Translating myosin-binding protein C and titin abnormalities to whole-heart function using a novel calcium-contraction coupling model.

Mutations in cardiac myosin-binding protein C (cMyBP-C) or titin may respectively lead to hypertrophic (HCM) or dilated (DCM) cardiomyopathies. The mechanisms leading to these phenotypes remain unclear because of the challenge of translating cellular abnormalities to whole-heart and system function. We developed and validated a novel computer model of calcium-contraction coupling incorporating the role of cMyBP-C and titin based on the key assumptions: 1) tension in the thick filament promotes cross-bridge attachment mechanochemically, 2) with increasing titin tension, more myosin heads are unlocked for attachment, and 3) cMyBP-C suppresses cross-bridge attachment. Simulated stationary calcium-tension curves, isotonic and isometric contractions, and quick release agreed with experimental data. The model predicted that a loss of cMyBP-C function decreases the steepness of the calcium-tension curve, and that more compliant titin decreases the level of passive and active tension and its dependency on sarcomere length. Integrating this cellular model in the CircAdapt model of the human heart and circulation showed that a loss of cMyBP-C function resulted in HCM-like hemodynamics with higher left ventricular end-diastolic pressures and smaller volumes. More compliant titin led to higher diastolic pressures and ventricular dilation, suggesting DCM-like hemodynamics. The novel model of calcium-contraction coupling incorporates the role of cMyBP-C and titin. Its coupling to whole-heart mechanics translates changes in cellular calcium-contraction coupling to changes in cardiac pump and circulatory function and identifies potential mechanisms by which cMyBP-C and titin abnormalities may develop into HCM and DCM phenotypes. This modeling platform may help identify distinct mechanisms underlying clinical phenotypes in cardiac diseases.

Assessment of ventricular electrical heterogeneity in left bundle branch pacing and left ventricular septal pacing by using various electrophysiological methods.

INTRODUCTION: Left bundle branch area pacing (LBBAP) comprises pacing at the left ventricular septum (LVSP) or left bundle branch (LBBP). The aim of the present study was to investigate the differences in ventricular electrical heterogeneity between LVSP, LBBP, right ventricular pacing (RVP) and intrinsic conduction with different dyssynchrony measures using the ECG, vectorcardiograpy, ECG belt, and Ultrahigh frequency (UHF-)ECG. METHODS: Thirty-seven patients with a pacemaker indication for bradycardia or cardiac resynchronization therapy underwent LBBAP implantation. ECG, vectorcardiogram, ECG belt and UHF-ECG signals were recorded during RVP, LVSP and LBBP, and intrinsic activation. QRS duration (QRSd) was measured from the ECG, QRS area was calculated from the vectorcardiogram, LV activation time (LVAT) and standard deviation of activation time (SDAT) from ECG belt and electrical dyssynchrony (e-DYS16) from UHF-ECG. RESULTS: Both LVSP and LBBP significantly reduced ventricular electrical heterogeneity as compared to underlying LBBB and RV pacing in terms of QRS area (p < .001), SDAT (p < .001), LVAT (p < .001) and e-DYS16 (p < .001). QRSd was only reduced as compared to RV pacing(p < .001). QRS area was similar during LBBP and normal intrinsic conduction, e-DYS16 was similar during LVSP and normal intrinsic conduction, whereas SDAT was similar for LVSP, LBBP and normal intrinsic conduction. For all these variables there was no significant difference between LVSP and LBBP. CONCLUSION: Both LVSP and LBBP resulted in a more synchronous LV activation than LBBB and RVP. Especially LBBP resulted in levels of LV synchrony comparable to normal intrinsic conduction.

Left Atrial Function in Patients with Titin Cardiomyopathy.

