Association of Antiarrhythmic Drug Therapy With Syncope and Pacemaker Implantation in Patients With Atrial Fibrillation.

BACKGROUND: Early rhythm control therapy mainly with antiarrhythmic drugs (AADs) for new-onset atrial fibrillation (AF) reduces major adverse cardiovascular events. However, negative dromotropic effects of AADs via ion channel blocking may cause bradyarrhythmias. OBJECTIVES: This study aimed to evaluate the association between AAD use and the risk of pacemaker implantation or syncope in patients with new-onset AF receiving early rhythm control therapy with AADs. METHODS: This study was based on data from the Korean National Health Insurance Service system. We screened all new-onset AF diagnoses that occurred from 2013 to 2019 and identified patients who were prescribed AADs within 1 year of AF diagnosis. The risk of pacemaker implantation or syncope was compared between AAD users and nonusers. RESULTS: A total of 770,977 new-onset AF cases were identified and 142,141 patients were prescribed AADs. After multivariate adjustment, use of AADs was associated with 3.5-, 2.0-, and 5.0-fold increased risk of pacemaker implantation or syncope, syncope, and pacemaker implantation, respectively. Propensity score-matched analysis revealed similar results, demonstrating a significant association between AAD use and the risk of pacemaker implantation or syncope. This association was consistent across various subgroups. Women were more susceptible to adverse effects of AADs than men. CONCLUSIONS: This study showed an association between AADs and risk of pacemaker implantation or syncope, a consistent finding across various subgroups. Precise evaluation of such risk should be undertaken before prescription of AADs.

Alcohol and the risk of all-cause death, atrial fibrillation, ventricular arrhythmia, and sudden cardiac arrest.

The risk of having atrial fibrillation (AF) is associated with alcohol intake. However, it is not clear whether sudden cardiac arrest (SCA) and ventricular arrhythmia (VA) including ventricular tachycardia, flutter, or fibrillation have similar associations with alcohol. We aimed to evaluate the association of alcohol intake with all-cause death, new-onset AF, VA, and SCA using single cohort with a sufficient sample size. A total of 3,990,373 people without a prior history of AF, VAs, or SCA was enrolled in this study based on nationwide health check-up in 2009. We classified the participants into four groups according to weekly alcohol consumption, and evaluated the association of alcohol consumption with each outcome. We observed a significant association between mild (hazard ratio [HR] = 0.826; 95% confidence interval [CI] = 0.815-0.838) to moderate (HR = 0.930; 95% CI = 0.912-0.947) drinking with decreased risk of all-cause mortality. However heavy drinking (HR = 1.108; 95% CI = 1.087-1.129) was associated with increased all-cause death. The risk of new-onset AF was significantly associated with moderate (HR = 1.129; 95% CI = 1.097-1.161) and heavy (HR = 1.298; 95% CI = 1.261-1.337) drinking. However, the risk of SCA showed negative association with all degrees of alcohol intake: 20% (HR = 0.803; 95% CI = 0.769-0.839), 15% (HR = 0.853; 95% CI = 0.806-0.902), and 8% (HR = 0.918; 95% CI = 0.866-0.974) lower risk for mild, moderate, and heavy drinkers, respectively. Mild drinking was associated with reduced risk of VA with moderate and heavy drinking having no associations. In conclusion, the association between alcohol and various outcomes in this study were heterogeneous. Alcohol might have different influences on various cardiac disorders.

Association of temporal change in body mass index with sudden cardiac arrest in diabetes mellitus.

BACKGROUND: Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus. METHODS: Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005-2008) were retrospectively analyzed. BMI was measured at baseline (2005-2008) and 4-year follow-up health examination (2009-2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA. RESULTS: A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25-3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15-2.74]), and previous underweight (2.12, [1.77-2.53]). CONCLUSIONS: In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.

Temporal elevation of blood pressure is associated with increased risk of sudden cardiac arrest.

