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.

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.

Clinical impact and predictors of periprocedural myocardial injury among patients undergoing left bundle branch area pacing.

BACKGROUND: The clinical impact of Periprocedural myocardial injury (PMI) in patients undergoing permanent pacemaker implantation with Left Bundle Branch Area Pacing (LBBAP) is unknown. METHODS: 130 patients undergoing LBBAP from January 2020 to June 2021 and completing 12 months follow up were enrolled to assess the impact of PMI on composite clinical outcome (CCO) defined as any of the following: all-cause death, hospitalization for heart failure (HHF), hospitalization for acute coronary syndrome (ACS) and ventricular arrhythmias (VAs). High sensitivity Troponin T (HsTnT) was measured up to 24-h after intervention to identify the peak HsTnT values. PMI was defined as increased peak HsTnT values at least > 99th percentile of the upper reference limit (URL: 15 pg/ml) in patients with normal baseline values. RESULTS: PMI occurred in 72 of 130 patients (55%). ROC analysis yielded a post-procedural peak HsTnT cutoff of fourfold the URL for predicting the CCO (AUC: 0.692; p = 0.023; sensitivity 73% and specificity 71%). Of the enrolled patients, 20% (n = 26) had peak HsTnT > fourfold the URL. Patients with peak HsTnT > fourfold the URL exhibited a higher incidence of the CCO than patients with peak HsTnT ≤ fourfold the URL (31% vs. 10%; p = 0.005), driven by more frequent hospitalizations for ACS (15% vs. 3%; p = 0.010). Multiple (> 2) lead repositions attempts, the use of septography and stylet-driven leads were independent predictors of higher risk of PMI with peak HsTnT > fourfold the URL. CONCLUSIONS: PMI seems common among patients undergoing LBBAP and may be associated with an increased risk of clinical outcomes in case of more pronounced (peak HsTnT > fourfold the URL) myocardial damage occurring during the procedure.

Uncertainty Quantification of Regional Cardiac Tissue Properties in Arrhythmogenic Cardiomyopathy Using Adaptive Multiple Importance Sampling.

Introduction: Computational models of the cardiovascular system are widely used to simulate cardiac (dys)function. Personalization of such models for patient-specific simulation of cardiac function remains challenging. Measurement uncertainty affects accuracy of parameter estimations. In this study, we present a methodology for patient-specific estimation and uncertainty quantification of parameters in the closed-loop CircAdapt model of the human heart and circulation using echocardiographic deformation imaging. Based on patient-specific estimated parameters we aim to reveal the mechanical substrate underlying deformation abnormalities in patients with arrhythmogenic cardiomyopathy (AC). Methods: We used adaptive multiple importance sampling to estimate the posterior distribution of regional myocardial tissue properties. This methodology is implemented in the CircAdapt cardiovascular modeling platform and applied to estimate active and passive tissue properties underlying regional deformation patterns, left ventricular volumes, and right ventricular diameter. First, we tested the accuracy of this method and its inter- and intraobserver variability using nine datasets obtained in AC patients. Second, we tested the trueness of the estimation using nine in silico generated virtual patient datasets representative for various stages of AC. Finally, we applied this method to two longitudinal series of echocardiograms of two pathogenic mutation carriers without established myocardial disease at baseline. Results: Tissue characteristics of virtual patients were accurately estimated with a highest density interval containing the true parameter value of 9% (95% CI [0-79]). Variances of estimated posterior distributions in patient data and virtual data were comparable, supporting the reliability of the patient estimations. Estimations were highly reproducible with an overlap in posterior distributions of 89.9% (95% CI [60.1-95.9]). Clinically measured deformation, ejection fraction, and end-diastolic volume were accurately simulated. In presence of worsening of deformation over time, estimated tissue properties also revealed functional deterioration. Conclusion: This method facilitates patient-specific simulation-based estimation of regional ventricular tissue properties from non-invasive imaging data, taking into account both measurement and model uncertainties. Two proof-of-principle case studies suggested that this cardiac digital twin technology enables quantitative monitoring of AC disease progression in early stages of disease.

Uncertainty in model-based treatment decision support: Applied to aortic valve stenosis.

Patient outcome in trans-aortic valve implantation (TAVI) therapy partly relies on a patient's haemodynamic properties that cannot be determined from current diagnostic methods alone. In this study, we predict changes in haemodynamic parameters (as a part of patient outcome) after valve replacement treatment in aortic stenosis patients. A framework to incorporate uncertainty in patient-specific model predictions for decision support is presented. A 0D lumped parameter model including the left ventricle, a stenotic valve and systemic circulatory system has been developed, based on models published earlier. The unscented Kalman filter (UKF) is used to optimize model input parameters to fit measured data pre-intervention. After optimization, the valve treatment is simulated by significantly reducing valve resistance. Uncertain model parameters are then propagated using a polynomial chaos expansion approach. To test the proposed framework, three in silico test cases are developed with clinically feasible measurements. Quality and availability of simulated measured patient data are decreased in each case. The UKF approach is compared to a Monte Carlo Markov Chain (MCMC) approach, a well-known approach in modelling predictions with uncertainty. Both methods show increased confidence intervals as measurement quality decreases. By considering three in silico test-cases we were able to show that the proposed framework is able to incorporate optimization uncertainty in model predictions and is faster and the MCMC approach, although it is more sensitive to noise in flow measurements. To conclude, this work shows that the proposed framework is ready to be applied to real patient data.

3D-printed stenotic aortic valve model to simulate physiology before, during, and after transcatheter aortic valve implantation.

AIMS: Pressure loss versus transvalvular flow analysis challenges physiologic models of current aortic valve stenosis. New conceptual frameworks are needed to explain these real-world observations. METHODS AND RESULTS: A patient-specific, 3D-printed, silicon model of a stenotic valve was placed inside an in-vitro haemodynamic model of the circulatory system. Instantaneous pressure and flow in the aorta and left ventricle were simulated according to measured patient specific parameters. Thereafter, a realistic transcatheter aortic valve was implanted (TAVI) in the model. Simulated post-TAVI mean pressure gradients resembled patient observations (3.7 ± 0.7 mmHg vs 6.7 ± 2.3 mmHg), but pre-TAVI measurements underestimated the pressure gradient (35.1 ± 0.6 mmHg vs 45.3 ± 1.5 mmHg). CONCLUSION: Patient-specific 3D-printed stenotic aortic valve models could simulate baseline haemodynamics. A TAVI procedure was successfully performed on the 3D silicone rubber valve in a physiologic in-vitro model. Pre-TAVI haemodynamics in the model underestimated in-patient mean pressure gradient, whereas post TAVI pressure gradient was predicted correctly with the TAVI valve inside the 3D printed model. This study shows that these types of models could be used to study AS hemodynamics with the TAVI valve inside the 3D printed model. Improvements in the 3D-printed model, like addition of calcification and fine-tuning of the haemodynamic model, could further enhance accuracy of the simulation.