Related Experiment Video
Updated: May 3, 2026
Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix
Published on: June 14, 2016
Long-term localized high-frequency electric stimulation within the myocardial infarct: effects on matrix
Rupak Mukherjee1, William T Rivers, Jean Marie Ruddy
1Medical University of South Carolina, Charleston, 29425, USA. mukherr@musc.edu
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-beta 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.
Insights
Localized high-frequency stimulation (LHFS) of myocardial infarct (MI) scars improved left ventricular wall thickness and stiffness. This novel approach reduced matrix metalloproteinase (MMP) activity, offering a potential treatment for post-MI remodeling.
Area of Science:
- Cardiovascular Research
- Biomedical Engineering
- Regenerative Medicine
Background:
- Imbalance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMPs) post-myocardial infarct (MI) leads to left ventricular wall thinning and altered stiffness.
- Current therapeutic strategies for MI remodeling are limited.
Purpose of the Study:
- To test the hypothesis that localized high-frequency stimulation (LHFS) of a myocardial infarct (MI) scar can favorably alter MMP/TIMP levels and prevent left ventricular thinning.
- To investigate the efficacy of a targeted regional approach using low-amplitude electric pulses on MI remodeling.
Main Methods:
- Pigs with established MI were randomized to receive LHFS (240 bpm, 0.8 V, 0.05-ms pulses) or remain unstimulated (UNSTIM) for 4 weeks.
- Left ventricular wall thickness and regional stiffness were assessed using echocardiography and piezoelectric crystals, respectively.
- In vivo interstitial MMP activity, MMP-2, TIMP-1, collagen, and signaling pathway levels (TGF-β receptor 1, SMAD-2/3) were measured in the MI region.
Main Results:
- LHFS significantly increased left ventricular wall thickness and regional stiffness compared to the UNSTIM group.
- Interstitial MMP activity and MMP-2 levels were significantly lower in the LHFS group.
- TIMP-1 and collagen levels were significantly higher in the LHFS group, indicating reduced matrix degradation.
- LHFS treatment also modulated key signaling pathways involved in fibrosis and remodeling.
Conclusions:
- LHFS of the MI region effectively altered left ventricular wall thickness and material properties.
- The observed benefits are likely attributed to the reduction in regional MMP activity induced by LHFS.
- LHFS presents a novel therapeutic strategy for favorably modifying left ventricular remodeling after myocardial infarction.
