Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line-HK-2-that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screen and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection. We found a role for a secretory form of SARS-CoV-2 receptor, soluble angiotensin converting enzyme 2 (sACE2), in SARS-CoV-2 infection. Further investigation revealed that SARS-CoV-2 exploits receptor-mediated endocytosis through interaction between its spike with sACE2 or sACE2-vasopressin via AT1 or AVPR1B, respectively. Our identification of VDFs and the regulatory effect of sACE2 on SARS-CoV-2 infection shed insight into pathogenesis and cell entry mechanisms of SARS-CoV-2 as well as potential treatment strategies for COVID-19.

Investigation of the Nanoparticulation Method and Cell-Killing Effect following the Mitochondrial Delivery of Hydrophobic Porphyrin-Based Photosensitizers.

Photodynamic therapy is expected to be a less invasive treatment, and strategies for targeting mitochondria, the main sources of singlet oxygen, are attracting attention to increase the efficacy of photodynamic therapy and reduce its side effects. To date, we have succeeded in encapsulating the photosensitizer rTPA into MITO-Porter (MP), a mitochondria-targeted Drug Delivery System (DDS), aimed at mitochondrial delivery of the photosensitizer while maintaining its activity. In this study, we report the results of our studies to alleviate rTPA aggregation in an effort to improve drug efficacy and assess the usefulness of modifying the rTPA side chain to improve the mitochondrial retention of MITO-Porter, which exhibits high therapeutic efficacy. Conventional rTPA with anionic side chains and two rTPA analogs with side chains that were converted to neutral or cationic side chains were encapsulated into MITO-Porter. Low-MP (MITO-Porter with Low Drug/Lipid) exhibited high drug efficacy for all three types of rTPA, and in Low-MP, charged rTPA-encapsulated MP exhibited high drug efficacy. The cellular uptake and mitochondrial translocation capacities were similar for all particles, suggesting that differences in aggregation rates during the incorporation of rTPA into MITO-Porter resulted in differences in drug efficacy.

Prognostic significance of serial N-terminal pro-B-type natriuretic peptide levels in patients with acute myocardial infarction: A prospective study.

OBJECTS: This study aimed to investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at different sampling times and prognosis in patients with acute myocardial infarction (AMI) undergoing emergency percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between March 2017 and January 2020, 1,105 patients with AMI who underwent emergency PCI were included. NT-proBNP levels were measured on days 0, 1, 2, 3, and 7. A composite of all-cause death, MI recurrence (reMI), and rehospitalization due to heart failure, known as major adverse cardiovascular events (MACE), was recorded. During the 36.8-month follow-up, 175 patients (15.8%) experienced MACEs. When patients were grouped based on quartiles of NT-proBNP levels on days 0 and 7, the results demonstrated that patients in quartile 4 showed a substantially increased MACE risk compared to those in quartile 1 (hazard ratio [HR] 2.27, 95% confidence interval [CI]:1.27-4.08, P = .006; HR 2.20, 95%CI:1.23-3.94, P = .008). There were U-shaped relationships between the HR for MACE and NT-proBNP levels on days 2, 3, and 7, as well as peak NT-proBNP (P for nonlinearity = .007, .006, .004, and .009, respectively). A similar relationship was observed in the HR for reMI and NT-proBNP levels on days 2 and 3. For MACE at 3 years, serial NT-proBNP levels improved the predictive accuracy of the Global Registry of Acute Coronary Events (GRACE) risk score (concordance index [C-index]: 0.711; continuous net reclassification improvement [NRI]: 0.192, 95% CI: 0.022-0.445; integrated discrimination improvement [IDI]: 0.034, 95% CI: 0.016-0.064). For all-cause death at 3 years, the combination of NT-proBNP and GRACE score showed excellent performance, with C-index, continuous NRI, and IDI values of 0.801, 0.373 (95%CI: 0.072-0.853), and 0.051 (95%CI: 0.025-0.091), respectively. CONCLUSIONS: Early and sequential measurement of NT-proBNP levels could assist in predicting MACE risk. Moreover, the relationship between MACE risk and NT-proBNP levels was U-shaped. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

Prognostic impacts of diabetes status and lipoprotein(a) levels in patients with ST-segment elevation myocardial infarction: a prospective cohort study.

OBJECTS: This study aimed to investigate the impact of lipoprotein(a) [Lp(a)] levels on the prognosis of Chinese patients with ST-segment elevation myocardial infarction (STEMI), and to explore if the impact may differ in the diabetes mellitus (DM) and nonDM groups. METHODS: Between March 2017 and January 2020, 1543 patients with STEMI who underwent emergency percutaneous coronary intervention (PCI) were prospectively recruited. The primary outcome was a composite of all-cause death, MI recurrence (reMI), and stroke, known as major adverse cardiovascular events (MACE). Analyses involving the Kaplan-Meier curve, Cox regression, and restricted cubic spline (RCS) were conducted. RESULTS: During the 1446-day follow-up period, 275 patients (17.8%) experienced MACEs, including 141 with DM (20.8%) and 134 (15.5%) without DM. As for the DM group, patients with Lp(a) ≥ 50 mg/dL showed an apparently higher MACE risk compared to those with Lp(a) < 10 mg/dL (adjusted hazard ratio [HR]: 1.85, 95% confidence interval [CI]:1.10-3.11, P = 0.021). The RCS curve indicates that the HR for MACE appeared to increase linearly with Lp(a) levels exceeding 16.9 mg/dL. However, no similar associations were obtained in the nonDM group, with an adjusted HR value of 0.57 (Lp(a) ≥ 50 mg/dL vs. < 10 mg/dL: 95% CI 0.32-1.05, P = 0.071). Besides, compared to patients without DM and Lp(a) ≥ 30 mg/dL, the MACE risk of patients in the other three groups (nonDM with Lp(a) < 30 mg/dL, DM with Lp(a) < 30 mg/dL, and DM with Lp(a) ≥ 30 mg/dL) increased to 1.67-fold (95% CI 1.11-2.50, P = 0.013), 1.53-fold (95% CI 1.02-2.31, P = 0.041), and 2.08-fold (95% CI 1.33-3.26, P = 0.001), respectively. CONCLUSIONS: In this contemporary STEMI population, high Lp(a) levels were linked to an increased MACE risk, and very high Lp(a) levels (≥ 50 mg/dL) significantly indicated poor outcomes in patients with DM, while not for those without DM. TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study.

Lipoxin A4 (LXA4) is one of the specialized pro-resolving lipid mediators proved to suppress the progression of atherosclerosis in vivo, but its clinical impacts in atherosclerotic patients is unclear. In this study, we assessed the prognostic impacts of LXA4 in patients with acute myocardial infarction (AMI). A total of 1569 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Plasma samples of AMI patients were collected, and LXA4 levels were determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, ischemic stroke, or ischemia-driven revascularization. Cox regression was used to assess associations between LXA4 and clinical outcomes. Overall, the median level of LXA4 was 5.637 (3.047-9.014) ng/mL for AMI patients. During a median follow-up of 786 (726-1108) days, high LXA4 (≥ 5.637 ng/mL) was associated with lower risk of MACE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.60-0.89, P = 0.002), which was sustained in propensity score matching (HR: 0.73, 95% CI: 0.60-0.90, P = 0.004) and inverse probability weighting analysis (HR: 0.74, 95% CI: 0.61-0.90, P = 0.002). Combined with pro-inflammatory biomarker, patients with high levels of LXA4 (≥ 5.637 ng/mL) but low levels of high-sensitivity C-reactive protein (< 5.7 mg/L) acquired the lowest risk of MACE (HR: 0.68, 95% CI: 0.51-0.92, P = 0.012). In sum, high levels of LXA4 were associated with lower risk of recurrent ischemic events for AMI patients, which could serve as new therapeutic target to tackle cardiovascular inflammation.

Interleukin-11 Is Elevated in Patients with Atrial Fibrillation, Correlates with Serum Fibrosis Markers, and Represents a Therapeutic Target for Atrial Fibrosis.

