© 2017 The Authors. The Journal of Physiology published by John Wiley&Sons Ltd on behalf of The Physiological Society Key points: Continuous high-intensity constant-power exercise is unsustainable, with maximal oxygen uptake ((VO2max)) and the limit of tolerance attained after only a few minutes. Performing the same power intermittently reduces the O2cost of exercise and increases tolerance. The extent to which this dissociation is reflected in the intramuscular bioenergetics is unknown. We used pulmonary gas exchange and31P magnetic resonance spectroscopy to measure whole-body VO2, quadriceps phosphate metabolism and pH during continuous and intermittent exercise of different work:recovery durations. Shortening the work:recovery durations (16:32 s vs. 32:64 s vs. 64:128 s vs. continuous) at a work rate estimated to require 110% peak aerobic power reduced VO2, muscle phosphocreatine breakdown and muscle acidification, eliminated the glycolytic-associated contribution to ATP synthesis, and increased exercise tolerance. Exercise intensity(i.e. magnitude of intramuscular metabolic perturbations) can be dissociated from the external power using intermittent exercise with short work:recovery durations. Abstract: Compared with work-matched high-intensity continuous exercise, intermittent exercise dissociates pulmonary oxygen uptake ((VO2max)) from the accumulated work. The extent to which this reflects differences in O2storage fluctuations and/or contributions from oxidative and substrate-level bioenergetics is unknown. Using pulmonary gas-exchange and intramuscular31P magnetic resonance spectroscopy, we tested the hypotheses that, at the same power: ATP synthesis rates are similar, whereas peak VO2amplitude is lower in intermittent vs. continuous exercise. Thus, we expected that: intermittent exercise relies less upon anaerobic glycolysis for ATP provision than continuous exercise; shorter intervals would require relativelygreater fluctuations in intramuscular bioenergetics than in VO2compared to longer intervals. Six men performed bilateral knee-extensor exercise (estimated to require 110% peak aerobic power) continuously and with three different intermittent work:recovery durations (16:32, 32:64 and 64:128 s). Target work duration (576 s) was achieved in all intermittent protocols; greater than continuous (252 ± 174 s; P < 0.05). Mean ATP turnover rate was not different between protocols (∼43 mm min−1on average). However, the intramuscular phosphocreatine (PCr) component of ATP generation was greatest (∼30 mm min−1), and oxidative (∼10 mm min−1) and anaerobic glycolytic (∼1 mm min−1) components were lowest for 16:32 and 32:64 s intermittent protocols, compared to 64:128 s (18 ± 6, 21 ± 10 and 10 ± 4 mm min−1, respectively) and continuous protocols (8 ± 6, 20 ± 9 and 16 ± 14 mm min−1, respectively). As intermittent work duration increased towards continuous exercise, ATP production relied proportionally more upon anaerobic glycolysis and oxidative phosphorylation, and less upon PCr breakdown. However, performing the same high-intensity power intermittently vs. continuously reduced the amplitude of fluctuations in VO2and intramuscular metabolism, dissociating exercise intensity from the power output and work done.
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© 2017 Colman, Perez Alday, Holden and Benson. Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca2+-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate. Methods: We implemented a multi-scale (cell and tissue) in silico approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca2+dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates. Results: QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on INa. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia. Conclusion: The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.
