In recent years, blending mechanistic knowledge with machine learning has had a major impact in digital healthcare. In this work, we introduce a computational pipeline to build certified digital replicas of cardiac electrophysiology in paediatric patients with congenital heart disease. We construct the patient-specific geometry by means of semi-automatic segmentation and meshing tools. We generate a dataset of electrophysiology simulations covering cell-to-organ level model parameters and using rigorous mathematical models based on differential equations. We previously proposed Branched Latent Neural Maps (BLNMs) as an accurate and efficient means to recapitulate complex physical processes in a neural network. Here, we employ BLNMs to encode the parametrized temporal dynamics of in silico 12-lead electrocardiograms (ECGs). BLNMs act as a geometry-specific surrogate model of cardiac function for fast and robust parameter estimation to match clinical ECGs in paediatric patients. Identifiability and trustworthiness of calibrated model parameters are assessed by sensitivity analysis and uncertainty quantification.

For more than half a century, scientists have developed mathematical models to understand the behavior of the human heart. Today, we have dozens of heart tissue models to choose from, but selecting the best model is limited to expert professionals, prone to user bias, and vulnerable to human error. Here we take the human out of the loop and automate the process of model discovery. Towards this goal, we establish a novel incompressible orthotropic constitutive neural network to simultaneously discover both, model and parameters, that best explain human cardiac tissue. Notably, our network features 32 individual terms, 8 isotropic and 24 anisotropic, and fully autonomously selects the best model, out of more than 4 billion possible combinations of terms. We demonstrate that we can successfully train the network with triaxial shear and biaxial extension tests and systematically sparsify the parameter vector with L₁-regularization. Strikingly, we robustly discover a four-term model that features a quadratic term in the second invariant I₂, and exponential quadratic terms in the fourth and eighth invariants I_4f, I_4n, and I_8fs. Importantly, our discovered model is interpretable by design and has parameters with well-defined physical units. We show that it outperforms popular existing myocardium models and generalizes well, from homogeneous laboratory tests to heterogeneous whole heart simulations. This is made possible by a new universal material subroutine that directly takes the discovered network weights as input. Automating the process of model discovery has the potential to democratize cardiac modeling, broaden participation in scientific discovery, and accelerate the development of innovative treatments for cardiovascular disease. Our source code, data, and examples are available at https://github.com/LivingMatterLab/CANN.

Personalized treatment informed by computational models has the potential to markedly improve the outcome for patients with a type B aortic dissection. However, existing computational models of dissected walls significantly simplify the characteristic false lumen, tears and/or material behavior. Moreover, the patient-specific wall thickness and stiffness cannot be accurately captured non-invasively in clinical practice, which inevitably leads to assumptions in these wall models. It is important to evaluate the impact of the corresponding uncertainty on the predicted wall deformations and stress, which are both key outcome indicators for treatment optimization. Therefore, a physiology-inspired finite element framework was proposed to model the wall deformation and stress of a type B aortic dissection at diastolic and systolic pressure. Based on this framework, 300 finite element analyses, sampled with a Latin hypercube, were performed to assess the global uncertainty, introduced by 4 uncertain wall thickness and stiffness input parameters, on 4 displacement and stress output parameters. The specific impact of each input parameter was estimated using Gaussian process regression, as surrogate model of the finite element framework, and a δ moment-independent analysis. The global uncertainty analysis indicated minor differences between the uncertainty at diastolic and systolic pressure. For all output parameters, the 4^th quartile contained the major fraction of the uncertainty. The parameter-specific uncertainty analysis elucidated that the material stiffness and relative thickness of the dissected membrane were the respective main determinants of the wall deformation and stress. The uncertainty analysis provides insight into the effect of uncertain wall thickness and stiffness parameters on the predicted deformation and stress. Moreover, it emphasizes the need for probabilistic rather than deterministic predictions for clinical decision making in aortic dissections.

The lack of sex-specific cardiovascular disease criteria contributes to the underdiagnosis of women compared to that of men. For more than half a century, the Framingham Risk Score has been the gold standard to estimate an individual’s risk of developing cardiovascular disease based on the age, sex, cholesterol levels, blood pressure, diabetes status, and the smoking status. Now, machine learning can offer a much more nuanced insight into predicting the risk of cardiovascular diseases. The UK Biobank is a large database that includes traditional risk factors and tests related to the cardiovascular system: magnetic resonance imaging, pulse wave analysis, electrocardiograms, and carotid ultrasounds. Here, we leverage 20,542 datasets from the UK Biobank to build more accurate cardiovascular risk models than the Framingham Risk Score and quantify the underdiagnosis of women compared to that of men. Strikingly, for a first-degree atrioventricular block and dilated cardiomyopathy, two conditions with non-sex-specific diagnostic criteria, our study shows that women are under-diagnosed 2× and 1.4× more than men. Similarly, our results demonstrate the need for sex-specific criteria in essential primary hypertension and hypertrophic cardiomyopathy. Our feature importance analysis reveals that out of the top 10 features across three sexes and four disease categories, traditional Framingham factors made up between 40% and 50%; electrocardiogram, 30%–33%; pulse wave analysis, 13%–23%; and magnetic resonance imaging and carotid ultrasound, 0%–10%. Improving the Framingham Risk Score by leveraging big data and machine learning allows us to incorporate a wider range of biomedical data and prediction features, enhance personalization and accuracy, and continuously integrate new data and knowledge, with the ultimate goal to improve accurate prediction, early detection, and early intervention in cardiovascular disease management. Our analysis pipeline and trained classifiers are freely available at https://github.com/LivingMatterLab/CardiovascularDiseaseClassification.

