Towards a molecular understanding of contractility.

The contractile performance of the heart depends on the molecular force generators, the myosin crossbridges between thick and thin filaments. These are oscillating between two states, strong and weak, or force-generating and non-force-generating. Calcium activation of the contractile machinery increases the probability of forming force-generating crossbridges, whereas the speed of contraction depends on the probability of returning force-generating crossbridges into weak ones. It is inversely related to the energetic cost of contraction. The probabilities or rate constants describing the transitional states of the force generators (and denoted as g and f) describe not only the kinetic properties of the contractile system but also its responsiveness to the calcium activator. The development of force depends not only on the free calcium ion concentration in the myoplasm, but also on calcium responsiveness which is dependent both on crossbridge kinetics and the calcium affinity of the regulatory protein, troponin. In future, it will be important to find out how all these molecular properties of the force-generators are affected in diseased states as well by pharmacological interventions, such as the application of novel cardiotonic drugs.