In-silico investigations of the functional impact of KCNA5 mutations on atrial mechanical dynamics.

A recent study has identified six novel genetic variations (D322H, E48G, A305T, D469E, Y155C, P488S) in KCNA5 (encoding Kv1.5 which carries the atrial-specific ultra-rapid delayed rectifier current, IKur) in patients with early onset of lone atrial fibrillation. These mutations are distinctive, resulting in either gain-of-function (D322H, E48G, A305T) or loss-of-function (D469E, Y155C, P488S) of IKur channels. Though affecting potassium channels, they may modulate the cellular active force and therefore atrial mechanical functions, which remains to be elucidated. The present study aimed to assess the inotropic effects of the identified six KCNA5 mutations on the human atria. Multiscale electromechanical models of the human atria were used to investigate the impact of the six KCNA5 mutations on atrial contractile functions. It was shown that the gain-of-function mutations reduced active contractile force primarily through decreasing the calcium transient (CaT) via a reduction in the L-type calcium current (ICaL) as a secondary effect of modulated action potential, whereas the loss-of-function mutations mediated positive inotropic effects by increased CaT via enhancing the reverse mode of the Na+/Ca2+ exchanger. The 3D atrial electromechanical coupled model predicted different functional impacts of the KCN5A mutation variants on atrial mechanical contraction by either reducing or increasing atrial output, which is associated with the gain-of-function mutations or loss-of-function mutations in KCNA5, respectively. This study adds insights to the functional impact of KCNA5 mutations in modulating atrial contractile functions.

Physiological mechanisms of pulmonary hypertension.

Pulmonary hypertension is usually related to obstruction of pulmonary blood flow at the level of the pulmonary arteries (eg, pulmonary embolus), pulmonary arterioles (idiopathic pulmonary hypertension), pulmonary veins (pulmonary venoocclusive disease) or mitral valve (mitral stenosis and regurgitation). Pulmonary hypertension is also observed in heart failure due to left ventricle myocardial diseases regardless of the ejection fraction. Pulmonary hypertension is often regarded as a passive response to the obstruction to pulmonary flow. We review established fluid dynamics and physiology and discuss the mechanisms underlying pulmonary hypertension. The important role that the right ventricle plays in the development and maintenance of pulmonary hypertension is discussed. We use principles of thermodynamics and discuss a potential common mechanism for a number of disease states, including pulmonary edema, through adding pressure energy to the pulmonary circulation.

An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

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

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 tissue vulnerability, shortened ERP and altered atrial conduction velocity, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.

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 (I(Kr))-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 (APD(90)) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD(90) 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 I(Kr) 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.

Acidosis impairs the protective role of hERG K(+) channels against premature stimulation.

INTRODUCTION: Potassium channels encoded by human ether-à-go-go-related gene (hERG) underlie the cardiac rapid delayed rectifier K(+) channel current (I(Kr)). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including I(Kr) . The aim of this study was to characterize effects of extracellular acidosis on hERG current (I(hERG)), with particular reference to quantifying effects on I(hERG) elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli. METHODS AND RESULTS: I(hERG) recordings were made from hERG-expressing Chinese Hamster Ovary cells using whole-cell patch-clamp at 37°C. I(hERG) during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state I(hERG) activation were shifted by ∼+6 mV; maximal I(hERG) conductance was reduced. The voltage-dependence of I(hERG) inactivation was little-altered. Fast and slow time-constants of I(hERG) deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time-course of recovery of I(hERG) from inactivation was observed, but time-course of activation was unaffected. The amplitude of outward I(hERG) transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3. CONCLUSION: During acidosis the contribution of I(hERG) to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli.

In silico investigation of a KCNQ1 mutation associated with short QT syndrome.

Short QT syndrome (SQTS) is a rare condition characterized by abnormally 'short' QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 'gain-of-function' mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2.

Left ventricular ejection fraction is determined by both global myocardial strain and wall thickness.

OBJECTIVES: The 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. METHODS: The 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. RESULTS: The 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 (-%). CONCLUSION: The 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.

Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study.

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.

Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics - Insights from a 3D Model of the Human Atria.

AIMS: Atrial 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 RESULTS: A 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. CONCLUSIONS: This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients.

A 2D Electromechanical Model of Human Atrial Tissue Using the Discrete Element Method.

