Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs.
BACKGROUND
Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs.


METHODS
Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction.


RESULTS
Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05).


CONCLUSIONS
Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.
Yarbrough
William M
WM
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Mukherjee
Rupak
R
Brinsa
Theresa A
TA
Dowdy
Kathryn B
KB
Scott
Amelia A
AA
Escobar
G Patricia
GP
Joffs
Cassandra
C
Lucas
David G
DG
Crawford
Fred A
FA
Spinale
Francis G
FG
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D017548:Echocardiography, Transesophageal; D006439:Hemodynamics / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000517:prevention & control; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases