Effect of His Bundle Pacing on Abnormal Myocardial Fatty Acid and Glucose Metabolism Induced by Right Ventricular Pacing.

BACKGROUND: Metabolic disorder is noted for pacing-induced cardiomyopathy. The benefits of His bundle pacing over right ventricular (RV) pacing in preventing pacing-induced cardiomyopathy from a metabolic perspective are yet to be fully understood. METHOD AND RESULTS: Three pig groups were established for this study: sham control, RV pacing (RV pacing for 6 months), and His pacing (RV pacing for 6 months, followed by His bundle pacing for 3 months). Complete atrioventricular block was created in the last 2 groups. Left ventricular function and dyssynchrony were assessed via echocardiography, while proteins linked to metabolism, endoplasmic reticulum stress, and inflammation in left ventricular myocardium were examined. The RV pacing group had significantly more left ventricular mechanical dyssynchrony compared with the other groups. The RV pacing group exhibited triglyceride and diacylglycerol accumulation in cardiomyocytes and higher expression of binding immunoglobulin protein and tumor necrosis factor-α than the other groups. Additionally, the expression of CD36 was activated, while the expression of hormone-sensitive lipase was downregulated in the RV pacing group compared with the His pacing and sham control groups. Furthermore, the expressions of GLUT4 and pyruvate dehydrogenase were higher in the RV pacing group than the sham control and His pacing groups. Notably, the abnormal fatty acid and glucose metabolic pathways in the left ventricular myocardium during RV pacing could be corrected by His bundle pacing. CONCLUSIONS: His bundle pacing can mitigate the abnormal metabolism disorders, endoplasmic reticulum stress, and inflammation induced during RV pacing and may contribute to the superiority of conduction system pacing over RV pacing in reducing heart failure hospitalization.

Long non-coding RNA FKSG29 regulates oxidative stress and endothelial dysfunction in obstructive sleep apnea.

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.

Device-related infection and mortality in patients with chronic kidney disease receiving cardiac implantable electronic devices: a propensity score-matched cohort study.

BACKGROUND: Chronic kidney disease (CKD) was reported to be a risk factor of cardiac implantable electronic device (CIED) infection. The application of bundled skin antiseptic preparation before CIED implantation decreased the risk of CIED infection, even in patients undergoing complex procedures. However, the effect of bundled skin antiseptic preparation to prevent CIED infection in patients with CKD was not tested. METHODS: Between July 2012 and December 2019, 1668 patients receiving CIEDs comprised this retrospective cohort study and were categorized into two groups by the diagnosis of CKD: group with CKD (n = 750, 45%) and group without CKD (n = 918, 55%). The primary outcome was clinical CIED infection, including major and minor infection, and the secondary outcomes were cardiovascular mortality and all-cause mortality. Propensity score matching (PSM) was applied to reduce selection bias between the study groups. RESULTS: During a 4-year follow-up period, 30 patients (1.8%) had a CIED infection. After PSM, the incidence of CIED infection was similar between the patients with CKD and without CKD (1.0% vs. 1.8%). The incidences of cardiovascular mortality and all-cause mortality were higher in patients with CKD compared to patients without CKD (6.5% vs. 3.0%, P = 0.009; 22.8% vs. 11.8%, P < 0.001, respectively). CONCLUSION: The incidence of clinical CIED infection in patients with CKD was as lower as in patients without CKD after applying the bundled skin antiseptic preparation strategy. The cumulative incidences of cardiovascular mortality and all-cause mortality were significantly higher in the matched CIED recipients with CKD compared to the matched cohort without CKD.

Left bundle branch pacing preserved left ventricular myocardial work in patients with bradycardia.

