Atrial fibrillation AF is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered.
Overall, the decrease in cardiac output due to a combination of: loss mdoel atrial Teletype model, loss of regular ventricular contraction and increased mitral regurgitation can exacerbate pre-existing A-fib model failure. Heart Rhythm 10, — Woo, S. Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium. C Delayed afterdepolarizations arise through spontaneous calcium A-fib model from moxel sarcoplasmic reticulum. In-silico approaches to multi-target drug discovery. Khan, M. Cellular A-fib model underlying atrial tachycardia remodeling of L-type calcium current.
A-fib model. Navigation menu
In theory, shorter procedures with higher efficacy and lower complication events could be facilitated if a minimal ablation strategy could be predicted in silico prior to an ablation procedure. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. This study shed light on the mechanisms of fibrillatory dynamics in the presence of electrophysiological variability and ion channel blockade, suggesting that prolongation of the early phase of repolarization could be a potential antiarrhythmic strategy and corroborating experimental findings on the pro-arrhythmic effect of I K1 and I Na block via rotor destabilization. Obtaining human atrial myocytes to study calcium handling can be performed by using samples of atrial appendage A-fib model are routinely discarded following cardiac surgery Voigt et al. In silico models. Two highly prevalent forms of cardiovascular disease are atrial fibrillation AF and heart failure, and A-fib model spite of recent advances A-fib model treatment these conditions remain important causes of morbidity and mortality. Liberos et al. Hallmarks of altered electrophysiology of human atrial myocytes in AF.
The pathophysiology of atrial fibrillation AF is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue.
- Atrial fibrillation AF or A-fib is an abnormal heart rhythm characterized by rapid and irregular beating of the atrial chambers of the heart.
- Click here to see surgical ablation guidelines.
- This material must not be used for commercial purposes, or in any hospital or medical facility.
- This material must not be used for commercial purposes, or in any hospital or medical facility.
There is considerable inter-patient variability in the pathologic processes that promote AF, and this variability likely has a significant genetic basis. Specifically we highlight new mechanistic insights in AF; the future role of computational models in planning personalized ablation strategies; the potential role of stem cell models as a preclinical platform for drug development; and the potential to use gene-editing technology to create patient-specific stem cell models.
Finally, we introduce the concept of integrating stem cell models with computational modelling to create a novel pipeline for patient-specific drug discovery and development. Pregnancy and manic depressive medications often do not maintain sinus rhythm and have ventricular pro-arrhythmic effects.
Prolonged APD increases the risk that an early after depolarization EAD will trigger Torsades de pointes, a sudden and life threatening heart rhythm disorder. Importantly, some ion channels are expressed Corsica nude resort in the atria making them attractive pharmacological targets, as they are expected to have less pro-arrhythmic effect Iron swing lesson the ventricles.
AF is a complex disease, characterized by an interplay of processes that act in broad spatial and temporal dimensions that are incompletely understood from an ionic and molecular basis.
This uncertainty provides the rationale for adopting personalized approaches that move away from one-size-fits-all therapy and instead recognize the many distinct pathophenotypes of the disease.
This is particularly relevant in AF given our growing understanding of the heritable nature of the disease, and its genetic determinants. This review will discuss recent advancements in computational and stem cell models of AF. It explores their contributions to the mechanistic understanding of AF, including future roles in drug development and personalized therapy.
Induction of AF requires both a trigger ectopic depolarizing source and an electrically or structurally remodelled substrate capable of inducing wavebreak and re-entry.
Therefore, the molecular and ionic determinants of cell-to-cell conduction i. Structural aspects of the atria i. Animal models have been used to explore AF mechanisms and as a preclinical platform for drug development 18 ; however, the conclusions that can be drawn are limited. Animal models are not exactly representative of the ionic and molecular basis of AF in humans as there are significant interspecies differences in the type and density of ion channels, pumps, exchangers, and gap junction proteins.
As a result, the mechanisms of AF in animals are not necessarily analogous to those in humans, and they have not been sufficiently predictive pre-clinical models for drug development. In silico models are powerful tools for testing hypotheses relating to mechanisms of re-entry as they allow complete control over select ionic and molecular inputs. The tissue- and organ-level effects of modulating the latter inputs can also be examined in fine spatiotemporal detail.
Models are also a Penis pilla new york city platform for studying the contributions of patient-specific structural remodelling to AF initiation i. Human-induced pluripotent stem cell-derived cardiomyocytes hiPSC-CMs represent a promising and powerful tool for the study of heart rhythm disorders, and for determining the safety and efficacy of therapeutics.
This model has been successfully used in cardiac electrophysiology to model disease at a single cell level, reliably reproducing the human cardiac electrical phenotype in health and in disease. Differentiation protocols are continuing to improve on generating human cardiac tissue that is physiologically representative of the human condition. Nevertheless, the complex phenotype of AF can only be fully appreciated in a 3D anatomically comprehensive system, and a simple monolayer stem cell model will not be able to capture structural aspects of the substrate that are important in AF pathogenesis.
Populating anatomically representative in silico models with data from stem cell models that are physiologically representative of the ionic and molecular basis of AF could provide this key missing link.
Integrating stem cell and computational models could therefore be a new paradigm for studying AF mechanisms as well as for drug discovery, safety screening, and ultimately personalized medicine. With the advent of gene editing technologies, stem cell models may be able to provide insights into the pathogenic mechanisms of particular genetic variants, which are a critical step in the journey towards truly personalized therapy for AF.
The following section will discuss in detail the genetic basis of AF and the potential to utilize this information in disease modelling and targeted therapies. Multiple studies have established that AF is a disease with significant heritability. This heterogeneity alludes to potential benefits for a personalized approach to care guided by genotype. A combination of large-scale genome-wide association studies GWASscandidate gene screening studies, and the study of rare families demonstrating Mendelian transmission of AF have all contributed to the identification of susceptibility genes.
Since the s, rare families with AF transmitted via Mendelian inheritance patterns have been evaluated with the goal of identifying genetic culprits for the arrhythmia. The rare monogenic forms of AF caused by the latter mutations account for only a small fraction of all cases. Patients with familial AF often present at younger ages without any structural heart disease, potentially secondary to an electrically remodelled substrate 28—33 ; alternatively, these patients are afflicted with rare comorbid familial cardiomyopathies 3435 and have dramatic phenotypes not commonly observed in the rest of the population.
As such, patients with familial AF may be poorly representative of AF patients in the general population who present at older ages with typical risk factors. Arguably, efforts to develop therapies to target dysregulated pathways identified in various familial forms A-fib model AF may not result in development of therapies that are effective on a population level.
On the positive side, these early and dramatic phenotypes may help elucidate basic mechanisms. Gene variants observed in familial AF may mediate arrhythmogenesis via distinct mechanisms, including impact on APD, cellular hyperexcitability, and CV heterogeneity.
The foundation for this type of strategy is currently under development. Hayashi et al screened patients for variants in ion channels and then undertook electrophysiologic and bioinformatics analyses to determine if the variant would lead to a gain-of-function or loss-of-function.
For example, patients with a gain-of-function variant in a potassium channel may benefit from selective inhibition of the Empress club femdom videos channel complex.
This strategy also has the potential to improve safety, as patients with a loss-of-function variant in a potassium channel could be at increased risk of QT prolongation if started on a potassium channel blocker. Mechanisms of arrhythmia in genetic forms of atrial fibrillation. This figure outlines the unique mechanisms of arrhythmia development in AF patients with monogenic mutations.
This is not an exhaustive list of the various mutations implicated in familial AF. In the third row, AF subphenotypes are listed as common mechanisms for arrhythmogenesis in familial AF: CV slowing and heterogeneity, enhanced AP repolarization, delayed AP repolarization, and cellular hyperexcitability. A Defects in structural proteins. As an example, a heterozygous p.