BACKGROUND: Truncating variants in titin (TTNtv) are the most prevalent genetic etiology of dilated cardiomyopathy (DCM). Although TTNtv has been associated with atrial fibrillation, it remains unknown whether and how left atrial (LA) function differs between patients with DCM with and without TTNtv. We aimed to determine and compare LA function in patients with DCM with and without TTNtv and to evaluate whether and how left ventricular (LV) function affects the LA using computational modeling. METHODS AND RESULTS: Patients with DCM from the Maastricht DCM registry that underwent genetic testing and cardiovascular magnetic resonance (CMR) were included in the current study. Subsequent computational modeling (CircAdapt model) was performed to identify potential LV and LA myocardial hemodynamic substrates. In total, 377 patients with DCM (n = 42 with TTNtv, n = 335 without a genetic variant) were included (median age 55 years, interquartile range [IQR] 46-62 years, 62% men). Patients with TTNtv had a larger LA volume and decreased LA strain compared with patients without a genetic variant (LA volume index 60 mLm-2 [IQR 49-83] vs 51 mLm-2 [IQR 42-64]; LA reservoir strain 24% [IQR 10-29] vs 28% [IQR 20-34]; LA booster strain 9% [IQR 4-14] vs 14% [IQR 10-17], respectively; all P < .01). Computational modeling suggests that while the observed LV dysfunction partially explains the observed LA dysfunction in the patients with TTNtv, both intrinsic LV and LA dysfunction are present in patients with and without a TTNtv. CONCLUSIONS: Patients with DCM with TTNtv have more severe LA dysfunction compared with patients without a genetic variant. Insights from computational modeling suggest that both intrinsic LV and LA dysfunction are present in patients with DCM with and without TTNtv.

Diagnostic value of reversed differential cyanosis in (supra)cardiac total anomalous pulmonary venous return.

BACKGROUND: To investigate the occurrence of reversed differential cyanosis (RDC) in case of (supra)cardiac total anomalous pulmonary venous return (TAPVR), we explored the hemodynamic changes and oxygen saturation levels during the fetal-to-neonatal transition in (supra)cardiac TAPVR, thereby revealing determinant factors of RDC. METHODS: A computational model was used to simulate the cardiovascular fetal-to-neonatal transition up to 24 h after birth. Abnormalities associated with TAPVR, like patent ductus arteriosus (PDA) and persistent pulmonary hypertension of the neonate (PPHN), were imposed on the model. Hemodynamic impact on flow distribution and right-sided pressures as well as oxygen saturations were assessed. RESULTS: Model findings demonstrated that RDC in (supra)cardiac TAPVR was dependent on two key factors: (1) the type of pulmonary venous connection being supracardiac or cardiac, and (2) the presence of a patent ductus arteriosus exhibiting right-to-left shunting. Persistence of RDC was mainly determined by the latter; an increase in pulmonary-to-systemic pressure difference by PPHN or PDA-induced pulmonary over-circulation contributed to persistence of RDC. CONCLUSION: This study highlights the significance of RDC in (supra)cardiac TAPVR and suggests to incorporate early screening ( < 24 h after birth) and to consider RDC as an immediate fail in screening protocols to ensure prompt detection of (supra)cardiac TAPVR. IMPACT: Utilizing a validated computational model for the cardiovascular fetal-to-neonatal transition, this study sheds light on the complex hemodynamics in neonates with (supra)cardiac Total Anomalous Pulmonary Venous Return (TAPVR). Model findings suggest that the often-present pulmonary over-circulation in neonates with TAPVR might significantly contribute to the anomaly's frequent omission during pulse-oximetry screening beyond the first 24 h after birth. This study highlights the diagnostic value of reversed differential cyanosis in early screenings within the first 24 h after birth. By including RDC as an immediate fail in early pulse-oximetry screenings, the likelihood of missing (supra)cardiac TAPVR cases could be reduced.

How to assess and treat right ventricular electromechanical dyssynchrony in post-repair tetralogy of Fallot: insights from imaging, invasive studies, and computational modelling.

