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Meng-Na Wang,1,* Hai-Tao Yu,2,* Ya-Qian Li,1 Yun Zeng,1 Shuang Yang,3 Guo-Ping Yang,1,3– 6 Qi Pei,6 Jie Huang1,3 1Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Research and Development Center, Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd., Nanjing 210038, People’s Republic of China; 3Research Center of Drug Clinical Evaluation of Central South University, Changsha, Hunan 410013, People’s Republic of China; 4XiangYa School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, People’s Republic of China; 5National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology, Changsha, Hunan 410013, People’s Republic of China; 6Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Huang; Qi PeiThe Third Xiangya Hospital, Central South University, Yinpenling Street, Yuelu District, Changsha, Hunan 410013, People’s Republic of ChinaTel +86 15116469024Fax +86 731 8861 8326Email cellahuang1988@163.com; peiqi1028@126.comObjectives: This study was conducted to evaluate the bioequivalence (BE) of a generic form of obeticholic acid (OCA) and OcalivaTM under fasting and fed conditions and to determine the effects of food on the pharmacokinetic (PK) profiles of OCA in healthy Chinese subjects.Methods: A randomized, single-dose, three-sequence, three-period, partial replicated crossover study was conducted with a 21-day washout interval between periods under fasting (n=48) and fed (n=48) conditions. Blood samples for OCA and its metabolites Glyco-OCA and Tauro-OCA were collected up to 168 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios for PK parameters of the test to reference drug under fasting and fed conditions and their 90% confidence intervals were estimated. Safety evaluations were carried out all through the study.Results: A total of 91 subjects completed the study with 45 in a fasted state and 46 receiving a high-fat diet. There were no serious or unexpected drug-related adverse events occurring during the study. There was no significant difference in the main PK parameters of the two preparations, irrespective of the fasting or fed conditions. Under fasting and fed conditions, the SWR of lnCmax, lnAUC0-t and lnAUC0-∞ were 0.445, 0.370, 0.448, 0.340, 0.168, and 0.180, respectively. Thus, the average BE or the reference-scaled average BE was used to verify that the two preparations were bioequivalent under fasting and fed conditions. Compared with the fasting state, the AUC0-t of the test drug, the AUC0-t, and AUC0-∞ of the reference drug were higher in the fed state.Conclusion: The test drug and the reference drug were BE and well tolerated in Chinese healthy subjects under both fasting and fed conditions. Food-intake may cause a significant difference in the main PK parameters of the two preparations.Keywords: obeticholic acid, bioequivalence, pharmacokinetics, food effect

Abstract Objective: This study aimed to evaluate the association of mean and maximum blood glucose (BG) levels with in-hospital mortality and 30-day hospital readmission among patients in the intensive care unit (ICU) undergoing invasive cardiovascular (CV) surgery. Research design and methods: The retrospective database analysis consisted of data from 3132 patients from 17 hospitals who underwent an invasive CV surgery during 1/2000-12/2006. Patients with hyperglycemia were identified based on serum BG levels recorded from 12 hours prior to and 24 hours after ICU admission. Separate logistic regression models were used to examine the association of mean and maximum BG levels to in-hospital mortality and 30-day readmission, adjusting for patient demographics, comorbidities and laboratory values. Results: The adjusted odds ratio (OR) for in-hospital mortality was 1.07 (95% CI: 1.01-1.12; p < .001) for every 0.56-mmol/L increase in mean BG, and OR = 1.06 (95% CI: 1.03-1.08, p < .001) for every 0.56-mmol/L increase in maximum BG. Mean BG was not associated with 30-day readmission while maximum BG had a borderline association: OR = 1.02 (95% CI: 1.00-1.03, p = .06). Limitation: The results are not generalizable to all cardiovascular surgical patients since only those undergoing invasive procedures were included in the study. Conclusions: Higher mean and maximum BG levels were associated with increased risk of in-hospital mortality but not with 30-day readmission. Further research is needed to identify optimal BG targets and the effects of avoiding extreme hyperglycemia on patient outcomes. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain but undesirable side effects limit their clinical usefulness. Choline is a [alpha]7 nicotinic receptor agonist that has antinociceptive effects in a variety of pain models. Drug combination is a strategy in the management of pain to reduce side effects. The aim of the study was to evaluate the nature of the interaction between choline and aspirin in two distinct inflammatory pain models. The analgesic mechanism of choline was also investigated. In the writhing test, intravenous administration of choline or aspirin showed dose-dependent antinociceptive activity, and isobolographic analysis revealed a synergistic nature of the interaction between choline and aspirin. More importantly, coadministration choline with aspirin could significantly shorten the antinociceptive latency of aspirin and prolong the antinociceptive duration of aspirin in the writhing test. In the carrageenan test, single administration of choline or aspirin significantly attenuated carrageenan-induced thermal hyperalgesia in a dose-dependent relationship. Coadministration of non-analgesic doses of aspirin with choline significantly suppressed the thermal hyperalgesia, with a longer duration efficacy. Furthmore, we found that [alpha]7 nicotinic, muscarinic, and opioid-receptors are involved in the antinociceptive effect of choline in the writhing test and the antinociceptive effect produced by systemically administered choline may be via a peripheral mechanism. In conclusion, coadministration of choline and aspirin holds promise for development as a safe analgesic drug combination for inflammatory pain, with a higher potency and longer duration than either aspirin or choline alone. [ABSTRACT FROM AUTHOR]

The application of artificial intelligence (AI) algorithms to 12-lead electrocardiogram (ECG) provides promising age prediction models. We explored whether the gap between the pre-procedural AI-ECG age and chronological age can predict atrial fibrillation (AF) recurrence after catheter ablation. We validated a pre-trained residual network-based model for age prediction on four multinational datasets. Then we estimated AI-ECG age using a pre-procedural sinus rhythm ECG among individuals on anti-arrhythmic drugs who underwent de-novo AF catheter ablation from two independent AF ablation cohorts. We categorized the AI-ECG age gap based on the mean absolute error of the AI-ECG age gap obtained from four model validation datasets; aged-ECG (≥10 years) and normal ECG age (<10 years) groups. In the two AF ablation cohorts, aged-ECG was associated with a significantly increased risk of AF recurrence compared to the normal ECG age group. These associations were independent of chronological age or left atrial diameter. In summary, a pre-procedural AI-ECG age has a prognostic value for AF recurrence after catheter ablation., (© 2024. The Author(s).)

Background: Increased left atrial pressure (LAP) contributes to dyspnea and heart failure with preserved ejection fraction in patients with atrial fibrillation (AF). The purpose of this study was to investigate the differences in baseline LAP and LAP response to rapid pacing between paroxysmal and persistent AF., Methods and Results: This observational study prospectively enrolled 1369 participants who underwent AF catheter ablation, excluding those with reduced left ventricular ejection fraction. H 2 FPEF score was calculated by echocardiography and baseline characteristics. Patients underwent LAP measurements during AF, sinus rhythm, and heart rates of 90, 100, 110, and 120 beats per minute (bpm), induced by right atrial pacing and isoproterenol. The baseline LAP-peak in the persistent AF group consistently exceeded that in the paroxysmal AF (PAF) group across each H 2 FPEF score subgroup (all P <0.05). LAP-peak increased with pacing (19.5 to 22.5 mm Hg) but decreased with isoproterenol (20.4 to 18.4 mm Hg). Under pacing, patients with PAF exhibited a significantly lower LAP-peak (90 bpm) than those with persistent AF (17.7±8.2 versus 21.1±9.3 mm Hg, P <0.001). However, there was no difference in LAP-peak (120 bpm) between the 2 groups (22.1±8.1 versus 22.9±8.4 mm Hg, P =0.056) because the LAP-peak significantly increased with heart rate in the group with PAF., Conclusions: Patients with PAF exhibited lower baseline LAP with greater increases during rapid pacing compared with individuals with persistent AF, indicating a need to revise the H 2 FPEF score for distinguishing PAF from persistent AF and emphasizing the importance of rate and rhythm control in PAF for symptom control., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02138695.

Background:  This study aimed to evaluate racial differences in bleeding incidence by conducting an ecological epidemiological study using data from Korea and the United Kingdom., Methods:  We included healthy participants from the Korean National Health Insurance Service-Health Screening and the UK Biobank who underwent health examinations between 2006 and 2010 and had no comorbidities or history of medication use. Finally, 112,750 East Asians (50.7% men, mean age 52.6 years) and 210,995 Caucasians (44.7% men, mean age 55.0 years) were analyzed. The primary outcome was composed of intracranial hemorrhage (ICH) and bleeding from the gastrointestinal, respiratory, and genitourinary systems., Results:  During the follow-up, primary outcome events occurred in 2,110 East Asians and in 6,515 Caucasians. East Asians had a 38% lower 5-year incidence rate compared with Caucasians (3.88 vs. 6.29 per 1,000 person-years; incidence rate ratio [IRR]: 0.62, 95% confidence interval [CI]: 0.59-0.65). East Asians showed a lower incidence of major bleeding (IRR: 0.86, 95% CI: 0.81-0.91), bleeding from the gastrointestinal (IRR: 0.53, 95% CI: 0.49-0.56), and genitourinary systems (IRR: 0.49, 95% CI: 0.44-0.53) compared with Caucasians. The incidence rates of ICH (IRR: 3.20, 95% CI: 2.67-3.84) and bleeding from the respiratory system (IRR: 1.28, 95% CI: 1.11-1.47) were higher in East Asians. Notably, East Asians consuming alcohol ≥3 times/week showed a higher incidence of the primary outcome than Caucasians (IRR: 1.12, 95% CI: 1.01-1.25)., Conclusion:  This ecological study revealed significant racial differences in bleeding incidence, influenced by anatomical sites and lifestyle habits, underscoring the need for tailored approaches in bleeding management based on race., Competing Interests: B.J. has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi-Sankyo and received research funds from Medtronic and Abbott. No fees have been received directly or personally. G.Y.H.L. has been a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos. No fees are received personally. He is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement number 899871. The remaining authors have nothing to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background:  This study aimed to evaluate racial differences in the incidence of stroke by conducting an ecological epidemiological study using UK Biobank and Korean nationwide data., Methods:  This study used individual data from the Korean National Health Insurance Service-Health Screening and UK Biobank, which included participants who underwent health examinations between 2006 and 2010. We included 112,750 East Asians (50.7% men, mean age: 52.6 years) and 210,995 Caucasians (44.7% men, mean age: 55.0 years) who were not diagnosed with atrial fibrillation, cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease, or cancer. The primary outcome was defined as a composite of ischemic and hemorrhagic stroke., Results:  East Asians tended to have a lower body mass index (23.7 vs. 26.4 kg/m 2 , p  < 0.001) and a higher proportion of participants who did not engage in moderate-to-vigorous physical activity (49.6% vs. 10.7%, p  < 0.001) than Caucasians. During the follow-up, East Asians had higher 5-year incidence rates (presented as per 1,000 person-years) for primary outcome (1.73 vs. 0.50; IR ratio [IRR]: 3.48, 95% confidence interval [CI]: 3.13-3.88), ischemic stroke (1.23 vs. 0.33; IRR: 3.70, 95% CI: 3.25-4.21), hemorrhagic stroke (0.56 vs. 0.18; IRR: 3.20, 95% CI: 2.67-3.84), and atrial fibrillation-related stroke (0.19 vs. 0.09; IRR: 2.04, 95% CI: 1.55-2.68)., Conclusion:  Based on this ecological epidemiological study, racial differences in stroke incidence were robust to a variety of statistical analyses, regardless of the subtype. This suggests the need for region-specific approaches to stroke prevention., Competing Interests: B.J. has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi-Sankyo and received research funds from Medtronic and Abbott. No fees have been received directly or personally. G.Y.H.L. has been a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthem. No fees are received personally. He is a co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 899871. The remaining authors have nothing to declare., (Thieme. All rights reserved.)

Background: The ideal long-term antithrombotic strategy for patients after successful catheter-based atrial fibrillation (AF) ablation is still uncertain. Presently, practices vary, and the advantages of oral anticoagulation (OAC) for the post-ablation population are not clearly established. To date, no randomized trials have addressed this therapeutic question. This study aimed to evaluate whether no OAC therapy is superior to apixaban in reducing the risk of stroke, systemic embolism, or major bleeding among patients without apparent recurrent atrial arrhythmias for at least 1 year after their AF ablation procedure., Methods: The ALONE-AF trial is a prospective, multicenter, open-label, randomized study with blinded outcome assessment. Patients with AF who have at least one non-gender stroke risk factor (as determined by the CHA 2 DS 2 -VASc score) and no documented recurrences of atrial arrhythmia for at least 12 months post-ablation will be randomly assigned to apixaban 5 mg b.i.d. or no OAC therapy. The primary endpoint is a composite outcome of stroke, systemic embolism, and major bleeding. Key secondary outcomes include clinically relevant non-major bleeding, all-cause mortality, myocardial infarction, transient ischemic attack, quality of life, and frailty analysis. Participants will be followed for a period of 2 years. The estimated total sample size is 840 subjects, with 420 subjects in each arm., Conclusion: The ALONE-AF trial aims to provide robust evidence for the optimal anticoagulation strategy for patients with stroke risk factors following successful AF ablation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Boyoung Joung reports financial support was provided by Korea Ministry of Health and Welfare. Boyoung Joung reports financial support was provided by Samjin Pharm Co Ltd. Boyoung Joung has served as a speaker for 10.13039/100004326Bayer, BMS/10.13039/100004319Pfizer, Medtronic, and 10.13039/501100002973Daiichi-Sankyo and received research funds from Samjin, 10.13039/100019265Yuhan, Medtronic, Boston Scientifics and 10.13039/100008977Abbott Korea. No fees were received personally. The remaining authors have no conflicts of interest to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Atrial fibrillation (AF) is associated with impaired renal function and chronic kidney disease (CKD)., Objectives: This study assessed the effects of rhythm control on renal function compared with rate control among patients recently diagnosed with AF., Methods: A total of 20,886 patients with AF and available baseline estimated glomerular filtration rate (eGFR) data undergoing rhythm control (antiarrhythmic drugs or ablation) or rate control therapy, initiated within 1 year of AF diagnosis in 2005 to 2015, were identified from the Korean National Health Insurance Service database. The composite outcome of ≥30% decline in eGFR, acute kidney injury, kidney failure, or death from renal or cardiovascular causes was compared with the use of propensity overlap weighting between rhythm or rate control strategies in patients with or without significant CKD (eGFR <60 mL/min/1.73 m 2 )., Results: Of the included patients (median age 62 years, 32.7% female), 2,213 (10.6%) had eGFR <60 mL/min/1.73 m 2 . Among patients with significant CKD, early rhythm control, compared with rate control, was associated with a lower risk of the primary composite outcome (weighted incidence rate: 2.77 vs 3.92 per 100 person-years; weighted HR: 0.70; 95% CI: 0.52-0.95). In patients without significant CKD, there was no difference in the risk of the primary composite outcome between rhythm and rate control groups (weighted incidence rate: 3.41 vs 3.21 per 100 person-years; weighted HR: 1.06; 95% CI: 0.96-1.18). No differences in safety outcomes were found between rhythm and rate control strategies in patients without or with significant CKD., Conclusions: Among patients with AF and CKD, early rhythm control was associated with lower risks of adverse renal outcomes than rate control was., Competing Interests: Funding Support and Author Disclosures This research was supported by a grant from the Patient-Centered Clinical Research Coordinating Center funded by the Ministry of Health and Welfare, Republic of Korea (HC19C0130), a grant from the Korean Cardiac Research Foundation (202303-01), and a grant from the Korean Heart Rhythm Society (KHRS2023-2). Dr Lip has been consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthem, with no fees received personally; and is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 899871. Dr Joung has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi-Sankyo; and has received research funds from Medtronic and Abbott, with no fees received directly or personally. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to explore the psychological characteristics of the individuals with various suicide risks using computerized text analysis, in the hopes of a better understanding of suicide trajectories., Methods: 627 first-time callers' records were randomly selected from Taiwan An-Shin Hotline database between 2013 and 2018. The voice records were evaluated by two psychologists to determine the levels of suicide risk (156 with uncertainty of risk, 177 with low suicidal ideation, 157 with high suicidal ideation, and 137 with suicide preparation/attempt) and transcribed into text. The Linguistic Inquiry and Word Count 2015 (LIWC2015) program combined with Chinese dictionary were then used to calculate the frequency of word categories., Results: Exploratory factor analysis identified four mindsets of language characteristics, named "opposition and questioning", "active engagement", "negative rumination", and "focus on death". Psychological descriptions of the mindsets were also obtained through correlation analysis with the LIWC2015 categories and indicators. The four mindsets effectively distinguished the callers with different levels of suicide risk., Conclusion: The psychological characteristics of people with various suicide risks can be described and differentiated via the closed-word categories and composite indicators. These results provide useful information for practitioners and researchers., (© 2024 American Association of Suicidology.)

