Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2 and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I2=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I2=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I2=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m2), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

Development of a simple and miniaturized sandwich-like fluorescence polarization assay for rapid screening of SARS-CoV-2 main protease inhibitors.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible and has caused a pandemic named coronavirus disease 2019 (COVID-19), which has quickly spread worldwide. Although several therapeutic agents have been evaluated or approved for the treatment of COVID-19 patients, efficacious antiviral agents are still lacking. An attractive therapeutic target for SARS-CoV-2 is the main protease (Mpro), as this highly conserved enzyme plays a key role in viral polyprotein processing and genomic RNA replication. Therefore, the identification of efficacious antiviral agents against SARS-CoV-2 Mpro using a rapid, miniaturized and economical high-throughput screening (HTS) assay is of the highest importance at the present. RESULTS: In this study, we first combined the fluorescence polarization (FP) technique with biotin-avidin system (BAS) to develop a novel and step-by-step sandwich-like FP screening assay to quickly identify SARS-CoV-2 Mpro inhibitors from a natural product library. Using this screening assay, dieckol, a natural phlorotannin component extracted from a Chinese traditional medicine Ecklonia cava, was identified as a novel competitive inhibitor against SARS-CoV-2 Mpro in vitro with an IC50 value of 4.5 ± 0.4 µM. Additionally, dieckol exhibited a high affinity with SARS-CoV-2 Mpro using surface plasmon resonance (SPR) analysis and could bind to the catalytic sites of Mpro through hydrogen-bond interactions in the predicted docking model. CONCLUSIONS: This innovative sandwich-like FP screening assay enables the rapid discovery of antiviral agents targeting viral proteases, and dieckol will be an excellent lead compound for generating more potent and selective antiviral agents targeting SARS-CoV-2 Mpro.

[Prediction of anti-liver fibrosis effect of Piperis Longi Fructus based on network pharmacology].

Network pharmacology and liver fibrosis(LF) model in vitro were used to analyze the underly mechanism of anti-liver fibrosis effect that induced by Piperis Longi Fructus and its major active compounds. TCMSP and TCMIP were used to search for the chemical constituents of Piperis Longi Fructus, as well as the oral bioavailability(OB), drug-likeness(DL), intercellular permeability of intestinal epithelial cells(Caco-2) and Drug-likeness grading were set as limiting conditions. The related target genes of Piperis Longi Fructus were queried by TCMSP database, while related targets of LF were screened by GeneCards databases. Interaction network was constructed using Cytoscape 3.7.1. These above data were imported into STRING database for PPI network analysis. Enrichment of gene ontology(GO) and pathway analysis(KEGG) within Bioconductor database were utilized to note functions of related targets of Piperis Longi Fructus. Finally, the core targets and pathways were preliminarily verified by in vitro experiments. The effects of piperlongumine(PL), the major active component of Piperis Longi Fructus, on proliferation of rat liver stellate cells(HSC-T6) and expression of α smooth muscle actin(α-SMA) and collagen Ⅰ were investigated. The major factors TNF-α of tumor necrosis factor(TNF) pathway and NF-κB p65, IL-6 protein expressions of LF process were examined. A total of 12 active compounds such as PL were obtained by analyzing the bioavailability and drug-like properties, which inferred to 48 targets. The functional enrichment analysis of GO obtained 1 240 GO items, mainly involving in process of biology and molecular function. A total of 99 signaling pathways were enriched in the KEGG pathway enrichment analysis, including TNF signaling pathway, cGMP-PKG signaling pathway, calcium signaling pathways. CCK-8 assay showed that PL inhibited proliferation of HSC-T6 induced by transforming growth factor-ß1(TGF-ß1). Western blot analysis found that treated with PL suppressed the protein expressions of α-SMA, collagen Ⅰ, TNF-α and p65 in HSC-T6. Enzyme linked immunosorbent assay(ELISA) showed that PL inhibited the expressions of TNF-α and IL-6 in the cluture supertant of HSC-T6 cells. In conclusion, PL could play an anti-liver fibrosis role by regulating TNF/NF-κB signaling pathway. This study provided the mechanism basis of anti-LF effects induced by Piperis Longi Fructus and its major active compounds, which might help for the further study of the mechanism and key targets of Piperis Longi Fructus.