Personalized computational simulations have emerged as a vital tool to understand the biomechanical factors of a disease, predict disease progression, and design personalized intervention. Material modeling is critical for realistic biomedical simulations, and poor model selection can have life-threatening consequences for the patient. However, selecting the best model requires a profound domain knowledge and is limited to a few highly specialized experts in the field. Here we explore the feasibility of eliminating user involvement and automate the process of material modeling in finite element analyses. We leverage recent developments in constitutive neural networks, machine learning, and artificial intelligence to discover the best constitutive model from thousands of possible combinations of a few functional building blocks. We integrate all discoverable models into the finite element workflow by creating a universal material subroutine that contains more than 60,000 models, made up of 16 individual terms. We prototype this workflow using biaxial extension tests from healthy human arteries as input and stress and stretch profiles across the human aortic arch as output. Our results suggest that constitutive neural networks can robustly discover various flavors of arterial models from data, feed these models directly into a finite element simulation, and predict stress and strain profiles that compare favorably to the classical Holzapfel model. Replacing dozens of individual material subroutines by a single universal material subroutine—populated directly via automated model discovery—will make finite element simulations more user-friendly, more robust, and less vulnerable to human error. Democratizing finite element simulation by automating model selection could induce a paradigm shift in physics-based modeling, broaden access to simulation technologies, and empower individuals with varying levels of expertise and diverse backgrounds to actively participate in scientific discovery and push the boundaries of biomedical simulation.

Background: Maintaining balanced left and right cardiac outputs in a total artificial heart (TAH) is challenging due to the need for continuous adaptation to changing hemodynamic conditions. Proper balance in ventricular outputs of the left and right ventricles requires a preload-sensitive response and mechanisms to address the higher volumetric efficiency of the right ventricle. Methods: This review provides a comprehensive overview of various methods used to balance left and right ventricular outputs in pulsatile total artificial hearts, categorized based on their actuation mechanism. Results: Reported strategies include incorporating compliant materials and/or air cushions inside the ventricles, employing active control mechanisms to regulate ventricular filling state, and utilizing various shunts (such as hydraulic or intra-atrial shunts). Furthermore, reducing right ventricular stroke volume compared to the left often serves to balance the ventricular outputs. Individually controlled actuation of both ventricles in a pulsatile TAH seems to be the simplest and most effective way to achieve proper preload sensitivity and left–right output balance. Pneumatically actuated TAHs have the advantage to respond passively to preload changes. Conclusion: Therefore, a pneumatic TAH that comprises two individually actuated ventricles appears to be a more desirable option—both in terms of simplicity and efficacy—to respond to changing hemodynamic conditions.

Single ventricle patients, including those with hypoplastic left heart syndrome (HLHS), typically undergo three palliative heart surgeries culminating in the Fontan procedure. HLHS is associated with high rates of morbidity and mortality, and many patients develop arrhythmias, electrical dyssynchrony, and eventually ventricular failure. However, the correlation between ventricular enlargement and electrical dysfunction in HLHS physiology remains poorly understood. Here we characterize the relationship between growth and electrophysiology in HLHS using computational modeling. We integrate a personalized finite element model, a volumetric growth model, and a personalized electrophysiology model to perform controlled in silico experiments. We show that right ventricle enlargement negatively affects QRS duration and interventricular dyssynchrony. Conversely, left ventricle enlargement can partially compensate for this dyssynchrony. These findings have potential implications on our understanding of the origins of electrical dyssynchrony and, ultimately, the treatment of HLHS patients.

Impaired cardiac filling in response to increased passive myocardial stiffness contributes to the pathophysiology of heart failure. By leveraging cardiac MRI data and ventricular pressure measurements, we can estimate in vivo passive myocardial stiffness using personalized inverse finite element models. While it is well-known that this approach is subject to uncertainties, only few studies quantify the accuracy of these stiffness estimates. This lack of validation is, at least in part, due to the absence of ground truth in vivo passive myocardial stiffness values. Here, using 3D printing, we created soft, homogenous, isotropic, hyperelastic heart phantoms of varying geometry and stiffness and simulate diastolic filling by incorporating the phantoms into an MRI-compatible left ventricular inflation system. We estimate phantom stiffness from MRI and pressure data using inverse finite element analyses based on a Neo-Hookean model. We demonstrate that our identified softest and stiffest values of 215.7 and 512.3 kPa agree well with the ground truth of 226.2 and 526.4 kPa. Overall, our estimated stiffnesses revealed a good agreement with the ground truth (< 5.8 % error) across all models. Our results suggest that MRI-driven computational constitutive modeling can accurately estimate synthetic heart material stiffnesses in the range of 200–500 kPa.

Computational heart modeling is a promising approach for improving the prognosis of patients born with congenital heart defects. To create accurate physics-based digital cardiac twins of this population, it is crucial to accurately represent the highly diverse and unique subject-specific heart geometry. In young pediatric patients, this is a challenging endeavor given the lack of high-spatial-resolution imaging data and the risk of slice misalignment. In this study, we set up a multistep shape morphing and slice correction approach to accommodate these challenges and establish a population of biventricular heart models for a variety of healthy, Fallot, and Fontan pediatric patients.

Many drugs interact with ion channels in the cells of our heart and trigger heart rhythm disorders with potentially fatal consequences. Computational modeling can provide mechanistic insight into the onset and propagation of drug-induced arrhythmias, but the effect of drugs on the mechanical performance of the heart remains poorly understood. Here we establish a multiphysics framework that integrates the biochemical, electrical, and mechanical effects of drugs, from cellular excitation to cardiac contraction. For the example of the drug dofetilide, we show that drug concentrations of 5x and 8x increase the heart rate to 122 and 114 beats per minute, increase myofiber stretches by 5%, and decrease overall tissue relaxation by 6%. This results in inter-ventricular and atrial-ventricular dyssynchronies and changes in cardiac output by - 2.5 % and +7%. Our results emphasize the need for multiphysics modeling to better understand the mechanical implications of drug-induced arrhythmias. Knowing how different drug concentrations affect the performance of the heart has important clinical implications in drug safety evaluation and personalized medicine.

Cardiovascular disease in women remains under-diagnosed and under-treated. Recent studies suggest that this is caused, at least in part, by the lack of sex-specific diagnostic criteria. While it is widely recognized that the female heart is smaller than the male heart, it has long been ignored that it also has a different microstructural architecture. This has severe implications on a multitude of cardiac parameters. Here, we systematically review and compare geometric, functional, and structural parameters of female and male hearts, both in the healthy population and in athletes. Our study finds that, compared to the male heart, the female heart has a larger ejection fraction and beats at a faster rate but generates a smaller cardiac output. It has a lower blood pressure but produces universally larger contractile strains. Critically, allometric scaling, e.g., by lean body mass, reduces but does not completely eliminate the sex differences between female and male hearts. Our results suggest that the sex differences in cardiac form and function are too complex to be ignored: the female heart is not just a small version of the male heart. When using similar diagnostic criteria for female and male hearts, cardiac disease in women is frequently overlooked by routine exams, and it is diagnosed later and with more severe symptoms than in men. Clearly, there is an urgent need to better understand the female heart and design sex-specific diagnostic criteria that will allow us to diagnose cardiac disease in women equally as early, robustly, and reliably as in men. Systematic Review Registration: https://livingmatter.stanford.edu/.

Precision medicine is a new frontier in healthcare that uses scientific methods to customize medical treatment to the individual genes, anatomy, physiology, and lifestyle of each person. In cardiovascular health, precision medicine has emerged as a promising paradigm to enable cost-effective solutions that improve quality of life and reduce mortality rates. However, the exact role in precision medicine for human heart modeling has not yet been fully explored. Here, we discuss the challenges and opportunities for personalized human heart simulations, from diagnosis to device design, treatment planning, and prognosis. With a view toward personalization, we map out the history of anatomic, physical, and constitutive human heart models throughout the past three decades. We illustrate recent human heart modeling in electrophysiology, cardiac mechanics, and fluid dynamics and highlight clinically relevant applications of these models for drug development, pacing lead failure, heart failure, ventricular assist devices, edge-to-edge repair, and annuloplasty. With a view toward translational medicine, we provide a clinical perspective on virtual imaging trials and a regulatory perspective on medical device innovation. We show that precision medicine in human heart modeling does not necessarily require a fully personalized, high-resolution whole heart model with an entire personalized medical history. Instead, we advocate for creating personalized models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between clinical data and medical histories from cohorts of patients using machine learning. We anticipate that this perspective will shape the path toward introducing human heart simulations into precision medicine with the ultimate goals to facilitate clinical decision making, guide treatment planning, and accelerate device design.