Artificial Intelligence-Enabled Quantitative Coronary Plaque and Hemodynamic Analysis for Predicting Acute Coronary Syndrome.

BACKGROUND: A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization. OBJECTIVES: This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA). METHODS: Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort. RESULTS: Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA. CONCLUSIONS: AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328).

Impact of clonal haematopoiesis on atherosclerotic cardiovascular disease according to low-density lipoprotein cholesterol levels in general population.

AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the precise role of CHIP in the development of atherosclerotic cardiovascular disease (ASCVD) remains unclear. METHODS: Among 4,300 asymptomatic Korean participants aged 40-79 years, we investigated the risk of ASCVD by CHIP and the interplay between CHIP and conventional risk factors in ASCVD development. Additionally, we assessed changes in coronary arteries based on the presence of CHIP using coronary computed tomography angiography (CCTA). RESULTS: CHIP was present in 363 participants (8.4%), and its prevalence increased with age. Commonly mutated genes were DNMT3A, TET2 and ASXL1, in order. During follow-up (median, 4.7 years), 18 ASCVD cases (5.0%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (p < 0.001), indicating an elevated risk of ASCVD associated with CHIP (adjusted HR 2.49, 95% CI 1.45-4.29, p < 0.001). Notably, with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD (adjusted HR 6.20, 95% CI 3.14-12.23, p < 0.001), demonstrating synergism between CHIP and LDL cholesterol levels (S-index, 4.94; 95% CI 1.08-22.53, p = 0.039). Serial CCTAs confirmed that CHIP, in conjunction with high LDL cholesterol levels, had significant early impact on coronary arteries, revealing new measurable coronary atherosclerosis, mainly with unstable plaque, in proximal lesions. CONCLUSIONS: The presence of CHIP was significantly associated with the risk of ASCVD, promoting the early stage of atherosclerosis through synergy with high LDL cholesterol in the general population.

In this cohort study of 4,300 asymptomatic community-dwelling Korean adults, we demonstrated a detailed interplay between clonal haematopoiesis of indeterminate potential (CHIP) and conventional risk factors in the development of atherosclerotic cardiovascular disease (ASCVD).The presence of CHIP significantly increased the risk of ASCVD in the general population, displaying a notable synergistic effect with high levels of low-density lipoprotein (LDL) cholesterol.Analyses of serial coronary computed tomography angiography scans revealed that CHIP, in conjunction with high LDL cholesterol levels, may contribute to the promotion of "early" stage in coronary atherosclerosis, providing new insights into CHIP-associated atherosclerosis in the primary prevention.

Association between Cumulative Metabolic Risk Exposure and Cardiovascular Disease: A Nationwide Cohort of Over 3.6 Million Young Adults.

AIMS: Since lifetime accumulation of cardiovascular risk factors is getting important, early identification and management of risk factors are emphasised. The global prevalence of metabolic syndrome (MetS), a constellation of these risk factors, is increasing, particularly among young adults. We aimed to investigate the association between cumulative exposure to metabolic risk and cardiovascular disease (CVD) in young adults. METHODS: In this nationwide population-based cohort, we analysed 3,688,787 young adults (<40 years) with two biennial National Health Screening examinations from 2009 to 2012. Participants were categorised into MetS-free, MetS-developed, MetS-recovered, or MetS-persistent group, based on MetS presence at each examination. The endpoint was new CVD development, including myocardial infarction (MI), and ischaemic stroke. RESULTS: During follow-up (median, 7.7 years), CVD occurred in 19,219 individuals (0.5%). CVD incidence rates were 0.58, 1.17, 1.20, and 1.83 (1,000 person-year) in the MetS-free, MetS-developed, MetS-recovered, and MetS-persistent groups, respectively. CVD risk was proportionally associated with cumulative metabolic risk exposure, with a maximum 2-fold increase in the MetS-persistent group (aHR 1.94, 95% CI 1.84-2.04), and followed by the MetS-recovered and MetS-developed groups with similar risks. Among the MetS components, persistent exposure to elevated blood pressure (BP) had the greatest association with CVD risk (aHR 1.69, 95% CI 1.63-1.76). This tendency was consistent in the analyses of the risk of MI and ischaemic stroke. CONCLUSIONS: CVD risk increased in an exposure-dependent manner among young adults. Efforts to optimise cardiometabolic profile, particularly BP, even after the establishment of MetS, might help promote long-term cardiovascular prognosis.

