Wuhan Asia Heart Hospital

Importance: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective: To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants: Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention: Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures: Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results: Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.59 [95% CI, 0.22-1.59]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.95]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care. Conclusion and Relevance: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000029757.

BACKGROUND: The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. METHODS: At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. RESULTS: There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). CONCLUSIONS: There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

BACKGROUND: Previously, we reported that there was no significant difference at 30 days in the rate of a primary composite outcome of death, myocardial infarction, stroke, or new renal failure requiring dialysis between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report results on quality of life and cognitive function and on clinical outcomes at 1 year. METHODS: We enrolled 4752 patients with coronary artery disease who were scheduled to undergo CABG and randomly assigned them to undergo the procedure off-pump or on-pump. Patients were enrolled at 79 centers in 19 countries. We assessed quality of life and cognitive function at discharge, at 30 days, and at 1 year and clinical outcomes at 1 year. RESULTS: At 1 year, there was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (12.1% and 13.3%, respectively; hazard ratio with off-pump CABG, 0.91; 95% confidence interval [CI], 0.77 to 1.07; P=0.24). The rate of the primary outcome was also similar in the two groups in the period between 31 days and 1 year (hazard ratio, 0.79; 95% CI, 0.55 to 1.13; P=0.19). The rate of repeat coronary revascularization at 1 year was 1.4% in the off-pump group and 0.8% in the on-pump group (hazard ratio, 1.66; 95% CI, 0.95 to 2.89; P=0.07). There were no significant differences between the two groups at 1 year in measures of quality of life or neurocognitive function. CONCLUSIONS: At 1 year after CABG, there was no significant difference between off-pump and on-pump CABG with respect to the primary composite outcome, the rate of repeat coronary revascularization, quality of life, or neurocognitive function. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Lamy, André*; Devereaux, P.J.*; Prabhakaran, Dorairaj†; Taggart, David P.‡; Hu, Shengshou§; Paolasso, Ernesto∥; Straka, Zbynek¶; Piegas, Leopoldo S.#; Akar, Ahmet Ruchan**; Jain, Anil R.††; Noiseux, Nicolas‡‡; Padmanabhan, Chandrasekar§§; Bahamondes, Juan-Carlos∥∥; Novick, Richard J.¶¶; Vaijyanath, Prashant##; Reddy, Sukesh***; Tao, Liang†††; Olavegogeascoechea, Pablo A.‡‡‡; Airan, Balram§§§; Sulling, Toomas-Andres∥∥∥; Whitlock, Richard P.*; Ou, Yongning*; Ng, Jennifer*; Chrolavicius, Susan*; Yusuf, Salim* for the coronary investigators Author Information

BACKGROUND: We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). METHODS: A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. RESULTS: There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and $14,992, respectively; between-group difference, $115; 95% CI, -$697 to $927). There were no significant between-group differences in quality-of-life measures. CONCLUSIONS: In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .).

Coronavirus disease 2019 (COVID-19) has caused a global pandemic in just a few months, causing millions infected. Nearly 20% of COVID-19 patients present severe coagulation abnormalities, which may occur in almost all of the severe and critical ill COVID-19 cases. Concomitant venous thromboembolism (VTE), a potential cause of unexplained deaths, has been frequently reported in COVID-19 cases, but its management is still challenging due to the complexity between antithrombotic therapy and coagulation disorders. Based on frontline practical experience and comprehensive literature review, here a panel of experts and physicians from China and Europe developed an evidence and opinion-based consensus on the prophylaxis and management of VTE associated with COVID-19. This statement aims for clinicians treating COVID-19 and provides practical recommendations in detailed situations, for example, how to choose thromboprophylactic measures for patients with diverse severity of disease and bleeding risk, or which kind of anticoagulant should be prescribed. With limited experience on COVID19-associated VTE, this expert consensus statement should be helpful for clinicians worldwide with specific suggestions.

