Doxycycline reduces cardiac matrix metalloproteinase-2 activity but does not ameliorate myocardial dysfunction during reperfusion in coronary artery bypass patients undergoing cardiopulmonary bypass.
OBJECTIVE
Matrix metalloproteinase-2 proteolyzes intracellular proteins in the heart and induces acute myocardial contractile dysfunction in ischemia-reperfusion injury. Doxycycline, a matrix metalloproteinase inhibitor, prevented matrix metalloproteinase-2-induced troponin I cleavage in rat hearts and improved contractile function following ischemia-reperfusion. In patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass, increased atrial matrix metalloproteinase-2 activity was inversely correlated with cardiac mechanical function at 3 hours reperfusion. We performed a study in patients with coronary artery disease undergoing primary elective coronary artery bypass graft surgery with cardiopulmonary bypass to determine whether doxycycline reduces cardiac mechanical dysfunction, matrix metalloproteinase activity, and troponin I degradation after reperfusion.


METHODS
Randomized, double-blinded, placebo-controlled study.


METHODS
University of Alberta Hospital.


METHODS
Forty-two patients with coronary artery disease undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.


METHODS
Patients were randomized to receive either oral administration of 20 mg of doxycycline or matching placebo pill twice a day at least 2 days prior to surgery, on the day of surgery, and for the first 3 postoperative days.


RESULTS
Left ventricular stroke work index was examined prior to cardiopulmonary bypass and at 24 hours reperfusion. Right atrial biopsies were collected before cardiopulmonary bypass and 10 minutes after aortic cross-clamp release to determine matrix metalloproteinase-2 activity and troponin I level. Blood was collected to determine matrix metalloproteinase activity and interleukin-6, C-reactive protein, and troponin I levels. Cardiac 72-kDa matrix metalloproteinase-2 activity was lower upon reperfusion in biopsies from the doxycycline group (p = 0.01), and the increase of matrix metalloproteinase-2 activity in the placebo group due to reperfusion did not appear in the doxycycline group (p = 0.05). Doxycycline, however, did not ameliorate cardiac mechanical dysfunction following reperfusion or the cardiopulmonary bypass-coronary artery bypass graft-induced increased plasma matrix metalloproteinase-9, interleukin-6, and C-reactive protein levels. Cardiopulmonary bypass-coronary artery bypass graft or doxycycline did not change tissue or plasma troponin I levels at 10 minutes reperfusion.


CONCLUSIONS
Although doxycycline did not improve myocardial stunning following coronary artery bypass graft surgery with cardiopulmonary bypass, it reduced cardiac matrix metalloproteinase-2 activity in these patients. A larger trial and/or higher dose of doxycycline may yet be warranted.
1Division of Cardiac Surgery, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada. 2Department of Pediatrics, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada. 3Department of Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada. 4Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, Canada. 5EPICORE Centre, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Costas J
CJ
Schulze
Michele M
MM
Castro
Arulmozhi D
AD
Kandasamy
Jonathan
J
Cena
Courtney
C
Bryden
Shoa H
SH
Wang
Arvind
A
Koshal
Ross T
RT
Tsuyuki
Barry A
BA
Finegan
Richard
R
Schulz
D000368:Aged; D002097:C-Reactive Protein; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D015897:Comorbidity; D001026:Coronary Artery Bypass / Q000379:methods*; D004311:Double-Blind Method; D004318:Doxycycline / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage*; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D013318:Stroke Volume; D019210:Troponin I / Q000097:blood
D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D019210:Troponin I; D002097:C-Reactive Protein; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline