Abstract:

BACKGROUND AND OBJECTIVE: Radiomics extracts quantitative features from magnetic resonance images (MRI) and is especially useful in the presence of subtle pathological changes within human soft tissues. This scenario, however, may not cover the effects of intrinsic, e.g., aging-related, (physiological) neurodegeneration of normal brain tissue. The aim of the work was to study the repeatability of radiomic features extracted from an apparently normal area in longitudinally acquired T1-weighted MR brain images using three different intensity normalization approaches typically used in radiomics: Z-score, WhiteStripe and Nyul. METHODS: Fifty-nine images of hearing impaired, yet cognitively intact, patients were repeatedly acquired in two different time points within six months. Ninety-one radiomic features were obtained from an area within the pons region, considered to be a healthy brain tissue according to previous analyses and reports. The Intraclass Correlation Coefficient (ICC) and the Concordance Correlation Coefficient (CCC) in the repeatability study were used as metrics. RESULTS: Features extracted from the MRI normalized with Z-score showed results comparable in both ICC (0.90 (0.82-0.98)) and CCC (0.82 (0.69-0.95)) distribution values, in terms of median and quartiles, with those extracted from the images normalized with WhiteStripe (0.89 (0.84-0.92)) and (0.80 (0.73-0.84)), respectively. CONCLUSION: Our findings underline the importance of, providing useful guidelines for, the intensity normalization of brain MRI prior to a longitudinal radiomic analysis.

Abstract:

Radiotherapy (RT) is a cancer treatment technique that involves exposing cells to ionizing radiation, including X-rays, electrons, or protons. RT offers promise to treat cancer, however, some inherent limitations can hamper its performance. Radio-resistance, whether innate or acquired, refers to the ability of tumor cells to withstand treatment, making it a key factor in RT failure. This perspective hypothesizes that nanoscale surface topography can impact on the topology of cancer cells network under radiation, and that this understanding can possibly advance the assessment of cell radio-resistance in RT applications. An experimental plan is proposed to test this hypothesis, using cancer cells exposed to various RT forms. By examining the influence of 2D surface and 3D scaffold nanoscale architecture on cancer cells, this approach diverges from traditional methodologies, such as clonogenic assays, offering a novel viewpoint that integrates fields such as tissue engineering, artificial intelligence, and nanotechnology. The hypotheses at the base of this perspective not only may advance cancer treatment but also offers insights into the broader field of structural biology. Nanotechnology and label-free Raman phenotyping of biological samples are lenses through which scientists can possibly better elucidate the structure-function relationship in biological systems.

Abstract:

Regular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANCs). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus we investigated the effects of hypocalcaemia and sympathetic stimulation on the SANC beating rate (BR). The β-adrenergic receptor (β-AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca]) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) for a sufficient period of time to allow transient oscillations to equilibrate and reach a limit cycle. The β-AR cell response of the extended models was validated against new Langendorff-perfused rabbit heart experiments and literature data. The extended models revealed that decreased [Ca] necessitated an exponential-like increase in [ISO] to restore the basal BR. Specifically at 1.2 mM [Ca], the Severi and Fabbri models required 28.0 and 9.6 nM [ISO], respectively, to restore the initial BR. Further reduction in [Ca] to 0.6 mM required 170.0 and 43.6 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca] resulted in a loss of automaticity within seconds. These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the β-AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients. KEY POINTS: We extended the sinoatrial node cell (SANC) models of Severi et al. (rabbit) and Fabbri et al. (human) using the β-adrenergic receptor (β-AR) signalling cascade Behar et al. described. Simulations were conducted across various extracellular calcium ([Ca]) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) to reflect conditions in haemodialysis (HD) patients. An exponential-like increase in [ISO] compensated for hypocalcaemia-induced bradycardia in both models, whereas interspecies differences increased the sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone. The extended models may help to further understand the pathomechanisms of several cardiovascular diseases affecting pacemaking, such as the high occurrence of sudden cardiac death (SCD) in chronic kidney disease (CKD) patients.

Abstract:

Since the turn of the millennium, computational modelling of biological systems has evolved remarkably and sees matured use spanning basic and clinical research. While the topic of the peri-millennial debate about the virtues and limitations of 'reductionism and integrationism' seems less controversial today, a new apparent dichotomy dominates discussions: mechanistic vs. data-driven modelling. In light of this distinction, we provide an overview of recent achievements and new challenges with a focus on the cardiovascular system. Attention has shifted from generating a universal model of the human to either models of individual humans (digital twins) or entire cohorts of models representative of clinical populations to enable in silico clinical trials. Disease-specific parameterisation, inter-individual and intra-individual variability, uncertainty quantification as well as interoperable, standardised, and quality-controlled data are important issues today, which call for open tools, data and metadata standards, as well as strong community interactions. The quantitative, biophysical, and highly controlled approach provided by in silico methods has become an integral part of physiological and medical research. In silico methods have the potential to accelerate future progress also in the fields of integrated multi-physics modelling, multi-scale models, virtual cohort studies, and machine learning beyond what is feasible today. In fact, mechanistic and data-driven modelling can complement each other synergistically and fuel tomorrow's artificial intelligence applications to further our understanding of physiology and disease mechanisms, to generate new hypotheses and assess their plausibility, and thus to contribute to the evolution of preventive, diagnostic, and therapeutic approaches.

