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.
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.
Authors: Rupak Mukherjee; Theresa A Brinsa; Kathryn B Dowdy; Amelia A Scott; Julia M Baskin; Anne M Deschamps; Abigail S Lowry; G Patricia Escobar; David G Lucas; William M Yarbrough; Michael R Zile; Francis G Spinale Journal: Circulation Date: 2003-02-04 Impact factor: 29.690
Authors: Kyoko Soejima; William G Stevenson; William H Maisel; John L Sapp; Laurence M Epstein Journal: Circulation Date: 2002-09-24 Impact factor: 29.690
Authors: William M Yarbrough; Rupak Mukherjee; Theresa A Brinsa; Kathryn B Dowdy; Amelia A Scott; G Patricia Escobar; Cassandra Joffs; David G Lucas; Fred A Crawford; Francis G Spinale Journal: J Thorac Cardiovasc Surg Date: 2003-03 Impact factor: 5.209
Authors: Yvan Devaux; Melanie Bousquenaud; Sophie Rodius; Pierre-Yves Marie; Fatiha Maskali; Lu Zhang; Francisco Azuaje; Daniel R Wagner Journal: BMC Med Genomics Date: 2011-12-05 Impact factor: 3.063
Authors: André Uitterdijk; Tirza Springeling; Kevin C M Hermans; Daphne Merkus; Vincent J de Beer; Charlotte Gorsse-Bakker; Eric Mokelke; Evangelos P Daskalopoulos; Piotr A Wielopolski; Jack P M Cleutjens; W Matthijs Blankesteijn; Frits W Prinzen; Willem J van der Giessen; Robert-Jan M van Geuns; Dirk J Duncker Journal: Basic Res Cardiol Date: 2017-04-06 Impact factor: 17.165