INTRODUCTION: Inflammatory cytokines are closely associated with developing cardiac fibrosis. This research aimed to explore the significant role of IL-11 in atrial fibrosis progression and potential therapeutic targets. METHODS: 207 AF patients and 160 healthy subjects were included in the case-control study. Blood samples were analyzed for the level of IL-11 by enzyme-linked immunosorbent assay (ELISA). Angiotensin II (Ang II)-treated fibrosis mouse models were generated, and expression of IL-11 mRNA and protein was detected by RT-qPCR and Western blot. IL-11 antagonist was used to evaluating atrial fibrosis-related markers. RESULTS: The persistent atrial fibrillation patients (n = 76) had significantly larger left atrial size, higher serum levels of hypertrophic protein BNP, proinflammatory cytokine high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) compared to paroxysmal atrial fibrillation patients (n = 131), and healthy subjects (all p < 0.05). Pearson correlation analysis revealed significant positive correlation between serum IL-11 and cardiac fibrosis markers BNP (r = 0.394, p < 0.001), CTX-I (r = 0.418, p < 0.001), PICP (r = 0.306, p < 0.001), PIIINP (r = 0.335, p < 0.001), and TGF-ß1 (r = 0.273, p < 0.001). In the fibrosis mouse model, Ang II infusion significantly upregulated IL-11 mRNA and protein expression in the left atrium of mice (p < 0.05), as well as staining intensity of Masson trichrome, the intensity of α-SMA, and it increased mRNA expression of collagen I and III in atrial tissue. IL-11 antagonist treatment significantly attenuated Masson trichrome, number of α-SMA-positive myofibroblasts in atrial tissue. Also, it significantly reduced the p-ERK1/2 in atrial tissue of mice infused with Ang II (p < 0.05). CONCLUSIONS: IL-11 is upregulated in the serum of AF patients, and IL-11 inhibitor significantly inhibited Ang II-induced atrial fibrosis, a key pathological feature of AF. Therefore, IL-11 could be a potential therapeutic target for AF.

Association of PCSK9 with inflammation and platelet activation markers and recurrent cardiovascular risks in STEMI patients undergoing primary PCI with or without diabetes.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular outcomes in stable coronary artery disease with diabetes. We aimed to assess the relationship between PCSK9 and major adverse cardiovascular events (MACEs) in ST-segment elevation myocardial infarction (STEMI) patients with or without diabetes, as well as the relationships between PCSK9 and metabolism, inflammation and platelet activation markers. METHODS: A total of 1027 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and without prior lipid-lowering therapy were consecutively enrolled and the baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high and low PCSK9 groups according to PCSK9 median. All patients were followed up for the occurrence of MACEs. The associations of PCSK9 with metabolism, inflammation and platelet activation markers and MACEs were evaluated. RESULTS: PCSK9 levels were positively correlated with triglycerides, high-sensitivity C reactive protein, soluble CD40 ligand and soluble P-selectin levels, and the correlations were stronger in diabetic patients than in non-diabetic patients. In diabetic patients receiving ticagrelor, PCSK9 levels were positively correlated with maximal platelet aggregation measured by light transmittance aggregometry and maximum amplitude of adenosine diphosphate-induced platelet-fibrin clots measured by thrombelastography in the maintenance phase of treatment, whereas no correlations were found in non-diabetic patients. During a median follow-up of 2.0 years, 155 (15.1%) MACEs occurred. The Kaplan-Meier analysis displayed that the patients with high PCSK9 levels had lower event-free survival rate than those with low PCSK9 levels (P = 0.030). When participants were categorized into 4 subgroups according to PCSK9 levels and diabetes status, high PCSK9 levels plus diabetes subgroup had the lowest cumulative event-free survival rate (P = 0.043). Multivariable Cox regression analysis revealed that high PCSK9 levels were independently associated with MACEs in diabetic patients (hazard ratio 2.283, 95% confidence interval: 1.094-4.764, P = 0.028), but not in the whole cohort or non-diabetic patients. CONCLUSIONS: The study showed that high PCSK9 levels were independently associated with MACEs in STEMI patients with diabetes undergoing primary PCI, and the association may be due to stronger correlations of PCSK9 with inflammation and platelet activation markers in diabetic patients.

Excitation-Wavelength-Dependent Functionalities of Temporally Controlled Sensing and Generation of Singlet Oxygen by a Photoexcited State Engineered Rhodamine 6G-Anthracene Conjugate.

The present study provides design guidance for unique multipotent molecules that sense and generate singlet oxygen (1 O2 ). A rhodamine 6G-aminomethylanthracene-linked donor-acceptor molecule (RA) is designed and synthesized for demonstrating wavelength-dependent functionalities as follows; (i) RA acts as a conventional fluorogenic 1 O2 sensor molecule like the commercially available reagent, singlet oxygen sensor green (SOSG), when it absorbs ultraviolet (UV)-visible light and reacts with 1 O2 . (ii) RA acts as a temporally controlled 1 O2 sensing reagent under the longer wavelength (∼700 nm) photosensitization. RA enters an intermediate state after capturing 1 O2 and does not become strongly fluorescent until it is exposed to UV, blue, or green light. (iii) RA acts as an efficient photosensitizer to generate 1 O2 under green light illumination. The spin-orbit charge transfer mediated intersystem crossing (SOCT-ISC) process achieves this function, and RA shows a potential cancer-killing effect on pancreatic cancer cells. The wavelength-switchable functionalities in RA offer to promise molecular tools to apply 1 O2 in a spatiotemporal manner.

