Computational models of the cardiovascular system are powerful adjuncts to ground-based and in-flight experiments. They provide a rational framework that quantitatively defines interactions among complex cardiovascular parameters, supports the critical interpretation of experimental results and testing of hypotheses, and permits prediction of the impact of specific countermeasures.
Over the past three years we have implemented a computational model of the cardiovascular system capable of simulating the short term (zero-five minutes), transient response to orthostatic stress tests such as tilt/standing and lower body negative pressure (LBNP) in normals and microgravity adapted individuals. The model consists of a lumped parameter representation of the hemodynamic system and set-point representations of the cardiopulmonary and the arterial baroreflexes. The model allows for regional blood pooling in four systemic circulatory branches and three central venous compartments. Furthermore, we implemented non-linear venous pressure-volume characteristics for all dependent venous vascular compartments and allowed blood volume to change as a function of time and orthostatic stress to simulate blood plasma sequestration into the interstitium during orthostatic stress. We accounted for a reduction in the hydrostatic pressure component at the carotid sinus during tilt by making the input pressure to the arterial baroreflex a function of orientation in the gravitational field.
We verified the model under baseline (supine) conditions and after three minutes of orthostatic stress by comparing the model's predictions to a limited set of population-averaged data found in the medical literature. We also studied the transient response of the cardiovascular system to sudden gravitational stress. The experimental steady state and transient responses are well matched by the simulator.
By appropriately modifying some of the model's parameters we systematically simulated a number of proposed hypotheses of the mechanisms underlying post-flight orthostatic intolerance. The modeled hypotheses included hypovolemia, cardiac atrophy, increased leg venous compliance, decreased gain of the heart rate baroreflex, and a reduced ability to constrict venous and arterial smooth muscle. By simulating a tilt test response under these altered baseline conditions, we were able to compare the simulator's predictions to astronaut stand test data post-spaceflight. Our simulations indicate that although hypovolemia is the biggest single contributor, no single mechanism can account for the altered post-spaceflight heart rate dynamics. Rather, our simulations suggest that a superposition of reduced vasoconstriction of arterial and venous smooth muscle and hypovolemia can account for the dynamics of the heart rate response seen in astronauts post-flight.
The computational model was subsequently used to simulate the effects of a potential pharmacologic countermeasure, midodrine: an alpha agonist. We simulated the action of midodrine on a spaceflight adapted individual by increasing total peripheral resistance and decreasing unstressed venous volume by amounts compatible with experimental findings. The simulated post-flight heart rate response of a midodrine-treated individual demonstrates a significant reduction in the excessive tachycardia. The simulation suggests that the drug may have major potential benefit as a countermeasure for orthostatic intolerance, and human trials are warranted.