474 research outputs found
Na/K pump regulation of cardiac repolarization: Insights from a systems biology approach
The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most\ud
important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies
A comprehensive and biophysically detailed computational model of the whole human heart electromechanics
While ventricular electromechanics is extensively studied, four-chamber heart
models have only been addressed recently; most of these works however neglect
atrial contraction. Indeed, as atria are characterized by a complex physiology
influenced by the ventricular function, developing computational models able to
capture the physiological atrial function and atrioventricular interaction is
very challenging. In this paper, we propose a biophysically detailed
electromechanical model of the whole human heart that considers both atrial and
ventricular contraction. Our model includes: i) an anatomically accurate
whole-heart geometry; ii) a comprehensive myocardial fiber architecture; iii) a
biophysically detailed microscale model for the active force generation; iv) a
0D closed-loop model of the circulatory system; v) the fundamental interactions
among the different core models; vi) specific constitutive laws and model
parameters for each cardiac region. Concerning the numerical discretization, we
propose an efficient segregated-intergrid-staggered scheme and we employ
recently developed stabilization techniques that are crucial to obtain a stable
formulation in a four-chamber scenario. We are able to reproduce the healthy
cardiac function for all the heart chambers, in terms of pressure-volume loops,
time evolution of pressures, volumes and fluxes, and three-dimensional cardiac
deformation, with unprecedented matching (to the best of our knowledge) with
the expected physiology. We also show the importance of considering atrial
contraction, fibers-stretch-rate feedback and suitable stabilization
techniques, by comparing the results obtained with and without these features
in the model. The proposed model represents the state-of-the-art
electromechanical model of the iHEART ERC project and is a fundamental step
toward the building of physics-based digital twins of the human heart
The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model
Purpose: Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected.
Methods: In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation.
Results: We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue.
Conclusion: This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment
Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak
The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease
The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-chamber Heart Model
Atrial fibrillation is one of the most frequent cardiac arrhythmias in the
industrialized world and ablation therapy is the method of choice for many
patients. However, ablation scars alter the electrophysiological activation and
the mechanical behavior of the affected atria. Different ablation strategies
with the aim to terminate atrial fibrillation and prevent its recurrence exist
but their impact on the hemodynamic performance of the heart has not been
investigated thoroughly. In this work, we present a simulation study analyzing
five commonly used ablation scar patterns and their combinations in the left
atrium regarding their impact on the pumping function of the heart using an
electromechanical whole-heart model. We analyzed how the altered atrial
activation and increased stiffness due to the ablation scar affect atrial as
well as ventricular contraction and relaxation. We found that systolic and
diastolic function of the left atrium is impaired by ablation scars and that
the reduction of atrial stroke volume of up to 11.43% depends linearly on the
amount of inactivated tissue. Consequently, the end-diastolic volume of the
left ventricle, and thus stroke volume, was reduced by up to 1.4% and 1.8%,
respectively. During ventricular systole, left atrial pressure was increased by
up to 20% due to changes in the atrial activation sequence and the stiffening
of scar tissue. This study provides biomechanical evidence that atrial ablation
has acute effects not only on atrial contraction but also on ventricular
pumping function. Our results have the potential to help tailoring ablation
strategies towards minimal global hemodynamic impairment
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