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Background: Circulating levels of atrial natriuretic peptide and brain natriuretic peptide (BNP) are elevated in patients with cyanotic congenital heart disease and associated with the severity of ventricular dysfunction. We evaluated the effect of chronic hypoxemia on left ventricle pro-atrial natriuretic peptide and pro-BNP, the cytoplasmic precursors of the plasma hormones. Methods: Forty newborn piglets were randomized to placement of a pulmonary artery to left atrium shunt to create hypoxemia or sham thoracotomy. Animals were studied at 1 or 2 weeks after the procedure (four groups, n = 10 per group). Arterial oxygen tension and hematocrit were obtained. Left ventricular shortening fraction was measured by echocardiography. Left ventricular tissue was harvested and cytoplasm was extracted. Pro-BNP levels were determined by Western blot analysis. Pro-atrial natriuretic peptide levels were determined using enzyme-linked immunosorbent assay. Results: Significant differences among treatment groups were observed for arterial oxygen tension (p < 0.001) and hematocrit (p < 0.001). Pairwise comparisons indicated lower arterial oxygen tension and higher hematocrit for hypoxemic piglets compared with control piglets at 1 and 2 weeks. Left ventricular shortening fraction was not decreased in the hypoxemic animals at any time (p = 0.638). Left ventricular pro-atrial natriuretic peptide decreased in hypoxemic piglets (p = 0.029), whereas left ventricular pro-BNP increased in hypoxemic piglets at 2 weeks (p = 0.002). Conclusions: Chronic hypoxemia alone, even in the absence of cardiac dysfunction, is sufficient to increase ventricular levels of pro-BNP. This finding may have implications for the interpretation of BNP levels in the clinical management of patients with cyanotic congenital heart disease. [Copyright &y& Elsevier]

Objective: Cyanotic patients have potentially decreased tissue oxygen tension. Cytochrome oxidase catalyzes the reduction of oxygen and is integral to adenosine triphosphate production. Cytochrome oxidase subunit I, the active site, is encoded by mitochondrial DNA. Using a newborn swine model of chronic hypoxemia, we evaluated ventricular cytochrome oxidase subunit I mRNA and protein expression and assessed cytochrome oxidase activity. Methods: Thirty-two newborn piglets underwent thoracotomy and placement of a pulmonary artery–to–left atrium shunt or sham operation. Two weeks later, partial pressure of arterial oxygen, hematocrit, and left ventricular shortening fraction values were compared with baseline values. Northern blot hybridization and protein immunoblotting for ventricular cytochrome oxidase subunit I were performed. Cytochrome oxidase kinetic activity was measured. Heme a,a3 content and turnover number were determined. Significance was assessed with a t test. Results: Baseline partial pressure of arterial oxygen and hematocrit values were similar. Hypoxemic piglets had a lower partial pressure of arterial oxygen of 38 ± 10 mm Hg (P < .001) and higher hematocrit value of 31.4% ± 2.9% (P < .001) compared with a partial pressure of arterial oxygen of 140 ± 47 mm Hg and hematocrit value of 24.6% ± 3.9% after the sham operation. Baseline and postprocedure left ventricular shortening fraction were similar within and between groups. Chronic hypoxemia increased right ventricular and left ventricular cytochrome oxidase I mRNA and protein by more than 1.4-fold. Cytochrome oxidase activity increased significantly in hypoxemia by 2.5-fold compared with that seen after the sham operation. Heme a,a3 content and turnover number increased by 1.5-fold during hypoxemia. Conclusions: Chronic hypoxemia increases cytochrome oxidase I message, protein expression, and activity. The increase in kinetics was due to increased enzyme content and catalytic activity. This is a possible adaptive mechanism that might preserve organ function during chronic hypoxemia. [Copyright &y& Elsevier]

Background: Pulmonary artery (PA)-left atrial (LA) shunt models in piglets have been described, but technical details critical to limit morbidity/mortality and promote study of chronic cyanosis are lacking. Accordingly, we describe our experience with an optimized technique. Materials and Methods: In 25 6- to 8-wk-old Yorkshire piglets, a beveled, 8 mm, polytetrafluoroethylene tube graft was anastomosed to the PA and LA. Systemic pressure was maintained at >60 mmHg. Saturation targets were met by adjusting a Teflon band on the graft and distal PA. The target oxygen saturation (So2) was 85% on a 50% fraction of inspired oxygen (Fio2). If the So2 was <75% on a 50% Fio2, the graft was constricted to achieve a So2 ≥ 90% on a 100% Fio2 and 75%–80% on a 21% Fio2. Complications affecting mortality were neutralized with a stepwise strategy to minimize risk. Results: Thrombosis, blood loss, and arrhythmia were determinants of survival. Protocol optimization over time increased survival while assuring chronic cyanosis. Survival approached 90%, with a So2 of 80% to 90%, 3 to 5 wk postoperatively. Complications included bleeding, excessive hypoxemia, uncontrolled shunt flow, arrhythmias, and thrombosis. Conclusions: Refinement of surgical technique, shunt adjustment via graft banding, and thrombotic and arrhythmia prophylaxis are the keys to success with this model. [Copyright &y& Elsevier]