Hypertension is a known risk factor for sudden cardiac arrest (SCA). However, the role of temporal changes in blood pressure on the risk of SCA is not fully understood. This study was conducted to determine whether a temporal increase or decrease in blood pressure is associated with the risk of SCA. This study was based on nationwide healthcare insurance data. Individuals who underwent nationwide health check-ups in 2009 and 2011 were analyzed. A total of 2,801,153 individuals were evaluated for 8100 SCA events during the 17, 740, 420 person-years of follow-up. In a multivariate analysis, there were linear association between the degree of temporal elevation of systolic blood pressure (SBP) and the risk of SCA: (i) adjusted-hazard ratio (HR) 1.11 (p = 0.001) in 10 ≤ ΔSBP < 20 (mmHg) group; (ii) adjusted-HR 1.40 (p < 0.001) in 20 ≤ ΔSBP < 40 group; and (iii) adjusted-HR 1.88 (p < 0.001) in 40 ≤ ΔSBP group as compared with the reference group (- 10 ≤ ΔSBP < 10). Temporal increase in diastolic blood pressure (DBP) also a showed significant association with SCA risk with the highest risk observed in ∆DBP ≥ 25 group (adjusted-HR 1.61; p < 0.001) as compared with the reference group (- 5 ≤ ΔDBP < 5). The association between SBP and SCA was not affected by age, sex, presence of diabetes mellitus, or baseline SBP. In conclusion, a temporal increase in blood pressure was significantly associated with the occurrence of SCA, and this association was consistent across all subgroups. However, a temporary decrease in blood pressure does not reduce the risk of SCA. Prevention of elevated blood pressure may play an important role in preventing SCA.

[Supersulfides to Regulate Electrophilic Stress].

Environmental electrophiles modify thiol groups of proteins in organs, disrupting cellular functions carried out by the modified proteins and increasing the risk of various diseases. The transcription factor NF-E2-related factor 2 (Nrf2) plays a crucial role in detoxifying electrophiles by forming glutathione adducts and subsequently excreting them into extracellular spaces. Supersulfides such as cysteine persulfides (CysSSH) produced by cystathionine γ-lyase (CSE) capture environmental electrophiles through sulfur adduct formation. However, the Nrf2 and CSE contributions to blocking environmental electrophile-mediated toxicity have yet to be evaluated. Therefore, we assessed the individual and combined roles of Nrf2 and CSE in suppressing toxicity induced by environmental electrophiles using Nrf2 knockout (KO), CSE KO, and Nrf2/CSE double KO (DKO) mice. Our findings indicate that CSE/Nrf2 DKO mice are more sensitive to environmental electrophiles compared to their single KO counterparts, highlighting the distinct mechanisms through which both pathways mitigate the toxic effects of reactive electrophiles. Moreover, diverse metabolites produced by symbiotic gut bacteria in the human body are known to exert various effects on host organ functions beyond the intestinal tract. We observed reduced blood supersulfide levels in mice lacking gut microflora compared to normal mice. Furthermore, we identified intestinal bacteria belonging to the families Ruminococcaceae and Lachnospiraceae as high CysSSH-producing bacteria. This suggests that the gut microbiota serves as a source of in vivo supersulfide molecules. These findings suggest that supersulfide derived from gut bacteria may act protectively against environmental electrophilic exposure in the host.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19.

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

Identification of concealed cardiomyopathy using next-generation sequencing-based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation.

AIMS: Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF. METHODS AND RESULTS: This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. CONCLUSION: Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy.

Impact of pulmonary artery pressure on recurrence after catheter ablation in patients with atrial fibrillation.