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Phase 2 pulmonary oxygen uptake kinetics (ϕ2 τVO2P) reflect muscle oxygen consumption dynamics and are sensitive to changes in state of training or health. This study identified an unbiased method for data collection, handling and fitting to optimize VO2P kinetics estimation. A validated computational model of VO2P kinetics and a Monte Carlo approach simulated 2 x 10(5) moderate intensity transitions using a distribution of metabolic and circulatory parameters spanning normal health. Effects of averaging (interpolation, binning, stacking or separate fitting of up to 10 transitions) and fitting procedures (bi-exponential fitting, orϕ2 isolation by time removal, statistical or derivative methods followed by mono-exponential fitting) on accuracy and precision of ϕ2 τVO2P estimation were assessed. The optimal strategy to maximize accuracy and precision of τVO2P estimation was 1-s interpolation of 4 bouts, ensemble averaged, with the first 20 s of exercise data removed. Contradictory to previous advice, we found optimal fitting procedures removed no more than 20 s of ϕ1 data. Averaging method was less critical: interpolation, bin averaging and stacking gave similar results, each with greater accuracy compared to analyzing repeated bouts separately. The optimal procedure resulted in ϕ2 τVO2P estimates for transitions from an unloaded or loaded baseline that averaged 1.97±2.08 and 1.04±2.30 s from true, but were within 2 s of true in only 47-62% of simulations. Optimized 95% confidence intervals for τVO2P ranged from 4.08-4.51 s, suggesting a minimally important difference of ~5 s to determine significant changes in τVO2P during interventional and comparative studies.
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Copyright© 2016 the American Physiological Society. The pulmonary O2uptake (VO2p) response to ramp-incremental (RI) exercise increases linearly with work rate (WR) after an early exponential phase, implying that a single time constant (τ) and gain (G) describe the response. However, variability in τ and Gof VO2pkinetics to different step increments in WR is documented. We hypothesized that the "linear" VO2p-WR relationship during RI exercise results from the conflation between WR-dependent changes in τ and G. Nine men performed three or four repeats of RI exercise (30 W/min) and two step-incremental protocols consisting of four 60-W increments beginning from 20 W or 50 W. During testing, breath-by-breath VO2pwas measured by mass spectrometry and volume turbine. For each individual, the VO2pRI response was characterized with exponential functions containing either constant or variable τ andG values. A relationship between τ and G vs. WR was determined from the step-incremental protocols to derive the variable model parameters. τ and G increased from 21 ± 5 to 98 ± 20 s and from 8.7± 0.6 to 12.0 ± 1.9 ml min-1W-1for WRs of 20-230 W, respectively, and were best described by a second-order (τ) and a first-order (G) polynomial function of WR (lowest Akaike information criterion score). The sum of squared residuals was not different (P>0.05) when the VO2pRI response was characterized with either the constant or variable models, indicating that they described the response equally well. Results suggest thatτ and G increase progressively with WR during RI exercise. Importantly, these relationships may conflate to produce a linear VO2p-WR response, emphasizing the influence of metabolic heterogeneity in determining the apparent VO2p-WR relationship during RI exercise.
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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.
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The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.
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The short QT syndrome (SQTS) is a recently identified genetic disorder associated with ventricular and/or atrial arrhythmias and increased risk of sudden cardiac death. The SQTS variant 1 (SQT1) N588K mutation to the hERG gene causes a gain-of-function to IKr which shortens the ventricular effective refractory period (ERP), as well as reducing the potency of several drugs which block the hERG channel. This study used computational modelling to assess the effects of disopyramide (DISO), a class 1a anti-arrhythmic agent, on human ventricular electro-physiology in SQT1. The O'Hara Rudy dynamic (ORd) model of the human ventricle action potential (AP) was modified to incorporate a Markov chain model of IKr/hERG including formulations for wild type (WT) and SQT1 N588K mutant hERG channels. The blocking effects of DISO on IKr, INa, ICaL, and Ito were modelled using IC50 and Hill coefficient values from the literature. The ability of DISO to prolong the QT interval was evaluated using a 1D model of human ventricular cells with transmural heterogeneities and the corresponding pseudo-ECG. At a clinically-relevant concentration of 10μM DISO, the action potential duration (APD) at the single cell level was increased significantly through inhibition of mutant SQT1-hERG channels. The corrected QT interval in tissue was prolonged. This study provides further evidence that DISO is a suitable treatment for hERG-mediated SQTS.
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© 2016 CCAL. 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 theparasite 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]plasmachanges. The model can quantitatively reproduce the tachycardia and QTcprolongation seen in the adult, and shortening seen in the child during malarial fever.
