Prevalence of glucose metabolism disorders and its association with left atrial remodelling before and after catheter ablation in patients with atrial fibrillation.

AIMS: To investigate the exact prevalence of glucose metabolism disorders, and their impact on left atrial (LA) remodelling and reversibility in patients with atrial fibrillation (AF). METHODS AND RESULTS: We examined 204 consecutive patients with AF who underwent their first catheter ablation (CA). Oral glucose tolerance test was used to evaluate glucose metabolism disorders in 157 patients without known diabetes mellitus (DM). Echocardiography was performed before and 6 months after CA. Oral glucose tolerance test identified abnormal glucose metabolism in 86 patients [11 with newly diagnosed DM, 74 with impaired glucose tolerance (IGT) and 1 with impaired fasting glucose (IFG)]. Ultimately, 65.2% of patients had abnormal glucose metabolism. Diabetes mellitus group had the worst LA reservoir strain and LA stiffness (both P < 0.05), while there was no significant difference in baseline LA parameters between normal glucose tolerance (NGT) group and IGT/IFG group. The prevalence of LA reverse remodelling (≥15% decrease in the LA volume index at 6 months after CA) was significantly higher in NGT group compared with IGT/IFG and DM group (64.1 vs. 38.6 vs. 41.5%, P = 0.006). Both DM and IFG/IGT carry a significant risk of lack of LA reverse remodelling independent of baseline LA size and AF recurrence. CONCLUSION: Approximately 65% of patients with AF who underwent their first CA had abnormal glucose metabolism. Patients with DM had significantly impaired LA function compared with non-DM patients. Impaired glucose tolerance/IFG as well as DM carries significant risk of unfavourable LA reverse remodelling. Our observations may provide valuable information regarding the mechanisms and therapeutic strategies of glucose metabolism-related AF.

A long noncoding RNA regulates inflammation resolution by mouse macrophages through fatty acid oxidation activation.

Proper resolution of inflammation is vital for repair and restoration of homeostasis after tissue damage, and its dysregulation underlies various noncommunicable diseases, such as cardiovascular and metabolic diseases. Macrophages play diverse roles throughout initial inflammation, its resolution, and tissue repair. Differential metabolic reprogramming is reportedly required for induction and support of the various macrophage activation states. Here we show that a long noncoding RNA (lncRNA), lncFAO, contributes to inflammation resolution and tissue repair in mice by promoting fatty acid oxidation (FAO) in macrophages. lncFAO is induced late after lipopolysaccharide (LPS) stimulation of cultured macrophages and in Ly6Chi monocyte-derived macrophages in damaged tissue during the resolution and reparative phases. We found that lncFAO directly interacts with the HADHB subunit of mitochondrial trifunctional protein and activates FAO. lncFAO deletion impairs resolution of inflammation related to endotoxic shock and delays resolution of inflammation and tissue repair in a skin wound. These results demonstrate that by tuning mitochondrial metabolism, lncFAO acts as a node of immunometabolic control in macrophages during the resolution and repair phases of inflammation.

Prediction of Atrial Fibrillation Being Asymptomatic at First Onset by Cardiac Pacing.

Asymptomatic or silent atrial fibrillation (AF) has long been a clinical problem due to the incidence of ischemic stroke. A method is needed to predict the development of silent AF before the occurrence of ischemic stroke. This study was focused on the symptoms of AF, especially palpitation, in pacemaker patients. We assessed the hypothesis that absence of palpitation during rapid ventricular pacing could be a predictor of future onset AF being asymptomatic.In this study, we assessed the presence of symptoms during RV pacing and AF symptoms on 145 pacemaker patients at the outpatient clinic by VVI pacing at 120 ppm. The relationship between symptoms during RV pacing and symptom during AF was assessed. The predictive value of absence of symptom during RV pacing on AF being asymptomatic was assessed.Of 145 patients, 74 had previous AF episode. Among the AF patients, absence of symptom during VVI pacing was associated with AF being asymptomatic.Of 145 patients, 71 had no previous AF events. There were 14 patients who had new-onset AF or atrial flutter (AFL) after the device implantation. Four of the 14 patients (28.6%) were symptomatic during first AF/AFL episode, and 10 (71.4%) were asymptomatic during first-onset AF. All ten patients who were asymptomatic during cardiac pacing test were asymptomatic during their initial episodes of AF as well.This study showed that absence of symptoms during rapid ventricular pacing was associated with first-onset AF being asymptomatic.

Pseudo-elevation of conduction system pacing threshold through parallel connection of an intracardiac electrogram recording system.

Parallel connection of an electrophysiology recording system (EP system) to equipment for conduction system pacing (CSP) has been widely used for fine monitoring of intracardiac electrograms and pacing evaluation. We experienced a case showing unexpected pacing threshold exacerbation under specific conditions when the EP system was connected in parallel. We evaluated the underlying mechanism using an ex vivo model. An ex vivo pacing and intracardiac electrogram monitoring model was generated using an oscilloscope, pacing system analyzer (PSA), EP system, and simulated heart. The discrepancy between expected output at the PSA and the actual measured output value at the simulated heart was measured under various conditions and using various combinations of pacing equipment. Parallel connection of the EP system was associated with reduced electrical output from the PSA as recorded at the simulated heart. The unexpected adverse effects were particularly noticeable when using an RMC-5000 EP system with the pacing function on. The trouble is completely resolved by simply turning off the pacing function of the system. There is a possibility that the EP system might increase the pacing threshold in CSP when the PSA and EP system is are deployed in parallel. The issue may provoke pseudo failure of CSP due to the high pacing threshold. When the RMC-5000 is used for conduction system pacing in parallel with a PSA for the pacing test, the pacing function of RMC-5000 should be turned off.

Pulseless Electric Activity with Pre-Excitation.

A 41-year-old man developed cardiac arrest. A resting 12-lead electrocardiogram showed a delta wave, suggestive of preexcitation syndrome. An electrophysiological test revealed the existence of inducible atrial fibrillation and a fasciculoventricular accessory pathway (FVAP). After these examinations, idiopathic ventricular arrhythmia was suspected. For evaluating concealed Brugada syndrome, pilsicainide was administered, which diminished the delta wave and no Brugada-like electrocardiogram was observed. Ventricular double extra-stimulation from the RV apex easily induced VF, which could not be defibrillated by an external defibrillator, and later stopped spontaneously. These results established the diagnosis of FVAP and idiopathic VF, and not pre-excited atrial fibrillation or Brugada syndrome.

Periprocedural Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation Without Discontinuation of a Vitamin K Antagonist and Direct Oral Anticoagulants.

BACKGROUND: Periprocedural anticoagulation is important in catheter ablation (CA) of atrial fibrillation (AF) and there is increasing evidence that uninterrupted vitamin K antagonist (VKA) therapy is superior to interrupted anticoagulation strategies. Since the emergence of direct oral anticoagulants (DOACs), numerous studies have shown promising results for their use in uninterrupted strategies. However, further studies are needed to further define the efficacy and safety of performing AF ablation with uninterrupted factor XA inhibitors or direct thrombin inhibitors.Methods and Results:We have performed CA of AF without discontinuation of either VKA or DOAC therapy since April 2014. A total of 376 patients with AF underwent CA including pulmonary vein isolation. All of the patients were divided into 2 groups (uninterrupted VKA or uninterrupted DOACs). Anticoagulation with DOACs was associated with fewer complications than uninterrupted VKA therapy (P=0.04). There were significant differences between groups in the rates of congestive heart failure, left ventricular ejection fraction, body weight, and estimated glomerular filtration rate and of the CHADS2, CHA2DS2-VASc and HAS-BLED scores. Therefore, we also analyzed the results using the propensity score-matching method. We found no significant difference in periprocedural complications between uninterrupted VKA or DOACs therapy (P=0.65). CONCLUSIONS: CA of AF without discontinuation of DOACs is not inferior to CA without discontinuation of a VKA, with regard to ischemic or hemorrhagic complications.

Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol.

The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepared using Tween 60 and polyvinyl alcohol (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-saponification-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion containing LL-810 was prepared with a reduced amount of Tween 60. However, the area under the blood concentration-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion containing a small amount of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion containing a large amount of Tween 60 showed the highest AUC, dispersed droplets containing Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concentration profile, dispersed droplets in MCT-LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion containing LL-810 permeated rapidly through the mucus layer and intestinal membrane, and Tween 60 incorporated in dispersed droplets interacted with P-gp-mediated efflux, increasing the bioavailability of morin.

A Case of a Cardiac Resynchronization Therapy-Defibrillator Exhibiting a Lower and Alternately Variable Basic Rate.

