Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA.

DddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs) catalyze targeted base editing of mitochondrial DNA (mtDNA) in eukaryotic cells, a method useful for modeling of mitochondrial genetic disorders and developing novel therapeutic modalities. Here, we report that A-to-G-editing TALEDs but not C-to-T-editing DdCBEs induce tens of thousands of transcriptome-wide off-target edits in human cells. To avoid these unwanted RNA edits, we engineered the substrate-binding site in TadA8e, the deoxy-adenine deaminase in TALEDs, and created TALED variants with fine-tuned deaminase activity. Our engineered TALED variants not only reduced RNA off-target edits by >99% but also minimized off-target mtDNA mutations and bystander edits at a target site. Unlike wild-type versions, our TALED variants were not cytotoxic and did not cause developmental arrest of mouse embryos. As a result, we obtained mice with pathogenic mtDNA mutations, associated with Leigh syndrome, which showed reduced heart rates.

Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila.

All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions.

Response of the microbiome-gut-brain axis in Drosophila to amino acid deficit.

A balanced intake of macronutrients-protein, carbohydrate and fat-is essential for the well-being of organisms. An adequate calorific intake but with insufficient protein consumption can lead to several ailments, including kwashiorkor1. Taste receptors (T1R1-T1R3)2 can detect amino acids in the environment, and cellular sensors (Gcn2 and Tor)3 monitor the levels of amino acids in the cell. When deprived of dietary protein, animals select a food source that contains a greater proportion of protein or essential amino acids (EAAs)4. This suggests that food selection is geared towards achieving the target amount of a particular macronutrient with assistance of the EAA-specific hunger-driven response, which is poorly understood. Here we show in Drosophila that a microbiome-gut-brain axis detects a deficit of EAAs and stimulates a compensatory appetite for EAAs. We found that the neuropeptide CNMamide (CNMa)5 was highly induced in enterocytes of the anterior midgut during protein deprivation. Silencing of the CNMa-CNMa receptor axis blocked the EAA-specific hunger-driven response in deprived flies. Furthermore, gnotobiotic flies bearing an EAA-producing symbiotic microbiome exhibited a reduced appetite for EAAs. By contrast, gnotobiotic flies with a mutant microbiome that did not produce leucine or other EAAs showed higher expression of CNMa and a greater compensatory appetite for EAAs. We propose that gut enterocytes sense the levels of diet- and microbiome-derived EAAs and communicate the EAA-deprived condition to the brain through CNMa.

Phf7 has impacts on the body growth and bone remodeling by regulating testicular hormones in male mice.

PHD finger protein 7 (Phf7) is a member of the PHF family proteins, which plays important roles in spermiogenesis. Phf7 is expressed in the adult testes and its deficiency causes male infertility. In this study, we tried to find the causal relationship between Phf7 deficiency and reduced growth retardation which were found in null knock-out (Phf7-/-) mice. Phf7-/- mice were born normally in the Mendelian ratio. However, the Phf7-/- males showed decreased body weight gain, bone mineral density, and bone mineral content compared to those in wild-type (WT) mice. Histological analysis for tibia revealed increased number of osteoclast cells in Phf7-/- mice compared with that in WT mice. When we analyzed the expressions for marker genes for the initial stage of osteoclastogenesis, such as receptor activator of nuclear factor kappa B (Rank) in tibia, there was no difference in the mRNA levels between Phf7-/- and WT mice. However, the expression of tartrate-resistant acid phosphatase (Trap), a mature stage marker gene, was significantly higher in Phf7-/- mice than in WT mice. In addition, the levels of testosterone and dihydrotestosterone (DHT), more potent and active form of testosterone, were significantly reduced in the testes of Phf7-/- mice compared to those in WT mice. Furthermore, testicular mRNA levels for steroidogenesis marker genes, namely Star, Cyp11a1, Cyp17a1 and 17ß-hsd, were significantly lower in Phf7-/- mice than in WT mice. In conclusion, these results suggest that Phf7 deficiency reduces the production of male sex hormones and thereby impairs associated bone remodeling.

Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Usefulness of cardiopulmonary exercise test combined with exercise stress echocardiography in mild chronic thromboembolic pulmonary disease.

PURPOSE: Chronic thromboembolic pulmonary disease (CTEPD) can lead to exercise limitations even without right ventricular (RV) dysfunction or pulmonary hypertension at rest. Combining exercise stress echocardiography with cardiopulmonary exercise testing (ESE-CPET) for RV function and pressure changes combined measuring overall function may be useful for CTEPD evaluation. This study aims to investigate CPET and ESE results to elucidate the mechanisms of exercise limitation in mild CTEPD cases. METHODS: Among our CTEPD registry, 50 patients who performed both right heart catheterization data of mild disease (less than 30 mm Hg of mean pulmonary arterial pressure (mPAP)) and ESE-CPET were enrolled. Echocardiography and CPET-derived parameters were compared with hemodynamic parameters measured through right heart catheterization. RESULTS: Peak VO2 (maximal oxygen consumption) was decreased in overall population (71.3 ± 16.3% of predictive value). Peak VO2 during exercise was negatively correlate with mPAP and pulmonary vascular resistance at rest. A substantial increase in RV systolic pressure (RVSP) was observed during exercise (RVSP: pre-exercise 37.2 ± 11.8 mm Hg, postexercise 64.3 ± 24.9 mm Hg, p-value < .001). Furthermore, RV function deteriorated during exercise when compared to the baseline (RV fractional area change: 31.5 ± 10.0% to 37.8 ± 7.0%, p-value < .001; RV global longitudinal strain: -17.1 ± 4.2% to -17.7 ± 3.3%, p-value < .001) even though basal RV function was normal. While an excessive increase in RVSP during exercise was noticed in both groups, dilated RV and RV dysfunction during exercise were demonstrated only in the impaired exercise capacity group. CONCLUSION: CTEPD patients with mild PH or without PH exhibited limited exercise capacity alongside an excessive increase in RVSP during exercise. Importantly, RV dysfunction during exercise was significantly associated with exercise capacity. ESE-CPET could aid in comprehending the primary cause of exercise limitation in these patients.

COVID-19 vaccination-related myocarditis: a Korean nationwide study.

AIMS: A comprehensive nationwide study on the incidence and outcomes of COVID-19 vaccination-related myocarditis (VRM) is in need. METHODS AND RESULTS: Among 44 276 704 individuals with at least 1 dose of COVID-19 vaccination, the incidence and clinical courses of VRM cases confirmed by the Expert Adjudication Committee of the Korea Disease Control and Prevention Agency were analyzed. COVID-19 VRM was confirmed in 480 cases (1.08 cases per 100 000 persons). Vaccination-related myocarditis incidence was significantly higher in men than in women (1.35 vs. 0.82 per 100 000 persons, P < 0.001) and in mRNA vaccines than in other vaccines (1.46 vs. 0.14 per 100 000 persons, P < 0.001). Vaccination-related myocarditis incidence was highest in males between the ages of 12 and 17 years (5.29 cases per 100 000 persons) and lowest in females over 70 years (0.16 cases per 100 000 persons). Severe VRM was identified in 95 cases (19.8% of total VRM, 0.22 per 100 000 vaccinated persons), 85 intensive care unit admission (17.7%), 36 fulminant myocarditis (7.5%), 21 extracorporeal membrane oxygenation therapy (4.4%), 21 deaths (4.4%), and 1 heart transplantation (0.2%). Eight out of 21 deaths were sudden cardiac death (SCD) attributable to VRM proved by an autopsy, and all cases of SCD attributable to VRM were aged under 45 years and received mRNA vaccines. CONCLUSION: Although COVID-19 VRM was rare and showed relatively favorable clinical courses, severe VRM was found in 19.8% of all VRM cases. Moreover, SCD should be closely monitored as a potentially fatal complication of COVID-19 vaccination.

Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice.

Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.

Clinical Implication of Left Atrial Appendage Emptying Velocity in Thoracoscopic Ablation of Atrial Fibrillation.

