Positional obstructive sleep apnea and periodic limb movement during sleep: A large multi-center study.

Objectives: The relationships among positional obstructive sleep apnea (POSA), obstructive sleep apnea (OSA), and periodic limb movement during sleep (PLMS) are unclear. We analyzed these relationships according to OSA severity and explored the underlying mechanisms. Methods: We retrospectively reviewed 6,140 eligible participants who underwent full-night diagnostic polysomnography in four clinical centers over a period of 5 years with eventsynchronized analysis. The PLMS index (PLMI) and periodic limb movements with arousal index (PLMAI) were evaluated. The effects of POSA on the PLMI, PLMAI, and PLMS were analyzed according to OSA severity. Results: The mean PLMI and PLMAI, as well as PLMS prevalence, were significantly lower in those with severe OSA than in those with mild and moderate OSA. The mean PLMI was higher in mild OSA group than in control group. The mean PLMI (4.80 ± 12.71 vs. 2.59 ± 9.82 events/h, p < 0.001) and PLMAI (0.89 ± 3.66 vs. 0.53 ± 3.33 events/h, p < 0.001), and the prevalence of PLMS (11% vs. 5.3%, p < 0.001) were higher in patients with POSA than patients with non-POSA. This trend was particularly marked in severe OSA group (OR 1.55, 95%CI [1.07-2.27]) and less so in mild (OR 0.56, 95%CI [0.30-1.03]) and moderate (OR 1.82, 95%CI [0.99-3.34]) OSA groups. Conclusion: The POSA group tended to have a higher prevalence of PLMS, particularly in those with severe OSA. If PLMS is prominent, diagnosis and treatment of POSA and OSA may be considered.

Erratum: Correction of Figures in the Article "Angiotensin II Type 1 Receptor Blocker, Fimasartan, Reduces Vascular Smooth Muscle Cell Senescence by Inhibiting the CYR61 Signaling Pathway".

This corrects the article on p. 615 in vol. 49, PMID: 31074217.

Alcohol is neither a risk factor nor a protective factor for sudden cardiac death and/or fatal ventricular arrhythmia: A population-based study with genetic traits and alcohol consumption in the UK Biobank.

BACKGROUND: The association between alcohol consumption and the risk of sudden cardiac death and/or fatal ventricular arrhythmia remains controversial. OBJECTIVE: We analyzed the association between alcohol consumption, genetic traits for alcohol metabolism, and the risk of sudden cardiac death and/or fatal ventricular arrhythmia. METHODS: We identified 397,164 individuals enrolled between 2006 and 2010 from the UK Biobank database and followed them until 2021. Alcohol consumption was categorized as current nondrinkers (nondrinkers and ex-drinkers), mild drinkers, moderate drinkers, or heavy drinkers. Genetic traits of alcohol metabolism were stratified according to the polygenic risk score tertiles. The primary and secondary outcomes were a composite of sudden cardiac death and fatal ventricular arrhythmia as well as their individual components. RESULTS: During follow-up (median 12.5 years), 3543 cases (0.89%) of clinical outcomes occurred. Although mild, moderate, and heavy drinkers showed deceased risks of outcomes compared with current nondrinkers, there was no prognostic difference among nondrinkers, mild drinkers, moderate drinkers, and heavy drinkers. Ex-drinkers showed an increased risk in univariate analysis, but the significance was attenuated after adjusting covariates (hazard ratio 1.19; 95% confidence interval 0.94-1.50). As a continuous variable, alcohol consumption was not associated with clinical outcomes (hazard ratio 1.01; 95% confidence interval 0.99-1.02). Consistent with these findings, there was no association between genetic traits for alcohol metabolism and the risk of clinical outcomes. CONCLUSION: Alcohol consumption was neither a protective factor nor a risk factor for sudden cardiac death or fatal ventricular arrhythmia. Genetic traits of alcohol metabolism were not associated with the clinical prognosis.

Next-Generation Cardiac Interfacing Technologies Using Nanomaterial-Based Soft Bioelectronics.

