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.

Cardiac digital twins (Cardiac Digital Twin (CDT)s) of human electrophysiology (Electrophysiology (EP)) are digital replicas of patient hearts derived from clinical data that match like-for-like all available clinical observations. Due to their inherent predictive potential, CDTs show high promise as a complementary modality aiding in clinical decision making and also in the cost-effective, safe and ethical testing of novel EP device therapies. However, current workflows for both the anatomical and functional twinning phases within CDT generation, referring to the inference of model anatomy and parameters from clinical data, are not sufficiently efficient, robust and accurate for advanced clinical and industrial applications. Our study addresses three primary limitations impeding the routine generation of high-fidelity CDTs by introducing; a comprehensive parameter vector encapsulating all factors relating to the ventricular EP; an abstract reference frame within the model allowing the unattended manipulation of model parameter fields; a novel fast-forward electrocardiogram (Electrocardiogram (ECG)) model for efficient and bio-physically-detailed simulation required for parameter inference. A novel workflow for the generation of CDTs is then introduced as an initial proof of concept. Anatomical twinning was performed within a reasonable time compatible with clinical workflows (<4h) for 12 subjects from clinically-attained magnetic resonance images. After assessment of the underlying fast forward ECG model against a gold standard bidomain ECG model, functional twinning of optimal parameters according to a clinically-attained 12 lead ECG was then performed using a forward Saltelli sampling approach for a single subject. The achieved results in terms of efficiency and fidelity demonstrate that our workflow is well-suited and viable for generating biophysically-detailed CDTs at scale.

Being able to map a particular set of cardiac ventricles to a generic topologically equivalent representation has many applications, including facilitating comparison of different hearts, as well as mapping quantities and structures of interest between them. In this paper we describe Universal Ventricular Coordinates (UVC), which can be used to describe position within any biventricular heart. UVC comprise four unique coordinates that we have chosen to be intuitive, well defined, and relevant for physiological descriptions. We describe how to determine these coordinates for any volumetric mesh by illustrating how to properly assign boundary conditions and utilize solutions to Laplace's equation. Using UVC, we transferred scalar, vector, and tensor data between four unstructured ventricular meshes from three different species. Performing the mappings was very fast, on the order of a few minutes, since mesh nodes were searched in a KD tree. Distance errors in mapping mesh nodes back and forth between meshes were less than the size of an element. Analytically derived fiber directions were also mapped across meshes and compared, showing < 5° difference over most of the ventricles. The ability to transfer gradients was also demonstrated. Topologically variable structures, like papillary muscles, required further definition outside of the UVC framework. In conclusion, UVC can aid in transferring many types of data between different biventricular geometries.

Aims: Catheter ablation is an effective technique for terminating atrial arrhythmia. However, given a high atrial fibrillation (AF) recurrence rate, optimal ablation strategies have yet to be defined. Computer modelling can be a powerful aid but modelling of fibrosis, a major factor associated with AF, is an open question. Several groups have proposed methodologies based on imaging data, but no comparison to determine which methodology best corroborates clinically observed reentrant behaviour has been performed. We examined several methodologies to determine the best method for capturing fibrillation dynamics. Methods and results: Patient late gadolinium-enhanced magnetic resonance imaging data were transferred onto a bilayer atrial computer model and used to assign fibrosis distributions. Fibrosis was modelled as conduction disturbances (lower conductivity, edge splitting, or percolation), transforming growth factor-β1 ionic channel effects, myocyte-fibroblast coupling, and combinations of the preceding. Reentry was induced through pulmonary vein ectopy and the ensuing rotor dynamics characterized. Non-invasive electrocardiographic imaging data of the patients in AF was used for comparison. Electrograms were computed and the fractionation durations measured over the surface. Edge splitting produced more phase singularities from wavebreaks than the other representations. The number of phase singularities seen with percolation was closer to the clinical values. Addition of fibroblast coupling had an organizing effect on rotor dynamics. Simple tissue conductivity changes with ionic changes localized rotors over fibrosis which was not observed with clinical data. Conclusion: The specific representation of fibrosis has a large effect on rotor dynamics and needs to be carefully considered for patient specific modelling.

Integrating spatial information about atrial physiology and anatomy in a single patient from multimodal datasets, as well as generalizing these data across patients, requires a common coordinate system. In the atria, this is challenging due to the complexity and variability of the anatomy. We aimed to develop and validate a Universal Atrial Coordinate (UAC) system for the following applications: combination and assessment of multimodal data; comparison of spatial data across patients; 2D visualization; and construction of patient specific geometries to test mechanistic hypotheses. Left and right atrial LGE-MRI data were segmented and meshed. Two coordinates were calculated for each atrium by solving Laplace's equation, with boundary conditions assigned using five landmark points. The coordinate system was used to map spatial information between atrial meshes, including scalar fields measured using different mapping modalities, and atrial anatomic structures and fibre directions from a reference geometry. Average error in point transfer from a source mesh to a destination mesh and back again was less than 0.1 mm for the left atrium and 0.02 mm for the right atrium. Patient specific meshes were constructed using the coordinate system and phase singularity density maps from arrhythmia simulations were visualised in 2D. In conclusion, we have developed a universal atrial coordinate system allowing automatic registration of imaging and electroanatomic mapping data, 2D visualisation, and patient specific model creation.

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.