Association between lipoprotein (a) and heart failure with reduced ejection fraction development.

BACKGROUND: The current study aimed to evaluate the relationship between baseline serum lipoprotein (a) [Lp(a)] level and heart failure with reduced ejection fraction (HFrEF) development. METHODS: This was a retrospective study, and participants were enrolled from the outpatient clinic. All data were extracted from the electronic health record of the outpatient clinic system. The follow-up was performed through reviewing the clinical notes at the outpatient clinic system, and study outcome of the current study was the first diagnosis of HFrEF. Participants were divided into low Lp(a) (<30 mg/dl, n = 336) and high Lp(a) (≥30 mg/dl, n = 584) groups. RESULTS: Individuals in the high Lp(a) group were more likely to be men and have diabetes mellitus (DM) and dyslipidemia. Increased Lp(a) at baseline was positively associated with serum N-terminal pro-B natriuretic peptide level while negatively associated with left ventricular ejection fraction (LVEF) at follow-up. After adjusting for covariates, per 10 mg/dl increase in baseline Lp(a) remained significantly associated with HFrEF, with odds ratio of 1.17 (95% confidence interval of 1.05, 1.46). The magnitude of association between baseline Lp(a) level and HFrEF was greater in men and in individuals with DM or coronary heart disease (CHD), while it was weaker in individuals treated with beta-blocker at baseline. CONCLUSION: Increased Lp(a) at baseline was associated with HFrEF development. The adverse effects of Lp(a) were greater on men and individuals with DM or CHD, which were mitigated by beta-blocker therapy. These findings together underscore the possibility and usefulness of Lp(a) as a new risk factor to predict HFrEF.

Broad-spectrum Respiratory Virus Entry Inhibitors.

With the increasing global human population, travel, and socioeconomic activities, more and more novel pathogenic viruses will emerge or re-emerge. While more than 260 viruses are known to infect humans, only a small minority of these viral diseases are treatable by clinically approved antiviral drugs. Apart from these identified viruses, new emerging viruses and drug-resistant viruses are also important challenges to our public health and healthcare systems. The COVID-19 and influenza pandemics remind us the importance of getting broad-spectrum antivirals against emerging and re-emerging respiratory viruses. Broad-spectrum antivirals against different viral families for fighting the currently known viruses and novel emerging viruses are urgently needed. Viral entry is the universal first step for viral infection, and therefore is a promising target for identifying broad-spectrum antivirals. In this chapter, we mainly focus on discussing the risks of respiratory viruses, the challenge of finding broad-spectrum antivirals, the entry processes of respiratory viruses, the current studies on broad-spectrum entry inhibitors for respiratory viruses, and the directions for discovering broad-spectrum antivirals in the future.

RNA-seq identifies circulating miRNAs as potential biomarkers for plaque rupture in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Plaque rupture (PR) and plaque erosion (PE) are the two major pathological phenotypes in acute coronary syndrome. Since microRNAs have been found to be involved in the mechanisms of PR and PE, we investigated the diagnostic utility of microRNAs in differentiating between patients with PR and patients with PE. METHODS: MicroRNA sequencing was performed on plasma from 21 patients with PR, 20 patients with PE and 17 healthy control subjects (HCs). 24 miRNAs were selected for validation in 20 PR patients and 20 PE patients and 8 miRNAs were further validated in an independent replication cohort (82 patients with PR, 84 patients with PE and 59 HCs) by applying quantitative real-time polymerase chain reaction. Then we analyzed pathways associated with significant miRNAs in PR. RESULTS: MiR-744-3p, miR-324-3p and miR-330-3p were significantly upregulated in the PR group compared with the PE group (Log10miR-744-3p: 0.26[--0.28-1.57] versus -0.41[-0.83--0.03], padj < 0.001; Log10miR-324-3p: 0.40[-0.09-0.84] versus -0.12[-0.53-0.29], padj < 0.001; Log10miR-330-3p: 0.34[0.08-0.93] versus -0.07[-0.65-0.22], padj < 0.001), The area under the receiver operating characteristic curve for the combination of these three miRNAs in distinguishing between PR from PE in training and test set was 0.764 (0.679-0.850, sensitivity = 86.2%, specificity = 54.4%, P < 0.001) and 0.768 (0.637-0.898, sensitivity,65.4%, specificity:80.0%, P = 0.001), respectively. CONCLUSION: A set of circulating microRNAs (miR-744-3p, miR-330-3p, and miR-324-3p) is associated with PR and has clinical utility as a diagnostic marker for distinguishing the plaque phenotype in STEMI patients.

Comparison of Cell Fusions Induced by Influenza Virus and SARS-CoV-2.

Virus-cell fusion is the key step for viral infection in host cells. Studies on virus binding and fusion with host cells are important for understanding the virus-host interaction and viral pathogenesis for the discovery of antiviral drugs. In this review, we focus on the virus-cell fusions induced by the two major pandemic viruses, including the influenza virus and SARS-CoV-2. We further compare the cell fusions induced by the influenza virus and SARS-CoV-2, especially the pH-dependent fusion of the influenza virus and the fusion of SARS-CoV-2 in the type-II transmembrane serine protease 2 negative (TMPRSS2-) cells with syncytia formation. Finally, we present the development of drugs used against SARA-CoV-2 and the influenza virus through the discovery of anti-fusion drugs and the prevention of pandemic respiratory viruses.

Differential role of sphingomyelin in influenza virus, rhinovirus and SARS-CoV-2 infection of Calu-3 cells.

Host cell lipids play a pivotal role in the pathogenesis of respiratory virus infection. However, a direct comparison of the lipidomic profile of influenza virus and rhinovirus infections is lacking. In this study, we first compared the lipid profile of influenza virus and rhinovirus infection in a bronchial epithelial cell line. Most lipid features were downregulated for both influenza virus and rhinovirus, especially for the sphingomyelin features. Pathway analysis showed that sphingolipid metabolism was the most perturbed pathway. Functional study showed that bacterial sphingomyelinase suppressed influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, but promoted rhinovirus replication. These findings suggest that sphingomyelin pathway can be a potential target for antiviral therapy, but should be carefully evaluated as it has opposite effects on different respiratory viruses. Furthermore, the differential effect of sphingomyelinase on rhinovirus and influenza virus may explain the interference between rhinovirus and influenza virus infection.

Triglyceride glucose index combined with plaque characteristics as a novel biomarker for cardiovascular outcomes after percutaneous coronary intervention in ST-elevated myocardial infarction patients: an intravascular optical coherence tomography study.

BACKGROUND AND AIM: This prospective study explored plaque morphology according to the underlying culprit lesion pathology (rupture versus erosion) in relation to the triglyceride glucose (TyG) index in patients with acute ST-elevated myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention and optical coherence tomography (OCT) for culprit lesions to elucidate the effects of the TyG index and type of plaque on the incidence of major adverse cardiovascular events (MACEs). METHODS AND OUTCOMES: A total of 274 patients with STEMI aged ≥ 18 years who underwent pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019 were enrolled. The TyG index was calculated using the formula ln[fasting TG (mg/dL) × fasting glucose (mg/dL)/2]. Patients with plaque rupture (PR) and plaque erosion (PE) were divided into three groups across the TyG tertiles. MACEs were defined as a composite of all-cause death, myocardial infarction (MI) recurrence, and ischaemic stroke. In fully adjusted analyses, the middle tertile of TyG was significantly associated with greater rates of MACEs in patients with PR but not in those with PE (relative to the low tertile, HR [hazard ratio], 6.01; 95% confidence interval [CI], 1.25-28.88; P = 0.025). Cox regression models indicated a significantly higher HR for MACEs in patients in the middle tertile of TyG than in those in the low tertile of TyG after full additional adjustment (HR, 5.45; 95% CI, 1.10-27.09; P = 0.038). However, being in the high tertile of TyG independently and significantly increased the risk of major bleeding events among patients with PE (HR, 2.50; 95% CI, 1.11-5.65; P = 0.028). The area under the receiver operating characteristic curve for predicting MACEs to evaluate the diagnostic value of the TyG index combined with the morphological characteristics of plaque after full adjustment was 0.881 (sensitivity = 94.74%, specificity = 78.04%, cut-off level = 0.73). Kaplan-Meier curves were generated for the cumulative incidence of MACEs for up to a median of 1.98 years stratified by tertiles of TyG among the PR and PE subgroups. Among patients with PR, there were significant differences among the tertiles of TyG (p = 0.030). CONCLUSION AND RELEVANCE: Microstructural OCT features of culprit lesions in combination with the TyG index, a surrogate estimate of insulin resistance, can be used in clinical practice to support risk stratification and predict adverse events in patients with STEMI.

