Optimal Dose of Edoxaban for Very Elderly Atrial Fibrillation Patients at High Risk of Bleeding: The LEDIOS Registry.

BACKGROUND AND OBJECTIVES: Optimal anticoagulation in very elderly patients is challenging due to the high risk of anticoagulant-induced bleeding. The aim of this study was to assess outcomes of on-label reduced-dose edoxaban (30 mg) in very elderly patients who had additional risk factors for bleeding. METHODS: This was a multi-center, prospective, non-interventional observational study to evaluate the efficacy and safety of on-label reduced-dose edoxaban in atrial fibrillation (AF) patients 80 years of age or older and who had more than 1 risk factor for bleeding. RESULTS: A total of 2448 patients (mean age 75.0±8.3 years, 801 [32.7%] males) was included in the present study, and 586 (23.9%) were 80 years of age or older with additional risk factors for bleeding. Major bleeding events occurred frequently among very elderly AF patients who had additional bleeding risk factors compared to other patients (unadjusted hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.16-4.02); however, there were no significant differences in stroke incidence (HR, 1.86; 95% CI, 0.98-3.55). There were no significant differences for either factor after adjusting for age and sex (adjusted HR, 1.65; 95% CI, 0.75-3.62 for major bleeding; adjusted HR, 1.13; 95% CI, 0.51-2.50 for stroke). CONCLUSIONS: In very elderly AF patients with comorbidities associated with greater risk of bleeding, the incidence of major bleeding events was significantly increased. In addition, risk of stroke showed tendency to increase in same population. Effective anticoagulation therapy might be important in these high-risk population, and close observation of bleeding events might also be required. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03554837.

Utilizing stem cell-secreted molecules as a versatile toolbox for skin regenerative medicine.

Stem cells are recognized as an important target and tool in regenerative engineering. In this study, we explored the feasibility of engineering amniotic fluid-derived mesenchymal stem cell-secreted molecules (afMSC-SMs) as a versatile bioactive material for skin regenerative medicine applications in a time- and cost-efficient and straightforward manner. afMSC-SMs, obtained in powder form through ethanol precipitation, effectively contributed to preserving the self-renewal capacity and differentiation potential of primary human keratinocytes (pKCs) in a xeno-free environment, offering a potential alternative to traditional culture methods for their long-term in vitro expansion, and allowed them to reconstitute a fully stratified epithelium sheet on human dermal fibroblasts. Furthermore, we demonstrated the flexibility of afMSC-SMs in wound healing and hair regrowth through injectable hydrogel and nanogel-mediated transdermal delivery systems, respectively, expanding the pool of regenerative applications. This cell-free approach may offer several potential advantages, including streamlined manufacturing processes, scalability, controlled formulation, longer shelf lives, and mitigation of risks associated with living cell transplantation. Accordingly, afMSC-SMs could serve as a promising therapeutic toolbox for advancing cell-free regenerative medicine, simplifying their broad applicability in various clinical settings.

CLINICAL CHARACTERIZATION OF AQUEOUS AND VITREOUS RETINOL-BINDING PROTEIN 3 CONCENTRATIONS IN RELATION TO DIABETIC RETINOPATHY SEVERITY, RETINAL STRUCTURES, AND SYSTEMIC COMPLICATIONS.

PURPOSE: To evaluate Retinol-Binding Protein 3 (RBP3) from photoreceptors in aqueous and its association with vitreous concentrations, diabetic retinopathy (DR) severity, retinal layer thickness, and clinical characteristics in people with diabetes. METHODS: RBP3 concentration was measured by custom-developed enzyme-linked immunosorbent assay in aqueous and correlated with vitreous concentrations in patients from the 50-Year Medalist study and Beetham Eye Institute at Joslin Diabetes Center. RESULTS: Aqueous RBP3 concentration (N = 131) was elevated in eyes with no to mild DR (mean ± SD 0.7 nM ± 0.2) and decreased in eyes with moderate to severe DR (0.65 nM ± 0.3) and proliferative DR (0.5 nM ± 0.2, P < 0.001) compared to eyes without diabetes. Aqueous and vitreous RBP3 concentrations correlated with each other (r = 0.34, P = 0.001) and between fellow eyes (P < 0.0001). History of retinal surgery did not affect aqueous RBP3 concentrations, but cataract surgery affected both vitreous and aqueous levels. Elevated aqueous RBP3 concentration associated with increased thickness of the outer nuclear layer (P = 0.004) and correlated with hemoglobin A1c, whereas vitreous RBP3 concentrations correlated with diabetic systemic complications. CONCLUSION: These findings suggest that aqueous RBP3 concentration may be an important endogenous clinical retinal protective factor, a biomarker for DR severity, and a promising VEGF-independent clinical intervention target in DR.

