Filip Ježek

Moderate to extreme preterm birth (< 32 weeks gestation) affects cardiopulmonary structure and function and is associated with increased risk of heart failure through adulthood. The rat hyperoxia (Hx) model (term born; postnatal Hx exposure) captures biventricular changes, including at the cell and organ scale, and pulmonary vascular remodeling seen in preterm humans. However, synthesizing these measures across scales and organ systems is challenging. We hypothesized that in silico modeling of biventricular mitochondrial, myofiber, and organ-scale function plus circulatory function could capture key features of cardiopulmonary abnormalities due to preterm birth. Therefore, we calibrated a multiscale model to subject-specific biventricular pressure–volume data previously obtained from Hx rats alongside normoxic (Nx) controls to investigate the abnormalities in cardiopulmonary function at multiple scales in this animal model of human preterm birth. The calibrated model demonstrates excellent agreement with the data and captures the expected pulmonary vascular changes and right ventricular dilation seen in preterm-born children. Our multiscale modeling approach captures cardiopulmonary abnormalities across spatial scales and provides an innovative approach to explore the consequences of preterm birth beyond preclinical experimental data alone. This is a foundational step in understanding the impact of preterm birth on cardiopulmonary disease in childhood as well as adulthood.

Moderate to extreme preterm birth (<32 weeks gestation) affects cardiopulmonary structure and function and is associated with increased risk of heart failure through adulthood. The rat hyperoxia (Hx) model (term born; postnatal Hx exposure) captures biventricular changes, including at the cell- and organ-scale, and pulmonary vascular remodeling seen in preterm humans. However, synthesizing these measures across scales and organ systems is challenging. We hypothesized that in-silico modeling of biventricular mitochondrial, myofiber, and organ-scale function plus circulatory function could capture key features of cardiopulmonary abnormalities due to preterm birth. Therefore, we calibrated a multiscale model to subject-specific biventricular pressure-volume data previously obtained from Hx rats alongside normoxic (Nx) controls to investigate the abnormalities in cardiopulmonary function at multiple scales in this animal model of human preterm birth. The calibrated model demonstrates excellent agreement with the data and captures the expected pulmonary vascular changes and right ventricular dilation seen in preterm born children. Our multiscale modeling approach captures cardiopulmonary abnormalities across spatial scales and provides an innovative approach to explore the consequences of preterm birth beyond preclinical experimental data alone. This is a foundational step in understanding the impact of preterm birth on cardiopulmonary disease in childhood as well as adulthood.

This study investigates the passive viscoelastic properties of cardiac muscle by introducing a theoretical model that explains the observed power‐law kinetics of murine cardiac trabeculae passive stress decay. The model accounts for two parallel processes contributing to passive mechanics: an elastic component and a viscoelastic component designed to simulate stress/strain‐mediated unfolding of serial domains in the titin molecule. Under stress, serial globular domains within the elastic region of the titin molecule reversibly unfold. This unfolding phenomenon contributes to both hysteresis (a lag in stress between loading and unloading) and preconditioning effects in simulated mechanics. Experimental evidence indicates that stress relaxation in cardiac muscle follows a power law and that the muscle's non‐linear stress–strain relationship and hysteresis behaviour are calcium‐dependent. To analyse these phenomena, we simulate the apparent viscous element as a mesoscopic‐scale ensemble of chains, each composed of serial globular domains that unfold in a stress‐dependent manner. The observed increase in passive tension with increased Ca²⁺ concentration is attributed to Ca²⁺‐mediated: (1) PEVK attachment to actin; (2) stiffening of the proximal element; and (3) stabilization of folded conformations of serial domains in the titin chain. Although the model was developed to represent the behaviour of titin, it equivalently represents any contributing process involving a linked series of domains that undergo stress‐mediated unfolding. By providing a unified basis for the observed viscoelastic and preconditioning effects, calcium dependency, and power‐law stress relaxation phenomena, this study offers a novel theoretical basis for understanding and simulating the role of titin in striated muscle mechanics. image Key points: Passive stress relaxation of cardiac muscle follows a power‐law decay, a phenomenon that is explained using a theoretical model of dynamic unfolding of globular domains along polymer chain. The theoretical model simulates the behaviour of titin, a giant sarcomere protein linking myosin thick filaments to the Z disk and providing passive restoring force during muscle stretch. The theoretical model is able to account the observed effects of Ca²⁺ on the effective viscoelastic passive mechanics of cardiac muscle. This model provides a theoretical basis for understanding passive viscocelastic properties and titin's role in striated muscle mechanics.