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© the American Physiological Society. During whole body exercise in health, maximal oxygen uptake (VO2max) is typically attained at or immediately before the limit of tolerance (LoT). At the VO2maxand LoT of incremental exercise, a fundamental, but unresolved, question is whether maximal evocable power can be increased above the task requirement, i.e., whether there is a "power reserve" at the LoT. Using an instantaneous switch from cadence-independent (hyperbolic) to isokinetic cycle ergometry, we determined maximal evocable power at the limit of ramp-incremental exercise. We hypothesized that in endurance-trained men at LoT, maximal (4 s) isokinetic power would not differ from the power required by the task. Baseline isokinetic power at 80 rpm (Piso; measured at the pedals) and summed integrated EMG from five leg muscles (ΣiEMG) were measured in 12 endurance-trained men (VO2max= 4.2± 1.0 l/min). Participants then completed a ramp incremental exercise test (20-25 W/min), with instantaneous measurement of Pisoand ΣiEMG at the LoT. Pisodecreased from 788 ± 103 W at baseline to 391 ± 72 W at LoT, which was not different from the required ramp-incremental flywheel power (352 ±58 W; P>0.05). At LoT, the relative reduction in Pisowas greater than the relative reduction in the isokineticΣiEMG (50 ± 9 vs. 63 ± 10% of baseline; P<0.05). During maximal ramp incremental exercise in endurance-trained men, maximum voluntary power is not different from the power required by the task and is consequent to both central and peripheral limitations in evocable power. The absence of a power reserve suggests both the perceptual and physiological limits of maximum voluntary power production are not widely dissociated at LoT in this population.
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© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society New Findings: What is the central question of this study? The finding that pulmonary oxygen uptake ((Formula presented.)o2p) kinetics on transition to moderate exercise is invariant and exponential is consistent with a first-order reaction controlling (Formula presented.)o2p. However, slowed (Formula presented.)o2pkinetics when initiating exercise from raised baseline intensities challenges this notion. What is the main finding and its importance? Here, we demonstrate how a first-order system can respond with non-first-order response dynamics. Data suggest that progressive recruitment of muscle fibre populations having progressively lower mitochondrial density and slower microvascular blood flow kinetics can unify the seemingly contradictory evidence for the control of (Formula presented.)o2pon transition to exercise. We examined the relationship amongst baseline work rate (WR), phase II pulmonary oxygen uptake ((Formula presented.)o2p) time constant (τ(Formula presented.)o2p) and functional gain (Gp=△(Formula presented.)o2p/△WR) during moderate-intensity exercise. Transitions were initiated from aconstant or variable baseline WR. A validated circulatory model was used to examine the role of heterogeneity in muscle metabolism ((Formula presented.)o2m) and blood flow ((Formula presented.)m) in determining (Formula presented.)o2pkinetics. We hypothesized that τ(Formula presented.)o2pand GPwould be invariant in the constant baseline condition but would increase linearly with increased baseline WR. Fourteen men completed three to five repetitions of ∆40 W step transitions initiated from 20, 40, 60, 80, 100 and 120 W on a cycle ergometer. The ∆40 W step transitions from 60, 80, 100 and 120 W were preceded by 6 min of 20 W cycling, from which the progressive ΔWR transitions (constant baseline condition) were examined. The (Formula presented.)o2pwas measured breath by breath using mass spectrometry and a volume turbine. For a given ΔWR, both τ(Formula presented.)o2p(22–35 s) and GP(8.7–10.5 ml min−1 W−1) increased (P < 0.05) linearly as a function of baseline WR (20–120 W). The τ(Formula presented.)o2pwas invariant (P < 0.05) in transitions initiated from 20 W, but GPincreased with ΔWR (P < 0.05). Modelling the summed influence of multiple muscle compartments revealed that τ(Formula presented.)o2pcould appear fast (24 s), and similar to in vivo measurements (22 ± 6 s), despite being derived from τ(Formula presented.)o2pvalues with a range of 15–40 s and τ(Formula presented.)mwith a range of 20–45 s, suggesting that within the moderate-intensity domain phase II (Formula presented.)o2pkinetics are slowed dependent on the pretransition WR and are strongly influenced by muscle metabolic and circulatory heterogeneity.