Excessive blood pressure rise and cardiovascular remodeling in marathon runners.

Exercise-induced hypertension (EIH) is thought to be associated with increased cardiovascular (CV) risks. However, no previous studies have investigated the effects of EIH on CV systems in marathon runners without CV risk factors using both 24-hr ambulatory blood pressure (BP) monitoring and exercise stress echocardiography (ESE). This study firstly described differences in CV adaptations according to EIH assessed by both exams. Marathon runners between 35 and 64 years of age without CV risk factors were eligible. All the participants underwent both 24-hr ambulatory BP monitoring and ESE. EIH was defined as a maximal exercise systolic BP ≥210 mmHg. The EIH group (n = 19) had shorter training history and higher exercise intensity compared to the non-EIH group (n = 23). The average systolic BP was higher in the EIH group than in the non-EIH group. Left cardiac chamber size and left ventricular mass (LVM) were also higher in the EIH group compared to the non-EIH group. Maximal BP during ESE was positively correlated with both parameters. Exaggerated BP response during exercise needs to be monitored for pre-emptive measurements before it results in progressive cardiovascular maladaptation.

Possible Mechanisms for Adverse Cardiac Events Caused by Exercise-Induced Hypertension in Long-Distance Middle-Aged Runners: A Review.

Sudden cardiac death (SCD) is rare among athletes. However, hypertrophic cardiomyopathy is the leading cause of SCD among those <35 years of age. Meanwhile, coronary artery disease (CAD) is the primary SCD cause among those ≥35 years of age. CAD-induced plaque ruptures are believed to be a significant cause of cardiovascular diseases in middle-aged individuals who participate in extreme long-distance running activities such as marathons. A total of 1970 articles related to EIH were identified using search terms. Out of these, 1946 studies were excluded for reasons such as arterial hypertension, exercise-induced pulmonary hypertension, the absence of exercise stress testing (EST), and a lack of relevance to EIH. The study analyzed 24 studies related to both long-distance runners with exercise-induced hypertension (EIH) and the general public. Among these, 11 studies were quasi-experimentally designed studies used in randomized controlled trials (RCTs) on long-distance runners with EIH. Additionally, 12 studies utilized cohort designs, and one study with a quasi-experimental design was conducted among the general population. Recent studies suggest that an imbalance between oxygen demand and supply due to ventricular hypertrophy may be the actual cause of cardiovascular disease, regardless of CAD. Exercising excessively over an extended period can reduce endothelial function and increase arterial stiffness, which in turn increases afterload and leads to an excessive increase in blood pressure during exercise. Exercise-induced hypertension (EIH), which increases the morbidity rate of resting hypertension and is a risk factor for cardio-cerebro-vascular diseases, is more prevalent in middle-aged long-distance runners than in runners from other age groups, and it increases the prevalence of critical arrhythmias, such as atrial fibrillation or ventricular arrhythmias. EIH is associated with angiotensin II activity, and angiotensin II receptor blockers show promising effects in middle-aged runners. Further, guidelines for preventing excessive participation in races and restricting exercise intensity and frequency would be useful. This review identifies EIH as a potential risk factor for cardiovascular diseases and describes how EIH induces SCD.

Comparison of High- and Low-Dose Rivaroxaban Regimens in Elderly East Asian Patients With Atrial Fibrillation.

BACKGROUND: In the Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban 20 mg was the on-label dose, and the dose-reduction criterion for rivaroxaban was a creatinine clearance of < 50 mL/min. Some Asian countries are using reduced doses label according to the J-ROCKET AF trial. The aim of this study was to assess the safety and efficacy of a high-dose rivaroxaban regimen (HDRR, 20/15 mg) and low-dose rivaroxaban regimen (LDRR, 15/10 mg) among elderly East Asian patients with atrial fibrillation (AF) in real-world practice. METHODS: This study was a multicenter, prospective, non-interventional observational study designed to evaluate the efficacy and safety of rivaroxaban in AF patients > 65 years of age with or without renal impairment. RESULTS: A total of 1,093 patients (mean age, 72.8 ± 5.8 years; 686 [62.9%] men) were included in the analysis, with 493 patients allocated to the HDRR group and 598 patients allocated to the LDRR group. A total of 765 patients received 15 mg of rivaroxaban (203 in the HDRR group and 562 in the LDRR group). There were no significant differences in the incidence rates of major bleeding (adjusted hazard ratio [HR], 0.64; 95% confidential interval [CI], 0.21-1.93), stroke (adjusted HR, 3.21; 95% CI, 0.54-19.03), and composite outcomes (adjusted HR, 1.13; 95% CI, 0.47-2.69) between the HDRR and LDRR groups. CONCLUSION: This study revealed the safety and effectiveness of either dose regimen of rivaroxaban in an Asian population for stroke prevention of AF. Considerable numbers of patients are receiving LDRR therapy in real-world practice in Asia. Both regimens were safe and effective for these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04096547.

Association Between ECG Abnormalities and Mortality in a Low-Risk Population.

BACKGROUND: The ECG is a simple, noninvasive screening method for cardiovascular disease and arrhythmia. The impact of ECG abnormality on mortality is not certain in low-risk populations. To address this, we evaluated the association between ECG abnormality and mortality. METHODS AND RESULTS: We retrospectively assessed baseline ECG and all-cause mortality and cardiovascular mortality in 660 383 patients presenting for medical check-ups. Baseline ECG abnormalities were classified according to the Minnesota Code. Among the total 660 383 participants, 23 609 (3.6%) had major and 110 038 (16.7%) had minor ECG abnormalities. All-cause mortality occurred in 7751 patients (1.1%) and cardiovascular mortality in 1180 (0.18%) over a median follow-up period of 8.8 years. Major ECG abnormalities were associated with all-cause mortality (hazard ratio [HR], 1.11 [95%, 1.03-1.2]) and cardiovascular mortality (HR, 1.92 [95% CI, 1.63-2.27]) compared with no ECG abnormalities. All-cause mortality was associated with right atrial enlargement (HR, 2.11 [95% CI, 1.1-4.07]), left atrial enlargement (HR, 1.76 [95% CI, 1.1-2.84]), sinus tachycardia (HR, 1.52 [95% CI, 1.15-2.01]), complete atrioventricular block (HR, 2.1 [95% CI, 1.05-4.2]), atrial fibrillation (HR, 1.52 [95% CI, 1.26-1.84]), and left ventricular hypertrophy (HR, 1.15 [95% CI, 1.02-1.3]). Cardiovascular mortality was associated with left atrial enlargement (HR, 4.52 [95% CI, 2.15-9.5]), atrial fibrillation (HR, 3.22 [95% CI, 2.33-4.46]), left ventricular hypertrophy (HR, 1.72 [95% CI, 1.35-2.19]), major Q-wave abnormality (HR, 1.6 [95% CI, 1.08-2.39]), and major ST-T abnormality (HR, 1.76 [95% CI, 1.01-3.04]). CONCLUSIONS: ECG abnormalities, including left atrial enlargement, left ventricular hypertrophy, atrial fibrillation, and major Q-wave and ST-T abnormalities, were associated with cardiovascular mortality in a low-risk population.

Protective Factors and the Pathogenesis of Complications in Diabetes.

Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.

Validation of the Short Physical Performance Battery via Plantar Pressure Analysis Using Commercial Smart Insoles.

