Raúl Benítez

Universitat Politècnica de Catalunya

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Leif Hove‐Madsen

Hospital de Sant Pau

Anna Llach

Université Paris-Saclay

S.R. Wayne Chen

Libin Cardiovascular Institute of Alberta

Alexander Vallmitjana

University of California, Irvine

Alex Vallmitjana

Universitat Politècnica de Catalunya

Carmen Tarifa

Spanish National Centre for Cardiovascular Research

Juan Cinca

Hospital de Sant Pau

Adela Herraiz‐Martínez

Institut d'Investigacions Biomèdiques de Barcelona

Verónica Jiménez-Sábado

Centro de Investigación Biomédica en Red

Ruiwu Wang

Libin Cardiovascular Institute of Alberta

Cooperative Institutions

Universitat Politècnica de Catalunya

Hospital de Sant Pau

Universitat Autònoma de Barcelona

Centro de Investigación Biomédica en Red

University of Calgary

Instituto de Salud Carlos III

Libin Cardiovascular Institute of Alberta

Institut de Recerca Sant Joan de Déu

Universitat de Barcelona

Centro de Investigación en Red en Enfermedades Cardiovasculares

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Increased Ca ²⁺ Transient Underlies RyR2-Related Left Ventricular Noncompaction

Circulation Research (2023)

Mingke Ni Yanhui Li Jinhong Wei Zhenpeng Song Hui Wang

A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function.We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation.As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type.The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.

10.1161/circresaha.123.322504

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Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes

Cardiovascular Research (2015)

Adela Herraiz‐Martínez Jesús Álvarez‐García Anna Llach Cristina E. Molina Jacqueline Fernandes

Ageing-related cardiac disorders such as heart failure and atrial fibrillation often present with intracellular calcium homeostasis dysfunction. However, knowledge of the intrinsic effects of ageing on cellular calcium handling in the human heart is sparse. Therefore, this study aimed to analyse how ageing affects key mechanisms that regulate intracellular calcium in human atrial myocytes. Whole membrane currents and intracellular calcium transients were measured in isolated human right atrial myocytes from 80 patients with normal left atrial dimensions and no history of atrial fibrillation. Patients were categorized as young (<55 years, n = 21), middle aged (55–74 years, n = 42), and old (≥75 years, n = 17). Protein levels were determined by western blot. Ageing was associated with the following electrophysiological changes: (i) a 3.2-fold decrease in the calcium transient (P < 0.01); (ii) reduction of the L-type calcium current (ICa) amplitude (2.4 ± 0.3 pA/pF vs. 1.4 ± 0.2 pA/pF, P < 0.01); (iii) lower levels of L-type calcium channel alpha-subunit (P < 0.05); (iv) lower rates of both fast (14.5 ± 0.9 ms vs. 20.9 ± 1.9, P < 0.01) and slow (73 ± 3 vs. 120 ± 12 ms, P < 0.001) ICa inactivation; and (v) a decrease in the sarcoplasmic reticulum calcium content (10.1 ± 0.8 vs. 6.4 ± 0.6 amol/pF, P < 0.005) associated with a significant decrease in both SERCA2 (P < 0.05) and calsequestrin-2 (P < 0.05) protein levels. In contrast, ageing did not affect spontaneous sarcoplasmic reticulum calcium release. Ageing is associated with depression of SR calcium content, L-type calcium current, and calcium transient amplitude that may favour a progressive decline in right atrial contractile function with age.

Calsequestrin

Calcium in biology

Homeostasis

Calcium ATPase

10.1093/cvr/cvv046

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Detection of Abnormal Cardiac Response Patterns in Cardiac Tissue Using Deep Learning

Mathematics (2022)

Xavier Marimon Sara Traserra Marcel Jiménez Andrés Ospina Raúl Benítez

This study reports a method for the detection of mechanical signaling anomalies in cardiac tissue through the use of deep learning and the design of two anomaly detectors. In contrast to anomaly classifiers, anomaly detectors allow accurate identification of the time position of the anomaly. The first detector used a recurrent neural network (RNN) of long short-term memory (LSTM) type, while the second used an autoencoder. Mechanical contraction data present several challanges, including high presence of noise due to the biological variability in the contraction response, noise introduced by the data acquisition chain and a wide variety of anomalies. Therefore, we present a robust deep-learning-based anomaly detection framework that addresses these main issues, which are difficult to address with standard unsupervised learning techniques. For the time series recording, an experimental model was designed in which signals of cardiac mechanical contraction (right and left atria) of a CD-1 mouse could be acquired in an automatic organ bath, reproducing the physiological conditions. In order to train the anomaly detection models and validate their performance, a database of synthetic signals was designed (n = 800 signals), including a wide range of anomalous events observed in the experimental recordings. The detector based on the LSTM neural network was the most accurate. The performance of this detector was assessed by means of experimental mechanical recordings of cardiac tissue of the right and left atria.