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© 2015 CCAL. 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 anda 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 10-9to 10-1/s.
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We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca(2+)]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a lessstable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations.Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.
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AIMS: We aim to engineer a computational model of propagation during normal sinus rhythm in the foetal human heart, by modifying models for adult cardiac tissue to match foetal electrocardiogram (fECG) characteristics. The model will be partially validated by fECG data, and applied to explore possible mechanisms of arrhythmogenesis in the foetal heart. METHODS AND RESULTS: Foetal electrocardiograms have been recorded during pregnancy, with P- and T-waves, and the QRS complex, identified by averaging and signal processing. Intervals of the fECG are extracted and used to modify currently available human adult cardiomyocyte models. RR intervals inform models of the pacemaking cells by constraining their rate, the QT interval and its rate dependence constrain models of ventricular cells, and the width of the P-wave, the QR and PR intervals constrain propagation times, conduction velocities, and intercellular coupling. These cell models are coupled into a one-dimensional (1D) model of propagation during normal sinus rhythm in the human foetal heart. We constructed a modular, heterogeneous 1D model for propagation in the foetal heart, and predicted the effects of reduction in L-type Ca(++) current. These include bradycardia and atrioventricular conduction blocks. These may account quantitatively for congenital heart block produced by positive IgG antibodies. CONCLUSION: The fECG can be interpreted mechanistically and quantitatively by using a simple computational model for propagation. After further validation, by clinical recordings of the fECG and the electrophysiological experiments on foetal cardiac cells and tissues, the model may be used to predict the effects of maternally administered pharmaceuticals on the fECG.
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BACKGROUND: The cardiac conduction system consists of the sinus node, nodal extensions, atrioventricular (AV) node, penetrating bundle, bundle branches, and Purkinje fibers. Node-like AV ring tissue also exists at the AV junctions, and the right and left rings unite at the retroaortic node. The study aims were to (1) construct a 3-dimensional anatomical model of the AV rings and retroaortic node, (2) map electrical activation in the right ring and study its action potential characteristics, and (3) examine gene expression in the right ring and retroaortic node. METHODS AND RESULTS: Three-dimensional reconstruction (based on magnetic resonance imaging, histology, and immunohistochemistry) showed the extent and organization of the specialized tissues (eg, how the AV rings form the right and left nodal extensions into the AV node). Multiextracellular electrode array and microelectrode mapping of isolated right ring preparations revealed robust spontaneous activity with characteristic diastolic depolarization. Using laser microdissection gene expression measured at the mRNA level (using quantitative PCR) and protein level (using immunohistochemistry and Western blotting) showed that the right ring and retroaortic node, like the sinus node and AV node but, unlike ventricular muscle, had statistically significant higher expression of key transcription factors (including Tbx3, Msx2, and Id2) and ion channels (including HCN4, Cav3.1, Cav3.2, Kv1.5, SK1, Kir3.1, and Kir3.4) and lower expression of other key ion channels (Nav1.5 and Kir2.1). CONCLUSIONS: The AV rings and retroaortic node possess gene expression profiles similar to that of the AV node. Ion channel expression and electrophysiological recordings show the AV rings could act as ectopic pacemakers and a source of atrial tachycardia.
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Non-invasive measures of the fetal ECG provide quantitative information on pacemaking rate, propagation times and velocities during normal sinus rhythm.© 2013 CCAL.
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Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of -1.03± 0.59 and -0.26 ± 0.13 for rat and pig, respectively (p<0.0001). In rat, maximal dispersion of APD was 11.0± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p<0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonicmodulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.
