Multiscale Modeling of Cardiovascular Function Predicts That the End-Systolic Pressure Volume Relationship Can Be Targeted via Multiple Therapeutic Strategies

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 molecularlevel 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, pressurevolume 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 Ca 2+ reuptake via sarco/endoplasmic reticulum Ca 2+-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.

Effects of mavacamten on Ca2+ sensitivity of contraction as sarcomere length varied in human myocardium

“…We also note that our data only quantify isometric force‐length relationships and the rates of cross‐bridge recruitment and detachment. Cardiac function ultimately depends on the power generated by myocytes during loaded shortening and future studies investigating the effect of mavacamten on the force‐velocity relationship and/or pressure‐volume loops in the whole heart would be useful (Campbell et al, 2020).…”

A multiscale model of the cardiovascular system that regulates arterial pressure via closed loop baroreflex control of chronotropism, cell-level contractility, and vascular tone

“…Campbell et al's initial publication (7) investigated how system-level behavior (metrics such as cardiac output and systolic arterial pressure) varied as module-level parameters (including ion channel permeabilities and myosin rate constants) were varied. Heart rate was kept constant throughout these simulations.…”

“…The limits for these parameters were set so that increased arterial pressure reduced the amplitude and prolonged the duration of Ca 2+ transients. M 4 and M 5 modulated the k 1 and k on parameters in the MyoSim framework (7,9). The k 1 parameter defines how quickly myosin heads transition from the super-relaxed (SRX) to the disordered relaxed (DRX) state (11) while k on is the second-order rate constant for Ca 2+ -activation of binding sites on actin.…”

“…The default parameter values used to initialize all the simulations and the M para,i and M sump,i limits for each mapping function are shown in File S1. (7) and is included here for completeness. The current work focuses on the baroreflex with most of the figures showing simulations that include at least 100 heart beats.…”

“…Instead of elevating cardiac output (which is intrinsically linked to arterial pressure), the system-level responses to the myotrope might include a slower heart-rate (and thus a potential decrease in myocardial energy use) and reduced vascular tone. This manuscript adds baroreflex control to the multiscale model previously described by Campbell et al (7). The control algorithm is inspired by the underlying biology and is based on a kinetic model that is driven by an afferent signal derived from arterial pressure.…”