Predicting impaired cardiopulmonary exercise capacity in patients with atrial fibrillation using a simple echocardiographic marker.

BACKGROUND: Exercise intolerance is a common symptom associated with atrial fibrillation (AF). However, echocardiographic markers that can predict impaired exercise capacity are lacking. OBJECTIVE: This study aimed to investigate the association between echocardiographic parameters and exercise capacity assessed by cardiopulmonary exercise testing in patients with AF. METHODS: This single-center prospective study enrolled patients with AF who underwent echocardiography and cardiopulmonary exercise testing to evaluate exercise capacity at a tertiary center for AF management from 2020 to 2022. Patients with valvular heart disease, reduced left ventricular ejection fraction, or documented cardiomyopathy were excluded. RESULTS: Of the 188 patients, 134 (71.2%) exhibited impaired exercise capacity (peak oxygen consumption ≤85%), including 4 (2.1%) having poor exercise capacity (peak oxygen consumption <50%). Echocardiographic findings revealed that these patients had an enlarged left atrial end-systolic diameter (LA); smaller left ventricular end-diastolic diameter (LVEDD); and increased relative wall thickness, tricuspid regurgitation velocity, and LA/LVEDD and E/e' ratios. In addition, they exhibited lower peak systolic velocity of the mitral annulus and LA reservoir strain. In the multivariate regression model, LA/LVEDD remained the only significant echocardiographic parameter after adjustment for age, sex, and body mass index (P = .020). This significance persisted even after incorporation of heart rate reserve, N-terminal pro-B-type natriuretic peptide level, and beta-blocker use into the model. CONCLUSION: In patients with AF, LA/LVEDD is strongly associated with exercise capacity. Further follow-up and validation are necessary to clarify its clinical implications in patient care.

Sex-based differences in obstructive sleep apnea and atrial fibrillation: Implication of atrial fibrillation burden.

Background: Obstructive sleep apnea (OSA) is a risk factor for atrial fibrillation (AF); however, it is unclear whether AF increases the risk of OSA. Furthermore, sex differences among patients with both AF and OSA remain unclear. We aimed to determine the association between an increased AF burden and OSA and investigate the differences in clinical characteristics between women and men with AF and OSA. Methods: This was a descriptive, cross-sectional analysis from a prospective cohort study. Patients with non-valvular AF were recruited from the cardiac electrophysiology clinic of a tertiary center; they underwent a home sleep apnea test and 14-day ambulatory electrocardiography. Moderate-to-severe OSA was defined as an apnea-hypopnea index of ≥15. Results: Of 320 patients with AF, 53.4% had moderate-to-severe OSA, and the mean body mass index (BMI) was 25.6 kg/m2. Less women (38.2%) had moderate-to-severe OSA than men (59.3%) (p < 0.001). In the multivariate analysis, age, being a man, and BMI were significantly associated with moderate-to-severe OSA. AF burden was associated with moderate-to-severe OSA only in men (odds ratio: 1.008; 95% confidence interval: 1.001-1.014). Women and men with OSA had similar BMI (p = 0.526) and OSA severity (p = 0.754), but women were older than men (70.1 ± 1.3 vs. 63.1 ± 0.9 years, p < 0.001). Women with moderate-to-severe OSA had a lower AF burden than men did (27.6 ± 7.1 vs. 49.5 ± 3.9%, p = 0.009). Conclusions: AF burden is a sex-specific risk factor for OSA and is limited to men. In contrast, women with both AF and OSA have a lower AF burden than men, despite being older and having similar OSA severity and body habitus. Thus, AF may develop later in women with OSA than in men.

Novel scoring system derived from meta-analysis and validated in cohort population for predicting 1-year atrial fibrillation recurrence after cryoballoon catheter ablation: The HeLPS-Cryo score.

BACKGROUND: Atrial fibrillation (AF) recurrence rates in 1 year after cryoballoon ablation catheter (CBCA) are still high. We purposed to identify strong predictors for AF recurrence after the successful CBCA procedure and develop a new scoring system based only on pre-procedural parameters. METHODS: In the derivation phase, a systematic review and meta-analysis identified the strong predictors of AF recurrence after the CBCA. The pooled hazard ratio (HR) was used to create the new scoring system. The second phase validated the new scoring system in the cohort population. RESULTS: A meta-analysis including 29 cohort studies with 16196 participants confirmed that persistent AF, stroke, heart failure, and left atrial diameter (LAD) >40 mm were powerful predictors for AF recurrence after the CBCA procedure. The HeLPS-Cryo (heart failure [1], left atrial dilatation [1], persistent AF [2], and stroke [2]) was developed based on those pre-procedural predictors. It was validated in 140 patients receiving CBCA procedures and revealed excellent predictive performance for 1-year AF recurrence (AUC = 0.8877; 95% CI = 0.8208 to 0.9546). The HeLPS-Cryo score of ≥3 could predict 1-year AF recurrence with sensitivity and specificity of 78.9% and 87.9%, respectively. The positive predictive value was 66.7%, and the negative predictive value was 93.1%. CONCLUSION: The HeLPS-Cryo score can help the physician estimate the probability of 1-year AF recurrence after the successful CBCA procedure. Patients with HeLPS-Cryo score <3 are good candidates for the CBCA procedure.

Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding.

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and, perhaps, diagnosis.

Recommended assessment and management of sleep disordered breathing in patients with atrial fibrillation, hypertension and heart failure: Taiwan Society of Cardiology/Taiwan Society of sleep Medicine/Taiwan Society of pulmonary and Critical Care Medicine joint consensus statement.

Sleep disordered breathing (SDB) is highly prevalent and may be linked to cardiovascular disease in a bidirectional manner. The Taiwan Society of Cardiology, Taiwan Society of Sleep Medicine and Taiwan Society of Pulmonary and Critical Care Medicine established a task force of experts to evaluate the evidence regarding the assessment and management of SDB in patients with atrial fibrillation (AF), hypertension and heart failure with reduced ejection fraction (HFrEF). The GRADE process was used to assess the evidence associated with 15 formulated questions. The task force developed recommendations and determined strength (Strong, Weak) and direction (For, Against) based on the quality of evidence, balance of benefits and harms, patient values and preferences, and resource use. The resulting 11 recommendations are intended to guide clinicians in determining which the specific patient-care strategy should be utilized by clinicians based on the needs of individual patients.

Effective superior vena cava isolation using a novel C-shaped approach.

Introduction: Superior vena cava (SVC) isolation has been proposed as part of the ablation strategy for atrial fibrillation. However, circumferential isolation of the SVC can lead to late-onset complications, such as SVC stenosis. Methods: We describe a detailed observation of the SVC conduction pattern and present a newly developed approach for SVC isolation that involves creating a C-shaped non-circumferential ablation line while sparing the lateral segment. Results: Twelve consecutive patients were included in the study, all of whom achieved bidirectional block during the ablation procedure. Discussion: This approach to SVC isolation is effective and has the potential to reduce ablation related complications; however, larger studies and long-term follow-up is warranted to confirm these findings.

Minimal Fluoroscopic Catheter Ablation for Adult Patients with Paroxysmal Supraventricular Tachycardia without the Assistance of Intracardiac Echocardiography.

Background: Radiation exposure during fluoroscopic procedures increases the risk of cancer for both patients and operators. Objectives: The aim of this study was to investigate the safety and efficacy of adopting a three-dimensional electroanatomical mapping (3D EAM) system during ablation for paroxysmal supraventricular tachycardia (PSVT), without the assistance of intracardiac echocardiography (ICE), for both right- and left-chamber cardiac procedures. Methods: We retrospectively enrolled all patients with PSVT from September 2018 to December 2020. The patients were grouped according to the use of the 3D EAM system (3D-guided group, n = 102 vs. conventional group, n = 226). Results: The acute success rates were high in both groups (100% vs. 99.1%). The fluoroscopy time was significantly lower in the 3D-guided group than in the conventional group (2.4 ± 4.4 vs. 19.0 ± 10.8 min); the procedure time was significantly increased in the 3D-guided group (104.5 ± 29.9 vs. 94.0 ± 31.9 min), and this was associated with the post-electrophysiology test diagnosis after adjustment for multiple variables [standardized B coefficient (ß) 0.188]. There was no learning curve for each electrophysiologist in terms of fluoroscopy and procedure times. Conclusions: The 3D EAM system, without the assistance of ICE, was safe and effective in guiding PSVT ablation in both left- and right-chamber ablation.

Photo-expansion microscopy enables super-resolution imaging of cells embedded in 3D hydrogels.