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At the onset of muscular exercise, the kinetics of pulmonary O2 uptake (V̇o2P) reflect the integrated dynamic responses of the ventilatory, circulatory, and neuromuscular systems for O2 transport and utilization. Muscle O2 uptake (V̇o2m) kinetics, however, are dissociated from V̇o2P kinetics by intervening O2 capacitances and the dynamics of the circulation and ventilation. We developed a multicompartment computational model (MCM) to investigate these dynamic interactions and optimized and validated the MCM using previously published, simultaneously measured V̇o2m, alveolar O2 uptake (V̇o2A), and muscle blood flow (Q̇m) in healthy young men during cycle ergometry. The model was used to show that 1) the kinetics of V̇o2A during exercise transients are very sensitive to preexercise blood flow distribution and the absolute value of Q̇m, 2) a low preexercise Q̇m exaggerates the magnitude of the transient fall in venous O2 concentration for any given V̇o2m kinetics, necessitating a tighter coupling of Q̇m/V̇o2m (or a reduction in the available work rate range) during the exercise transient to avoid limits to O2 extraction, and 3) information regarding exercise-related alterations in O2 uptake and blood flow in nonexercising tissues and their effects on mixed venous O2 concentration is required to accurately predict V̇o2A kinetics from knowledge of V̇o2m and Q̇m dynamics. Importantly, these data clearly demonstrate that V̇o2A kinetics are nonexponential, nonlinear distortions of V̇o2m kinetics that can be explained in a MCM by interactions among circulatory and cellular respiratory control processes before and during exercise.
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We construct the components for a family of computational models of the electrophysiology of the human foetal heart from 60 days gestational age (DGA) to full term. This requires both cell excitation models that reconstruct the myocyte action potentials, and datasets of cardiac geometry and architecture. Fast low-angle shot and diffusion tensor magnetic resonance imaging (DT-MRI) of foetal hearts provides cardiac geometry with voxel resolution of approximately 100µm. DT-MRI measures the relative diffusion of protons and provides a measure of the average intravoxel myocyte orientation, and the orientation of any higher order orthotropic organization of the tissue. Such orthotropic organization in the adult mammalian heart has been identified with myocardialsheets and cleavage planes between them. During gestation, the architecture of the human ventricular wall changes from being irregular and isotropic at 100 DGA to an anisotropic and orthotropic architecture by 140 DGA, when it has the smooth, approximately 120° transmural change in myocyte orientation that is characteristic of the adult mammalian ventricle. The DT obtained from DT-MRI provides the conductivity tensor that determines the spread of potential within computational models of cardiac tissue electrophysiology. The foetal electrocardiogram (fECG) can be recorded from approximately 60DGA, and RR, PR and QT intervals between the P, R, Q and T waves of the fECG can be extracted by averaging from approximately 90 DGA. The RR intervals provide a measure of the pacemaker rate, the QT intervals an index of ventricular action potential duration, and its rate-dependence, and so these intervals constrain and inform models of cell electrophysiology. The parameters of models of adult human sinostrial node and ventricular cells that are based on adult cell electrophysiology and tissue molecular mapping have been modified to construct preliminary models of foetal cell electrophysiology, which reproduce these intervals from fECG recordings. The PR and QR intervals provide an index of conduction times, and hence propagation velocities (approx. 1–10 cm s−1, increasing during gestation) and so inform models of tissue electrophysiology. Although the developing foetal heart is small and the cells are weakly coupled, it can support potentially lethal re-entrant arrhythmia.
