Progression of Gastrointestinal Injury During Antiplatelet Therapy After Percutaneous Coronary Intervention: A Secondary Analysis of the OPT-PEACE Randomized Clinical Trial.

Importance: Gastrointestinal injury progression induced by antiplatelet therapy in patients after percutaneous coronary intervention (PCI) has not been well studied. Objective: To assess the association of aspirin, clopidogrel, and their combination with gastrointestinal injury progression among patients without high bleeding risk after PCI. Design, Setting, and Participants: This secondary analysis assessed data from the Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by ANKON Magnetically Controlled Capsule Endoscopy (OPT-PEACE) double-masked, placebo-controlled, multicenter randomized clinical trial. The OPT-PEACE trial was conducted at 28 centers in China, and recruitment took place from July 13, 2017, to July 13, 2019. The trial included patients with stable coronary artery disease or acute coronary syndromes without ST-segment elevation after PCI. Statistical analysis was conducted from September 13, 2022, to January 23, 2023. Interventions: Patients underwent magnetically controlled capsule endoscopy (MCE) at baseline and after 6 months of dual antiplatelet therapy (DAPT) with aspirin (100 mg/d) plus clopidogrel (75 mg/d). Those with no evidence of gastrointestinal ulcers or bleeding (ie, the intention-to-treat [ITT] cohort) were randomized (1:1:1) to aspirin (100 mg/d) plus matching placebo (aspirin alone), clopidogrel (75 mg/d) plus matching placebo (clopidogrel alone), or DAPT for an additional 6 months. A third MCE was performed 12 months after PCI. Main Outcomes and Measures: The primary outcome was the rate of gastric injury progression as assessed with the results of the 3 MCEs (at baseline, 6 months, and 12 months) in the modified intention-to-treat (mITT) population. The key secondary outcome was the rate of small-intestinal injury progression. Gastric or small-intestinal injury progression was defined as a quantitative increase in erosions or ulcers between the second and third MCEs (at 6 and 12 months, respectively). Results: This study included the 394 patients in the mITT cohort. Their mean (SD) age was 56.9 (8.7) years, and most were men (296 [75.1%]). A total of 132 patients were randomized to aspirin alone, 132 to clopidogrel alone, and 130 to DAPT. Gastric injury progression occurred in 49 aspirin users (37.1%), 64 clopidogrel users (48.5%), and 69 DAPT users (53.1%) (P = .02), reflecting a lower rate of gastric injury progression among aspirin users vs DAPT users (risk ratio [RR], 0.70 [95% CI, 0.49-0.99]; P = .009). No significant difference was observed between clopidogrel alone and DAPT (48.5% vs 53.1%; P = .46) or between aspirin alone and clopidogrel alone (37.1% vs 48.5%; P = .06). A total of 51 aspirin users (38.6%), 65 clopidogrel users (49.2%), and 71 DAPT users (54.6%) (P = .03) developed progressive small-intestinal injury, reflecting a lower rate of small-intestinal injury among aspirin users vs DAPT users (RR, 0.71 [95% CI, 0.50-0.99]; P = .01). No difference was observed between patients treated with clopidogrel vs DAPT (49.2% vs 54.6%; P = .38) or with aspirin vs clopidogrel (38.6% vs 49.2%; P = .08). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ongoing use of aspirin, clopidogrel, or their combination between 6 and 12 months after PCI was associated with progressive gastric and small-intestinal injury in a substantial proportion of patients, more so with DAPT than with monotherapy. Clopidogrel was at least as likely as aspirin to induce gastrointestinal injury progression. Future research is warranted to determine what impact the findings from MCEs would have on decision-making of antiplatelet therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03198741.

Elastin Degradation and Lung Function Deterioration with Remote Secondhand Tobacco Smoke Exposure in Never-smokers.