Autoencoder

Anomaly (physics)

10.3390/math10152786

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Citations (7)

Unveiling Cnn Learning Trends with Dmd: A Dynamic Mode Decomposition Analysis of Convolutional Neural Networks

O. K. Sikha Raúl Benítez

The use of pre-trained deep neural networks is widespread in the field of artificial intelligence, but there is a challenge in evaluating these models due to the lack of access to complete information such as the training data, test data, loss function, and hyperparameter values. The traditional evaluation metrics, such as accuracy, precision, and recall, require the availability of train and test data, making it difficult to determine the expected performance or quality of these models. This paper presents a solution to the challenge of evaluating the performance and quality of pre-trained Deep Convolutional Neural Networks (DCNNs) without access to complete training data, test data, and model information. We propose a comprehensive empirical analysis of DCNNs using Dynamic Decomposition (DMD) Theory. By modeling DCNNs as a linear dynamical system and using the feature maps generated by the convolutional layers, we construct snapshots for DMD analysis and decompose the system's dynamics into individual modes and eigenvalues, providing a linear approximation of the complex DCNN. We also introduce several DMD-based metrics, including entropy of DMD-eigenvalues, DMD eigen gap/spectral gap, and zero amplitude DMD modes, to quantify the effectiveness and quality of the learned DCNN (well-trained vs poorly-trained) without test data. Additionally, we present a novel approach for interpreting DCNNs using the stable DMD modes and their associated eigenvalues. The proposed approach has been extensively evaluated on various shallow and deep models trained on different datasets, showing its efficacy in quantifying the learning evolution and effectiveness of DCNNs. The code used for experimentation is publicly available at: https://github.com/sikha2552/DMD_XAI .

Dynamic Mode Decomposition

Mode (computer interface)

10.2139/ssrn.4363660

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STOCHASTIC PHASE-FIELD SIMULATIONS OF SYMMETRIC ALLOY SOLIDIFICATION

Fluctuation and Noise Letters (2004)

Raúl Benítez L. Ramı́rez-Piscina

We study initial transient stages in directional solidification by means of a non-variational phase field model with fluctuations. This model applies for the symmetric solidification of dilute binary solutions and does not invoke fluctuation-dissipation theorem to account for the fluctuation statistics. We devote our attention to the transient regime during which concentration gradients are building up and fluctuations act to destabilize the interface. To this end, we calculate both the temporally dependent growth rate of each mode and the power spectrum of the interface evolving under the effect of fluctuations. Quantitative agreement is found when comparing the phase-field simulations with theoretical predictions.

Transient (computer programming)

Binary alloy

Directional solidification

Fluctuation spectrum

10.1142/s0219477504002063

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Citations (2)

Evaluation of a deep learning (DL) algorithm to detect the presence of Arteriovenous Malformations (AVM) in pediatric arterial spin labeling sequences (ASL)

Julia Romagosa Sandra Bernaus Christian Stephan‐Otto Raúl Benítez A Valls

Arterial spin labeling

Arteriovenous malformation

Intracranial Arteriovenous Malformations

10.26226/m.64ae6f4f56241620f72a77a6

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Citations (0)

DICA enhanced SVM classification approach to fault diagnosis for chemical processes

Computer-aided chemical engineering/Computer aided chemical engineering (2009)

Isaac Monroy Raúl Benítez Gerard Escudero Moisès Graells

Benchmark (surveying)

Component (thermodynamics)

Feature (linguistics)

10.1016/s1570-7946(09)70045-8

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Citations (3)

Simultaneous Detection and Colocalization of Calcium Sparks and Ryanodine Receptor Clusters in Cardiac Myocytes

Biophysical Journal (2015)

Alex Vallmitjana Florian Hiess S.R. Wayne Chen Leif Hove‐Madsen Raúl Benítez

Colocalization

Cardiac myocyte

10.1016/j.bpj.2014.11.1447

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54Detection, quantification and visualization of ryanodine receptor phosphorylation in human atrial myocytes using a novel ratiometric immunofluorescent analysis