The safety and efficacy of bivalirudin compared with heparin with or without glycoprotein IIb/IIIa inhibitors in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are uncertain.To determine if bivalirudin is superior to heparin alone and to heparin plus tirofiban during primary PCI.Multicenter, open-label trial involving 2194 patients with AMI undergoing primary PCI at 82 centers in China between August 2012 and June 2013.Patients were randomly assigned to receive bivalirudin with a post-PCI infusion (n = 735), heparin alone (n = 729), or heparin plus tirofiban with a post-PCI infusion (n = 730). Among patients treated with bivalirudin, a postprocedure 1.75 mg/kg/h infusion was administered for a median of 180 minutes (IQR, 148-240 minutes).The primary end point was 30-day net adverse clinical events, a composite of major adverse cardiac or cerebral events (all-cause death, reinfarction, ischemia-driven target vessel revascularization, or stroke) or bleeding. Additional prespecified safety end points included the rates of acquired thrombocytopenia at 30 days, and stent thrombosis at 30 days and 1 year.Net adverse clinical events at 30 days occurred in 65 patients (8.8%) of 735 who were treated with bivalirudin compared with 96 patients (13.2%) of 729 treated with heparin (relative risk [RR], 0.67; 95% CI, 0.50-0.90; difference, -4.3%, 95% CI, -7.5% to -1.1%; P = .008); and 124 patients (17.0%) of 730 treated with heparin plus tirofiban (RR for bivalirudin vs heparin plus tirofiban, 0.52; 95% CI, 0.39-0.69; difference, -8.1%, 95% CI, -11.6% to -4.7%; P < .001). The 30-day bleeding rate was 4.1% for bivalirudin, 7.5% for heparin, and 12.3% for heparin plus tirofiban (P < .001). There were no statistically significant differences between treatments in the 30-day rates of major adverse cardiac or cerebral events (5.0% for bivalirudin, 5.8% for heparin, and 4.9% for heparin plus tirofiban, P = .74), stent thrombosis (0.6% vs 0.9% vs 0.7%, respectively, P = .77), acquired thrombocytopenia (0.1% vs 0.7% vs 1.1%; P = .07), or in acute (<24-hour) stent thrombosis (0.3% in each group). At the 1-year follow-up, the results remained similar.Among patients with AMI undergoing primary PCI, the use of bivalirudin with a median 3-hour postprocedure PCI-dose infusion resulted in a decrease in net adverse clinical events compared with both heparin alone and heparin plus tirofiban. This finding was primarily due to a reduction in bleeding events with bivalirudin, without significant differences in major adverse cardiac or cerebral events or stent thrombosis.clinicaltrials.gov Identifier: NCT01696110.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is a fatal cardiovascular emergency requiring rapid reperfusion treatment. During the coronavirus disease-2019 (COVID-19) pandemic, medical professionals need to strike a balance between providing timely treatment for STEMI patients and implementing infection control procedures to prevent nosocomial spread of COVID-19 among health care workers and other vulnerable cardiovascular patients. OBJECTIVES: This study evaluates the impact of the COVID-19 outbreak and China Chest Pain Center's modified STEMI protocol on the treatment and prognosis of STEMI patients in China. METHODS: Based on the data of 28,189 STEMI patients admitted to 1,372 Chest Pain Centers in China between December 27, 2019 and February 20, 2020, the study analyzed how the COVID-19 outbreak and China Chest Pain Center's modified STEMI protocol influenced the number of admitted STEMI cases, reperfusion strategy, key treatment time points, and in-hospital mortality and heart failure for STEMI patients. RESULTS: The COVID-19 outbreak reduced the number of STEMI cases reported to China Chest Pain Centers. Consistent with China Chest Pain Center's modified STEMI protocol, the percentage of patients undergoing primary percutaneous coronary intervention declined while the percentage of patients undergoing thrombolysis increased. With an average delay of approximately 20 min for reperfusion therapy, the rate of in-hospital mortality and in-hospital heart failure increased during the outbreak, but the rate of in-hospital hemorrhage remained stable. CONCLUSIONS: There were reductions in STEMI patients' access to care, delays in treatment timelines, changes in reperfusion strategies, and an increase of in-hospital mortality and heart failure during the COVID-19 pandemic in China.