Association between Plasma N-6 Polyunsaturated Fatty Acids Levels and the Risk of Cardiovascular Disease in a Community-based Cohort Study.

Most studies support that saturated fatty acid replacement with polyunsaturated fatty acids (PUFAs) may reduce the risk of cardiovascular diseases (CVDs) and put emphasis on the effects of N-3 PUFAs. The reported relationships between N-6 PUFAs and CVD risks vary. We aimed to examine the associations between N-6 PUFA concentrations and CVD risks. In this community-based prospective cohort study on CVD-free patients at baseline (N = 1835, age: 60.6 ± 10.5 years, women: 44.5%), we measured the fatty acid concentrations in the blood using gas chromatography. Four hundred twenty-four participants developed CVDs during follow up. The total N-6 PUFA concentration was inversely associated with the CVD risk, with a 48% lower risk in the highest N-6 PUFA concentration quartile (hazard ratio = 0.52; P for trend <0.001). The estimated population attributable risk of N-6 PUFAs indicated that approximately 20.7% of CVD events would have been prevented if the plasma N-6 PUFA concentration had been higher than the median value. The total N-6 PUFA concentration presented the highest net reclassification improvement (NRI = 7.2%, P = 0.03) for predicting incident CVD. Further studies on N-6 PUFAs, diet habits, and their relationships with healthcare are warranted.

Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

Comparison of phase mapping and electrogram-based driver mapping for catheter ablation in atrial fibrillation.

INTRODUCTION: Adjunctive driver-guided ablation in addition to pulmonary vein isolation has been proposed as a strategy to improve procedural success and outcomes for various populations with atrial fibrillation (AF). First, this study aimed to evaluate the different mapping techniques for driver/rotor identification and second to evaluate the benefits of driver/rotor-guided ablation in patients with paroxysmal and persistent AF (PerAF). METHODS: We searched the electronic database in PubMed using the keywords "atrial fibrillation," "rotor," "rotational driver," "atrial fibrillation source," and "drivers" for both randomized controlled trials and observational controlled trials. Clinical studies reporting efficacy or safety outcomes of driver-guided ablation for paroxysmal AF or (PerAF) were identified. We performed subgroup analyses comparing different driver mapping methods in patients with PerAF. The odds ratios (ORs) with random effects were analyzed. RESULTS: Out of 175 published articles, seven met the inclusion criteria, of which two were randomized controlled trials, one was quasiexperimental study, and four observational studies (three case-controlled studies and one cross-sectional study). Overall, adjunctive driver-guided ablation was associated with higher rates of acute AF termination (OR: 4.62, 95% confidence interval [CI]: 2.12-10.08; P < 0.001), lower recurrence of any atrial arrhythmia (OR: 0.44, 95% CI: 0.30-0.065; P < 0.001), and comparable complication incidence. CONCLUSIONS: Adjunctive driver-guided catheter ablation suggested an increased freedom from AF/AT relative to conventional strategies, irrespective of the mapping techniques. Furthermore, phase mapping appears to be superior to electrogram-based driver mapping in PerAF ablation.

Immunomodulatory Effects of the Stout Camphor Medicinal Mushroom, Taiwanofungus camphoratus (Agaricomycetes)-Based Health Food Product in Mice.

Taiwanofungus camphoratus is a unique medicinal mushroom endemic to Taiwan, and it is used as a folk medicine in East Asian countries. The aim of the present study was to investigate the immunomodulatory effects of "leader Antrodia cinnamomea capsule" (LAC), a health food product containing solid-state cultivated mycelial powder of T. camphoratus. For the in vivo studies, mice were orally administered LAC (76, 250, and 760 mg/kg b.w.) for 30 days, and its effects on cell-mediated humoral immune function were examined. The results of the concanavalin A-induced splenic lymphocyte proliferation test showed that LAC significantly increased splenic lymphocyte proliferation compared with the control. In addition, serum hemolysin analysis showed that LAC treatment significantly increased the half value of serum hemolysin (HC50) in mice compared with the control. Moreover, treatment with LAC significantly increased the phagocytic index as measured by carbon clearance and natural killer cell activity. Taken together, these findings provide strong evidence that LAC can modulate immune function.

Effects of Taiwanofungus camphoratus on non-specific and specific immune activities in mice.

Taiwanofungus camphoratus is a precious medicinal fungus endemic to Taiwan and has been used as traditional medicine for a long time. Many pharmacological studies have revealed that T. camphoratus possessed various biological activities, such as immunomodulatory effects, anticancer activity and liver protective function. The aim of this study is to investigate the non-specific and antigen (ovalbumin [OVA])-specific immunomodulation effects of solid-state cultivated powder of T. camphoratus (Leader Antrodia cinnamomea [LAC]) in BABL/c male mice. In non-specific and antigen-specific immune function studies, 8-week-old mice were orally administered with LAC for 6 and 8 weeks, respectively. The results have shown that the proliferation of splenic immune cells, phagocytic activity of macrophages and cytolytic activity of natural killer cells were enhanced by LAC. Additionally, LAC increased the levels of IL-2, TNF-α, INF-γ, GM-CSF and serum OVA-IgG and OVA-IgM. These findings provided evidences that LAC had the immunomodulation effects on both antigen-specific and non-specific immune responses in mice.

Novel electrophysiological criteria for septal ventricular outflow tract tachycardias requiring a sequential bilateral ablation.

BACKGROUND: Septal ventricular outflow tract ventricular arrhythmias (OT-VAs) are defined as septal origin VAs from the right ventricular or left ventricular OT. Patients with septal OT-VAs may require a sequential bilateral OT ablation. This study aimed to evaluate the electrophysiological characteristics and ablation outcome in patients with septal OT-VAs. METHODS: We retrospectively analyzed the electrocardiography and electrophysiological parameters in 96 patients (mean age 49 ± 15 years, 49 male) undergoing bilateral activation mapping before catheter ablation of idiopathic septal OT-VAs. The patients were categorized into three groups based on the successful ablation sites, including the right ventricular outflow tract (RVOT), RVOT/left ventricular outflow tract (LVOT), and LVOT. RESULTS: Mapping in the three groups demonstrated a gradually decreasing and increasing trend in the earliest activation time obtained from the RVOT and LVOT, respectively. The absolute earliest activation time discrepancy (AEAD) of ≤18 milliseconds could predict the requirement for a sequential bilateral ablation with a sensitivity and specificity of 100.0% and 93.7%, respectively. The small AEAD (≤21 milliseconds) was associated with a higher recurrence rate in patients receiving a successful unilateral ablation, while patients with a longer distance between the bilateral OT earliest activation sites (DEA > 26 mm) increased future recurrences after an initially successful sequential bilateral ablation. CONCLUSIONS: The application of bilateral OT-VA activation mapping and the measurement of the AEAD and DEA provided not only pivotal information for the ablation strategy, but also prognostic implications for recurrences in patients with septal OT-VAs.

