Increased frequency of CD4+CD57+ senescent T cells in patients with newly diagnosed acute heart failure: exploring new pathogenic mechanisms with clinical relevance

Recent animal studies showed T cells have a direct pathogenic role in the development of heart failure (HF). However, which subsets of T cells contribute to human HF pathogenesis and progression remains unclear. We characterized immunologic properties of various subsets of T cells and their clinical implications in human HF. Thirty-eight consecutive patients with newly diagnosed acute HF (21 males, mean age 66 ± 16 years) and 38 healthy control subjects (21 males, mean age 62 ± 12 years) were enrolled. We found that pro-inflammatory mediators, including CRP, IL-6 and IP-10 and the frequencies of CD57+ T cells in the CD4+ T cell population were significantly elevated in patients with acute HF compared to control subjects. A functional analysis of T cells from patients with acute HF revealed that the CD4+CD57+ T cell population exhibited a higher frequency of IFN-γ- and TNF-α- producing cells compared to the CD4+CD57- T cell population. Furthermore, the frequency of CD4+CD57+ T cells at baseline and its elevation at the six-month follow-up were significantly related with the development of cardiovascular (CV) events, which were defined as CV mortality, cardiac transplantation, or rehospitalization due to HF exacerbation. In conclusion, CD4+CD57+ senescent T cells showed more inflammatory features and polyfunctionality and were associated with clinical outcome in patients with acute HF. More detailed study for senescent T cells might offer new opportunities for the prevention and treatment of human HF.ope

Phenotypic and Functional Analysis of Human NK Cell Subpopulations According to the Expression of FcεRIγ and NKG2C

Human memory-like NK cells are commonly defined by either a lack of FcεRIγ or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56dim NK cell subpopulations according to the expression of FcεRIγ and NKG2C in a large cohort (n = 127). Although the frequency of FcεRIγ- and NKG2C+ NK cells positively correlated, the FcεRIγ- and NKG2C+ NK cell populations did not exactly overlap. The FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, FcεRIγ-NKG2C+ NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, FcεRIγ-NKG2C+ NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, FcεRIγ-NKG2C+ NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas FcεRIγ+NKG2C+ NK cells had strong effector functions in both settings. Anatomically, the FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by FcεRIγ and NKG2C and suggest both markers be utilized to better define these cells.ope

Physical Activity and Risk of Atrial Fibrillation: A Nationwide Cohort Study in General Population

Although exercise prevents cardiovascular disease and mortality, vigorous exercise and endurance athletics can cause atrial fibrillation (AF). However, no large cohort study has assessed the relationship between physical activity and AF in the general population. We assessed the effect of physical activity at different energy expenditures on the incidence of AF. We studied 501,690 individuals without pre-existing AF (mean age, 47.6 ± 14.3 years; 250,664 women [50.0%]) included in the Korean National Health Insurance Service database. The physical activity level was assessed using a standardized self-reported questionnaire at baseline. During a median follow-up of 4 years, 3,443 participants (1,432 women [41.6%]) developed AF. The overall incidence of AF at follow-up was 1.79 per 1,000 person-years. The subjects who met the recommended physical activity level (500-1,000 metabolic equivalent task [MET] minutes/week) had a 12% decreased AF risk (adjusted hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.80-0.97), but not the insufficiently (1-500 MET-minutes/week; HR: 0.94, 95% CI: 0.86-1.03) and highly active subjects (≥1,000 MET-minutes/week; HR: 0.93, 95% CI: 0.85-1.03). The recommended minimum key target range of physical activity level was associated with the maximum benefit for reduced AF risk in the general population. The dose-response relationship between physical activity level and AF risk showed a U-shaped pattern. Although exceeding the key target range attenuated this benefit, it did not increase the AF risk beyond that during inactivity.ope

Variations of Prevalence and Incidence of Atrial Fibrillation and Oral Anticoagulation Rate According to Different Analysis Approaches

The reported incidence and prevalence of atrial fibrillation (AF) has been inconsistent across published studies. Using the National Health Insurance Service database of Korea, the prevalence and incidence of AF, and oral anticoagulation (OAC) use of AF patients were explored according to three different approaches; 'formal approach', considering individual AF diagnosis and mortality; 'limited diagnosis approach', using upper 5 main diagnosis; and 'medical use approach', using the number of medical use AF population by year without considering individual AF history and mortality. The AF prevalence progressively increased by 2.46-fold from 0.50% in 2004 to 1.54% in 2015 when using a 'formal approach' (p for trend <0.001). The overall prevalence was 1.09% and 0.97% when using a 'formal approach' and 'limited diagnosis approaches', respectively. Overall prevalence decreased to 0.52% with a 'medical use approach'. The trend of annual AF incidence was stable when using a 'formal approach', but increased by 15% when using a 'medical use approach'. OAC rate in 2015 was 2.1 times higher when using a 'medical use approach' compared to using a 'formal approach' (40.3% vs. 19.1%, p < 0.001). Given the wide variability in prevalence and incidence figures with different analysis approaches, careful attention to the analysis methodology is needed.ope

