Effects of Dietary Protein Intake Levels on Peripheral Circadian Rhythm in Mice.

The regulation of the circadian clock plays an important role in influencing physiological conditions. While it is reported that the timing and quantity of energy intake impact circadian regulation, the underlying mechanisms remain unclear. This study investigated the impact of dietary protein intake on peripheral clocks. Firstly, transcriptomic analysis was conducted to investigate molecular targets of low-protein intake. Secondly, mPer2::Luc knock-in mice, fed with either a low-protein, normal, or high-protein diet for 6 weeks, were analyzed for the oscillation of PER2 expression in peripheral tissues and for the expression profiles of circadian and metabolic genes. Lastly, the candidate pathway identified by the in vivo analysis was validated using AML12 cells. As a result, using transcriptomic analysis, we found that the low-protein diet hardly altered the circadian rhythm in the central clock. In animal experiments, expression levels and period lengths of PER2 were different in peripheral tissues depending on dietary protein intake; moreover, mRNA levels of clock-controlled genes and endoplasmic reticulum (ER) stress genes were affected by dietary protein intake. Induction of ER stress in AML12 cells caused an increased amplitude of Clock and Bmal1 and an advanced peak phase of Per2. This result shows that the intake of different dietary protein ratios causes an alteration of the circadian rhythm, especially in the peripheral clock of mice. Dietary protein intake modifies the oscillation of ER stress genes, which may play key roles in the regulation of the circadian clock.

Long-term clinical outcomes of image-guided percutaneous coronary intervention in acute myocardial infarction from the Korea Acute Myocardial Infarction Registry.

Imaging modalities for percutaneous coronary intervention (PCI), such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), have increased in the current PCI era. However, their clinical benefits in acute myocardial infarction (AMI) have not been fully elucidated. This study investigated the long-term outcomes of image-guided PCI in patients with AMI using data from the Korean Acute Myocardial Infarction Registry. A total of 9,271 patients with AMI, who underwent PCI with second-generation drug-eluting stents between November 2011 and December 2015, were retrospectively examined, and target lesion failure (TLF) at 3 years (defined as the composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) was evaluated. From the registry, 2,134 patients (23.0%) underwent image-guided PCI (IVUS-guided: n = 1,919 [20.6%]; OCT-guided: n = 215 patients [2.3%]). Based on propensity score matching, image-guided PCI was associated with a significant reduction in TLF (hazard ratio: 0.76; 95% confidence interval: 0.59-0.98, p = 0.035). In addition, the TLF incidence in the OCT-guided PCI group was comparable to that in the IVUS-guided PCI group (5.3% vs 4.7%, p = 0.903). Image-guided PCI, including IVUS and OCT, is associated with favorable clinical outcomes in patients with AMI at 3 years post-intervention. Additionally, OCT-guided PCI is not inferior to IVUS-guided PCI in patients with AMI.

Screening and diagnosis of atrial fibrillation using wearable devices.

In recent years, the development and use of various devices for the screening of atrial fibrillation (AF) have significantly increased. Such devices include 12-lead electrocardiogram (ECG), photoplethysmography systems, and single-lead ECG and ECG patches. This review outlines several studies that have focused on the feasibility and efficacy of such devices for AF screening, and summarizes the risks and benefits involved in the initiation of anticoagulant therapy after early detection of AF. We also describe several ongoing trials on unresolved issues associated with AF screening. Overall, this review provides a comprehensive summary of the current state of AF screening and its implications for patient care.

H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2.

RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.

Factors associated with clinical nurses' preconception health behavior in Korea: a cross-sectional survey.

PURPOSE: Nurses have been reported to be at an increased risk for miscarriage and preterm labor. However, there is limited knowledge regarding nurses' preconception health behaviors. Therefore, this study aimed to identify factors influencing these behaviors. METHODS: One hundred sixty nurses, who were planning their first pregnancy within the upcoming year, participated in an online survey from August 11 to October 31, 2021. Data on preconception health behavior, perceived health status, pregnancy anxiety, nursing practice environment, and social support were analyzed using the t-test, Pearson correlation coefficients, and multiple regression analysis. RESULTS: Age (р=.024), educational level (р=.010), marital status (р=.003), work experience (р=.003), satisfaction with the work department (р<.001), smoking status (р=. 039), and previous health problems related to pregnancy outcomes (р=.004) were significantly associated with nurses' preconception health behaviors. Furthermore, perceived health status (р<.001), pregnancy anxiety (р=.011), nursing practice environment (р=.003), and social support (р<.001) showed significant correlations with preconception health behaviors. Social support (ß=. 28, р=.001), satisfaction with the work department (ß=.23, р=.032), marital status (ß=.22, р=.002), and perceived health status (ß=.23, р=.002) were confirmed as factors associated with preconception health behaviors. These factors explained 40.9% of the variance in preconception health behaviors (F=6.64, р<.001). CONCLUSION: Clinical nurses' preconception health behaviors were influenced by social support, perceived health status, satisfaction with the work department, and marital status. Interventions to improve clinical nurses' preconception health behaviors should target social support and perceived health status. A preconception health behavior education program considering clinical nurses' marital status and satisfaction with the workplace can also be implemented.

Associations of meal timing and sleep duration with incidence of obesity: a prospective cohort study.

OBJECTIVES: Late mealtime and short sleep are known to be associated with obesity risk due to a misaligned circadian rhythm. This study aimed to investigate the relationship between obesity and mealtime and sleep duration using the Korean Genome and Epidemiology Study (KoGES) data. DESIGN: Longitudinally prospective cohort study. SETTING: Population-based. PARTICIPANTS: KoGES analysed data from 9,474 Korean adults with an average age of 54- years old at baseline. MEASUREMENTS: Meal timing was defined as the eating occasions of the day reported by the participant eating a 24-h dietary recall method. Sleep duration was categorized as <6, 6-7, 7-8, and ≥8 h. The Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident obesity according to meal timing, sleep duration, and nightly fasting duration. RESULTS: During a mean follow-up of 3.5 years, 826 participants developed obesity. In the multivariable-adjusted analysis, midnight snack eating (HR, 1.20; 95% CI, 1.02-1.41) and higher energy intake from midnight snacks (HR, 1.26; 95% CI, 1.06-1.49) were associated with a higher risk of obesity. Sleeping 8 h or more (HR, 0.67; 95% CI, 0.53-0.85) was associated with a lower risk of obesity. CONCLUSIONS: Our findings highlight the importance of meal and sleep times and suggest that healthy eating habits related to the time of day.

Anti-obesity effect of butyrate links to modulation of gut microbiome and epigenetic regulation of muscular circadian clock.

The role of the muscle circadian clock in regulating oxidative metabolism exerts a significant influence on whole-body energy metabolism; however, research on the connection between the muscle circadian clock and obesity is limited. Moreover, there is a lack of studies demonstrating the regulatory effects of dietary butyrate on muscle circadian clock and the resulting antiobesity effects. This study aimed to investigate the impacts of dietary butyrate on metabolic and microbiome alterations and muscle circadian clock in a diet-induced obesity model. Male Sprague-Dawley rats were fed a high-fat diet with or without butyrate. Gut microbiota and serum metabolome were analyzed, and molecular changes were examined using tissues and a cell line. Further correlation analysis was performed on butyrate-induced results. Butyrate supplementation reduced weight gain, even with increased food intake. Gut microbiome analysis revealed an increased abundance of Firmicutes in butyrate group. Serum metabolite profile in butyrate group exhibited reduced amino acid and increased fatty acid content. Muscle circadian clock genes were upregulated, resulting in increased transcription of fatty acid oxidation-related genes. In myoblast cells, butyrate also enhanced pan-histone acetylation via histone deacetylase inhibition, particularly modulating acetylation at the promoter of circadian clock genes. Correlation analysis revealed potential links between Firmicutes phylum, including certain genera within it, and butyrate-induced molecular changes in muscle as well as phenotypic alterations. The butyrate-driven effects on diet-induced obesity were associated with alterations in gut microbiota and a muscle-specific increase in histone acetylation, leading to the transcriptional activation of circadian clock genes and their controlled genes.

Function of NAD metabolism in white adipose tissue: lessons from mouse models.

