Effects of pacing site on global and regional left ventricular function in the setting of dyssynchronous heart failure

Regional estimates of left ventricular function are important for understanding normal cardiac function. In the presence of electrical dyssynchrony and heart failure, substantial remodeling of left ventricular geometry and cellular function occurs, resulting in discoordinate mechanical contraction. However, the determinants of regional left ventricular function during altered electrical activation in the failing heart are unclear. Thus, we sought to investigate the effects of ventricular activation on left ventricular function in dyssynchronously failing hearts. Regional mechanics were measured in the anterolateral left ventricle in open-chest canine hearts. We found that the transmural location of the left ventricular pacing lead and its position in relation to the baseline activation sequence were important determinants of cardiac function. Specifically, improvements in hemodynamic function increased with activation time at the pacing site during endocardial, but not epicardial, biventricular pacing. At the inner wall, radial strain was increased during local endocardial pacing compared with epicardial pacing. In paced failing ventricles, regional differences in myofiber shortening were observed. End-systolic strains were significantly correlated with peak fiber prestretch. Additionally, the onset of sub-endocardial fiber relengthening and fiber shortening duration increased with local activation time, which may be due differences in fiber length. In model simulations, the effects of fiber length and shortening velocity on differences in fiber shortening magnitude, relengthening onset, and shortening duration were investigated. Removing both length and velocity dependence from the active stress model attenuated these differences, compared to baseline. Finally, we studied the effects of sheet structure and transmural activation sequence on regional function. Sheet angle was less radially oriented in failing hearts, compared with control, resulting in a reduced contribution of sheet extension. In failing hearts, reversal of the transmural activation sequence reduced the absolute magnitudes of sheet thickening and shearing at the inner wall, and altered the relative contributions to end-systolic wall thickening compared with normal. Overall, these findings provide insights into the mechanisms by which the amount of electrical dyssynchrony determines left ventricular function in the failing hear