The Burden and Risk Factors for Infection of Transvenous Cardiovascular Implantable Electronic Device: a Nationwide Cohort Study

BACKGROUND AND OBJECTIVES: There are limited published data on the incidence and cost associated with cardiac implantable electrical device (CIED) infection for Asian patients. We analyzed the infection burden associated with the implantation of CIEDs in Korea. METHODS: In the Health Insurance Review & Assessment Service (HIRA) database during the period from January 1, 2014 to December 31, 2016, we identified 16,908 patients with CIED implantation. CIED infection was defined as either: 1) Infection-related diagnosis code by the Korean Standard Classification of Diseases after any CIED procedure; or 2) CIED removal along with systemic infection. RESULTS: The proportions of first implantation and replacement were 77.6% and 22.4%, respectively. During the follow-up period of 17.1±10.6 months, a total of 462 patients had CIED infection with incidence of 1.95 per 100 person-years with higher infection rate in replacement than first implantation (3.97 vs. 1.4 per 100 person-years, p<0.001). The average cost per person was US$16,584 (pacemaker,$13,736; implantable cardioverter defibrillator, $28,402; cardiac resynchronization therapy,$29,674). The risk factors of CIED infection were generator replacement (adjusted hazard ratio [aHR], 3.14; 95% confidence interval [CI], 2.60-3.78), diabetes mellitus (aHR, 1.94; 95% CI, 1.58-2.38), and congestive heart failure (aHR, 1.86; 95% CI, 1.51-2.28). CONCLUSIONS: The rate of CIED infection in Korea was 1.95 per 100 person-years with average cost of US$ 16,584. The most important risk factor was generator replacement. This result suggests that generator replacement should be performed cautiously to avoid CIED infection.ope

Gender Difference in Catheter Ablation: Atrial Fibrillations from Mars and Venus?

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Prevalence and Predictors of Clinically Relevant Atrial High-Rate Episodes in Patients with Cardiac Implantable Electronic Devices

Background and objectives: Atrial high-rate episodes (AHREs) can be continuously detected by cardiovascular implantable electronic devices (CIEDs); however, the predictors of clinically relevant AHREs are unclear. Methods: This prospective multicenter study monitored 816 patients (median age 73 years, 40.4% male) without atrial fibrillation (AF) from September 2017 to July 2020. AHREs was defined as a programmed atrial detection rate >220 beats/min. The reference values of 6 minutes and 6 hours were set to analyze clinical implication of AHREs based on previously published data that the 6 minutes excluded most episodes of oversensing. Results: During a median follow-up of 18 months (interquartile interval 9-26 months), AHREs with the longest durations of >15 seconds, >6 minutes, and >6 hours and clinically documented AF by electrocardiography were noted in 246 (30.1%), 112 (13.7%), 49 (6.0%), and 24 (2.9%) patients, respectively. Among patients developing AHREs >6 minutes, 102 (91.1%) of 112 patients were identified at the 6-month visit. Patients with AHREs >6 minutes had higher proportions of sick sinus syndrome, subjects with atrial premature beat >1% on Holter monitoring, and larger left atrium (LA) size than patients with AHREs ≤6 minutes. Multivariable logistic regression analysis showed that LA diameter >41 mm (odds ratio [OR], 2.08; 95% confidence interval [95% CI], 1.25-3.45), and sick sinus syndrome (OR, 3.22; 95% CI, 1.91-5.43) were associated with AHREs >6 minutes. Conclusions: In patients with LA diameter >41 mm, and sick sinus syndrome before CIEDs implantation is associated with risk of developing AHREs >6 minutes. Trial registration: ClinicalTrials.gov Identifier: NCT03303872.ope

Oral Anticoagulation Therapy in Atrial Fibrillation Patients with Advanced Chronic Kidney Disease: CODE-AF Registry