Cardiac interfacing devices are essential components for the management of cardiovascular diseases, particularly in terms of electrophysiological monitoring and implementation of therapies. However, conventional cardiac devices are typically composed of rigid and bulky materials and thus pose significant challenges for effective long-term interfacing with the curvilinear surface of a dynamically beating heart. In this regard, the recent development of intrinsically soft bioelectronic devices using nanocomposites, which are fabricated by blending conductive nanofillers in polymeric and elastomeric matrices, has shown great promise. The intrinsically soft bioelectronics not only endure the dynamic beating motion of the heart and maintain stable performance but also enable conformal, reliable, and large-area interfacing with the target cardiac tissue, allowing for high-quality electrophysiological mapping, feedback electrical stimulations, and even mechanical assistance. Here, we explore next-generation cardiac interfacing strategies based on soft bioelectronic devices that utilize elastic conductive nanocomposites. We first discuss the conventional cardiac devices used to manage cardiovascular diseases and explain their undesired limitations. Then, we introduce intrinsically soft polymeric materials and mechanical restraint devices utilizing soft polymeric materials. After the discussion of the fabrication and functionalization of conductive nanomaterials, the introduction of intrinsically soft bioelectronics using nanocomposites and their application to cardiac monitoring and feedback therapy follow. Finally, comments on the future prospects of soft bioelectronics for cardiac interfacing technologies are discussed.

Mildly Reduced Renal Function Is Associated With Increased Heart Failure Admissions in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The association between renal dysfunction and cardiovascular outcomes has yet to be determined in patients with hypertrophic cardiomyopathy (HCM). We aimed to investigate whether mildly reduced renal function is associated with the prognosis in patients with HCM. METHODS: Patients with HCM were enrolled at two tertiary HCM centers. Patients who were on dialysis, or had a previous history of heart failure (HF) or stroke were excluded. Patients were categorized into 3 groups by estimated glomerular filtration rate (eGFR): stage I (eGFR ≥ 90 mL/min/1.73 m², n = 538), stage II (eGFR 60-89 mL/min/1.73 m², n = 953), and stage III-V (eGFR < 60 mL/min/1.73 m², n = 265). Major adverse cardiovascular events (MACEs) were defined as a composite of cardiovascular death, hospitalization for HF (HHF), or stroke during median 4.0-year follow-up. Multivariable Cox regression model was used to adjust for covariates. RESULTS: Among 1,756 HCM patients (mean 61.0 ± 13.4 years; 68.1% men), patients with stage III-V renal function had a significantly higher risk of MACEs (adjusted hazard ratio [aHR], 2.71; 95% confidence interval [CI], 1.39-5.27; P = 0.003), which was largely driven by increased incidence of cardiovascular death and HHF compared to those with stage I renal function. Even in patients with stage II renal function, the risk of MACE (vs. stage I: aHR, 2.21' 95% CI, 1.23-3.96; P = 0.008) and HHF (vs. stage I: aHR, 2.62; 95% CI, 1.23-5.58; P = 0.012) was significantly increased. CONCLUSION: This real-world observation showed that even mildly reduced renal function (i.e., eGFR 60-89 mL/min/1.73 m²) in patients with HCM was associated with an increased risk of MACEs, especially for HHF.

Differing Efficacy of Dapagliflozin Versus Empagliflozin on the Risk of Incident Atrial Fibrillation in Patients With Type 2 Diabetes: A Real-World Observation Using a Nationwide, Population-Based Cohort.

BACKGROUND: Meta-analyses of large clinical trials investigating SGLT2 (sodium-glucose cotransporter-2) inhibitors have suggested their protective effects against atrial fibrillation in patients with type 2 diabetes. However, the results were predominantly driven from trials involving dapagliflozin. METHODS AND RESULTS: We used a nationwide, population-based cohort of patients with type 2 diabetes who initiated either dapagliflozin or empagliflozin between May 2016 and December 2018. An active-comparator, new-user design was used, and the 2 groups of patients were matched using propensity scores. The primary outcome was incident nonvalvular atrial fibrillation, which was analyzed using both the main intention-to-treat and sensitivity analysis that censored patients who skipped their medications for ≥30 days. Men ≥55 years of age and women ≥60 years of age with ≥1 traditional risk factor or those with established cardiovascular disease were categorized as high cardiovascular risk group. Patients not included in the high-risk group were categorized as low risk. After 1:1 propensity-score matching, a total of 137 928 patients (mean age, 55 years; 58% men) were included and followed up for 2.2±0.6 years. The risk of incident atrial fibrillation was significantly lower in the dapagliflozin group in both the main (hazard ratio [HR], 0.885 [95% CI, 0.789-0.992]) and sensitivity analyses (HR, 0.835 [95% CI, 0.719-0.970]). Notably, this was consistent in both the low and high cardiovascular risk groups. There was no effect modification by age, sex, body mass index, duration of diabetes, or renal function. CONCLUSIONS: This real-world, population-based study demonstrates that patients with type 2 diabetes using dapagliflozin may have a lower risk of developing nonvalvular atrial fibrillation than those using empagliflozin.