Background: The pulmonary veins play a major role in the pathogenesis of atrial fibrillation (AF) and may be affected by cardiac remodeling due to pulmonary vascular dysfunction. It remains to be determined whether pulmonary artery pressure (PAP) is associated with the recurrence of AF after radiofrequency catheter ablation (RFCA). Methods: Consecutive patients with paroxysmal and persistent AF who underwent RFCA, including wide circumferential pulmonary vein isolation, were analyzed. Systolic PAP was measured using transthoracic echocardiography, and clinical outcomes were compared between patients with PAP <35 mmHg and those with PAP ≥35 mmHg. Results: Among 2,379 patients (mean age 56.7 ± 10.6 years, 77% men), 1,893 (79.6%) had PAP <35 mmHg and 486 (20.4%) had PAP ≥35 mmHg. During the median follow-up of 25.4 months, in patients with paroxysmal AF (n = 1,294), the recurrence rate was significantly greater in the PAP ≥35 mmHg group than in the PAP <35 mmHg group (35.1% vs. 23.8%, log-rank p = 0.008). However, in patients with persistent AF (n = 1,085), the recurrence rate was not significantly different between the two groups (52.2% vs. 49.7%, log-rank p = 0.409). Multivariate analysis using Cox regression showed that PAP ≥35 mmHg was significantly associated with clinical recurrence (hazard ratio 1.19, 95% confidence interval 1.02-1.40, p = 0.027). Conclusion: This study showed that a higher PAP was associated with an increased risk of recurrence after RFCA in patients with paroxysmal AF, suggesting a mechanism by which a pulmonary vascular pathology may cause impairment of the pulmonary veins and remodeling of the left atrium.

Clinical and Genetic Features of Korean Inherited Arrhythmia Probands.

BACKGROUND AND OBJECTIVES: Inherited arrhythmia (IA) is a more common cause of sudden cardiac death in Asian population, but little is known about the genetic background of Asian IA probands. We aimed to investigate the clinical characteristics and analyze the genetic underpinnings of IA in a Korean cohort. METHODS: This study was conducted in a multicenter cohort of the Korean IA Registry from 2014 to 2017. Genetic testing was performed using a next-generation sequencing panel including 174 causative genes of cardiovascular disease. RESULTS: Among the 265 IA probands, idiopathic ventricular fibrillation (IVF) and Brugada Syndrome (BrS) was the most prevalent diseases (96 and 95 cases respectively), followed by long QT syndrome (LQTS, n=54). Two-hundred-sixteen probands underwent genetic testing, and 69 probands (31.9%) were detected with genetic variant, with yield of pathogenic or likely pathogenic variant as 6.4%. Left ventricular ejection fraction was significantly lower in genotype positive probands (54.7±11.3 vs. 59.3±9.2%, p=0.005). IVF probands showed highest yield of positive genotype (54.0%), followed by LQTS (23.8%), and BrS (19.5%). CONCLUSIONS: There were significant differences in clinical characteristics and genetic yields among BrS, LQTS, and IVF. Genetic testing did not provide better yield for BrS and LQTS. On the other hand, in IVF, genetic testing using multiple gene panel might enable the molecular diagnosis of concealed genotype, which may alter future clinical diagnosis and management strategies.

Dysfunction of Foxp3+ Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen.

Foxp3+ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes.

Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor.

Introduction: Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. Methods: We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs). Results: The genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs. Discussion: Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Obesity Is Indirectly Associated with Sudden Cardiac Arrest through Various Risk Factors.

Although obesity is a well-established risk factor of cardiovascular event, the linkage between obesity and sudden cardiac arrest (SCA) is not fully understood. Based on a nationwide health insurance database, this study investigated the impact of body weight status, measured by body-mass index (BMI) and waist circumference, on the SCA risk. A total of 4,234,341 participants who underwent medical check-ups in 2009 were included, and the influence of risk factors (age, sex, social habits, and metabolic disorders) was analyzed. For 33,345,378 person-years follow-up, SCA occurred in 16,352 cases. The BMI resulted in a J-shaped association with SCA risk, in which the obese group (BMI ≥ 30) had a 20.8% increased risk of SCA compared with the normal body weight group (18.5 ≤ BMI < 23.0) (p < 0.001). Waist circumference showed a linear association with the risk of SCA, with a 2.69-fold increased risk of SCA in the highest waist circumference group compared with the lowest waist circumference group (p < 0.001). However, after adjustment of risk factors, neither BMI nor waist circumference was associated with the SCA risk. In conclusion, obesity is not independently associated with SCA risk based on the consideration of various confounders. Rather than confining the findings to obesity itself, comprehensive consideration of metabolic disorders as well as demographics and social habits might provide better understanding and prevention of SCA.

Being Underweight Is Associated with Increased Risk of Sudden Cardiac Death in People with Diabetes Mellitus.

BACKGROUND: Diabetes mellitus (DM) can cause various atherosclerotic cardiovascular disease including sudden cardiac death (SCD). The impact of being underweight on the risk of SCD in people with DM remains to be revealed. We aimed to evaluate the risk of SCD according to body-mass index (BMI; kg/m2) level in DM population. METHODS: We used a nationwide healthcare insurance database to conduct this study. We identified people with DM among those who underwent nationwide health screening during 2009 to 2012. Medical follow-up data was available until December 2018. RESULTS: A total of 2,602,577 people with DM with a 17,851,797 person*year follow-up were analyzed. The underweight group (BMI < 18.5) showed 2.4-fold increased risk of SCD during follow-up (adjusted-hazard ratio [HR] = 2.40; 95% confidence interval [CI] = 2.26-2.56; p < 0.001). When normal-BMI group (18.5 ≤ BMI < 23) was set as a reference, underweight group (adjusted-HR = 2.01; 95% CI = 1.88-2.14) showed even higher risk of SCD compared with the obesity group (BMI ≥ 30; adjusted-HR = 0.89; 95% CI = 0.84-0.94). When BMI was stratified by one unit, BMI and SCD risk showed a U-curve association with the highest risk observed at low BMI levels. The lowest risk was observed in 27 ≤ BMI < 28 group. The association between being underweight and increased SCD risk in DM people was maintained throughout various subgroups. CONCLUSIONS: Being underweight is significantly associated with an increased risk of SCD in the DM population. A steep rise in the risk of SCD was observed as the BMI level decreased below 23. The lowest risk of SCD was observed in 27 ≤ BMI < 28 group.

Association between low-density lipoprotein cholesterol and sudden cardiac arrest in people with diabetes mellitus.

BACKGROUND: Dyslipidemia measured as low-density lipoprotein (LDL)-cholesterol is an established risk factor of cardiovascular disease, which is more pronounced in diabetes population. Less is known about the association of LDL-cholesterol level and sudden cardiac arrest (SCA) risk in diabetes mellitus patients. This study investigated the association of LDL-cholesterol level and SCA risk in diabetes population. METHODS: This study was based on Korean National Health Insurance Service database. Patients who received general examination from 2009 to 2012 and diagnosed as type 2 diabetes mellitus were analyzed. Primary outcome was defined as SCA event identified with International Classification of Disease code. RESULTS: A total of 2,602,577 patients were included, with total follow-up duration of 17,851,797 person * year. Mean follow-up duration was 6.86 years, and 26,341 SCA cases were identified. Overall incidence of SCA was highest in the lowest LDL-cholesterol group (< 70 mg/dL) and decreased in a linear manner as LDL-cholesterol rises, till 160 mg/dL. Adjustment of covariates resulted in U-shape association, with highest risk of SCA in the highest LDL-cholesterol group (≥ 160 mg/dL) followed by lowest LDL-cholesterol group (< 70 mg/dL). In subgroup analysis, U-shape association between SCA risk and LDL-cholesterol was more pronounced in male, non-obese people, and those who did not use statins. CONCLUSIONS: In people with diabetes, the association between SCA and LDL-cholesterol level was U-shaped with highest and lowest LDL-cholesterol group having higher risk of SCA than others. Low LDL-cholesterol level can be a surrogate marker for increased risk of SCA in people with diabetes mellitus and this paradoxical association should be recognized and extended to clinical preventive measures.