Abstract:

Cardiac fibrosis is a key factor in electrical conduction disturbances, yet its specific impact on conduction remains unclear, hindering predictive insight of cardiac electrophysiology and arrhythmogenesis. Among the different cardiac disorders, arrhythmogenic cardiomyopathy (ACM) is known to be associated with massive fibrotic remodelling of the myocardium, and it accounts for most cases of stress-related arrhythmic sudden death. To explore ACM further, we employed a Desmoglein-2-mutant mouse model and developed a correlative imaging approach to integrate macro-scale cardiac electrophysiology with 3D micro-scale reconstructions of the ventricles, to characterise the dynamics of conduction wavefronts and relate them to the underlying structural substrate. Our findings confirm that this ACM model shows localised replacement of cardiomyocytes with collagen and non-myocytes, contributing to electrical dysfunction. Moreover, we observed that conduction through fibrotic tissue areas shows a frequency-dependent behaviour, where conduction fails at high stimulation frequencies, promoting re-entrant arrhythmias, even in regions that were electrophysiologically inconspicuous at lower stimulation rates. Using a computational model, informed by high- resolution structural data, we found that frequency-dependent conduction through fibrotic tissue cannot be explained solely by collagen deposition or cardiomyocyte re-organisation. Indeed, fibrotic areas feature electrophysiological remodelling which acts as a low-pass filter for conduction, which can be quantitatively explained by electrotonic coupling of cardiomyocytes with non-myocytes. Collectively, our study provides a novel structure-function mapping pipeline and describes a previously unrecognised pro-arrhythmogenic mechanism in ACM, underscoring the need for dynamic assessment of functional conduction block in fibrotic myocardium using multiple diagnostic pacing protocols.

Abstract:

Background: Computer models for simulating cardiac electrophysiology are valuable tools for research and clinical applications. Traditional reaction-diffusion (RD) models used for these purposes are computationally expensive. While eikonal models offer a faster alternative, they are not well-suited to study cardiac arrhythmias driven by reentrant activity. The present work extends the diffusion-reaction eikonal alternant model (DREAM), incorporating conduction velocity (CV) restitution for simulating complex cardiac arrhythmias. Methods: The DREAM modifies the fast iterative method to model cyclical behavior, dynamic boundary conditions, and frequency-dependent anisotropic CV. Additionally, the model alternates with an approximated RD model, using a detailed ionic model for the reaction term and a triple-Gaussian to approximate the diffusion term. The DREAM and monodomain models were compared, simulating reentries in 2D manifolds with different resolutions. Results: The DREAM produced similar results across all resolutions, while experiments with the monodomain model failed at lower resolutions. CV restitution curves obtained using the DREAM closely approximated those produced by the monodomain simulations. Reentry in 2D slabs yielded similar results in vulnerable window and mean reentry duration for low CV in both models. In the left atrium, most inducing points identified by the DREAM were also present in the high-resolution monodomain model. DREAM's reentry simulations on meshes with an average edge length of 1600$\mu$m were 40x faster than monodomain simulations at 200$\mu$m. Conclusion: This work establishes the mathematical foundation for using the accelerated DREAM simulation method for cardiac electrophysiology. Cardiac research applications are enabled by a publicly available implementation in the openCARP simulator.

Abstract:

BACKGROUND: Longitudinal Displacement (LD) is the relative motion of the intima-media upon adventitia of the arterial wall during the cardiac cycle, probably linked to atherosclerosis. It has a direction, physiologically first backward in its main components with respect to the arterial flow. Here, LD was investigated in various disease and in presence of a unilateral carotid stent. METHODS: Carotid acquisitions were performed by ultrasound imaging on both body sides of 75 participants (150 Arteries). LD was measured in its percent quantity and direction. RESULTS: Obesity (p = 0.001) and carotid plaques (p = 0.01) were independently associated to quantity decrease of LD in the whole population. In a subgroup analysis, it was respectively 143% in healthy (n = 48 carotids), 129% (n = 34) in presence of cardiovascular risk factors, 121% (n = 20) in MACE patients, 119% (n = 24) in the carotid contralateral to a stent, 110% (n = 24) in carotids with stents. Regarding the direction of LD, in a subgroup analysis an inverted movement was identified in aged (p = 0.001) and diseased (p = 0.001) participants who also showed less quantity of LD (p = 0.001), but independently with age only (p = 0.002) in the whole population. CONCLUSIONS: This observational study suggests that LD within carotid wall layers is lower additively with ageing, cardiovascular risk factors, cardiovascular diseases, and stent. Even if stent is surely beneficial, these data might shed some light on stent restenosis, emphasising the need for interventional studies.

