Long-term localized high-frequency electric stimulation within the myocardial infarct: effects on matrix metalloproteinases and regional remodeling.
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.


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.
Mukherjee
Rupak
R
Medical University of South Carolina, Charleston, 29425, USA. mukherr@musc.edu
Rivers
William T
WT
Ruddy
Jean Marie
JM
Matthews
Robert G
RG
Koval
Christine N
CN
Plyler
Rebecca A
RA
Chang
Eileen I
EI
Patel
Risha K
RK
Kern
Christine B
CB
Stroud
Robert E
RE
Spinale
Francis G
FG
D000818:Animals; D003971:Diastole; D004452:Echocardiography; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D005347:Fibroblasts / Q000502:physiology; D006339:Heart Rate; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D010138:Pacemaker, Artificial / Q000662:veterinary; D015203:Reproducibility of Results; D013318:Stroke Volume; D013552:Swine; D013599:Systole; D017180:Tachycardia, Ventricular / Q000209:etiology; D013908:Thoracotomy; D016212:Transforming Growth Factor beta / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9