bluuebunny/crossref_metadata_2025 huggingface dataset:
DULoc: quantitatively unmixing protein subcellular location patterns in immunofluorescence images based on deep learning features
Authors: Xue Min-Qi , Zhu Xi-Liang , Wang Ge , Xu Ying-Ying
Published: October 2021

Motivation

Knowledge of subcellular locations of proteins is of great significance for understanding their functions. The multi-label proteins that simultaneously reside in or move between more than one subcellular structure usually involve with complex cellular processes. Currently, the subcellular location annotations of proteins in most studies and databases are descriptive terms, which fail to capture the protein amount or fractions across different locations. This highly limits the understanding of complex spatial distribution and functional mechanism of multi-label proteins. Thus, quantitatively analyzing the multiplex location patterns of proteins is an urgent and challenging task.

Results

In this study, we developed a deep-learning-based pattern unmixing pipeline for protein subcellular localization (DULoc) to quantitatively estimate the fractions of proteins localizing in different subcellular compartments from immunofluorescence images. This model used a deep convolutional neural network to construct feature representations, and combined multiple nonlinear decomposing algorithms as the pattern unmixing method. Our experimental results showed that the DULoc can achieve over 0.93 correlation between estimated and true fractions on both real and synthetic datasets. In addition, we applied the DULoc method on the images in the human protein atlas database on a large scale, and showed that 70.52% of proteins can achieve consistent location orders with the database annotations.

Availability and implementation

The datasets and code are available at: https://github.com/PRBioimages/DULoc.

Supplementary information

Supplementary data are available at Bioinformatics online.
Effective connectivity extracts clinically relevant prognostic information from resting state activity in stroke
Authors: Adhikari Mohit H , Griffis Joseph , Siegel Joshua S , Thiebaut de Schotten Michel , Deco Gustavo , Instabato Andrea , Gilson Matthieu , Corbetta Maurizio
Published: October 2021

Recent resting-state functional MRI studies in stroke patients have identified two robust biomarkers of acute brain dysfunction: a reduction of inter-hemispheric functional connectivity between homotopic regions of the same network, and an abnormal increase of ipsi-lesional functional connectivity between task-negative and task-positive resting-state networks. Whole-brain computational modelling studies, at the individual subject level, using undirected effective connectivity derived from empirically measured functional connectivity, have shown a reduction of measures of integration and segregation in stroke as compared to healthy brains. Here we employ a novel method, first, to infer whole-brain directional effective connectivity from zero-lagged and lagged covariance matrices, then, to compare it to empirically measured functional connectivity for predicting stroke versus healthy status, and patient performance (zero, one, multiple deficits) across neuropsychological tests. We also investigated the accuracy of functional connectivity versus model effective connectivity in predicting the long-term outcome from acute measures. Both functional and effective connectivity predicted healthy from stroke individuals significantly better than the chance-level; however, accuracy for the effective connectivity was significantly higher than for functional connectivity at 1- to 2-week, 3-month and 1-year post-stroke. Predictive functional connections mainly included those reported in previous studies (within-network inter-hemispheric and between task-positive and -negative networks intra-hemispherically). Predictive effective connections included additional between-network links. Effective connectivity was a better predictor than functional connectivity of the number of behavioural domains in which patients suffered deficits, both at 2-week and 1-year post-onset of stroke. Interestingly, patient deficits at 1-year time-point were better predicted by effective connectivity values at 2 weeks rather than at 1-year time-point. Our results thus demonstrate that the second-order statistics of functional MRI resting-state activity at an early stage of stroke, derived from a whole-brain effective connectivity, estimated in a model fitted to reproduce the propagation of neuronal activity, has pertinent information for clinical prognosis.
Nigral diffusivity, but not free water, correlates with iron content in Parkinson’s disease
Authors: Langley Jason , Huddleston Daniel E , Hu Xiaoping
Published: October 2021

The loss of melanized neurons in the substantia nigra pars compacta is a primary feature in Parkinson’s disease. Iron deposition occurs in conjunction with this loss. Loss of nigral neurons should remove barriers for diffusion and increase diffusivity of water molecules in regions undergoing this loss. In metrics from single-compartment diffusion tensor imaging models, these changes should manifest as increases in mean diffusivity and reductions in fractional anisotropy as well as increases in the free water compartment in metrics derived from bi-compartment models. However, studies examining nigral diffusivity changes from Parkinson’s disease with single-compartment models have yielded inconclusive results and emerging evidence in control subjects indicates that iron corrupts diffusivity metrics derived from single-compartment models. We aimed to examine Parkinson’s disease-related changes in nigral iron and diffusion measures from single- and bi-compartment models as well as assess the effect of iron on these diffusion measures in two separate Parkinson’s cohorts. Iron-sensitive data and diffusion data were analysed in two cohorts: First, a discovery cohort consisting of 71 participants (32 control participants and 39 Parkinson’s disease participants) was examined. Second, an external validation cohort, obtained from the Parkinson’s Progression Marker’s Initiative, consisting of 110 participants (58 control participants and 52 Parkinson’s disease participants) was examined. The effect of iron on diffusion measures from single- and bi-compartment models was assessed in both cohorts. Measures sensitive to the free water compartment (discovery cohort: P = 0.006; external cohort: P = 0.01) and iron content (discovery cohort: P < 0.001; validation cohort: P = 0.02) were found to increase in substantia nigra of the Parkinson’s disease group in both cohorts. However, diffusion markers derived from the single-compartment model (i.e. mean diffusivity and fractional anisotropy) were not replicated across cohorts. Correlations were seen between single-compartment diffusion measures and iron markers in the discovery cohort (iron-mean diffusivity: r = −0.400, P = 0.006) and validation cohort (iron-mean diffusivity: r = −0.387, P = 0.003) but no correlation was observed between a measure from the bi-compartment model related to the free water compartment and iron markers in either cohort. In conclusion, the variability of nigral diffusion metrics derived from the single-compartment model in Parkinson’s disease may be attributed to competing influences of increased iron content, which tends to drive diffusivity down, and increases in the free water compartment, which tends to drive diffusivity up. In contrast to diffusion metrics derived from the single-compartment model, no relationship was seen between iron and the free water compartment in substantia nigra.
AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice
Authors: Ozes Burcak , Moss Kyle , Myers Morgan , Ridgley Alicia , Chen Lei , Murrey Darren , Sahenk Zarife
Published: October 2021