Long-term increase in fasting blood glucose is associated with increased risk of sudden cardiac arrest.

BACKGROUND: Diabetes mellitus (DM) is associated with various cardiovascular complications, including sudden cardiac arrest (SCA). Furthermore, the severity of DM, as assessed by fasting blood glucose (FBG), is associated with the risk of SCA. However, whether long-term changes in FBG influence on SCA risk remains to be determined. METHODS: This study used sequential nationwide health screening data from 2009 and 2011. FBG was measured at each health screening, and ΔFBG was calculated as FBG in 2011-FBG in 2009. RESULTS: Overall, 2,801,153 people were analyzed, and the mean follow-up duration was 6.33 years. Compared with the euglycemic group (- 20 ≤ ΔFBG < 20), the 20 ≤ ΔFBG < 40, 40 ≤ ΔFBG < 100, and ΔFBG ≥ 100 groups had increased SCA risks of 25% (adjusted hazard ratio [HR] = 1.25; 95% confidence interval [CI] 1.16-1.35; p < 0.001), 66% (adjusted HR = 1.66; 95% CI 1.49-1.86; p < 0.001), and 2.9-fold (adjusted HR = 2.85; 95% CI 2.37-3.44; p < 0.001), respectively. The association between ΔFBG and SCA was maintained in people with DM but not in people without DM. However, sex, age, blood pressure, and presence of heart failure did not affect the association between ΔFBG and SCA. A decrease in ΔFBG over time was not associated with reduced risk of SCA: the adjusted HR was 1.11 (95% CI 0.98-1.27; p = 0.113) for the ΔFBG < -40 group and 1.12 (95% CI 1.03-1.22; p = 0.009) for the - 40 ≤ ∆FBG < - 20 group. CONCLUSIONS: A long-term increase in ΔFBG can be associated with increased risk of SCA in people with DM. However, a long-term decrease in ΔFBG was not associated with reduced risk of SCA. Actions to prevent increase in FBG can have significant effects on public health in terms of SCA prevention.

SCIATIC DENERVATION-INDUCED SKELETAL MUSCLE ATROPHY IS ASSOCIATED WITH PERSISTENT INFLAMMATION AND INCREASED MORTALITY DURING SEPSIS.

ABSTRACT: Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group ( P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP ( P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP ( P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP ( P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress ( P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1ß: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.

Atrial Cardiomyopathy with Impaired Functional Reserve in Patients with Paroxysmal Atrial Fibrillation.

BACKGROUND: Impaired atrial functional reserve during exercise may represent an early stage of atrial cardiomyopathy. To test this hypothesis, the authors evaluated left atrial (LA) and left ventricular (LV) function reserve during exercise in patients with paroxysmal atrial fibrillation (PAF). METHODS: Sixty-one patients with PAF undergoing radiofrequency catheter ablation and 38 healthy control subjects were prospectively enrolled. LV global longitudinal strain and LA reservoir strain (RS) were measured at rest and during supine bicycle exercise. To identify the early stage of atrial cardiomyopathy without LA structural remodeling, patients with PAF were divided into two groups according to LA volume index (LAVI): atrial fibrillation (AF) group 1 (LAVI ≥ 34 mL/m2) and AF group 2 (LAVI < 34 mL/m2). RESULTS: LV ejection fraction and global longitudinal strain did not differ between patients with AF and control subjects. LAVI and LA RS did not differ between AF group 2 and control subjects. During exercise, LV global longitudinal strain improved in all groups. Increases in LA RS were attenuated in both AF groups, which also exhibited lower LA functional reserve index than the control subjects. Although resting LA RS was similar between AF group 2 and control subjects, LA functional reserve index was significantly lower in AF group 2. LA functional reserve index was associated with risk for AF recurrence (hazard ratio, 0.852; 95% CI, 0.736-0.988). CONCLUSIONS: Atrial cardiomyopathy can be anticipated by impaired LA functional reserve during exercise in patients with AF, even in those with normal-sized left atria. Atrial cardiomyopathy occurs independently of changes in LV function and is associated with the recurrence of AF in patients with PAF after radiofrequency catheter ablation.