BACKGROUND: There are limited data about predictors of atrial fibrillation (AF) recurrence after totally thoracoscopic ablation (TTA). This study investigated the clinical implication of left atrial appendage emptying velocity (LAAV) in patients undergoing TTA.Methods and Results: Patients who underwent TTA between 2012 and 2015 at a tertiary hospital were prospectively enrolled in this study. LAAV was measured and averaged over five heart beats from preoperative transesophageal echocardiography. The primary outcome was a freedom from recurrent AF or atrial flutter (AFL) detected on 24-h Holter monitoring or an electrocardiogram over a 3-year period after TTA. In all, 129 patients were eligible for analysis in this study. The mean (±SD) patient age was 54.4±8.8 years, and 95.3% were male. During the 3 years after TTA, the overall event-free survival rate was 65.3%. LAAV was an independent predictor of recurrent AF/AFL during the 3-year period after TTA (per 1-cm/s increase, adjusted hazard ratio [aHR] 0.95; 95% confidence interval [CI] 0.91-0.99; P=0.016). Event-free survival was significantly lower among patients with a low LAAV (<20 cm/s; n=21) compared with those with a normal (≥40 cm/s; n=38; aHR 6.11; 95% CI 1.42-26.15; P=0.015) or intermediate (LAAV ≥20 and <40 cm/s; n=70; aHR 2.74, 95% CI 1.29-5.83; P=0.009) LAAV. CONCLUSIONS: In patients with AF, LAAV was significantly associated with the risk of long-term recurrence of AF after TTA.

mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation.

mTORC1 plays a key role in autophagy as a negative regulator. The currently known targets of mTORC1 in the autophagy pathway mainly function at early stages of autophagosome formation. Here, we identify that mTORC1 inhibits later stages of autophagy by phosphorylating UVRAG. Under nutrient-enriched conditions, mTORC1 binds and phosphorylates UVRAG. The phosphorylation positively regulates the association of UVRAG with RUBICON, thereby enhancing the antagonizing effect of RUBICON on UVRAG-mediated autophagosome maturation. Upon dephosphorylation, UVRAG is released from RUBICON to interact with the HOPS complex, a component for the late endosome and lysosome fusion machinery, and enhances autophagosome and endosome maturation. Consequently, the dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. These results demonstrate that mTORC1 engages in late stages of autophagy and endosome maturation, defining a broader range of mTORC1 functions in the membrane-associated processes.

Prognosis of Chronic Kidney Disease and Metabolic Syndrome in Adults With Congenital Heart Disease.

BACKGROUND: Few studies have examined the incidence of chronic kidney disease (CKD) and metabolic syndrome (MS) and their combined prognostic effects in adult congenital heart disease (ACHD). Our aims were to identify the incidence and prognostic implications of CKD and MS in ACHD. METHODS: This is retrospective cohort study. We included 2,462 ACHD ≥ 20 years of age who were treated at a tertiary hospital in Korea from 2006 to 2018. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m². MS was diagnosed based on the presence of abnormal metabolic parameters: blood sugar level, obesity, dyslipidemia, and hypertension. The primary outcome was all-cause mortality from 2006 through 2019 using data from the Ministry of the Interior and Safety in Korea. RESULTS: The incidence of CKD and MS in ACHD was 7.6% and 35.9%, respectively. The coexistence rate of CKD and MS was 4.6%. Although MS was not independently associated with mortality in the multiple analysis (adjusted hazard ratio [aHR], 1.07; 95% confidence interval [CI], 0.79-1.46), it was closely related to the presence of CKD (adjusted odds ratio, 2.62; 95% CI, 1.89-3.63). ACHD patients with CKD had a significantly increased risk of mortality compared with those without CKD (aHR, 2.84; 95% CI, 2.00-4.04). CONCLUSIONS: In patients with ACHD, the distribution of MS is higher, and both MS and its components were associated with CKD. Given the CKD was independently associated with mortality, close monitoring and management of renal dysfunction and metabolic parameters in ACHD patients is needed.

Factors influencing neonatal intensive care unit nurses' parent partnership development.