OBJECTIVES: This study sought to evaluate the safety and efficacy of rosuvastatin in preventing contrast-induced acute kidney injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). BACKGROUND: CI-AKI is an important complication after contrast medium injection. While small studies have shown positive results with statin therapy, the role of statin therapy in prevention of CI-AKI remains unknown. METHODS: We randomized 2,998 patients with type 2 DM and concomitant CKD who were undergoing coronary/peripheral arterial angiography with or without percutaneous intervention to receive rosuvastatin, 10 mg/day (n = 1,498), for 5 days (2 days before, and 3 days after procedure) or standard-of-care (n = 1,500). Patients' renal function was assessed at baseline, 48 h, and 72 h after exposure to contrast medium. The primary endpoint of the study was the development of CI-AKI, which was defined as an increase in serum creatinine concentration ≥0.5 mg/dl (44.2 μmol/l) or 0.25% above baseline at 72 h after exposure to contrast medium. RESULTS: Patients randomized to the rosuvastatin group had a significantly lower incidence of CI-AKI than controls (2.3% vs. 3.9%, respectively; p = 0.01). During 30 days' follow-up, the rate of worsening heart failure was significantly lower in the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p = 0.02). CONCLUSIONS: Rosuvastatin significantly reduced the risk of CI-AKI in patients with DM and CKD undergoing arterial contrast medium injection. (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes [TRACK-D]; NCT00786136).

Background: Short-term exposure to ambient air pollution has been linked with daily hospitalization and mortality from acute coronary syndrome (ACS); however, the associations of subdaily (hourly) levels of criteria air pollutants with the onset of ACS and its subtypes have rarely been evaluated. Methods: We conducted a time-stratified case-crossover study among 1 292 880 patients with ACS from 2239 hospitals in 318 Chinese cities between January 1, 2015, and September 30, 2020. Hourly concentrations of fine particulate matter (PM 2.5 ), coarse particulate matter (PM 2.5–10 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), carbon monoxide (CO), and ozone (O 3 ) were collected. Hourly onset data of ACS and its subtypes, including ST-segment–elevation myocardial infarction, non–ST-segment–elevation myocardial infarction, and unstable angina, were also obtained. Conditional logistic regressions combined with polynomial distributed lag models were applied. Results: Acute exposures to PM 2.5 , NO 2 , SO 2 , and CO were each associated with the onset of ACS and its subtypes. These associations were strongest in the concurrent hour of exposure and were attenuated thereafter, with the weakest effects observed after 15 to 29 hours. There were no apparent thresholds in the concentration–response curves. An interquartile range increase in concentrations of PM 2.5 (36.0 μg/m 3 ), NO 2 (29.0 µg/m 3 ), SO 2 (9.0 µg/m 3 ), and CO (0.6 mg/m 3 ) over the 0 to 24 hours before onset was significantly associated with 1.32%, 3.89%, 0.67%, and 1.55% higher risks of ACS onset, respectively. For a given pollutant, the associations were comparable in magnitude across different subtypes of ACS. NO 2 showed the strongest associations with all 3 subtypes, followed by PM 2.5 , CO, and SO 2 . Greater magnitude of associations was observed among patients older than 65 years and in the cold season. Null associations of exposure to either PM 2.5–10 or O 3 with ACS onset were observed. Conclusions: The results suggest that transient exposure to the air pollutants PM 2.5 , NO 2 , SO 2 , or CO, but not PM 2.5–10 or O 3 , may trigger the onset of ACS, even at concentrations below the World Health Organization air quality guidelines.

Background: Coronavirus disease 2019 (COVID-19) has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic. Methods: We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fibrillation, atrial flutter, supraventricular tachycardia, nonsustained or sustained ventricular tachycardia, ventricular fibrillation, atrioventricular block, or marked sinus bradycardia (heart rate&lt;40 bpm) were classified as having arrhythmia. Deidentified data was provided by each institution and analyzed. Results: Data were collected for 4526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia. Cardiac comorbidities were common in patients with arrhythmia: 69% had hypertension, 42% diabetes, 30% had heart failure, and 24% had coronary artery disease. Most had no prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had bradyarrhythmia. Regional differences suggested a lower incidence of atrial fibrillation in Asia compared with other continents (34% versus 63%). Most patients in North America and Europe received hydroxychloroquine, although the frequency of hydroxychloroquine therapy was constant across arrhythmia types. Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge. Many institutions reported drastic decreases in electrophysiology procedures performed. Conclusions: Cardiac arrhythmias are common and associated with high morbidity and mortality among patients hospitalized with COVID-19 infection. There were significant regional variations in the types of arrhythmias and treatment approaches.