Background: Prolonged past exposure to secondhand tobacco smoke (SHS) in never-smokers is associated with abnormal lung function and reduced diffusing capacity suggestive of an associated lung tissue injury and damage. The mechanisms by which past SHS exposure may contribute to lung tissue damage are unknown. Elastin is a major constituent of extracellular matrix in lung parenchyma. Objective: To determine whether past exposure to SHS is associated with ongoing lung tissue damage as indicated by elevated elastin degradation products that are linked to lung function. Methods: We measured the plasma levels of elastin degradation markers (EDM) from 193 never-smoking flight attendants with a history of remote SHS exposure in aircraft cabins and 103 nonsmoking flight attendants or sea-level control participants without such history of cabin SHS exposure and examined those levels versus their lung function with adjustment for covariates. The cabin SHS exposure was estimated based on airline employment history and years of the smoking ban enactment. Results: The median [interquartile range] plasma EDM level for all participants was 0.30 [0.24-0.36] ng/mL with a total range of 0.16-0.65 ng/mL. Plasma EDM levels were elevated in those with a history of exposure to cabin SHS compared to those not exposed (0.33±0.08 versus 0.26±0.06 ng/mL; age- and sex-adjusted P<0.001). In those with a history of cabin SHS exposure, higher EDM levels were associated with a lower diffusing capacity (parameter estimate [PE] 95% [confidence interval(CI)]=4.2 [0.4-8.0] %predicted decrease per 0.1 ng/mL increase in EDM; P=0.030). Furthermore, EDM levels were inversely associated with forced expiratory volume in 1 second (FEV1), FEV1 to forced vital capacity (FVC) ratio , and forced expiratory flow rate between 25% and 75% ( FEF25%-75%) (PE [95%CI]=5.8 [2.1-9.4], 4.0 [2.2-5.7], and 12.5 [5.8-19.2] %predicted decrease per 0.1 ng/mL increase in EDM, respectively; P<0.001). Plasma EDM mediated a substantial fraction of the association of SHS with FEV1, FVC, and FEF25%-75% (P<0.05). Conclusions: Long after past exposure to SHS, there is ongoing elastin degradation beyond what is expected from the aging process, which likely contributes to lower lung function and a reduced pulmonary capillary bed as seen in chronic obstructive pulmonary disease (COPD).

New common bile duct morphological subtypes: Risk predictors of common bile duct stone recurrence.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is the primary treatment for removing common bile duct (CBD) stones. The risk factors for CBD stone recurrence after ERCP have been discussed for many years. However, the influence of CBD morphology has never been noticed. AIM: To evaluate CBD morphology and other predictors affecting CBD stone recurrence in average patients. METHODS: A retrospective analysis of 502 CBD stone patients who underwent successful therapeutic ERCP for stone extraction at our centre from February 2020 to January 2021 was conducted. CBD morphology and other predictors affecting CBD stone recurrence were examined by univariate analysis and multivariate logistic regression analysis. RESULTS: CBD morphology (P < 0.01), CBD diameter ≥ 1.5 cm [odds ratio (OR) = 2.20, 95%CI: 1.08-4.46, P = 0.03], and endoscopic biliary sphincterotomy with balloon dilation (ESBD) (OR = 0.35, 95%CI: 0.17-0.75, P < 0.01) are three independent risk factors for CBD stone recurrence. Furthermore, the recurrence rate of patients with the S type was 6.61-fold that of patients with the straight type (OR = 6.61, 95%CI: 2.61-16.77, P < 0.01). The recurrence rate of patients with the polyline type was 2.45-fold that of patients with the straight type (OR = 2.45, 95%CI: 1.14-5.26, P = 0.02). The recurrence rate of S type patients was 2.70-fold that of patients with the polyline type (OR = 2.70, 95%CI: 1.08-6.73, P = 0.03). Compared with no-ESBD, ESBD could decrease the risk of recurrence. CONCLUSION: CBD diameter ≥ 1.5 cm and CBD morphology, especially S type and polyline type, were associated with increased recurrence of CBD stones. In addition, ESBD was related to decreased recurrence. Patients with these risk factors should undergo periodic surveillance and standard prophylactic therapy.

Magnetically Controlled Capsule Endoscopy for Assessment of Antiplatelet Therapy-Induced Gastrointestinal Injury.

