Modulation of Cardiac Function : Titin Springs into Action

Sympathetic stimulation has become a central tenet in our understanding of how cardiac contractility is dynamically altered to accommodate the changing demands of the organism. The mechanisms by which acute and chronic sympathetic stimulation of the heart modulates cardiac output remain incompletely understood, however. Beyond the increase in heart rate driven by sympathetic stimulation of the sino-atrial node, the β-adrenergic receptor (β-AR)–mediated cascade increases contractile force development (inotropy) and accelerates relaxation (lusitropy). Numerous proteins have been discovered to be involved in the β-AR–stimulated response, including calcium handling proteins, myofilament proteins, G-proteins, and regulators of myocardial metabolism (Bers, 2002). The newest player on the field is titin (Fig. 1), the giant myofilament protein that serves as an entropic spring that imparts both the passive and the restoring forces during diastole and systole, respectively. Additional roles for titin have been proposed, including regulation...