Liraglutide reduces coronary endothelial cells no-reflow damage through activating MAPK/ERK signaling pathway.

Coronary no-reflow damage is caused by endothelial cell damage although little drug is available to intervene in coronary no-reflow. Liraglutide is a kind of anti-diabetic drug and its cardioprotective role has been widely reported. In this study, we explored the role of liraglutide in regulating coronary endothelial cell damage. We used hydrogen peroxide to mimic coronary no-reflow damage in vitro. After exposure to hydrogen peroxide, endothelial cells' viability was significantly reduced, an effect that was followed by an increase in cell apoptosis. Interestingly, liraglutide treatment obviously upregulated endothelial cell viability and thus prevented cell apoptosis. Further, we also found that liraglutide inhibited the activation of caspase-3 in hydrogen peroxide-treated endothelial cells. Besides, cellular metabolism, as reflected by mitochondrial membrane potential, was disrupted by hydrogen peroxide and reversed to normal levels with liraglutide. Further, we found that the ERK pathway is a potential downstream effector of liraglutide. Administration of liraglutide significantly promoted the activation of ERK and this effect may contribute to endothelial cell survival. Altogether, our results illustrated that hydrogen peroxide-mediated endothelial cell damage could be attenuated by liraglutide through modulation of the MAPK/ERK signaling pathway. This finding will pave a novel road for the intervention of coronary no-reflow damage in patients suffering from myocardial infarction.

Prognostic impacts of ß-blockers in acute coronary syndrome patients without heart failure treated by percutaneous coronary intervention.

BACKGROUND: The use of ß-blockers for acute coronary syndrome (ACS) patients without heart failure (HF) is controversial, and lacks of evidence in the era of reperfusion and intensive secondary preventions. This study aimed to investigate the prognostic impacts of ß-blockers on patients with ACS but no HF treated by percutaneous coronary intervention (PCI). METHODS: A total of 2397 consecutive patients with ACS but no HF treated by PCI were retrospectively recruited from January 2010 to June 2017. Univariable Cox regression was used to assess the prognostic impacts of ß-blockers, followed by adjusted analysis, one-to-one propensity score matching (PSM), and inverse probability treatment weighting (IPTW) analysis, in order to control for systemic between-group differences. The primary outcome was all-cause death. RESULTS: Among the included patients, 2060 (85.9%) were prescribed with ß-blockers at discharge. The median follow-up time was 727 (433-2016) days, with 55 (2.3%) cases of all-cause death. Unadjusted analysis showed that the use of ß-blockers was associated with lower risk of death (hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.23-0.76, P = 0.004), which was sustained in adjusted analysis (HR: 0.53, 95% CI: 0.29-0.98, P = 0.044), PSM analysis (HR: 0.44, 95% CI: 0.20-0.96, P = 0.039) and IPTW analysis (HR: 0.49. 95% CI: 0.35-0.70, P < 0.001). Risk reduction was also seen in ß-blocker users for cardiac death, but not for major adverse cardiovascular events. CONCLUSIONS: The use of ß-blockers was associated with reduced long-term mortality for ACS-PCI patients without HF.

Prognostic Value of D-dimer in patients with acute coronary syndrome treated by percutaneous coronary intervention: a retrospective cohort study.

