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.

Background

Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated.

Methods and results

Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation.

Conclusions

IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.