Tyrosine Kinase Inhibitor Antitumor Therapy and Atrial Fibrillation: Potential Off-Target Effects on Mitochondrial Function and Cardiac Substrate Utilization

Tyrosine kinase inhibitors (TKIs) are a novel category of antitumor agents with remarkable efficacy in extending patient 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 perturbing 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 effects

Outstanding Chiroptical Features of Thin Films of Chiral Oligothiophenes

A chiral benzo[1, 2-​b:4,​5-​b']​dithiophene-​based oligothiophene with the very uncommon chiroptical property of signal inversion on sample flipping was recently described. This property is due to the interference between linear dichroism and linear birefringence, called LDLB effect, which is theor. well understood, but to date very rarely reported in the literature. Samples with very large LDLB effect lead to the unique possibility of discriminating the direction of sample illumination (i. e., from the front or back)​. This article presents a set of analog compds., in which small structural changes are introduced to uncover which factors det. the very large LDLB effect or true CD connected to supramol. chirality. It also reveals the impact of the deposition technique, in which spin coating may exert a primary role, and results in films with outstanding chiroptical features. These features are made even more relevant due to the semiconducting properties of oligothiophenes, which are interesting for optical sensing applications

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

A Convenient Fluorescence-Based Assay for the Detection of Sucrose Transport and the Introduction of a Sucrose Transporter from Potato into Clostridium Strains

A convenient and effective sucrose transport assay for Clostridium strains is needed. Traditional methods, such as 14C-sucrose isotope labelling, use radioactive materials and are not convenient for many laboratories. Here, a sucrose transporter from potato was introduced into Clostridium, and a fluorescence assay based on esculin was used for the analysis of sucrose transport in Clostridium strains. This showed that the heterologously expressed potato sucrose transporter is functional in Clostridium. Recombinant engineering of high-level sucrose transport would aid sucrose fermentation in Clostridium strains. The assay described herein provides an important technological platform for studying sucrose transporter function following heterologous expression in Clostridium

ABC-AF-Stroke score predicts thromboembolism in non-anticoagulated patients following successful atrial fibrillation ablation: a report from the Chinese Atrial Fibrillation Registry.

BackgroundThe age, biomarkers, and clinical history (ABC)-atrial fibrillation (AF)-Stroke score have been proposed to refine stroke risk stratification, beyond what clinical risk scores such as the CHA2DS2-VASc score can offer. This study aimed to identify risk factors associated with thromboembolism and evaluate the performance of the ABC-AF-Stroke score in predicting thromboembolism in non-anticoagulated AF patients following successful ablations.MethodsA total of 2692 patients who underwent successful ablations with discontinued anticoagulation after a 3-month blanking period in the Chinese Atrial Fibrillation Registry (CAFR) between 2013 and 2019 were included. Cox regression analysis was conducted to present the association of risk factors with thromboembolism risk. The ABC-AF-Stroke score was evaluated in terms of discrimination, including concordance index (C-index), net reclassification improvement (NRI) and integrated discrimination improvement (IDI), clinical utilization by decision curve analysis (DCA), and calibration by comparing the predicted risk with the observed annualized event rate.ResultsAfter a median follow-up of 3.5 years, 64 patients experienced thromboembolism events. Age, prior history of stroke/transient ischemic attack (TIA), high-sensitivity cardiac troponin T (cTnT-hs), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independently associated with thromboembolism risk. The ABC-AF-Stroke score performed statistically significantly better than the CHA2DS2-VASc score in terms of C-index (0.67, 95% confidence interval [CI]: 0.59-0.74 vs. 0.60, 95% CI: 0.52-0.67, P = 0.030) and reclassification capacity. The DCA implied that the ABC-AF-Stroke score could identify more thromboembolism events without increasing the false positive rate compared to the CHA2DS2-VASc score. The calibration curve showed that the ABC-AF-Stroke score was well calibrated in this population.ConclusionsIn this real-world study enrolling non-anticoagulated AF patients following successful ablations, age, prior history of stroke/TIA, level of NT-proBNP, and cTnT-hs were independently associated with an increased risk of thromboembolism. The ABC-AF-Stroke score was well-calibrated and statistically significantly outperformed the CHA2DS2-VASc score in predicting thromboembolism risk

Associations of anemia with death and major bleeding in patients with atrial fibrillation: A report from the Chinese Atrial Fibrillation Registry Study

BACKGROUND: Anemia is a common comorbidity in patients with atrial fibrillation (AF). Reports on the association of anemia and adverse events in patients with AF, especially from Asia, are limited. METHODS AND RESULTS: Based on data from the Chinese Atrial Fibrillation Registry Study (CAFR), a total of 18,106 AF patients enrolled between August 2011 and December 2018 had hemoglobin (Hb) values recorded at baseline. Patients were classified into three groups according to Hb levels: 15,606 patients (86.2%) into the no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 (9.9%) with mild anemia (male 110≤Hb<129 g/L; female 110≤Hb<119 g/L), and 700 (3.9%) with moderate to severe anemia (Hb≤109 g/L). Multivariable Cox regression models were used to determine if anemia was independently associated with all‐cause death, cardiovascular death, or major bleeding, after adjusting for confounders. Anemia was present in 13.8% of the population at baseline. During a median follow‐up of 4.01 years, the incidences of all‐cause death (1.8, 4.9, and 8.9 per 100 person‐years), cardiovascular death (1.0, 2.9, and 4.5 per 100 person‐years), and major bleeding (0.5, 0.6, and 0.7 per 100 person‐years) were gradually accentuated in patients with no anemia, mild anemia, and moderate to severe anemia, respectively. Compared with patients with no anemia, those with anemia had higher risks for all‐cause death (mild anemia; adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.08–1.38; moderate to severe anemia; adjusted HR: 1.53, 95% CI: 1.31–1.77); and cardiovascular death (mild anemia; adjusted HR: 1.29, 95% CI: 1.10–1.52; moderate to severe anemia; adjusted HR: 1.27, 95% CI: 1.03–1.57), but not for major bleeding. The association between anemia and all‐cause death was similar among subgroups stratified by sex, kidney function, anticoagulant, or ablation therapy. CONCLUSIONS: Anemia was associated with increased risks of all‐cause death, cardiovascular death, but no major bleeding in AF patients. The effect of anemia correction on the prognosis of patients with AF requires further study

Genetic Evidence for Causal Association Between Atrial Fibrillation and Dementia: A Mendelian Randomization Study

Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2‐sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance–weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023–1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076–1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953–1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926–1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small‐vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention

Impact of Sodium‐Glucose Cotransporter 2 Inhibitor on Recurrence After Catheter Ablation for Atrial Fibrillation in Patients With Diabetes: A Propensity‐Score Matching Study and Meta‐Analysis

Background The association between sodium‐glucose cotransporter 2 inhibitors (SGLT2i) and atrial fibrillation (AF) recurrence after catheter ablation among patients with diabetes and AF remains unclear. Methods and Results Patients with AF undergoing initial catheter ablation with a history of diabetes from the China AF registry were included. Patients using SGLT2i were identified and matched by propensity score with non‐SGLT2i patients in a 1:3 ratio. The main outcome was AF recurrence during the 18‐month follow‐up. A total of 138 patients with diabetes with SGLT2i therapy and 387 without SGLT2i were analyzed. AF recurrence occurred in 37 patients (26.8%) in the SGLT2i group and 152 patients (39.3%) in the non‐SGLT2i group during a total of 593.3 person‐years follow‐up. The SGLT2i group was associated with lower AF recurrence compared with the non‐SGLT2i group (hazard ratio, 0.63 [95% CI, 0.44–0.90], P=0.007). A total of 4 studies were analyzed in our meta‐analysis demonstrating that SGLT2i was associated with lower AF recurrence after catheter ablation (odds ratio, 0.61 [95% CI, 0.54–0.69]; P<0.001, I2=0.0%). Conclusions Our prospective study coupled with a meta‐analysis demonstrated a lower risk of AF recurrence with the use of SGLT2i among patients with diabetes after AF ablation