In this large-scale nationwide cohort comprising 3,688,787 asymptomatic young adults under 40 years, we showed that the long-term risk of cardiovascular disease (CVD) increased in proportion with cumulative exposure to metabolic risk, as assessed by the temporal changes in metabolic syndrome (MetS) status, with blood pressure (BP) demonstrating the greatest impact. The risk of CVD exhibited a gradual increase in accordance with cumulative metabolic risk exposure, with a 2-fold increment in the MetS-persistent group. Among the MetS components, persistent exposure to elevated BP had the most profound impact to increase the risk of CVD, and the optimisation of BP levels might be helpful to promote long-term cardiovascular health in young adults.

Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.

BACKGROUND AND AIMS: Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. METHODS: Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort. RESULTS: The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). CONCLUSIONS: CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.

Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

The effect of non-optimal lipids on the progression of coronary artery calcification in statin-naïve young adults: results from KOICA registry.

Background: Despite the importance of attaining optimal lipid levels from a young age to secure long-term cardiovascular health, the detailed impact of non-optimal lipid levels in young adults on coronary artery calcification (CAC) is not fully explored. We sought to investigate the risk of CAC progression as per lipid profiles and to demonstrate lipid optimality in young adults. Methods: From the KOrea Initiative on Coronary Artery calcification (KOICA) registry that was established in six large volume healthcare centers in Korea, 2,940 statin-naïve participants aged 20-45 years who underwent serial coronary calcium scans for routine health check-ups between 2002 and 2017 were included. The study outcome was CAC progression, which was assessed by the square root method. The risk of CAC progression was analyzed according to the lipid optimality and each lipid parameter. Results: In this retrospective cohort (mean age, 41.3 years; men 82.4%), 477 participants (16.2%) had an optimal lipid profile, defined as triglycerides <150 mg/dl, LDL cholesterol <100 mg/dl, and HDL cholesterol >60 mg/dl. During follow-up (median, 39.7 months), CAC progression was observed in 434 participants (14.8%), and more frequent in the non-optimal lipid group (16.5% vs. 5.7%; p < 0.001). Non-optimal lipids independently increased the risk of CAC progression [adjusted hazard ratio (aHR), 1.97; p = 0.025], in a dose-dependent manner. Even in relatively low-risk participants with an initial calcium score of zero (aHR, 2.13; p = 0.014), in their 20 s or 30 s (aHR 2.15; p = 0.041), and without other risk factors (aHR 1.45; p = 0.038), similar results were demonstrable. High triglycerides had the greatest impact on CAC progression in this young adult population. Conclusion: Non-optimal lipid levels were significantly associated with the risk of CAC progression in young adults, even at low-risk. Screening and intervention for non-optimal lipid levels, particularly triglycerides, from an early age might be of clinical value.