Prognostic implication of early recurrence after cryoballoon ablation in patients with atrial fibrillation.

BACKGROUND: It remains uncertain whether the implication of early recurrence and blanking period can be applied to patients with atrial fibrillation (AF) treated with cryoballoon ablation (CBA). We aimed to explore the prognostic value of early recurrence in patients with AF treated with CBA. METHODS: We studied consecutive AF patients who were treated with CBA between April 2019 and September 2020 in two tertiary medical institutes and followed for up to 12 months. The endpoint was the late recurrence of atrial arrhythmia, including AF, atrial flutter, and atrial tachycardia, following a 90-day blanking period. Atrial arrhythmia during the blanking period was defined as early recurrence and was not considered as an endpoint. RESULTS: This study included 406 patients with AF who underwent CBA. During the follow-up, 147 (36.2%) cases of late recurrence were observed. Of the 104 patients with early recurrence, 85 experienced late recurrence during follow-up. Early recurrence was associated with an increased risk of late recurrence in the univariate and multivariate analyses (P < 0.001). When we classified the patients into paroxysmal AF and persistent AF groups, early recurrence was still significantly associated with a higher risk of late recurrence (P = 0.005 and P < 0.001, respectively). CONCLUSION: Early recurrence after CBA was an independent risk factor for late recurrence in all patients as well as in those with paroxysmal AF and persistent AF. Therefore, further prospective studies could be considered to verify the risks and benefits of early rhythm control in patients with early recurrence.

J-shaped association between LDL cholesterol and cardiovascular events: A longitudinal primary prevention cohort of over 2.4 million people nationwide.

INTRODUCTION: Low-density lipoprotein (LDL) cholesterol-lowering treatment is beneficial for the secondary or primary prevention of high-risk atherosclerotic cardiovascular disease (ASCVD). However, the prognostic implications of low LDL cholesterol levels in patients without previous ASCVD and without statin use remain elusive. METHODS: From a nationwide cohort, 2,432,471 participants without previous ASCVD or statin use were included. For myocardial infarction (MI) and ischemic stroke (IS), participants were followed-up from 2009 to 2018. They were stratified according to 10-year ASCVD risk (<5 %, 5 %-<7.5 %, 7.5 %-<20 %, and ≥20 %) and LDL cholesterol level (<70, 70-99, 100-129, 130-159, 160-189, and ≥190 mg/dL). RESULTS: The relationship between LDL cholesterol levels and ASCVD events exhibited a J-shaped curve for both MI and IS. After classification according to the ASCVD risk, this J-shaped relationship was consistently observed for the composite of MI and IS. Participants with an LDL cholesterol level <70 mg/dL showed a higher MI risk than those with a level of 70-99 mg/dL or 100-129 mg/dL in the low-ASCVD risk group. The J-shaped curve between LDL cholesterol levels and MI risk was attenuated across ASCVD risk groups. For IS, participants with an LDL cholesterol level <70 mg/dL demonstrated increased risks compared with those with a level of 70-99 mg/dL, 100-129 mg/dL, or 130-159 mg/dL in the borderline, intermediate, and high ASCVD risk groups, respectively. In contrast, a linear association was observed in participants taking statins. Interestingly, a J-shaped association was observed between LDL cholesterol and high-sensitivity C-reactive protein (hs-CRP) levels; the mean hs-CRP level and the proportion of individuals with increased hs-CRP levels were relatively high among individuals with an LDL cholesterol level <70 mg/dL. CONCLUSIONS: Although high LDL cholesterol levels increase the risk of ASCVD, low LDL cholesterol levels do not warrant safety from ASCVD. Therefore, individuals with low LDL cholesterol levels should be carefully monitored.

Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Risk of newly developed atrial fibrillation by alcohol consumption differs according to genetic predisposition to alcohol metabolism: a large-scale cohort study with UK Biobank.

BACKGROUND: The predictive relationship between mild-to-moderate alcohol consumption and the risk of incident atrial fibrillation (AF) remains controversial. OBJECTIVE: We investigated whether the relationship between alcohol consumption and the risk of incident AF could be associated with the genetic predisposition to alcohol metabolism. METHODS: A total of 399,329 subjects with genetic data from the UK Biobank database, enrolled between 2006 and 2010, were identified and followed for incident AF until 2021. Genetic predisposition to alcohol metabolism was stratified according to the polygenic risk score (PRS) tertiles. Alcohol consumption was categorized as non-drinkers, mild-to-moderate drinkers (< 30 g/day), and heavy drinkers (≥ 30 g/day). RESULTS: During the follow-up (median 12.2 years), 19,237 cases of AF occurred. When stratified by PRS tertiles, there was a significant relationship between genetic predisposition to alcohol metabolism and actual alcohol consumption habits (P < 0.001). Mild-to-moderate drinkers showed a decreased risk of AF (HR 0.96, 95% CI 0.92-0.99), and heavy drinkers showed an increased risk of AF (HR 1.06, 95% CI 1.02-1.10) compared to non-drinkers. When stratified according to PRS tertiles for genetic predisposition to alcohol metabolism, mild-to-moderate drinkers had equivalent AF risks, and heavy drinkers showed increased AF risk in the low PRS tertile group. However, mild-to-moderate drinkers had decreased AF risks and heavy drinkers showed similar risks of AF in the middle/high PRS tertile groups. CONCLUSIONS: Differential associations between alcohol consumption habits and incident AF across genetic predisposition to alcohol metabolism were observed; individuals with genetic predisposition to low alcohol metabolism were more susceptible to AF.

Sacubitril/valsartan and the risk of incident dementia in heart failure: a nationwide propensity-matched cohort study.

BACKGROUND: Sacubitril acts to inhibit neprilysin and as neprilysin is involved in amyloid-beta degradation in the central nervous system, and there is concern that sacubitril/valsartan may increase the risk of dementia. We aimed to compare the risk of incident dementia associated with sacubitril/valsartan and angiotensin II receptor blockers (ARBs). METHODS: Patients with heart failure with reduced ejection fraction treated with either sacubitril/valsartan or ARB, identified from the Korean National Health Insurance Service database, were matched in a 1:2 ratio using propensity scores (6789 on sacubitril/valsartan and 13,578 on ARBs) and followed up for incident dementia. RESULTS: During a mean follow-up of 2.5 years, 526 (2.6%) patients were newly diagnosed with dementia: Alzheimer dementia in 282, vascular dementia in 8, and other dementia in 236. There was no significant difference in the risk of overall dementia (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.70-1.01), Alzheimer dementia (HR 0.85, 95% CI 0.67-1.10), vascular dementia (HR 0.98, 95% CI 0.23-4.11), and all other dementias (HR 0.81, 95% CI 0.62-1.07) between sacubitril/valsartan users and ARB users. These results were consistent regardless of initial sacubitril/valsartan dose and subgroups including old age, previous mild cognitive impairment, previous stroke, and concomitant antiplatelet or anticoagulation. Sensitivity analysis with a 1-year lag period for dementia assessment confirmed the main analysis. Meanwhile, risk of incident stroke was lower in sacubitril/valsartan users compared to ARBs users. CONCLUSIONS: In a nationwide propensity-matched cohort of patients with heart failure, sacubitril/valsartan was not associated with an increased risk of incident dementia compared to ARBs. Sacubitril/valsartan and the risk of incident dementia in heart failure. ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor.

Prognostic and Safety Implications of Renin-Angiotensin-Aldosterone System Inhibitors in Hypertrophic Cardiomyopathy: A Real-World Observation Over 2,000 Patients.