Glycyl–tRNA synthetase mutations are associated to the Charcot–Marie–Tooth disease type-2D. The GarsP278KY/+ model for Charcot–Marie–Tooth disease type-2D is known best for its early onset severe neuropathic phenotype with findings including reduced axon size, slow conduction velocities and abnormal neuromuscular junction. Muscle involvement remains largely unexamined. We tested the efficacy of neurotrophin 3 gene transfer therapy in two Gars mutants with severe (GarsP278KY/+) and milder (GarsΔETAQ/+) phenotypes via intramuscular injection of adeno-associated virus setoype-1, triple tandem muscle creatine kinase promoter, neurotrophin 3 (AAV1.tMCK.NT-3) at 1 × 1011 vg dose. In the GarsP278KY/+ mice, the treatment efficacy was assessed at 12 weeks post-injection using rotarod test, electrophysiology and detailed quantitative histopathological studies of the peripheral nervous system including neuromuscular junction and muscle. Neurotrophin 3 gene transfer therapy in GarsP278KY/+ mice resulted in significant functional and electrophysiological improvements, supported with increases in myelin thickness and improvements in the denervated status of neuromuscular junctions as well as increases in muscle fibre size along with attenuation of myopathic changes. Improvements in the milder phenotype GarsΔETAQ/+ was less pronounced. Furthermore, oxidative enzyme histochemistry in muscles from Gars mutants revealed alterations in the content and distribution of oxidative enzymes with increased expression levels of Pgc1a. Cox1, Cox3 and Atp5d transcripts were significantly decreased suggesting that the muscle phenotype might be related to mitochondrial dysfunction. Neurotrophin 3 gene therapy attenuated these abnormalities in the muscle. This study shows that neurotrophin 3 gene transfer therapy has disease modifying effect in a mouse model for Charcot–Marie–Tooth disease type-2D, leading to meaningful improvements in peripheral nerve myelination and neuromuscular junction integrity as well as in a unique myopathic process, associated with mitochondria dysfunction, all in combination contributing to functional outcome. Based on the multiple biological effects of this versatile molecule, we predict neurotrophin 3 has the potential to be beneficial in other aminoacyl-tRNA synthetase-linked Charcot–Marie–Tooth disease subtypes.
Tackling clinical heterogeneity across the amyotrophic lateral sclerosis–frontotemporal dementia spectrum using a transdiagnostic approach
Authors: Ahmed Rebekah M , Bocchetta Martina , Todd Emily G , Tse Nga Yan , Devenney Emma M , Tu Sicong , Caga Jashelle , Hodges John R , Halliday Glenda M , Irish Muireann , Kiernan Matthew C , Piguet Olivier , Rohrer Jonathan D
Published: October 2021

The disease syndromes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant FTD (n = 58) and ALS–FTD (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-ALS patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the ALS–FTD and behavioural variant FTD groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76–90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in ALS–FTD relative to pure-ALS. In contrast, pure-ALS displayed significantly greater parietal atrophy. Both behavioural variant FTD and ALS–FTD were characterized by volume decrease in the frontal lobes relative to pure-ALS. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in ALS–FTD compared with pure-ALS, and greater left motor cortex and insula atrophy relative to behavioural variant FTD. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the ALS–FTD spectrum, with key structures including the motor cortex and insula. Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum.
Hippocampus- and thalamus-related fiber-specific white matter reductions in mild cognitive impairment
Authors: Zhou Yu , Si Xiaopeng , Chen Yuanyuan , Chao Yiping , Lin Ching-Po , Li Sicheng , Zhang Xingjian , Ming Dong , Li Qiang
Published: October 2021

Early diagnosis of mild cognitive impairment (MCI) fascinates screening high-risk Alzheimer’s disease (AD). White matter is found to degenerate earlier than gray matter and functional connectivity during MCI. Although studies reveal white matter degenerates in the limbic system for MCI, how other white matter degenerates during MCI remains unclear. In our method, regions of interest with a high level of resting-state functional connectivity with hippocampus were selected as seeds to track fibers based on diffusion tensor imaging (DTI). In this way, hippocampus-temporal and thalamus-related fibers were selected, and each fiber’s DTI parameters were extracted. Then, statistical analysis, machine learning classification, and Pearson’s correlations with behavior scores were performed between MCI and normal control (NC) groups. Results show that: 1) the mean diffusivity of hippocampus-temporal and thalamus-related fibers are significantly higher in MCI and could be used to classify 2 groups effectively. 2) Compared with normal fibers, the degenerated fibers detected by the DTI indexes, especially for hippocampus-temporal fibers, have shown significantly higher correlations with cognitive scores. 3) Compared with the hippocampus-temporal fibers, thalamus-related fibers have shown significantly higher correlations with depression scores within MCI. Our results provide novel biomarkers for the early diagnoses of AD.
Olfactory loss and aging: connections with health and well-being
Authors: Papazian Emily J , Pinto Jayant M
Published: October 2021

Age-related olfactory dysfunction, or presbyosmia, is a common sensory impairment in aging adults. People in this demographic group with comorbid conditions or exposure to viral, traumatic, or environmental insults remain at the greatest risk for impairment. Several methods for assessing olfaction exist, but they are only available in special settings and require consideration of age, sex, ancestry, and cognition. Perhaps most importantly, olfactory dysfunction has been suggested as an early sign of Alzheimer’s and Parkinson’s disease and therefore may serve as a tool in the diagnosis and prognosis of these neurodegenerative conditions. Outside of this context, olfactory loss also impacts nutrition, safety, and social relationships, and even predicts mortality itself. This review covers the detection and manifestations of olfactory decline in aging individuals and the myriad ways in which olfactory impairment is connected to their health and well-being.
A case report: intracoronary acetylcholine testing without a pacemaker may be one option in the left coronary artery
Authors: Sueda Shozo , Sakaue Tomoki
Published: October 2021

Background

The intracoronary acetylcholine (ACh) and ergonovine (ER) test is employed as a pharmacological spasm provocation test. ACh causes vasoconstriction in patients with coronary endothelial dysfunction such as coronary atherosclerosis, while ER induces coronary vasoconstriction through the activation of coronary smooth muscle.

Case summary

An 84-year-old Japanese man was admitted to our hospital due to resting angina and syncope. Computed tomography coronary angiography (CTCAG) revealed severe proximal left anterior descending (LAD) coronary artery stenosis, but hybrid images of CTCAG and thallium-adenosine myocardial scintigraphy revealed no ischaemia. During syncope, inverted T waves on V5, V6 leads were recognized. After coronary arteriography, mild atherosclerotic stenosis (50%) was found at the proximal LAD artery, and we administered intracoronary ER 104 µg and 80 µg into the left and right coronary arteries because of suspected coronary spasm. However, no provoked spasm was obtained in either vessel. We administered 20, 50, and 100 µg intracoronary ACh into the left coronary artery (LCA) for 30 s without a pacemaker, because neither bradycardia nor cardiac arrest has occurred. Diffuse distal spasm was provoked after the administration of 100 µg ACh and the patient complained of typical chest pain and prodrome before syncope. The patient was diagnosed with coronary spastic angina by the ACh test but not the ER test.

Discussion

Different coronary responses between ACh and ER were observed in this case. Intracoronary ACh testing without a pacemaker may be one option in the LCA if no bradycardia or arrest occurs.
The association of stroke rate with low density lipoprotein and statin exposure in patients with atrial fibrillation (AF)
Authors: Shweikialrefaee B , Abdel-Qadir H , Pang A , Austin P , Singh S , Jackevicius C , Tu K , Dorian P , Lee D , Ko D
Published: October 2021

Background

There are limited data on the association between cholesterol levels and stroke risk in atrial fibrillation (AF).

Objective

To quantify the association of stroke rate in AF with low-density lipoprotein (LDL) levels and statin use.

Methods

Using linked administrative databases in Ontario, Canada, we conducted a population-based retrospective cohort study of patients aged ≥66 years, diagnosed with AF between 2009–2019. We used cause-specific hazard regression to determine the association of statin use with stroke rate. We developed a second cause-specific regression model for patients with at least one lipid profile measurement in the year before AF diagnosis to study the association of LDL levels with stroke rate, while adjusting for statin use. LDL levels were modeled using restricted cubic splines (RCS). Both models were adjusted for age, sex, heart failure, hypertension, diabetes, stroke or transient ischemic attack, and vascular disease at baseline, plus anticoagulation as a time-varying covariate.

Results

We studied 261,659 qualifying patients (median age 78 years, 49% female), of whom 3,954 (1.5%) developed a stroke during one-year follow-up. A total of 142,834 (54.6%) patients were treated with statins and 145,775 (55.7%) had lipid measurements before AF diagnosis. The adjusted RCS analyses (see Figure) indicated increasing hazard ratios (HRs) for stroke with increasing low-density lipoprotein (LDL) values above 1.5mmol/L. Statin use was associated with a lower stroke rate relative to non-users (hazard ratio 0.87, 95% confidence interval 0.81–0.93, p-value <0.0001).

