Poly(ADP-ribose) polymerase inhibition improves postischemic myocardial function after cardioplegia-cardiopulmonary bypass.
BACKGROUND
Poly(ADP-ribose) polymerase activation has been shown to contribute to the pathogenesis of myocardial ischemia-reperfusion injury. We hypothesized that a novel poly(ADP-ribose) polymerase inhibitor, INO-1001, provides myocardial protection and improves cardiac function after regional ischemia and cardioplegia-cardiopulmonary bypass (CPB).


METHODS
Pigs were subjected to 30 minutes of regional ischemia by distal left anterior descending coronary artery ligation followed by CPB (60 minutes) with hyperkalemic cardioplegia (45 minutes). The myocardium then was reperfused post-CPB for 90 minutes. After 15 minutes of ischemia, the treatment group (n = 6) received an INO-1001 bolus (1mg/kg) before a continuous infusion (1mg/kg/hour). Control pigs (n = 6) received vehicle solution. Left ventricular pressure was monitored, from which the maximum, positive first derivative of left ventricular pressure over time (+dP/dt) was calculated. Regional myocardial function in the ischemic area was determined by sonomicrometric analysis. Infarct size was measured as the percent of the ischemic area by tetrazolium staining. Myocardial sections were immunohistochemically stained for poly(ADP-ribose) as a measure of poly(ADP-ribose) polymerase activity and inhibition.


RESULTS
Pigs treated with INO-1001 showed improvements in the +dP/dt at 60 and 90 minutes of post-CPB reperfusion (both p = 0.03) and percent segmental shortening at 30, 60, and 90 minutes of post-CPB reperfusion (p = 0.03, 0.009, and 0.03, respectively). Infarct size was decreased in the treatment group (18.5 +/- 5.7% versus 52.0 +/- 7.7%, INO-1001 versus control, p = 0.03). Poly(ADP-ribose) was reduced in myocardial sections from INO-1001-treated animals compared with controls.


CONCLUSIONS
These results suggest that INO-1001 provides myocardial protection by reducing the extent of infarction and improves cardiac function after regional ischemia and cardioplegia-CPB.
Khan
Tanveer A
TA
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Ruel
Marc
M
Bianchi
Cesario
C
Voisine
Pierre
P
Komjáti
Katalin
K
Szabo
Csaba
C
Sellke
Frank W
FW
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects*; D023421:Models, Animal; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents / Q000494:pharmacology*; D013552:Swine; D016276:Ventricular Function / Q000187:drug effects
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents