Biophysical Modeling to Determine the Optimization of Left Ventricular Pacing Site and AV/VV Delays in the Acute and Chronic Phase of Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac anatomy and function adapt in response to chronic cardiac resynchronization therapy (CRT). The effects of these changes on the optimal left ventricle (LV) lead location and timing delay settings have yet to be fully explored. OBJECTIVE: To predict the effects of chronic CRT on the optimal LV lead location and device timing settings over time. METHODS: Biophysical computational cardiac models were generated for 3 patients, immediately post-implant (ACUTE) and after at least 6 months of CRT (CHRONIC). Optimal LV pacing area and device settings were predicted by pacing the ACUTE and CHRONIC models across the LV epicardium (49 sites each) with a range of 9 pacing settings and simulating the acute hemodynamic response (AHR) of the heart. RESULTS: There were statistically significant differences between the distribution of the AHR in the ACUTE and CHRONIC models (P < 0.0005 in all cases). The site delivering the maximal AHR shifted location between the ACUTE and CHRONIC models but provided a negligible improvement (<2%). The majority of the acute optimal LV pacing regions (76-100%) and device settings (76-91%) remained optimal chronically. CONCLUSION: Optimization of the LV pacing location and device settings were important at the time of implant, with a reduced benefit over time, where the majority of the acute optimal LV pacing region and device settings remained optimal with chronic CRT.

The relative role of patient physiology and device optimisation in cardiac resynchronisation therapy: A computational modelling study.

Cardiac resynchronisation therapy (CRT) is an established treatment for heart failure, however the effective selection of patients and optimisation of therapy remain controversial. While extensive research is ongoing, it remains unclear whether improvements in patient selection or therapy planning offers a greater opportunity for the improvement of clinical outcomes. This computational study investigates the impact of both physiological conditions that guide patient selection and the optimisation of pacing lead placement on CRT outcomes. A multi-scale biophysical model of cardiac electromechanics was developed and personalised to patient data in three patients. These models were separated into components representing cardiac anatomy, pacing lead location, myocardial conductivity and stiffness, afterload, active contraction and conduction block for each individual, and recombined to generate a cohort of 648 virtual patients. The effect of these components on the change in total activation time of the ventricles (ΔTAT) and acute haemodynamic response (AHR) was analysed. The pacing site location was found to have the largest effect on ΔTAT and AHR. Secondary effects on ΔTAT and AHR were found for functional conduction block and cardiac anatomy. The simulation results highlight a need for a greater emphasis on therapy optimisation in order to achieve the best outcomes for patients.

Analysis of lead placement optimization metrics in cardiac resynchronization therapy with computational modelling.

AIMS: The efficacy of cardiac resynchronization therapy (CRT) is known to vary considerably with pacing location, however the most effective set of metrics by which to select the optimal pacing site is not yet well understood. Computational modelling offers a powerful methodology to comprehensively test the effect of pacing location in silico and investigate how to best optimize therapy using clinically available metrics for the individual patient. METHODS AND RESULTS: Personalized computational models of cardiac electromechanics were used to perform an in silico left ventricle (LV) pacing site optimization study as part of biventricular CRT in three patient cases. Maps of response to therapy according to changes in total activation time (ΔTAT) and acute haemodynamic response (AHR) were generated and compared with preclinical metrics of electrical function, strain, stress, and mechanical work to assess their suitability for selecting the optimal pacing site. In all three patients, response to therapy was highly sensitive to pacing location, with laterobasal locations being optimal. ΔTAT and AHR were found to be correlated (ρ < -0.80), as were AHR and the preclinical activation time at the pacing site (ρ ≥ 0.73), however pacing in the last activated site did not result in the optimal response to therapy in all cases. CONCLUSION: This computational modelling study supports pacing in laterobasal locations, optimizing pacing site by minimizing paced QRS duration and pacing in regions activated late at sinus rhythm. Results demonstrate information content is redundant using multiple preclinical metrics. Of significance, the correlation of AHR with ΔTAT indicates that minimization of QRSd is a promising metric for optimization of lead placement.

Patient-specific modeling of left ventricular electromechanics as a driver for haemodynamic analysis.

AIMS: Models of blood flow in the left ventricle (LV) and aorta are an important tool for analysing the interplay between LV deformation and flow patterns. Typically, image-based kinematic models describing endocardial motion are used as an input to blood flow simulations. While such models are suitable for analysing the hemodynamic status quo, they are limited in predicting the response to interventions that alter afterload conditions. Mechano-fluidic models using biophysically detailed electromechanical (EM) models have the potential to overcome this limitation, but are more costly to build and compute. We report our recent advancements in developing an automated workflow for the creation of such CFD ready kinematic models to serve as drivers of blood flow simulations. METHODS AND RESULTS: EM models of the LV and aortic root were created for four pediatric patients treated for either aortic coarctation or aortic valve disease. Using MRI, ECG and invasive pressure recordings, anatomy as well as electrophysiological, mechanical and circulatory model components were personalized. RESULTS: The implemented modeling pipeline was highly automated and allowed model construction and execution of simulations of a patient's heartbeat within 1 day. All models reproduced clinical data with acceptable accuracy. CONCLUSION: Using the developed modeling workflow, the use of EM LV models as driver of fluid flow simulations is becoming feasible. While EM models are costly to construct, they constitute an important and nontrivial step towards fully coupled electro-mechano-fluidic (EMF) models and show promise as a tool for predicting the response to interventions which affect afterload conditions.

Improvement of Right Ventricular Hemodynamics with Left Ventricular Endocardial Pacing during Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular epicardial (BV-CS) or endocardial left ventricular (LV) stimulation (BV-EN) improves LV hemodynamics. The effect of CRT on right ventricular function is less clear, particularly for BV-EN. Our objective was to compare the simultaneous acute hemodynamic response (AHR) of the right and left ventricles (RV and LV) with BV-CS and BV-EN in order to determine the optimal mode of CRT delivery. METHODS: Nine patients with previously implanted CRT devices successfully underwent a temporary pacing study. Pressure wires measured the simultaneous AHR in both ventricles during different pacing protocols. Conventional epicardial CRT was delivered in LV-only (LV-CS) and BV-CS configurations and compared with BV-EN pacing in multiple locations using a roving decapolar catheter. RESULTS: Best BV-EN (optimal AHR of all LV endocardial pacing sites) produced a significantly greater RV AHR compared with LV-CS and BV-CS pacing (P < 0.05). RV AHR had a significantly increased standard deviation compared to LV AHR (P < 0.05) with a weak correlation between RV and LV AHR (Spearman rs = -0.06). Compromised biventricular optimization, whereby RV AHR was increased at the expense of a smaller decrease in LV AHR, was achieved in 56% of cases, all with BV-EN pacing. CONCLUSIONS: BV-EN pacing produces significant increases in both LV and RV AHR, above that achievable with conventional epicardial pacing. RV AHR cannot be used as a surrogate for optimizing LV AHR; however, compromised biventricular optimization is possible. The beneficial effect of endocardial LV pacing on RV function may have important clinical benefits beyond conventional CRT.

Personalized computational modeling of left atrial geometry and transmural myofiber architecture.

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by complete absence of coordinated atrial contraction and is associated with an increased morbidity and mortality. Personalized computational modeling provides a novel framework for integrating and interpreting the role of atrial electrophysiology (EP) including the underlying anatomy and microstructure in the development and sustenance of AF. Coronary computed tomography angiography data were segmented using a statistics-based approach and the smoothed voxel representations were discretized into high-resolution tetrahedral finite element (FE) meshes. To estimate the complex left atrial myofiber architecture, individual fiber fields were generated according to morphological data on the endo- and epicardial surfaces based on local solutions of Laplace's equation and transmurally interpolated to tetrahedral elements. The influence of variable transmural microstructures was quantified through EP simulations on 3 patients using 5 different fiber interpolation functions. Personalized geometrical models included the heterogeneous thickness distribution of the left atrial myocardium and subsequent discretization led to high-fidelity tetrahedral FE meshes. The novel algorithm for automated incorporation of the left atrial fiber architecture provided a realistic estimate of the atrial microstructure and was able to qualitatively capture all important fiber bundles. Consistent maximum local activation times were predicted in EP simulations using individual transmural fiber interpolation functions for each patient suggesting a negligible effect of the transmural myofiber architecture on EP. The established modeling pipeline provides a robust framework for the rapid development of personalized model cohorts accounting for detailed anatomy and microstructure and facilitates simulations of atrial EP.

The impact of beat-to-beat variability in optimising the acute hemodynamic response in cardiac resynchronisation therapy.

