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

Objective:The hypothesis is that partial nuclear factor-kappaB (NF-&kgr;B) 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. Design:Animal case study. Subjects:Two-week-old piglets (5–7 kg). Interventions:Piglets received 100 &mgr;g/kg of SN50, a peptide inhibitor of NF-&kgr;B translocation and activation, 1 hour before CPB. The control group received saline. Animals were cooled to 18°C with CPB, the piglets were in DHCA for 120 minutes, and the piglets were then rewarmed on CPB to 38°C and maintained for 120 minutes after CPB/DHCA. Measurements:Sonomicrometry and pressure catheters collected hemodynamic data. Transmural left and right ventricular tissues were obtained at the terminal time point for determination of NF-&kgr;B activity by enzyme-linked immunosorbent assay. Data are expressed as mean ± sd. Main Points: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−1·cm−5) 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-&kgr;B 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-&kgr;B, 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). Conclusions:Improvement of cardiopulmonary function after ischemia/reperfusion was associated with the reduction of NF-&kgr;B 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-&kgr;B activity may reduce ischemia and reperfusion injury after pediatric cardiac surgery.