Conclusion

LDL levels above 1.5mmol/L were independently associated with higher stroke rates in patients with AF, while statins were associated with lower stroke rates independent of anticoagulation. This suggests that LDL measurements may improve stroke risk stratification in AF, while statins may offer an underutilized pathway to lower stroke risk in AF.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): 1) Heart and stroke foundation of Canada HR for Stroke and LDL level
Left atrial dysfunction still exists in patients who obtain normal left atrial volume after successful ablation of atrial fibrillation
Authors: Kawakami H , Inoue K , Nagai T , Fujii A , Sasaki Y , Shikano Y , Sakuoka N , Miyazaki M , Takasuka Y , Ikeda S , Yamaguchi O
Published: October 2021

Introduction

Atrial fibrillation (AF) promotes left atrial (LA) remodeling and vice versa. LA volume index (LAVI) ≥34 mL/m2 is an established cut-off value for identifying an enlarged left atrium. Catheter ablation has become an established therapy for AF and provides a reduction of LA volume by maintaining sinus rhythm (reverse remodeling). However, the definition of LA reverse remodeling after AF ablation is undetermined.

Purpose

We hypothesized that patients with LA dilatation who obtain normal LA volume (LAVI <34 mL/m2) after AF ablation would have better long-term outcomes than those who do not. Furthermore, we investigated whether patients with a normal LA volume could also obtain normal LA function with AF ablation.

Methods

We enrolled 140 AF patients with baseline LAVI ≥34 mL/m2, without AF recurrence for 1 year after the initial AF ablation. We acquired conventional and speckle-tracking echocardiographic parameters within 24 h and at 1 year after the procedure. Late recurrence was defined as AF recurrence >1 year after the initial ablation. To define the normal range of LA function, age-and sex-matched 140 controls without a history of AF were also enrolled.

Results

After restoration of sinus rhythm, overall LA structural and functional parameters were significantly improved, and 75 patients (54%) had normal LA volume at the time of follow-up (Table). During a median follow-up of 44 (31–61) months, 32 patients (23%) experienced a late recurrence of AF. Patients who obtained normal LA volume after AF ablation had fewer late recurrences than those who did not (P<0.01) (Figure). However, LA functional abnormalities still existed in AF patients, even if LA volume was normalized as in controls (Table).

Conclusion

Patients who obtain normal LA volume have better long-term outcomes of AF ablation than those who do not. Although AF ablation promotes beneficial effects on LA structure and function, LA function cannot be normalized even in patients who obtain normal LA volume after successful ablation. Thus, physicians should carefully consider long-term follow-up and residual AF risks, regardless of sinus rhythm restoration by catheter ablation.

Funding Acknowledgement

Type of funding sources: None.
Differences in quality of life improvement with pulmonary vein isolation alone vs. more extensive ablation of persistent atrial fibrillation: insights from the EARNEST-PVI trial
Authors: Kanda T , Masuda M , Inoue K , Furukawa Y , Hirata A , Egami Y , Watanabe T , Minamiguchi H , Miyoshi M , Matsuda Y , Sunaga A , Sotomi Y , Dohi T , Hikoso S , Sakata Y
Published: October 2021

Background

Improving the quality of life (QoL) is one of the main purposes of catheter ablation (CA) of persistent atrial fibrillation (AF). QoL improvement in persistent AF patients has not been fully clarified. The EARNEST-PVI trial was a multi-center randomized trial comparing clinical outcomes of pulmonary vein isolation (PVI) alone and more intensive ablation in addition to PVI including complex fractionated atrial electrogram (CFAE) and linear ablation (PVI plus).

Purpose

To investigate the QoL change after persistent AF ablation and the differences between the PVI-alone strategy and the PVI plus strategy.

Methods

In the EARNEST-PVI trial, patients with persistent AF who underwent an initial catheter ablation (n=512) were randomly assigned in a 1:1 ratio to either PVI alone or PVI plus. Quality of life was assessed at baseline and at 12 months after ablation for AF using the 36-Item Short Form Health Survey. Scores were also converted to a physical health component summary (PCS), a mental health component summary (MCS) and a role/social component summary (RCS).

Results

In the EARNEST-PVI trial, the PVI alone strategy was associated with higher recurrence rate compared with the PVI plus additional ablation strategy. After excluding 68 patients for whom preoperative or postoperative QoL assessment was not available, 222 patients were evaluated respectively. Overall, significant improvements in PCS (46.2±11.4 to 48.7±11.4]), MCS (50.1±8.8 to 54.3±8.6) and RCS (44.6±13.3 to 48.6±11.3) occurred 12 months after ablation (P<0.001, respectively). Although significant QoL improvement occurred in both PVI alone and PLI plus strategies, the changes in PCS was greater in the PVI-plus than that in PVI-alone (3.5±10.3 vs 1.5±10.6, P=0.04).

Conclusions

Ablation for persistent atrial fibrillation improved both physical and mental quality of life. The PVI-plus strategy showed greater improvement in physical QoL.