BACKGROUND: Acute indicators of response to cardiac resynchronisation therapy (CRT) are critical for developing lead optimisation algorithms and evaluating novel multi-polar, multi-lead and endocardial pacing protocols. Accounting for beat-to-beat variability in measures of acute haemodynamic response (AHR) may help clinicians understand the link between acute measurements of cardiac function and long term clinical outcome. METHODS AND RESULTS: A retrospective study of invasive pressure tracings from 38 patients receiving an acute pacing and electrophysiological study was performed. 602 pacing protocols for left ventricle (LV) (n = 38), atria-ventricle (AV) (n = 9), ventricle-ventricle (VV) (n = 12) and endocardial (ENDO) (n = 8) optimisation were performed. AHR was measured as the maximal rate of LV pressure development (dP/dtMx) for each beat. The range of the 95% confidence interval (CI) of mean AHR was ~ 7% across all optimisation protocols compared with the reported CRT response cut off value of 10%. A single clear optimal protocol was identifiable in 61%, 22%, 25% and 50% for LV, AV, VV and ENDO optimisation cases, respectively. A level of service (LOS) optimisation that aimed to maximise the expected AHR 5th percentile, minimising variability and maximising AHR, led to distinct optimal protocols from conventional mean AHR optimisation in 34%, 78%, 67% and 12.5% of LV, AV, VV and ENDO optimisation cases, respectively. CONCLUSION: The beat-to-beat variation in AHR is significant in the context of CRT cut off values. A LOS optimisation offers a novel index to identify the optimal pacing site that accounts for both the mean and variation of the baseline measurement and pacing protocol.

Verification of cardiac mechanics software: benchmark problems and solutions for testing active and passive material behaviour.

Models of cardiac mechanics are increasingly used to investigate cardiac physiology. These models are characterized by a high level of complexity, including the particular anisotropic material properties of biological tissue and the actively contracting material. A large number of independent simulation codes have been developed, but a consistent way of verifying the accuracy and replicability of simulations is lacking. To aid in the verification of current and future cardiac mechanics solvers, this study provides three benchmark problems for cardiac mechanics. These benchmark problems test the ability to accurately simulate pressure-type forces that depend on the deformed objects geometry, anisotropic and spatially varying material properties similar to those seen in the left ventricle and active contractile forces. The benchmark was solved by 11 different groups to generate consensus solutions, with typical differences in higher-resolution solutions at approximately 0.5%, and consistent results between linear, quadratic and cubic finite elements as well as different approaches to simulating incompressible materials. Online tools and solutions are made available to allow these tests to be effectively used in verification of future cardiac mechanics software.

An automatic service for the personalization of ventricular cardiac meshes.

Computational cardiac physiology has great potential to improve the management of cardiovascular diseases. One of the main bottlenecks in this field is the customization of the computational model to the anatomical and physiological status of the patient. We present a fully automatic service for the geometrical personalization of cardiac ventricular meshes with high-order interpolation from segmented images. The method is versatile (able to work with different species and disease conditions) and robust (fully automatic results fulfilling accuracy and quality requirements in 87% of 255 cases). Results also illustrate the capability to minimize the impact of segmentation errors, to overcome the sparse resolution of dynamic studies and to remove the sometimes unnecessary anatomical detail of papillary and trabecular structures. The smooth meshes produced can be used to simulate cardiac function, and in particular mechanics, or can be used as diagnostic descriptors of anatomical shape by cardiologists. This fully automatic service is deployed in a cloud infrastructure, and has been made available and accessible to the scientific community.

Quality metrics for high order meshes: analysis of the mechanical simulation of the heart beat.

The quality of a computational mesh is an important characteristic for stable and accurate simulations. Quality depends on the regularity of the initial mesh, and in mechanical simulations it evolves in time, with deformations causing changes in volume and distortion of mesh elements. Mesh quality metrics are therefore relevant for both mesh personalization and the monitoring of the simulation process. This work evaluates the significance, in meshes with high order interpolation, of four quality metrics described in the literature, applying them to analyse the stability of the simulation of the heart beat. It also investigates how image registration and mesh warping parameters affect the quality and stability of meshes. Jacobian-based metrics outperformed or matched the results of coarse geometrical metrics of aspect ratio or orthogonality, although they are more expensive computationally. The stability of simulations of a complete heart cycle was best predicted with a specificity of 61%, sensitivity of 85%, and only nominal differences were found changing the intra-element and per-element combination of quality values. A compromise between fitting accuracy and mesh stability and quality was found. Generic geometrical quality metrics have a limited success predicting stability, and an analysis of the simulation problem may be required for an optimal definition of quality.