CONTEXT: Baicalin is an active compound which demonstrates cardioprotection effects against myocardial ischaemia/reperfusion injury (MI/RI). OBJECTIVE: To investigate how baicalin protects against myocardial injury and to explore its potential mechanism. We hypothesized that baicalin-modulated macrophages change from M1 (pro-inflammatory subset) to M2 (anti-inflammatory subset) under I/R stress. MATERIALS AND METHODS: = 10): control, I/R, I/R + baicalin (20 mg/kg), I/R + baicalin (60 mg/kg) and I/R + baicalin (120 mg/kg). Cardiac function was detected by echocardiography, HE staining and ELISA, respectively. Macrophage phenotype was examined by flow cytometry. Furthermore, IHC, qRT-PCR and WB were employed to analyse the related mechanisms. RESULTS: It was confirmed that baicalin alleviated post-I/R myocardial injury and reduced inflammation via JAK/STAT pathway, and baicalin treatment might be recommended as a new approach for myocardial ischaemic complications.

Abstract Rationale Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

[Figure: see text].

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10(-7)), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci-PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser-also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

Abstract Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on “NLRP3 inflammasome-NETs” inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1β and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8 −/− diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1β, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8 −/− neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1β/IL-18 were significantly elevated in Mfge8 −/− macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the “NLRP3 inflammasome-NETs” inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.

Background: Timely primary percutaneous coronary intervention (PPCI) cannot be offered to all patients with ST-segment–elevation myocardial infarction (STEMI). Pharmaco-invasive (PhI) strategy has been proposed as a valuable alternative for eligible patients with STEMI. We conducted a randomized study to compare the efficacy and safety of a PhI strategy with half-dose fibrinolytic regimen versus PPCI in patients with STEMI. Methods: The EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment–Elevation Myocardial Infarction) was an investigator-initiated, prospective, multicenter, randomized, noninferiority trial comparing a PhI strategy with half-dose alteplase versus PPCI in patients with STEMI 18 to 75 years of age presenting ≤6 hours after symptom onset but with an expected PCI-related delay. The primary end point of the study was complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3, thrombolysis in myocardial infarction myocardial perfusion grade 3, and ST-segment resolution ≥70%. We also measured infarct size and left ventricular ejection fraction with cardiac magnetic resonance and recorded 30-day clinical and safety outcomes. Results: A total of 344 patients from 7 centers were randomized to PhI (n=171) or PPCI (n=173). PhI was noninferior (and even superior) to PPCI for the primary end point (34.2% versus 22.8%, P noninferiority &lt;0.05, P superiority =0.022), with no significant differences in the frequency of the individual components of the combined end point: thrombolysis in myocardial infarction flow 3 (91.3% versus 89.2%, P =0.580), thrombolysis in myocardial infarction myocardial perfusion grade 3 (65.8% versus 62.9%, P =0.730), and ST-segment resolution ≥70% (50.9% versus 45.5%, P =0.377). Infarct size (23.3%±11.3% versus 25.8%±13.7%, P =0.101) and left ventricular ejection fraction (52.2%±11.0% versus 51.4%±12.0%, P =0.562) were similar in both groups. No significant differences occurred in 30-day rates of total death (0.6% versus 1.2%, P =1.0), reinfarction (0.6% versus 0.6%, P =1.0), heart failure (13.5% versus 16.2%, P =0.545), major bleeding events (0.6% versus 0%, P =0.497), or intracranial hemorrhage (0% versus 0%), but minor bleeding (26.9% versus 11.0%, P &lt;0.001) was observed more often in the PhI group. Conclusions: For patients with STEMI presenting ≤6 hours after symptom onset and with an expected PCI-related delay, a PhI strategy with half-dose alteplase and timely PCI offers more complete epicardial and myocardial reperfusion when compared with PPCI. Adequately powered trials with this reperfusion strategy to assess clinical and safety outcomes are warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01930682.