BACKGROUND: Neonatal nurses play an important role in the development of effective partnerships, as they have more consistent interactions with the patients' parents and can encourage parental involvement. This study aimed to identify factors influencing neonatal intensive care unit (NICU) nurses' development of partnerships with parents of high-risk infants in South Korea based on King's interacting systems theory. METHODS: We collected data utilizing a structured questionnaire, which included the following variables: developmental supportive nursing competency, empowerment, emotional intelligence, patient-centered communication skills, interpersonal competence, nursing work environment, and nurse-parent partnership. The participants were 140 pediatric nurses with at least one year of NICU experience in South Korea. We used SPSS/WIN 26.0 to analyze the data. FINDINGS: Of the factors evaluated, empowerment (ß = 0.35, p < 0.001), patient-centered communication skills (ß = 0.25, p < 0.01), interpersonal competence (ß = -0.27, p = 0.001), emotional intelligence (ß = 0.25, p = 0.005), age (ß = -0.15, p < 0.01), and gender (ß = 0.12, p = 0.03) explained 62.4% of the total variance of the nurse-parent partnership. Our results identify the factors affecting NICU nurses' development of partnerships with parents of high-risk infants. IMPLICATIONS FOR PRACTICE: Strategies and efforts to enhance the nurse-parent relationship must consider improving nurse empowerment, intelligence, and interpersonal factors.

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle.

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.

Predictor of atrial fibrillation recurrence in patients who underwent a tricuspid valve operation with modified Cox maze procedure.

BACKGROUND: Recurrence of any atrial arrhythmia after surgical ablation is known as a negative predictor of cardiovascular events and total mortality. However, there have been no focused studies for atrial fibrillation (AF) recurrence prediction in patients with significant tricuspid regurgitation (TR), and the risk-benefit estimation of surgical ablation in tricuspid valve (TV) surgery is not fully established. METHOD: We screened 385 patients who underwent a TV operation between 2001 and 2017. After excluding patients who did not undergo a maze operation, 158 patients were enrolled. Enrolled patients were divided by recurrence of AF. We analyzed the difference between the AF recurrence group and no AF recurrence group, and AF recurrence factors in terms of clinical risk factors and echocardiographic risk factors. The hazard ratio (HR) and 95% confidence intervals (CIs) were presented using a Cox proportional hazard model. RESULTS: Among 158 patients, AF recurred in 65 patients within 10 years. For AF prediction, age was most the important clinical factor and right atrium (RA) diameter was the most important echocardiographic parameters. In patients with a larger RA diameter over 49.2 mm, the prevalence of AF recurrence was higher (HR 4.322, 95% CI [2.185-8.549], log rank p value < .001). In clinical outcome, there was no significant difference between the AF recurrence group and the no recurrence group in terms of death, TR recurrence, heart failure, and stroke. However, the risk of permanent pacemaker (PPM) insertion was higher in the AF recurrence group (HR 10.240, 95% CI [1.257-83.480], log rank p value .007) compared to the no recurrence group. CONCLUSION: Age and RA enlargement are key predictors of AF recurrence after TV operation with the CM procedure in patients with significant TR.

A Retrospective Population-Based Survival Study of Idiopathic Pulmonary Arterial Hypertension in Korea.

BACKGROUND: Few studies used nationwide data to assess the survival rates (SRs) and death risk for idiopathic pulmonary arterial hypertension (IPAH; ICD-10 I27.0) in Korea. METHODS: IPAH data (N = 9,017; female:male = 6:4) were collected from the National Health Insurance Service in Korea, from 2006 through 2017. The data consisted of primary diagnoses related to IPAH. The Kaplan-Meier method and Cox proportional-hazards analyses were carried out. RESULTS: The mean age was 62.3 (± 19.4) years, 64.2 (± 18.9) years in female and 59.4 (± 19.8) years in male (P < 0.001). The one-, three-, five- and 10-year SRs for IPAH were 89.0%, 79.8%, 72.3% and 57.0%, respectively. The adjusted hazard ratio (HR) of IPAH was 1.81 (95% confidence interval [CI], 1.26-2.59) in 60-69 age group, 3.42 (95% CI, 2.40-4.87) in 70-79, and 7.73 (95% CI, 5.43-11.0) in 80s. Other risk factors were male, low-income status, diabetes, myocardial infarction, atrial fibrillation, ischemic stroke, hemorrhagic stroke, and malignant neoplasm. CONCLUSION: The 10-year SR of IPAH was 57% in Korea. The HR for IPAH was significantly high in patients with older age and other risk factors.