Background: Left bundle branch pacing (LBBP) is an emerging physiological pacing modality. Left ventricular (LV) myocardial work (MW) incorporates afterload and LV global longitudinal strain to estimate global and segmental myocardial contractility. However, the effect of LBBP on LV MW remains unknown. This study aimed to evaluate the impact of LBBP on LV MW in patients receiving pacemaker for bradyarrhythmia. Methods: We prospectively enrolled 70 bradycardia patients with normal LV systolic function receiving LBBP (n = 46) and non-selective His-bundle pacing (NS-HBP) (n = 24). For comparative analysis, patients receiving right ventricular pacing (RVP) (n = 16) and control subjects (n = 10) were enrolled. Two-dimensional speckle tracking echocardiography was performed. The LV pressure-strain loop was non-invasively constructed to assess global LV MW. Results: After 6-month follow-up, LBBP group (with >40% ventricular pacing during 6 months) had shorter peak strain dispersion (PSD) compared with RVP group, and higher LV global longitudinal strain compared with RVP group and NS-HBP group, but had no difference in left intraventricular mechanical dyssynchrony, including septal-to-posterior wall motion delay and PSD, compared with NS-HBP group. During ventricular pacing, LBBP group had higher global MW index (GWI) (2,189 ± 527 vs. 1,493 ± 799 mmHg%, P = 0.002), higher global constructive work (GCW) (2,921 ± 771 vs. 2,203 ± 866 mmHg%, P = 0.009), lower global wasted work (GWW) (211 ± 161 vs. 484 ± 281 mmHg%, P < 0.001) and higher global MW efficiency (GWE) (91.4 ± 5.0 vs. 80.9 ± 8.3%, P < 0.001) compared with RVP group, and had lower GWW (211 ± 161 vs. 406 ± 234 mmHg%, P < 0.001) and higher GWE (91.4 ± 5.0 vs. 86.4 ± 8.1%, P < 0.001) compared with NS-HBP group. Conclusions: In this study we found that in patients with mid-term (6-month) high ventricular pacing burden (>40%), LBBP preserved more LV MW compared with NS-HBP and RVP. Further studies are warranted to assess the association between LV MW and long-term clinical outcomes in LBBP with high ventricular pacing burden.

Interleukin-18 and Gelsolin Are Associated with Acute Kidney Disease after Cardiac Catheterization.

Patients undergoing cardiac catheterization are at high risk of post-procedure acute kidney injury (AKI) and may experience persistent renal damage after an initial insult, a state known as acute kidney disease (AKD). However, the association between AKD and urinary renal biomarkers has not yet been evaluated in this population. We enrolled 94 patients who underwent elective cardiac catheterization to investigate patterns of urinary renal biomarkers and their associations with post-procedure AKD. Serial urinary renal biomarker levels were measured during pre-procedure, early post-procedure (12-24 h), and late post-procedure (7-10 days) periods. In our investigation, 42.55% of the enrolled patients developed AKD during the late post-procedure period. While the liver-type free-fatty-acid-binding protein level increased sharply during the early post-procedure period, it returned to baseline during the late post-procedure period. In contrast, interleukin-18 (IL-18) levels increased steadily during the post-procedure period. Early post-procedure ratios of IL-18 and gelsolin (GSN) were independently associated with subsequent AKD (odds ratio (95% confidence interval), 4.742 (1.523-14.759) for IL-18 ratio, p = 0.007; 1.812 (1.027-3.198) for GSN ratio, p = 0.040). In conclusion, post-procedure AKD is common and associated with early changes in urinary IL-18 and GSN in patients undergoing cardiac catheterization.

Optimizing exercise testing-based risk stratification to predict poor prognosis after acute heart failure.

AIMS: The timely selection of severe heart failure (HF) patients for cardiac transplantation and advanced HF therapy is challenging. Peak oxygen consumption (VO2 ) values obtained by the cardiopulmonary exercise testing are used to determine the transplant recipient list. This study reassessed the prognostic predictability of peak VO2 and compared it with the Heart Failure Survival Score (HFSS) in the modern optimized guideline-directed medical therapy (GDMT) era. METHODS AND RESULTS: We retrospectively selected 377 acute HF patients discharged from the hospital. The primary outcome was a composite of all-cause mortality, or urgent cardiac transplantation. We divided these patients into the more GDMT (two or more types of GDMT) and less GDMT groups (fewer than two types of GDMT) and compared the performance of their peak VO2 and HFSS in predicting primary outcomes. The median follow-up period was 3.3 years. The primary outcome occurred in 57 participants. Peak VO2 outperformed HFSS when predicting 1 year (0.81 vs. 0.61; P = 0.017) and 2 year (0.78 vs. 0.58; P < 0.001) major outcomes. The cutoff peak VO2 for predicting a 20% risk of a major outcome within 2 years was 10.2 (11.8-7.0) for the total cohort. Multivariate Cox regression analyses showed that peak VO2 , sodium, previous implantable cardioverter defibrillator (ICD) implantation, and estimated glomerular filtration rate were significant predictors of major outcomes. CONCLUSIONS: Optimizing the cutoff value of peak VO2 is required in the current GDMT era for advanced HF therapy. Other clinical factors such as ICD use, hyponatraemia, and chronic kidney disease could also be used to predict poor prognosis. The improvement of resource allocation and patient outcomes could be achieved by careful selection of appropriate patients for advanced HF therapies, such as cardiac transplantation.

Delta Increment in Pacing QRS Duration Predicts Cardiovascular Mortality in Patients with Pre-Existing Bundle Branch Block Receiving Permanent Pacemakers.

Background: The clinical implication of pre-existing intraventricular conduction disturbance (IVCD) in permanent pacemaker (PPM) recipients is unknown. Objectives: To explore the clinical outcomes in patients with pre-existing IVCD after implantation of PPMs. Methods: A total of 1424 patients who received PPMs were categorized into three groups by pre-procedural electrocardiography: patients without IVCD (n = 1045), patients with right bundle branch block (RBBB) (n = 309), and patients with left bundle branch block (LBBB) (n = 70). The primary outcome was cardiovascular (CV) mortality. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off values of variable in predicting CV mortality. Results: During follow-up, there was no significant difference in CV mortality between patients with and without IVCD. In multivariate analysis, independent predictors of CV mortality were age [hazard ratio (HR): 1.03; 95% confidence interval (95% CI): 1.00-1.05; p = 0.026], history of heart failure [HR: 1.98; 95% CI: 1.19-3.29; p = 0.009], chronic kidney disease [HR: 1.75; 95% CI: 1.11-2.74; p = 0.015] and increment in pacing QRS duration [HR: 1.01; 95% CI: 1.00-1.04; p = 0.038]. Delta increments in pacing QRS duration ≥ 43 msec [HR: 2.91; 95% CI: 1.23-6.83; p = 0.014] in patients with pre-existing RBBB, and ≥ 33 msec [HR: 11.44; 95% CI: 2.03-64.30; p = 0.006] in patients with pre-existing LBBB were independent determinants of CV mortality. Conclusions: There was no difference in CV mortality between patients with or without IVCD. However, wider pacing QRS duration increased the risk of CV mortality in PPM recipients, and delta increment in pacing QRS duration increased the risk of CV mortality in patients with pre-existing IVCD.

Outcomes With Multidisciplinary Cardiac Rehabilitation in Post-acute Systolic Heart Failure Patients-A Retrospective Propensity Score-Matched Study.

