Cardiac resynchronization therapy (CRT) guidelines are based on clinical trials with limited female representation and inconsistent left bundle branch block (LBBB) definitions. Conventional QRS duration (QRSd) criteria show variable diagnostic accuracy between sexes, partly due to differences in heart size and remodelling. We evaluated the influence of sex, heart size, LBBB, and conduction delay on QRSd and assessed the diagnostic performance of conventional and indexed QRSd criteria using a population-based modelling approach. Simulated QRSd were derived from electrophysiological simulations conducted in 2627 UK Biobank healthy participants and 359 patients with ischaemic heart disease, by modelling LBBB and normal activation combined with/without conduction delay. QRSd criteria under-selected LBBB females and over-selected non-LBBB patients. Indexing by LVEDV and LV mass reduced sex disparities but increased the over-selection in non-LBBB patients. Height-indexed QRSd effectively resolved sex differences and maintained low non-LBBB selection rates, demonstrating superior performance and potential for more equitable CRT selection. These results uncover a key mechanistic driver of sex differences in LBBB detection that may contribute to CRT outcomes and underscore the importance of incorporating sex-specific considerations into updated CRT guidelines to ensure equitable and effective treatment.

Electrocardiogram (ECG) recordings are affected by the heart's three-dimensional orientation within the thorax, i.e., the anatomical axis. Various cardiac conditions can cause the anatomical axis to shift and/or alter the pattern of electrical activation, leading to changes in the electrical axis. Nevertheless, there remains a lack of a formal, population-level study of the interplay between the cardiac anatomical and electrical axes and the factors that affect them. In this context, this study aimed to: (1) propose standardised definitions for the cardiac anatomical and electrical axes, (2) characterise their population-wide interplay in healthy conditions, (3) evaluate the impact of hypertension on their distribution and (4) identify associations with phenotypical and disease characteristics. Using cardiac magnetic resonance images and 12-lead ECGs from ~39,000 UK Biobank participants, patient-specific, paired biventricular geometries and vectorcardiograms were constructed. Five anatomical and four electrical axis definitions were computed, with the optimal pair of definitions selected based on their mutual alignment in 3D space within 28,000 healthy subjects. Accordingly, the anatomical axis was defined as the vector from the apex to the spatial centre of the four valves, and the electrical axis as the direction of the maximum QRS dipole. Mean angular separation in 3D, [Formula: see text], was 145.0° ± 16.8° in the healthy cohort. The electrical axes exhibited a much larger variability, and strong evidence of anatomical-electrical coupling was identified. Increasing BMI notably affected the anatomical axis, rotating the heart more horizontally-a pattern mirrored by the electrical axis. Both axes were also significantly influenced by sex and, to a lesser extent, age. The axes were then studied in the sub-cohort of ~3,500 UK BioBank participants with primary hypertension, where a similar rotational pattern as that with increasing BMI was revealed. Finally, phenome-wide association studies in the 39,000 participants reveal associations between the axes angular metrics and phenotypes signalling an increased afterload, and an association to hypertension among other clinical conditions. These findings underscore the complex anatomical-electrical interplay and highlight the potential of cardiac axes biomarkers for an improved clinical ECG interpretation and disease characterisation.

Large-cohort imaging and diagnostic studies often assess cardiac function but overlook underlying biological mechanisms. Cardiac digital twins (CDTs) are personalized physics-constrained and physiology-constrained in silico representations, uncovering multi-scale insights tied to these mechanisms. In this study, we constructed 3,461 CDTs from the UK Biobank and another 359 from an ischemic heart disease (IHD) cohort, using cardiac magnetic resonance images and electrocardiograms. We show here that sex-specific differences in QRS duration were fully explained by myocardial anatomy while their myocardial conduction velocity (CV) remains similar across sexes but changes with age and obesity, indicating myocardial tissue remodeling. Longer QTc intervals in obese females were attributed to larger delayed rectifier potassium conductance G KrKs . These findings were validated in the IHD cohort. Moreover, CV and G KrKs were associated with cardiac function, lifestyle and mental health phenotypes, and CV was also linked with adverse clinical outcomes. Our study demonstrates how CDT development at scale reveals biological insights across populations.

Whole-heart segmentation from CT and MRI scans is crucial for cardiovascular disease analysis, yet existing methods struggle with modality-specific biases and the need for extensive labeled datasets. To address these challenges, we propose a foundation model for whole-heart segmentation using a self-supervised learning (SSL) framework based on a student-teacher architecture. Our model is pretrained on a large, unlabeled dataset of CT and MRI scans, leveraging the xLSTM backbone to capture long-range spatial dependencies and complex anatomical structures in 3D medical images. By incorporating multi-modal pretraining, our approach ensures strong generalization across both CT and MRI modalities, mitigating modality-specific variations and improving segmentation accuracy in diverse clinical settings. The use of large-scale unlabeled data significantly reduces the dependency on manual annotations, enabling robust performance even with limited labeled data. We further introduce an xLSTM-UNet-based architecture for downstream whole-heart segmentation tasks, demonstrating its effectiveness on few-label CT and MRI datasets. Our results validate the robustness and adaptability of the proposed model, highlighting its potential for advancing automated whole-heart segmentation in medical imaging.

A cardiac digital twin is a virtual replica of a patient’s heart for screening, diagnosis, prognosis, risk assessment, and treatment planning of cardiovascular diseases. This requires an anatomically accurate patient-specific 3D structural representation of the heart, suitable for electro-mechanical simulations or study of disease mechanisms. However, generation of cardiac digital twins at scale is demanding and there are no public repositories of models across demographic groups. We describe an automatic open-source pipeline for creating patient-specific left and right ventricular meshes from cardiovascular magnetic resonance images, its application to a large cohort of ~55k participants from UK Biobank, and the construction of the most comprehensive cohort of adult heart models to date, comprising 1423 representative meshes across sex (male, female), body mass index (range: 16–42 kg/m 2 ) and age (range: 49–80 years). Our code is available at https://github.com/cdttk/biv-volumetric-meshing/tree/plos2025 , and pre-trained networks, representative volumetric meshes with fibers and UVCs are available at https://doi.org/10.5281/zenodo.15649643 .

Cardiac resynchronization therapy (CRT) guidelines are based on clinical trials with limited female representation and inconsistent left bundle branch block (LBBB) definitions. Conventional QRS duration (QRSd) criteria show variable diagnostic accuracy between sexes, partly due to differences in heart size and remodeling. We evaluated the influence of sex, heart size, LBBB, and conduction delay on QRSd and assessed the diagnostic performance of conventional and indexed QRSd criteria using a population-based modelling approach. Simulated QRSd were derived from electrophysiological simulations conducted in 2627 UK Biobank healthy participants and 359 patients with ischemic heart disease, by modelling LBBB and normal activation combined with/without conduction delay. QRSd criteria under-selected LBBB females and over-selected non-LBBB patients. Indexing by LVEDV and LV mass reduced sex disparities but increased the over-selection in non-LBBB patients. Height-indexed QRSd effectively resolved sex differences and maintained low non-LBBB selection rates, demonstrating superior performance and potential for more equitable CRT selection.

The Framingham heart study has shown that diabetic patients have an increased risk of cardiovascular disease. Hyperglycemia causes a wide range of multi-scale remodeling mechanisms, but their contribution towards cardiac function deterioration is not well characterized and it may differ between patients. In this study, we performed a one-at-a-time sensitivity analysis on 46 parameters using whole-heart electromechanics models generated from ten UK Biobank datasets (50 EDV_LV ) were the left heart unloading pressure, the reference pressure of the systemic veins, and the pulmonary resistance, in this order consistently across the cohort. Similarly, the EDV of the right ventricle (RV) strongly depended on the right heart unloading pressure, the reference pressure of the systemic veins, and the systemic resistance. However, the order of the parameters was not consistent between patients, indicating that the RV volume features may be more sensitive to cardiac anatomy. Some of the biomarkers’ sensitivities also differed between sexes (LV end-systolic volume vs systemic resistance sensitivity: male [0.84, 0.99] vs female [0.63, 0.83]). This demonstrates that the male and the female heart may adapt differently to the same remodeling mechanism. Our results show how multi-scale whole-heart models can be used to assess how biomarkers relate to multi-scale cardiac function, and which of these relationships are more sensitive to cardiac anatomy and sex.