BACKGROUND: Gastrointestinal bleeding is the most frequent major complication of antiplatelet therapy. In patients at low bleeding risk, however, clinically overt gastrointestinal bleeding is relatively uncommon. OBJECTIVES: The authors sought to assess the effects of different antiplatelet regimens on gastrointestinal mucosal injury by means of a novel magnetically controlled capsule endoscopy system in patients at low bleeding risk. METHODS: Patients (n = 505) undergoing percutaneous coronary intervention in whom capsule endoscopy demonstrated no ulcerations or bleeding (although erosions were permitted) after 6 months of dual antiplatelet therapy (DAPT) were randomly assigned to aspirin plus placebo (n = 168), clopidogrel plus placebo (n = 169), or aspirin plus clopidogrel (n = 168) for an additional 6 months. The primary endpoint was the incidence of gastrointestinal mucosal injury (erosions, ulceration, or bleeding) at 6-month or 12-month capsule endoscopy. RESULTS: Gastrointestinal mucosal injury through 12 months was less with single antiplatelet therapy (SAPT) than with DAPT (94.3% vs 99.2%; P = 0.02). Aspirin and clopidogrel monotherapy had similar effects. Among 68 patients without any gastrointestinal injury at randomization (including no erosions), SAPT compared with DAPT caused less gastrointestinal injury (68.1% vs 95.2%; P = 0.006), including fewer new ulcers (8.5% vs 38.1%; P = 0.009). Clinical gastrointestinal bleeding from 6 to 12 months was less with SAPT than with DAPT (0.6% vs 5.4%; P = 0.001). CONCLUSIONS: Despite being at low risk of bleeding, nearly all patients receiving antiplatelet therapy developed gastrointestinal injury, although overt bleeding was infrequent. DAPT for 6 months followed by SAPT with aspirin or clopidogrel from 6 to 12 months resulted in less gastrointestinal mucosal injury and clinical bleeding compared with DAPT through 12 months. (OPT-PEACE [Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by Ankon Magnetically Controlled Capsule Endoscopy]; NCT03198741).

Common bile duct morphology is associated with recurrence of common bile duct stones in Billroth II anatomy patients.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is the primary choice for removing common bile duct (CBD) stones in Billroth II anatomy patients. The recurrence of CBD stones is still a challenging problem. AIM: To evaluate CBD morphology and other predictors affecting CBD stone recurrence. METHODS: A retrospective case-control analysis was performed on 138 CBD stones patients with a history of Billroth II gastrectomy, who underwent therapeutic ERCP for stone extraction at our center from January 2011 to October 2020. CBD morphology and other predictors affecting CBD stone recurrence were examined by univariate analysis and multivariate logistic regression analysis. RESULTS: CBD morphology (P < 0.01) and CBD diameter ≥ 1.5 cm (odds ratio [OR] = 6.15, 95% confidence interval [CI]: 1.87-20.24, P < 0.01) were the two independent risk factors. In multivariate analysis, the recurrence rate of patients with S type was 16.79 times that of patients with straight type (OR = 16.79, 95%CI: 4.26-66.09, P < 0.01), the recurrence rate of patients with polyline type was 4.97 times that of patients with straight type (OR = 4.97, 95%CI: 1.42-17.38, P = 0.01), and the recurrence rate of S type patients was 3.38 times that of patients with polyline type (OR = 3.38, 95%CI: 1.07-10.72, P = 0.04). CONCLUSION: CBD morphology, especially S type and polyline type, is associated with increased recurrence of CBD stones in Billroth II anatomy patients.

A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

INTRODUCTION: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD. METHODS: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry. RESULTS: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group. CONCLUSIONS: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.

Endoscopic radiofrequency ablation plus plastic stent placement versus stent placement alone for unresectable extrahepatic biliary cancer: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: We sought to compare the efficacy and safety between endoscopic radiofrequency ablation (RFA) and stent placement alone in patients with unresectable extrahepatic biliary cancer (EBC). METHODS: In this randomized controlled trial, patients with locally advanced or metastatic cholangiocarcinoma (CCA) or ampullary cancer who were unsuitable for surgery were recruited from 3 tertiary centers. Eligible patients were randomly assigned to RFA plus plastic stent placement (RFA group) or plastic stent placement alone (stent placement alone group) in a 1:1 ratio. Both groups underwent 2 scheduled interventions with an interval of approximately 3 months. The primary outcome was overall survival (OS). RESULTS: Altogether, 174 participants completed the 2 index endoscopic interventions. No significant differences in baseline characteristics were noted between the 2 groups. The median OS was significantly higher in the RFA group (14.3 vs 9.2 months; hazard ratio, .488; 95% confidence interval, .351-.678; P < .001). A survival benefit was also shown in patients with CCA (13.3 vs 9.2 months; hazard ratio, .546; 95% confidence interval, .386-.771; P < .001). However, no significant between-group differences were found in jaundice control or stent patency duration. The postprocedural Karnofsky performance scores were significantly higher in the RFA group until 9 months (all P < .001). Adverse events were comparable between the 2 groups (27.6% vs 19.5%, P = .211), except for acute cholecystitis, which was more frequently observed in the RFA group (9 vs 0, P = .003). CONCLUSIONS: Compared with stent placement alone, additional RFA may improve OS and quality of life of patients with inoperable primary EBC who do not undergo systemic treatments. (Clinical trial registration number: NCT01844245.).

The Proinflammatory Activity of Structurally Altered Elastic Fibers.

The mechanisms responsible for the increased loss of pulmonary function following acute lung inflammation in chronic obstructive pulmonary disease remain poorly understood. To investigate this process, our laboratory developed a hamster model that uses a single intratracheal instillation of LPS to superimpose an inflammatory response on lungs treated with intratracheal elastase 1 week earlier. Parameters measured at 2 days after LPS included total leukocyte content and percent neutrophils in BAL fluid (BALF), and BALF levels of both total and peptide-free elastin-specific crosslinks, desmosine and isodesmosine (DID). Airspace enlargement, measured by the mean linear intercept method, and relative interstitial elastic fiber surface area were determined at 1 week after LPS. Compared with animals only treated with elastase, those receiving elastase/LPS showed statistically significant increases in mean linear intercept (156.2 vs. 85.5 µm), BALF leukocytes (187 vs. 37.3 × 104 cells), neutrophils (39% vs. 3.4%), and free DID (182% vs. 97% of controls), which exceeded the sum of the individual effects of the two agents. Despite increased elastin breakdown, the elastase/LPS group had significantly greater elastic fiber surface area than controls (49% vs. 26%) owing to fragmentation and splaying of the fibers. Additional experiments showed that the combination of elastin peptides and LPS significantly enhanced their separate effects on BALF neutrophils and BALF DID in vivo and leukocyte chemotaxis in vitro. The results suggest that structural changes in elastic fibers have proinflammatory activity and may contribute to the decline in pulmonary function related to chronic obstructive pulmonary disease exacerbations.

Cystic fibrosis disease severity correlates with plasma levels of desmosine and isodesmosine, biomarkers of elastin degradation.

Novel methodological approaches now demonstrate that the unique elastin degradation products desmosine and isodesmosine are detectable in plasma of cystic fibrosis patients and correlate to lung function, exacerbation frequency and disease progression http://bit.ly/2VwZOcx.

YINGLONG: A Multicenter, Prospective, Non-Interventional Study Evaluating the Safety and Tolerability of Ticagrelor in Chinese Patients with Acute Coronary Syndrome.

INTRODUCTION: Ticagrelor is an oral, reversible, direct-acting P2Y12 receptor inhibitor approved for the prevention of cardiovascular events in acute coronary syndrome (ACS). In China, drug intensive monitoring regulations for new drugs require additional safety data post-approval. METHODS: YINGLONG, a single-arm, phase-IV, 1-year, non-interventional study, described the safety of ticagrelor 90 mg twice daily in Chinese patients (≥ 18 years) with ACS treated with ≥ 1 dose of ticagrelor. Primary outcomes were the incidence of adverse events (AEs), in particular, PLATelet inhibition and patient Outcomes (PLATO)-defined bleeding AEs, and other serious AEs during the 1-year follow-up. Key secondary outcomes were the incidence of major cardiovascular events. RESULTS: Patients (n = 1041, median age 61.0 years) had started ticagrelor and had post-dose data. Median duration of ticagrelor treatment was 357 days; 577 patients (55.4%) completed 1-year ticagrelor treatment; 973 patients (93.5%) completed 1-year follow-up. Overall, 38.7% of patients reported an AE during treatment. The most common AEs were dyspnea (n = 37, 3.6%), petechiae (n = 30, 2.9%), and chest discomfort (n = 28, 2.7%). Serious AEs, excluding bleeding, were reported in 9.8% of patients during treatment. Incidence of PLATO-defined major bleeding events was 1.1% (n = 11). Of the 21 deaths that occurred during the study (8 post-treatment), 1 was a fatal bleed. Major cardiovascular events were reported in 37 patients (3.6%). CONCLUSIONS: Ticagrelor was well tolerated with a low rate of PLATO-defined major bleeding events in Chinese ACS patients. Safety results were consistent with the known ticagrelor profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02430493. FUNDING: AstraZeneca Investment (China) Co., Ltd.

The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial.

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven.Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy.Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained.Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val360), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers.Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).

Protective effect of inducible aldo-keto reductases on 4-hydroxynonenal- induced hepatotoxicity.

4-Hydroxynonenal (HNE), an end-product of lipid peroxidation generated in response to oxidative stress, has been implicated in the pathophysiology of chronic liver diseases. HNE is very reactive that forms Michael adducts with nucleophilic sites in DNA, lipids and proteins. At high concentrations, HNE causes rapid cell death associated with depletion of sulfhydryl groups and inhibition of key metabolic enzymes. At low concentrations, HNE stimulates expression of genes that are part of an adaptive response. In this study, we show that sub-lethal concentrations of HNE induce mRNA expression levels of heme oxygenase-1 (HO-1) (2.5-fold), NADPH:quinone oxidoreductase (NQO1) (4.5-fold), AKR1C3 (2-fold) and AKR7A2 (3-fold) enzymes. Protein expression levels of AKR1C and AKR7A2 are induced by 2- and 1.5-fold following exposure to HNE. The role of AKR1C3 and AKR7A2 in protecting HepG2 cells against HNE toxicity was investigated through using RNAi. Results show that AKR7A2, but not AKR1C3 contributes to the protection against HNE toxicity in HepG2 cells. Moreover, transcriptional factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is activated by HNE through translocation to the nucleus. Overexpressing AKR7A2 could rescue the effect of knocking down Nrf2 on HNE-induced cytotoxicity. Furthermore, a natural compound 7-hydroxycoumain, an AKR7A2 inducer, shows hepatoprotection against HNE via AKR7A2 induction. Hence, the inducible AKR7A2 has provided a new therapeutic target to treat chronic liver disease.

Free Desmosine is a Sensitive Marker of Smoke-Induced Emphysema.

PURPOSE: While the elastin-specific crosslinks, desmosine and isodesmosine (DID), are increased in blood, urine, and sputum of patients with clinically documented pulmonary emphysema, the usefulness of DID in detecting early lung injury remains untested. To this end, our laboratory has measured DID in a hamster model of smoke-induced emphysema, involving only minimal alveolar wall damage. METHODS: Animals were either treated with cigarette smoke for 2 h/day, 5 days/week, or exposed only to room air (controls) for a period of 3 months. DID levels in bronchoalveolar lavage fluid (BALF) and whole lungs were determined at monthly intervals, using liquid chromatography and tandem mass spectrometry. Lung surface area was also determined, as a measure of airspace enlargement. RESULTS: The portion of BALF DID not bound to peptides (free DID) was significantly higher in smoke-exposed animals at 2 months (9.2 vs 4.4 pg/mg protein; p < 0.05), whereas total BALF DID showed no significant increases over the course of the study, and total lung DID remained unchanged. There was a mild, but significant, loss of lung surface area in the smoke-exposed group at 2 months (28.8% vs 25.2%, p < 0.05), which showed no further progression, consistent with the return of free DID to control levels at 3 months. CONCLUSIONS: These findings support the hypothesis that free DID are sensitive indicators of smoke-induced lung injury. Measurement of free DID in smokers with minimally decreased lung mass may help determine the utility of this parameter as a test for incipient pulmonary emphysema.

Clinical effect of selective interventional therapy on sub-acute ST-segment elevation myocardial infarction under the guidance of fractional flow reserve and coronary arteriography.

OBJECTIVE: This study aims to compare the clinical effects of selective interventional therapy (PCI) under the guidance of fractional flow reserve (FFR) and coronary arteriography. METHODS: Patients with sub-acute ST-segment elevation myocardial infarction (sub-acute STEMI), who were under selective PCI treatment between April 2012 and June 2014, were included into this study. These patients were divided into two groups, based on FFR measurements: FFR-PCI group and radiography-PCI group. Then, differences in clinical symptoms, coronary angiography, intervention, and endpoint events were compared between these two groups. RESULTS: A total of 592 patients with sub-acute STEMI were included in this study (207 patients in the FFR-PCI group and 385 patients in the radiography-PCI group). No statistical differences were observed in baseline clinical data and coronary angiography results between these two groups. Mean stent number was greater in the radiography-PCI group (1.22 ± 0.32) than in the FFR-PCI group (1.10 ± 0.29), and the difference was statistically significant (P = 0.019). During the follow-up period, 78 adverse events occurred (21 adverse events in the FFR-PCI group and 57 adverse events in the radiography-PCI group); and no statistical significance was observed between these two groups (log-rank P = 0.112). CONCLUSION: Selective PCI treatment in patients with sub-acute STEMI under FFR acquired similar effects, compared to PCI treatment under the guidance of radiography, which can reduce the mean stent number.

The Therapeutic Potential of Hyaluronan in COPD.

Insights into the clinical course of COPD indicate the need for new therapies for this condition. The discovery of alpha-1 antitrypsin deficiency (AATD) led to the protease-antiprotease imbalance hypothesis, which was applied to COPD related to AATD as well as COPD not related to AATD. The discovery of AATD brought recognition to the importance of elastin fibers in maintaining lung matrix structure. Two cross-linking amino acids, desmosine and isodesmosine (DI), are unique to mature elastin and can serve as biomarkers of the degradation of elastin. The intravenous augmentation treatment and lung density in severe alpha-1 antitrypsin deficiency (RAPID) study shows a correlation of an anatomic index of COPD (on CT imaging) correlating with a chemical indicator of matrix injury in COPD, DI. The results suggest that preservation of lung elastin structure may slow the progression of COPD. Hyaluronan aerosol decreases the severity of elastase-induced emphysema in animals and has induced reductions in DI levels in preliminary human studies. Hyaluronan deserves further development as a therapy for COPD.

A pilot clinical trial to determine the safety and efficacy of aerosolized hyaluronan as a treatment for COPD.

A novel therapy for COPD involving the use of aerosolized hyaluronan (HA) was tested on a small cohort of COPD patients to determine both its safety and efficacy in reducing levels of desmosine and isodesmosine (DID), biomarkers for elastin degradation. In a 2-week, randomized, double-blind trial, 8 patients receiving 150 kDa HA (mean molecular weight) and 3 others given placebo did not show significant adverse effects with regard to spirometry, electrocardiograms, and hematological indices. Furthermore, measurements of DID in plasma from HA-treated patients indicated a progressive decrease over a 3-week period following initiation of treatment (r=-0.98; p=0.02), whereas patients receiving placebo showed no reduction in DID (r=-0.70; p=0.30). Measurements of sputum in the HA-treated group also revealed a progressive decrease in DID (r=-0.97; p=0.03), but this finding was limited by the absence of similar measurements in the placebo group. Nevertheless, the results of this small, pilot study support a longer-term trial of HA in a larger population of COPD patients.