BACKGROUND AND AIMS: Right bundle branch block (RBBB) and resulting right ventricular (RV) electromechanical discoordination are thought to play a role in the disease process of subpulmonary RV dysfunction that frequently occur post-repair tetralogy of Fallot (ToF). We sought to describe this disease entity, the role of pulmonary re-valvulation, and the potential added value of RV cardiac resynchronization therapy (RV-CRT). METHODS: Two patients with repaired ToF, complete RBBB, pulmonary regurgitation, and significantly decreased RV function underwent echocardiography, cardiac magnetic resonance, and an invasive study to evaluate the potential for RV-CRT as part of the management strategy. The data were used to personalize the CircAdapt model of the human heart and circulation. Resulting Digital Twins were analysed to quantify the relative effects of RV pressure and volume overload and to predict the effect of RV-CRT. RESULTS: Echocardiography showed components of a classic RV dyssynchrony pattern which could be reversed by RV-CRT during invasive study and resulted in acute improvement in RV systolic function. The Digital Twins confirmed a contribution of electromechanical RV dyssynchrony to RV dysfunction and suggested improvement of RV contraction efficiency after RV-CRT. The one patient who underwent successful permanent RV-CRT as part of the pulmonary re-valvulation procedure carried improvements that were in line with the predictions based on his Digital Twin. CONCLUSION: An integrative diagnostic approach to RV dysfunction, including the construction of Digital Twins may help to identify candidates for RV-CRT as part of the lifetime management of ToF and similar congenital heart lesions.

Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination.

BACKGROUND: Integration of a patient's non-invasive imaging data in a digital twin (DT) of the heart can provide valuable insight into the myocardial disease substrates underlying left ventricular (LV) mechanical discoordination. However, when generating a DT, model parameters should be identifiable to obtain robust parameter estimations. In this study, we used the CircAdapt model of the human heart and circulation to find a subset of parameters which were identifiable from LV cavity volume and regional strain measurements of patients with different substrates of left bundle branch block (LBBB) and myocardial infarction (MI). To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB (study ID: 2018-0863, registration date: 2019-10-07), of which four were non-ischemic (LBBB-only) and three had previous MI (LBBB-MI), and six narrow QRS patients with MI (MI-only) (study ID: NL45241.041.13, registration date: 2013-11-12). Morris screening method (MSM) was applied first to find parameters which were important for LV volume, regional strain, and strain rate indices. Second, this parameter subset was iteratively reduced based on parameter identifiability and reproducibility. Parameter identifiability was based on the diaphony calculated from quasi-Monte Carlo simulations and reproducibility was based on the intraclass correlation coefficient ( ICC ) obtained from repeated parameter estimation using dynamic multi-swarm particle swarm optimization. Goodness-of-fit was defined as the mean squared error ( χ 2 ) of LV myocardial strain, strain rate, and cavity volume. RESULTS: A subset of 270 parameters remained after MSM which produced high-quality DTs of all patients ( χ 2 < 1.6), but minimum parameter reproducibility was poor ( ICC min = 0.01). Iterative reduction yielded a reproducible ( ICC min = 0.83) subset of 75 parameters, including cardiac output, global LV activation duration, regional mechanical activation delay, and regional LV myocardial constitutive properties. This reduced subset produced patient-resembling DTs ( χ 2 < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05). CONCLUSIONS: By applying sensitivity and identifiability analysis, we successfully determined a parameter subset of the CircAdapt model which can be used to generate imaging-based DTs of patients with LV mechanical discoordination. Parameters were reproducibly estimated using particle swarm optimization, and derived LV myocardial work distribution was representative for the patient's underlying disease substrate. This DT technology enables patient-specific substrate characterization and can potentially be used to support clinical decision making.

Electrophysiological effects of stretch-activated ion channels: a systematic computational characterization.

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano-electric feedback through stretch-activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC-induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium-selective, calcium-selective and non-selective SACs in the Tomek-Rodriguez-O'Hara-Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter-species differences, and disease-related remodelling of SACs. SAC-mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10-ms stretch stimuli of 15-18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch-induced modulation of sodium and L-type calcium channel gating. These effects were more pronounced with disease-related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease-related SACs remodelling and may contribute to cardiac arrhythmogenesis. KEY POINTS: The interplay between cardiac electrophysiology and mechanics is mediated by mechano-electric feedback through stretch-activated ion channels (SACs). These channels may be pro-arrhythmic, but their precise effect on electrophysiology remains unclear. Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter-species differences as well as disease-related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology. Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence. The pro-arrhythmic effects of stretch strongly depend on disease-related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms.

Comparison of novel ventricular pacing strategies using an electro-mechanical simulation platform.

