Timing and magnitude of systolic stretch affect myofilament activation and mechanical work.

Dyssynchronous activation of the heart leads to abnormal regional systolic stretch. In vivo studies have suggested that the timing of systolic stretch can affect regional tension and external work development. In the present study, we measured the direct effects of systolic stretch timing on the magnitude of tension and external work development in isolated murine right ventricular papillary muscles. A servomotor was used to impose precisely timed stretches relative to electrical activation while a force transducer measured force output and strain was monitored using a charge-couple device camera and topical markers. Stretches taking place during peak intracellular Ca(2+) statistically increased peak tension up to 270%, whereas external work due to stretches in this interval reached values of 500 J/m. An experimental analysis showed that time-varying elastance overestimated peak tension by 100% for stretches occurring after peak isometric tension. The addition of the force-velocity relation explained some effects of stretches occurring before the peak of the Ca(2+) transient but had no effect in later stretches. An estimate of transient deactivation was measured by performing quick stretches to dissociate cross-bridges. The timing of transient deactivation explained the remaining differences between the model and experiment. These results suggest that stretch near the start of cardiac tension development substantially increases twitch tension and mechanical work production, whereas late stretches decrease external work. While the increased work can mostly be explained by the time-varying elastance of cardiac muscle, the decreased work in muscles stretched after the peak of the Ca(2+) transient is largely due to myofilament deactivation.

Biomechanics of cardiac electromechanical coupling and mechanoelectric feedback.

Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling. Dysregulation of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, electrical dyssynchrony leads to mechanical alterations and exacerbates pump dysfunction in heart failure. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred as cardiac mechanoelectric feedback and thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. At the cellular scale, most investigations of myocyte mechanoelectric feedback have focused on the roles of stretch-activated ion channels, though mechanisms that are independent of ionic currents have also been described. Here we review excitation-contraction coupling and mechanoelectric feedback at the cellular and organ scales, and we identify the need for new multicellular tissue-scale model systems and experiments that can help us to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart.

Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.