Purpose: Advanced chronic kidney disease (CKD), including end-stage renal disease (ESRD) on dialysis, increases thromboembolic risk among patients with atrial fibrillation (AF). This study examined the comparative safety and efficacy of direct-acting oral anticoagulant (DOAC) compared to warfarin or no oral anticoagulant (OAC) in AF patients with advanced CKD or ESRD on dialysis. Materials and methods: Using data from the COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, 260 non-valvular AF patients with advanced CKD (defined as estimated glomerular filtration rate <30 mL/min per 1.73/m²) or ESRD on dialysis were enrolled from June 2016 to July 2020. The study population was categorized into DOAC, warfarin, and no OAC groups; and differences in major or clinically relevant non-major (CRNM) bleeding, stroke/systemic embolism (SE), myocardial infarction/critical limb ischemia (CLI), and death were assessed. Results: During a median 24 months of follow-up, major or CRNM bleeding risk was significantly reduced in the DOAC group compared to the warfarin group [hazard ratio (HR) 0.11, 95% confidence interval (CI) 0.01 to 0.93, p=0.043]. In addition, the risk of composite adverse clinical outcomes (major or CRNM bleeding, stroke/SE, myocardial infarction/CLI, and death) was significantly reduced in the DOAC group compared to the no OAC group (HR 0.16, 95% CI 0.03 to 0.91, p=0.039). Conclusion: Among AF patients with advanced CKD or ESRD on dialysis, DOAC was associated with a lower risk of major or CRNM bleeding compared to warfarin and a lower risk of composite adverse clinical outcomes compared to no OAC. ClinicalTrials.gov (NCT02786095).ope

Artificial intelligence predicts clinically relevant atrial high-rate episodes in patients with cardiac implantable electronic devices

To assess the utility of machine learning (ML) algorithms in predicting clinically relevant atrial high-rate episodes (AHREs), which can be recorded by a pacemaker. We aimed to develop ML-based models to predict clinically relevant AHREs based on the clinical parameters of patients with implanted pacemakers in comparison to logistic regression (LR). We included 721 patients without known atrial fibrillation or atrial flutter from a prospective multicenter (11 tertiary hospitals) registry comprising all geographical regions of Korea from September 2017 to July 2020. Predictive models of clinically relevant AHREs were developed using the random forest (RF) algorithm, support vector machine (SVM) algorithm, and extreme gradient boosting (XGB) algorithm. Model prediction training was conducted by seven hospitals, and model performance was evaluated using data from four hospitals. During a median follow-up of 18 months, clinically relevant AHREs were noted in 104 patients (14.4%). The three ML-based models improved the discrimination of the AHREs (area under the receiver operating characteristic curve: RF: 0.742, SVM: 0.675, and XGB: 0.745 vs. LR: 0.669). The XGB model had a greater resolution in the Brier score (RF: 0.008, SVM: 0.008, and XGB: 0.021 vs. LR: 0.013) than the other models. The use of the ML-based models in patient classification was associated with improved prediction of clinically relevant AHREs after pacemaker implantation.ope

Ganglionated plexi stimulation induces pulmonary vein triggers and promotes atrial arrhythmogenecity: In silico modeling study

BACKGROUND: The role of the autonomic nervous system (ANS) on atrial fibrillation (AF) is difficult to demonstrate in the intact human left atrium (LA) due to technical limitations of the current electrophysiological mapping technique. We examined the effects of the ANS on the initiation and maintenance of AF by employing a realistic in silico human left atrium (LA) model integrated with a model of ganglionated plexi (GPs). METHODS: We incorporated the morphology of the GP and parasympathetic nerves in a three-dimensional (3D) realistic LA model. For the model of ionic currents, we used a human atrial model. GPs were stimulated by increasing the IK[ACh], and sympathetic nerve stimulation was conducted through a homogeneous increase in the ICa-L. ANS-induced wave-dynamics changes were evaluated in a model that integrated a patient's LA geometry, and we repeated simulation studies using LA geometries from 10 different patients. RESULTS: The two-dimensional model of pulmonary vein (PV) cells exhibited late phase 3 early afterdepolarization-like activity under 0.05μM acetylcholine (ACh) stimulation. In the 3D simulation model, PV tachycardia was induced, which degenerated to AF via GP (0.05μM ACh) and sympathetic (7.0×ICa-L) stimulations. Under sustained AF, local reentries were observed at the LA-PV junction. We also observed that GP stimulation reduced the complex fractionated atrial electrogram (CFAE)-cycle length (CL, p<0.01) and the life span of phase singularities (p<0.01). GP stimulation also increased the overlap area of the GP and CFAE areas (CFAE-CL≤120ms, p<0.01). When 3 patterns of virtual ablations were applied to the 3D AF models, circumferential PV isolation including the GP was the most effective in terminating AF. CONCLUSION: Cardiac ANS stimulations demonstrated triggered activity, automaticity, and local reentries at the LA-PV junction, as well as co-localized GP and CFAE areas in the 3D in silico GP model of the LA.ope