AIMS: Focus of pacemaker therapy is shifting from right ventricular (RV) apex pacing (RVAP) and biventricular pacing (BiVP) to conduction system pacing. Direct comparison between the different pacing modalities and their consequences to cardiac pump function is difficult, due to the practical implications and confounding variables. Computational modelling and simulation provide the opportunity to compare electrical, mechanical, and haemodynamic consequences in the same virtual heart. METHODS AND RESULTS: Using the same single cardiac geometry, electrical activation maps following the different pacing strategies were calculated using an Eikonal model on a three-dimensional geometry, which were then used as input for a lumped mechanical and haemodynamic model (CircAdapt). We then compared simulated strain, regional myocardial work, and haemodynamic function for each pacing strategy. Selective His-bundle pacing (HBP) best replicated physiological electrical activation and led to the most homogeneous mechanical behaviour. Selective left bundle branch (LBB) pacing led to good left ventricular (LV) function but significantly increased RV load. RV activation times were reduced in non-selective LBB pacing (nsLBBP), reducing RV load but increasing heterogeneity in LV contraction. LV septal pacing led to a slower LV and more heterogeneous LV activation than nsLBBP, while RV activation was similar. BiVP led to a synchronous LV-RV, but resulted in a heterogeneous contraction. RVAP led to the slowest and most heterogeneous contraction. Haemodynamic differences were small compared to differences in local wall behaviour. CONCLUSION: Using a computational modelling framework, we investigated the mechanical and haemodynamic outcome of the prevailing pacing strategies in hearts with normal electrical and mechanical function. For this class of patients, nsLBBP was the best compromise between LV and RV function if HBP is not possible.

Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy.

AIMS: Identifying heart failure (HF) patients who will benefit from cardiac resynchronization therapy (CRT) remains challenging. We evaluated whether virtual pacing in a digital twin (DT) of the patient's heart could be used to predict the degree of left ventricular (LV) reverse remodelling post-CRT. METHODS AND RESULTS: Forty-five HF patients with wide QRS complex (≥130 ms) and reduced LV ejection fraction (≤35%) receiving CRT were retrospectively enrolled. Echocardiography was performed before (baseline) and 6 months after CRT implantation to obtain LV volumes and 18-segment longitudinal strain. A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements. From each DT, baseline septal-to-lateral myocardial work difference (MWLW-S,DT) and maximum rate of LV systolic pressure rise (dP/dtmax,DT) were derived. Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location. Virtual pacing-induced changes ΔMWLW-S,DT and ΔdP/dtmax,DT were correlated with real-world LV end-systolic volume change at 6-month follow-up (ΔLVESV). The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02). CONCLUSION: Our results suggest that the reduction of septal-to-lateral work imbalance by virtual pacing in the DT can predict real-world post-CRT LV reverse remodelling. This DT approach could prove to be an additional tool in selecting HF patients for CRT and has the potential to provide valuable insights in optimization of CRT delivery.

Accuracy of continuous photoplethysmography-based 1 min mean heart rate assessment during atrial fibrillation.

AIMS: Although mobile health tools using photoplethysmography (PPG) technology have been validated for the detection of atrial fibrillation (AF), their utility for heart rate assessment during AF remains unclear. Therefore, we aimed to evaluate the accuracy of continuous PPG-based 1 min mean heart rate assessment during AF. METHODS AND RESULTS: Persistent AF patients were provided with Holter electrocardiography (ECG) (for ≥24 h) simultaneously with a PPG-equipped smartwatch. Both the PPG-based smartwatch and Holter ECG automatically and continuously monitored patients' heart rate/rhythm. ECG and PPG recordings were synchronized and divided into 1 min segments, from which a PPG-based and an ECG-based average heart rate estimation were extracted. In total, 47 661 simultaneous ECG and PPG 1 min heart rate segments were analysed in 50 patients (34% women, age 73 ± 8 years). The agreement between ECG-determined and PPG-determined 1 min mean heart rate was high [root mean squared error (RMSE): 4.7 bpm]. The 1 min mean heart rate estimated using PPG was accurate within ±10% in 93.7% of the corresponding ECG-derived 1 min mean heart rate segments. PPG-based 1 min mean heart rate estimation was more often accurate during night-time (97%) than day-time (91%, P < 0.001) and during low levels (96%) compared to high levels of motion (92%, P < 0.001). A neural network with a 10 min history of the recording did not further improve the PPG-based 1 min mean heart rate assessment [RMSE: 4.4 (95% confidence interval: 3.5-5.2 bpm)]. Only chronic heart failure was associated with a lower agreement between ECG-derived and PPG-derived 1 min mean heart rates (P = 0.040). CONCLUSION: During persistent AF, continuous PPG-based 1 min mean heart rate assessment is feasible in 60% of the analysed period and shows high accuracy compared with Holter ECG for heart rates <110 bpm.

