Cell to whole organ global sensitivity analysis on a four-chamber heart electromechanics model using Gaussian processes emulators.

Cardiac pump function arises from a series of highly orchestrated events across multiple scales. Computational electromechanics can encode these events in physics-constrained models. However, the large number of parameters in these models has made the systematic study of the link between cellular, tissue, and organ scale parameters to whole heart physiology challenging. A patient-specific anatomical heart model, or digital twin, was created. Cellular ionic dynamics and contraction were simulated with the Courtemanche-Land and the ToR-ORd-Land models for the atria and the ventricles, respectively. Whole heart contraction was coupled with the circulatory system, simulated with CircAdapt, while accounting for the effect of the pericardium on cardiac motion. The four-chamber electromechanics framework resulted in 117 parameters of interest. The model was broken into five hierarchical sub-models: tissue electrophysiology, ToR-ORd-Land model, Courtemanche-Land model, passive mechanics and CircAdapt. For each sub-model, we trained Gaussian processes emulators (GPEs) that were then used to perform a global sensitivity analysis (GSA) to retain parameters explaining 90% of the total sensitivity for subsequent analysis. We identified 45 out of 117 parameters that were important for whole heart function. We performed a GSA over these 45 parameters and identified the systemic and pulmonary peripheral resistance as being critical parameters for a wide range of volumetric and hemodynamic cardiac indexes across all four chambers. We have shown that GPEs provide a robust method for mapping between cellular properties and clinical measurements. This could be applied to identify parameters that can be calibrated in patient-specific models or digital twins, and to link cellular function to clinical indexes.

A computational study on the influence of antegrade accessory pathway location on the 12-lead electrocardiogram in Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White syndrome is a cardiovascular disease characterized by abnormal atrio-ventricular conduction facilitated by accessory pathways (APs). Invasive catheter ablation of the AP represents the primary treatment modality. Accurate localization of APs is crucial for successful ablation outcomes, but current diagnostic algorithms based on the 12 lead electrocardiogram (ECG) often struggle with precise determination of AP locations. In order to gain insight into the mechanisms underlying localization failures observed in current diagnostic algorithms, we employ a virtual cardiac model to elucidate the relationship between AP location and ECG morphology. We first introduce a cardiac model of electrophysiology that was specifically tailored to represent antegrade APs in the form of a short atrio-ventricular bypass tract. Locations of antegrade APs were then automatically swept across both ventricles in the virtual model to generate a synthetic ECG database consisting of 9271 signals. Regional grouping of antegrade APs revealed overarching morphological patterns originating from diverse cardiac regions. We then applied variance-based sensitivity analysis relying on polynomial chaos expansion on the ECG database to mathematically quantify how variation in AP location and timing relates to morphological variation in the 12 lead ECG. We utilized our mechanistic virtual model to showcase limitations of AP localization using standard ECG-based algorithms and provide mechanistic explanations through exemplary simulations. Our findings highlight the potential of virtual models of cardiac electrophysiology not only to deepen our understanding of the underlying mechanisms of Wolff-Parkinson-White syndrome but also to potentially enhance the diagnostic accuracy of ECG-based algorithms and facilitate personalized treatment planning.

Effect of scar and His-Purkinje and myocardium conduction on response to conduction system pacing.

INTRODUCTION: Conduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as a valuable cardiac resynchronization therapy (CRT) delivery method. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing-induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (His-optimized CRT [HOT-CRT]), and LBBP with LV epicardial lead (LBBP-optimized CRT [LOT-CRT]) in patients with different conduction disease presentations using computational modeling. METHODS: We simulated ventricular activation on 24 four-chamber heart geometries, including His-Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His-Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of the healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (90% of biventricular activation time [BIVAT-90]). RESULTS: Severe LV His-Purkinje conduction disease favored CRT (BIVAT-90: HBP 101.5 ± 7.8 ms vs. CRT 93.0 ± 8.9 ms, p < .05), with additional electrical synchrony induced by HOT-CRT (87.6 ± 6.7 ms, p < .05) and LOT-CRT (73.9 ± 7.6 ms, p < .05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT-90: CRT 134.5 ± 24.1 ms; HBP 97.1 ± 9.9 ms, p < .01; LBBP: 101.5 ± 10.7 ms, p < .01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT-90: baseline 119.1 ± 10.8 ms vs. CRT 85.1 ± 14.9 ms, p < .01). CONCLUSION: Severe LV His-Purkinje conduction disease attenuates the benefits of CSP, with additional improvements achieved with HOT-CRT and LOT-CRT. Septal but not lateral wall scars make CSP ineffective.

Detection of focal source and arrhythmogenic substrate from body surface potentials to guide atrial fibrillation ablation.

Focal sources (FS) are believed to be important triggers and a perpetuation mechanism for paroxysmal atrial fibrillation (AF). Detecting FS and determining AF sustainability in atrial tissue can help guide ablation targeting. We hypothesized that sustained rotors during FS-driven episodes indicate an arrhythmogenic substrate for sustained AF, and that non-invasive electrical recordings, like electrocardiograms (ECGs) or body surface potential maps (BSPMs), could be used to detect FS and AF sustainability. Computer simulations were performed on five bi-atrial geometries. FS were induced by pacing at cycle lengths of 120-270 ms from 32 atrial sites and four pulmonary veins. Self-sustained reentrant activities were also initiated around the same 32 atrial sites with inexcitable cores of radii of 0, 0.5 and 1 cm. FS fired for two seconds and then AF inducibility was tested by whether activation was sustained for another second. ECGs and BSPMs were simulated. Equivalent atrial sources were extracted using second-order blind source separation, and their cycle length, periodicity and contribution, were used as features for random forest classifiers. Longer rotor duration during FS-driven episodes indicates higher AF inducibility (area under ROC curve = 0.83). Our method had accuracy of 90.6±1.0% and 90.6±0.6% in detecting FS presence, and 93.1±0.6% and 94.2±1.2% in identifying AF sustainability, and 80.0±6.6% and 61.0±5.2% in determining the atrium of the focal site, from BSPMs and ECGs of five atria. The detection of FS presence and AF sustainability were insensitive to vest placement (±9.6%). On pre-operative BSPMs of 52 paroxysmal AF patients, patients classified with initiator-type FS on a single atrium resulted in improved two-to-three-year AF-free likelihoods (p-value < 0.01, logrank tests). Detection of FS and arrhythmogenic substrate can be performed from ECGs and BSPMs, enabling non-invasive mapping towards mechanism-targeted AF treatment, and malignant ectopic beat detection with likely AF progression.

Correction: Linking statistical shape models and simulated function in the healthy adult human heart.

[This corrects the article DOI: 10.1371/journal.pcbi.1008851.].

A computational model of pig ventricular cardiomyocyte electrophysiology and calcium handling: Translation from pig to human electrophysiology.

The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K+-currents (IKr and IK1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca2+ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca2+-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca2+ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O'Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of IK1, while IKr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca2+ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca2+-handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.

Linking statistical shape models and simulated function in the healthy adult human heart.

Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes (n = 20) from cardiac CT images in asymptomatic subjects and created a SSM from 19 cases. Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average (R = 0.49 ± 0.17, 0.37 ± 0.23 and 0.34 ± 0.17 respectively). We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.

On the nature of delays allowing anatomical re-entry involving the Purkinje network: a simulation study.