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New findings:• What is the central question of the study? Does a transient overshoot in skeletal muscle deoxygenation (reflecting a kinetic mismatch of microvascular O delivery to consumption) and/or its spatial distribution slow the adjustment of oxidative energy provision at the onset of exercise? • What is the main finding and its importance? Slowed oxidative energy provision at the onset of exercise was correlated with the transient skeletal muscle deoxygenation peak and the reduced spatial distribution, measured by quantitative near-infrared spectroscopy. It was not correlated with a microvascularO delivery-to-consumption mismatch per se. This suggests that an absolute, rather than kinetic, mismatch of microvascular O delivery and consumption limits the kinetics of muscular oxidative energy provision, but only when muscle deoxygenation reaches some 'critical' level. It remains unclear whether an overshoot in skeletal muscle deoxygenation (HHb; reflecting a microvascular kinetic mismatch of O delivery to consumption) contributes to the slowed adjustment of oxidative energy provision at the onset of exercise. We progressively reduced the fractional inspired O concentration. to investigate the relationship between slowed pulmonary O uptake. kinetics and the dynamics and spatial distribution of absolute [HHb]. Seven healthy men performed 8 min cycling transitions during normoxia, moderate hypoxia. and severe hypoxia. uptake was measured using a flowmeter and gas analyser system. Absolute [HHb] was quantified by multichannel, time-resolved near-infrared spectroscopy from the rectus femoris and vastus lateralis (proximal and distal regions), and corrected for adipose tissue thickness. The phase II time constant was slowed (P<0.05) as decreased (normoxia, 17± 3 s; moderate hypoxia, 22 ± 4 s; and severe hypoxia, 29 ± 9 s). The [HHb] overshoot was unaffected by hypoxia, but the transient peak [HHb] increased with the reduction in (P<0.05). Slowed kinetics in hypoxia were positively correlated with increased peak [HHb] in the transient (r= 0.45; P<0.05), but poorly related to the [HHb] overshoot. A reduction of spatial heterogeneity in peak [HHb] was inversely correlated with slowed kinetics (r= 0.49; P<0.05). These data suggest that aerobic energy provision at the onset of exercise may be limited by the following factors: (i) the absolute ratio (i.e. peak [HHb]) rather than the kinetic ratio (i.e. [HHb] overshoot) of microvascular O delivery to consumption; and (ii) a reduced spatial distribution in the ratio of microvascular O delivery to consumption across the muscle.© 2013 The Physiological Society.
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During non-steady-state exercise, dynamic changes in pulmonary oxygen uptake ( {Mathematical expression}) are dissociated from skeletal muscle {Mathematical expression} ( {Mathematical expression}) by changes in lung and venous O concentrations (CvO), and the dynamics and distribution of cardiac output (CO) between active muscle and remaining tissues ( {Mathematical expression}). Algorithms can compensate for fluctuations in lung O stores, but the influences of CO and CvO kinetics complicate estimation of {Mathematical expression} from cardio-pulmonary measurements. We developed an algorithm to estimate {Mathematical expression} kinetics from {Mathematical expression} and heart rate (HR) during exercise. 17 healthy volunteers (28 ± 7 years; 71 ± 12 kg; 7 females) performed incremental exercise using recumbent cycle ergometry ( {Mathematical expression} 52 ± 8 ml min kg). Participants completed a pseudo-random binary sequence (PRBS) test between 30 and 80 W. {Mathematical expression} and HR were measured, andCO was estimated from HR changes and steady-state stroke volume. {Mathematical expression} was derived from a circulatory model and time series analyses, by solving for the unique combination of venous volume and the perfusion of non-exercising tissues that provided close to mono-exponential {Mathematical expression} kinetics. Independent simulations showed that this approach recovered the {Mathematical expression} time constant (τ) to within 7 % (R = 0.976). Estimates during PRBS were venous volume 2.96 ± 0.54 L; {Mathematical expression} 3.63 ± 1.61 L min; τHR 27 ± 11 s; τ{Mathematical expression} 33 ± 8 s; τ {Mathematical expression} 43 ± 14 s; {Mathematical expression} time delay 19 ± 8 s. The combination of stochastic test signals, time series analyses, and a circulatory model permitted non-invasive estimates of {Mathematical expression} kinetics. Large kinetic dissociations exist between muscular and pulmonary {Mathematical expression} during rapid exercise transients. © 2013 Springer-Verlag Berlin Heidelberg.