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

// Jing-Jun Yan 1, 2 , Yu-Nan Zhang 1 , Jia-Zhi Liao 1 , Kun-peng Ke 3 , Ying Chang 1 , Pei-Yuan Li 1 , Min Wang 2 , Ju-Sheng Lin 1 , Xing-Xing He 1 1 Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2 Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 3 Department of Cardiac Surgery, Wuhan Asia Heart Hospital, Wuhan 430022, China Correspondence to: Xing-Xing He, e-mail: xxhe@tjh.tjmu.edu.cn Keywords: hepatocellular carcinoma, microRNA, tumor biology, cancer Received: April 01, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: August 10, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: August 21, 2015 ABSTRACT Hepatocellular carcinoma (HCC) is a worldwide malignance and displays marked vascular abnormalities and active metastasis. MicroRNAs (miRNAs) have been shown to play important roles in regulating tumor properties in cancer, however, whether miR-497 contributes to HCC angiogenesis or metastasis remains unclear. In this study, we found that miR-497 was significantly down-regulated in HCC tissue samples and cell lines. Gain-of-function and loss-of-function studies revealed that miR-497 could repress both the pro-angiogenic and metastatic ability of HCC cells. Subsequent investigations disclosed that miR-497 directly inhibited the 3&prime;-untranslated regions (UTRs) of vascular endothelial growth factor A (VEGFA) and astrocyte elevated gene-1 (AEG-1). Furthermore, overexpression of these targets antagonized the function of miR-497. Based on nude mouse models, we demonstrated that overexpression of miR-497 significantly repressed microvessel densities in xenograft tumors and reduced pulmonary metastasis. In conclusion, our findings indicate that miR-497 downregulation contributes to angiogenesis and metastasis in HCC.

Importance: Success rates of pulmonary vein isolation (PVI) are modest for persistent atrial fibrillation (AF). Additional linear ablation beyond PVI has not been proved superior to PVI alone in randomized trials. Ethanol infusion of the vein of Marshall (EIVOM) facilitates ablation at the mitral isthmus and may lead to improved effectiveness of a linear ablation strategy. Objective: To determine whether linear ablation with radiofrequency energy combined with EIVOM added to PVI improves sinus rhythm maintenance compared with PVI alone in patients with persistent AF. Design, Setting, and Participants: The PROMPT-AF trial is an investigator-initiated, multicenter, open-label, randomized trial involving 12 tertiary hospitals in China. A total of 498 patients aged 18 to 80 years, with AF persisting for more than 3 months, undergoing first-time AF ablation, were enrolled and randomized from August 27, 2021, to July 16, 2023. Interventions: Patients were randomized to undergo PVI alone or PVI plus EIVOM and linear ablation (intervention). The latter group first underwent EIVOM, followed by PVI and linear ablation of the left atrial roof, mitral isthmus, and cavotricuspid isthmus. Main Outcomes and Measures: The primary end point was freedom from any documented atrial arrhythmias lasting more than 30 seconds, without the use of antiarrhythmic drugs within 12 months. Secondary outcomes included freedom from atrial arrhythmia recurrence, AF, atrial arrhythmia recurrence after multiple procedures, and documented atrial tachycardia or atrial flutter with or without antiarrhythmic drugs; AF burden; and improvement in quality of life. Patients were monitored with wearable single-lead electrocardiographic (ECG) patches, worn for 24 hours a week, supplemented by symptom-triggered ECGs and Holter monitoring. Results: Among 498 randomized patients, 495 (99.4%) were included in the primary analysis (mean age, 61.1 years [SD, 9.7] years, 361 male [72.9%]). After 12 months, 174 of 246 patients (70.7%) assigned to undergo PVI plus EIVOM and linear ablation and 153 of 249 patients (61.5%) assigned to undergo PVI alone remained free from atrial arrhythmias without taking antiarrhythmic drugs (hazard ratio, 0.73; 95% CI, 0.54-0.99, P = .045). The intervention effect was consistent across all prespecified subgroups. The comparison of secondary outcomes did not demonstrate significant results. Conclusion: Among patients with persistent AF, linear ablation combined with EIVOM in addition to PVI significantly improved freedom from atrial arrhythmias within 12 months compared with PVI alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04497376.