Hydrogels are extensively used as tunable, biomimetic three-dimensional cell culture matrices, but optically deep, high-resolution images are often difficult to obtain, limiting nanoscale quantification of cell-matrix interactions and outside-in signalling. Here we present photopolymerized hydrogels for expansion microscopy that enable optical clearance and tunable ×4.6-6.7 homogeneous expansion of not only monolayer cell cultures and tissue sections, but cells embedded within hydrogels. The photopolymerized hydrogels for expansion microscopy formulation relies on a rapid photoinitiated thiol/acrylate mixed-mode polymerization that is not inhibited by oxygen and decouples monomer diffusion from polymerization, which is particularly beneficial when expanding cells embedded within hydrogels. Using this technology, we visualize human mesenchymal stem cells and their interactions with nascently deposited proteins at <120 nm resolution when cultured in proteolytically degradable synthetic polyethylene glycol hydrogels. Results support the notion that focal adhesion maturation requires cellular fibronectin deposition; nuclear deformation precedes cellular spreading; and human mesenchymal stem cells display cell-surface metalloproteinases for matrix remodelling.

Association between atrial fibrillation burden and cognitive function in patients with atrial fibrillation.

BACKGROUND: Accumulating evidence has demonstrated an association between clinical atrial fibrillation (AF) and cognitive impairment. This study aimed to further clarify the impact of AF burden on cognitive function based on detailed electrophysiological recordings and standardized assessments of cognitive function. METHODS: This prospective cohort study, conducted at the Cardiac Electrophysiology Clinic of a tertiary center, included patients with non-valvular AF. AF burden was evaluated using 14-day patch-based electrocardiography. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). RESULTS: Enrolled patients (n = 253) were grouped according to the median AF burden (13.52%). Patients with higher AF burden were significantly older and had larger left atrium size, a worse ejection fraction, and a lower MoCA score than those with lower AF burden. Predictors of MoCA score included age, CHA2DS2-VASc score, AF burden, and Center for Epidemiologic Studies Depression Scale scores. The association between MoCA scores and AF burden remained significant after adjustment for demographic characteristics, underlying diseases, and echocardiographic parameters (standardized beta coefficient: -0.159, 95% confidence interval: -0.020 to -0.004, p = 0.004). CONCLUSION: AF burden is associated with cognitive function in patients with AF. Further studies are required to determine whether reducing AF burden can preserve cognitive function in these patients.

Taxonomic synopsis of Berberis (Berberidaceae) from the northern Hengduan mountains region in China, with descriptions of seven new species.

Though Berberis (Berberidaceae) is widely distributed across the Eurasian landmass it is most diverse in the Himalaya-Hengduan Mountain (HHM) region. There are more than 200 species in China where it is one of the most common mountain shrubs. The study on the taxonomy and evolution of Berberis in this region can thus provide an important insight into the origin and diversification of its flora. A prerequisite to this is mapping and describing the various species of Berberis in the region - a task that despite recent progress is by no means complete. It is clear that in China there may be a significant number of species still to be described and that even with published species much about their distribution remains to be discovered. As a contribution to the first of these tasks seven new species from the northern Hengduan Mountain of N. Sichuan and S. Qinghai: Berberis chinduensis, Berberis degexianensis, Berberis jiajinshanensis, Berberis jinwu, Berberis litangensis, Berberis longquensis and Berberis riparia, are described here. Differences in overall morphology and especially in floral structures with each other and with similar species of Berberis in the same region are presented. The report is the result of phylogenetic analyses based on plastome and partial nrDNA sequences of both the seven proposed new species and a significant number of similar species already published. Provisional conclusions as to the insights provides on the history of the genetic divergence are discussed.

Impact of recording length and other arrhythmias on atrial fibrillation detection from wrist photoplethysmogram using smartwatches.

This study aimed to evaluate whether quantitative analysis of wrist photoplethysmography (PPG) could detect atrial fibrillation (AF). Continuous electrocardiograms recorded using an electrophysiology recording system and PPG obtained using a wrist-worn smartwatch were simultaneously collected from patients undergoing catheter ablation or electrical cardioversion. PPG features were extracted from 10, 25, 40, and 80 heartbeats of the split segments. Machine learning with a support vector machine and random forest approach were used to detect AF. A total of 116 patients were evaluated. We annotated > 117 h of PPG. A total of 6475 and 3957 segments of 25-beat pulse-to-pulse intervals (PPIs) were annotated as AF and sinus rhythm, respectively. The accuracy of the 25 PPIs yielded a test area under the receiver operating characteristic curve (AUC) of 0.9676, which was significantly better than the AUC for the 10 PPIs (0.9453; P < .001). PPGs obtained from another 38 patients with frequent premature ventricular/atrial complexes (PVCs/PACs) were used to evaluate the impact of other arrhythmias on diagnostic accuracy. The new AF detection algorithm achieved an AUC of 0.9680. The appropriate data length of PPG for optimizing the PPG analytics program was 25 heartbeats. Algorithm modification using a machine learning approach shows robustness to PVCs/PACs.

