Abstract 816: Low-Amplitude, High Frequency Electrical Stimulation of the Infarct Region Decreases Matrix Metalloproteinase Abundance and Increases Levels of Tissue Inhibitors of the Metalloproteinases and Collagen Content

Abstract

Discordant alterations in the balance between matrix metalloproteinases (MMP) and endogenous MMP inhibitors (TIMPs) within a myocardial infarct (MI) contribute to alterations in LV geometry and ultrastructure, which lead to LV wall thinning at the MI region. While systemic pharmacological approaches can globally alter LV remodeling post-MI, a targeted regional approachto modify MMP/TIMP balance and MI structure has not been explored. We tested the hypothesis that application of localized high frequency stimulation (LHFS) using low amplitude electrical pulses within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning. A uniform and discrete MI was surgically induced in pigs (n=17). At 3 wks post-MI, pigs were randomized for LHFS (n=7, electrical stimulation at 240 bpm, using 0.8V, 0.05ms pulses at the center of the MI region) or unstimulated (UNSTIM, n=10). At 4 wks post-MI, LV wall thickness (echo), and stiffness (piezoelectric crystals with LV preload reduction) were measured. MMP-2, MMP-9, TIMP-1 (zymography or immunoblotting) levels, and fibrillar collagen content (COLL, histology) in the remote and MI regions were determined and normalized to values in LV samples obtained from non-MI pigs (n=5, 100%). LV wall thickness at the MI region was higher with LHFS than UNSTIM (0.89±0.07 vs 0.67±0.08 cm, p<0.05). With LHFS, MMP-2 levels were lower, and TIMP-1 and COLL levels higher than UNSTIM values in the MI region (TABLE ). Myocardial stiffness in the MI region was higher with LHFS than UNSTIM (14.70±2.08 vs 9.11±1.24, respectively, p<0.05). These findings, for the first time, demonstrate that sub-threshold electrical stimulation of the MI region altered MMP/TIMP balance and collagen content, which directly affected LV wall thickness and stiffness. Thus, LHFS may represent a novel, selective means to favorably modify MI scar remodeling and attenuate the progressive LV wall thinning that occurs post-MI.