Determinants of Exercise Capacity in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Reduced exercise capacity reflects symptom severity and clinical outcomes in patients with hypertrophic cardiomyopathy (HCM). The present study aimed to identify factors that may affect exercise capacity in patients with HCM. METHODS: In 294 patients with HCM and preserved left ventricular (LV) ejection fraction, we compared peak oxygen consumption (peak VO2) evaluated by cardiopulmonary exercise testing as a representative parameter of exercise tolerance with clinical and laboratory data, including N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP), diastolic parameters on echocardiography, and the grade of myocardial fibrosis on cardiac magnetic resonance imaging (CMR). RESULTS: Median peak VO2, was 29.0 mL/kg/min (interquartile range [IQR], 25.0-34.0). Age (estimated ß = -0.140, P < 0.001), female sex (ß = -5.362, P < 0.001), NT-proBNP (ß = -1.256, P < 0.001), and E/e' ratio on echocardiography (ß = -0.209, P = 0.019) were significantly associated with exercise capacity. Peak VO2 was not associated with the amount of myocardial fibrosis on CMR (mean of late gadolinium enhancement 12.25 ± 9.67%LV). CONCLUSION: Decreased exercise capacity was associated with age, female sex, increased NT-proBNP level, and E/e' ratio on echocardiography. Hemodynamic changes and increased filling pressure on echocardiography should be monitored in this population for improved outcomes.

Autophagic defects observed in fibroblasts from a patient with ß-propeller protein-associated neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects in a patient with BPAN. We assayed autophagic markers using western blot analysis and immunocytochemistry and applied transmission electron microscopy (TEM) to visualize the autophagic structures in fibroblasts from a 7-year-old Korean female with WDR45 splice-site mutation (c.977-1G>A; NM_007075.3). The protein and mRNA expression levels of WDR45 gene were decreased in the patient-derived fibroblasts. The amount of increase in LC3-II upon treatment with an autophagy inducer and inhibitor was reduced in mutant cells compared to control cells, suggesting decreased autophagic flux. TEM showed the accumulation of large vacuoles in mutant cells with a decrease of autophagosomes. Our study demonstrated that the WDR45 mutation in this patient impaired autophagy and provided additional insight into ultrastructural changes of autophagic structures.

Impact of Atrial Fibrillation on Survival in Adults with Congenital Heart Disease: a Retrospective Population-based Study.

BACKGROUND: The number of adults with congenital heart disease (ACHD) with atrial fibrillation (AF) is expected to increase. We sought to assess the impact of AF on survival in Korean ACHD. METHODS: Records of AF in ACHD were extracted from the records of the Korea National Health Insurance Service from 2006 through 2015. Multiple Cox proportional hazards analyses were carried out after adjustment for age, sex, income level, AF, and comorbidities. Survival rates (SRs) with and without AF were compared. The death records from 2006 through 2016 were included. RESULTS: A total of 3,999 ACHD had AF (51.4% were male) and 62,691 ACHD did not have AF (43.5% were male); the proportion of ACHD who were 60 years and older was 53.0% and 27.0% in those with and without AF, respectively (P < 0.001). The age-standardized incidence rate for AF was 1,842.0 persons per 100,000 people in the Korean general population from 2006 through 2015. For AF in ACHD, it was 5,996.4 persons per 100,000 ACHD during the same period, which was higher than that in the general population (P < 0.001). Significantly higher proportion of death (20.9%) occurred in ACHD with AF than without AF (8.3%) (P < 0.001). The adjusted hazard ratio for AF of death in ACHD was 1.39 (95% confidence interval, 1.29-1.50). The ten-year SR of ACHD with AF was 69.7% whereas it was 87.5% in non-AF (P < 0.001). CONCLUSION: In ACHD, AF occurs more frequently and has a worse prognosis than seen in the non-valvular general population in Korea. AF is associated with increased death in ACHD, especially with aging.