Heterogeneous distribution of substrates between the endocardium and epicardium promotes ventricular fibrillation in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Aims: Whether the distribution of scar in arrhythmogenic right ventricular cardiomyopathy (ARVC) plays a role in predicting different types of ventricular arrhythmias is unknown. This study aimed to investigate the prognostic value of scar distribution in patients with ARVC. Methods and results: We studied 80 consecutive ARVC patients (46 men, mean age 47 ± 15 years) who underwent an electrophysiological study with ablation. Thirty-four patients receive both endocardial and epicardial mapping. Abnormal endocardial substrates and epicardial substrates were characterized. Three groups were defined according to the epicardial and endocardial scar gradient (<10%: transmural, 10-20%: intermediate, >20%: horizontal, as groups 1, 2, and 3, respectively). Sinus rhythm electrograms underwent a Hilbert-Huang spectral analysis and were displayed as 3D Simultaneous Amplitude Frequency Electrogram Transformation (SAFE-T) maps, which represented the arrhythmogenic potentials. The baseline characteristics were similar between the three groups. Group 3 patients had a higher incidence of fatal ventricular arrhythmias requiring defibrillation and cardiac arrest during the initial presentation despite having fewer premature ventricular complexes. A larger area of arrhythmogenic potentials in the epicardium was observed in patients with horizontal scar. The epicardial-endocardial scar gradient was independently associated with the occurrence of fatal ventricular arrhythmias after a multivariate adjustment. The total, ventricular tachycardia, and VF recurrent rates were higher in Group 3 during 38 ± 21 months of follow-up. Conclusion: For ARVC, the epicardial substrate that extended in the horizontal plane rather than transmurally provided the arrhythmogenic substrate for a fatal ventricular arrhythmia circuit.

Increased risk of ventricular tachycardia and cardiovascular death in patients with myocarditis during the long-term follow-up: A national representative cohort from the National Health Insurance Research Database.

The incidence of acute myocarditis complicated with ventricular tachycardia (VT) is unknown. This study aimed to investigate the association between myocarditis and the incidence of VT and mortality. We also aimed to determine the independent predictors that increased the VT risk in those patients. From 2000 to 2004, 13,250 patients with a history of myocarditis were identified from the Taiwan National Health Insurance Research Database. The same number of individuals without heart disease with a matched sex and underlying diseases were selected as the control group. The long-term risks of life-threatening ventricular arrhythmias and mortality in patients with a history of myocarditis were investigated by an adjusted Cox proportional hazards regression. After a mean follow-up of 10.4 ±â€Š2.94 years (interquartile range: 12, 10.19-12), the myocarditis patients showed a higher incidence of new onset VT events compared with healthy controls (5.4% [519 per 100,000 person-year] in the myocarditis group vs, 0.47% [43 per 100,000 person-year] in the healthy controls; adjusted hazard ratio [HR]: 16.1, 95% confidence interval [CI]: 12.4-20.9; P < .001). A higher incidence of cardiovascular death was noted in the myocarditis group than healthy controls (6.52% vs 3.18%; HR: 2.42, 95% CI: 2.14-2.73; P < .001) after adjusting for the multivariate confounders including sex, age, underlying comorbidities, and medications. The results of this study suggested that there was higher incidence of life-threatening VT and mortality during the very long-term follow-up in patients with a history of myocarditis. Future work should focus on an in-depth risk stratification of VT in myocarditis patients.

History of hyperthyroidism and long-term outcome of catheter ablation of drug-refractory atrial fibrillation.

BACKGROUND: Hyperthyroidism is a known reversible cause of atrial fibrillation (AF). However, some patients remain in AF despite restoration of euthyroid status. OBJECTIVE: The purpose of this study was to compare the electrophysiologic characteristics and long-term ablation outcome in AF patients with and without history of hyperthyroidism. METHODS: The study enrolled 717 consecutive patients with AF who underwent first AF ablation, which involved pulmonary vein (PV) isolation in paroxysmal AF and additional substrate modification in nonparoxysmal AF patients. Eighty-four patients (12%) with hyperthyroidism history were compared to those without. Euthyroid status was achieved for ≥3 months before ablation in hyperthyroid patients. RESULTS: Patients with hyperthyroid history were associated with older age, more female gender, lower mean right atrial voltage, higher number of PV ectopic foci (1.3 ± 0.4 vs 1.0 ± 0.2, P < .01), and higher prevalence of non-PV foci (42% vs 23%, P < .01). Ectopic foci from ligament of Marshall were demonstrated more often in hyperthyroid patients (7.1% vs 1.6%, P < .01) in whom alcohol ablations were required. After propensity score matching for potential covariates, history of hyperthyroidism was an independent predictor of AF recurrence after single procedure (hazard ratio 2.07, 95% confidence interval 1.27-3.38). AF recurrence rates after multiple procedures were not different between patients with and those without hyperthyroid history. CONCLUSION: Patients with hyperthyroid history had a significantly higher number of PV ectopies and higher prevalence of non-PV ectopic foci compared to euthyroid patients, which resulted in a higher AF recurrence rate after a single procedure.