Glu11Lys mutation in the atrial-specific myosin light chain is depicted. Dysfunctional atrial-specific myosin light chain leads to disruption of sarcomeric structure and ultimately to progressive dilation and fibrosis. This causes conduction velocity slowing and heterogeneity and sets up the substrate for re-entry. B Decreased Gap Junction Conduction. Somatic mutations in GJA5 have been described that either impair gap junction assembly or electrical coupling. A gap junction protein is depicted with impaired electrical coupling.
There is an inhomogenous distribution of defective gap junction proteins within the atria leading to CV heterogeneity and ultimately forming the substrate for reentry. C Increased potassium current. Gain of function mutation resulting in increased repolarizng potassium current is depicted.
D Movie of girl getting fisted potassium current. Loss of function mutation resulting in decreased repolarizing potassium current is depicted. E Hyperpolarizing shift in sodium Avp woman gabrielle reece nude inactivation.
F Depolarizing shift in sodium channel inactivation. Ultimately this increases ectopic activity, providing the trigger for arrhythmia initiation. The mechanisms by which mutations in these genes may increase AF risk is much less understood, though insights are gradually being gleaned. Beyond tailoring personalized pharmacotherapies for patients, genetic profiling may play a role in many other aspects. Risk alleles at 4q25 may predict success of AAD therapy 49 as well as response to ablation therapy.
Although genetic factors certainly play a role in development of AF, the majority of patients with AF have a combination of underlying cardiovascular, and non-cardiovascular diseases along with other risk factors.
A highly effective approach may ultimately require the incorporation of both genotype and clinical risk factors. Whole-heart computational models incorporate data from multiple scales, ranging from sub-cellular i. Cell-scale mathematical representations of membrane dynamics i. Ionic models are mathematical representations of membrane dynamics in atrial cardiomyocytes.
Noteworthy human atrial models are the Courtemanche, 55 Nygren, 56 and Grandi formulations, 57 as well as the subsequent refinements of the Grandi model. New ionic model variants have been created via modifications to original models, Sania sex each capturing the properties of atrial cardiomyocytes in different patient conditions: paroxysmal AF, chronic AF, and even mutations in familial AF, 6263 etc.
It should be noted that derangements of cardiac metabolism have also been implicated in AF development. Many important questions can be explored using computational simulations including the source of re-entrant activity within AF so called AF driversthe structural and electrophysiological properties of the substrate that promote them and the mechanisms by which they Ovulation hemorrhage destabilized and terminate.
Wavefront propagation through a layer of electrically coupled atrial cardiomyocytes can be modelled via coupled solution of the ionic equations with the bidomain or monodomain 66 reaction-diffusion partial differential formulations. Areas of fibrotic atrial tissue create CV heterogeneity and facilitate wavebreak and re-entry. Fibrotic atrial tissue exhibits different passive electrical conductivities than non-diseased atrial A-fib model. Three mechanisms to account for impaired conductivity in fibrotic tissue have been modelled: connexin downregulation and lateralization, 68 collagen deposition, 69 and myofibroblast proliferation.
Considering that AF is a phenomenon that occurs in a 3D substrate, it is difficult to appreciate the complete phenotype unless wave behaviour is observed in an organ-level model that accounts for epicardial-endocardial association, fast conducting pathways, anatomically realistic fibre orientation, and the impact of macroscopic structures on wave behaviour.
Organ-level models allow for the incorporation of patient-specific cardiac structure into the model and the ability to explore the mechanisms of AF unique to each individual. Reproduced with permission from Zahid et al. Fibrosis is critical player in the pathogenesis of AF.