Background: Cardiac rehabilitation (CR) is recommended for patients with acute heart failure (HF). However, the results of outcome studies and meta-analyses on CR in post-acute care are varied. We aimed to assess the medium- to long-term impact of CR and ascertain the predictors of successful CR. Methods: In this propensity score-matched retrospective cohort study, records of consecutive patients who survived acute HF (left ventricular ejection fraction <40) and participated in a multidisciplinary HF rehabilitation program post-discharge between May 2014 and July 2019 were reviewed. Patients in the CR group had at least one exercise session within 3 months of discharge; the others were in the non-CR group. After propensity score matching, the primary (all-cause mortality) and secondary (HF readmission and life quality assessment) outcomes were analyzed. Results: Among 792 patients, 142 attended at least one session of phase II CR. After propensity score matching for covariates related to HF prognosis, 518 patients were included in the study (CR group, 137 patients). The all-cause mortality rate was 24.9% and the HF rehospitalization rate was 34.6% in the median 3.04-year follow-up. Cox proportional hazard analysis revealed that the CR group had a significant reduction in all-cause mortality compared to the non-CR group (hazard ratio [HR]: 0.490, 95% confidence interval [CI]: 0.308-0.778). A lower risk of the primary outcome with CR was observed in patients on renin-angiotensin-aldosterone system (RAAS) inhibitors, but was not seen in patients who were not prescribed this class of medications (interaction p = 0.014). Conclusions: Cardiac rehabilitation participation was associated with reduced all-cause mortality after acute systolic heart failure hospital discharge. Our finding that the benefit of CR was decreased in patients not prescribed RAAS inhibitors warrants further evaluation.

Diabetes Increases Risk of Cardiovascular Events in Patients Receiving Permanent Pacemaker: A Propensity Score-Matched Cohort Study.

Background: Type 2 diabetes was associated with a higher risk for permanent pacemaker (PPM) treatment. The difference in cardiovascular outcomes between patients with and without diabetes receiving PPM treatment remains unexplored. Method: Between January 2003 and December 2017, 1742 patients receiving naïve PPM treatment comprised this retrospective cohort study and were categorized into two groups by the diagnosis of diabetes: group with diabetes (n = 632, 36.3%) and group without diabetes (n = 1110, 63.7%). The primary outcome was cardiovascular events including heart failure (HF) hospitalization and acute myocardial infarction (AMI). The secondary outcomes of this study included pacemaker infection, pacing-induced cardiomyopathy, cerebrovascular accident, cardiovascular mortality, and all-cause mortality. Propensity score matching (PSM) was applied to reduce selection bias between the study groups. Result: During a mean follow-up period of 7.8 ± 4.8 years, 264 patients had a cardiovascular event. Before PSM, the incidence of cardiovascular events was higher in patients with diabetes compared to patients without diabetes (19.8% vs. 12.5%, P < 0.001), and the incidences of pacing-induced cardiomyopathy, cardiovascular mortality, and all-cause mortality were all higher in patients with diabetes compared to patients without diabetes. After PSM, the incidence of cardiovascular events was higher in patients with diabetes compared to patients without diabetes (18.8% vs. 12.3%, P = 0.015). The incidence of HF hospitalization was higher in patients with diabetes compared to patients without diabetes (15.3% vs. 10.2%, P = 0.037), whereas the incidence of AMI did not differ between the two groups. Moreover, after PSM, patients with diabetes had higher cumulative incidences of pacing-induced cardiomyopathy and all-cause mortality compared to patients without diabetes. Conclusions: The prevalence of diabetes was over one-third of naïve PPM recipients of this cohort, and diabetes increased the risk of cardiovascular events in PPM recipients, especially for HF hospitalization.

DLK2 Acts as a Potential Prognostic Biomarker for Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis.

Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with a high mortality. It has been reported that delta-like 1 homologue (DLK1) participates in the tumor microenvironmental remodeling of ccRCC, but the relationship between delta-like 2 homologue (DLK2, a DLK1 homologue) and ccRCC is still unclear. Thus, this study aims to investigate the role of DLK2 in the biological function and disease prognosis of ccRCC using bioinformatics analysis. The TNMplot database showed that DLK2 was upregulated in ccRCC tissues. From the UALCAN analysis, the overexpression of DLK2 was associated with advanced stage and high grade in ccRCC. Moreover, the Kaplan-Meier plotter (KM Plotter) database showed that DLK2 upregulation was associated with poor survival outcome in ccRCC. By the LinkedOmics analysis, DLK2 signaling may participated in the modulation of ccRCC extracellular matrix (ECM), cell metabolism, ribosome biogenesis, TGF-ß signaling and Notch pathway. Besides, Tumor Immune Estimation Resource (TIMER) analysis showed that the macrophage and CD8+ T cell infiltrations were associated with good prognosis in ccRCC patients. Finally, DLK2 overexpression was associated with the reduced macrophage recruitments and the M1-M2 polarization of macrophage in ccRCC tissues. Together, DLK2 may acts as a novel biomarker, even therapeutic target in ccRCC. However, this study lacks experimental validation, and further studies are required to support this viewpoint.

Statins to prevent pacing-induced cardiomyopathy: Evidence from the bench applied to clinical studies.

BACKGROUND: Pacing-induced cardiomyopathy is an undesired outcome in patients with atrioventricular block (AVB), and our animal model showed lipotoxic cardiomyopathy after pacing. OBJECTIVES: The purpose of this study was to explore the mechanisms and clinical outcomes of statins in AVB patients receiving pacing. METHODS: Rat ventricular cardiomyocytes were treated with atorvastatin, liver X receptor (LXR) agonist, and LXR antagonist during pacing. Pigs were divided into 3 groups: right ventricular pacing, pacing with concomitant atorvastatin treatment, and sham control. Clinically, we enrolled 1717 AVB patients who had received a permanent pacemaker from Chang Gung Memorial Hospital Medical database. The primary outcome (cardiovascular death or heart failure [HF] hospitalization) and individual outcome were compared between statin and nonstatin groups after inverse probability of treatment weighting. RESULTS: Lipid accumulation in rat cardiomyocytes by pacing was significantly reduced by treatment with LXR agonist and atorvastatin, whereas LXR antagonist counteracted the atorvastatin effect on lipid expression. Left ventricular ejection fraction (LVEF) was significantly lower in the AVB pig pacing group compared to the group concomitantly treated with atorvastatin. Moreover, lipid accumulation and fibronectin expression were significantly ameliorated by concomitant treatment with atorvastatin. In the clinical study, the statin group had a significantly lower risk of the primary outcome event (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56-0.84), less HF hospitalization (HR 0.45; 95% CI 0.30-0.67), and higher LVEF than the nonstatin group. CONCLUSION: In experimental models, atorvastatin ameliorated lipid accumulation in cardiomyocytes and fibrosis in left ventricular myocardium induced by pacing. Clinically, treatment with statins was associated with less HF hospitalization and cardiovascular death in AVB patients receiving pacemaker therapy.