This study investigates the passive viscoelastic mechanical properties of cardiac muscle by introducing a theoretical model that explains the power-law kinetics of passive stress decay. The model accounts for two parallel processes contributing to passive mechanics: an elastic component and a viscoelastic component designed to simulate stress/strain-mediated unfolding of serial domains in the titin molecule. Under stress, serial globular domains within the elastic region of the titin molecule reversibly unfold. This unfolding phenomenon contributes to both hysteresis (a lag in stress between loading and unloading) and preconditioning effects in simulated striated muscle mechanics. Moreover, experimental evidence indicates that stress relaxation in cardiac muscle follows a power law, and that the muscle’s nonlinear stress-strain relationship and hysteresis behavior are calcium-dependent. To analyze these mechanical phenomena, we simulate the apparent viscous element as a mesoscopic-scale ensemble of chains, each composed of serial globular domains that unfold in a stress-dependent manner. Although the model was developed to represent the behavior of titin, it equivalently represents any contributing process involving a linked series of domains that undergo stress-mediated unfolding. By providing a unified basis for the observed viscoelastic and preconditioning effects, calcium dependency, and power-law stress relaxation phenomena, this study offers a novel theoretical basis for understanding and simulating the role of titin in striated muscle mechanics. 1 Key points: Passive stress relaxation of cardiac muscle follows a power-law decay, a phenomenon that is explained using a theoretical model of dynamic unfolding of globular domains along polymer chain. The theoretical model simulates the behavior of titin, a giant sarcomere protein linking myosin thick filaments to the Z disk and providing passive restoring force during muscle stretch. The theoretical model is able to account the observed effects of calcium on the effective viscoelastic passive mechanics of cardiac muscle. This model provides a theoretical basis for understanding passive visocelastic properties and titin’s role in striated muscle mechanics.

In addition to activation of muscle contraction by Ca ²⁺ , recent studies suggest that Ca ²⁺ also affects muscle passive mechanical properties. The goal of this study was to determine if Ca ²⁺ regulates the stiffness of cardiac muscle, independent of active contraction. The mechanical response to stretch for mouse demembranated cardiac trabeculae was probed at different Ca ²⁺ levels after eliminating active contraction using a combination of two myosin ATPase inhibitors: para -nitroblebbistatin (PNB, 50 μM), plus mavacampten (Mava, 50 μM). Myocardial force level was assessed during large stretches (≍ 20% initial muscle length) with a range of stretch velocities. For relaxed muscle, in response to stretch, muscle force rose to a peak and then decayed toward a lower steady-state level, consistent with the viscoelastic nature of cardiac muscle. Peak force was higher with faster stretch velocity, but the steady-state force was independent of stretch velocity, consistent with the presence of both apparent viscous and elastic components of the stretch response. In the presence of the inhibitors PNB plus Mava, when Ca ²⁺ level was increased, active contraction was completely prevented. However, the viscoelastic force response to stretch was markedly increased by high Ca ²⁺ and was > 6-fold higher than at low Ca ²⁺ level. The relationship of viscous force to Ca ²⁺ level had a similar form to the relationship of active force to Ca ²⁺ (measured in the absence of inhibitors), suggesting a common regulatory mechanism is involved. As expected, Ca ²⁺ -activated contraction was inhibited by lowering the temperature from 21°C to 10°C. In contrast, the Ca ²⁺ -activated viscous property was not inhibited at lower temperature, further suggesting that active contraction and the viscous property involve distinct mechanisms. This study demonstrates that in addition to triggering activation of contraction, Ca ²⁺ also increases the apparent viscous property of cardiac muscle. New and Noteworthy: Ca ²⁺ is well-known to trigger activation of muscle contraction. This study demonstrates a new mechanical role for Ca ²⁺ in cardiac muscle involving a >6-fold increase in the apparent muscle viscoelasticity. Activation of a viscous element by Ca ²⁺ might influence the mechanical properties of activated cardiac muscle.

