Ventricular dyskinesis induced loss of contractile function and epicardial inflammation : role of cellular adhesion molecules
- Author(s): Yamazaki, Katrina Go;
- et al.
Ventricular dyssynchrony as induced by epicardial ventricular pacing has been the subject of investigations for many years. It has been shown that dyssynchrony is characterized by regions of wall thinning and hypertrophy and is detrimental to left ventricular (LV) function. The mechanisms that trigger these changes are unknown. Therefore, I hypothesize that dyskinesis, secondary to LV pacing, triggers local inflammation, reactive oxygen species (ROS) generation, and matrix metalloproteinase (MMP) activation. To gain further mechanistic insight, I wish to determine two-dimensional and/or three-dimensional changes in myocardial function and inflammation induced by myocardial dyskinesis. I also want to determine if inflammatory responses induced by dyskinesis are mediated by a vascular event via cellular adhesion molecules (CAM). A canine model was used to determine regional and transmural differences in LV contractile function and inflammatory responses associated with local early contraction. Results investigating regional differences in LV contractile function demonstrate that local dyskinesis creates regions of early shortening at the pace site, as well as in areas immediately surrounding the pace site. Evaluation of inflammatory responses showed increases in neutrophil infiltration and in MMP-9 in regions undergoing early shortening. Results investigating the transmural differences in LV function indicate that 4 h of LV pacing results in a 30% local loss of endocardial wall thickening (p<0.01). Transmural assessment of neutrophil infiltration showed a significant 5 fold increase in myeloperoxidase (MPO) activity in the epicardium vs midwall/endocardium. Matrix metalloproteinase-9 (MMP- 9) activity increased ̃2 fold in the epicardium and reactive oxygen species (ROS) generation ̃2.5 fold. In a mouse model, results showed a significant 3 fold increase in MPO, 2 fold increase in ROS, and 3 fold increase in MMP-9 activity in dyskinetic hearts vs controls. In canine subjects anesthetized with propofol, a known cardioprotectant, and ICAM-1 or p-selectin null mice, dyskinesis failed to increase neutrophil infiltration or MMP-9 activity in early activated dyskinetic LV. Early activated dyskinetic regions demonstrate depressed endocardial contractile function, and epicardial inflammation. The upregulation of CAM appears necessary to trigger these inflammatory responses, thus suggesting inflammation is induced by vascular events. Over the long-term, these events may contribute to adverse changes in LV structure/function.