AIMS: Clinical observations suggest that the Purkinje network can be part of anatomical re-entry circuits in monomorphic or polymorphic ventricular arrhythmias. However, significant conduction delay is needed to support anatomical re-entry given the high conduction velocity within the Purkinje network. METHODS AND RESULTS: We investigated, in computer models, whether damage rendering the Purkinje network as either an active lesion with slow conduction or a passive lesion with no excitable ionic channel, could explain clinical observations. Active lesions had compromised sodium current and a severe reduction in gap junction coupling, while passive lesions remained coupled by gap junctions, but modelled the membrane as a fixed resistance. Both types of tissue could provide significant delays of over 100 ms. Electrograms consistent with those obtained clinically were reproduced. However, passive tissue could not support re-entry as electrotonic coupling across the delay effectively increased the proximal refractory period to an extremely long interval. Active tissue, conversely, could robustly maintain re-entry. CONCLUSION: Formation of anatomical re-entry using the Purkinje network is possible through highly reduced gap junctional coupling leading to slowed conduction.

The 'Digital Twin' to enable the vision of precision cardiology.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.

A computationally efficient physiologically comprehensive 3D-0D closed-loop model of the heart and circulation.

Computer models of cardiac electro-mechanics (EM) show promise as an effective means for the quantitative analysis of clinical data and, potentially, for predicting therapeutic responses. To realize such advanced applications methodological key challenges must be addressed. Enhanced computational efficiency and robustness is crucial to facilitate, within tractable time frames, model personalization, the simulation of prolonged observation periods under a broad range of conditions, and physiological completeness encompassing therapy-relevant mechanisms is needed to endow models with predictive capabilities beyond the mere replication of observations. Here, we introduce a universal feature-complete cardiac EM modeling framework that builds on a flexible method for coupling a 3D model of bi-ventricular EM to the physiologically comprehensive 0D CircAdapt model representing atrial mechanics and closed-loop circulation. A detailed mathematical description is given and efficiency, robustness, and accuracy of numerical scheme and solver implementation are evaluated. After parameterization and stabilization of the coupled 3D-0D model to a limit cycle under baseline conditions, the model's ability to replicate physiological behaviors is demonstrated, by simulating the transient response to alterations in loading conditions and contractility, as induced by experimental protocols used for assessing systolic and diastolic ventricular properties. Mechanistic completeness and computational efficiency of this novel model render advanced applications geared towards predicting acute outcomes of EM therapies feasible.

Validation of quantitative measure of repolarization reserve as a novel marker of drug induced proarrhythmia.

Repolarization reserve, the robustness of a cell to repolarize even when one of the repolarization mechanisms is failing, has been described qualitatively in terms of ionic currents, but has not been quantified by a generic metric that is applicable to drug screening. Prolonged repolarization leading to repolarization failure is highly arrhythmogenic. It may lead to ventricular tachycardia caused by triggered activity from early afterdepolarizations (EADs), or it may promote the occurrence of unidirectional conduction block and reentry. Both types of arrhythmia may deteriorate into ventricular fibrillation (VF) and death. We define the Repolarization Reserve Current (RRC) as the minimum constant current necessary to prevent normal repolarization of a cell. After developing and testing RRC for nine computational ionic models of various species, we applied it experimentally to atrial and ventricular human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), and isolated guinea-pig ventricular cardiomyocytes. In simulations, repolarization was all-or-none with a precise, model-dependent critical RRC, resulting in a discrete shift in the Action Potential Duration (APD) - RRC relation, in the occurrence of EADs and repolarization failure. These data were faithfully reproduced in cellular experiments. RRC allows simple, fast, unambiguous quantification of the arrhythmogenic propensity in cardiac cells of various origins and species without the need of prior knowledge of underlying currents and is suitable for high throughput applications, and personalized medicine applications.

Propagation Failure by TRPM4 Overexpression.