ExCel: Super-Resolution Imaging of C. elegans with Expansion Microscopy.

Studies of C. elegans will benefit from a powerful method for super-resolution imaging of proteins and mRNAs at any 3-D locations throughout the entire animal. Conventional methods of super-resolution imaging in C. elegans, such as STORM, PALM, SR-SIM and STED, are limited by imaging depths that are insufficient to map the entire depth of adult worms, and involve hardware that may not be accessible to all labs. We recently developed expansion of C. elegans (ExCel), a method for physically magnifying fixed whole animals of C. elegans with high isotropy, which provides effective resolutions finer than the diffraction limit, across the entire animal, on conventional confocal microscopes. In this chapter, we present a family of three detailed ExCel protocols. The standard ExCel protocol features simultaneous readout of diverse molecules (fluorescent proteins, RNA, DNA, and general anatomy), all at ~70 nm resolution (~3.5× linear expansion). The epitope-preserving ExCel protocol enables imaging of endogenous proteins with off-the-shelf antibodies, at a ~ 100 nm resolution (~2.8× linear expansion). The iterative ExCel protocol allows readout of fluorescent proteins at ~25 nm resolution (~20× linear expansion). The protocols described here comprise a versatile toolbox for super-resolution imaging of C. elegans.

Clinical manifestations and genetic characteristics in the Taiwan thoracic aortic aneurysm and dissection cohort - a prospective cohort study.

BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a devastating but treatable disease if detected early. The clinical manifestations and genetic characteristics underlying TAAD patients in Taiwan, however, remain unclear. METHODS: We consecutively recruited patients referred for TAAD screening and/or management at a tertiary medical center in Taiwan. All patients received a comprehensive survey of the clinical manifestations and a genetic testing with a 29-gene next-generation sequencing (NGS) panel. RESULTS: Patients (n = 107) were referred for different reasons, and could be grouped into 4 categories: known aortic aneurysm or dissection (AoAD) (n = 57), Marfanoid features (n = 36), having family members of suspected AoAD (n = 11), and ectopic lens (n = 3). AoAD were confirmed in 73 (68.2%) of the entire cohort. Among all the clinical manifestations, skin striae distensae was the only physical sign that showed significant association with AoAD (p = 0.007 after adjusted). Disease-causing genes/variants were identified in 46 patients (43.0%); FBN1 was the most prevalent disease-causing gene, followed by TGFBR1, TGFBR2 and FBN2. A positive genetic testing was not only an independent predictor of AoAD (hazard ratio (HR) 3.468, 95% confidence interval (CI) [1.541-7.807], p = 0.003), but also had a higher chance of dissection among the patients with known dilated aorta (HR 4.552, 95% CI [1.578-13.135], p = 0.005). CONCLUSION: The presence of skin striae distensae may serve as a clinical cue for physicians to search for AoAD in subjects who are at risk. The NGS panel test not only helps confirm the diagnosis, but also stratify the risk of dissection among patients with dilated aorta.

Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1.

Human pancreatic ductal adenocarcinoma (PDAC) harboring one KRAS mutant allele often displays increasing genomic loss of the remaining wild-type (WT) allele (known as LOH at KRAS) as tumors progress to metastasis, yet the molecular ramification of this WT allelic loss is unknown. In this study, we showed that the restoration of WT KRAS expression in human PDAC cell lines with LOH at KRAS significantly attenuated the malignancy of PDAC cells both in vitro and in vivo, demonstrating a tumor-suppressive role of the WT KRAS allele. Through RNA-Seq, we identified the HIPPO signaling pathway to be positively regulated by WT KRAS in PDAC cells. In accordance with this observation, PDAC cells with LOH at KRAS exhibited increased nuclear localization and activation of transcriptional co-activator YAP1. Mechanistically, we discovered that WT KRAS expression sequestered YAP1 from the nucleus, through enhanced 14-3-3zeta interaction with phosphorylated YAP1 at S127. Consistently, expression of a constitutively-active YAP1 mutant in PDAC cells bypassed the growth inhibitory effects of WT KRAS. In patient samples, we found that the YAP1-activation genes were significantly upregulated in tumors with LOH at KRAS, and YAP1 nuclear localization predicted poor survival for PDAC patients. Collectively, our results reveal that the WT allelic loss leads to functional activation of YAP1 and enhanced tumor malignancy, which explains the selection advantage of the tumor cells with LOH at KRAS during pancreatic cancer clonal evolution and progression to metastasis, and should be taken into consideration in future therapeutic strategies targeting KRAS.