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Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's 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.
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Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca(2+) handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca(2+) transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca(2+)-ATPase activity, increased sarcoplasmic reticular Ca(2+)-release fraction, and increased Ca(2+) spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca(2+) handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs.
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It has been shown by histology that cardiac myocytes are organized into laminae and this structure is important in function, both influencing the spread of electrical activation and enabling myocardial thickening in systole by laminar sliding. We have carried out high-spatial resolution three-dimensional MRI of the ventricular myolaminae of the entire volume of the isolated rat heart after contrast perfusion [dimeglumine gadopentate (Gd-DTPA)]. Four ex vivo rat hearts were perfused with Gd-DTPA and fixative and high-spatial resolution MRI was performed on a 9.4T MRI system. After MRI, cryosectioning followed by histology was performed. Images from MRI and histology were aligned, described, and quantitatively compared. In the three-dimensional MR images we directly show the presence of laminae and demonstrate that these are highly branching and are absent from much of the subepicardium. We visualized these MRI volumes to demonstrate laminar architecture and quantitatively demonstrated that the structural features observed are similar to those imaged in histology. We showed qualitatively and quantitatively that laminar architecture is similar in the four hearts. MRI can be used to image the laminar architecture of ex vivo hearts in three dimensions, and the images produced are qualitatively and quantitatively comparable with histology. We have demonstrated in the rat that: 1) laminar architecture is consistent between hearts; 2) myolaminae are absent from much of the subepicardium; and 3) although localized orthotropy is present throughout the myocardium, tracked myolaminae are branching structures and do not have a discrete identity.
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The study of cardiac arrhythmias is a major focus of computational biology, and undertaking biophysically detailed simulations is computationally demanding. An efficient coupled electromechanical solver to model cardiac tissue has been developed. This provides features to model fibre direction, and utilises computationally efficient techniques to reduce the simulation times. In this paper the break up of human re-entrant arrhythmias has been simulated. The results suggest that tissue deformation is a contributory factor in the break up of stable re-entrant spiral waves.© 2011 CCAL.
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During exercise below the lactate threshold (LT), the rate of adjustment (τ) of pulmonary VO(2) uptake (τ) is slowed when initiated from a raised work rate. Whether this is consequent to the intrinsic properties of newly recruited muscle fibres, slowed circulatory dynamics or the effects of a raised metabolism is not clear. We aimed to determine the influence of these factors on τV(O(2)) using combined in vivo and in silico approaches. Fifteen healthy men performed repeated 6 min bouts on a cycle ergometer with work rates residing between 20 W and 90% LT, consisting of the following: (1) two step increments in work rate (S1 and S2), one followed immediately by the other, equally bisecting 20 W to 90% LT; (2) two 20 W to 90% LT bouts separated by 30 s at 20 W to raise muscle oxygenation and pretransition metabolism (R1 and R2); and (3) two 20 W to 90% LT bouts separated by 12 min at 20 W allowing full recovery (F1 and F2). Pulmonary O(2) uptake was measuredbreath by breath by mass spectrometry and turbinometry, and quadriceps oxygenation using near-infrared spectroscopy. The influence of circulatory dynamics on the coupling of muscle and τV(O(2)) lung was assessed by computer simulations. The τV(O(2)) in R2 (32 ± 9 s) was not different (P>0.05) from S2 (30± 10 s), but both were greater (P<0.05) than S1 (20± 10 s) and the F control bouts (26 ± 10 s). The slowed V(O(2)) kinetics in R2 occurred despite muscle oxygenation being raised throughout, and could not be explained by slowed circulatory dynamics (τV(O(2)) predicted by simulations: S1 = R2<S2). These data therefore suggest that the dynamics of muscle O(2) consumption are slowed when exercise is initiated from a less favourable energetic state.