Cardiovascular fetal-to-neonatal transition: an in silico model.

BACKGROUND: Previous models describing the fetal-to-neonatal transition often lack oxygen saturation levels, homeostatic control mechanisms, phasic hemodynamic signals, or describe the heart with a time-varying elastance model. METHODS: We incorporated these elements in the adapted CircAdapt model with the one-fiber model for myocardial contraction, to simulate the hemodynamics of the healthy term human fetal circulation and its transition during the first 24 h after birth. The fetal-to-neonatal model was controlled by a time- and event-based script of changes occurring at birth, such as lung aeration and umbilical cord clamping. Model parameters were based on and validated with human and animal data. RESULTS: The fetal circulation showed low pulmonary blood flow, right ventricular dominance, and inverted mitral and tricuspid flow velocity patterns, as well as high mean ductus venosus flow velocity. The neonatal circulation showed oxygen saturation levels to gradually increase to 98% in the first 15 min after birth as well as temporary left ventricular volume overload. CONCLUSIONS: Hemodynamics of the term fetus and 24-h-old neonate, as well as the events occurring directly after birth and the transition during the first 24 h after birth, were realistically represented, allowing the model to be used for educational purposes and future research. IMPACT: With the addition of oxygen saturation levels, homeostatic pressure-flow control mechanisms, and the one-fiber model for myocardial contraction, a new closed-loop cardiovascular model was constructed to give more insight into the healthy term human fetal circulation and its cardiovascular transition during the first 24 h after birth. Extensive validation confirmed that the hemodynamics of the term fetus and the fetal-to-neonatal transition were realistically represented with the model. This well-validated and versatile model can serve as an education as well as a research platform for in silico investigation of fetal-to-neonatal hemodynamic changes under a wide range of physiological and pathophysiological conditions.

Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study. METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation. CONCLUSION: Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology.

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.

Electromechanical substrate characterization in arrhythmogenic cardiomyopathy using imaging-based patient-specific computer simulations.

AIMS: Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. The aim of this study is to use computer simulations to non-invasively estimate the individual patient's myocardial tissue substrates underlying regional right ventricular (RV) deformation abnormalities in a cohort of AC mutation carriers. METHODS AND RESULTS: In 68 AC mutation carriers and 20 control subjects, regional longitudinal deformation patterns of the RV free wall (RVfw), interventricular septum (IVS), and left ventricular free wall (LVfw) were obtained using speckle-tracking echocardiography. We developed and used a patient-specific parameter estimation protocol based on the multi-scale CircAdapt cardiovascular system model to create virtual AC subjects. Using the individual's deformation data as model input, this protocol automatically estimated regional RVfw and global IVS and LVfw tissue properties. The computational model was able to reproduce clinically measured regional deformation patterns for all subjects, with highly reproducible parameter estimations. Simulations revealed that regional RVfw heterogeneity of both contractile function and compliance were increased in subjects with clinically advanced disease compared to mutation carriers without clinically established disease (17 ± 13% vs. 8 ± 4%, P = 0.01 and 18 ± 11% vs. 10 ± 7%, P < 0.01, respectively). No significant difference in activation delay was found. CONCLUSION: Regional RV deformation abnormalities in AC mutation carriers were related to reduced regional contractile function and tissue compliance. In clinically advanced disease stages, a characteristic apex-to-base heterogeneity of tissue abnormalities was present in the majority of the subjects, with most pronounced disease in the basal region of the RVfw.

Both beat-to-beat changes in RR-interval and left ventricular filling time determine ventricular function during atrial fibrillation.

