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Multiscale Modeling of Cardiovascular Function Predicts That the End-Systolic Pressure Volume Relationship Can Be Targeted via Multiple Therapeutic Strategies
- Source :
- Frontiers in Physiology, Frontiers in Physiology, Vol 11 (2020)
- Publication Year :
- 2020
- Publisher :
- Frontiers Media SA, 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 1664042X
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Physiology
- Accession number :
- edsair.doi.dedup.....6bca930c7ee81396425cf1a67c4159a3