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:

Aims Chronic left atrial enlargement (LAE) increases the risk of atrial fibrillation. Electrocardiogram (ECG) criteria might provide a means to diagnose LAE and identify patients at risk; however, current criteria perform poorly. We seek to characterize the potentially differential effects of atrial dilation vs. hypertrophy on the ECG P-wave. Methods and results We predict effects on the P-wave of (i) left atrial dilation (LAD), i.e. an increase of LA cavity volume without an increase in myocardial volume, (ii) left atrial concentric hypertrophy (LACH), i.e. a thickened myocardial wall, and (iii) a combination of the two. We performed a computational study in a cohort of 72 anatomical variants, derived from four human atrial anatomies. To model LAD, pressure was applied to the LA endocardium increasing cavity volume by up to 100%. For LACH, the LA wall was thickened by up to 3.3 mm. P-waves were derived by simulating atrial excitation propagation and computing the body surface ECG. The sensitivity regarding changes beyond purely anatomical effects was analysed by altering conduction velocity by 25% in 96 additional model variants. Left atrial dilation prolonged P-wave duration (PWd) in two of four subjects; in one subject a shortening, and in the other a variable change were seen. Left atrial concentric hypertrophy, in contrast, consistently increased P-wave terminal force in lead V1 (PTF-V1) in all subjects through an enlarged amplitude while PWd was unaffected. Combined hypertrophy and dilation generally enhanced the effect of hypertrophy on PTF-V1. Conclusion Isolated LAD has moderate effects on the currently used P-wave criteria, explaining the limited utility of PWd and PTF-V1 in detecting LAE in clinical practice. In contrast, PTF-V1 may be a more sensitive indicator of LA myocardial hypertrophy.