BACKGROUND AND OBJECTIVES: The prognostic or safety implication of renin-angiotensin-aldosterone system inhibitors (RASi) in hypertrophic cardiomyopathy (HCM) are not well established, mainly due to concerns regarding left ventricular outflow tract (LVOT) obstruction aggravation. We investigated the implications of RASi in a sizable number of HCM patients. METHODS: We enrolled 2,104 consecutive patients diagnosed with HCM in 2 tertiary university hospitals and followed up for five years. RASi use was defined as the administration of RASi after diagnostic confirmation of HCM. The primary and secondary outcomes were all-cause mortality and hospitalization for heart failure (HHF). RESULTS: RASi were prescribed to 762 patients (36.2%). During a median follow-up of 48.1 months, 112 patients (5.3%) died, and 94 patients (4.5%) experienced HHF. Patients using RASi had less favorable baseline characteristics than those not using RASi, such as older age, more frequent history of comorbidities, and lower ejection fraction. Nonetheless, there was no difference in clinical outcomes between patients with and without RASi use (log-rank p=0.368 for all-cause mortality and log-rank p=0.443 for HHF). In multivariable analysis, patients taking RASi showed a comparable risk of all-cause mortality (hazard ratio [HR], 0.70, 95% confidence interval [CI], 0.43-1.14, p=0.150) and HHF (HR, 1.03, 95% CI, 0.63-1.70, p=0.900). In the subgroup analysis, there was no significant interaction of RASi use between subgroups stratified by LVOT obstruction, left ventricular (LV) ejection fraction, or maximal LV wall thickness. CONCLUSIONS: RASi use was not associated with worse clinical outcomes. It might be safely administered in patients with HCM if clinically indicated.

Left ventricular global longitudinal strain as a prognosticator in hypertrophic cardiomyopathy with a low-normal left ventricular ejection fraction.

AIMS: The aim of this study was to investigate the prognostic utility of left ventricular (LV) global longitudinal strain (LV-GLS) in patients with hypertrophic cardiomyopathy (HCM) and an LV ejection fraction (LVEF) of 50-60%. METHODS AND RESULTS: This retrospective cohort study included 349 patients with HCM and an LVEF of 50-60%. The primary outcome was a composite of cardiovascular death, including sudden cardiac death (SCD) and SCD-equivalent events. The secondary outcomes were SCD/SCD-equivalent events, cardiovascular death (including SCD), and all-cause death. The final analysis included 349 patients (mean age 59.2 ± 14.2 years, men 75.6%). During a median follow-up of 4.1 years, the primary outcome occurred in 26 (7.4%), while the secondary outcomes of SCD/SCD-equivalent events, cardiovascular death, and all-cause death occurred in 15 (4.2%), 20 (5.7%), and 34 (9.7%), respectively. After adjusting for age, atrial fibrillation, ischaemic stroke, LVEF, and left atrial volume index, absolute LV-GLS (%) was independently associated with the primary outcome [adjusted hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.788-0.988, P = 0.029]. According to receiver operating characteristic analysis, 10.5% is an optimal cut-off value for absolute LV-GLS in predicting the primary outcome. Patients with an absolute LV-GLS ≤ 10.5% had a higher risk of the primary outcome than those with an absolute LV-GLS > 10.5% (adjusted HR 2.54, 95% CI 1.117-5.787, P = 0.026). Absolute LV-GLS ≤ 10.5% was an independent predictor for each secondary outcome (P < 0.05). CONCLUSIONS: LV-GLS was an independent predictor of a composite of cardiovascular death, including SCD/SCD-equivalent events, in patients with HCM and an LVEF of 50-60%. Therefore, LV-GLS can help in risk stratification in these patients.

The accuracy and difference of scoring rules and methods to score respiratory event-related leg movements in obstructive sleep apnea patients.

