Key result
The End Systolic Pressure Volume Relationship (ESPVR) was approximately 50% more sensitive to molecular-level parameter changes than any other system-level property in a multiscale cardiovascular model.
Why the study?
Heart failure drug development remains challenging partly because predicting how drug-induced molecular perturbations scale up to system-level properties is difficult, which computer modeling may help address.
This multiscale computational model demonstrates that the End Systolic Pressure Volume Relationship is highly sensitive to multiple molecular-level parameters, suggesting it can be targeted via diverse therapeutic strategies for heart failure.
May identify ESPVR as versatile HF target; leaves open translation from this animal computational model.
Most patients who develop heart failure are unable to elevate their cardiac output on demand due to impaired contractility and/or reduced ventricular filling. Despite decades of research, few effective therapies for heart failure have been developed. In part, this may reflect the difficulty of predicting how perturbations to molecular-level mechanisms that are induced by drugs will scale up to modulate system-level properties such as blood pressure. Computer modeling might help with this process and thereby accelerate the development of better therapies for heart failure. This manuscript presents a new multiscale model that uses a single contractile element to drive an idealized ventricle that pumps blood around a closed circulation. The contractile element was formed by linking an existing model of dynamically coupled myofilaments with a well-established model of myocyte electrophysiology. The resulting framework spans from molecular-level events (including opening of ion channels and transitions between different myosin states) to properties such as ejection fraction that can be measured in patients. Initial calculations showed that the model reproduces many aspects of normal cardiovascular physiology including, for example, pressure-volume loops. Subsequent sensitivity tests then quantified how each model parameter influenced a range of system level properties. The first key finding was that the End Systolic Pressure Volume Relationship, a classic index of cardiac contractility, was ~50% more sensitive to parameter changes than any other system-level property. The second important result was that parameters that primarily affect ventricular filling, such as passive stiffness and Ca2+ reuptake via sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), also have a major impact on systolic properties including stroke work, myosin ATPase, and maximum ventricular pressure. These results reinforce the molecular-level basis for the Frank-Starling mechanism, and identify the End Systolic Pressure Volume Relationship as a particularly sensitive system-level property that can be targeted using multiple therapeutic strategies.
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Campbell et al. (2020) studied Cardiovascular function. Parameter changes in multiscale cardiovascular model vs. Base parameter values was evaluated on Sensitivity of system-level properties to parameter changes. The End Systolic Pressure Volume Relationship (ESPVR) was approximately 50% more sensitive to molecular-level parameter changes than any other system-level property in a multiscale cardiovascular model.
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