Clonal hematopoiesis as a novel risk factor for type 2 diabetes mellitus in patients with hypercholesterolemia.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with atherosclerosis and cardiovascular disease. It has been suggested that CHIP may be related to diabetes, so we investigated the association between CHIP and new-onset type 2 diabetes. Methods: This study included 4,047 subjects aged >=40 years without diabetes. To detect CHIP, targeted gene sequencing of genomic DNA from peripheral blood cells was performed. The incidence of new-onset type 2 diabetes during the follow-up period was evaluated. Results: Of the total subjects, 635 (15.7%) had CHIP. During the median follow-up of 5.1 years, the incidence of new-onset diabetes was significantly higher in CHIP carriers than in subjects without CHIP (11.8% vs. 9.1%, p = 0.039). In a univariate analysis, CHIP significantly increased the risk of new-onset diabetes (HR 1.32, 95% CI 1.02-1.70, p = 0.034), but in a multivariate analysis, it was not significant. The CHIP-related risk of new onset diabetes differed according to LDL cholesterol level. In the hyper-LDL cholesterolemia group, CHIP significantly increased the risk of diabetes (HR 1.64, 95% CI 1.09-2.47, p = 0.018), but it did not increase the risk in the non-hyper-LDL cholesterolemia group. The subjects with CHIP and hyper-LDL-cholesterolemia had approximately twice the risk of diabetes than subjects without CHIP and with low LDL cholesterol (HR 2.05, 95% CI 1.40-3.00, p < 0.001). Conclusion: The presence of CHIP was a significant risk factor for new-onset type 2 diabetes, especially in subjects with high LDL cholesterol. These results show the synergism between CHIP and high LDL cholesterol as a high-risk factor for diabetes.

Deep learning-based prediction for significant coronary artery stenosis on coronary computed tomography angiography in asymptomatic populations.

Background: Although coronary computed tomography angiography (CCTA) is currently utilized as the frontline test to accurately diagnose coronary artery disease (CAD) in clinical practice, there are still debates regarding its use as a screening tool for the asymptomatic population. Using deep learning (DL), we sought to develop a prediction model for significant coronary artery stenosis on CCTA and identify the individuals who would benefit from undergoing CCTA among apparently healthy asymptomatic adults. Methods: We retrospectively reviewed 11,180 individuals who underwent CCTA as part of routine health check-ups between 2012 and 2019. The main outcome was the presence of coronary artery stenosis of ≥70% on CCTA. We developed a prediction model using machine learning (ML), including DL. Its performance was compared with pretest probabilities, including the pooled cohort equation (PCE), CAD consortium, and updated Diamond-Forrester (UDF) scores. Results: In the cohort of 11,180 apparently healthy asymptomatic individuals (mean age 56.1 years; men 69.8%), 516 (4.6%) presented with significant coronary artery stenosis on CCTA. Among the ML methods employed, a neural network with multi-task learning (19 selected features), one of the DL methods, was selected due to its superior performance, with an area under the curve (AUC) of 0.782 and a high diagnostic accuracy of 71.6%. Our DL-based model demonstrated a better prediction than the PCE (AUC, 0.719), CAD consortium score (AUC, 0.696), and UDF score (AUC, 0.705). Age, sex, HbA1c, and HDL cholesterol were highly ranked features. Personal education and monthly income levels were also included as important features of the model. Conclusion: We successfully developed the neural network with multi-task learning for the detection of CCTA-derived stenosis of ≥70% in asymptomatic populations. Our findings suggest that this model may provide more precise indications for the use of CCTA as a screening tool to identify individuals at a higher risk, even in asymptomatic populations, in clinical practice.

The role of retinal vessel geometry as an indicator of systemic arterial stiffness assessed by cardio-ankle vascular index.

Objective: To determine whether retinal vessel geometry is associated with systemic arterial stiffness, as determined by the cardio-ankle vascular index (CAVI). Methods: This single-center retrospective cross-sectional study included 407 eyes of 407 subjects who underwent routine health exams, including CAVI and fundus photography. Retinal vessel geometry was measured using a computer-assisted program (Singapore "I" Vessel Assessment). Subjects were classified into two groups based on CAVI values: high CAVI (≥9) or low CAVI (<9). The main outcome measures included the association of retinal vessel geometry and CAVI value evaluated using multivariable logistic regression models. Results: Three hundred forty-three subjects (343, 84.3%) were in the low CAVI group, and 64 (15.7%) subjects were in the high CAVI group. Multivariable logistic linear regression analyses adjusted for age, sex, body mass index, smoking status, mean arterial pressure, and the presence of hypertension, diabetes mellitus, and dyslipidemia showed a significant association between high CAVI values and the following retinal vessel geometry parameters: central retinal arteriolar equivalent caliber (CRAE; adjusted odds ratio [AOR], 0.95; 95% confidence interval [CI], 0.89-1.00; P = 0.043), fractal dimension of arteriolar network (FDa; AOR, 4.21 × 10-4; 95% CI, 2.32 × 10-7-0.77; P = 0.042), and arteriolar branching angle (BAa; AOR, 0.96; 95% CI, 0.93-0.99; P = 0.007). Conclusions: Increased systemic arterial stiffness had a significant association with retinal vessel geometry related to arterial narrowing (CRAE), less branching complexity of the arterial tree (FDa), and acute arteriolar bifurcation (BAa).