A cardiac resynchronization therapy defibrillator (CRT-D) (Medtronic Inc. Protecta XT) was implanted in a 67-year-old man who had cardiac sarcoidosis with extremely low cardiac function. He had ventricular tachycardia which was controlled by catheter ablation, medication and pacing. The programmed mode was DDI, lower rate was 90 beats/minute, paced AV delay was 150 ms, and the noncompetitive atrial pacing (NCAP) function was programmed as 300 ms.After his admission for pneumonia and heart failure, we changed his DDI mode to a DDD mode because he had atrial tachycardia, which led to inadequate bi-ventricular pacing. After a while, there were cycle lengths which were longer than his device setting and alternately varied. We were able to avoid this phenomenon with AV delay of 120 ms and NCAP of 200 ms.NCAP is an algorithm which creates a gap above a certain period after the detection of an atrial signal during the postventricular atrial refractory period of the pacemaker. This is to prevent atrial tachycardia and repetitive non-reentrant ventriculoatrial (VA) synchrony in the presence of retrograde VA conduction. But in this case, NCAP algorithm induced much lower rate than the programmed basic lower rate. This situation produced some arrhythmias and exacerbated symptoms of heart failure. This had to be paid attention to, especially when the device was programmed at high basic heart rate.

Prediction of pacemaker-induced cardiomyopathy using a convolutional neural network based on clinical findings prior to pacemaker implantation.

Risk factors for pacemaker-induced cardiomyopathy (PICM) have been previously reported, including a high burden of right ventricular pacing, lower left ventricular ejection fraction, a wide QRS duration, and left bundle branch block before pacemaker implantation (PMI). However, predicting the development of PICM remains challenging. This study aimed to use a convolutional neural network (CNN) model, based on clinical findings before PMI, to predict the development of PICM. Out of a total of 561 patients with dual-chamber PMI, 165 (mean age 71.6 years, 89 men [53.9%]) who underwent echocardiography both before and after dual-chamber PMI were enrolled. During a mean follow-up period of 1.7 years, 47 patients developed PICM. A CNN algorithm for prediction of the development of PICM was constructed based on a dataset prior to PMI that included 31 variables such as age, sex, body mass index, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left atrial diameter, severity of mitral regurgitation, severity of tricuspid regurgitation, ischemic heart disease, diabetes mellitus, hypertension, heart failure, New York Heart Association class, atrial fibrillation, the etiology of bradycardia (sick sinus syndrome or atrioventricular block) , right ventricular (RV) lead tip position (apex, septum, left bundle, His bundle, RV outflow tract), left bundle branch block, QRS duration, white blood cell count, haemoglobin, platelet count, serum total protein, albumin, aspartate transaminase, alanine transaminase, estimated glomerular filtration rate, sodium, potassium, C-reactive protein, and brain natriuretic peptide. The accuracy, sensitivity, specificity, and area under the curve of the CNN model were 75.8%, 55.6%, 83.3% and 0.78 respectively. The CNN model could accurately predict the development of PICM using clinical findings before PMI. This model could be useful for screening patients at risk of developing PICM, ensuring timely upgrades to physiological pacing to avoid missing the optimal intervention window.

Association of Atrial Fibrillation Progression With Left Atrial Functional Reserve and Its Reversibility.

BACKGROUND: Atrial fibrillation (AF) progression is closely related to heart failure occurrence, and catheter ablation carries a beneficial effect for heart failure prevention. Recently, particular attention has been given to left atrial (LA) function and functional reserve in the pathogenesis linking AF and heart failure, although its significance and reversibility is not well studied. METHODS AND RESULTS: We prospectively investigated 164 patients with AF with normal left ventricular systolic function and free from heart failure who underwent first catheter ablation and pre-/postprocedural echocardiography. Conventional and speckle-tracking echocardiography were performed at rest and during passive leg lifting to assess LA size, LA reservoir strain (LARS), and functional reserve calculated as passive leg lifting-LARS - rest-LARS. Patients were categorized into 3 AF subtypes: paroxysmal AF (N=95), persistent AF (PeAF; N=50), and long-standing persistent AF (LS-PeAF; N=19). The PeAF and LS-PeAF groups had larger LA size and reduced LARS compared with the paroxysmal AF group (all P<0.05). LA functional reserve was significantly impaired in the LS-PeAF group (P=0.003). In multivariable analysis, LS-PeAF and advanced age were significantly associated with impaired LA functional reserve. Among 149 patients with sinus rhythm 1 to 2 days after catheter ablation, LARS was significantly improved in both PeAF and LS-PeAF groups but was still lower than that in the paroxysmal AF group. Sinus rhythm restoration also led to amelioration of LA functional reserve in patients with LS-PeAF. CONCLUSIONS: AF progression was related to impaired LARS and LA functional reserve, and restoration of sinus rhythm might contribute to early LA reverse remodeling.

Body Fat Distribution and Left Atrial Reverse Remodeling After Catheter Ablation for Atrial Fibrillation.

Background: Emerging evidence suggests a pathophysiological link between obesity and atrial fibrillation (AF). However, the contribution of body fat distribution to left atrial (LA) remodeling and its reversibility remain unclear in nonobese AF patients. Objectives: The purpose of this study was to investigate the association of body fat distribution with LA size and reverse remodeling (LARR). Methods: In total, 116 nonobese patients with AF (88 men, age 63 ± 11 years) who underwent first catheter ablation (CA) were included. Body fat distribution was assessed with bioelectrical impedance, and body fat percentage (BF%) and central fat percentage (CF%) were calculated. Patients were categorized by body size metrics (body mass index [BMI] and waist-to-hip [W/H] ratio) and fat parameters (BF% and CF%). Echocardiography was performed before and 6 months after CA. Multivariable logistic regression was used to examine the association between the 4 metrics (ie, BMI, W/H ratio, BF%, and CF%) and a lack of LARR (<15% reduction or increase in the LA volume index). Results: Body size metrics and adiposity measures were not independently associated with baseline LA size. Six months after CA, the higher W/H ratio and CF% groups exhibited persistent LA enlargement compared to their counterparts (both P < 0.01). In the multivariable analysis, W/H ratio and CF% were associated with a lack of LARR (adjusted ORs of 3.86 and 2.81 per 0.10 and 10% increase, respectively, both P < 0.01). The combined assessment of CF% with W/H ratio provided complementary risk stratification for persistent LA enlargement. Conclusions: Central adiposity was associated with a lack of LARR after CA, highlighting the importance of assessing body fat distribution even in nonobese patients.

Heart failure promotes multimorbidity through innate immune memory.

Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-ß (TGF-ß) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-ß signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."

[Metastatic micropapillary variant of urothelial carcinoma of the urinary bladder responding to gemcitabine and cisplatin chemotherapy].

A 69-year-old man was admitted to our hospital with a chief complaint of lymphatic edema of left arm. He had a past history of transurethral resection of the bladder tumor 5 years ago, and pathological diagnosis was urothelial carcinoma with micropapillary variant, G3 = G2, pT1. CT scan revealed bladder tumor with invasion of the rectum, and multiple lymph nodes swelling in the axilla, retroperitoneum and pelvis (cT4bN3M1). The patient underwent biopsies of the bladder wall and the left axillary lymph nodes, and pathologic examination revealed micropapillary carcinoma. Five courses of gemcitabine plus cisplatin (GC therapy) were perfomed, and bladder tumor and lymph node metastases reduced remarkably, with serum CA19-9 level decreasing from 172,000 U/ml to 106 U/ml. However, the patient died from recurrence 23 months after the start of GC therapy.

Rapid-Scan Fourier Transform Infrared Monitoring of the Photoactivation Process in Cyanobacterial Photosystem II.

The catalytic site of photosynthetic water oxidation, the Mn4CaO5 cluster, in photosystem II (PSII) is known to be formed by a light-induced process called photoactivation. However, details of its molecular mechanism remain unresolved. In this study, we monitored the photoactivation process in cyanobacterial PSII using rapid-scan, time-resolved Fourier transform infrared (FTIR) spectroscopy. The Mn3+/Mn2+ FTIR difference spectra of PSII, in which D1-D170 was specifically 13C labeled, and PSII from the D1-D170A, D1-E189A, and D1-D342A mutants provide strong evidence that the initial Mn2+ is coordinated by D1-D170 and D1-E189. Protein conformational changes and relocation of photo-oxidized Mn3+ in the dark rearrangement process were detected as slow-phase signals in the amide I and carboxylate regions, whereas similar signals were not observed in D1-E189A PSII. It is thus proposed that relocation of Mn3+ via D1-E189 induces the conformational changes of the proteins to form proper Mn binding sites in the mature protein conformation.