Funding Acknowledgement

Type of funding sources: None. QoL improvement
Stepwise endo-/epicardial catheter ablation for atrial fibrillation: the Mediterranea approach
Authors: Compagnucci P , De Martino G , Mancusi C , Vassallo E , Calvanese C , Della Ratta G , Librera M , Franciulli M , Marino L , Dello Russo A , Casella M
Published: October 2021

Background

Outcomes of catheter ablation (CA) among patients with non-paroxysmal atrial fibrillation (AF) are largely disappointing.

Purpose

We sought to evaluate the feasibility, effectiveness, and safety of a single-stage stepwise endo-/epicardial approach in patients with persistent/longstanding-persistent AF.

Methods

We enrolled 25 consecutive patients with symptomatic persistent (n=4) or longstanding-persistent (n=21) AF and at least one prior endocardial procedure, who underwent CA using an endo-/epicardial approach. Our anatomical stepwise protocol included multiple endocardial as well as epicardial (Bachmann's bundle [BB] and ligament of Marshall ablations) components, and entailed ablation of atrial tachycardias emerging during the procedure. The primary outcome was freedom from any AF/atrial tachycardia episode after a 3-month blanking period. The secondary outcome was patients' symptom status during follow-up.

Results

The stepwise endo-/epicardial approach allowed sinus rhythm restoration in 72% of patients, either directly (n=6, 24%) or after AF organization into atrial tachycardia (n=12, 48%). BB's ablation was commonly implicated in arrhythmia termination. After a median follow-up of 266 days (interquartile range, 96 days), survival free from AF/atrial tachycardia was 88%. Antiarrhythmic drugs could be discontinued in 22 patients (88%). As compared to baseline, more patients were asymptomatic at 9-month follow-up (0% vs- 56%, p=0.02). Five patients (20%) developed mild medical complications, whereas one subject (4%) had severe kidney injury requiring dialysis.

Conclusion

A single-stage endo-/epicardial CA resulted in favorable rhythm and symptom outcomes in a cohort of patients with symptomatic persistent/longstanding-persistent AF and one or more prior endocardial procedures. Epicardial ablation of BB was commonly implicated in procedural success.

Funding Acknowledgement

Type of funding sources: None.
Predictors of early and late recurrence of atrial fibrillation after catheter ablation: two sides of the same coin?
Authors: Ribeiro Da Silva M , Santos Silva G , Ribeiro Queiros P , Teixeira R , Almeida J , Fonseca P , Oliveira M , Goncalves H , Rodrigues A , Primo J , Fontes-Carvalho R
Published: October 2021

Background

Recurrence of atrial fibrillation (AF) after catheter ablation (CA) is estimated to be between 20% and 45%. Recurrent AF early after ablation is generally classified as benign as a part of a blanking period, but recently has been associated with later recurrent AF. The prediction of early and late AF recurrence after CA remains challenging as well as the predictive value of early AF recurrence in the blanking period.

Purpose

We aimed to determine the clinical and procedural factors associated with early and late recurrence of AF after CA.

Methods

Single-centre retrospective study that included all patients who underwent AF CA between January 2017 and October 2019. Ablation procedures included radiofrequency and second-generation cryoballoon CA. Early recurrence of AF (ERAF) was defined as any recurrence of AF >30 seconds within 90 days after CA and late recurrence (LR) was defined as any recurrence of AF >30 seconds after 90 days of CA. The independent association between clinical and procedural variables and AF recurrence was evaluated with logistic regression analysis.

Results

We included 399 patients, 64,7% male, with a mean age of 56,8±11,6 years, most of them had paroxysmal AF with a mean duration until CA of 3,5±3,4 years.

Early recurrence of AF occurred in 51 patients (12,8%). After multivariate logistic regression, we identify left atrium (LA) diameter [odds ratio (OR) 1,1, 95% confidence interval (CI) 1,03–1,18; p=0,007] as the only independent predictor associated with recurrent AF.

Late recurrence of AF was observed in 104 patients (26,1%), on average, 12,8±8,7 months after CA. After multivariable adjustment, LA diameter (OR 1,1, 95% CI 1,01–1,12; p=0,032) and intraprocedural electric cardioversion (OR 1,8, 95% CI 1,03–3,12; p=0,040) were independently associated with recurrent AF.

Regarding patients with ERAF, most of them also had late recurrent AF (64,7%), whereas in patients without ERAF, only 20,4% had LR (p<0,001). After including ERAF in the multivariate logistic regression, we identify ERAF as the only independent predictor of late recurrence of AF (OR 5,23, 95% CI 2,56–10,72; p<0,001).

Conclusions

In our cohort, late recurrence of AF after catheter ablation was significantly higher in patients with recurrence within the blanking period, which was the only independent predictor of AF late recurrence.

Funding Acknowledgement

Type of funding sources: None.
Defining the optimal blanking period duration after cryoballoon pulmonary vein isolation in patients with atrial fibrillation who have never been treated with an antiarrhythmic drug
Authors: Milstein N , Saberito M , Bhatt A , Habibi M , Sichrovsky T , Preminger M , Shaw R , Mittal S , Musat D
Published: October 2021

Background

Cryoballoon (CB) pulmonary vein isolation (PVI) is an approved method for ablation in patients with paroxysmal (PAF) or persistent (PeAF) atrial fibrillation (AF). Although the first 90 days post-ablation are considered within the blanking period (BP), the optimal duration of the BP remains undefined.