Abstract:

Cardiac arrhythmias are a leading cause of morbidity and mortality, with atrial fibrillation (AF) being the most prevalent sustained arrhythmia, significantly impacting global public health. Despite its importance, AF treatment strategies remain insufficient due to an incom- plete understanding of the underlying mechanisms. Computational models are valuable tools for advancing research in cardiac electrophysiology and enhancing patient diagnostics and treatment. While reaction diffusion (RD) models are widely used, they are computationally intensive. In contrast, the eikonal model is computationally less demanding, making it attractive for large-scale simulations and clinical scenarios where faster computation times are critical. However, several limitations hinder its application in realistic settings. This work aims to explore how the eikonal model can be better understood and expanded to improve research, diagnosis, and treatment of atrial arrhythmias.To investigate the standard eikonal model, it was first compared to RD models by simulating single beats under sinus rhythm, both with and without fibrosis. Then, the standard eikonal model was modified to provide additional outputs, including conduction velocity (CV) magnitude and wavefront propagation direction under anisotropic conditions, alongside activation times. These outputs served as ground truth to evaluate the radial basis function method, which estimates CV based on activation times while ignoring anisotropy.The eikonal model was then extended by combining it with the RD model, forming the diffusion-reaction eikonal alternant model (DREAM). A new cyclical fast iterative method (cycFIM) was introduced to solve the anisotropic eikonal equation while enabling reactivations, a complex challenge for iterative methods.To address the eikonal model’s limitations, particularly its inability to account for source- sink mismatch, regression models were developed. Bidomain simulations examined the effects of wall thickness and tissue curvature on CV. Moreover, monodomain simulations investigated pacing frequency and source-sink mismatch effects on diffusion current (DC) amplitude. These findings were integrated into regression models for the eikonal model. To facilitate the regression, a new method was introduced to quantify source-sink mismatch based solely on activation times and node coordinates.Comparison with RD models showed that the eikonal model reasonably simulates sinus rhythm in non-fibrotic atrial geometry but significantly declines in performance with fibrosis due to its inability to capture source-sink mismatches. Additionally, when assessing the radial basis function it was found that neglecting anisotropic propagation when estimating CV can lead to significant errors up to 700 mm/s. DREAM simulations maintained low computational costs while effectively simulating action potentials, node reactivations, and reentries. Investigating CV restitution revealed that the steepness of restitution curves can modulate the dynamics of the vulnerable window and the average duration of reentry. Regression models based on RD simulations successfully predicted key factors in cardiac electrophysiology, such as CV and DC amplitude, using data available during eikonal simulations, including activation times and geometric factors like wall thickness and tissue curvature.This research highlights the eikonal model’s potential in advancing the understanding and clinical management of cardiac arrhythmias. As a computationally efficient alternative to more complex models, it provides valuable insights into arrhythmia mechanisms, diagnosis, and treatment, making it ideal for large-scale simulations and clinical settings with limited computing resources. The DREAM was applied to explore the role of personalized CV restitution curves in reentry dynamics. This study paves the way for broader applications of eikonal-based models in cardiac electrophysiology, ultimately improving patient outcomes. Additionally, the new cycFIM, embedded in the DREAM, could be used to simulate cyclical wave propagation in other fields beyond medical applications.

Abstract:

Sudden cardiac death (SCD) presents a significantly elevated risk to patients with chronickidney disease (CKD), a risk compounded by the electrolyte fluctuations induced duringhaemodialysis (HD). These fluctuations directly impact cardiac pacemaking, particularlythe sinoatrial node (SAN). Furthermore, the autonomic nervous system (ANS) exerts sig-nificant control over cardiac rhythm, making ANS modulation an important component ofaccurate sinoatrial node cell (SANC) modeling. Finally, the continuous advancements inelectrophysiology necessitate a flexible and adaptable approach to update and refine existingSANC models, ensuring incorporation of new experimental data and current formulations.This thesis addressed these challenges by pursuing two interconnected objectives. Therefore,an enhanced human SANC model based on experimental data collected by Verkerk et al.,incorporating dynamic concentrations of intracellular potassium concentration ([K+]i) andintracellular sodium concentration ([Na+]i) as well as the effects of ANS modulation wasdeveloped. Moreover, a robust and adaptable optimization pipeline, aiming at the parametersof the underlying current equations, was implemented.Thus, the resulting model was based on a combination of components of the Fabbri et al. andLoewe et al. model, both of which already aligned well with the experimental data, while theformer lacked dynamic formulations of [Na+]i and [K+]i and the latter showed an impairmentin terms of ANS stimulation. The Nelder Mead method was leveraged to optimize 16 selectedparameters based on a cost function consisting of the action potential (AP) and calciumtransient markers (CaT) markers obtained from parallel openCARP simulations comparedagainst experimental data.The achieved AP markers of the adapted model using an optimized parameter set yieldedgood accordance with the experimental data and improved on the original Fabbri and Loewemodels with regard to the overshoot (OS). The optimized model incorporated dynamic[Na+]i and [K+]i and correct effects of isoprenaline (ISO) and acetylcholine (ACh) for ANSmodulation. During the model development process, an adaptable and flexible optimizationpipeline was successfully established, and provides a great tool for further research in thistopic.