This cross-sectional study, conducted at a tertiary care hospital's rehabilitation clinic, aimed to validate Short Physical Performance Battery (SPPB) results obtained through plantar pressure analysis using commercial smart insoles (SPPB-SI) and to compare these results to manually acquired results by an experienced examiner (SPPB-M). This study included 40 independent-walking inpatients and outpatients aged 50 or older. SPPB-SI and SPPB-M were administered concurrently, with the smart insoles providing plantar pressure data that were converted into time-pressure curves. Two interpreters assessed the curves, determining component completion times for the SPPB-SI scores. Among the 40 participants (mean age: 72.98, SD: 9.27), the mean total SPPB-SI score was 7.72 ± 2.50, and the mean total SPPB-M score was 7.95 ± 2.63. The time recordings and measured scores of each SPPB-SI component exhibited high reliability with inter- and intra-interpreter correlation coefficients of 0.9 and 0.8 or higher, respectively. The intraclass correlation coefficient between the total SPPB-SI and SPPB-M scores was 0.831 (p < 0.001), and that between the component scores of the two measurements ranged from 0.837 to 0.901 (p < 0.001). Consistent correlations with geriatric functional parameters were observed for both SPPB-SI and SPPB-M. This study underscores the potential of commercial smart insoles as reliable tools for conducting SPPB assessments.

Exercise capacity and risk of incident atrial fibrillation in healthy adults.

BACKGROUND/AIMS: Atrial fibrillation (AF) is a common arrhythmia and is associated with cardiovascular morbidity and mortality. It is important to identify and control the modifiable risk factors of AF. We aimed to examine the association of exercise capacity with the risk of incident AF within 3 years in healthy subjects. METHODS: We evaluated asymptomatic adults who had undergone more than two consecutive health checkups. We included subjects who exhibited normal sinus rhythm on the first health examination and who developed AF on the second or subsequent health examinations. Subjects who underwent cardiopulmonary exercise testing within 3 years before the diagnosis of AF were examined. RESULTS: The study population in the analyses included 428 cases (mean age 58.4 ± 7.6 yr, male 95.6%). There were significant differences in maximal systolic blood pressure (SBP; case 169.4 ± 24.2 vs. control 173.9 ± 22.3 mmHg), peak VO2 (29.5 ± 5.4 vs. 30.4 ± 4.8 mL/kg per minute), and maximal metabolic equivalents (METs; 8.5 ± 1.6 vs. 8.7 ± 1.4) between the two groups. In the multivariable logistic models, adjusted odds ratios were 0.99 for maximal SBP (95% confidence interval [CI] 0.98-0.99), 0.97 for peak VO2 (95% CI 0.95-0.99), and 0.91 for maximal METs (95% CI 0.83-0.98). CONCLUSION: We demonstrated that poorer exercise capacity was associated with the development of AF in a healthy population. A prospective, systematic trial is necessary to confirm that appropriate exercise training will be beneficial in preventing the development of AF in such patients.

Totally Thoracoscopic Ablation in Patients With Recurrent Atrial Fibrillation After Catheter Ablation.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of totally thoracoscopic ablation (TTA) in patients with recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). METHODS: From February 2012 to May 2020, 460 patients who underwent TTA were classified into two groups: CA (presence of RFCA history, n = 74) and nCA groups (absence of RFCA history, n = 386). Inverse probability of treatment weighting (IPTW) analyses were used to adjust for confounders. The primary endpoint was freedom from the composite of AF, typical atrial flutter, atypical atrial flutter and any atrial tachyarrhythmia, lasting more than 30 seconds during the follow-up. All patients were followed up at 3, 6, and 12 months via electrocardiogram and 24-hour Holter monitoring. RESULTS: Bilateral pulmonary vein isolation (PVI) was conducted in all patients and the conduction block tests were confirmed. In the CA group, difficult PVI occasionally occurred due to structural changes, such as pericardial adhesion and fibrosis of the pulmonary venous structure, caused by a previous catheter ablation. Early complications such as stroke and pacemaker insertion were not different between the two groups. The normal sinus rhythm was maintained in 70.1% (317/460) patients after a median follow-up period of 38.1 months. The IPTW-weighted Kaplan-Meier curves revealed that freedom from AF events at 5 years was 68.4% (95% confidence interval, 62.8-74.5) in the nCA group and 31.2% (95% confidence interval, 16.9-57.5) in the CA group (P < 0.001). In IPTW-weighted Cox regression, preoperative left atrial diameter, persistent or long-standing AF, the presence of congestive heart failure and catheter ablation history were associated with AF events. CONCLUSION: Patients in the CA group showed a higher recurrence rate of AF than those in the nCA group, while TTA was safely performed in both the groups.

Association of right bundle branch block or intraventricular conduction delay with recurrence of atrial fibrillation after catheter ablation.

BACKGROUND: The association between bundle branch block (BBB) and recurrence of atrial fibrillation (AF) after catheter ablation is unclear. The aim of this study was to determine whether AF combined with BBB is associated with AF recurrence after catheter ablation. METHODS: A total of 477 consecutive AF patients who underwent catheter ablation were included. The AF patients were divided into three groups according to BBB: AF without BBB (n = 427), AF with right bundle branch block (AF with RBBB) (n = 16), and AF with intraventricular conduction delay (AF with IVCD) (n = 34). RESULTS: Of the 477 AF patients (mean age 57 years, 81% men, median CHA2 DS2 -VASc score of 1), 16 (3.4%) patients had RBBB, and 34 (7.1%) patients had IVCD. During a mean follow-up of 15.2 ± 6.7 months, 119 patients (24.9%) had recurrence of AF. Of these, 111 (26%) patients were in the AF without BBB group, with 2 (12.5%) and 6 (17.6%) patients in the RBBB and IVCD groups, respectively. The Kaplan-Meier estimate of the rate of recurrent AF was not significantly different among the three groups (p = .39). Multivariable analysis showed that persistent AF (HR 1.7, 95% CI 1.15-2.50, p = .007), chronic kidney disease (HR 2.94, 95% CI 1.20-7.17, p = .01), and left atrial diameter (HR 1.04, 95% CI 1.009-1.082, p = .01) were significantly associated with AF recurrence. CONCLUSION: AF with BBB was not significantly associated with the recurrence of AF after catheter ablation in middle-aged patients with low-risk cardiovascular profile.

Non-Invasive Risk Assessment and Prediction of Mortality in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Objectives: Heart rate turbulence (HRT) and T-wave alternans (TWA), non-invasive markers of cardiac autonomic dysfunction, and ventricular repolarization abnormality, reportedly, predict the risk of cardiovascular death after myocardial infarction. We investigated whether pre-operative assessment of HRT and/or TWA could predict long-term mortality following coronary artery bypass graft (CABG) surgery. Methods: From May 2010 to December 2017, patients undergoing elective CABG and receiving 24 h ambulatory electrocardiogram monitoring 1 to 5 days prior to CABG surgery were prospectively enrolled. Pre-operative HRT and TWA were measured using a 24 h ambulatory electrocardiogram. The relative risk of cardiac or overall death was assessed according to abnormalities of HRT, TWA, or left ventricular ejection fraction (LV EF). Results: During the mean follow-up period of 4.6 ± 3.9 years, 40 adjudicated overall (5.9%/yr) and 5 cardiac deaths (0.9%/yr) occurred in 146 enrolled patients (64.9 ± 9.3 years; 108 males). Patients with abnormal HRT exhibited significantly higher relative risks of cardiac death (adjusted hazard ratio [HR] 24.9, 95% confidence interval [CI] 1.46-427) and all-cause death (adjusted HR 5.77, 95% CI 2.34-14.2) compared to those with normal HRT. Moreover, abnormal HRT plus abnormal TWA and LV EF < 50% was associated with a greater elevation in cardiac and overall mortality risk. The predictive role of abnormal HRT with/without abnormal TWA for all-cause death was likely more prominent in patients with mildly reduced (35 to 50%) or preserved (≥50%) LV EF. Abnormal HRT plus abnormal TWA and LV EF < 50% showed high negative predictive value in cardiac and overall mortality risk. Conclusions: Assessment of pre-operative HRT and/or TWA predicted mortality risk in patients undergoing elective CABG. Combined analysis of HRT, TWA, and LVEF enhanced the prognostic power. In particular, the predictive value of HRT was enhanced in patients with preserved or mid-range LV EF.

Human induced neural stem cells support functional recovery in spinal cord injury models.

