Sanjay Kharche

Pro‐arrhythmogenic effects of atrial fibrillation‐induced electrical remodelling: insights from the three‐dimensional virtual human atria

•  Previous studies have shown that atrial electrical properties are altered (remodelled) by atrial fibrillation (AF) and that the recurrence of AF is high following remodelling. However, demonstrating a causal link between atrial remodelling in experimental models and the increased risk of AF is a challenge. •  AF‐induced electrical remodelling abbreviated atrial action potential duration (APD) non‐uniformly across the atria; this resulted in relatively short APDs co‐existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. •  It increases tissue vulnerability to re‐entry initiation and maintenance at these tissue junctions. •  The AF‐induced electrical remodelling also stabilized and accelerated re‐entrant excitation waves, leading to rapid and sustained re‐entry. •  This study provides novel insights towards understanding the mechanisms underlying the pro‐arrhythmic effects of the AF‐induced electrical remodelling in atrial tissue.

A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases

Genetically modified mice are popular experimental models for studying the molecular bases and mechanisms of cardiac arrhythmia. A postgenome challenge is to classify the functional roles of genes in cardiac function. To unveil the functional role of various genetic isoforms of ion channels in generating cardiac pacemaking action potentials (APs), a mathematical model for spontaneous APs of mouse sinoatrial node (SAN) cells was developed. The model takes into account the biophysical properties of membrane ionic currents and intracellular mechanisms contributing to spontaneous mouse SAN APs. The model was validated by its ability to reproduce the physiological exceptionally short APs and high pacing rates of mouse SAN cells. The functional roles of individual membrane currents were evaluated by blocking their coding channels. The roles of intracellular Ca2+-handling mechanisms on cardiac pacemaking were also investigated in the model. The robustness of model pacemaking behavior was evaluated by means of one- and two-parameter analyses in wide parameter value ranges. This model provides a predictive tool for cellular level outcomes of electrophysiological experiments. It forms the basis for future model development and further studies into complex pacemaking mechanisms as more quantitative experimental data become available.

Effects of streptozotocin-induced diabetes on connexin43 mRNA and protein expression in ventricular muscle.

Abnormal QT prolongation with the associated arrhythmias is a significant predictor of mortality in diabetic patients. Gap junctional intercellular communication allows electrical coupling between heart muscle cells. The effects of streptozotocin (STZ)-induced diabetes mellitus on the expression and distribution of connexin 43 (Cx43) in ventricular muscle have been investigated. Cx43 mRNA expression was measured in ventricular muscle by quantitative PCR. The distribution of total Cx43, phosphorylated Cx43 (at serine 368) and non-phosphorylated Cx43 was measured in ventricular myocytes and ventricular muscle by immunocytochemistry and confocal microscopy. There was no significant difference in Cx43 mRNA between diabetic rat ventricle and controls. Total and phosphorylated Cx43 were significantly increased in ventricular myocytes and ventricular muscle and dephosphorylated Cx43 was not significantly altered in ventricular muscle from diabetic rat hearts compared to controls. Disturbances in gap junctional intercellular communication, which in turn may be attributed to alterations in balance between total, phosphorylated and dephosporylated Cx43, might partly underlie prolongation of QRS and QT intervals in diabetic heart.

Pro-arrhythmogenic effects of the S140G KCNQ1 mutation in human atrial fibrillation - insights from modelling.

•  A previous study has identified a gene mutation (KCNQ1 S140G) in some patients with a familial form of atrial fibrillation, one of the most common cardiac rhythm disturbances causing morbidity and mortality. A causal link between the mutation and genesis of atrial fibrillation has not yet been directly demonstrated. •  Increased IKs arising from the KCNQ1 S140G mutation abbreviated atrial action potential duration (APD) and effective refractory period (ERP) and flattened APD and ERP restitution curves. It reduced atrial conduction velocity at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. •  The mutation increased tissue susceptibility for initiation and maintenance of atrial arrhythmias. •  The mutation stabilizes and accelerates re‐entrant excitation waves, leading to rapid and sustained re‐entry. •  This study provides novel insights towards understanding the mechanisms underlying the pro‐arrhythmic effects of the KCNQ1 S140G mutation.

Virtual tissue engineering of the human atrium: modelling pharmacological actions on atrial arrhythmogenesis.

Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmanns bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.

Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus

Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology.We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and in silico clinical diagnosis and treatment of PTL.