AIMS: The irregular atrial electrical activity during atrial fibrillation (AF) is associated with a variable left ventricular (LV) systolic function. The mechanisms determining LV function during AF remain incompletely understood. We aimed at elucidating how changes in RR-interval and LV preload affect LV function during AF. METHODS AND RESULTS: Beat-to-beat speckle-tracking echocardiography was performed in 10 persistent AF patients. We evaluated the relation between longitudinal LV peak strain and preceding RR-interval during AF. We used the CircAdapt computational model to evaluate beat-to-beat preload and peak strain during AF for each patient by imposing the patient-specific RR-interval sequences and a non-contractile atrial myocardium. Generic simulations with artificial RR-interval sequences quantified the haemodynamic changes induced by sudden irregular beats. Clinical data and simulations both showed a larger sensitivity of peak strain to changes in preceding RR-interval at slow heart rate (HR) (cycle length, CL <750 ms) than at faster HR. Simulations explained this by a difference in preload of the current beat. Generic simulations confirmed a larger sensitivity of peak strain to preceding RR-interval at fast HR (CL = 600 ms: Δ peak strain = 3.7% vs. 900 ms: Δ peak strain = 0.3%) as in the patients. They suggested that longer LV activation with respect to preceding RR-interval is determinant for this sensitivity. CONCLUSIONS: During AF, longitudinal LV peak strain is highly variable, particularly at fast HR. Beat-to-beat changes in preload explain the differences in LV systolic function. Simulations revealed that a reduced diastolic LV filling time can explain the increased variability at fast HR.

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.

Differentiating the effects of ß-adrenergic stimulation and stretch on calcium and force dynamics using a novel electromechanical cardiomyocyte model.

Cardiac electrophysiology and mechanics are strongly interconnected. Calcium is crucial in this complex interplay through its role in cellular electrophysiology and sarcomere contraction. We aim to differentiate the effects of acute ß-adrenergic stimulation (ß-ARS) and cardiomyocyte stretch (increased sarcomere length) on calcium-transient dynamics and force generation, using a novel computational model of cardiac electromechanics. We implemented a bidirectional coupling between the O'Hara-Rudy model of human ventricular electrophysiology and the MechChem model of sarcomere mechanics through the buffering of calcium by troponin. The coupled model was validated using experimental data from large mammals or human samples. Calcium transient and force were simulated for various degrees of ß-ARS and initial sarcomere lengths. The model reproduced force-frequency, quick-release, and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in ß-ARS increased the amplitudes of force (augmented inotropy) and calcium transient, and shortened both force and calcium-transient duration (lusitropy). An increase in sarcomere length increased force amplitude even more, but decreased calcium-transient amplitude and increased both force and calcium-transient duration. Finally, a gradient in relaxation along the thin filament may explain the nonmonotonic decay in cytosolic calcium observed with high tension. Using a novel coupled human electromechanical model, we identified differential effects of ß-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and ß-ARS to the reduction of calcium and force duration. We showed that their combination, rather than individual contributions, is key to ensure force generation, rapid relaxation, and low diastolic calcium levels.NEW & NOTEWORTHY This work identifies the contribution of electrical and mechanical alterations to regulation of calcium and force under exercise-like conditions using a novel human electromechanical model integrating ventricular electrophysiology and sarcomere mechanics. By better understanding their individual and combined effects, this can uncover arrhythmogenic mechanisms in exercise-like situations. This publicly available model is a crucial step toward understanding the complex interplay between cardiac electrophysiology and mechanics to improve arrhythmia risk prediction and treatment.

Impact of paced left ventricular dyssynchrony on left ventricular reverse remodeling after cardiac resynchronization therapy.

