Long-Term Localized High-Frequency Electric Stimulation Within the Myocardial Infarct
Effects on Matrix Metalloproteinases and Regional Remodeling
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Background— Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning.
Methods and Results— At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.8 V, 0.05-ms pulses) or were left unstimulated (UNSTIM; n=10). At 4 weeks after MI, left ventricular wall thickness (echocardiography; 0.89±0.07 versus 0.67±0.08 cm; P<0.05) and regional stiffness (piezoelectric crystals; 14.70±2.08 versus 9.11±1.24; P<0.05) were higher with LHFS than in UNSTIM. In vivo interstitial MMP activity (fluorescent substrate cleavage; 943±59 versus 1210±72 U; P<0.05) in the MI region was lower with LHFS than in UNSTIM. In the MI region, MMP-2 levels were lower and TIMP-1 and collagen levels were higher with LHFS than in UNSTIM (all P<0.05). Transforming growth factor-β receptor 1 and phosphorylated SMAD-2/3 levels within the MI region were higher with LHFS than in UNSTIM. Electric stimulation (4 Hz) of isolated fibroblasts resulted in reduced MMP-2 and MT1-MMP levels but increased TIMP-1 levels compared with unstimulated fibroblasts.
Conclusions— These unique findings demonstrate that LHFS of the MI region altered left ventricular wall thickness and material properties, likely as a result of reduced regional MMP activity. Thus, LHFS may provide a novel means to favorably modify left ventricular remodeling after MI.
Received March 31, 2009; accepted May 10, 2010.