Transient receptor potential melastatin member 4 (TRPM4) channels are nonselective monovalent cationic channels found in human atria and conduction system. Overexpression of TRPM4 channels has been found in families suffering from inherited cardiac arrhythmias, notably heart block. In this study, we integrate a mathematical formulation of the TRPM4 channel into a Purkinje cell model (Pan-Rudy model). Instead of simply adding the channel to the model, a combination of existing currents equivalent to the TRPM4 current was constructed, based on TRPM4 current dynamics. The equivalent current was then replaced by the TRPM4 current to preserve the model action potential. Single-cell behavior showed early afterdepolarizations for increases in TRPM4 channel expression above twofold. In a homogeneous strand of tissue, propagation conducted faithfully for lower expression levels but failed completely for more than a doubling of TRPM4 channel expression. Only with a heterogeneous distribution of channel expression was intermittent heart block seen. This study suggests that in Purkinje fibers, TRPM4 channels may account for sodium background current (INab), and that a heterogeneous expression of TRPM4 channels in the His/Purkinje system is required for type II heart block, as seen clinically.

New insights on the cardiac safety factor: Unraveling the relationship between conduction velocity and robustness of propagation.

Cardiac conduction disturbances are linked with arrhythmia development. The concept of safety factor (SF) has been derived to describe the robustness of conduction, but the usefulness of this metric has been constrained by several limitations. For example, due to the difficulty of measuring the necessary input variables, SF calculations have only been applied to synthetic data. Moreover, quantitative validation of SF is lacking; specifically, the practical meaning of particular SF values is unclear, aside from the fact that propagation failure (i.e., conduction block) is characterized by SF < 1. This study aims to resolve these limitations for our previously published SF formulation and explore its relationship to relevant electrophysiological properties of cardiac tissue. First, HL-1 cardiomyocyte monolayers were grown on multi-electrode arrays and the robustness of propagation was estimated using extracellular potential recordings. SF values reconstructed purely from experimental data were largely between 1 and 5 (up to 89.1% of sites characterized). This range is consistent with values derived from synthetic data, proving that the formulation is sound and its applicability is not limited to analysis of computational models. Second, for simulations conducted in 1-, 2-, and 3-dimensional tissue blocks, we calculated true SF values at locations surrounding the site of current injection for sub- and supra-threshold stimuli and found that they differed from values estimated by our SF formulation by <10%. Finally, we examined SF dynamics under conditions relevant to arrhythmia development in order to provide physiological insight. Our analysis shows that reduced conduction velocity (Θ) caused by impaired intrinsic cell-scale excitability (e.g., due to sodium current a loss-of-function mutation) is associated with less robust conduction (i.e., lower SF); however, intriguingly, Θ variability resulting from modulation of tissue scale conductivity has no effect on SF. These findings are supported by analytic derivation of the relevant relationships from first principles. We conclude that our SF formulation, which can be applied to both experimental and synthetic data, produces values that vary linearly with the excess charge needed for propagation. SF calculations can provide insights helpful in understanding the initiation and perpetuation of cardiac arrhythmia.

Variability in pulmonary vein electrophysiology and fibrosis determines arrhythmia susceptibility and dynamics.

Success rates for catheter ablation of persistent atrial fibrillation patients are currently low; however, there is a subset of patients for whom electrical isolation of the pulmonary veins alone is a successful treatment strategy. It is difficult to identify these patients because there are a multitude of factors affecting arrhythmia susceptibility and maintenance, and the individual contributions of these factors are difficult to determine clinically. We hypothesised that the combination of pulmonary vein (PV) electrophysiology and atrial body fibrosis determine driver location and effectiveness of pulmonary vein isolation (PVI). We used bilayer biatrial computer models based on patient geometries to investigate the effects of PV properties and atrial fibrosis on arrhythmia inducibility, maintenance mechanisms, and the outcome of PVI. Short PV action potential duration (APD) increased arrhythmia susceptibility, while longer PV APD was found to be protective. Arrhythmia inducibility increased with slower conduction velocity (CV) at the LA/PV junction, but not for cases with homogeneous CV changes or slower CV at the distal PV. Phase singularity (PS) density in the PV region for cases with PV fibrosis was increased. Arrhythmia dynamics depend on both PV properties and fibrosis distribution, varying from meandering rotors to PV reentry (in cases with baseline or long APD), to stable rotors at regions of high fibrosis density. Measurement of fibrosis and PV properties may indicate patient specific susceptibility to AF initiation and maintenance. PV PS density before PVI was higher for cases in which AF terminated or converted to a macroreentry; thus, high PV PS density may indicate likelihood of PVI success.

