Background It is unclear whether catheter ablation(CA)for atrial fibrillation(AF)affects the long-term prognosis in the elderly.This study aims to evaluate the relationship between CA and long-term outcomes in elderly...Background It is unclear whether catheter ablation(CA)for atrial fibrillation(AF)affects the long-term prognosis in the elderly.This study aims to evaluate the relationship between CA and long-term outcomes in elderly patients with AF.Methods Patients more than 75 years old with non-valvular AF were prospectively enrolled between August 2011 and December 2017 in the Chinese Atrial Fibrillation Registry Study.Participants who underwent CA at baseline were propensity score matched(1:1)with those who did not receive CA.The outcome events included all-cause mortality,cardiovascular mortality,stroke/transient ischemic attack(TIA),and cardiovascular hospitalization.Results Overall,this cohort included 571 ablated patients and 571 non-ablated patients with similar characteristics on 18 dimensions.During a mean follow-up of 39.75±19.98 months(minimum six months),24 patients died in the ablation group,compared with 60 deaths in the non-ablation group[hazard ratio(HR)=0.49,95%confidence interval(CI):0.30-0.79,P=0.0024].Besides,6 ablated and 29 non-ablated subjects died of cardiovascular disease(HR=0.25,95%CI:0.11-0.61,P=0.0022).A total of 27 ablated and 40 non-ablated patients suffered stroke/TIA(HR=0.79,95%CI:0.48-1.28,P=0.3431).In addition,140 ablated and 194 non-ablated participants suffered cardiovascular hospitalization(HR=0.84,95%CI:0.67-1.04,P=0.1084).Subgroup analyses according to gender,type of AF,time since onset of AF,and anticoagulants exposure in initiation did not show significant heterogeneity.Conclusions In elderly patients with AF,CA may be associated with a lower incidence of all-cause and cardiovascular mortality.展开更多
Background:Left bundle branch block(LBBB)-induced cardiomyopathy has been proposed,but the association between LBBB and cardiac resynchronization therapy(CRT)response remains unclear and practical criteria for selecti...Background:Left bundle branch block(LBBB)-induced cardiomyopathy has been proposed,but the association between LBBB and cardiac resynchronization therapy(CRT)response remains unclear and practical criteria for selecting CRT candidates are needed.Methods:One hundred and seventeen consecutive heart failure patients were reviewed,24 of whom received CRT.Only two patients had a clear temporal relation between cardiomyopathy and LBBB.Results:Compared with the patient with“cardiomyopathy-induced LBBB,”the patient with“LBBB-induced cardiomyopathy”had higher left ventricular(LV)wall thickness,higher LV wall thickening rate,higher peak circumferential strain,and longer peak circumferential strain delay.The LV deformation patterns in the two patients were obviously distinct on cardiovascular magnetic resonance tissue tracking.During follow-up,the patient with LBBB-induced cardiomyopathy had a good response to CRT(LV ejection fraction 23 before CRT vs.30%at 6 months vs.29 at 12 months vs.32%at 18 months;LV end-diastolic diameter 77 mm before CRT vs.66 mm at 6 months vs.62 mm at 12 months vs.63 mm at 18 months),and the other patient had no response to CRT(LV ejection fraction 29 before CRT vs.29%at 6 months vs.26 at 12 months vs.22%at 24 months;LV end-diastolic diameter 85 mm before CRT vs.88 mm at 6 months vs.85 mm at 12 months vs.84 mm at 24 months).Conclusion:The temporal relation between cardiomyopathy and LBBB could be a determinant for CRT response.Cardiovascular magnetic resonance tissue tracking may be a useful tool to identify the chronological order and a principal consideration for selecting candidates for CRT.Larger prospective clinical trials are needed to study the prevalence of,time course of,and risk factors for LBBB-induced cardiomyopathy.展开更多
BACKGROUND Chronic kidney disease(CKD)is highly prevalent in patients with atrial fibrillation(AF).However,the asso-ciation between CKD and clinical consequences in AF patients is still under debate.METHODS We include...BACKGROUND Chronic kidney disease(CKD)is highly prevalent in patients with atrial fibrillation(AF).However,the asso-ciation between CKD and clinical consequences in AF patients is still under debate.METHODS We included 19,079 nonvalvular AF patients with available estimated glomerular filtration rate(eGFR)values in the Chinese Atrial Fibrillation Registry from 2011 to 2018.Patients were classified into no CKD(eGFR≥90 mL/min per 1.73 m2),mild CKD(60≤eGFR<90 mL/min per 1.73 m2),moderate CKD(30≤eGFR<60 mL/min per 1.73 m2),and severe CKD(eGFR<30 mL/min per 1.73 m2)groups.The risks of thromboembolism,major bleeding,and cardiovascular mortality were estimated with Fine-Gray regression analysis according to CKD status.Cox regression was performed to assess the risk of all-cause mortal-ity associated with CKD.RESULTS Over a mean follow-up of 4.1±1.9 years,there were 985 thromboembolic events,414 major bleeding events,956 car-diovascular deaths,and 1,786 all-cause deaths.After multivariate adjustment,CKD was not an independent risk factor of throm-boembolic events.As compared to patients with no CKD,those with mild CKD,moderate CKD,and severe CKD had a 45%,47%,and 133%higher risk of major bleeding,respectively.There was a graded increased risk of cardiovascular mortality associated with CKD status compared with no CKD group:adjusted hazard ratio[HR]was 1.34(95%CI:1.07−1.68,P=0.011)for mild CKD group,2.17(95%CI:1.67−2.81,P<0.0001)for moderate CKD group,and 2.95(95%CI:1.97−4.41,P<0.0001)for severe CKD group,respectively.Risk of all-cause mortality also increased among patients with moderate or severe CKD.CONCLUSIONS CKD status was independently associated with progressively higher risks of major bleeding and mortality,but didn’t seem to be an independent predictor of thromboembolism in AF patients.展开更多
Background:Elderly adults with atrial fi brillation(AF)are at increased risk of frailty and thromboembolic complications.However,studies on the prevalence of frailty in AF patients and data on the relationship between...Background:Elderly adults with atrial fi brillation(AF)are at increased risk of frailty and thromboembolic complications.However,studies on the prevalence of frailty in AF patients and data on the relationship between frailty and the use of anticoagulants are limited.Methods:We conducted a cross-sectional study involving 500 participants.Patients aged 65 years or older were consecutively selected from the Chinese Atrial Fibrillation Registry study.The patient’s frailty status was assessed with use of the Canadian Study of Health and Aging Clinical Frailty Scale.We assessed the prevalence of and factors associated with frailty,and how frailty affects anticoagulant therapy.Results:In 500 elderly adults with AF(age 75.2±6.7 years;51.6%female),201 patients(40.2%)were frail.The prevalence of frailty was higher in females(P=0.002)and increased with age and CHA 2 DS 2-VASc score(P for trend less than 0.001 for both).The factors associated with frailty were a history of heart failure(odds ratio[OR]2.40,95%confi dence interval[CI]1.39–4.14),female sex(OR 2.09,95%CI 1.27–3.43),and advanced age(OR 1.13,95%CI 1.09–1.17).Frail patients were signifi cantly less likely to have ever been prescribed anticoagulants compared with nonfrail patients(81.7 vs.54.9%,P<0.001).Conclusions:Frailty is prevalent in elderly adults with AF,especially in females,those of advanced age,and those with heart failure.Frailty status has a signifi cant impact on prescription of anticoagulants for high-risk AF patients.展开更多
Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fib...Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fibrillation(AF).Recent studies have revealed that TKIs induce metabolic alterations and remodeling in cardiomyocytes,thus perturb-ing energy metabolism.Specifically,mitochondrial dysfunction and shifts in cardiac substrate utilization have been implicated in the mechanisms underlying TKI-induced AF.In light of these findings,this article reviews the energy metabolism-associated pathways involved in TKI-induced AF,identifies precise therapeutic targets for managing this condition,and discusses evidence that may contribute to the development of novel TKIs without cardiac adverse ef-fects.展开更多
Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF...Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.展开更多
Background:Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation(AF).Even though only 6%to 8%of AF patients die from stroke,about 90%are indicated for...Background:Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation(AF).Even though only 6%to 8%of AF patients die from stroke,about 90%are indicated for anticoagulants according to the current AF management guidelines.Therefore,we aimed to develop an accurate and easy-to-use new risk model for 1-year thromboembolic events(TEs)in Chinese AF patients.Methods:From the prospective China Atrial Fibrillation Registry cohort study,we identified 6601 AF patients who were not treated with anticoagulation or ablation at baseline.We selected the most important variables by the extreme gradient boosting(XGBoost)algorithm and developed a simplified risk model for predicting 1-year TEs.The novel risk score was internally validated using bootstrapping with 1000 replicates and compared with the CHA2DS2-VA score(excluding female sex from the CHA2DS2-VASc score).Results:Up to the follow-up of 1 year,163 TEs(ischemic stroke or systemic embolism)occurred.Using the XGBoost algorithm,we selected the three most important variables(congestive heart failure or left ventricular dysfunction,age,and prior stroke,abbreviated as CAS model)to predict 1-year TE risk.We trained a multivariate Cox regression model and assigned point scores proportional to model coefficients.The CAS scheme classified 30.8%(2033/6601)of the patients as low risk for TE(CAS score=0),with a corresponding 1-year TE risk of 0.81%(95%confidence interval[CI]:0.41%–1.19%).In our cohort,the C-statistic of CAS model was 0.69(95%CI:0.65–0.73),higher than that of CHA2DS2-VA score(0.66,95%CI:0.62–0.70,Z=2.01,P=0.045).The overall net reclassification improvement from CHA2DS2-VA categories(low=0/high≥1)to CAS categories(low=0/high≥1)was 12.2%(95%CI:8.7%–15.7%).Conclusion:In Chinese AF patients,a novel and simple CAS risk model better predicted 1-year TEs than the widely-used CHA2DS2-VA risk score and identified a large proportion of patients with low risk of TEs,which could potentially improve anticoagulation decision-making.Trial Registration:www.chictr.org.cn(Unique identifier No.ChiCTR-OCH-13003729).展开更多
Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history.After investigation of U.rhynchophylla,eleven monoterpene indole alkaloids,including four new compounds uncarialin...Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history.After investigation of U.rhynchophylla,eleven monoterpene indole alkaloids,including four new compounds uncarialins J-M(1-4)and seven known analogues(5-11),were isolated and identified.Their structural characterization was conducted using HRESIMS,1D and 2D NMR,electronic circular dichroism(ECD)spectra,and quantum chemical computations.Compounds 1,2,7,and 9-11 displayed significant ag-onistic effects towards 5-HT_(1A) receptor,and their EC_(50) values were 7.86,732,2.24,1.18,1.52,and 3.75μmol/L,respectively.Furthermore,in vivo experimental results fully revealed that hirsuteine(7)displayed a significant antidepression effect in unpredictable chronic mild stress(UCMS)-induced depression mice mainly via regulating 5-HT_(1A) signaling pathway.Molecular docking and site-directed amino acid mutation verified that amino acid residues Aspll6 and Asn386 were the binding sites of hirsuteine(7)with 5-HT_(1A) receptor.In addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine(7),which further demonstrated that 5-HT_(1A) receptor was a potential target of hirsuteine(7)to effectively treat depression.These findings indicated the therapeutic material basis of U.rhynchophylla and the anti-depression underlying mechanism of hirsuteine(7),and further provided the useful guidance for the development of hirsuteine(7)as a potential antidepressant candidate.展开更多
To the Editor： Current treatment guidelines for patients with acute coronary syndrome （ACS） undergoing percutaneous coronary intervention （PCI） recommend dual antiplatelet therapy, a combination of aspirin and a ...To the Editor： Current treatment guidelines for patients with acute coronary syndrome （ACS） undergoing percutaneous coronary intervention （PCI） recommend dual antiplatelet therapy, a combination of aspirin and a P2YI2 inhibitor （i.e., clopidogrel, prasugrel, and ticagrelor） for a minimum of 12 months. Ticagrelor, an oral reversibly binding platelet P2Y 12 receptor inhibitor, generates a greater and more consistent inhibitory effect with rapid onset of action as compared to clopidogrel.展开更多
基金the National Key Research and Development Program of China(2017YFC0908803&2018YFC1312501&2016YFC0900901&2016YFC1301002&2020YFC2004803).
文摘Background It is unclear whether catheter ablation(CA)for atrial fibrillation(AF)affects the long-term prognosis in the elderly.This study aims to evaluate the relationship between CA and long-term outcomes in elderly patients with AF.Methods Patients more than 75 years old with non-valvular AF were prospectively enrolled between August 2011 and December 2017 in the Chinese Atrial Fibrillation Registry Study.Participants who underwent CA at baseline were propensity score matched(1:1)with those who did not receive CA.The outcome events included all-cause mortality,cardiovascular mortality,stroke/transient ischemic attack(TIA),and cardiovascular hospitalization.Results Overall,this cohort included 571 ablated patients and 571 non-ablated patients with similar characteristics on 18 dimensions.During a mean follow-up of 39.75±19.98 months(minimum six months),24 patients died in the ablation group,compared with 60 deaths in the non-ablation group[hazard ratio(HR)=0.49,95%confidence interval(CI):0.30-0.79,P=0.0024].Besides,6 ablated and 29 non-ablated subjects died of cardiovascular disease(HR=0.25,95%CI:0.11-0.61,P=0.0022).A total of 27 ablated and 40 non-ablated patients suffered stroke/TIA(HR=0.79,95%CI:0.48-1.28,P=0.3431).In addition,140 ablated and 194 non-ablated participants suffered cardiovascular hospitalization(HR=0.84,95%CI:0.67-1.04,P=0.1084).Subgroup analyses according to gender,type of AF,time since onset of AF,and anticoagulants exposure in initiation did not show significant heterogeneity.Conclusions In elderly patients with AF,CA may be associated with a lower incidence of all-cause and cardiovascular mortality.
基金the Ministry of Science and Technology of the People’s Republic of China(grants 2016YFC1301000 and 2016YFC0900900).
文摘Background:Left bundle branch block(LBBB)-induced cardiomyopathy has been proposed,but the association between LBBB and cardiac resynchronization therapy(CRT)response remains unclear and practical criteria for selecting CRT candidates are needed.Methods:One hundred and seventeen consecutive heart failure patients were reviewed,24 of whom received CRT.Only two patients had a clear temporal relation between cardiomyopathy and LBBB.Results:Compared with the patient with“cardiomyopathy-induced LBBB,”the patient with“LBBB-induced cardiomyopathy”had higher left ventricular(LV)wall thickness,higher LV wall thickening rate,higher peak circumferential strain,and longer peak circumferential strain delay.The LV deformation patterns in the two patients were obviously distinct on cardiovascular magnetic resonance tissue tracking.During follow-up,the patient with LBBB-induced cardiomyopathy had a good response to CRT(LV ejection fraction 23 before CRT vs.30%at 6 months vs.29 at 12 months vs.32%at 18 months;LV end-diastolic diameter 77 mm before CRT vs.66 mm at 6 months vs.62 mm at 12 months vs.63 mm at 18 months),and the other patient had no response to CRT(LV ejection fraction 29 before CRT vs.29%at 6 months vs.26 at 12 months vs.22%at 24 months;LV end-diastolic diameter 85 mm before CRT vs.88 mm at 6 months vs.85 mm at 12 months vs.84 mm at 24 months).Conclusion:The temporal relation between cardiomyopathy and LBBB could be a determinant for CRT response.Cardiovascular magnetic resonance tissue tracking may be a useful tool to identify the chronological order and a principal consideration for selecting candidates for CRT.Larger prospective clinical trials are needed to study the prevalence of,time course of,and risk factors for LBBB-induced cardiomyopathy.
基金National Key Research and Development Program of China(grant number:2017YFC0908803,2018YFC1312501,2020YFC2004803)the National Natural Science Foundation of China(82100326)Beijing Municipal Commission of Science and Technology(Z1811000001618011).
文摘BACKGROUND Chronic kidney disease(CKD)is highly prevalent in patients with atrial fibrillation(AF).However,the asso-ciation between CKD and clinical consequences in AF patients is still under debate.METHODS We included 19,079 nonvalvular AF patients with available estimated glomerular filtration rate(eGFR)values in the Chinese Atrial Fibrillation Registry from 2011 to 2018.Patients were classified into no CKD(eGFR≥90 mL/min per 1.73 m2),mild CKD(60≤eGFR<90 mL/min per 1.73 m2),moderate CKD(30≤eGFR<60 mL/min per 1.73 m2),and severe CKD(eGFR<30 mL/min per 1.73 m2)groups.The risks of thromboembolism,major bleeding,and cardiovascular mortality were estimated with Fine-Gray regression analysis according to CKD status.Cox regression was performed to assess the risk of all-cause mortal-ity associated with CKD.RESULTS Over a mean follow-up of 4.1±1.9 years,there were 985 thromboembolic events,414 major bleeding events,956 car-diovascular deaths,and 1,786 all-cause deaths.After multivariate adjustment,CKD was not an independent risk factor of throm-boembolic events.As compared to patients with no CKD,those with mild CKD,moderate CKD,and severe CKD had a 45%,47%,and 133%higher risk of major bleeding,respectively.There was a graded increased risk of cardiovascular mortality associated with CKD status compared with no CKD group:adjusted hazard ratio[HR]was 1.34(95%CI:1.07−1.68,P=0.011)for mild CKD group,2.17(95%CI:1.67−2.81,P<0.0001)for moderate CKD group,and 2.95(95%CI:1.97−4.41,P<0.0001)for severe CKD group,respectively.Risk of all-cause mortality also increased among patients with moderate or severe CKD.CONCLUSIONS CKD status was independently associated with progressively higher risks of major bleeding and mortality,but didn’t seem to be an independent predictor of thromboembolism in AF patients.
基金This work was supported by the National Key Research and Development Program of China(2016YFC0900901,2016YFC1301002,2017YFC0908803,2018YFC1312501)a grant from the National Natural Science Foundation of China(81530016).
文摘Background:Elderly adults with atrial fi brillation(AF)are at increased risk of frailty and thromboembolic complications.However,studies on the prevalence of frailty in AF patients and data on the relationship between frailty and the use of anticoagulants are limited.Methods:We conducted a cross-sectional study involving 500 participants.Patients aged 65 years or older were consecutively selected from the Chinese Atrial Fibrillation Registry study.The patient’s frailty status was assessed with use of the Canadian Study of Health and Aging Clinical Frailty Scale.We assessed the prevalence of and factors associated with frailty,and how frailty affects anticoagulant therapy.Results:In 500 elderly adults with AF(age 75.2±6.7 years;51.6%female),201 patients(40.2%)were frail.The prevalence of frailty was higher in females(P=0.002)and increased with age and CHA 2 DS 2-VASc score(P for trend less than 0.001 for both).The factors associated with frailty were a history of heart failure(odds ratio[OR]2.40,95%confi dence interval[CI]1.39–4.14),female sex(OR 2.09,95%CI 1.27–3.43),and advanced age(OR 1.13,95%CI 1.09–1.17).Frail patients were signifi cantly less likely to have ever been prescribed anticoagulants compared with nonfrail patients(81.7 vs.54.9%,P<0.001).Conclusions:Frailty is prevalent in elderly adults with AF,especially in females,those of advanced age,and those with heart failure.Frailty status has a signifi cant impact on prescription of anticoagulants for high-risk AF patients.
基金This work was supported by the National Science Foundation of China(grant No.81770318)Beijing Municipal Natural Science Foundation(grant No.7192051).
文摘Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fibrillation(AF).Recent studies have revealed that TKIs induce metabolic alterations and remodeling in cardiomyocytes,thus perturb-ing energy metabolism.Specifically,mitochondrial dysfunction and shifts in cardiac substrate utilization have been implicated in the mechanisms underlying TKI-induced AF.In light of these findings,this article reviews the energy metabolism-associated pathways involved in TKI-induced AF,identifies precise therapeutic targets for managing this condition,and discusses evidence that may contribute to the development of novel TKIs without cardiac adverse ef-fects.
基金supported by the National Natural Science Foundation of China(Grant Nos.82170318,81870243,82170310,and 82300315)the Guangdong Province Basic and Applied Basic Research Fund Project(No.2024A1515012174).
文摘Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.
基金supported by the National Key Research and Development Program of China(Nos.2017YFC0908803,2018YFC1312501,and 2020YFC2004803)a grant from the Beijing Municipal Commission of Science and Technology(No.D171100006817001)supported by grants from Bristol-Myers Squibb,Pfizer,Johnson&Johnson,Boehringer-Ingelheim,and Bayer.
文摘Background:Accurate prediction of ischemic stroke is required for deciding anticoagulation use in patients with atrial fibrillation(AF).Even though only 6%to 8%of AF patients die from stroke,about 90%are indicated for anticoagulants according to the current AF management guidelines.Therefore,we aimed to develop an accurate and easy-to-use new risk model for 1-year thromboembolic events(TEs)in Chinese AF patients.Methods:From the prospective China Atrial Fibrillation Registry cohort study,we identified 6601 AF patients who were not treated with anticoagulation or ablation at baseline.We selected the most important variables by the extreme gradient boosting(XGBoost)algorithm and developed a simplified risk model for predicting 1-year TEs.The novel risk score was internally validated using bootstrapping with 1000 replicates and compared with the CHA2DS2-VA score(excluding female sex from the CHA2DS2-VASc score).Results:Up to the follow-up of 1 year,163 TEs(ischemic stroke or systemic embolism)occurred.Using the XGBoost algorithm,we selected the three most important variables(congestive heart failure or left ventricular dysfunction,age,and prior stroke,abbreviated as CAS model)to predict 1-year TE risk.We trained a multivariate Cox regression model and assigned point scores proportional to model coefficients.The CAS scheme classified 30.8%(2033/6601)of the patients as low risk for TE(CAS score=0),with a corresponding 1-year TE risk of 0.81%(95%confidence interval[CI]:0.41%–1.19%).In our cohort,the C-statistic of CAS model was 0.69(95%CI:0.65–0.73),higher than that of CHA2DS2-VA score(0.66,95%CI:0.62–0.70,Z=2.01,P=0.045).The overall net reclassification improvement from CHA2DS2-VA categories(low=0/high≥1)to CAS categories(low=0/high≥1)was 12.2%(95%CI:8.7%–15.7%).Conclusion:In Chinese AF patients,a novel and simple CAS risk model better predicted 1-year TEs than the widely-used CHA2DS2-VA risk score and identified a large proportion of patients with low risk of TEs,which could potentially improve anticoagulation decision-making.Trial Registration:www.chictr.org.cn(Unique identifier No.ChiCTR-OCH-13003729).
基金the Dalian Science and Technology Leading Talents Project(No.2019RD15)the Distinguished Professor of Liaoning Province,the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning(No.CNLZD1801)+2 种基金the Natural Science Foundation of Liaoning Province(No.2020-MS-256)the Dalian Young Star of Science and Technology(No.2019RQ123)the Shanghai"Rising Stars of Medical Talent" Youth Development Program-Youth Medical Talents-Clinical Pharmacist Program(No.SHWJRS(2019)_072).
文摘Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history.After investigation of U.rhynchophylla,eleven monoterpene indole alkaloids,including four new compounds uncarialins J-M(1-4)and seven known analogues(5-11),were isolated and identified.Their structural characterization was conducted using HRESIMS,1D and 2D NMR,electronic circular dichroism(ECD)spectra,and quantum chemical computations.Compounds 1,2,7,and 9-11 displayed significant ag-onistic effects towards 5-HT_(1A) receptor,and their EC_(50) values were 7.86,732,2.24,1.18,1.52,and 3.75μmol/L,respectively.Furthermore,in vivo experimental results fully revealed that hirsuteine(7)displayed a significant antidepression effect in unpredictable chronic mild stress(UCMS)-induced depression mice mainly via regulating 5-HT_(1A) signaling pathway.Molecular docking and site-directed amino acid mutation verified that amino acid residues Aspll6 and Asn386 were the binding sites of hirsuteine(7)with 5-HT_(1A) receptor.In addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine(7),which further demonstrated that 5-HT_(1A) receptor was a potential target of hirsuteine(7)to effectively treat depression.These findings indicated the therapeutic material basis of U.rhynchophylla and the anti-depression underlying mechanism of hirsuteine(7),and further provided the useful guidance for the development of hirsuteine(7)as a potential antidepressant candidate.
文摘To the Editor： Current treatment guidelines for patients with acute coronary syndrome （ACS） undergoing percutaneous coronary intervention （PCI） recommend dual antiplatelet therapy, a combination of aspirin and a P2YI2 inhibitor （i.e., clopidogrel, prasugrel, and ticagrelor） for a minimum of 12 months. Ticagrelor, an oral reversibly binding platelet P2Y 12 receptor inhibitor, generates a greater and more consistent inhibitory effect with rapid onset of action as compared to clopidogrel.