Assessment of Normal Systolic Blood Pressure Maintenance with the Risk of Coronary Artery Calcification Progression in Asymptomatic Metabolically Healthy Korean Adults with Normal Weight, Overweight, and Obesity.

Metabolically healthy obesity (MHO) is known to have a close association with subclinical coronary atherosclerosis. Despite recent data on the benefit of intensive systolic blood pressure (SBP) control in diverse clinical conditions, little is known regarding the association of normal SBP maintenance (SBPmaintain) with coronary artery calcification (CAC) progression in MHO. This study included 2724 asymptomatic adults (48.8 ± 7.8 years; 77.9% men) who had no metabolic abnormalities except overweight and obesity. Participants with normal weight (44.2%), overweight (31.6%), and obesity (24.2%) were divided into two groups: normal SBPmaintain (follow-up SBP < 120 mm Hg) and ≥elevated SBPmaintain (follow-up SBP ≥ 120 mm Hg). CAC progression was defined using the SQRT method, a difference of ≥2.5 between the square root (√) of the baseline and follow-up coronary artery calcium score. During a mean follow-up of 3.4 years, the proportion of normal SBPmaintain (76.2%, 65.2%, and 59.1%) and the incidence of CAC progression (15.0%, 21.3%, and 23.5%) was different in participants with normal weight, overweight, and obesity (all p < 0.05, respectively). The incidence of CAC progression was lower in the normal SBPmaintain group than in the ≥elevated SBPmaintain group in only participants with obesity (20.8% vs. 27.4%, p = 0.048). In multiple logistic models, compared to participants with normal weight, those with obesity had a higher risk of CAC progression. Normal SBPmaintain was independently associated with the decreased risk of CAC progression in participants with obesity. MHO had a significant association with CAC progression. Normal SBPmaintain reduced the risk of CAC progression in asymptomatic adults with MHO.

Association between fatty liver index and risk of end-stage renal disease stratified by kidney function in patients with type 2 diabetes: A nationwide population-based study.

OBJECTIVE: The effects of nonalcoholic fatty liver disease on the risk of end-stage renal disease (ESRD) remain unclear. We investigated the association between the fatty liver index (FLI) and risk of ESRD in patients with type 2 diabetes. METHODS: This population-based observational cohort study enrolled patients with diabetes who underwent health screening between 2009 and 2012 and utilized data from the Korean National Health Insurance Services. The FLI functioned as a surrogate marker for the presence of hepatic steatosis. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m² calculated using the Modification of Diet in Renal Disease equation. We performed Cox proportional hazards regression. RESULTS: Incident ESRD developed in 19,476 of 1,900,598 patients with type 2 diabetes during a median follow-up of 7.2 years. After adjusting for conventional risk factors, patients with high FLI scores had a higher risk for ESRD: FLI, 30-59 [hazard ratio (HR) = 1.124; 95% confidence interval (CI), 1.083-1.166]; FLI ≥ 60 [HR = 1.278; 95% CI, 1.217-1.343] compared with those with FLI < 30. The association between a high FLI score (≥ 60) and incident ESRD was more prominent in women than in men (male, FLI ≥60: HR, 1.106; 95% CI = 1.041-1.176 and female, FLI ≥ 60: HR, 1.835; 95% CI = 1.689-1.995). The association between a high FLI score (≥ 60) and the risk of ESRD differed according to baseline kidney function. High FLI scores increased the risk of ESRD (HR = 1.268; 95% CI, 1.198-1.342) in patients with CKD at baseline. CONCLUSION: High FLI scores are associated with a greater risk of ESRD in patients with type 2 diabetes with CKD at baseline. Close monitoring and appropriate management of hepatic steatosis may aid in preventing the progression of kidney dysfunction in patients with type 2 diabetes and CKD.

Alcohol consumption and the risk of new-onset uterine leiomyomas: a nationwide population-based study in 2.5 million Korean women aged 20 to 39 years.

BACKGROUND: Uterine leiomyomas are the most common benign tumors in women of childbearing age. Although there are several studies reporting the positive association of drinking alcohol with the incidence of uterine leiomyomas, studies targeting Korean women are lacking. OBJECTIVE: This study aimed to investigate the association between alcohol consumption and the risk of new-onset uterine leiomyomas in Korean women of early reproductive-age. STUDY DESIGN: This was a retrospective nationwide population-based cohort study using the Korean National Health Insurance Service database. Participants comprised 2,512,384 asymptomatic Korean women aged 20 to 39 years who underwent a national health examination from 2009 to 2012. The follow-up period was from the date of the first national health examination to the date of diagnosis of new-onset uterine leiomyomas or December 2018 if no uterine leiomyomas were detected. The diagnosis of uterine leiomyomas required 2 outpatient records within a year or 1 inpatient record of International Classification of Diseases, Tenth Revision (ICD-10) codes of uterine leiomyomas (D25) in the Korean National Health Insurance Service. Exclusion criteria were previously diagnosed uterine leiomyomas during the screening period (January 2002 to the date of first health examination) or uterine leiomyoma diagnosis within 1 year of baseline examination. The associations of alcohol consumption, amount drunk per drinking session, and sustained drinking over time with the risk of new-onset uterine leiomyomas were investigated. RESULTS: Approximately 6.1% of women aged 20 to 39 years were diagnosed with uterine leiomyomas after an average of 4.3 years. Alcohol consumption was associated with an increased incidence of new-onset uterine leiomyomas of 12% to 16% (hazard ratio, 1.12; 95% confidence interval, 1.11-1.14 for mild-to-moderate drinkers; hazard ratio, 1.16; 95% confidence interval, 1.12-1.20 for heavy drinkers). Drinking ≥1 days per week was associated with increased risk of uterine leiomyomas (hazard ratio, 1.11; 95% confidence interval, 1.10-1.12 for drinking 1 day per week; hazard ratio, 1.15; 95% confidence interval, 1.12-1.17 for drinking ≥3 days per week), and the association increased proportionately to the amount of alcohol consumed per drinking session (hazard ratio, 1.17; 95% confidence interval, 1.15-1.19 for ≥7 glasses per drinking session). Women who also reported alcohol consumption in the questionnaire administered 2 years later (sustained drinkers) exhibited a 20% increased risk of new-onset uterine leiomyomas (hazard ratio, 1.20; 95% confidence interval, 1.17-1.22) compared with women who answered that they did not drink alcohol at both times (sustained nondrinkers). In women who discontinued drinking, the risk was 3% (hazard ratio, 1.03; 95% confidence interval, 1.01-1.06), whereas in women who became drinkers, the risk was 14% (hazard ratio, 1.14; 95% confidence interval, 1.11-1.16). CONCLUSION: Having an alcohol drinking habit, the amount of alcohol consumed per drinking session, and sustained drinking over 2 years were significantly associated with the risk of new-onset uterine leiomyomas. Avoiding or discontinuing drinking could lower the risk of new-onset uterine leiomyomas in early reproductive-age women.

Dynamic Alterations in Cerebral Hemodynamics Measured by Portable Near-Infrared Spectroscopy in Orthostatic Hypotension and Intolerance.

BACKGROUND: We aimed to evaluate dynamic alterations in cerebral total hemoglobin concentration (HbT) in individuals with orthostatic hypotension (OH) and orthostatic intolerance (OI) symptoms using a portable near-infrared spectroscopy (NIRS) system. METHODS: Participants comprised 238 individuals (mean age, 47.9 years) without a history of cardiovascular, neurodegenerative, or cerebrovascular diseases, including those with unexplained OI symptoms and healthy volunteers. Participants were categorized by the presence of OH based on the supine-to-stand blood pressure (BP) drop and OI symptoms using on OH questionnaires: classic OH (OH-BP), OH symptoms alone (OH-Sx), and control groups. Random case-control matching sets were constructed, resulting in 16 OH-BP and 69 OH-Sx-control sets. The time-derivative of HbT change in the prefrontal cortex during the squat-to-stand maneuver was measured using a portable NIRS system. RESULTS: There were no differences in demographics, baseline BP, and heart rate among matched sets. The peak time of maximum slope variation in HbT change, indicating the recovery rate and speed of cerebral blood volume (CBV) change, was significantly longer in OH-Sx and OH-BP groups than in the control group under transition to a standing position after squatting. In the OH-BP subgrouping, the peak time of maximum slope variation in HbT change was significantly longer only in OH-BP with OI symptoms, but did not differ between OH-BP without OI symptoms and controls. CONCLUSIONS: Our results suggest that OH and OI symptoms are associated with dynamic alterations in cerebral HbT. Regardless of the severity of the postural BP drop, OI symptoms are associated with prolonged CBV recovery.

Clonal hematopoiesis with DNMT3A mutation is associated with lower white matter hyperintensity volume.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) increases the risk of cerebrovascular events, while its association with cerebral white matter hyperintensity (WMH) is undemonstrated. We evaluated the effect of CHIP and its major driving mutations on cerebral WMH severity. METHODS: From an institutional cohort of a routine health check-up program with a DNA repository database, subjects who were ≥50 years of age, with one or more cardiovascular risk factors but no central nervous system disorder, and performed brain MRI were included. Along with the presence of CHIP and its major driving mutations, clinical and laboratory data were obtained. WMH volume was measured in total, periventricular, and subcortical regions. RESULTS: Among the total 964 subjects, 160 subjects were classified as CHIP positive group. CHIP was most frequently associated with DNMT3A mutation (48.8%), followed by TET2 (11.9%) and ASXL1 (8.1%) mutations. Linear regression analysis adjusting for age, sex, and conventional cerebrovascular risk factors suggested that CHIP with DNMT3A mutation was associated with the lower log-transformed total WMH volume, unlike other CHIP mutations. When classified according to variant allele fraction (VAF) value of DNMT3A mutation, higher VAF classes were associated with the lower log-transformed total WMH and the lower log-transformed periventricular WMH volume, but not with the log-transformed subcortical WMH volumes. CONCLUSIONS: Clonal hematopoiesis with DNMT3A mutation is quantitatively associated with a lower volume of cerebral WMH, especially in the periventricular region. CHIP with DNMT3A mutation might have a protective role in the endothelial pathomechanism of WMH.

Atrial Functional Tricuspid Regurgitation: Importance of Atrial Fibrillation and Right Atrial Remodeling and Prognostic Significance.

BACKGROUND: Little is known about the determinants and outcomes of significant atrial functional tricuspid regurgitation (AFTR). OBJECTIVES: The authors aimed to identify risk factors for significant TR in relation to atrial fibrillation-flutter (AF-AFL) and assess its prognostic implications. METHODS: The authors retrospectively studied patients with mild TR with follow-up echocardiography examinations. Significant TR was defined as greater than or equal to moderate TR. AFTR was defined as TR, attributed to right atrial (RA) remodeling or isolated tricuspid annular dilatation, without other primary or secondary etiology, except for AF-AFL. The Mantel-Byar test was used to compare clinical outcomes by progression of AFTR. RESULTS: Of 833 patients with mild TR, 291 (34.9%) had AF-AFL. During the median 4.6 years, significant TR developed in 35 patients, including 33 AFTRs. Significant AFTR occurred in patients with AF-AFL more predominantly than in those patients without AF-AFL (10.3% vs 0.6%; P < 0.001). In Cox analysis, AF-AFL was a strong risk factor for AFTR (adjusted HR: 8.33 [95% CI: 2.34-29.69]; P = 0.001). Among patients with AF-AFL, those who developed significant AFTR had larger baseline RA areas (23.8 vs 19.4 cm2; P < 0.001) and RA area-to-right ventricle end-systolic area ratio (3.0 vs 2.3; P < 0.001) than those who did not. These parameters were independent predictors of AFTR progression. The 10-year major adverse cardiovascular event was significantly higher after progression of AFTR than before or without progression (79.8% vs 8.6%; Mantel-Byar P < 0.001). CONCLUSIONS: In patients with mild TR, significant AFTR developed predominantly in patients with AF-AFL, conferring poor prognosis. RA enlargement, especially with increased RA area-to-right ventricle end-systolic area ratio, was a strong risk factor for progression of AFTR.

Vacuoles isolated from Saccharomyces cerevisiae inhibit differentiation of 3T3-L1 adipocyte.

Yeast vacuoles contain various hydrolytic enzymes including lipase. They play important roles in intracellular signaling and metabolism. Using these characteristics, the aim of this study is to determine effects of yeast vacuoles on the triglyceride accumulation and differentiation of pre-adipocytes to adipocytes using 3T3-L1 cells. The accumulation of lipid droplets and triglyceride were reduced after treatment with vacuoles. As a result of not maintaining the expression of C/EBPß and C/EBPδ in vacuole-treated adipocytes, expression levels of C/EBPα and PPARγ in vacuole-treated adipocytes were significantly reduced. The expression of adiponectin in the late differentiation stage was increased compared to that in the control. By confirming that vacuolar enzymes also inhibit differentiation of adipocytes same as vacuoles, it can be concluded that the adipogenesis inhibitory effect of vacuoles is by lipase of vacuolar enzymes. Yeast-derived vacuoles could be an important source for inhibiting accumulation of lipids and obesity-related inflammation by suppressing adipogenesis.

Risk of incident mental disorders in hypertrophic cardiomyopathy: a nationwide propensity-matched study.

AIMS: We sought to determine the risk of mental disorders in patients with hypertrophic cardiomyopathy (HCM) compared with those without HCM. METHODS AND RESULTS: This is a retrospective propensity score-matched cohort study using nationwide population-based data from the Korean National Health Insurance Service. Overall, 4046 patients with HCM and 12138 matched individuals were followed up until the first diagnosis of mental disorders or the end of the follow up. The primary outcome was a composite of incident mood, anxiety, stress-related, or somatoform disorders. Secondary outcomes included two components of the primary outcome (i.e. mood disorders and anxiety/stress-related/somatoform disorders). During a median follow-up period of 4.1 years, the incidence rate of the primary outcome was 54.4 and 31.5/1000 person-years among the HCM and control groups, respectively, resulting in a hazard ratio (HR) of 1.719 (95% confidence interval: 1.589-1.860). Within the first month after HCM diagnosis, the HR for the primary outcome was 3.074 (2.096-4.508). Beyond 1 month, the HRs decreased, ranging from 2.281 (1.952-2.665) during 1-12 months, to 2.087 (1.831-2.380) during 12-36 months and 1.258 (1.090-1.452) after 36 months of follow up. Similar results were observed for the secondary outcomes. In sensitivity analysis, the risk of the specific categories of mental disorders, including single or recurrent depressive episodes and anxiety disorders, was also higher in patients with HCM than matched controls. CONCLUSION: HCM was significantly associated with the risk of incident mental disorders, particularly within 1 year after HCM diagnosis, underscoring the importance of screening mental health problems, including mood and anxiety disorders, in patients with HCM.