Cardiovascular Research (2014)

Alex Vallmitjana Patricia E. Molina Adela Herraiz J Montiel Juan Cinca

Purpose: Calcium release through the ryanodine receptor (RyR2) plays a central role in the regulation of cardiac contraction and rhythm, and is modulated by RyR2 phosphorylation. However, little is known about the distribution of phosphorylated RyR2s in isolated cardiac myocytes and the purpose of the present study was to develop an immunofluorescent ratio-metric approach to quantify and visualize the spatial distribution of phosphorylated RyR2s. Methods: Forty-nine human atrial myocytes from nine patients were labeled with anti-phospho Ser-2808 (Red) and anti-RyR2 (Green) antibodies and detected automatically using a custom made algorithm based on: 1) Enhancing the contrast of both green and red-labeled images using a histogram stretching intensity transformation. 2) Removing background noise by using an adaptive median filter that estimates the noise level. 3) Enhancing the location of all green-labeled RyRs with a 2D Gaussian filter with a standard deviation of 0.5 microns followed by segmentation using a multilevel watershed algorithm. 4) Eliminating non-specific staining by setting the maximal RyR diameter to 1.2 microns. 5) Detection of red-labeled ser2808 phosphorylated RyR2s by checking if a cluster of red pixels was present at the location of each green labeled RyR2. Red clusters that overlapped at least 20% of the area of a green-labeled RyR2 were accepted if the normalized intensity of the overlapping area was above 15%. Results: Superimposing detected RyR2s on the original confocal image revealed a detection efficiency near 95%, and visual inspection of superimposed original confocal images confirmed that all red ser2808 clusters coincided with a green RyR2. Moreover, stimulation of RyR2 phosphorylation with the beta-adrenergic agonist was used as a positive control, and it significantly increased the ser2808:total RyR2 ratio from 0.32±0.03 to 0.52±0.06 (p<0.01). Conclusion: We have developed a novel immunofluorescent ratiometric approach that allows quantifying and visualizing RyR2 phosporylation in isolated human atrial myocytes. This approach may also apply to other proteins with a punctate distribution that are modulated by phosphorylation, and should be useful to study how disease affects the distribution of such proteins under basal or phosphorylating conditions.

Atrial myocytes

10.1093/cvr/cvu081.2

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Citations (1)

β2‐adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co‐activation of ryanodine receptor clusters

Acta Physiologica (2021)

C Nolla-Colomer S Casabella-Ramon Verónica Jiménez-Sábado Alexander Vallmitjana Carmen Tarifa

Abstract Aims It is unknown how β‐adrenergic stimulation affects calcium dynamics in individual RyR2 clusters and leads to the induction of spontaneous calcium waves. To address this, we analysed spontaneous calcium release events in green fluorescent protein (GFP)‐tagged RyR2 clusters. Methods Cardiomyocytes from mice with GFP‐tagged RyR2 or human right atrial tissue were subjected to immunofluorescent labelling or confocal calcium imaging. Results Spontaneous calcium release from single RyR2 clusters induced 91.4% ± 2.0% of all calcium sparks while 8.0% ± 1.6% were caused by release from two neighbouring clusters. Sparks with two RyR2 clusters had 40% bigger amplitude, were 26% wider, and lasted 35% longer at half maximum. Consequently, the spark mass was larger in two‐ than one‐cluster sparks with a median and interquartile range for the cumulative distribution of 15.7 ± 20.1 vs 7.6 ± 5.7 a.u. ( P < .01). β2‐adrenergic stimulation increased RyR2 phosphorylation at s2809 and s2815, tripled the fraction of two‐ and three‐cluster sparks, and significantly increased the spark mass. Interestingly, the amplitude and mass of the calcium released from a RyR2 cluster were proportional to the SR calcium load, but the firing rate was not. The spark mass was also higher in 33 patients with atrial fibrillation than in 36 without (22.9 ± 23.4 a.u. vs 10.7 ± 10.9; P = .015). Conclusions Most sparks are caused by activation of a single RyR2 cluster at baseline while β‐adrenergic stimulation doubles the mass and the number of clusters per spark. This mimics the shift in the cumulative spark mass distribution observed in myocytes from patients with atrial fibrillation.

10.1111/apha.13736

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Citations (8)