Association of typical atrial flutter and cavotricuspid isthmus ablation on clinical recurrence after cryoballoon ablation for atrial fibrillation.

Typical atrial flutter commonly occurs in patients with atrial fibrillation (AF). Limited information exists regarding the effects of concurrent atrial flutter on the long-term outcomes of rhythm control. This study investigated the association between concurrent typical atrial flutter and cavotricuspid isthmus (CTI) ablation and the recurrence of atrial arrhythmia. The data were obtained from a multicenter registry of cryoballoon ablation for AF (n = 2,689). Patients who were screened for typical atrial flutter were included in the analysis (n = 1,907). All the patients with typical atrial flutter underwent CTI ablation. The primary endpoint was the late recurrence of atrial arrhythmia, including AF, atrial flutter, and atrial tachycardia. Among the 1,907 patients, typical atrial flutter was detected in 493 patients (25.9%). Patients with concurrent atrial flutter had a lower incidence of persistent AF and a smaller size of the left atrium. Patients with atrial flutter had a significantly lower recurrence rate of atrial arrhythmia (19.7% vs. 29.9%, p < 0.001). In patients with atrial flutter, the recurrence rate of atrial tachycardia or atrial flutter was more frequent (7.3% vs. 4.7%, p = 0.028), but the recurrence rate of AF was significantly lower (17.0% vs. 29.4%, p < 0.001). Atrial flutter has been identified as an independent predictor of the primary endpoint (adjusted hazard ratio, 0.704; 95% confidence interval, 0.548-0.906; p = 0.006). Typical atrial flutter in patients with AF may serve as a positive marker of the recurrence of atrial arrhythmia, and performing CTI ablation in this population is associated with a reduced likelihood of AF recurrence. Performing routine screening and ablation procedures for coexisting atrial flutter may improve the clinical outcomes of AF.

Clinical Significance of Adenosine-Induced Atrial Fibrillation after Complete Pulmonary Vein Isolation.

BACKGROUND: Adenosine can cause dormant electrical conduction between the pulmonary vein and left atrium after pulmonary vein isolation (PVI). Adenosine can also induce atrial fibrillation (AF) during catheter ablation. However, the clinical outcomes and effects of additional ablation for the trigger sites of adenosine-induced AF (AIAF) are unknown. This study therefore aimed to evaluate the clinical significance of AIAF. METHODS: Between January 2010 and September 2019, we analyzed 616 consecutive patients with paroxysmal AF (PAF) who underwent radiofrequency catheter ablation (RFCA), including wide-area circumferential pulmonary vein isolation (PVI) and post-PVI adenosine testing. RESULTS: Among 616 patients, 134 (21.7%) and 34 (5.5%) showed dormant conduction and AIAF, respectively. Eight patients (1.3%) had both dormant conduction and AIAF. The AF recurrence rate was not significantly different between patients with and without AIAF (16.7% vs. 18.6%, log-rank p = 0.827) during a mean follow-up period of 17.9 ± 18 months. Additional RFCA for the trigger site was attempted in 10 patients with AIAF; however, the recurrence rate of atrial arrhythmias was also not different between the groups with and without additional ablation (20% vs. 16.7%, log-rank p = 0.704). CONCLUSIONS: AIAF after PVI was not clinically associated with recurrence during long-term follow-up. Ablation of the trigger site in AIAF did not improve the clinical outcomes.