As an essential macronutrient, phosphorus (P) is often a limiting nutrient because of its low availability and mobility in soils. Drought is a major environmental stress that reduces crop yield. How plants balance and combine P-starvation responses (PSRs) and drought resistance is unclear. In this study, we identified the transcription factor ZmPHR1 as a major regulator of PSRs that modulates phosphate (Pi) signaling and homeostasis. We found that maize zmphr1 mutants had reduced P concentration and were sensitive to Pi starvation, whereas ZmPHR1-OE lines displayed elevated Pi concentration and yields. In addition, 57% of PSR genes and nearly 70% of ZmPHR1-regulated PSR genes in leaves were transcriptionally responsive to drought. Under moderate and early drought conditions, the Pi concentration of maize decreased, and PSR genes were up-regulated before drought-responsive genes. The ZmPHR1-OE lines exhibited drought-resistant phenotypes and reduced stomatal apertures, whereas the opposite was true of the zmphr1 mutants. ZmPT7-OE lines and zmspx3 mutants, which had elevated Pi concentration, also exhibited drought resistance, but zmpt7 mutants were sensitive to drought. Our results suggest that ZmPHR1 plays a central role in integrating Pi and drought signals and that Pi homeostasis improves the ability of maize to combat drought., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: The impact of delaying atrial fibrillation catheter ablation (AFCA) for antiarrhythmic drug (AAD) management on the disease course remains unclear. This study investigated AFCA rhythm outcomes based on the diagnosis-to-ablation time (DAT) and AAD responsiveness in participants with persistent AF (PeAF)., Methods: We included data from 1038 AAD-resistant PeAF participants, all of whom had a clear time point for AF diagnosis, especially PeAF at diagnosis time, and had undergone an AFCA for the first time. Participants who experienced recurrences of paroxysmal type on AAD therapy were analyzed as a cohort of AAD-partial responders; those maintaining PeAF on AAD were AAD-non-responders. We determined the DAT cutoff for best discriminating long-term rhythm outcomes using a maximum log-likelihood estimation method based on the Cox proportional hazard regression model., Results: Of the participants (79.8% male; median age 61), 806 (77.6%) were AAD-non-responders. AAD-non-responders had a higher body mass index and a larger left atrial diameter than AAD-partial-responders. They also had a higher incidence of AF recurrence after AFCA (adjusted hazard ratio 1.75, 95% confidence interval 1.33-2.30; log-rank p  < .001) compared to AAD-partial-responders. The maximum log-likelihood estimation showed bimodal cutoffs at 22 and 40 months. The optimal DAT cutoff rhythm outcome was 22 months, which discriminated better in the AAD-partial-responders than in the AAD-non-responders., Conclusions: Both DAT and AAD responsiveness influenced AFCA rhythm outcomes. Delaying AFCA to a DAT of longer than 22 months was inadvisable, particularly in the participants in whom PeAF was changed to paroxysmal AF during AAD therapy., Competing Interests: Authors declare no conflict of interests for this article., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

The evidence about the associations of leukocyte telomere length (LTL) and intermediary cardiovascular phenotypes with adverse cardiovascular outcomes is inconclusive. This study assessed these relationships with cardiovascular imaging, electrocardiography, and the risks of sudden cardiac death (SCD), coronary events, and heart failure (HF) admission. We conducted a cross-sectional analysis of UK Biobank participants enrolled between 2006 and 2010. LTL was measured using quantitative polymerase chain reactions. Electronic health records were used to determine the incidence of SCD, coronary events, and HF admission. Cardiovascular measurements were made using cardiovascular magnetic resonance imaging and machine learning. The associations of LTL with SCD, coronary events, and HF admission and cardiac magnetic resonance imaging, electrocardiogram parameters of 33,043 and 19,554 participants were evaluated by multivariate regression. The median (interquartile range) follow-up period was 11.9 (11.2-12.6) years. Data was analyzed from January to May 2023. Among the 403,382 white participants without coronary artery disease or HF, 181,637 (45.0%) were male with a mean age of 57.1 years old. LTL was independently negatively associated with a risk of SCD (LTL third quartile vs first quartile: hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.72-0.92), coronary events (LTL third quartile vs first quartile: HR: 0.88, 95% CI: 0.84-0.92), and HF admission (LTL fourth quartile vs first quartile: HR: 0.84, 95% CI: 0.74-0.95). LTL was also independently positively associated with cardiac remodeling, specifically left ventricular mass index, left-ventricular-end systolic and diastolic volumes, mean left ventricular myocardial wall thickness, left ventricular stroke volume, and with electrocardiogram changes along the negative degree of T-axis. Cross-sectional study results showed that LTL was positively associated with heart size and cardiac function in middle age, but electrocardiography results did not show these associations, which could explain the negative association between LTL and risk of SCD, coronary events, and HF admission in UK Biobank participants., (© 2024. The Author(s).)

Background: Data on off-label reduced dose risk among patients with atrial fibrillation (AF) who qualify for a single-dose reduction of apixaban is scarce., Objectives: We prospectively assessed apixaban dosing and clinical characteristics in AF patients meeting a dose reduction criterion., Methods: The multicentre, prospective cohort study, the efficAcy and Safety of aPixaban In REal-world practice in Korean frail patients with AF (ASPIRE), encompasses patients with AF who met the criteria for a single-dose reduction of apixaban and were given varying doses of apixaban, either the on-label standard dose or the off-label reduced dose., Results: Of 2,000 patients (mean age 74.3 ± 7.9 years, 55.8% women), 29.7% were ≥80 years, 62.6% weighed ≤60 kg, and 7.8% had serum creatinine ≥1.5 mg/dL. Of these, 51.3% were prescribed an off-label reduced dose of apixaban. The off-label group was characterized with older age, more comorbidities, and antiplatelet agents, while the on-label group had more prior strokes. Physicians preferred off-label reduced dose in the "marginal zone," defined as age 75-80 years, weight 60-65 kg, and creatinine levels 1.2-1.5 mg/dL., Conclusions: In real-world clinical setting of the Korean population, off-label reduced dose apixaban was administered to nearly half of the patients who qualified for a single dose reduction. This reduced dosage was more commonly prescribed to patients with frail characteristics, while patients with a history of stroke were more often given the standard dose as per the label. A future study is planned to contrast the safety and effectiveness of the standard dose against the reduced dose of apixaban in this population., Competing Interests: S-RL: Speaking fees from Bayer, BMS/Pfizer, Biosense Webster, Daiichi-Sankyo, Sanofi-Aventis, Daewoong Pharmaceutical Co., Samjinpharm, Seers Technology, Biotronik, Boston Scientific and Medtronic. Consultant for Biosense Webster. SL: Research grant and/or honoraria from Bayer, BMS/Pfizer, Biosense Webster, Biotronik, Boston Scientific, Chong Kun Dang, Daewoong Pharmaceutical Co., Daiichi-Sankyo, Medtronic, Norvatis, Seers Technology and Skylabs. E-KC: Research grants or speaking fees from Abbott, Bayer, BMS/Pfizer, Biosense Webster, Chong Kun Dang, Daewoong Pharmaceutical Co., Daiichi-Sankyo, DeepQure, Dreamtech Co., Ltd., Jeil Pharmaceutical Co. Ltd., Medtronic, Samjinpharm, Seers Technology, and Skylabs. GL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Anthos, and Daiichi-Sankyo. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871. No fees are received personally, and no fees are related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Choi, Lee, Kwon, Ahn, Lee, Park, Choi, Lee, Heo, Oh, On, Yu, Lee, Kim, Park, Lee, Shin, Oh, Lip, Han and Choi.)

Objective: Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM)., Methods: Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/β-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot., Results: Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of β-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05)., Conclusions: Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters between HCM subtypes and those without HCM at AF catheter ablation (AFCA) and analyzed post-AFCA reverse remodeling and AF recurrence based on HCM presence and subtype., Methods: Among 5161 consecutive patients who underwent de novo AFCA, we included HCM patients and control patients who were age-, gender-, and AF type-matched. Between AF-HCM patients and controls, we compared baseline values for left atrium (LA) wall thickness (LAWT), reverse remodeling at 1-year follow-up, and procedural outcomes over the course of follow-up between two groups., Results: A total of 122 AF-HCM patients and 318 control patients were included. AF-HCM patients had more frequent heart failure and higher LA diameter, E/Em, and LA pressure (all, p  < .001). However, LAWT did not differ from control group. A year after AFCA, degree of LA reverse remodeling was significantly lower in AF-HCM than in control group (ΔLA dimension, p  = .025). Nonapical HCM (HR 1.71; 95% CI 1.05-2.80), persistent AF (HR 1.46; 95% CI 1.05-2.04), and LA dimension (HR 1.04; 95% CI 1.01-1.06) were independent risk factors for AF recurrence. During 78.0 months of follow-up, nonapical HCM patients showed higher AF recurrence rate than both apical HCM (log-rank p  = .005) and control patients (log-rank p  = .002)., Conclusions: The presence of HCM, particularly nonapical HCM, displayed increased LA hemodynamic loading with diastolic dysfunction and had poorer rhythm outcomes after AFCA compared to both apical HCM and control group., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background: The reason for higher incidence of atrial fibrillation (AF) in Europe compared with East Asia is unclear. We aimed to investigate the association between modifiable lifestyle factors and lifetime risk of AF in Europe and East Asia, along with race/ethnic similarities and disparities., Methods: 1:1 propensity score matched pairs of 242,763 East Asians and 242,763 White Europeans without AF were analyzed. Modifiable lifestyle factors considered were blood pressure, body mass index, cigarette smoking, diabetes, alcohol consumption, and physical activity, categorized as non-adverse or adverse levels. Lifetime risk of AF was estimated from the index age of 45 years to the attained age of 85 years, accounting for the competing risk of death., Results: The overall lifetime risk of AF was higher in White Europeans than East Asians (20.9% vs 15.4%, p < 0.001). The lifetime risk of AF was similar between the two races in individuals with non-adverse lifestyle factor profiles (13.4% vs 12.9%, p = 0.575), whereas it was higher in White Europeans with adverse lifestyle factor profiles (22.1% vs 15.8%, p < 0.001). The difference in the lifetime risk of AF between the two races increased as the burden of adverse lifestyle factors worsened (1 adverse lifestyle factor; 4.3% to ≥ 3 adverse lifestyle factors; 11.2%). Compared with East Asians, the relative risk of AF in White Europeans was 23% and 62% higher for one (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.16-1.29) and ≥ 3 adverse lifestyle factors (HR 1.62, 95% CI 1.51-1.75), respectively., Conclusions: The overall higher lifetime risk of AF in White Europeans compared with East Asians might be attributable to adverse lifestyle factors. Adherence to healthy lifestyle factors was associated with the lifetime risk of AF of about 1 in 8 regardless of race/ethnicity., (© 2024. The Author(s).)

Background: Polypharmacy is commonly observed in atrial fibrillation (AF) and is associated with poorer clinical outcomes. Our study aimed to elucidate the polypharmacy prevalence, its associated risk factors, and its relationship with adverse clinical outcomes using a 'real-world' database., Methods: This study included 451,368 subjects without prior history of AF (median age, 54 [interquartile range, 48.0-63.0] years; 207,748 [46.0%] female) from the Korea National Health Insurance Service-Health Screening (NHIS-HealS) database between 2002 and 2013. All concomitant medications prescribed were collected, and the intake of five or more concomitant drugs was defined as polypharmacy. During the follow-up, all-cause death, major bleeding events, transient ischemic attack (TIA) or ischemic stroke, and admission due to worsened heart failure were recorded., Results: Based on up to 7.7 (6.8-8.3) years of follow-up and 768,306 person-years, there were 12,241 cases of new-onset AF identified. Among patients with new-onset AF (40.0% females, median age 63.0 [54.0-70.0] years), the polypharmacy prevalence was 30.9% (3784). For newly diagnosed AF, factors, such as advanced age (with each increase of 10 years, odds ratios (OR) 1.32, 95% confidence interval (CI) 1.26-1.40), hypertension (OR 4.00, 95% CI 3.62-4.43), diabetes mellitus (OR 3.25, 95% CI 2.86-3.70), chronic obstructive pulmonary disease (COPD) (OR 3.00, 95% CI 2.51-3.57), TIA/ischemic stroke (OR 2.36, 95% CI 2.03-2.73), dementia history (OR 2.30, 95% CI 1.06-4.98), end-stage renal disease (ESRD) or chronic kidney disease (CKD) (OR 1.97, 95% CI 1.38-2.82), and heart failure (OR 1.95, 95% CI 1.69-2.26), were found to be independently correlated with the incidence of polypharmacy. Polypharmacy significantly increased the incidence and risk of major bleeding (adjusted hazard ratio (aHR) 1.26, 95% CI 1.12-1.41). The study observed a statistically significant increase in the incidence of all-cause mortality, however, the risk for all-cause mortality elevated but did not show significance (aHR 1.11, 95% CI 0.99-1.24). The risk of stroke and admission for heart failure did not change with polypharmacy., Conclusions: In our investigation using data from a nationwide database, polypharmacy was widespread in new-onset AF population and was related to major bleeding events. However, polypharmacy does not serve as an independent risk factor for adverse outcomes, with exception of major bleeding event. For AF patients, ensuring tailored medication for comorbidities as well as reducing polypharmacy are essential considerations., Competing Interests: The authors declare no conflict of interest. Boyoung Joung is serving as one of the Editorial Board members of this journal. We declare that Boyoung Joung had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Vladimir M. Pokrovskii and Buddhadeb Dawn. BYJ has been a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi-Sankyo and has received research funds from Medtronic and Abbott. No fees were received, either directly or personally. The remaining authors have no other relationships or activities that could appear to have influenced the submitted work., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: A study was designed to investigate whether the coronary artery disease polygenic risk score (CAD-PRS) may guide lipid-lowering treatment initiation as well as deferral in primary prevention beyond established clinical risk scores., Methods and Results: Participants were 311 799 individuals from the UK Biobank free of atherosclerotic cardiovascular disease, diabetes, chronic kidney disease, and lipid-lowering treatment at baseline. Participants were categorized as statin indicated, statin indication unclear, or statin not indicated as defined by the European and US guidelines on statin use. For a median of 11.9 (11.2-12.6) years, 8196 major coronary events developed. CAD-PRS added to European-Systematic Coronary Risk Evaluation 2 (European-SCORE2) and US-Pooled Cohort Equation (US-PCE) identified 18% and 12% of statin-indication-unclear individuals whose risk of major coronary events were the same as or higher than the average risk of statin-indicated individuals and 16% and 12% of statin-indicated individuals whose major coronary event risks were the same as or lower than the average risk of statin-indication-unclear individuals. For major coronary and atherosclerotic cardiovascular disease events, CAD-PRS improved C-statistics greater among statin-indicated or statin-indication-unclear than statin-not-indicated individuals. For atherosclerotic cardiovascular disease events, CAD-PRS added to the European evaluation and US equation resulted in a net reclassification improvement of 13.6% (95% CI, 11.8-15.5) and 14.7% (95% CI, 13.1-16.3) among statin-indicated, 10.8% (95% CI, 9.6-12.0) and 15.3% (95% CI, 13.2-17.5) among statin-indication-unclear, and 0.9% (95% CI, 0.6-1.3) and 3.6% (95% CI, 3.0-4.2) among statin-not-indicated individuals., Conclusions: CAD-PRS may guide statin initiation as well as deferral among statin-indication-unclear or statin-indicated individuals as defined by the European and US guidelines. CAD-PRS had little clinical utility among statin-not-indicated individuals.

Background: Both anticoagulation and antiplatelet therapies are recommended after percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF). Although contemporary guidelines recommend discontinuation of antiplatelet therapy 1 year after drug-eluting stent (DES) implantation due to excessive bleeding risk, supporting randomized trials are still lacking., Methods: The ADAPT AF-DES trial is a multicenter, prospective, open-label, randomized, non-inferiority trial, enrolling 960 patients with AF with a CHA 2 DS 2 -VASc score > 1, who underwent PCI with DES implantation at least 12 months before enrollment. Eligible patients are randomly assigned to receive either non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy or NOAC plus clopidogrel combination therapy. The primary outcome is net adverse clinical event (NACE) at 1 year after randomization, defined as a composite of all-cause death, myocardial infarction, stent thrombosis, stroke, systemic embolism, and major or clinically relevant non-major bleeding, as defined by the International Society on Thrombosis and Hemostasis criteria. We hypothesize that NOAC monotherapy would be non-inferior to NOAC plus clopidogrel combination therapy for NACE in patients with AF beyond 12 months after DES implantation., Conclusions: The ADAPT AF-DES trial will evaluate the efficacy and safety of NOAC monotherapy versus NOAC plus clopidogrel combination therapy in patients with AF beyond 12 months after PCI with DES implantation. The ADAPT AF-DES trial will provide robust evidence for an optimal antithrombotic strategy in patients with AF after DES implantation., Clinical Trial Registration: https://www., Clinicaltrials: gov. Unique identifier: NCT04250116., Competing Interests: Disclosure J-SK reported receiving grants from Samjin Pharmaceutical and speaker's fees from Abbott Vascular., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3β, the elevated PAX6 in turn inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3β and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments., (© 2024. The Author(s).)

Background and Objective: The effects of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) on right ventricular (RV) function are not well known., Methods: Patients who underwent RFCA for AF and underwent pre- and post-procedural echocardiography were enrolled consecutively. Fractional area change (FAC), RV free-wall longitudinal strain (RVFWSL), and RV 4-chamber strain including the ventricular septum (RV4CSL) were measured. Changes in FAC, RVFWSL, and RV4CSL before and after RFCA were compared among paroxysmal AF (PAF), persistent AF (PeAF), and long-standing persistent AF (LSPeAF) groups., Results: A total of 164 participants (74 PAF, 47 PeAF, and 43 LSPeAF; age, 60.8 ± 9.8 years; men, 74.4%) was enrolled. The patients with PeAF and LSPeAF had worse RV4CSL (p<0.001) and RVFWSL (p<0.001) than those with PAF and reference values. Improvements in RVFWSL and RV4CSL after RFCA were significant in the PeAF group compared with the PAF and LSPeAF groups (ΔRV4CSL, 8.4% [5.1, 11.6] in PeAF vs. 1.0% [-1.0, 4.1] in PAF, 1.9% [-0.2, 4.4] in LSPeAF, p<0.001; ΔRVFWSL, 9.0% [6.9, 11.5] in PeAF vs. 0.9% [-1.4, 4.9] in PAF, 1.0% [-1.0, 3.6] in LSPeAF, p<0.001). In patients without recurrence, improvements in RVFWSL and RV4CSL after RFCA were significant in the PeAF group compared to the LSPeAF group., Conclusions: RV systolic function is more impaired in patients with PeAF and LSPeAF than in those with PAF. RV systolic function is more improved after RFCA in patients with PeAF than in those with PAF or LSPeAF., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2024. The Korean Society of Cardiology.)