The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K+ current (IKr)-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD90) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD90 and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of IKr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.

Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.

During acidosis the contribution of I(hERG) to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli.

Introduction: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable to re-entry. Potential electromechanical consequences of the SQTS are less well-understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS.Methods and Results: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K+ channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on [Ca2+]i transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch-activated channel current (Isac). Without Isac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca2+]i transients, sarcomere length shortening and contractile force. When Isac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca2+ transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control.Conclusion: The incorporation of Isac appears to be an important consideration in modeling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

ObjectivesThe purpose of this study was to determine the mathematical relationship between left ventricular ejection fraction and global myocardial strain. A reduction in myocardial strain would be expected to cause a fall in ejection fraction. However, there is abundant evidence that abnormalities of myocardial strain can occur with a normal ejection fraction. Explanations such as a compensatory increase in radial or circumferential strain are not supported by clinical studies. We set out to determine the biomechanical relationship between ejection fraction, wall thickness and global myocardial strain.MethodsThe study used an established abstract model of left ventricular contraction to examine the effect of global myocardial strain and wall thickness on ejection fraction. Equations for the relationship between ejection fraction, wall thickness and myocardial strain were obtained using curve fitting methods.ResultsThe mathematical relationship between ejection fraction, ventricular wall thickness and myocardial strain was derived as follows: φ = e(0.14Ln(ε) + 0.06)ω + (0.9Ln(ε) + 1.2), where φ is ejection fraction (%), ω is wall thickness (cm) and ε is myocardial strain (−%).ConclusionThe findings of this study explain the coexistence of reduced global myocardial strain and normal ejection fraction seen in clinical observational studies. Our understanding of the pathophysiological processes in heart failure and associated conditions is substantially enhanced. These results provide a much better insight into the biophysical inter-relationship between myocardial strain and ejection fraction. This improved understanding provides an essential foundation for the design and interpretation of future clinical mechanistic and prognostic studies.

Key points• 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 I Ks 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.Abstract Functional analysis has shown that the missense gain-in-function KCNQ1 S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I Ks ). Through computer modelling, this study investigated mechanisms by which the KCNQ1 S140G mutation promotes and perpetuates atrial fibrillation. In simulations, Courtemanche et al.'s model of human atrial cell action potentials (APs) was modified to incorporate experimental data on changes of I Ks induced by the KCNQ1 S140G mutation. The cell models for wild type (WT) and mutant type (MT) I Ks were incorporated into homogeneous multicellular 2D and 3D tissue models. Effects of the mutation were quantified on AP profile, AP duration (APD) restitution, effective refractory period (ERP) restitution, and conduction velocity (CV) restitution. Temporal and spatial vulnerabilities of atrial tissue to genesis of re-entry were computed. Dynamic behaviours of re-entrant excitation waves (lifespan (LS), tip meandering patterns and dominant frequency) in 2D and 3D models were characterised. It was shown that the KCNQ1 S140G mutation abbreviated atrial APD and ERP and flattened APD and ERP restitution curves. It reduced atrial CV at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. Although it increased slightly tissue temporal vulnerability for initiating re-entry, it reduced markedly the minimal substrate size necessary for sustaining re-entry (increasing the tissue spatial vulnerability). In the 2D and 3D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. In the 3D model, scroll waves under the mutation condition MT conditions also degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, increased I Ks due to the KCNQ1 S140G mutation increases atrial susceptibility to arrhythmia due to increased tissu...

AimsAtrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics.Methods and ResultsA 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2–3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished.ConclusionsThis study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients.

Heart failure with preserved ejection fraction (HFpEF) accounts for about 50% of heart failure cases. It has features of incomplete relaxation and increased stiffness of the left ventricle. Studies from clinical electrophysiology and animal experiments have found that HFpEF is associated with impaired calcium homeostasis, ion channel remodeling and concentric left ventricle hypertrophy (LVH). However, it is still unclear how the abnormal calcium homeostasis, ion channel and structural remodeling affect the electro-mechanical dynamics of the ventricles. In this study we have developed multiscale models of the human left ventricle from single cells to the 3D organ, which take into consideration HFpEF-induced changes in calcium handling, ion channel remodeling and concentric LVH. Our simulation results suggest that at the cellular level, HFpEF reduces the systolic calcium level resulting in a reduced systolic contractile force, but elevates the diastolic calcium level resulting in an abnormal residual diastolic force. In our simulations, these abnormal electro-mechanical features of the ventricular cells became more pronounced with the increase of the heart rate. However, at the 3D organ level, the ejection fraction of the left ventricle was maintained due to the concentric LVH. The simulation results of this study mirror clinically observed features of HFpEF and provide new insights toward the understanding of the cellular bases of impaired cardiac electromechanical functions in heart failure.