Patient-specific simulations predict efficacy of ablation of interatrial connections for treatment of persistent atrial fibrillation.

AIMS: Treatments for persistent atrial fibrillation (AF) offer limited efficacy. One potential strategy aims to return the right atrium (RA) to sinus rhythm (SR) by ablating interatrial connections (IAC) to isolate the atria, but there is limited clinical data to evaluate this ablation approach. We aimed to use simulation to evaluate and predict patient-specific suitability for ablation of IAC to treat AF. METHODS AND RESULTS: Persistent AF was simulated in 12 patient-specific geometries, incorporating electrophysiological heterogeneity and fibres, with IAC at Bachmann's bundle, the coronary sinus, and fossa ovalis. Simulations were performed to test the effect of left atrial (LA)-to-RA frequency gradient and fibrotic remodelling on IAC ablation efficacy. During AF, we simulated ablation of one, two, or all three IAC, with or without pulmonary vein isolation and determined if this altered or terminated the arrhythmia. For models without structural remodelling, ablating all IAC terminated RA arrhythmia in 83% of cases. Models with the LA-to-RA frequency gradient removed had an increased success rate (100% success). Ablation of IACs is less effective in cases with fibrotic remodelling (interstitial fibrosis 50% success rate; combination remodelling 67%). Mean number of phase singularities in the RA was higher pre-ablation for IAC failure (success 0.6 ± 0.8 vs. failure 3.2 ± 2.5, P < 0.001). CONCLUSION: This simulation study predicts that IAC ablation is effective in returning the RA to SR for many cases. Patient-specific modelling approaches have the potential to stratify patients prior to ablation by predicting if drivers are located in the LA or RA. We present a platform for predicting efficacy and informing patient selection for speculative treatments.

Determinants of new wavefront locations in cholinergic atrial fibrillation.

AIMS: Atrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation. METHODS AND RESULTS: Arrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers. CONCLUSION: We were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings.

Interplay among distinct Ca2+ conductances drives Ca2+ sparks/spontaneous transient outward currents in rat cerebral arteries.

KEY POINTS: Distinct Ca2+ channels work in a coordinated manner to grade Ca2+ spark/spontaneous transient outward currents (STOCs) in rat cerebral arteries. The relative contribution of each Ca2+ channel to Ca2+ spark/STOC production depends upon their biophysical properties and the resting membrane potential of smooth muscle. Na+ /Ca2+ exchanger, but not TRP channels, can also facilitate STOC production. ABSTRACT: Ca2+ sparks are generated in a voltage-dependent manner to initiate spontaneous transient outward currents (STOCs), events that moderate arterial constriction. In this study, we defined the mechanisms by which membrane depolarization increases Ca2+ sparks and subsequent STOC production. Using perforated patch clamp electrophysiology and rat cerebral arterial myocytes, we monitored STOCs in the presence and absence of agents that modulate Ca2+ entry. Beginning with CaV 3.2 channel inhibition, Ni2+ was shown to decrease STOC frequency in cells held at hyperpolarized (-40 mV) but not depolarized (-20 mV) voltages. In contrast, nifedipine, a CaV 1.2 inhibitor, markedly suppressed STOC frequency at -20 mV but not -40 mV. These findings aligned with the voltage-dependent profiles of L- and T-type Ca2+ channels. Furthermore, computational and experimental observations illustrated that Ca2+ spark production is intimately tied to the activity of both conductances. Intriguingly, this study observed residual STOC production at depolarized voltages that was independent of CaV 1.2 and CaV 3.2. This residual component was insensitive to TRPV4 channel modulation and was abolished by Na+ /Ca2+ exchanger blockade. In summary, our work highlights that the voltage-dependent triggering of Ca2+ sparks/STOCs is not tied to a single conductance but rather reflects an interplay among multiple Ca2+ permeable pores with distinct electrophysiological properties. This integrated orchestration enables smooth muscle to grade Ca2+ spark/STOC production and thus precisely tune negative electrical feedback.

Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.

Premature ventricular complexes (PVCs), the first initiating beats of a variety of cardiac arrhythmias, have been associated with spontaneous calcium release (SCR) events at the cell level. However, the mechanisms underlying the degeneration of such PVCs into arrhythmias are not fully understood. The objective of this study was to investigate the conditions under which SCR-mediated PVCs can lead to ventricular arrhythmias. In particular, we sought to determine whether sodium (Na+) current loss-of-function in the structurally normal ventricles provides a substrate for unidirectional conduction block and reentry initiated by SCR-mediated PVCs. To achieve this goal, a stochastic model of SCR was incorporated into an anatomically accurate compute model of the rabbit ventricles with the His-Purkinje system (HPS). Simulations with reduced Na+ current due to a negative-shift in the steady-state channel inactivation showed that SCR-mediated delayed afterdepolarizations led to PVC formation in the HPS, where the electrotonic load was lower, conduction block, and reentry in the 3D myocardium. Moreover, arrhythmia initiation was only possible when intrinsic electrophysiological heterogeneity in action potential within the ventricles was present. In conclusion, while benign in healthy individuals SCR-mediated PVCs can lead to life-threatening ventricular arrhythmias when combined with Na+ channelopathies.

Ca(V)3.2 channels and the induction of negative feedback in cerebral arteries.

RATIONALE: T-type (CaV3.1/CaV3.2) Ca(2+) channels are expressed in rat cerebral arterial smooth muscle. Although present, their functional significance remains uncertain with findings pointing to a variety of roles. OBJECTIVE: This study tested whether CaV3.2 channels mediate a negative feedback response by triggering Ca(2+) sparks, discrete events that initiate arterial hyperpolarization by activating large-conductance Ca(2+)-activated K(+) channels. METHODS AND RESULTS: Micromolar Ni(2+), an agent that selectively blocks CaV3.2 but not CaV1.2/CaV3.1, was first shown to depolarize/constrict pressurized rat cerebral arteries; no effect was observed in CaV3.2(-/-) arteries. Structural analysis using 3-dimensional tomography, immunolabeling, and a proximity ligation assay next revealed the existence of microdomains in cerebral arterial smooth muscle which comprised sarcoplasmic reticulum and caveolae. Within these discrete structures, CaV3.2 and ryanodine receptor resided in close apposition to one another. Computational modeling revealed that Ca(2+) influx through CaV3.2 could repetitively activate ryanodine receptor, inducing discrete Ca(2+)-induced Ca(2+) release events in a voltage-dependent manner. In keeping with theoretical observations, rapid Ca(2+) imaging and perforated patch clamp electrophysiology demonstrated that Ni(2+) suppressed Ca(2+) sparks and consequently spontaneous transient outward K(+) currents, large-conductance Ca(2+)-activated K(+) channel mediated events. Additional functional work on pressurized arteries noted that paxilline, a large-conductance Ca(2+)-activated K(+) channel inhibitor, elicited arterial constriction equivalent, and not additive, to Ni(2+). Key experiments on human cerebral arteries indicate that CaV3.2 is present and drives a comparable response to moderate constriction. CONCLUSIONS: These findings indicate for the first time that CaV3.2 channels localize to discrete microdomains and drive ryanodine receptor-mediated Ca(2+) sparks, enabling large-conductance Ca(2+)-activated K(+) channel activation, hyperpolarization, and attenuation of cerebral arterial constriction.