Multiple treatment approach to limit cardiac ischemia-reperfusion injury.
BACKGROUND
This study evaluates a multiple treatment approach (ie, pharmacologic preconditioning [diazoxide], sodium-proton exchange inhibition [cariporide], and controlled reperfusion) to improve the outcome from severe cardiac ischemia-reperfusion injury that occurs during a cardiac operation.


METHODS
Five groups of 10 pigs (group 1: control, group 2: diazoxide, group 3: cariporide, group 4: controlled reperfusion, and group 5: combination of diazoxide and cariporide-controlled reperfusion) underwent 75 minutes of left anterior descending occlusion, 1 hour of cardioplegic arrest, and 2 hours of reperfusion. Prior to occlusion, each group received an infusion of vehicle alone (ie, dimethylsulfoxide for the control and the controlled reperfusion groups) or vehicle with drug (ie, diazoxide or cariporide, or both for all other groups). Infarct size (primary outcome) was measured and was normalized to the region at risk. Regional function (secondary outcome) was measured using preload recruitable work area.


RESULTS
Infarct size as a function of area at risk was decreased by cariporide-controlled reperfusion, and combination treatment compared with the control group (14 +/- 6%, 15 +/- 8%, and 9 +/- 4% vs 24 +/- 9%; p < 0.02), and variation in infarct size was decreased by combination treatment compared with the controlled reperfusion group alone (p < 0.02). Recovery of systolic function during reperfusion significantly improved in the left anterior descending region in the cariporide and combination groups compared with the control, controlled reperfusion, or diazoxide groups (group-time effect, p < 0.05).


CONCLUSIONS
Combined use of controlled reperfusion, cariporide, and diazoxide decreases myocyte necrosis and loss of systolic function compared with an untreated control group. Combination treatment has the potential to improve the results of cardiac surgery, however further improvements are needed before clinical application.
Davies
James E
JE
Department of Surgery, University of Alabama, Birmingham, Alabama 35294-0007, USA.
Digerness
Stanley B
SB
Killingsworth
Cheryl R
CR
Zaragoza
Corinne
C
Katholi
Charles R
CR
Justice
Robert K
RK
Goldberg
Steven P
SP
Holman
William L
WL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D003131:Combined Modality Therapy / Q000379:methods; D003981:Diazoxide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006146:Guanidines / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020127:Recovery of Function; D012016:Reference Values; D013450:Sulfones / Q000627:therapeutic use*; D013552:Swine; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D013450:Sulfones; D014665:Vasodilator Agents; C093373:cariporide; D003981:Diazoxide