Purpose

To objectively define the BP duration in pts undergoing CB PVI by evaluating a cohort never treated with an antiarrhythmic drug (AAD).

Methods

We enrolled consecutive pts with either PAF or PeAF who underwent initial CB PVI; all pts had an implantable loop recorder (ILR) for long-term ECG monitoring. No pt received an AAD either before or after ablation. We determined the time to last AF episode within the first 90 days of ablation. We then correlated this to the likelihood a patient had recurrent AF between 91 and 365 days of ablation.

Results

There were 45 pts (67±8 years; 26 [58%] male; 40 [89%] PAF; CHA2DS2-VASc 2.6±1.3). We defined 4 distinct groups post ablation based on whether or not they had AF in the BP: (1) no AF days 0–90 (n=19 [42%]), (2) last AF days 0–30 (n=11 [24%]), (3) last AF days 31–60 (n=3 [7%]), and (4) last AF days 61–90 (n=12 [27%]). After the 90-day BP, 15 (33%) pts had AF recurrence. Pts with no AF and those with AF only within 30 days of ablation had similar long-term outcome; however, recurrent AF more than 32 days after ablation predicted long-term ablation failure (Figure).

Conclusion

The post CB PVI blanking period is just a month. AF recurrences beyond a month in patients not on an AAD are associated with AF recurrence in the majority of pts.

Funding Acknowledgement

Type of funding sources: None. Blanking Group by AF Recurrence
Association of female sexual hormones with QTc time in hypertensive subjects
Authors: Grubler M , Verheyen N.D , Meinitzer A , Tascharre M , Fiedler L , Roithinger F.X , Maerz W , Tomaschitz A , Pilz S
Published: October 2021

Background/Introduction

The rate corrected QT time (QTc) is the most commonly used ECG derived parameter to identify and risk-stratify inherited and acquired arrhythmia risk. Among the many potentially influencing factors, the female menstrual cycle has been described to lead to minor intra-individual changes, but the overall influence of sexual hormones on the QTc is incompletely understood. We therefore aimed to elucidate this relationship in hypertensive subjects.

Purpose

To identify confounding factors in QTc determination and elucidate potential endocrine causes of variable QTc time.

Methods

The Styrian Hypertension study is a cohort study aiming to identify novel cardiovascular risk factors. Subjects were recruited from a tertiary care center outpatient clinic. QTc was calculated according to Framingham and linear regression formulas adhering to the AHA/ACCF/HRS 2009 guideline for surface ECG interpretation. Plasma concentrations of estrone (E1), estradiol (E2), 17α-Hydroxyprogesterone and progesterone were measured by Biocrates AbsoluteIDQ Stero17 Kit. Patients on QTc altering medication were excluded from the present analyses.

Results

A total of 142 participants (mean [SD] age, 59.4 [11.7] years; 52% women, 80,1% post-menopause) were eligible for the present analyses. Linear regression analyses adjusted for potassium, HbA1c, NTproBNP and mean systolic blood pressure revealed only an association of QTc with progesterone (beta coefficient [95% CI]) of 0.38 [0.14 – 0.62] (P=0.002) in males. Detailed analyses revealed an U-shaped association. The other hormones showed no significant association in the present cohort of patients. Subgroups of premenopausal women and of patients without elevated blood pressure revealed no statistically significant results.

Conclusions

Contrary to previous evidence we found no sign. association between female sexual hormones and QTc time. We observed increased QTc time in males depending on their progesterone plasma concentrations, but the isolated finding may be a statistical outlier.

Funding Acknowledgement

Type of funding sources: None.
Mutation in a non-desmosomal gene is associated with poor outcome of endo-epicardial ventricular tachycardia ablation in patients with nonischaemic cardiomyopathy
Authors: Peichl P , Krebsova A , Wichterle D , Piherova L , Norambuena P , Stranecky V , Kmoch S , Macek M , Cihak R , Kautzner J
Published: October 2021

Background

Nonischaemic cardiomyopathy (NICM) represents a heterogenic disorder with a variable arrhythmogenic substrate. Its location is often epicardial and catheter ablation in this location proved to be an effective therapeutic modality in NICM patients with recurrent ventricular tachycardias (VTs).

Purpose

To determine the impact of the type of genetic mutation on the long-term outcome of endo-epicardial ablation in patients with NICM.

Methods

We investigated 82 patients (age 47±15 years, 10 women) with NICM who underwent endo-epicardial ablation for frequent VTs. Of them, 59% had a history of failed endocardial ablation. Patients had a left ventricular ejection fraction of 44±14% and all were implanted with cardioverter-defibrillator. One hundred candidate genes were examined using the new generation sequencing technique.

