ≥ 8) patients could benefit from it. CONCLUSIONS: The PIANO score had potential prognostic value in patients with AMI undergoing primary PCI. It might also be helpful for identifying patients who would benefit from TA. These observations require further confirmation in future studies.

Unveiling a rare case: Cardiac rupture secondary to acute occlusion of the distal left circumflex artery detected by contrast-enhanced spiral CT.

A 79-year-old female patient was admitted to the hospital due to intense chest pain. Emergency percutaneous coronary intervention (PCI) revealed an occlusion in the distal portion of the left circumflex artery (LCx). The patient suffered from cardiac rupture, an uncommon yet extremely perilous condition, within 30 minutes following the procedure. This was verified through a computed tomography angiography (CTA) scan and bedside echocardiography. The etiology of cardiac rupture remains elusive, yet potential factors such as the patient's age, gender, initial acute myocardial infarction (AMI), and single-vessel disease without collateral circulation may be linked to this occurrence. This case report emphasizes that occluded tiny distal coronary arteries can also induce cardiac rupture and that a sufficient level of suspicion for the diagnosis of cardiac rupture should be raised when adequate fluid resuscitation fails to alleviate hypotension. Additionally, contrast-enhanced spiral computed tomography (CESCT) is highly effective in revealing certain pathological features associated with cardiac rupture.