Modulation of nuclear factor-kappaB improves cardiac dysfunction associated with cardiopulmonary bypass and deep hypothermic circulatory arrest.

Abstract

The hypothesis is that partial nuclear factor-kappaB (NF-kappaB) inhibition can alleviate cardiopulmonary dysfunction associated with ischemia and reperfusion injury following cardiopulmonary bypass and deep hypothermic circulatory arrest (CPB/DHCA) in a pediatric model. Animal case study. Two-week-old piglets (5-7 kg). Piglets received 100 microg/kg of SN50, a peptide inhibitor of NF-kappaB translocation and activation, 1 hour before CPB. The control group received saline. Animals were cooled to 18 degrees C with CPB, the piglets were in DHCA for 120 minutes, and the piglets were then rewarmed on CPB to 38 degrees C and maintained for 120 minutes after CPB/DHCA. Sonomicrometry and pressure catheters collected hemodynamic data. Transmural left and right ventricular tissues were obtained at the terminal time point for determination of NF-kappaB activity by enzyme-linked immunosorbent assay. Data are expressed as mean +/- sd. Oxygen delivery was maintained at 76 +/- 13 mL/min at baseline and 75 +/- 5 mL/min at 120 minutes after CPB/DHCA (p = 0.75) in SN50-treated animals vs. 99 +/- 26 mL/min at baseline and 63 +/- 20 mL/min at 120 minutes in the untreated group (p = 0.0001). Pulmonary vascular resistance (dynes.sec.cm) increased from 124 +/- 59 at baseline to 369 +/- 104 at 120 minutes in the untreated piglets (p = 0.001) compared with SN50-treated animals (100 +/- 24 at baseline and 169 +/- 88 at 120 minutes, p = 0.1). NF-kappaB activity was reduced by 74% in left ventricles of SN50-treated compared with SN50-untreated animals (p < 0.001). Plasma endothelin-1 (pg/mL), an important vasoconstrictor regulated by NF-kappaB, increased from 2.1 +/- 0.4 to 14.2 +/- 5.7 in untreated animals (p = 0.004) but was elevated to only 4.5 +/- 2 with SN50 treatment (p = 0.005). Improvement of cardiopulmonary function after ischemia/reperfusion was associated with the reduction of NF-kappaB activity in piglet hearts. Maintenance of systemic oxygen delivery and alleviation of pulmonary hypertension after CPB/DHCA in piglets administered SN50, possibly through a reduction of circulating endothelin-1, suggest that selective inhibition of NF-kappaB activity may reduce ischemia and reperfusion injury after pediatric cardiac surgery.