Endogenous driving and synchronization in cardiac and uterine virtual tissues: bifurcations and local coupling

Cardiac and uterine muscle cells and tissue can be either autorhythmic or excitable. These behaviours exchange stability at bifurcations produced by changes in parameters, which if spatially localized can produce an ectopic pacemaking focus. The effects of these parameters on cell dynamics have been identified and quantified using continuation algorithms and by numerical solutions of virtual cells. The ability of a compact pacemaker to drive the surrounding excitable tissues depends on both the size of the pacemaker and the strength of electrotonic coupling between cells within, between, and outside the pacemaking region. We investigate an ectopic pacemaker surrounded by normal excitable tissue. Cell–cell coupling is simulated by the diffusion coefficient for voltage. For uniformly coupled tissues, the behaviour of the hybrid tissue can take one of the three forms: (i) the surrounding tissue electrotonically suppresses the pacemaker; (ii) depressed rate oscillatory activity in the pacemaker but no propagation; and (iii) pacemaker driving propagations into the excitable region. However, real tissues are heterogeneous with spatial changes in cell–cell coupling. In the gravid uterus during early pregnancy, cells are weakly coupled, with the cell–cell coupling increasing during late pregnancy, allowing synchronous contractions during labour. These effects are investigated for a caricature uterine tissue by allowing both excitability and diffusion coefficient to vary stochastically with space, and for cardiac tissues by spatial gradients in the diffusion coefficient.

Pro-arrhythmogenic Effects of Atrial Fibrillation Induced Electrical Remodelling- Insights from 3D Virtual Human Atria

•  Previous studies have shown that atrial electrical properties are altered (remodelled) by atrial fibrillation (AF) and that the recurrence of AF is high following remodelling. However, demonstrating a causal link between atrial remodelling in experimental models and the increased risk of AF is a challenge. •  AF‐induced electrical remodelling abbreviated atrial action potential duration (APD) non‐uniformly across the atria; this resulted in relatively short APDs co‐existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. •  It increases tissue vulnerability to re‐entry initiation and maintenance at these tissue junctions. •  The AF‐induced electrical remodelling also stabilized and accelerated re‐entrant excitation waves, leading to rapid and sustained re‐entry. •  This study provides novel insights towards understanding the mechanisms underlying the pro‐arrhythmic effects of the AF‐induced electrical remodelling in atrial tissue.

Simulating the effects of atrial fibrillation induced electrical remodeling: A comprehensive simulation study

Mechanisms underlying atrial fibrillation (AF) are poorly understood. In this study, we computationally evaluated the functional roles of AF induced electrical remodeling (AFER) on atrial electrical excitations. Experimental data of AFER on human atrial myocytes were incorporated into a biophysically detailed model of human atrial cells to simulate the effects of AFER at cellular and tissue levels. Our results show that AFER dramatically abbreviated atrial action potential duration (APD90) and effective refractory period that were quantitatively consistent with experimental data. A typical feature of loss in rate dependent accommodation of APD90 was observed. AFER slowed down atrial conduction velocity, but facilitated atrial conduction at high excitation rates. AFER increased tissues spatial vulnerability for initiation and maintenance of AF remarkably. The overall susceptibility of human atrium to arrhythmia was increased. Most importantly AFER increased the stability of reentrant waves in 2D and 3D models prolonging their lifespan. While reentrant excitation waves self-terminated under Control conditions, the same became persistent or degenerated into multiple wavelets leading to spatio-temporal chaos under AFER conditions with accelerated re-entrant excitation rates. There was an increase in dominant frequency. In conclusion, our simulations substantiated a link between AFER and persistence of AF, providing mechanistic insights towards better understanding of “AF begets AF”.

Scroll waves in 3D virtual human atria: a computational study

Atrial fibrillation (AF) induced electrical remodelling of ionic channels shortens action potential duration and reduces atrial excitability. Experimental data of AF-induced electrical remodelling (AFER) from two previous studies on human atrial myocytes were incorporated into a human atrial cell computer model to simulate their effects on atrial electrical behaviour. The dynamical behaviors of excitation scroll waves in an anatomical 3D homogenous model of human atria were studied for control and AF conditions. Under control condition, scroll waves meandered in large area and became persistent when entrapped by anatomical obstacles. In this case, a mother rotor dominated atrial excitation. Action potentials from several sites behaved as if the atrium were paced rapidly. Under AF conditions, AFER increased the stability of re-entrant scroll waves by reducing meander. Scroll wave break up leads to wavelets underpinning sustained chronic AF. Our simulation results support the hypothesis that AF-induced electrical remodelling perpetuates and sustains AF.