Prevalence and clinical significance of cardiovascular magnetic resonance adenosine stress-induced myocardial perfusion defect in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is thought to be associated with microvascular dysfunction. Adenosine stress-perfusion cardiovascular magnetic resonance imaging (CMR) is a sensitive method for assessing microvascular perfusion abnormalities. We evaluated the prevalence and clinical characteristics of HCM patients with adenosine-induced perfusion defects on CMR. METHODS: Among 189 consecutive patients with HCM who underwent adenosine-stress perfusion CMR, 115 patients who had clinical, echocardiography, 24-h Holter monitoring and treadmill exercise test data were analyzed. We calculated myocardial perfusion ratio index from the intensity-over-time curve to quantify perfusion defects. The presence and extent of the stress-induced perfusion defect were compared with clinical characteristics, presence and extent of late gadolinium enhancement (LGE), left ventricular (LV) mass index and volume, presence of non-sustained ventricular tachycardia (NSVT) and results of treadmill exercise test. RESULTS: The mean age of enrolled patients was 51.8 ± 11.3 years. Most patients were asymptomatic except 25 subjects presented with New York Heart Association Class II dyspnea and 16 patients with atypical non-exertional chest discomfort. LGE was present in 103 (89.6%) subjects. Adenosine stress-induced perfusion defects were present in 48 (42%) subjects. None of the perfusion defects corresponded with a single or multiple coronary artery territories, showing a multiple patchy pattern in 24 (50.0%), a concentric subendocardial pattern in 20 subjects (41.7%), and as a single blot-like defect in the remaining 4 (8.3%). A perfusion defect was associated with NSVT, LV apical aneurysm, higher LV mass index, and higher LGE volume on univariate analysis. Multivariate analysis revealed female gender (P = 0.008), presence of apical aneurysm and NSVT (P = 0.036 and 0.047, respectively), and LV mass index (P = 0.022) to be independently associated with adenosine stress-induced perfusion defects. CONCLUSIONS: In patients with HCM, adenosine-stress perfusion defects on CMR are present in more than 40% of subjects. This perfusion defect is associated with NSVT, higher LV mass index, and apical aneurysms. The prognostic value of this finding needs further elucidation.

The Long-term Effectiveness of the Automatic Position-Adaptive System in Spinal Cord Stimulation: A Retrospective Comparative Study with a Two-Year Follow-up.

OBJECTIVE: To compare the nonadaptive manual system with the position-adaptive system in subjects with permanent spinal cord stimulator (SCS) implantation over a two-year follow-up period. DESIGN: Retrospective study. SETTING: Tertiary university-based national hospital. SUBJECTS: Patients who underwent permanent SCS implantation procedures. METHODS: Patients were divided into an adaptive group and a nonadaptive group according to the type of implanted SCS device. The primary outcome was the change (%) in pain intensity from baseline between the adaptive and nonadaptive groups at 24 months after SCS implantation. The secondary outcomes were comparisons of detailed clinical variables such as the scores of patient pain and satisfaction during the two-year follow-up after SCS therapy. Further, the number of subjects with SCS removal or revision within two years after SCS implantation was investigated. RESULTS: Of 187 patients with permanent SCS implantation, 85 in the nonadaptive group and 64 in the position-adaptive group were finally analyzed. The reduction in pain intensity at 24 months was higher in the adaptive group (-38.6%) than in the nonadaptive group (-30.8%, P = 0.05). Similarly, patient satisfaction with the SCS treatment at 24 months was superior in the adaptive group than in the nonadaptive group (85.7% vs 67.5% were satisfied in each group, respectively, P = 0.024). During the two years, 5.3% of patients (N = 10) underwent SCS removal and 7.0% (N = 13) underwent revision procedures. CONCLUSIONS: There was a trend of a sustained reduction in pain intensity as well as improvement in patient satisfaction at two-year follow-up in the position-adaptive system, suggesting long-term benefit over the nonadaptive manual system during SCS treatment.