Cardiac re-entry dynamics & self-termination in DT-MRI based model of Human Foetal Heart

The effect of heart geometry and anisotropy on cardiac re-entry dynamics and self-termination is studied here in anatomically realistic computer simulations of human foetal heart. 20 weeks of gestational age human foetal heart isotropic and anisotropic anatomy models from diffusion tensor MRI data sets are used in the computer simulations. The fibre orientation angles of the heart were obtained from the DT-MRI primary eigenvalues. In a spatially homogeneous electrophysiological mono domain model with the DT-MRI based heart geometries, we initiate simplified Fitz-Hugh-Nagumo kinetics cardiac re-entry at a prescribed location in a 2D slice, and in the full 3D anatomy model. In a slice of the heart, the MRI based fibre anisotropy changes the re-entry dynamics from pinned to anatomical re-entry. In the full 3D MRI based model, the foetal heart fibre anisotropy changes the re-entry dynamics from a persistent re-entry to the re-entry self-termination

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats

We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na⁺-channel blocker (5 μM) ranolazine or the intracellular Ca²⁺ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand

Computational Modelling of Cardiac Electrophysiological Changes in Malarial Fever

Cardiac function is impaired in severe malarial fever, and ECGs show changes associated with repolarization. These could contribute to mortality via ventricular arrhythmia. The cardiac effects could be due to the malarial parasite load in the heart, specific cardio-toxic effects of the parasite or cardio-toxic effects of antimalarial agents. We construct a simple 1-dimensional electrophysiological model for the physico-chemical changes clinically observed during malarial fever: with temperature, pH and [ionic]plasma changes. The model can quantitatively reproduce the tachycardia and QTc prolongation seen in the adult, and shortening seen in the child during malarial fever

Self-terminating re-entrant cardiac arrhythmias: quantitative characterization

Atrial and ventricular tachyarrhythmia are often sustained by re-entrant propagation, and explained by deterministic models. A quantitative, stochastic description of self-termination provides an alternative to the current paradigm for re-entrant tachyarrhythmia - that of triggers and a substrate, modelled by parametrically heterogeneous deterministic partial differential equations. Atrial and ventricular data was from recordings obtained during routine clinical monitoring and treatment, either noninvasively or invasively. Atrial and ventricular tachycardia are characterised by their initiation times and durations, re-presented as instantaneous rates, whose means estimate transition probabilities/s for onset and termination. These estimated probabilities range from 10(-9) to 10(-1)/s

Transcriptomic Approaches to Modelling Long Term Changes in Human Cardiac Electrophysiology

Slow changes in the activity of the heart occur with time scales from days through to decades, and may in part result from changes in cardiomyocyte properties. The cellular mechanisms of the cardiomyocyte action potential have time scales from < ms to hundreds of ms. Although the quantitative dynamic relations between mRNA transcription, protein synthesis, trafficking, recycling, and membrane protein activity are unclear, mRNA-Seq can be used to inform parameters in cell excitation equations. We use such transcriptomic data from a non-human primate to scale maximal conductances in the O’Hara-Rudy (2011) family of human ventricular cell models, and to predict diurnal changes in human ventricular action potential durations. These are related to circadian changes in the incidence of sudden cardiac deaths. Transcriptomic analysis of human fetal hearts between 9 and 16 weeks gestational age is beginning to be used to inform ventricular cell and tissue models of the electrophysiology of the developing fetal heart

Diffusion Tensor Imaging determines three-dimensional architecture of human cervix: a cross sectional study

Objective To determine the microarchitecture of the cervix using high-resolution diffusion tensor (DT) magnetic resonance imaging (MRI). Design Cross-sectional study. Setting Leeds, UK. Sample Women undergoing hysterectomy for benign pathology. Methods Ex-vivo DT-MRI measurements were obtained using a 9.4-T Bruker nuclear magnetic resonance (NMR) spectrometer on seven fixed human cervices obtained at hysterectomy. A deterministic fibre-tracking algorithm was used to indirectly visualise underlying fibre organisation. Inter-regional differences in tissue structure were sought using quantitative measurements of diffusion. Main outcome measure The identification of an occlusive structure in the region corresponding to the internal cervical os. Results Fibre tracking demonstrated two regions: an outer circular and inner longitudinal layer. The total circumferential tract volume (TV) was greatest in the proximal region of the cervix (TV: proximal, 271 ± 198 mm3; middle, 186 ± 119 mm3; distal, 38 ± 36 mm3). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) measurements were significantly different between regions in all samples (P < 0.0005), indicating greater tract density and organisation towards the internal os. Conclusion Fibre tracking infers a system of dense, well-defined, encircling fibres in the proximal region of the cervix, corresponding to the location of the internal os. These findings may provide evidence of specific anatomic microarchitecture within the cervix able to resist intrauterine forces associated with pregnancy

Multichannel electrocardiogram diagnostics for the diagnosis of arrhythmogenic right ventricular dysplasia

Aims: The identification of arrhythmogenic right ventricular dysplasia (ARVD) from 12-channel standard electrocardiogram (ECG) is challenging. High density ECG data may identify lead locations and criteria with a higher sensitivity. Methods and results: Eighty-channel ECG recording from patients diagnosed with ARVD and controls were quantified by magnitude and integral measures of QRS and T waves and by a measure (the average silhouette width) of differences in the shapes of the normalized ECG cycles. The channels with the best separability between ARVD patients and controls were near the right ventricular wall, at the third intercostal space. These channels showed pronounced differences in P waves compared to controls as well as the expected differences in QRS and T waves. Conclusion: Multichannel recordings, as in body surface mapping, add little to the reliability of diagnosing ARVD from ECGs. However, repositioning ECG electrodes to a high anterior position can improve the identification of ECG variations in ARVD. Additionally, increased P wave amplitude appears to be associated with ARVD

Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension

Background: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. Methods and Results: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. Conclusions: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease

Three-Dimensional and Chemical Mapping of Intracellular Signaling Nanodomains in Health and Disease with Enhanced Expansion Microscopy

Nanodomains are intracellular foci which transduce signals between major cellular compartments. One of the most ubiquitous signal transducers, the ryanodine receptor (RyR) calcium channel, is tightly clustered within these nanodomains. Super-resolution microscopy has previously been used to visualize RyR clusters near the cell surface. A majority of nanodomains located deeper within cells have remained unresolved due to limited imaging depths and axial resolution of these modalities. A series of enhancements made to expansion microscopy allowed individual RyRs to be resolved within planar nanodomains at the cell periphery and the curved nanodomains located deeper within the interiors of cardiomyocytes. With a resolution of ∼ 15 nm, we localized both the position of RyRs and their individual phosphorylation for the residue Ser2808. With a three-dimensional imaging protocol, we observed disturbances to the RyR arrays in the nanometer scale which accompanied right-heart failure caused by pulmonary hypertension. The disease coincided with a distinct gradient of RyR hyperphosphorylation from the edge of the nanodomain toward the center, not seen in healthy cells. This spatial profile appeared to contrast distinctly from that sustained by the cells during acute, physiological hyperphosphorylation when they were stimulated with a β-adrenergic agonist. Simulations of RyR arrays based on the experimentally determined channel positions and phosphorylation signatures showed how the nanoscale dispersal of the RyRs during pathology diminishes its intrinsic likelihood to ignite a calcium signal. It also revealed that the natural topography of RyR phosphorylation could offset potential heterogeneity in nanodomain excitability which may arise from such RyR reorganization