The Association of Smoking Status and Clustering of Obesity and Depression on the Risk of Early-Onset Cardiovascular Disease in Young Adults: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVES: To evaluate the impact of smoking in young adults on the risk of cardiovascular disease (CVD) and the clustering effect of behavioral risk factors such as smoking, obesity, and depression. METHODS: A Korean nationwide population-based cohort of a total of 3,280,826 participants aged 20-39 years old who underwent 2 consecutive health examinations were included. They were followed up until the date of CVD (myocardial infarction [MI] or stroke), or December 2018 (median, 6 years). RESULTS: Current smoking, early age of smoking initiation, and smoking intensity were associated with an increased risk of CVD incidence. Even after quitting smoking, the risk of MI was still high in quitters compared with non-smokers. Cigarette smoking, obesity, and depression were independently associated with a 1.3-1.7 times increased risk of CVD, and clustering of 2 or more of these behavioral risk factors was associated with a 2-3 times increased risk of CVD in young adults. CONCLUSIONS: In young adults, cigarette smoking was associated with the risk of CVD, and the clustering of 2 or more behavioral risk factors showed an additive risk of CVD.

Changes in metabolic syndrome burden and risk of coronary artery calcification progression in statin-naïve young adults.

BACKGROUND AND AIMS: We aimed to investigate the association between metabolic syndrome (MetS) and coronary artery calcium (CAC) progression in statin-naïve young adults. METHODS: From the KOrea Initiatives on Coronary Artery calcification registry, we included asymptomatic young adults aged 20-45 years who underwent serial CAC scans for routine health check-ups. The primary endpoint was CAC progression. We estimated the risk of CAC progression based on the presence and burden of MetS. Among participants with MetS, the temporal relationship between changes in metabolic burden and CAC progression was evaluated. RESULTS: Of 2151 young adults (mean age 41.3 ± 3.8 years; male 85.4%), 488 (22.7%) had MetS. The mean CAC score was 10.8 and 81.3% of them had a CAC score of zero at baseline. During follow-up (median, 2.1 years), CAC progression was observed in 325 (15.1%) adults. MetS was associated with an approximately 1.8-fold increased risk of CAC progression (adjusted hazard ratio [aHR] 1.83, p < 0.001). The risk of CAC progression was directly proportional to the metabolic burden. Elevated blood pressure and elevated triglyceride levels were independent components related to CAC progression, with the strongest contribution being made by elevated blood pressure (aHR 2.00, p < 0.001). A reduction in at least two metabolic burdens was associated with a halved risk of CAC progression in young adults having MetS (odds ratio 0.41, p = 0.018). CONCLUSIONS: In statin-naïve young adults, the metabolic burden was associated with a risk of CAC progression in a dose-dependent manner. Improvement in metabolic imbalance may have a preventive effect on CAC progression.

Pyruvate Prevents Dopaminergic Neurodegeneration and Motor Deficits in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopamine(DA)rgic neurons in the substantia nigra of the midbrain, and primarily causes motor symptoms. While the pathological cause of PD remains uncertain, oxidative damage, neuroinflammation, and energy metabolic perturbation have been implicated. Pyruvate has been shown neuroprotective in animal models for many neurological disorders, presumably owing to its potent anti-oxidative, anti-inflammatory, and energy metabolic properties. We therefore investigated whether exogenous pyruvate could also protect nigral DA neurons from degeneration and reverse the associated motor deficits in an animal model of PD using the DA neuron-specific toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP (20 mg/kg) was injected four times every 2 h into the peritoneum of mice, which resulted in a massive loss of DA neurons as well as an increase in neuronal death and cytosolic labile zinc overload. There were rises in inflammatory and oxidative responses, a drop in the striatal DA level, and the emergence of PD-related motor deficits. In comparison, when sodium pyruvate was administered intraperitoneally at a daily dose of 250 mg/kg for 7 days starting 2 h after the final MPTP treatment, significant relief in the MPTP-induced neuropathology, neurodegeneration, DA depletion, and motor symptoms was observed. Equiosmolar dose of NaCl had no neuroprotective effect, and lower doses of sodium pyruvate did not have any statistically significant effects. These findings suggest that pyruvate has therapeutic potential for the treatment of PD and related neurodegenerative diseases.