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CLINICAL STUDY

Release of matrix metalloproteinases following alcohol septal ablation in hypertrophic obstructive cardiomyopathy

William S. Bradham, Jr, PhD^*, Himali Gunasinghe, BS^*, Jennifer R. Holder, BS^*, Marlina Multani, MS^*, Donna Killip, RN^*, Marianne Anderson, RN, Denise Meyer, RN, William H. Spencer, III, MD, FACC^*, Guillermo Torre-Amione, MD, FACC and Francis G. Spinale, MD, PhD, FACC^*,*

^* Medical University of South Carolina, Charleston, South Carolina, USA
Baylor College of Medicine, Houston, Texas, USA

Manuscript received May 10, 2002; revised manuscript received July 22, 2002, accepted September 6, 2002.

^* Reprint requests and correspondence: Dr. Francis G. Spinale, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty Street, Charleston, South Carolina 29425, USA.
wilburnm{at}musc.edu

OBJECTIVES: This study examined plasma levels of certain matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) species before and after alcohol-induced myocardial infarction (MI) in patients with hypertrophic obstructive cardiomyopathy (HOCM).

BACKGROUND: Matrix metalloproteinases contribute to tissue remodeling, and endogenous control of MMP activity is achieved by the concordant release and binding of TIMPs. Animal models of MI have demonstrated a role for MMP activation in myocardial remodeling. However, the temporal relationship of MMP and TIMP release following a controlled myocardial injury in humans remains unknown.

METHODS: Plasma levels for the gelatinases MMP-2 and MMP-9, and for the collagenases MMP-8 and MMP-13, as well as TIMP-1 profiles were examined (by enzyme-linked immunosorbent assay) at baseline and serially up to 60 h following alcohol injection into the septal perforator artery in order to induce an MI in 51 patients with HOCM (age 55 ± 2 years).

RESULTS: Plasma creatine kinase (MB isoform), indicating myocardial injury, increased 2,150% 18 h post-MI (p < 0.05). Plasma MMP-9 increased by over 400% and MMP-8 by over 100% from baseline values by 12 h post-MI (p < 0.05 vs. baseline). A similar temporal profile was not observed for MMP-2 and MMP-13. In addition, a concomitant increase in plasma TIMP-1 levels did not occur post-MI. As a result, MMP/TIMP stoichiometry (MMP-9/TIMP-1 ratio) increased significantly post-MI, suggestive of reduced TIMP-1 mediated MMP-9 inhibition, which would potentially enhance extracellular myocardial remodeling.

CONCLUSIONS: These unique results demonstrated that induction of a controlled myocardial injury in humans, specifically through alcohol-induced MI, caused species- and time-dependent perturbations of MMP/TIMP stoichiometry that would facilitate myocardial remodeling in the early post-MI setting.

Abbreviations and Acronyms   ANOVA   analysis of variance   CHF   congestive heart failure   CK   creatine kinase   HOCM   hypertrophic obstructive cardiomyopathy   LV   left ventricle/ventricular   LVOT   left ventricular outflow tract   MI   myocardial infarction   MMP   matrix metalloproteinases   TIMP   tissue inhibitor of matrix metalloproteinases

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