*1.2. Titin's Structure Is Essential to Normal Cardiac Function, Passive Tension, and Length Dependent Activation*

The structure of titin domains provides essential functions to the cardiomyocyte and overall physiology of the heart. The elasticity of titin that is derived from the spring-like I-band is a major contributor to the length dependent activation described in the Frank-Starling effect. In normal cardiac function, increased blood volume in the ventricle during diastole (measured by left ventricular end diastolic pressure) leads to increased force of contraction during systole (measured by stroke volume; see Figure 2). The Frank-Starling effect is an essential principal of cardiac function that allows the heart to compensate for physiological changes and increased demands for cardiac output [15]. While there are many factors that influence the relationship between diastolic filling and stroke volume, titin's ability to stretch is an essential contributor. As the sarcomere expands in diastole, the springy Ig-like domains of titin's I-band elongate, thereby increasing tension that is released as restorative force during systole. This increased diastolic tension also modulates actomyosin interactions to increase the force of contraction during systole [16,17]. Because titin spans the entirety of the sarcomere, its length and elasticity are major contributors to the passive tension of the ventricle including diastolic tension and diastolic volume [18]. In addition to the mechanical support titin provides to the sarcomere, stretching of titin leads to cellular signaling activation that promotes myocyte growth and contributes to chronic changes of the myocardium [15].

**Figure 2.** Titin's I-band serves as a molecular spring that contributes to passive tension of the heart. The I-band is extensible due to Ig-like domains that serve as molecular springs. Because titin spans the sarcomere, the extensibility of the I-band imparts much of the resting tension of the cardiomyocyte. In addition, the I-band provides increased restorative forces when the ventricle and sarcomeres are stretched and contributes to the length dependent activation described in the Frank-Starling Curve.