INTRODUCTION: We investigated whether pacing-induced electrical dyssynchrony at the time of cardiac resynchronization therapy (CRT) device implantation was associated with chronic CRT response. METHODS AND RESULTS: We included a total of 69 consecutive heart failure patients who received a CRT device. Left (LVp-RVs) and right (RVp-LVs) pacing-induced interlead delays were measured intraoperatively and used to determine if there was paced left ventricular (LV) dyssynchrony, defined as present when LVp-RVs is larger than RVp-LVs. CRT response was defined as a reduction in LV end-systolic volume ≥15%, 6 months after implantation. Paced left ventricular dyssynchrony (PLVD) was associated with ischemic cardiomyopathy (ICM) (χ2 : 8; P = .005) but not with QRS morphology nor with pacing lead positions. In a univariate analysis, PLVD (odds ratio [OR], 6.53; 95% confidence interval [CI], 2.2-18.9; P = .001), atypical left bundle branch block (LBBB) (OR, 3.3; 95% CI, 1.2-9.4; P = .022), and ICM (OR, 5.2; 95% CI, 1.6-17; P = .006) were associated with nonresponse. In a multivariate analysis, both PLVD (OR, 9.74; 95% CI, 2.8-33.9; P < .0001) and atypical LBBB (OR, 5.6; 95% CI, 1.5-20.3; P = .009) were independently associated with nonresponse. Adding PLVD to a model based on QRS morphology provided a significant and meaningful incremental value to predict LV reverse remodeling after CRT (χ2 to enter: 8; P < .005). Computer simulations corroborate these findings by showing that, while intrinsic electrical dyssynchrony is a prerequisite, the level of pacing-induced dyssynchrony modulates acute CRT response. CONCLUSION: In addition to the intrinsic electrical substrate, PLVD is strongly associated with less LV reverse remodeling, demonstrating that measuring the electrical substrate during pacing has additional value for prediction of CRT response in an already well-selected patient population.

Large vessels as a tree of transmission lines incorporated in the CircAdapt whole-heart model: A computational tool to examine heart-vessel interaction.

We developed a whole-circulation computational model by integrating a transmission line (TL) model describing vascular wave transmission into the established CircAdapt platform of whole-heart mechanics. In the present paper, we verify the numerical framework of our TL model by benchmark comparison to a previously validated pulse wave propagation (PWP) model. Additionally, we showcase the integrated CircAdapt-TL model, which now includes the heart as well as extensive arterial and venous trees with terminal impedances. We present CircAdapt-TL haemodynamics simulations of: 1) a systemic normotensive situation and 2) a systemic hypertensive situation. In the TL-PWP benchmark comparison we found good agreement regarding pressure and flow waveforms (relative errors ≤ 2.9% for pressure, and ≤ 5.6% for flow). CircAdapt-TL simulations reproduced the typically observed haemodynamic changes with hypertension, expressed by increases in mean and pulsatile blood pressures, and increased arterial pulse wave velocity. We observed a change in the timing of pressure augmentation (defined as a late-systolic boost in aortic pressure) from occurring after time of peak systolic pressure in the normotensive situation, to occurring prior to time of peak pressure in the hypertensive situation. The pressure augmentation could not be observed when the systemic circulation was lumped into a (non-linear) three-element windkessel model, instead of using our TL model. Wave intensity analysis at the carotid artery indicated earlier arrival of reflected waves with hypertension as compared to normotension, in good qualitative agreement with findings in patients. In conclusion, we successfully embedded a TL model as a vascular module into the CircAdapt platform. The integrated CircAdapt-TL model allows detailed studies on mechanistic studies on heart-vessel interaction.

Parameter subset reduction for patient-specific modelling of arrhythmogenic cardiomyopathy-related mutation carriers in the CircAdapt model.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Patient-specific computational models could help understand the disease progression and may help in clinical decision-making. We propose an inverse modelling approach using the CircAdapt model to estimate patient-specific regional abnormalities in tissue properties in AC subjects. However, the number of parameters (n = 110) and their complex interactions make personalized parameter estimation challenging. The goal of this study is to develop a framework for parameter reduction and estimation combining Morris screening, quasi-Monte Carlo (qMC) simulations and particle swarm optimization (PSO). This framework identifies the best subset of tissue properties based on clinical measurements allowing patient-specific identification of right ventricular tissue abnormalities. We applied this framework on 15 AC genotype-positive subjects with varying degrees of myocardial disease. Cohort studies have shown that atypical regional right ventricular (RV) deformation patterns reveal an early-stage AC disease. The CircAdapt model of cardiovascular mechanics and haemodynamics has already demonstrated its ability to capture typical deformation patterns of AC subjects. We, therefore, use clinically measured cardiac deformation patterns to estimate model parameters describing myocardial disease substrates underlying these AC-related RV deformation abnormalities. Morris screening reduced the subset to 48 parameters. qMC and PSO further reduced the subset to a final selection of 16 parameters, including regional tissue contractility, passive stiffness, activation delay and wall reference area. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.