Spinal cord injury (SCI) is a clinical condition that leads to permanent and/or progressive disabilities of sensory, motor, and autonomic functions. Unfortunately, no medical standard of care for SCI exists to reverse the damage. Here, we assessed the effects of induced neural stem cells (iNSCs) directly converted from human urine cells (UCs) in SCI rat models. We successfully generated iNSCs from human UCs, commercial fibroblasts, and patient-derived fibroblasts. These iNSCs expressed various neural stem cell markers and differentiated into diverse neuronal and glial cell types. When transplanted into injured spinal cords, UC-derived iNSCs survived, engrafted, and expressed neuronal and glial markers. Large numbers of axons extended from grafts over long distances, leading to connections between host and graft neurons at 8 weeks post-transplantation with significant improvement of locomotor function. This study suggests that iNSCs have biomedical applications for disease modeling and constitute an alternative transplantation strategy as a personalized cell source for neural regeneration in several spinal cord diseases.

Long-term outcome of thoracoscopic ablation and radiofrequency catheter ablation for persistent atrial fibrillation as a de novo procedure.

AIMS: Limited data are available regarding the efficacy of thoracoscopic ablation as the first procedure for persistent atrial fibrillation (AF). We sought to compare the long-term efficacy of thoracoscopic ablation vs. radiofrequency (RF) catheter ablation as the first procedure for persistent AF. METHODS AND RESULTS: Between February 2011 and December 2020, 575 patients who underwent ablation for persistent AF were studied. Among them, thoracoscopic ablation was performed in 281 patients, RF catheter ablation in 228, and hybrid ablation in 66. Rhythm, clinical, and safety outcomes during 7-year follow-up were compared. The patients who underwent thoracoscopic ablation were older, had a higher prevalence of stroke, and had a larger left atrial volume than those who underwent RF catheter ablation. In the propensity score-matched population (n = 306), incidences of atrial tachyarrhythmia recurrence were 51.4% in the thoracoscopic ablation group and 62.5% in the RF catheter ablation group [adjusted hazard ratio (HR) 0.869, 95% confidence interval (CI) 0.618-1.223, P = 0.420]. Stroke and total procedural adverse events were not significantly different between thoracoscopic and RF catheter ablation (2.7 vs. 2.5%, P = 0.603, and 7.1 vs. 4.8%, P = 0.374, respectively). The hybrid ablation group showed similar rhythm outcomes compared with both the thoracoscopic and the RF catheter ablation groups. At the redo procedure, pulmonary vein gaps were more frequently observed in the RF catheter ablation group (32.6%) than in the thoracoscopic ablation group (7.9%) and in the hybrid ablation group (8.8%) (P < 0.001). CONCLUSION: As a first procedure in persistent AF, thoracoscopic ablation and RF catheter ablation showed comparable efficacy, clinical, and safety outcomes during long-term follow-up.

Dysregulation of CXCL1 Expression and Neutrophil Recruitment in Insulin Resistance and Diabetes-Related Periodontitis in Male Mice.

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by a high-fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared with their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1ß, and IL-17A, exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared with controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin-induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes. ARTICLE HIGHLIGHTS: The mechanism for the increased risks for periodontitis in the gingival tissues due to insulin resistance and diabetes is unclear. We investigated how insulin action in gingival fibroblasts modulates the progression of periodontitis in resistance and diabetes. Insulin upregulated the lipopolysaccharide-induced neutrophil chemoattractant, CXCL1, production in gingival fibroblasts via insulin receptors and Akt activation. Enhancing CXCL1 expression in the gingiva normalized diabetes and insulin resistance-induced delays in neutrophils recruitment and periodontitis. Targeting dysregulation of CXCL1 in fibroblasts is potentially therapeutic for periodontitis and may also improve wound healing in insulin resistance and diabetes.

Association of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease and retinopathy in type 2 diabetes.

BACKGROUND: Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D). MATERIALS AND METHODS: Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders. RESULTS: Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06-1.72), p = 0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01-1.55), p = 0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02-1.53), p = 0.022), but not osteocalcin. CONCLUSIONS: In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Occurrence of Ischemic Stroke in Patients With Atrial Fibrillation Receiving Non-Vitamin K Oral Anticoagulants: Causes and Prevention Strategies.

Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, which is often fatal or disabling. Prevention of stroke is crucial in AF management, and anticoagulation with non-vitamin K oral anticoagulants (NOACs) is the mainstay of AF management for stroke prevention. Because NOAC prescriptions have been surging worldwide, the development of acute ischemic stroke in patients with AF who receive NOAC treatment is an increasingly important issue in clinical practice. Moreover, these patients show a high risk of recurrence, with more than a 50% higher risk, than do patients with AF and no prior anticoagulation therapy. Careful evaluation is mandatory to determine possible causes of ischemic stroke during NOAC therapy. Differentiation of AF-unrelated stroke and demonstration of combined cardiac disease/systemic coagulopathy are important in these patients and may provide improved results in their treatment. In addition, ensuring appropriate dosing and good adherence to NOAC treatment is important. Cardioembolism, despite sufficient anticoagulation and no other causes, is the most common and challenging complication because switching to anticoagulants or adding antiplatelets to the treatment regimen does not reduce the risk of recurrent stroke, and there are no guidelines for this specific situation. This review article aimed to present the most updated data on the prevalence, causes, and secondary prevention strategies, specifically focusing on non-pharmacological approaches, together with relevant cases of AF in patients who developed ischemic stroke on NOAC therapy.

New Oral Anticoagulant Versus Vitamin K Antagonists for Thoracoscopic Ablation in Patients With Persistent Atrial Fibrillation: A Randomized Controlled Trial.

Anticoagulation could not be currently stopped even after successful thoracoscopic ablation of atrial fibrillation for at least 2 months. The aim of this study is to compare the safety and efficacy outcomes between a new oral anticoagulant and warfarin after thoracoscopic ablation. This trial was a single-center, prospective, randomized controlled study comparing edoxaban and warfarin in patients undergoing thoracoscopic ablation of atrial fibrillation. This study enrolled 60 patients randomly assigned into 2 groups. The primary endpoint was efficacy outcomes, including stroke and systemic thromboembolic events. The secondary endpoint was safety outcomes including major bleeding and pericarditis. The patients were evaluated at discharge, 2 weeks, 3 months, and 6 months postoperatively. No stroke and thromboembolic events were noted in both treatment groups during the follow-up period. During the 6 months follow-up period, 4 (13%) of 30 patients in the edoxaban group experienced minor bleeding events, whereas none were noted in the warfarin group. Five anticoagulation-related events (bleeding, and prolongation of international normalized ratio), including pericarditis, were noted in both the edoxaban and warfarin groups. No statistically significant difference existed between the 2 groups. In conclusion, this study showed the comparable results of edoxaban to warfarin during the window period of post-thoracoscopic ablation of atrial fibrillation. Moreover, anticoagulation-related events were rather affected by patient factors and not by the anticoagulant type.

Clinical Outcomes of Rhythm Control Strategies for Asymptomatic Atrial Fibrillation According to the Quality-of-Life Score: The CODE-AF (Comparison Study of Drugs for Symptom Control and Complication Prevention of Atrial Fibrillation) Registry.

Background Atrial fibrillation (AF) is associated with an increased risk of poor cardiovascular outcomes; appropriate rhythm control can reduce the incidence of these adverse events. Therefore, catheter ablation is recommended in symptomatic patients with AF. The aims of this study were to compare AF-related outcomes according to a baseline symptom scale score and to determine the best treatment strategy for asymptomatic patients with AF. Methods and Results This study enrolled all patients who completed a baseline Atrial Fibrillation Effect on Quality-of-Life (AFEQT) survey in a prospective observational registry. The patients were divided into 2 groups according to AFEQT score at baseline; scores ≤80 were defined as symptomatic, whereas scores >80 represented asymptomatic patients. The primary outcome was defined as a composite of hospitalization for heart failure, ischemic stroke, or cardiac death. This study included 1515 patients (mean age: 65.7±10.5 years; 998 [65.9%] men). The survival curve showed a poorer outcome in the symptomatic group compared with the asymptomatic group (log-rank P=0.04). Rhythm control led to a significantly lower risk of a composite outcome in asymptomatic patients (hazard ratio [HR], 0.47 [95% CI, 0.27-0.84], P=0.01). Rhythm control was associated with more favorable composite outcomes in the asymptomatic group with paroxysmal AF, left atrium diameter ≤50 mm, and CHA2DS2-VASc score ≥3. Conclusions Symptomatic patients with AF experienced more adverse outcomes compared with asymptomatic patients. In asymptomatic patients with AF, a strategy of rhythm control improved the outcomes, especially with paroxysmal AF, smaller left atrium size, or higher stroke risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02786095.