A prospective and randomized comparison of limited versus extensive atrial substrate modification after circumferential pulmonary vein isolation in nonparoxysmal atrial fibrillation.

INTRODUCTION: The optimal substrate ablation approach in patients with persistent atrial fibrillation (Per AF) remains unclear. This was a prospective randomized study comparing the efficacy of limited (continuous complex fractionated atrial electrogram, CFAE: <60 milliseconds) versus extensive (continuous CFAE plus variable CFAE: <120 milliseconds) atrial substrate modification in Per AF patients. METHODS AND RESULTS: We enrolled 120 Per AF patients in the study, and 30 patients with AF termination after pulmonary vein isolation (PVI) were excluded. In the remaining 90 patients, 45 were treated with limited approach (Group 1) and 45 with an extensive approach (Group 2). The end point of the study was the incidence of an atrial arrhythmia recurrence postblanking period. The patients were followed up for 15 months with 3-month clinical reviews, electrograms (ECGs), Holter recordings, and echocardiographic monitoring. Procedural AF termination and the single procedural efficacy were statistically comparable between the 2 groups (48.9% vs. 63.4% in Groups 1 and 2, respectively, P = 0.289). During the follow-up, patients who received limited ablation had a lower incidence of recurrent AFL (P = 0.04), and better reverse remodeling of the left atrium (LA, P = 0.04). After 2 procedures, the freedom from any atrial arrhythmia was better in Group 2 (62.2% vs. 87.8%, P = 0.009). Those with longstanding AF and a larger baseline LA size responded better to the extensive ablation. CONCLUSIONS: In the Per AF patients who failed to achieve AF termination after PVI alone, a specific atrial substrate modification approach targeting only continuous CFAEs could be considered as an initial ablation strategy.

Prevalence, characteristics, mapping, and catheter ablation of potential rotors in nonparoxysmal atrial fibrillation.

BACKGROUND: Identification of critical atrial substrates in patients with nonparoxysmal atrial fibrillation (AF) failing to respond to pulmonary vein isolation is important. This study investigated the signal characteristics, substrate nature, and ablation results of rotors during AF. METHODS AND RESULTS: In total, 53 patients (age=55±8), 31 with persistent AF and 22 with long-lasting AF, underwent pulmonary vein isolation and substrate modification of complex fractionated atrial electrograms. Small-radius-reentrant rotors were identified from signal analyses of the dominant frequency and fractionation interval and nonlinear analyses (newly developed, beat-to-beat nonlinear measurement of the repetitiveness of the electrogram morphology>6 seconds). In 15% of the patients, activation maps demonstrated occurrences of rotor-like small-radius reentrant circuits (n=9; 1.1 per patient; cycle length=110±21 ms; diameter=11±6 mm) with fibrillation occurring outside these areas. Rotors were identified by conventional point-by-point mapping and signal analyses and were subsequently eradicated by catheter ablation in these patients. Persistent AF for <1 year, a smaller left atrial size, substrates with higher mean voltages and shorter total activation durations predicted a higher incidence of rotors (all P<0.05). In the multivariable model, areas of reentrant circuits exhibited a higher dominant frequency, kurtosis, and higher degree of a beat-to-beat electrogram similarity than areas without or outside the rotors (all P<0.05). CONCLUSIONS: Rotor-like re-entry with fibrillatory conduction was found in a limited number of patients with nonparoxysmal AF after pulmonary vein isolation. Those areas were characterized by rapid repetitive activity with a high degree of electrogram similarity.