OBJECTIVE: To compare manual scoring: 1) to the American Academy of Sleep Medicine (AASM) auto-scoring rules. 2) to the AASM and World Association of Sleep Medicine (WASM) rules, and evaluate the accuracy of the AASM and WASM for respiratory event-related limb movements (RRLM) in diagnostic and continuous positive airway pressure (CPAP) titration polysomnography (PSG). METHODS: We retrospectively, re-scored diagnostic and CPAP titration PSGs of 16 patients with obstructive sleep apnea (OSA), using manual re-scoring by the AASM (mAASM) and WASM (mWASM) criteria for RRLM, periodic limb movements during sleep (PLMS), and limb movements (LM), which were compared to auto-scoring by the AASM (aAASM). RESULTS: In diagnostic PSG, significant differences were found in LMs (p < 0.05), RRLM (p = 0.009) and the mean duration of PLMS sequences (p = 0.013). In CPAP titration PSG, there was a significant difference in RRLM (p = 0.008) and PLMS with arousal index (p = 0.036). aAASM underestimated LM and RRLM, especially in severe OSA. Changes in RRLM and PLMS with arousal index between diagnostic and titration PSG were significantly different between aAASM and mAASM, but there was no significant difference between scoring by mAASM and mWASM. The ratio of PLMS and RRLM changes between diagnostic and CPAP titration PSG was 0.257 in mAASM and 0.293 in mWASM. CONCLUSIONS: In addition to the overestimation of RRLM by mAASM compared to aAASM, mAASM may also be more sensitive than aAASM in detecting RRLM changes in the titration PSG. Despite intuitive differences in the definition of RRLM between AASM and WASM rules, RRLM results between mAASM and mWASM were not significant and about 30% of RRLMs might be scored as PLMS by both scoring rules.

Enzymatic Hydrolysis of Tenebrio molitor (Mealworm) Using Nuruk Extract Concentrate and an Evaluation of Its Nutritional, Functional, and Sensory Properties.

Enzymatic protein hydrolysis is a well-established method for improving the quality of dietary proteins, including edible insects. Finding effective enzymes from natural sources is becoming increasingly important. This study used nuruk extract concentrate (NEC), an enzyme-rich fermentation starter, to produce protein hydrolysate from defatted Tenebrio molitor (also called mealworm, MW). The nutritional, functional, and sensorial properties of the hydrolysate were then compared to those obtained using commercial proteases (alcalase and flavourzyme). The protease activities of the crude nuruk extract (CNE), NEC, alcalase, and flavourzyme were 6.78, 12.71, 11.07, and 12.45 units/mL, respectively. The degree of hydrolysis and yield of MW hydrolysis by NEC were 15.10 and 35.92% (w/w), respectively. MW hydrolysate was obtained using NEC and had a significantly higher free amino acid content (90.37 mg/g) than alcalase (53.01 mg/g) and flavourzyme (79.64 mg/g) hydrolysates. Furthermore, the NEC hydrolysis of MW increased the antioxidant and angiotensin-converting enzyme inhibitory activity, with IC50 values of 3.07 and 0.15 mg/mL, respectively. The enzymatic hydrolysis also improved sensory properties, including umaminess, sweetness, and saltiness. Overall, this study found that the NEC hydrolysis of MW outperformed commercial proteases regarding nutritional quality, sensory attributes, and biological activity. Therefore, nuruk could potentially replace commercial proteases, lowering the cost of enzymatic protein hydrolysis.

Increased cardiovascular events in young patients with mental disorders: a nationwide cohort study.

AIMS: It remains unclear whether young patients with mental disorders have a higher risk of cardiovascular diseases than does the general population. Using a nationwide database, we investigated the prognostic association between the risks of myocardial infarction (MI), ischaemic stroke (IS), and mental disorders in young patients. METHODS AND RESULTS: Young patients aged between 20 and 39 years old who underwent nationwide health examinations between 2009 and 2012 were screened. A total of 6 557 727 individuals were identified and subsequently classified according to mental disorders including depressive disorder, bipolar disorder, schizophrenia, insomnia, anxiety disorder, post-traumatic stress disorder, personality disorder, somatoform disorder, eating disorder, and substance use disorder. Patients were then followed up for MI and IS until December 2018. Patients with mental disorders did not show unfavourable lifestyle behaviours or worse metabolic profiles than their counterparts. During the follow-up period (median, 7.6 years; interquartile range, 6.5-8.3), 16 133 cases of MI and 10 509 cases of IS occurred. Patients with mental disorders had higher risks of MI (log-rank P = 0.033 in eating disorder and log-rank P < 0.001 in all other mental disorders). Patients with mental disorders had higher risks of IS except post-traumatic stress disorder (log-rank P = 0.119) and eating disorder (log-rank P = 0.828). After adjusting for covariates, the overall diagnosis and each mental disorder were independently associated with increased cardiovascular endpoints. CONCLUSION: Mental disorders in young patients may have deleterious effects which increase the incidence of MI and IS. Prevention efforts are needed to prevent MI and IS in young patients with mental disorders.