Nicotinamide Adenine Dinucleotide (NAD) is an endogenous substance in redox reactions and regulates various functions in metabolism. NAD and its precursors are known for their anti-ageing and anti-obesity properties and are mainly active in the liver and muscle. Boosting NAD+ through supplementation with the precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), enhances insulin sensitivity and circadian rhythm in the liver, and improves mitochondrial function in the muscle. Recent evidence has revealed that the adipose tissue could be another direct target of NAD supplementation by attenuating inflammation and fat accumulation. Moreover, murine studies with genetically modified models demonstrated that nicotinamide phosphoribosyltransferase (NAMPT), a NAD regulatory enzyme that synthesizes NMN, played a critical role in lipogenesis and lipolysis in an adipocyte-specific manner. The tissue-specific effects of NAD+ metabolic pathways indicate a potential of the NAD precursors to control metabolic stress particularly via focusing on adipose tissue. Therefore, this narrative review raises an importance of NAD metabolism in white adipose tissue (WAT) through a variety of studies using different mouse models.

Protein Restriction in Metabolic Health: Lessons from Rodent Models.

Consumption of protein-rich diets and supplements has been increasingly advocated by individuals seeking to optimize metabolic health and mitigate the effects of aging. Protein intake is postulated to support muscle mass retention and enhance longevity, underscoring its perceived benefits in age-related metabolic regulation. However, emerging evidence presents a paradox; while moderate protein consumption contributes to health maintenance, an excessive intake is associated with an elevated risk of chronic diseases, notably obesity and diabetes. Furthermore, recent studies suggest that reducing the ratio of protein intake to macronutrients improves metabolic parameters and extends lifespan. The aim of this study is to review the current evidence concerning the metabolic effects of protein-restricted diets and their potential mechanisms. Utilizing rodent models, investigations have revealed that protein-restricted diets exert a notable influence over food intake and energy consumption, ultimately leading to body weight loss, depending on the degree of dietary protein restriction. These phenotypic alterations are primarily mediated by the FGF21 signaling pathway, whose activation is likely regulated by ATF4 and the circadian clock. The evidence suggests that protein-restricted diets as an alternative approach to calorie-restricted regimes, particularly in overweight or obese adults. However, more research is needed to determine the optimal level of restriction, duration, and long-term effects of such interventions.

The Associations between Intakes of One-Carbon Metabolism-Related Vitamins and Breast Density among Young Women.

BACKGROUND: Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism-related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer. METHODS: Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years. RESULTS: Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04). CONCLUSIONS: Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings. IMPACT: Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.

Short-Term Effects of Weight-Loss Meal Replacement Programs with Various Macronutrient Distributions on Gut Microbiome and Metabolic Parameters: A Pilot Study.

It has emerged the gut microbiome is crucially linked to metabolic health and obesity. Macronutrient distribution has been discussed as a key parameter in weight-loss programs, but little is known about its impact on the gut microbiome. We investigated the effects of weight-loss meal replacement programs with different macronutrient ratios on the gut microbiota and metabolic parameters in subjects with overweight and obesity. Three low-calorie meal replacement programs with different ratios of carbohydrates, proteins, and lipids were designed: a balanced diet (Group B, 60:15:30), a high-lipid-low-carbohydrate diet (Group F, 35:20:55), and a protein-enriched diet (Group P, 40:25:35). Sixty overweight or obese participants were provided with the meals twice daily for 3 weeks. In all groups, diet intervention resulted in reduced body weight and BMI. The relative abundance of Bacteroidetes and Firmicutes phyla decreased and increased, respectively, which increased the Firmicutes/Bacteroidetes (F/B) ratio in all subjects, particularly in Groups B and P. Alpha- and beta-diversity were augmented at the phylum level in Group P. In conclusion, short-term interventions with weight-loss meal replacement programs increased butyrate-producing bacteria and the F/B ratio. Moreover, the protein-enriched diet significantly increased alpha- and beta-diversity compared to the balanced diet and the high-lipid-low-carbohydrate diet.

Impact of Positron Emission Tomography Viability Imaging: Guided Revascularizations on Clinical Outcomes in Patients With Myocardial Scar on Single-Photon Emission Computed Tomography Scans.

BACKGROUND: Positron emission tomography (PET) viability scan is used to determine whether patients with a myocardial scar on single-photon emission computed tomography (SPECT) may need revascularization. However, the clinical utility of revascularization decision-making guided by PET viability imaging has not been proven yet. The purpose of this study was to investigate the impact of PET to determine revascularization on clinical outcomes. METHODS: Between September 2012 and May 2021, 53 patients (37 males; mean age = 64 ± 11 years) with a myocardial scar on MIBI SPECT who underwent PET viability test were analyzed in this study. The primary outcome was a temporal change in echocardiographic findings. The secondary outcome was all-cause mortality. RESULTS: Viable myocardium was presented by PET imaging in 29 (54.7%) patients. Revascularization was performed in 26 (49.1%) patients, including 18 (34.0%) with percutaneous coronary intervention (PCI) and 8 (15.1%) with coronary artery bypass grafting. There were significant improvements in echocardiographic findings in the revascularization group and the viable myocardium group. All-cause mortality was significantly lower in the revascularization group than in the medical therapy-alone group (19.2% vs. 44.4%, log-rank P = 0.002) irrespective of viable (21.4% vs. 46.7%, log-rank P = 0.025) or non-viable myocardium (16.7% vs. 41.7%, log-rank P = 0.046). All-cause mortality was significantly lower in the PCI group than in the medical therapy-alone group (11.1% vs. 44.4%, log-rank P < 0.001). CONCLUSION: Revascularization improved left ventricular systolic function and survival of patients with a myocardial scar on SPECT scans, irrespective of myocardial viability on PET scans.

Long-term impact of angiotensin receptor-neprilysin inhibitor based on short-term treatment response in heart failure.

AIMS: The long-term effect of angiotensin receptor-neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment. METHODS AND RESULTS: The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow-up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all-cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow-up (median follow-up, 44 [interquartile range, 34-51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. CONCLUSIONS: Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.

Association between use of vitamin and mineral supplement and non-alcoholic fatty liver disease in hypertensive adults.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder in hypertensive adults. Impaired metabolism of micronutrients may increase NAFLD risk by exacerbating oxidative stress, insulin resistance, and inflammation among hypertensive adults. In this first cross-sectional analysis of 7,376 hypertensive adults with 2,015 NAFLD cases in the Korea National Health and Nutrition Examination Survey, vitamin and mineral supplements (VMS) use was identified via questionnaire. NAFLD was defined by a hepatic steatosis index > 36. Multivariable-adjusted odds ratios (MVOR) and 95% confidence intervals (CIs) were calculated using logistic regression models. In our study, 18.6% were current users of VMS; of these, 76.7% used multi-vitamin/mineral supplements. Current VMS users had significantly lower odds of NAFLD, compared with non-users (MVOR [95% CI]: 0.73 [0.58-0.92]). The inverse association became attenuated and non-significant among those consuming VMS at higher frequency (≥ 2 times/day), for longer duration (> 16 months), and taking ≥ 2 VMS products. The inverse association with current use of VMS was only evident in those aged < 56 years (MVOR [95% CI]: 0.54 [0.40-0.72]) and men (MVOR [95% CI]: 0.56 [0.40-0.80])(Pinteraction ≤ 0.04). Our results suggest that VMS use may lower NAFLD risk, particularly among younger or male hypertensive adults, if taken in moderation.

Meal-Based Intervention on Health Promotion in Middle-Aged Women: A Pilot Study.

Middle-aged women belong to a risk group for metabolic dysregulation and menopausal symptoms, mainly due to a dramatic hormonal shift. Supplementation with functional compounds or a single nutrient has been dominantly explored as a nutritional approach for improving aging-related health parameters. However, a meal-based approach might be another strategy for promoting the overall health of the target population. This pilot study aimed to develop a meal-based intervention for middle-aged women and to evaluate its potential health benefits. Considering the nutrient intake status of Korean middle-aged women, diets enriched with four major nutrients (isoflavone, omega-3, fiber, and calcium) were designed and provided to forty-nine women aged 50 to 65 with mild levels of menopausal symptoms for 8 weeks. In the post-intervention phase, they showed reduced body weight and body fat, and improved biochemical metabolic parameters with decreased levels of cholesterol, low-density lipoprotein-cholesterol, ApoB, and fasting insulin. Moreover, bone resorption markers and menopause symptoms were lower in the post-intervention phase. In conclusion, the meal-based intervention might be a prominent strategy for overall health promotion in relatively healthy middle-aged women and further investigation is needed to test its efficacy with a randomized controlled study.

Association of NAFLD with FGF21 Polygenic Hazard Score, and Its Interaction with Protein Intake Level in Korean Adults.

Fibroblast growth factor 21 (FGF21) is a hormone that participates in the regulation of energy homeostasis and is induced by dietary protein restriction. Preclinical studies have suggested that FGF21 induction exerts a protective effect against non-alcoholic fatty liver disease (NAFLD), while human studies have revealed elevated levels of and potential resistance to FGF21 in patients with NAFLD. However, whether the FGF21 pathway also contributes to NAFLD risk at the genetic level remains uncertain. A few attempts to investigate the impact of individual genetic variants at the loci encoding FGF21 and its receptors on NAFLD risk have failed to establish a clear association due to a limited effect size. Therefore, this study aimed to (1) develop a polygenic hazard score (PHS) for FGF21-related loci that are associated with NAFLD risk and (2) investigate the effect of its interaction with protein intake level on NAFLD risk. Data on 3501 participants of the Korean Genome Epidemiology Study (Ansan-Ansung) were analyzed. Eight single-nucleotide polymorphisms of fibroblast growth factor receptors and beta-klotho were selected for PHS determination using forward stepwise analysis. The association between the PHS and NAFLD was validated (p-trend: 0.0171 for men and <0.0001 for women). Moreover, the association was significantly modulated by the protein intake level in all participants as well as women (p-interaction = 0.0189 and 0.0131, respectively) but not in men. In particular, the women with the lowest PHS values and a protein intake lower than the recommended nutrient intake (RNI) exhibited a greater NAFLD risk (HR = 2.021, p-trend = 0.0016) than those with an intake equal to or greater than the RNI; however, those with higher PHS values had a high risk, regardless of protein intake level. These findings demonstrate the contribution of FGF21-related genetic variants and restricted protein intake to NAFLD incidence.

Associations of Food Insecurity with Dietary Inflammatory Potential and Risk of Low Muscle Strength.

Food insecurity refers to the uncertain availability of or limited access to nutritious food. Poor diets prevalent among food insecure populations may incite an inflammatory state and subsequently negatively affect skeletal muscle metabolism. To examine the inflammatory mechanistic potential of the association between food insecurity and the risk of low muscle strength, we analyzed cross-sectional data from 8624 adults aged ≥20 years from the Korean National Health and Nutrition Examination Survey 2014-2015. Household food security status was assessed using an 18-item food security survey module. The inflammatory potential of diets was estimated by the dietary inflammation index (DII). Low muscle strength was ascertained using hand grip strength. In the multivariable-adjusted model, greater food insecurity was significantly associated with a higher DII score and risk of low muscle strength. The multivariable-adjusted mean difference (95% confidence interval) on the DII, comparing the "moderate-to-severe" food insecurity group with the "food secure" group, was 0.43 (0.06-0.80) (P-trend: <0.001) and the odds ratio (95% confidence intervals) of low muscle strength for the same comparison groups was 2.06 (1.07-3.96) (P-trend: 0.005). Our results suggest that individuals with greater food insecurity may be susceptible to diets with greater inflammatory potential, which may contribute to a loss of muscle strength.

Predictors of stroke or systemic embolism in patients with non-valvular atrial fibrillation with CHA2 DS2 -VASc score of 0.

BACKGROUND: Anticoagulant therapy has been important for stroke prevention in patients with atrial fibrillation (AF). However, it was not recommended due to its relatively higher risk of bleeding than its lower risk of stroke in patients with a CHA2 DS2 -VASc score of 0. HYPOTHESIS: This study aimed to evaluate the predictors of stroke in AF patients with very low risk of stroke. METHODS: Between 1990 and 2020, 542 patients with non-valvular AF (NVAF) with a CHA2 DS2 -VASc score of 0 followed up for at least 6 months were enrolled. Patients with only being woman as a risk factor were included as a CHA2 DS2 -VASc score of 0 in this study. The primary outcome was stroke or systemic embolism. RESULTS: The primary outcome rate was 0.78%/year. In Cox hazard model, age of ≥50 years at diagnosis (hazard ratio [HR] 6.710, 95% confidence interval [CI] 1.811-24.860, p = .004), LVEDD of ≥46 mm (HR 4.513, 95% CI 1.038-19.626, p = .045), and non-paroxysmal AF (HR 5.575, 95% CI 1.621-19.175, p = .006) were identified as independent predictors of stroke or systemic embolism. Patients with all three independent predictors had a higher risk of stroke or systemic embolism (4.21%/year), whereas those without did not have a stroke or systemic embolism. CONCLUSION: The annual stroke or systemic embolism rate in NVAF patients with CHA2 DS2 -VASc score of 0 was 0.78%/year, and age at AF diagnosis, LVEDD, and non-paroxysmal AF were independent predictors of stroke or systemic embolism in patients considered to have a very low risk of stroke.