Results

Mutation in genes coding desmosomal complex (genes: PKP2, DSC, DSP, and DSG) was found in 30% of patients (“desmosomal” group). In 23% of patients, other gene mutations (genes: LMNA/C, MYH7, DES, TTN, RYR2, TPM1, MYPN, FLNC, and SCN5A) were detected (“non-desmosomal” group). In 46% of subjects no pathogenic mutation could be identified (“none” group). During a mean follow up of 34±33 months, patients in the “non-desmosomal” group were at significantly higher risk of VT recurrence and death/heart transplant compared to patients in the “desmosomal” group (Figure 1).

Conclusion

Potentially pathogenic mutation can be detected in about half of patients with NICM undergoing endo-epicardial VT ablation. Most commonly, mutations can be found in genes coding desmosomal complex and the endo-epicardial ablation is then associated with a satisfactory low VT recurrence rate and excellent survival in the long-term. On the other hand, patients with a mutation in non-desmosomal genes have poor outcomes despite endo-epicardial ablation.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by Ministry of Health of the Czech Republic, grant nr. NV18-02-00237 Figure 1
Predicting CRT outcome by combining markers from personalized ventricular models of electrophysiology and clinical data
Authors: Rokeakh R , Bazhutina A , Khamzin S , Dokuchaev A , Chumarnaya T , Zubarev S , Lyubimtseva T , Lebedeva V , Lebedev D , Solovyova O
Published: October 2021

Introduction

Up to 30% of chronic heart failure (CHF) patients undergoing cardiac resynchronization therapy (CRT) do not respond to the treatment. Low CRT response can be associated with incorrect pacing lead positioning in ventricles and not accounting for individual structural changes in myocardium. Therefore, patient stratification for CRT, operation planning and optimization of CRT device settings remain a challenge.

Purpose

In this study, we develop a predictive model of CRT outcomes based on a combination of clinical data recorded in patients before CRT and on simulations of the response to biventricular pacing in personalized computational models of the ventricles.

Methods

We used retrospective data from 27 CHF patients who underwent CRT device implantation. CRT responders were defined using clinical data in a year after therapy as showing a decrease in the end-systolic volume of the left ventricle (LV) and an increase in the ejection fraction. For each patient, an anatomical model of the heart and torso was reconstructed from CT images and used to compute ventricular activation and ECGs without pacing and under bi-ventricular pacing with various locations of stimulating leads. For building a predictive model of patient response to CRT, we used clinical data before CRT (12 features in total per patient) together with model-derived biomarkers under biventricular pacing with clinical lead position (16 features in total per a model). Using nested stratified cross-validation, logistic regression models were fitted to various combinations of datasets.

Results

The best classifier using a complete set of clinical and simulation data showed an average accuracy = 0.78, ROC AUC = 0.78, sensitivity = 0.75, specificity = 0.8, that were much higher than in the model built on the clinical data only. When the best model was fitted to all data on biventricular pacing with clinical lead position, all ten clinical non-responders were truly classified by the model (Fig. 1, left). Using simulations with optimal lead location as input data for this model, seven out of the ten patients were predicted as responders (Fig. 1, right). Blue and orange colours indicate clinical responders and non-responders. Red circles and numbers mark some clinical non-responding patients that are predicted as responders using optimal TAT values.

Conclusion

Our pilot results show that combination of clinical and simulation data significantly increases the accuracy of classification models for CRT outcomes. Our results suggest that model predictions on the optimal ventricular lead location may essentially increase the probability of CRT success.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Russian Science Foundation Figure 1
Conduction system pacing in cardiac resynchronization: short-mid term follow-up
Authors: Marcantoni L , Pastore G , Baracca E , Pellegrini N , Bartolomei M , Andreaggi S , Galuppi E , Centioni M , Rigatelli G , Roncon L , Zanon F
Published: October 2021

Background

Conduction system pacing (CSP) includes both His Bundle Pacing (HBP) and left bundle branch pacing (LBBP). It engages the conduction system ensuring synchronous activation of ventricles, potentially acting as cardiac resynchronization.

Purpose

The aim of the study is to report technical and clinical outcomes of CSP (HBP or LBBP) utilized in patients referred for cardiac resynchronization therapy.

Methods

CSP was applied in 51 patients (mean age 75±9 years; 47 males) referred for cardiac resynchronization therapy. 41 cases were de-novo implant and 10 were up-grading after PICM. Ischemic aetiology was present in 23 (45%) patients, hypertension in 31 (61%); diabetes in 19 (37%), severe kidney disease in 4 (8%). Devices were checked 48 hours and 1 month after implant and then remotely. Clinical, echocardiographic, electrocardiographic data were also collected.

Results

Conduction system pacing was successfully obtained in 45 (88.3%) patients. In 28 (62%) cases the lead was implanted in the His Bundle and in 17 (38%) in the left bundle. In 6 (11.7%) patients it was not possible to fix the lead in the His Bundle neither in the Left bundle, in these cases a standard quadripolar lead in the coronary sinus was implanted. In 28 (62%) patients was utilized the 3830 4 Fr lumen-less lead and in the remaining 17 (38%) cases a standard stylet-driven lead. Basal mean EF was 33±9% and improved to 42±9% (P<0.005) after a mean follow-up of 266±212 days. Baseline QRSd narrowed from 168±35 ms to135±12 ms. Four (8.8%) patients were hospitalized due to HF symptoms (in 2 cases fast AF was recorded and treated with AV nodal ablation, in 2 cases significant mitral regurgitation).