Although young patients with mental disorders did not show worse baseline characteristics in this nationwide study, mental disorders in young patients have deleterious effects on the incidence of both myocardial infarction (MI) and ischaemic stroke (IS) events, across depressive disorder, bipolar disorder, schizophrenia, insomnia, anxiety disorders, post-traumatic stress disorder, personality disorder, somatoform disorder, eating disorder, and substance use disorder. Patients with mental disorders are known to have a shorter life expectancy across schizophrenia, affective disorders, and other mental disorders than the general population; previous study verified that around 70% of deaths in those with mental disorders were due to physical diseases. If patients with mental disorders have higher risks of cardiovascular diseases, especially in young patients, prevention and surveillance of cardiovascular diseases among these young patients during their lifetime should be considered.A substantial number of young patients aged 20­39 years (13.1%) were diagnosed with mental disorders, and excessive risks of incident MI and IS were observed in patients with mental disorders including depressive disorder, bipolar disorder, schizophrenia, insomnia, anxiety disorder, post-traumatic stress disorder, personality disorder, somatoform disorder, eating disorder, and substance use disorder. In contrast to previous suggestion that unfavourable lifestyle behaviours and poor cardiometabolic profiles could lead to increased cardiovascular risks, patients with mental disorders did not show unfavourable lifestyle behaviours or worse metabolic profiles than their counterparts.

Surface Active Salivary Metabolites Indicate Oxidative Stress and Inflammation in Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA), a highly prevalent and potentially serious sleep disorder, requires effective screening tools. Saliva is a useful biological fluid with various metabolites that might also influence upper airway patency by affecting surface tension in the upper airway. However, little is known about the composition and role of salivary metabolites in OSA. Therefore, we investigated the metabolomics signature in saliva from the OSA patients and evaluated the associations between identified metabolites and salivary surface tension. METHODS: We studied 68 subjects who visited sleep clinic due to the symptoms of OSA. All underwent full-night in-lab polysomnography. Patients with apnea-hypopnea index (AHI) < 10 were classified to the control, and those with AHI ≥ 10 were the OSA groups. Saliva samples were collected before and after sleep. The centrifuged saliva samples were analyzed by liquid chromatography with high-resolution mass spectrometry (ultra-performance liquid chromatography-tandem mass spectrometry; UPLC-MS/MS). Differentially expressed salivary metabolites were identified using open source software (XCMS) and Compound Discoverer 2.1. Metabolite set enrichment analysis (MSEA) was performed using MetaboAnalyst 5.0. The surface tension of the saliva samples was determined by the pendant drop method. RESULTS: Three human-derived metabolites (1-palmitoyl-2-[5-hydroxyl-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [PHOOA-PC], 1-palmitoyl-2-[5-keto-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [KPOO-PC], and 9-nitrooleate) were significantly upregulated in the after-sleep salivary samples from the OSA patients compared to the control group samples. Among the candidate metabolites, only PHOOA-PC was correlated with the AHI. In OSA samples, salivary surface tension decreased after sleep. The differences in surface tension were negatively correlated with PHOOA-PC and 9-nitrooleate concentrations. Furthermore, MSEA revealed that arachidonic acid-related metabolism pathways were upregulated in the after-sleep samples from the OSA group. CONCLUSIONS: This study revealed that salivary PHOOA-PC was correlated positively with the AHI and negatively with salivary surface tension in the OSA group. Salivary metabolomic analysis may improve our understanding of upper airway dynamics and provide new insights into novel biomarkers and therapeutic targets in OSA.

Association between renin-angiotensin-aldosterone system blockade and clinical outcomes in patients with hypertension: real-world observation from a nationwide hypertension cohort.