The Impact of Intermittent Hypoxemia on Left Atrial Remodeling in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a significant risk factor for left atrial (LA) remodeling. Intermittent hypoxemia occurs during the sleep cycle in patients with OSAS and plays a crucial role in cardiovascular pathologies such as stroke, arrhythmia, and coronary artery disease. However, there is very little information about the role of intermittent hypoxemia in LA remodeling in patients with OSAS. In total, 154 patients with sleep-related breathing disorders (SRBD) were prospectively recruited for this study. All enrolled SRBD patients underwent polysomnography and echocardiography. Significant OSAS was defined as an oxygen desaturation index (ODI) of ≥10 per hour. Intermittent hypoxia/reoxygenation (IHR) stimulation was used to test the effect of hypoxia on the viability, reactive oxygen species, apoptosis, and inflammation-associated cytokine expression in the HL-1 cell line. To investigate the effect of patients' exosomes on HIF-1 and inflammation-associated cytokine expression, as well as the relationship between ODI and their expression, exosomes were purified from the plasma of 95 patients with SRBD and incubated in HL-1 cells. The LA size was larger in patients with significant OSAS than in those without. There was a significant association between ODI, lowest SpO2, mean SpO2, and LA size (all p < 0.05) but not between the apnea-hypopnea index and LA size. IHR condition caused increased LDH activity, reactive oxygen species (ROS) levels, and apoptosis in HL-1 cells and decreased cellular viability (all p < 0.05). The expression of HIF-1α, TNF-α, IL-6, and TGF-ß increased in the IHR condition compared with the control (all p < 0.05). The expression of HIF-1α, IL-1ß, and IL-6 increased in the HL-1 cells incubated with exosomes from those patients with significant OSAS than those without (all p < 0.05). There was a significantly positive correlation between ODI and the expression of HIF-1α, TNF-α, IL-1ß, IL-6, and TGF-ß; a significantly negative correlation between mean SpO2 and IL-6 and TGF-ß; and a significantly negative correlation between the lowest SpO2 and HIF-1α (all p < 0.05). In conclusion, intermittent hypoxemia was strongly associated with LA remodeling, which might be through increased ROS levels, LDH activity, apoptosis, and the expression of HIF-1α and inflammation-associated cytokines.

Differential Risk of Dementia Between Patients With Atrial Flutter and Atrial Fibrillation: A National Cohort Study.

Objectives: Atrial fibrillation (AF) is linked to an increased risk of stroke and dementia. Atrial flutter (AFL) is also linked to an increased risk of stroke but at a different level of risk as compared to AF. Little is known about the difference in the risk of dementia between AF and AFL. This study aims to investigate whether the risk of dementia is different between AF and AFL. Methods: Patients with newly diagnosed AF and AFL during 2001-2013 were retrieved from Taiwan's National Health Insurance Research Database. Patients with incomplete demographic data, aged <20 years, history of valvular surgery, rheumatic heart disease, hyperthyroidism, and history of dementia were excluded. The incidence of new-onset dementia was set as the primary outcome and analyzed in patients with AF and AFL after propensity score matching (PSM). Results: A total of 232,425 and 7,569 patients with AF and AFL, respectively, were eligible for analysis. After 4:1 PSM, we included 30,276 and 7,569 patients with AF and AFL, respectively, for analysis. Additionally, patients with AF (n = 29,187) and AFL (n = 451) who received oral anticoagulants were enrolled for comparison. The risk of dementia was higher in patients with AF compared with patients with AFL (subdistribution hazard ratio (SHR) = 1.52, 95% CI 1.39-1.66; p < 0.0001) before PSM and remained higher in patients with AF (SHR = 1.14, 95% CI 1.04-1.25; p = 0.0064) after PSM. The risk of dementia was higher in patients with AF without previous history of stroke after PSM but the risk did not differ between patients with AF and AFL with previous history of stroke. Among patients who received oral anticoagulants, the cumulative incidences of dementia were significantly higher in patients with AF than in patients with AFL before and after PSM (all P < 0.05). Conclusions: This study found that, among patients without history of stroke, the risk of dementia was higher in patients with AF than in patients with AFL, and CHA2DS2-VASc score might be useful for risk stratification of dementia between patients with AF and AFL.

Differential Presentations of Arterial Thromboembolic Events Between Venous Thromboembolism and Atrial Fibrillation Patients.

Objective: Atrial fibrillation (AF) and venous thromboembolism (VTE) share several risk factors related to arterial thromboembolism. No study has reported the differential contribution to arterial thromboembolic events and mortality between these two conditions in the same population. We therefore assessed the differential arterial thromboembolic events between AF and VTE. Methods: We included AF and VTE national cohorts derived from Taiwan National Health Insurance Research Database between 2001 and 2013. The eligible population was 314,861 patients in the AF cohort and 41,102 patients in the VTE cohort. The primary outcome was arterial thromboembolic events, including ischemic stroke, extracranial arterial thromboembolism (ECATE) and myocardial infarction (MI). Secondary outcomes were all-cause mortality and cardiovascular death. Results: After a 1:1 propensity matching, 32,688 patients in either group were analyzed. The risk of arterial thromboembolic events was lower in the VTE cohort than that in the AF cohort (subdistribution hazard ratio [SHR], 0.60; 95% confidence interval [CI], 0.57-0.62). The risk of ischemic stroke (SHR, 0.44; 95% CI, 0.42-0.46) and MI (SHR, 0.80; 95% CI, 0.72-0.89) were lower in the VTE cohort, while the risk of ECATE (SHR, 1.23; 95% CI, 1.14-1.33; particularly lower extremities) was higher in the VTE cohort. All-cause mortality rate was higher in the VTE cohort (HR, 1.18; 95% CI, 1.15-1.21) while the risk of cardiovascular death was lower in the VTE cohort (HR, 0.96; 95% CI, 0.93-0.995). Conclusions: Patients with AF had higher risks of arterial thromboembolic events compared to patients with VTE, despite having risk factors in common. The VTE cohort had higher risks of all-cause mortality and ECATE, particularly lower extremity events, compared to AF patients. The differential manifestations of thromboembolism sequelae and mortality between AF and VTE patients merit further investigation.

Macrophage Inflammatory Protein-1 Alpha, a Potential Biomarker for Predicting Left Atrial Remodeling in Patients With Atrial Fibrillation.

Objectives: Left atrial (LA) remodeling itself is an independent risk factor for ischemic stroke and mortality, with or without atrial fibrillation (AF). Macrophage inflammatory protein-1 alpha (MIP-1α) has been reported to be involved in the induction of autoimmune myocarditis and dilated cardiomyopathy. Little is known about whether MIP-1α can be used to predict LA remodeling, especially in patients with AF. Methods: We prospectively enrolled 78 patients who had received a cardiac implantable electronic device due to sick sinus syndrome in order to define AF accurately. AF was diagnosed clinically before enrollment, according to 12-lead electrocardiography (ECG) and 24-h Holter test in 54 (69%) patients. The serum cytokine levels and the mRNA expression levels of peripheral blood leukocytes were checked and echocardiographic study was performed on the same day within 1 week after the patients were enrolled into the study. The 12-lead ECG and 24-h Holter test were performed on the same day of the patients' enrollment, and the device interrogation was performed every 3 months after enrollment. The enrolled patients were clinically followed up for 1 year. Results: There was no difference in baseline characteristics, cytokine levels and mRNA expression between patients with and without AF. Larger LA volume was positively correlated with higher levels of MIP-1α (r = 0.461, p ≤ 0.001) and the atrial high-rate episodes (AHREs) burden (r = 0.593, p < 0.001), and negatively correlated with higher levels of transforming growth factor (TGF)-ß1 (r = -0.271, p = 0.047) and TGF-ß3 (r = -0.279, p = 0.041). The higher AHREs burden and MIP-1α level could predict LA volume independently. The mRNA expression of RORC was negatively associated with the MIP-1α level. Conclusions: This study showed that higher MIP-1α was significantly associated with LA remodeling and may have the potentials to predict LA remodeling in terms of a larger LA volume, and that circadian gene derangement might affect the expression of MIP-1α.

Corrigendum: Differential Risk of Dementia Between Patients With Atrial Flutter and Atrial Fibrillation: A National Cohort Study.

[This corrects the article DOI: 10.3389/fcvm.2021.787866.].