Sex-specific differences in cardiac resynchronization therapy (CRT) outcomes are known for patients with left bundle branch block (LBBB). This may be explained by the combination of differences in heart size and QRS duration between genders. We showed previously sex-specific differences in QRS duration are attributed to myocardial anatomy, rather than estimated myocardial conduction. However, the relative impact of dysfunctional bundle branches on QRS duration is poorly studied. Biophysically-based computational models allow us to isolate and quantify the impact of impaired His-Purkinje system (HPS) on QRS duration between genders, independently of anatomical and structural remodelling.

Cine cardiac magnetic resonance (CMR) imaging is considered the gold standard for cardiac function evaluation. However, cine CMR acquisition is inherently slow and in recent decades considerable effort has been put into accelerating scan times without compromising image quality or the accuracy of derived results. In this paper, we present a fully-automated, quality-controlled integrated framework for reconstruction, segmentation and downstream analysis of undersampled cine CMR data. The framework enables active acquisition of radial k-space data, in which acquisition can be stopped as soon as acquired data are sufficient to produce high quality reconstructions and segmentations. This results in reduced scan times and automated analysis, enabling robust and accurate estimation of functional biomarkers. To demonstrate the feasibility of the proposed approach, we perform realistic simulations of radial k-space acquisitions on a dataset of subjects from the UK Biobank and present results on in-vivo cine CMR k-space data collected from healthy subjects. The results demonstrate that our method can produce quality-controlled images in a mean scan time reduced from 12 to 4 seconds per slice, and that image quality is sufficient to allow clinically relevant parameters to be automatically estimated to within 5% mean absolute difference.

Large-cohort studies using cardiovascular imaging and diagnostic datasets have assessed cardiac anatomy, function, and outcomes, but typically do not reveal underlying biological mechanisms. Cardiac digital twins (CDTs) provide personalized physics- and physiology-constrained in-silico representations, enabling inference of multi-scale properties tied to these mechanisms. We constructed 3464 anatomically-accurate CDTs using cardiac magnetic resonance images from UK biobank and personalised their myocardial conduction velocities (CVs) from electrocardiograms (ECG), through an automated framework. We found well-known sex-specific differences in QRS duration were fully explained by myocardial anatomy, as CV remained consistent across sexes. Conversely, significant associations of CV with ageing and increased BMI suggest myocardial tissue remodelling. Novel associations were observed with left ventricular ejection fraction and mental-health phenotypes, through a phenome-wide association study, and CV was also linked with adverse clinical outcomes. Our study highlights the utility of population-based CDTs in assessing intersubject variability and uncovering strong links with mental health.

Domain shift refers to the difference in the data distribution of two datasets, normally between the training set and the test set for machine learning algorithms. Domain shift is a serious problem for generalization of machine learning models and it is well-established that a domain shift between the training and test sets may cause a drastic drop in the model's performance. In medical imaging, there can be many sources of domain shift such as different scanners or scan protocols, different pathologies in the patient population, anatomical differences in the patient population (e.g. men vs women) etc. Therefore, in order to train models that have good generalization performance, it is important to be aware of the domain shift problem, its potential causes and to devise ways to address it. In this paper, we study the effect of domain shift on left and right ventricle blood pool segmentation in short axis cardiac MR images. Our dataset contains short axis images from 4 different MR scanners and 3 different pathology groups. The training is performed with nnUNet. The results show that scanner differences cause a greater drop in performance compared to changing the pathology group, and that the impact of domain shift is greater on right ventricle segmentation compared to left ventricle segmentation. Increasing the number of training subjects increased cross-scanner performance more than in-scanner performance at small training set sizes, but this difference in improvement decreased with larger training set sizes. Training models using data from multiple scanners improved cross-domain performance.