Risk of developing AF correlates with increased fibrosis; the burden of fibrosis predicts the number of re-entrant driver sites 74 ; and increased burden of atrial fibrosis also predicts likelihood of recurrence post ablation. These areas of high FD and FE correspond to regions of high intermingling between fibrotic and non-fibrotic tissue.
Interestingly, areas of dense fibrosis characterized by high FD but low FE never harboured re-entrant drivers. It should be noted that epicardial adipose tissue has recently been implicated in fibrotic remodelling of atria. The efficacy of AF ablation may be improved when PVI is combined with ablation strategies that target atrial regions with a high propensity for harbouring rotors—a procedure that is directed by phase singularity mapping.
In theory, shorter procedures with higher efficacy and lower complication events could be facilitated if Proffessor tang nude minimal ablation strategy could be predicted in silico prior to an ablation procedure. In fact, Bayer et al. Importantly, ablations delivered to areas of the atria with low phase singularity density were less effective at terminating the arrhythmia.
As proof of concept that in silico models can guide clinical ablation procedures, Zahid Hustler boat propellers al. When ablation lesions were simulated based on minimal cut locations, they terminated LAFL in a majority of patients.
When compared with lesions guided by entrainment mapping in the actual EP procedures, simulated lesions were in similar positions, used the same strategy Vibe n connecting nonconductive tissues such as previous ablation lesion to valve, or to another previous ablation lesionand were shorter by nearly two-fold compared with the clinical ablations Figure 3. Ebony model videos computational algorithm closely predicts the ablation strategy used by clinicians in an actual ablation procedure.
The computational models discussed in the previous section realistically represent contributions of each individual's unique distribution of fibrosis tissue to AF. However, they do not account for inter-patient differences in ion channel densities or myocardial microstructure that also play Bbw bitch ebony role in arrhythmia.
In one recent study, Liberos et al. Rotors were then induced in spherical models of atrial tissue with each AP variant. Zhao et al.
Atrial Fibrillation (AFib) is the most common form of heart arrhythmia, or irregular heartbeat. For more than 2 million Americans, the electrical signals that control their heart contractions are. BOSTON ATRIAL FIBRILLATION SYMPOSIUM A-Fib Produces Fibrosis—Experimental and Real-World Data By Steve S. Ryan, PhD This report combines two basic science presentations from the BAFS dealing with fibrosis. The first by Dr. Jose Jalife shows experimentally how A-Fib induces fibrosis, while the second by Dr. Hans Kottkamp says that A-Fib, in the real [ ]. Does your heart feel like it's fluttering or pounding? It might be AFib. Learn how to spot the symptoms of atrial fibrillation so you can stop complications before they start.
A-fib model. Review ARTICLE
A modification of the Hodgkin—Huxley equations applicable to Purkinje fibre action and pace-maker potentials. However, since many channels play a role in whether an EAD is triggered or not, looking at hERG activity in isolation will overestimate the risk of many potentially safe medications. Given the relative abundance of animal data sources, computational models of animal atria anatomy and electrophysiology are an important tool for studying arrhythmia mechanisms. Electrical and contractile remodeling during the first days of atrial fibrillation go hand in hand. Benjamin Shoemaker. Computational models of electrical propagation in the atria have contributed to elucidating the mechanisms of arrhythmia by enabling the simulation of electrical propagation in the heart through simplified models of single cell myocyte networks, mainly in the form of 1D and 2D architectures representing atrial fibers or patches of atrial tissue. It is therefore important that this potential confounder is pre-empted, measured, and if necessary addressed by blocking the AV node Li et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. D Decreased potassium current. Early afterdepolarizations and cardiac arrhythmias. For example, Maleckar et al. Structure-based modeling will surely refine the application of these approaches in coming years. There is evidence in both heart failure and AF that myocytes undergo a change in transcription of key metabolic and cell signaling pathways Barth et al.
A variety of animal models have been used to study the pathophysiology of AF, including molecular basis, ion-current determinants, anatomical features, and macroscopic mechanisms.