Cardiac tissue is a syncytium of coupled cells with pronounced intrinsic discrete nature. Previous models of cardiac electromechanics often ignore such discrete properties and treat cardiac tissue as a continuous medium, which has fundamental limitations. In the present study, we introduce a 2D electromechanical model for human atrial tissue based on the discrete element method (DEM). In the model, single-cell dynamics are governed by strongly coupling the electrophysiological model of Courtemanche et al. to the myofilament model of Rice et al. with two-way feedbacks. Each cell is treated as a viscoelastic body, which is physically represented by a clump of nine particles. Cell aggregations are arranged so that the anisotropic nature of cardiac tissue due to fibre orientations can be modelled. Each cell is electrically coupled to neighbouring cells, allowing excitation waves to propagate through the tissue. Cell-to-cell mechanical interactions are modelled using a linear contact bond model in DEM. By coupling cardiac electrophysiology with mechanics via the intracellular Ca(2+) concentration, the DEM model successfully simulates the conduction of cardiac electrical waves and the tissue's corresponding mechanical contractions. The developed DEM model is numerically stable and provides a powerful method for studying the electromechanical coupling problem in the heart.

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling.

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 [Ca(2+)] 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 (I sac). Without I sac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca(2+)] i transients, sarcomere length shortening and contractile force. When I sac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca(2+) 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 I sac 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.

Development of biophysically detailed electrophysiological models for pacemaking and non-pacemaking human pulmonary vein cardiomyocytes.

Ectopic foci originating from the pulmonary veins (PVs) have been suggested as the underlying cause for generating atrial arrhythmias that include atrial fibrillation (AF). Recent experimental findings indicate two types of PV cells: pacemaking and non-pacemaking. In this study, we have developed two mathematical models for human PV cardiomyocytes with and without pacemaking activities. The models were reconstructed by modifying an existing model of the human right atrium to incorporate extant experimental data on the electrical differences between the two cell types. Differences in their action potential (AP) profiles and automaticity were reproduced by the models, which can be attributed to the observed differences in the current densities of I(NCX), I(to), I(Na) and I(Ca-L), as well as the difference in the channel kinetics of I(Ca-L) and inclusion of the I(f) and I(Ca-T) currents in the pacemaking cells. The developed models provide a useful tool suitable for studying the substrates for generating AF.

Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling.

AIMS: One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K(+) current (I(K1)). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias. METHODS AND RESULTS: The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I(K1) based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N 'mutant' I(K1) led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 'mutant' I(K1) also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry. CONCLUSION: 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.

Modeling the chronotropic effect of isoprenaline on rabbit sinoatrial node.

INTRODUCTION: ß-adrenergic stimulation increases the heart rate by accelerating the electrical activity of the pacemaker of the heart, the sinoatrial node (SAN). Ionic mechanisms underlying the actions of ß-adrenergic stimulation are not yet fully understood. Isoprenaline (ISO), a ß-adrenoceptor agonist, shifts voltage-dependent I(f) activation to more positive potentials resulting in an increase of I(f), which has been suggested to be the main mechanism underlying the effect of ß-adrenergic stimulation. However, ISO has been found to increase the firing rate of rabbit SAN cells when I(f) is blocked. ISO also increases I(CaL), I(st), I(Kr), and I(Ks); and shifts the activation of I(Kr) to more negative potentials and increases the rate of its deactivation. ISO has also been reported to increase the intracellular Ca(2+) transient, which can contribute to chronotropy by modulating the "Ca(2+) clock." The aim of this study was to analyze the ionic mechanisms underlying the positive chronotropy of ß-adrenergic stimulation using two distinct and well established computational models of the electrical activity of rabbit SAN cells. METHODS AND RESULTS: We modified the Boyett et al. (2001) and Kurata et al. (2008) models of electrical activity for the central and peripheral rabbit SAN cells by incorporating equations for the known dose-dependent actions of ISO on various ionic channel currents (I(CaL), I(st), I(Kr), and I(Ks)), kinetics of I(Kr) and I(f), and the intracellular Ca(2+) transient. These equations were constructed from experimental data. To investigate the ionic basis of the effects of ISO, we simulated the chronotropic effect of a range of ISO concentrations when ISO exerted all its actions or just a subset of them. CONCLUSION: In both the Boyett et al. and Kurata et al. SAN models, the chronotropic effect of ISO was found to result from an integrated action of ISO on I(CaL), I(f), I(st), I(Kr), and I(Ks), among which an increase in the rate of deactivation of I(Kr) plays a prominent role, though the effect of ISO on I(f) and [Ca(2+)](i) also plays a role.

Integration of genetics into a systems model of electrocardiographic traits using HumanCVD BeadChip.

BACKGROUND: Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death. METHODS AND RESULTS: In this study, 3 population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10(-6), including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG. CONCLUSIONS: These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.