BACKGROUND: Associations between D-dimer and outcomes of patients with acute coronary syndromes (ACS) remain controversial. This study aimed to investigate the prognostic value of D-dimer in ACS patients treated by percutaneous coronary intervention (PCI). METHODS: In this observational study, 3972 consecutive patients with ACS treated by PCI were retrospectively recruited. The X-tile program was used to determine the optimal D-dimer thresholds for risk stratifications. Cox regression with multiple adjustments was used for outcome analysis. Restricted cubic spline (RCS) analysis was performed to assess the dose-response association between D-dimer and outcomes. The C-index was calculated to evaluate the additional prognostic value of D-dimer when added to clinical risk factors and commonly used clinical risk scores, with internal validations using bootstrapping methods. The primary outcome was all-cause death. RESULTS: During a median follow-up of 720 days, 225 deaths occurred. Based on the thresholds generated by X-tile, ACS-PCI patients with median (420-1150 ng/mL, hazard ratio [HR]: 1.58, 95 % confidence interval [CI]: 1.14-2.20, P = 0.007) and high (≥ 1150 ng/mL, HR: 1.98, 95 % CI: 1.36-2.89, P < 0.001) levels of D-dimer showed substantially higher risk of death compared to those with low D-dimer (< 420 ng/mL). RCS analysis depicted a constant relation between D-dimer and various outcomes. The addition of D-dimer levels significantly improved risk predictions for all-cause death when combined with the fully adjusted models (C-index: 0.853 vs. 0.845, P difference = 0.021), the GRACE score (C-index: 0.826 vs. 0.814, P difference = 0.027), and the TIMI score (C-index: 0.804 vs. 0.776, P difference < 0.001). The predicted mortality at the median follow-up (two years) was 1.7 %, 5.2 %, and 10.9 % for patients with low, median, and high D-dimer, respectively, which was well matched with the observed mortality (low D-dimer group: 1.2 %, median D-dimer group: 5.2 %, and high D-dimer group: 12.6 %). CONCLUSIONS: For ACS patients treated by PCI, D-dimer level was an independent predictor for adverse outcomes, and provided additional prognostic value when combined with clinical risk factors and risk scores. Risk stratifications based on D-dimer was plausible to differentiate ACS-PCI patients with higher risk of death.

Prognostic value of characteristics of plaque combined with residual syntax score among patients with STEMI undergoing primary PCI: an intravascular optical coherence tomography study.

AIM: The present study aimed to explore these characteristics, particularly thin-cap fibroatheroma (TCFA), in relation to residual syntax score (rSS) in patients who presented with acute MI. METHODS AND OUTCOMES: A total of 434 consecutive patients with MI aged ≥18 years who had STEMI underwent primary PCI. Notably, compared with other subgroups, the presence of TCFA in culprit lesions and a higher level of rSS, were significantly associated with MACE. When rSS was divided into three groups, high rSS levels were associated with a higher incidence of MACE, in the subgroups of without TCFA (P = 0.005), plaque erosion (P = 0.045), macrophage infiltration (P = 0.026), and calcification (P = 0.002). AUC of ROC curve was 0.794 and 0.816, whereas the AUC of the survival ROC was 0.798 and 0.846. CONCLUSION: The results of this study could be used in clinical practice to support risk stratification. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov as NCT03593928 .

Association of plasma trimethylamine N-Oxide level with healed culprit plaques examined by optical coherence tomography in patients with ST-Segment elevation myocardial infarction.

BACKGROUND AND AIMS: Healed plaque is a hallmark of previous regional plaque rupture or erosion. We hypothesized that the plasma level of trimethylamine N-oxide (TMAO) is related to healed culprit plaque in ST-segment elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS: A prospective cohort of 206 patients with STEMI, who were examined by optical coherence tomography (OCT) was enrolled in our study. After exclusion, 156 patients were categorized into healed plaque (n = 54) and nonhealed plaque (n = 102) groups. Plasma TMAO levels were detected by stable isotope dilution liquid chromatography tandem mass spectrometry in these two groups. Increased age and low BMI were more common in patients with healed plaques than in those without healed plaques. Through OCT observation, plaque rupture (81.5% vs. 45.1%, p < 0.001), thin cap fibroatheroma (TCFA) and macrophages (42.6% vs. 20.6%, p = 0.004, 70.4% vs. 26.5%, p < 0.001, respectively) were more frequently seen in patients with healed plaques than in those without healed plaques. The TMAO level in patients with healed plaques was significantly higher than that in patients with nonhealed plaques (3.9 µM [2.6-5.1] vs. 1.8 µM [1.0-2.7], p < 0.001). Furthermore, the receiver operating characteristic curve showed that TMAO can be used as a potential biomarker to predict healed plaque presence with a cutoff value of 2.9 µM (AUC = 0.810, sensitivity: 72.2%, specificity: 81.4%). CONCLUSIONS: Healed plaque in STEMI patients is associated with a high level of plaque vulnerability and inflammation. A high level of plasma TMAO can be a useful biomarker to differentiate STEMI patients with healed culprit plaques.