Kelly M. McLean

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.

Current treatments for congenital aortic stenosis.

Purpose of review Congenital valvar aortic stenosis is a challenging disease that often requires repeated palliative procedures. Stenosis can range from mild and asymptomatic, not requiring intervention, to severe, as seen in hypoplastic left heart syndrome. New advances such as fetal balloon valvuloplasty, improvements in the Ross technique, and long-term studies of trans-catheter balloon valvuloplasty and surgical valvotomy warrant a review of the outcomes and optimal timing of the various interventions. Recent findings Fetal balloon valvuloplasty has shown promise. Despite some mortality and morbidity, some fetuses are showing significant growth in left ventricular structures, allowing biventricular repair. In neonates and infants with congenital aortic stenosis, excellent initial results are obtained with trans-catheter balloon valvuloplasty, although stenosis resistant to further balloon dilation or regurgitation may develop, necessitating surgical intervention. Midterm results from the Ross procedure are encouraging, demonstrating low rates of mortality, aortic insufficiency and re-intervention. Stenosis of the pulmonary allograft may be inevitable, and recent long-term follow-up suggests an increase in aortic insufficiency. Summary While availability of fetal balloon valvuloplasty is limited, it has promise for promoting in-utero left ventricle growth and improving function. The optimal procedure for infants and neonates is trans-catheter balloon valvuloplasty. For older patients, the Ross procedure is the repair of choice, although more long-term studies are needed to assess the natural course of the autograft. Outcomes should improve with advances in pulmonary allografts.

Glucocorticoids Improve Calcium Cycling in Cardiac Myocytes after Cardiopulmonary Bypass

BACKGROUND Glucocorticoids can reduce myocardial dysfunction associated with ischemia and reperfusion injury following cardiopulmonary bypass (CPB) and circulatory arrest. The hypothesis was that maintenance of cardiac function after CPB with methylprednisolone therapy results, in part, from preservation of myocyte calcium cycling. METHODS Piglets (5-7 kg) underwent CPB and 120 min of hypothermic circulatory arrest with (CPB-GC) or without (CPB) methylprednisolone (30 mgkg(-1)) administered 6h before and at CPB. Controls (No-CPB) did not undergo CPB or receive glucocorticoids (n=6 per treatment). Myocardial function was monitored in vivo for 120 min after CPB. Calcium cycling was analyzed using rapid line-scan confocal microscopy in isolated, fluo-3-AM-loaded cardiac myocytes. Phospholamban phosphorylation and sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) protein levels were determined by immunoblotting of myocardium collected 120 min after CPB. Calpain activation in myocardium was measured by fluorometric assay. RESULTS Preload recruitable stroke work in vivo 120 min after reperfusion decreased from baseline in CPB (47.4±12 versus 26.4±8.3 slope of the regression line, P<0.05), but was not different in CPB-GC (41±8.1 versus 37.6±2.2, P=0.7). In myocytes isolated from piglets, total calcium transient time remained unaltered in CPB-GC (368±52.5 ms) compared with controls (434.5±35.3 ms; P=0.07), but was prolonged in CPB myocytes (632±83.4 ms; P<0.01). Calcium transient amplitude was blunted in myocytes from CPB (757±168 nM) compared with controls (1127±126 nM, P<0.05) but was maintained in CPB-GC (1021±155 nM, P>0.05). Activation of calpain after CPB was reduced with glucocorticoids. Phospholamban phosphorylation and SERCA2a protein levels in myocardium were decreased in CPB compared with No-CPB and CPB-GC (P<0.05). CONCLUSIONS The glucocorticoid-mediated improvement in myocardial function after CPB might be due, in part, to prevention of calpain activation and maintenance of cardiac myocyte calcium cycling.

Acute β-blockade prevents myocardial β-adrenergic receptor desensitization and preserves early ventricular function after brain death

OBJECTIVE Beta-adrenergic receptor desensitization through activation of the G protein-coupled receptor kinase 2 is an important mechanism of early cardiac dysfunction after brain death. We hypothesized that acute beta-blockade can prevent myocardial beta-adrenergic receptor desensitization after brain death through attenuation of G protein-coupled receptor kinase 2 activity, resulting in improved cardiac function. METHODS Adult pigs underwent either sham operation, induction of brain death, or treatment with esmolol (beta-blockade) for 30 minutes before and 45 minutes after brain death (n = 8 per group). Cardiac function was assessed at baseline and for 6 hours after the operation. Myocardial beta-adrenergic receptor signaling was assessed 6 hours after operation by measuring sarcolemmal membrane adenylate cyclase activity, beta-adrenergic receptor density, and G protein-coupled receptor kinase 2 expression and activity. RESULTS Baseline left ventricular preload recruitable stroke work was similar among sham, brain death, and beta-blockade groups. Preload recruitable stroke work was significantly decreased 6 hours after brain death versus sham, and beta-blockade resulted in maintenance of baseline preload recruitable stroke work relative to brain death and not different from sham. Basal and isoproterenol-stimulated adenylate cyclase activities were preserved in the beta-blockade group relative to the brain death group and were not different from the sham group. Left ventricular G protein-coupled receptor kinase 2 expression and activity in the beta-blockade group were markedly decreased relative to the brain death group and similar to the sham group. Beta-adrenergic receptor density was not different among groups. CONCLUSION Acute beta-blockade before brain death attenuates beta-adrenergic receptor desensitization mediated by G protein-coupled receptor kinase 2 and preserves early cardiac function after brain death. These data support the hypothesis that acute beta-adrenergic receptor desensitization is an important mechanism in early ventricular dysfunction after brain death. Future studies with beta-blocker therapy immediately after brain death appear warranted.