OBJECTIVE: We investigated the association between the use of ACEi, ARB, or non-renin-angiotensin-aldosterone system inhibitors (non-RASi) and incident cardiovascular events in an unselected nationwide hypertension cohort. METHODS: The information regarding 2,025,849 patients who underwent general health checkup between 2010 and 2011 and were on antihypertensive medication was collected. Patients were allocated into ACEi, ARB, and non-RASi groups and followed until 2019. The outcomes of interest were myocardial infarction (MI), ischemic stroke (IS), atrial fibrillation (AF), heart failure (HF), and all-cause deaths. RESULTS: Patients on ACEi and ARB showed unfavorable baseline characteristics compared to those on non-RASi. After adjusting for covariates, the ACEi group showed lower risks of MI, AF, and all-cause deaths (HR (95% CI): 0.94 (0.89-0.99), 0.96 (0.92-1.00), and 0.93 (0.90-0.96), respectively), but similar risks of IS and HF (0.97 (0.92-1.01) and 1.03 (1.00-1.06), respectively), compared to the non-RASi group. Likewise, the ARB group showed decreased risks of MI, IS, AF, HF, and all-cause deaths (HR (95% CI): 0.93 (0.91-0.95), 0.88 (0.86-0.90), 0.86 (0.85-0.88), 0.94 (0.93-0.96), and 0.84 (0.83-0.85)), compared to the non-RASi group. Sensitivity analysis of patients taking a single antihypertensive medication showed similar results. In the propensity score matching (PSM) cohort, the ARB group showed similar risks of MI and decreased risks of IS, AF, HF, and all-cause deaths compared to the ACEi group. CONCLUSIONS: ACEi and ARB users were associated with decreased risks of MI, IS, AF, HF, and all-cause deaths, compared to non-RASi users.

Ventricular tachyarrhythmia treatment and prevention by subthreshold stimulation with stretchable epicardial multichannel electrode array.

The implantable cardioverter-defibrillator (ICD) is an effective method to prevent sudden cardiac death in high-risk patients. However, the transvenous lead is incompatible with large-area electrophysiological mapping and cannot accommodate selective multichannel precision stimulations. Moreover, it involves high-energy shocks, resulting in pain, myocardial damage, and recurrences of ventricular tachyarrhythmia (VTA). We present a method for VTA treatment based on subthreshold electrical stimulations using a stretchable epicardial multichannel electrode array, which does not disturb the normal contraction or electrical propagation of the ventricle. In rabbit models with myocardial infarction, the infarction was detected by mapping intracardiac electrograms with the stretchable epicardial multichannel electrode array. Then, VTAs could be terminated by sequential electrical stimuli from the epicardial multichannel electrode array beginning with low-energy subthreshold stimulations. Last, we used these subthreshold stimulations to prevent the occurrence of additional VTAs. The proposed protocol using the stretchable epicardial multichannel electrode array provides opportunities toward the development of innovative methods for painless ICD therapy.

Safety and effectiveness of anticoagulation with non-vitamin K antagonist oral anticoagulants and warfarin in patients on tuberculosis treatment.

Anti-tuberculosis treatment can cause significant drug-drug interaction and interfere with effective anticoagulation. However, there is a lack of evidence and conflicting data on the optimal oral anticoagulation in patients treated for tuberculosis. We investigated the safety and effectiveness of anticoagulation with non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in patients on anti-tuberculosis treatment. Patients on concomitant oral anticoagulation and anti-tuberculosis treatment including rifampin were identified from the Korean nationwide healthcare database. Subjects were censored at discontinuation of either anticoagulation or rifampin. The outcomes of interest were major bleeding, death, and ischemic stroke. A total 2090 patients (1153 on warfarin, 937 on NOAC) were included. NOAC users, compared to warfarin users, were older, had a lower prevalence of hypertension, heart failure, ischemic stroke, and aspirin use and a higher prevalence of cancer, with no significant differences in CHA2DS2-VASc or HAS-BLED scores. There were 18 major bleeding events, 106 deaths, and 50 stroke events during a mean follow-up of 2.9 months. After multivariable adjustment, the use of NOAC was associated with a lower risk of incident ischemic stroke (HR 0.51, 95% CI 0.27-0.94), while there was no significant difference in risk for major bleeding or death compared with warfarin. These results suggest that NOACs have better effectiveness for stroke prevention and similar safety compared with warfarin in patients on concomitant anti-tuberculosis treatment. This is the first study assessing the safety and effectiveness of NOACs compared to warfarin in this clinical scenario.