Conclusions

Conduction system pacing can act effectively as cardiac resynchronization in patients with severe cardiac disfunction and bundle branch block with high success rate, significantly narrowed QRS and improved EF at short-medium term follow-up.

Funding Acknowledgement

Type of funding sources: None. Case report: CRT-D including LB lead
Incidental finding of ”ghost” on echocardiography after transvenous lead extraction among systemic infection patients
Authors: Azari A , Kristjansdottir I , Gadler F
Published: October 2021

Background

Ghosts are described as cylindrical and oscillating structures diagnosed after transvenous lead extraction (TLE) and may consist of thrombi, vegetations and fibrous sheaths. Presence of ghosts is found to be associated with poor outcomes.

Purpose

The aim of this study was to estimate the proportion of patients with ghosts and to describe the characteristic features of `'ghosts” seen post-TLE in a retrospective series of systemic infection patients.

Methods

Medical journals including echocardiography studies of systemic infection patients undergoing TLE between January 1, 2010 and December 31, 2018 were analysed.

Results

A total of 258 patients (72% males, mean age 71±12 years), underwent TLE due to systemic infection. Staphylococcus aureus was the dominant microorganism isolated in blood cultures (40%). Echocardiography identified ghosts as incidental findings in 15 (6%) patients, 1–23 day(s) (median, 5; mean, 7±6 days) post-TLE and ghosts remained up to 51 days post-TLE. Ghosts were described as tubular, echodense and mobile tissues with variety of dimensions (2–50 mm) on echocardiography, mostly localised in right atrium (40%). Ghosts were visually described by surgeons as vegetations on tricuspid valve, organised thrombotic material in superior/inferior vena cavae and more loose thrombotic materials in right atrium in 2 patients who underwent open heart surgery after TLE. Echocardiography could not certainly differentiate between non-infectious tissue and infectious vegetations, thereby endocarditis treatment was prolonged to at least 12 days (mean, 29±14 days) post-TLE in the ghost group.

Conclusion

Although this was a retrospective analysis and ghosts were incidental findings rather than differential diagnosis, which may have underestimated the proportion ghosts identified, ghosts were relatively common in this cohort. Presence of ghosts caused management challenges for clinicians. There is a great need for large multicentre studies enabling establishment of guidelines for diagnosis and management of this common post-TLE finding.

Funding Acknowledgement

Type of funding sources: None. Table 1Figure 1
Labile iron derived from autophagy-mediated ferritin degradation in cardiomyocytes under pressure overload increases myocardial oxidative stress and develops heart failure in mice
Authors: Omiya S , Ito J , Otsu K
Published: October 2021

Introduction

Heart failure is the leading cause of morbidity and mortality in developed countries, and abnormal iron metabolism is common in patients with heart failure. While iron is essential for metabolic homeostasis, it can increase oxidative stress, such as lipid peroxidation resulting from the generation of harmful reactive hydroxyl radicals through the Fenton reaction. Iron is stored in ferritin, which consists of ferritin heavy (FTH1) and light chains. FTH1 has ferroxidase activity and sequestrates labile ferrous iron. Its protein expression is mediated through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear.

Methods

Cardiomyocyte-specific NCOA4-deficient (KO) mice were generated and subjected to pressure overload by transverse aortic constriction to induce heart failure. Cardiac remodelling was assessed by echocardiography and histological and molecular analyses four weeks after the operation. Furthermore, lipid peroxidation was inhibited by its potent inhibitor, ferrostatin-1.

Results

Deletion of NCOA4 in mouse hearts did not affect cardiac phenotypes and FTH1 protein level at baseline but improved cardiac systolic function (Fractional shortening, control littermates 21.9% vs KO 45.9%) accompanied by the attenuation of ferritin degradation (The protein level of FTH1, controls 42.9% vs. KO 67.2% of sham-operated hearts) 4 weeks after pressure overload compared to the control littermates. The number of LC3B (a marker of an autophagosome)- and FTH1-positive dots (controls 2.64/103μm2 vs KO 0.30/103μm2) and that of LAMP2a (a marker of a lysosome)- and FTH1-positive dots (controls 3.68/103μm2 vs KO 1.77/103μm2) increased in TAC-operated control hearts, which was attenuated in TAC-operated NCOA4-deficient hearts. The ratio of ferrous iron to the FTH1 protein level, which represents the non-binding fraction of labile ferrous iron to FTH1, was higher in TAC-operated control hearts than in the sham-operated controls and TAC-operated NCOA4–deficient hearts. Although pressure overload increased the level of malondialdehyde, a marker for lipid peroxidation in control hearts, its level was reduced by deletion of NCOA4 (controls 1.12 nmol/mg vs KO 0.68 nmol/mg). Ferrostatin-1 significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice (Fractional shortening, saline 21.4% vs ferrostatin-1 41.7%).

Conclusions

Pressure overload-induced ferritinophagy in cardiomyocytes increases myocardial labile iron pool and oxidative stress resulting in the development of heart failure in mice.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): British heart foundation