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 I4f, I4n, and I8fs. 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.@en

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.@en

Constitutive modeling is the cornerstone of computational and structural mechanics. In a finite element analysis, the constitutive model is encoded in the material subroutine, a function that maps local strains onto stresses. This function is called within every finite element, at each integration point, within every time step, at each Newton iteration. Today's finite element packages offer large libraries of material models to choose from. However, the scientific criteria for appropriate model selection remain highly subjective and prone to user bias. Here we fully automate the process of model selection, autonomously discover the best model and parameters from experimental data, encode all possible discoverable models into a single material subroutine, and seamlessly integrate this universal material subroutine into a finite element analysis. We prototype this strategy for incompressible, isotropic, hyperelastic soft matter systems that we characterize through a combination of twelve possible terms. These terms feature the first and second invariants, raised to the first and second powers, embedded in the identity, exponential, and logarithmic functions, generating 22×2×3= 4096 models in total. We demonstrate how to integrate these models into a single universal material subroutine that features the classical neo Hooke, Blatz Ko, Mooney Rivlin, Demiray, Gent, and Holzapfel models as special cases. Finite element simulations with our new universal material subroutine show that it specializes well to these widely used models, generalizes well to newly discovered models, and agrees excellently with both experimental data and previous simulations. It also performs well within realistic finite element simulations and accurately predicts stress concentrations in the human brain for six different head impact scenarios. We anticipate that integrating automated model discovery into a universal material subroutine will generalize naturally to more complex compressible, anisotropic, inelastic materials and to other nonlinear finite element platforms. Replacing dozens of individual material subroutines by a single universal material subroutine that is populated directly via automated model discovery – entirely without human interaction – makes finite element analyses more accessible, more robust, and less vulnerable to human error. This could forever change how we simulate materials and structures. Our source code, data, and examples are available at https://github.com/LivingMatterLab.@en

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.@en

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.@en

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.@en