Antithrombotic therapy strategies for atrial fibrillation patients undergoing percutaneous coronary intervention: A systematic review and network meta-analysis.

OBJECTIVE: The aim of this systematic review and network meta-analysis was to evaluate the comparative efficacy and safety of antiplatelet agents, vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify clinical trials comparing antiplatelet drugs with VKA and NOACs or their combination in AF patients undergoing PCI with a mean/median follow-up of at least 12 months. A network meta-analysis was conducted to directly and indirectly compare the efficacy and safety of competitive antithrombotic regimens with a Bayesian random-effects model. Results were presented as relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: A total of 15 studies enrolling 13,104 patients were included. Among 5 regimens, rivaroxaban 15 mg daily plus P2Y12 inhibitor treatment demonstrated significant superiority over dual- and triple-antiplatelet therapies (DAPT, TT) in reducing thromboembolic events (0.64 [0.38, 0.95] and 0.68 [0.43, 0.98], respectively) but showed the maximum possibility of major bleeding risk, while VKA plus single antiplatelet therapy (SAPT) seemed the safest. Significantly less risk of major bleeding was seen in DAPT group than that in TT group (0.63 [0.39, 0.99]). CONCLUSIONS: The present study suggests that combination of VKA and SAPT is the best choice for AF patients undergoing PCI considering both efficacy and safety. Rivaroxaban 2.5 mg twice daily plus DAPT treatment owns the highest probability to be the optimal alternative to VKA plus SAPT for these patients.

NLRC5 deficiency promotes myocardial damage induced by high fat diet in mice through activating TLR4/NF-κB.

The metabolic syndrome could be induced by high fat diet, leading to cardiovascular diseases, such as myocardial damage. Inflammation response and oxidative stress have been reported to be involved in high fat-induced heart injury, and the molecular mechanism is not fully understood. The NOD-like protein family member, NLRC5, could interact with IKKα to inhibit IKK complex activation. In our study, high fat diet-feeding mice showed cardiac fibrosis, inflammation and oxidative stress through collagen accumulation, TLR4/NF-κB and MAPKs signaling pathways activation. NLRC5 knockout mice fed with high fat showed accelerated fibrosis and inflammation response by promoting α-SMA, Collagen I, Collagen III, TLR4/MyD88, phosphorylated IKKα, IκBα and NF-κB expression. And no effect on oxidative stress was observed in wild type and NLRC5-deficiency samples in in vivo studies. Moreover, NLRC5-knockout and -knockdown cardiac muscle cells challenged with LPS also exhibited aggravated fibrosis levels and inflammatory response without any influences on ROS production in in vitro studies. In conclusion, the findings indicated that NLRC5 showed important effects on high fat-induced heart injury via fibrosis and inflammation modulation, providing an essential target for improving myocardial damage induced by high fat diet.

Hepatoprotective effect of 7-Hydroxycoumarin against Methyl glyoxal toxicity via activation of Nrf2.

Methyl glyoxal (MG), a major precursor of advanced glycation end-products, has been identified as significant in the progression of several diseases including aging, diabetes and neurodegenerative diseases as well as causing hepatic damages. 7-hydroxycoumarin (7-HC), a natural-occurring derivative of coumarin from fruits and plants, has been reported to exert antioxidant and free radical-scavenging properties, protecting cells from aldehydes and oxidants. In this study, the ability of 7-HC to protect human HepG2 cells against MG-induced toxicity and oxidative stress was investigated. Results show that 7-HC pretreatment significantly attenuates MG-induced cytotoxicity, apoptotic changes and ROS accumulation and that this protection is shown to be associated with the induction of the nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream detoxifying enzymes. In response to 7-HC, NRF2 protein translocates from cytosol to the nuclei. In addition, depletion of NRF2 by siRNA significantly reduces the protective effect of 7-HC against MG, suggesting that NRF2 plays an important role in the protective function of 7-HC. These findings highlight the potential for the interventional activation of the NRF2 induction via the non-toxic natural phytochemical 7-HC as a novel therapeutic approach towards the detoxification of MG, with the aim of halting the progression of diseases in which MG has been implicated.