Cine cardiac MRI is routinely acquired for the assessment of cardiac health, but the imaging process is slow and typically requires several breath-holds to acquire sufficient k-space profiles to ensure good image quality. Several undersampling-based reconstruction techniques have been proposed during the last decades to speed up cine cardiac MRI acquisition. However, the undersampling factor is commonly fixed to conservative values before acquisition to ensure diagnostic image quality, potentially leading to unnecessarily long scan times. In this paper, we propose an end-to-end quality-aware cine short-axis cardiac MRI framework that combines image acquisition and reconstruction with downstream tasks such as segmentation, volume curve analysis and estimation of cardiac functional parameters. The goal is to reduce scan time by acquiring only a fraction of k-space data to enable the reconstruction of images that can pass quality control checks and produce reliable estimates of cardiac functional parameters. The framework consists of a deep learning model for the reconstruction of 2D+t cardiac cine MRI images from undersampled data, an image quality-control step to detect good quality reconstructions, followed by a deep learning model for bi-ventricular segmentation, a quality-control step to detect good quality segmentations and automated calculation of cardiac functional parameters. To demonstrate the feasibility of the proposed approach, we perform simulations using a cohort of selected participants from the UK Biobank (n=270), 200 healthy subjects and 70 patients with cardiomyopathies. Our results show that we can produce quality-controlled images in a scan time reduced from 12 to 4 seconds per slice, enabling reliable estimates of cardiac functional parameters such as ejection fraction within 5% mean absolute error.

In the original version of the book, the following belated corrections are to be incorporated.

White matterWhite matter fibers constituteSupervised classification the main information transfer network of the brain and their accurate digital representation and classification is an important goal of neuroscience image computing. In current clinicalWhite matter practice, the reconstructionNeural networks of desired fibers generally involves manual selection of regions of interest by an expert, which is time-consuming and subject to user bias, expertise and fatigue. Hence, automation of the process is desired. To that end, we propose a supervised classificationSupervised classification approach that utilizes an ensemble of neural networks. EachNeural networks streamline is represented by the fiber orientation distributions in its neighborhood, while the resolved fiber orientations are obtained by generalized q-sampling imaging (GQI) and a subsequent diffusion decomposition method. In order to make the supervised fiber classification succeed in a real scenario where a substantial portion of reconstructed fiber tracts contain spurious fibers, we present a way to create an "invalid" class label through a dedicated training setTraining set creation scheme with an ensemble of networks. The performance of the proposed classification method is demonstrated on major fiber pathways in the brainstem. 30 subjects from Human Connectome Project (HCP)'s publicly available "WU-Minn 500 Subjects + MEG2 dataset" are used as the dataset.

Accurate digital representation of major white matter bundles in the brain is an important goal in neuroscience image computing since the representations can be used for surgical planning, intra-patient longitudinal analysis and inter-subject population connectivity studies. Reconstructing desired fiber bundles generally involves manual selection of regions of interest by an expert, which is subject to user bias and fatigue, hence an automation is desirable. To that end, we first present a novel anatomical representation based on Neighborhood Resolved Fiber Orientation Distributions (NRFOD) along the fibers. The resolved fiber orientations are obtained by generalized q-sampling imaging (GQI) and a subsequent diffusion decomposition method. A fiber-to-fiber distance measure between the proposed fiber representations is then used in a density-based clustering framework to select the clusters corresponding to the major pathways of interest. In addition, neuroanatomical priors are utilized to constrain the set of candidate fibers before density-based clustering. The proposed fiber clustering approach is exemplified on automation of the reconstruction of the major fiber pathways in the brainstem: corticospinal tract (CST); medial lemniscus (ML); middle cerebellar peduncle (MCP); inferior cerebellar peduncle (ICP); superior cerebellar peduncle (SCP). Experimental results on Human Connectome Project (HCP)'s publicly available "WU-Minn 500 Subjects + MEG2 dataset" and expert evaluations demonstrate the potential of the proposed fiber clustering method in brainstem white matter structure analysis.

Diffusion MRI(DMRI) provides us with the anatomy of the white matter fibers in the brain. Extracting shape information is a necessary step to analyze the deformation in the white matter fibers of a patient before and after brain surgery. We propose various measures with different invariance properties to explain deformations of different characteristics. The measures are presented for corticospinal tract and medial lemniscus fibers on a clinical dataset.