Keynote Lecture: Heart Failure

Understanding how calcium, cross-bridges and titin determine cardiac sarcomere mechanics: a result of interaction between experiment and model.

J. van der Velden, T. Arts

The heart pumps by coordinated contraction of the sarcomeres in the cardiomyocytes. After depolarization of the cardiomyocyte, calcium (Ca) enters the cell, reaching the sarcomere. Ca binds to troponin, located on the thin filaments, thus allowing attachment of cross-bridges (XB’s) protruding from the thick filaments.

Conventionally, XB formation is modeled using chemical and thermodynamic principles. Using such model, force-length-Ca relations did not fully agree with experimental measurements. Adding the MechChem hypothesis, implying that mechanical tension in the thin filament tightens chemical binding of Ca to troponin, model and experiment agreed much better. However, the experimentally observed increase of Ca sensitivity with sarcomere length was still not well simulated. Adding the hypothesis that compression of the titin ‘spaghetti’ structure adds a pressure component to the sarcomere interior, concerning the static [Ca]‑tension relation, simulation and experiment were in perfect agreement. As a next step we will focus on sarcomere dynamics.

Our models are used as try-outs of hypotheses on major working mechanisms. Comparison with experiments renders strenghts and weaknesses of the hypotheses, helping us to find better explanations. This type of modeling may help us to predict changes in behavior of the cardiomyocyte as induced by variants in sarcomere genes that cause e. g. cardiomyopathies. Ultimately, the obtained insights may help us to simulate outcomes of proposed treatments, helping us to find the best ones.