GJA1 Expression and Left Atrial Remodeling in the Incidence of Atrial Fibrillation in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is an important risk factor for atrial fibrillation (AF). GJA1 gene encoding connexin43, a major protein in cardiac gap junctions, plays a crucial role in the synchronized contraction of the heart and in cardiac arrhythmia. However, little is known regarding the role of GJA1 expression in the incidence of AF in patients with OSAS. All prospectively enrolled OSAS patients underwent polysomnography, electrocardiography, a 24-h Holter test, and echocardiography. Moderate-to-severe OSAS was defined as an apnea-hypopnea index (AHI) ≥ 15. Exosomes were purified from the plasma of all OSAS patients and incubated in HL-1 cells to investigate the effect of exosomes from patients with and without AF on GJA1 expression. A total of 129 patients were recruited for this study; 26 were excluded due to an AHI < 15. Of the 103 enrolled patients, 21 had AF, and 82 did not. Multivariate analysis showed diabetes mellitus, lower sleep efficiency, lower left ventricular ejection fraction, and larger left atrial (LA) size were independent predictors of AF occurrence in OSAS patients. The area under the receiver operating characteristic curve for LA with a size ≥38.5 mm for predicting AF occurrence in OSAS patients was 0.795 (95% confidence interval [0.666, 0.925]); p < 0.001). GJA1 expression in HL-1 cells incubated with exosomes from OSAS patients with AF was lower than that with exosomes from patients without AF after controlling for age and sex and was negatively correlated with the AHI and oxygen desaturation index (ODI), especially during the non-rapid eye movement period (NREM) of OSAS patients with AF (all p < 0.05). LA size was an independent predictor of AF occurrence in OSAS patients. The AHI and ODI in the NREM period of OSAS patients with AF were negatively correlated with GJA1 expression in HL-1 cells, which offers a hint that GJA1 may play a crucial role in the development of AF in patients with OSAS.

Sarcomeres Morphology and Z-Line Arrangement Disarray Induced by Ventricular Premature Contractions through the Rac2/Cofilin Pathway.

The most common ventricular premature contractions (VPCs) originate from the right ventricular outflow tract (RVOT), but the molecular mechanisms of altered cytoskeletons of VPC-induced cardiomyopathy remain unexplored. We created a RVOT bigeminy VPC pig model (n = 6 in each group). Echocardiography was performed. The histopathological alternations in the LV myocardium were analyzed, and next generation sequencing (NGS) and functional enrichment analyses were employed to identify the differentially expressed genes (DEGs) responsible for the histopathological alternations. Finally, a cell silencing model was used to confirm the key regulatory gene and pathway. VPC pigs had increased LV diameters in the 6-month follow-up period. A histological study showed more actin cytoskeleton disorganization and actin accumulation over intercalated disc, Z-line arrangement disarray, increased ß-catenin expression, and cardiomyocyte enlargement in the LV myocardium of the VPC pigs compared to the control pigs. The NGS study showed actin cytoskeleton signaling, RhoGDI signaling, and signaling by Rho Family GTPases and ILK Signaling presented z-scores with same activation states. The expressions of Rac family small GTPase 2 (Rac2), the p-cofilin/cofilin ratio, and the F-actin/G-actin ratio were downregulated in the VPC group compared to the control group. Moreover, the intensity and number of actin filaments per cardiomyocyte were significantly decreased by Rac2 siRNA in the cell silencing model. Therefore, the Rac2/cofilin pathway was found to play a crucial role in the sarcomere morphology and Z-line arrangement disarray induced by RVOT bigeminy VPCs.

Double Twist.

A rare complication about "Twiddler syndrome" is reported, and an interesting image about "double twist" is presented. A 78-year-old woman received a single-chamber implantable cardioverter defibrillator (ICD) for secondary prevention of ventricular arrhythmia. After she played mahjong (a traditional Chinese board game) overnight, her ICD lead sense amplitude decreased suddenly and did not recover. The intracardiac electrogram of ICD also found ventricular lead noise before this episode. Chest radiography revealed a twisted lead at the ICD pocket and a twisted and retracted ICD lead in the right atrium. An old ICD lead could not be straightened and removed, and a new ICD lead was implanted at the right ventricle. Anti-coagulation was used to prevent thrombosis for the old ICD lead.

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.