Poorer Exercise Accommodation of Regional Systolic Myocardial Motion after Spironolactone Treatment in Heart Failure Patients with Preserved Ejection Fraction and Ventricular Dyssynchrony.

Patients with heart failure and preserved ejection fraction (HFpEF) are known to have reduced systolic myocardial velocity (Sm) with impaired accommodation to exercise. We tested the impact of an aldosterone antagonist on Sm at rest and post-exercise. Forty-nine HFpEF patients (65 ± 11 years, 24 male) with HF signs/symptoms, mitral E/Ea (annular early diastolic velocity) > 8, and left ventricular (LV) EF > 50% were randomized to spironolactone (25 mg/day, 25 patients) or the Control. At baseline and 6 months, we analyzed Sm of basal LV segments at rest and after a 6 min treadmill exercise. At 6 months, post-exercise mean Sm in the spironolactone group became greater than that in the Control (9.2 ± 1.6 vs. 8.3 ± 1.0 cm/s, p = 0.021), mainly due to the increment of post-exercise % increase of lateral Sm (44 ± 30 vs. 30 ± 19% at baseline, p = 0.045). Further analyses showed the presence of systolic dyssynchrony (standard deviation of electromechanical delay of 6-basal LV segments > 35 ms) was independently associated with a poorer response to spironolactone, defined as a post-exercise % increase of lateral Sm < 50% (OR = 2.7, 95% CI = 1.8-4.2) and the increment of Ea < 1.5 cm/s (OR = 1.5, 95% CI = 1.1-2.3). Spironolactone could improve exercise accommodation of regional systolic myocardial velocity for HFpEF patients. However, its benefits could be decreased in those with ventricular dyssynchrony. This suggested possible therapeutic impacts from underlying heterogeneity within HFpEF patients.

Assessing the cognitive status of Drosophila by the value-based feeding decision.

Decision-making is considered an important aspect of cognitive function. Impaired decision-making is a consequence of cognitive decline caused by various physiological conditions, such as aging and neurodegenerative diseases. Here we exploited the value-based feeding decision (VBFD) assay, which is a simple sensory-motor task, to determine the cognitive status of Drosophila. Our results indicated the deterioration of VBFD is notably correlated with aging and neurodegenerative disorders. Restriction of the mushroom body (MB) neuronal activity partly blunted the proper VBFD. Furthermore, using the Drosophila polyQ disease model, we demonstrated the impaired VBFD is ameliorated by the dinitrosyl iron complex (DNIC-1), a novel and steady nitric oxide (NO)-releasing compound. Therefore we propose that the VBFD assay provides a robust assessment of Drosophila cognition and can be used to characterize additional neuroprotective interventions.

Social perception of young adults prolongs the lifespan of aged Drosophila.

Lifespan is modulated at distinct levels by multiple factors, including genetic backgrounds, the environment, behavior traits, metabolic status, and more interestingly, sensory perceptions. However, the effects of social perception between individuals living in the same space remain less clear. Here, we used the Drosophila model to study the influences of social perception on the lifespan of aged fruit flies. We found the lifespan of aged Drosophila is markedly prolonged after being co-housed with young adults of the same gender. Moreover, the changes of lifespan were affected by several experimental contexts: (1) the ratios of aged and young adults co-housed, (2) the chronological ages of two populations, and (3) the integrity of sensory modalities. Together, we hypothesize the chemical/physical stimuli derived from the interacting young adults are capable of interfering with the physiology and behavior of aged flies, ultimately leading to the alteration of lifespan.

Tetra-gel enables superior accuracy in combined super-resolution imaging and expansion microscopy.

The accuracy of expansion microscopy (ExM) depends on the structural preservation of samples embedded in a hydrogel. However, it has been unknown to what extent gel embedding alters the molecular positions of individual labeled sites. Here, we quantified the accuracy of gel embedding by using stochastic optical reconstruction microscopy (STORM) to image DNA origami with well-defined structures. We found that embedding in hydrogels based on polyacrylamide, the most widely used chemistry in ExM, resulted in random displacements of labeled sites with a standard deviation of ~ 16 nm. In contrast, we found that embedding in tetra-gel, a hydrogel that does not depend on free-radical chain-growth polymerization, preserved labeled sites with a standard deviation of less than 5 nm. By combining tetra-gel ExM with STORM, we were able to resolve 11-nm structural features without the loss in accuracy seen with polyacrylamide gels. Our study thus provides direct measurements of the single-molecule distortions resulting from hydrogel embedding, and presents a way to improve super-resolution microscopy through combination with tetra-gel ExM.