Summary: Background: Heart failure (HF) is a highly heterogeneous and complex condition. Although patient care generates vast amounts of clinical data, robust methods to synthesize available data for individualized management are lacking. Methods: A mechanistic computational model of cardiac and cardiovascular system mechanics was identified for each individual in a cohort of 343 patients with HF. The identified digital twins — comprising optimized sets of parameters and corresponding simulations of cardiovascular system function—for patients with HF in the cohort is used to inform both supervised and unsupervised approaches in identifying phenogroups and novel mechanistic drivers of cardiovascular death risk. Findings: The integration of digital twins into AI-based analyses of patient data enhances the performance and interpretability of prognostics AI models. Prognostics AI models trained with digital twin features are more generalizable than models trained with only clinical variables, as evaluated using an independent prospective cohort. In addition, the digital twin-based approach to phenomapping and predictive AI helps address inconsistencies and inaccuracies in clinical measurements, enables imputation of missing data, and estimates functional parameters that are otherwise unmeasurable directly. This approach provides a more comprehensive and accurate representation of the patient’s disease state than raw clinical data alone. Interpretation: The developed and validated digital twin-based AI framework has the potential to simulate patient-specific pathophysiologic parameters, thereby informing prognosis and guiding therapeutic options.Ultimately, this approach has the potential to enhance the ability to focus on the most critical aspects of a patient’s condition, leading to individualized care and management. Funding: National Institutes of Health and Joint Institute for Translational and Clinical Research (University of Michigan and Peking University Health Science Center)

Background & Aims: Paracentesis is commonly used to manage patient discomfort due to ascites. The relationship between ascites pressure, ascites volume, and patient discomfort has not been elucidated.Methods: We prospectively enrolled adult patients with non‐malignant ascites undergoing outpatient therapeutic paracenteses from 2021 to 2024 at a tertiary care hospital. Patients completed a validated symptom questionnaire (ASI‐7, maximum score 35) before, immediately after, and 1 week after paracentesis. An open‐ended manometer was used to measure ascites pressure at the beginning and end of paracentesis. Mixed effect linear regression was performed to evaluate the relationships between patient characteristics, pressure, volume, and symptoms.Results: One hundred and fifty paracentesis procedures among 48 unique patients with an average Model for End Stage Liver Disease‐Sodium 3.0 of 16.7 were included. An average of 6.5 L was drained, which reduced abdominal pressure from a mean of 13.7 to 6.0 cm H₂O (10.1 to 4.4 mmHg, p < 0.001) and mean symptom score from 22.6 to 6.5 (p < 0.001). Regression models identified that symptoms and abdominal pressure linearly correlated above a pressure of 6 cm H₂O or ASI‐7 score of 16 (p < 0.01). Taller patients required about 670 ml additional drainage per inch above the cohort mean height (5′8″) to achieve the same symptom relief.Conclusions: Pressure measured at the bedside can be used to explore changes in abdominal pressure during paracentesis. Pressure, volume, and patient level factors such as height contribute to patient symptoms but cannot fully explain discomfort associated with ascites and relief after paracentesis.

Background & Aims: As liver disease progresses, scarring results in worsening hemodynamics ultimately culminate in portal hypertension. This process has classically been quantified via the Hepatic Venous Pressure Gradient (HVPG), however HVPG alone does not predict a given patient’s clinical presentation with regards to Baveno stage of cirrhosis. In this study we propose that a patient’s ‘HVPG-sensitivity’ to venous remodelingcould explain disparate disease trajectories.