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We apply virtual tissue engineering to the full term human uterus with a view to reconstruction of the spatiotemporal patterns of electrical activity of the myometrium that control mechanical activity via intracellular calcium. The three-dimensional geometry of the gravid uterus has been reconstructed from segmented in vivo magnetic resonance imaging as well as ex vivo diffusion tensor magnetic resonance imaging to resolve fine scale tissue architecture. A late-pregnancy uterine smooth muscle cell model is constructed and bursting analysed using continuation algorithms. These cell models are incorporated into partial differential equation models for tissue synchronisation and propagation. The ultimate objective is to develop a quantitative and predictive understanding of the mechanisms that initiate and regulate labour.
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Transmural myocardial activation is influenced by myocardial structure, including structural differences between the compacta (Cta) and the trabeculata (Tta), although this has not been fully explained. Hearts from rats were Langendorff perfused, stained with DI-4-ANEPPS, the apex was cut off and fluorescence acquired from the exposed short-axis surface. The hearts were stimulated at 160 ms cycle length at the anterior, lateral, posterior left ventricle (LV) and septal sub-epicardial sites. Conduction velocity perpendicular to the wave front orientation was measured in each pixel using a gradient-based approach. After optical mapping the cut surface was imaged using a light microscope and the extent of the Cta and Tta mapped and validated against 50 u, m isotropic MRI images. We used a 3D rat ventricle computational model, with architecture obtained from 200 u, m isotropic diffusion tensor MRI and kinetics from the modified Pandit model to determine the relative roles of fibers and sheets on propagation. We show in the experimental study that circumferential propagation around the LV cavity is fast in the Cta: 63.2±19.5 and is slower in the Tta: 32.7±11.0(∗) (mean ± s.d cms-1, ∗ p<0.01 by two sample t test). In the simulation study the pattern and velocity are not replicated in an isotropic model (I), are partially replicated in a simulation study including fiber anisotropy (A) and is more fully replicated in orthotropic (O) ventricles (fiber and sheet anisotropy), where the circumferential propagation velocity is, I: Cta: 54.2±3.9; Tta:54.3±3.9; A: Cta:43.6±3.2; Tta: 40.6±6.6; O: Cta: 63.2±19.5; Tta: 32.7±11.9(∗). We show that sheet orientation is important in understanding activation differences between Cta and Tta.
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Ventricular tachycardia and fibrillation are dangerous cardiac arrhythmias. Anti-arrhythmic drugs such as lidocaine (a class I drug) reinstate normal sinus rhythm, but they have pro-arrhythmic side effects and their mechanisms of action are poorly understood. We used computational models of human ventricular tissues to elucidate and quantify these mechanisms.
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We examine the effects of cardiac geometry and axchitecture on re-entrant scroll wave dynamics by quantifying the scroll wave filament in two biophysically-detailed heterogeneous models of the human left ventricular free wall - a simple cuboid model and a wedge model constructed using DT-MRI data. For any given geometry, changing the architecture results in changes to the filament meander pattern, increases in filament length, changes to the filament curvature and local filament twist, and increases in the maximum twist along a single filament. Changes to the geometry also affect scroll wave dynamics, mainly due to the size of the tissue. We conclude that such differences in re-entrant scroll wave dynamics should be taken into account when interpreting results from simulations that use simple cardiac geometries and architectures.
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It has been assumed that myocardial structure is uniform amongst individuals of a species, and between higher mammalian species. However, recent studies show that myolaminar structure, a critical component in myocardial function, varies markedly between dogs. Diffusion tensor magnetic resonance imaging (DT-MRI) data from 12 canine hearts is visualised and described qualitatively and quantitatively. Large confluent zones of primarily positive or negative sheet angles intersect at approximately 90◦. The location of these stacks and their zones of intersection differ between dog hearts, but their overall morphology is consistent. As such there is no single model of adult canine heart structure; rather cardiac form belongs to a constrained distribution between extremes of structure. This variation must be considered in the construction of averaged anatomical atlases of myocardial architecture, where a range of maps may be required. These could be produced from DT-MRI datasets grouped by myolaminar structure.
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