Prevalence, Associated Factors, and Echocardiographic Estimation of Left Atrial Hypertension in Patients With Atrial Fibrillation.

Background Elevated left atrial (LA) pressure predisposes individuals to the initiation and persistence of atrial fibrillation (AF), and LA hypertension is associated with AF recurrence after catheter ablation (CA). However, the exact frequency and factors associated with LA hypertension are unknown, and its noninvasive estimation is challenging. This study aimed to investigate the prevalence and determinants of LA hypertension in patients with AF who underwent first CA. Methods and Results We examined 183 patients with AF who underwent conventional and speckle-tracking echocardiography before CA to assess LA size, reservoir strain, and stiffness. Direct LA pressure was measured at the time of CA, and LA hypertension was defined as mean LA pressure >15 mm Hg. Thirty-three (18.0%) patients exhibited LA hypertension. Patients with LA hypertension had a significantly larger LA volume index (40.2 [28.4-52.1] versus 34.1 [26.9-42.4] mL/m2, P=0.025), reduced LA reservoir strain (15.1 [10.4-21.7] versus 22.7 [14.4-32.3] %, P=0.002) and increased LA stiffness (0.69 [0.34-0.99] versus 0.36 [0.24-0.54], P<0.001). Multivariable analyses showed that waist circumference, C-reactive protein level, LA reservoir strain, and LA stiffness were independently associated with LA hypertension (all P<0.05), while LA volume and E/e' ratio were not. Among echocardiographic parameters, receiver operating characteristic curve analysis identified LA stiffness as the best predictor of LA hypertension. Conclusions Approximately 20% of patients with AF who underwent CA had LA hypertension. Central obesity and inflammation might be involved in the pathophysiological mechanisms of LA hypertension, and echocardiography-derived LA stiffness may have clinical utility for the detection of LA hypertension before CA.

The estimated glomerular filtration rate predicts pacemaker-induced cardiomyopathy.

Clinical predictors for pacemaker-induced cardiomyopathy (PICM) (e.g., a wide QRS duration and left bundle branch block at baseline) have been reported. However, factors involved in the development of PICM in patients with preserved left ventricular ejection fraction (LVEF) remain unknown. This study aimed to determine the risk factors for PICM in patients with preserved LVEF. The data of 113 patients (average age: 71.3 years; men: 54.9%) who had echocardiography before and after pacemaker implantation (PMI) among 465 patients undergoing dual-chamber PMI were retrospectively analyzed. Thirty-three patients were diagnosed with PICM (18.0/100 person-years; 95% CI 12.8-25.2). A univariate Cox regression analysis showed that an estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 (HR 3.47; 95% CI 1.48-8.16) and a past medical history of coronary artery disease (CAD) (HR 2.76; 95% CI 1.36-5.60) were significantly associated with the onset of PICM. After adjusting for clinical variables, an eGFR ≤ 30 mL/min/1.73 m2 (HR 2.62; 95% CI 1.09-6.29) and a medical history of CAD (HR 2.32; 95% CI 1.13-4.80) were independent risk factors for developing PICM. A medical history of CAD and low eGFR are independent risk factors for PICM in patients with preserved LVEF at baseline. These results could be helpful in predicting a decreased LVEF by ventricular pacing before PMI. Close follow-up by echocardiography is recommended to avoid a delay in upgrading to physiological pacing, such as cardiac resynchronization therapy or conduction system pacing.

Post-translational amino acid conversion in photosystem II as a possible origin of photosynthetic oxygen evolution.

Photosynthetic oxygen evolution is performed at the Mn cluster in photosystem II (PSII). The advent of this reaction on ancient Earth changed its environment by generating an oxygenic atmosphere. However, how oxygen evolution originated during the PSII evolution remains unknown. Here, we characterize the site-directed mutants at the carboxylate ligands to the Mn cluster in cyanobacterial PSII. A His residue replaced for D1-D170 is found to be post-translationally converted to the original Asp to recover oxygen evolution. Gln/Asn residues in the mutants at D1-E189/D1-D342 are also converted to Glu/Asp, suggesting that amino-acid conversion is a common phenomenon at the ligand sites of the Mn cluster. We hypothesize that post-translational generation of carboxylate ligands in ancestral PSII could have led to the formation of a primitive form of the Mn cluster capable of partial water oxidation, which could have played a crucial role in the evolutionary process of photosynthetic oxygen evolution.