Multiscale Modeling of Cardiovascular Function Predicts That the End-Systolic Pressure Volume Relationship Can Be Targeted via Multiple Therapeutic Strategies
| Autor: | Brianna Sierra Chrisman, Stuart G. Campbell, Kenneth S. Campbell |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cardiac output medicine.medical_specialty Physiology 030204 cardiovascular system & hematology lcsh:Physiology 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine medicine Frank-Starling computer modeling Original Research Frank–Starling law of the heart Ejection fraction lcsh:QP1-981 business.industry medicine.disease multiscale modeling Cardiovascular physiology 030104 developmental biology Blood pressure medicine.anatomical_structure Ventricle Heart failure Ventricular pressure Cardiology ventricular function cardiac function business |
| Zdroj: | Frontiers in Physiology Frontiers in Physiology, Vol 11 (2020) |
| ISSN: | 1664-042X |
| DOI: | 10.3389/fphys.2020.01043 |
| Popis: | 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 impact of diastolic function on ventricular performance and identify the End Systolic Pressure Volume Relationship as a particularly sensitive system-level property that can be targeted using multiple therapeutic strategies. |
| Databáze: | OpenAIRE |
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