Ann Thorac Surg 2008;85:618-623. doi:10.1016/j.athoracsur.2007.08.041
© 2008 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Chronic Hypoxemia Increases Ventricular Brain Natriuretic Peptide Precursors in Neonatal Swine
Azeem R. Khan, MDa,
Mariusz Birbach, MDa,
Meryl S. Cohen, MDb,
Richard F. Ittenbach, PhDc,
Thomas L. Spray, MDa,
Richard J. Levy, MDd,
J. William Gaynor, MDa,*
a Division of Cardiothoracic Surgery, Department of Surgery, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
b Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
c Biostatistics and Data Management Core, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
d Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Accepted for publication August 21, 2007.
* Address correspondence to Dr Gaynor, Division of Cardiothoracic Surgery, Department of Surgery, The Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd, Suite 8527, Philadelphia, PA 19106 (Email: gaynor{at}email.chop.edu).
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Abstract
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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.
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Introduction
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The cardiac natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are hormones secreted predominantly by the heart [1]. Both peptides are synthesized by cardiac muscle as preprohormones and stored in secretory granules in the cardiomyocyte cytoplasm as prohormones. The prohormones are proteolytically cleaved within the cardiomyocyte into the biologically active C-terminal peptide and the biologically inactive N-terminal fragment and secreted into the circulation in response to various stimuli [2, 3]. Cardiomyocyte wall stretch is thought to be the primary stimulus for natriuretic peptide secretion. Previous studies have also shown that hypoxia stimulates natriuretic peptide secretion in the atrium [4]. Although the half-life of each of the biologically active plasma hormones is limited (ANP, approximately 2 to 4 minutes; BNP, approximately 22 minutes), the half-life of the cytoplasmic prohormone is much more stable [1].
Atrial natriuretic peptide and BNP compose a dual vasoactive natriuretic peptide system in the form of major secretory products of the endocrine myocardium mediating natriuresis, diuresis, and vasodilation through the guanylyl cyclase–linked membrane natriuretic peptide receptor-A [5, 6]. The natriuretic peptide system has been shown to be a key hormonal system critical to blood pressure homeostasis. Additionally, growing evidence supports the role of the natriuretic peptide system as a compensatory neurohumoral mechanism that, in contrast to other compensatory neurohumoral systems (such as renin-angiotensin-aldosterone and sympathetic nervous systems), functions to retard rather than promote the progression of heart failure [3]. The close relationship of plasma cardiac natriuretic peptide levels with cardiac loading conditions has led to their use as biomarkers for cardiac health, with diagnostic and prognostic application in clinical practice [1]. More recently, synthetic forms of the natriuretic peptides are being studied for their effects in cardiovascular disease when administered as therapeutic agents.
Circulating natriuretic peptide level determinations may provide useful diagnostic information in patients with heart failure; further investigation is needed in elucidating the full relationship between hypoxia and the natriuretic peptide system [4]. Using a newborn porcine model of hypoxemia to mimic cyanotic congenital heart disease (CHD), we studied the relationship between hypoxemia and natriuretic peptides.
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Material and Methods
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All experiments were conducted in accord with a protocol approved by the Institutional Animal Care and Use Committee of The Children’s Hospital of Philadelphia. All animals were cared for humanely in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 96-03, revised 1996).
Animal Model
Forty 7- to 10-day-old neonatal piglets (3.3 to 4.6 kg) were randomly assigned to receive either thoracotomy and creation of a pulmonary artery to left atrium shunt (shunt group, n = 20) or thoracotomy alone (sham group, n = 20). Animals were randomly sacrificed at 1 or 2 weeks after the procedure (four groups, n = 10 per group).
Anesthesia
Induction of anesthesia was achieved with intramuscular ketamine (30 mg/kg) and acepromazine (1.2 mg/kg). Electrocardiography, pulse oximetry, and noninvasive cuff blood pressure were monitored throughout the procedure. After tracheal intubation with an appropriately sized tube, mechanical ventilation (Servoventilator 900C; Siemens, Iselin, NJ) was initiated. General anesthesia was maintained with isoflurane (1.5%) in oxygen (40%). Baseline left ventricular shortening fraction (LVSF) was measured in the parasternal short-axis using two-dimensional and M-mode transthoracic echocardiography (Acuson 128, 7.0 MHz Acuson V7 probe; Siemens, Malvern, PA). Left ventricular shortening fraction was measured and calculated using Teicholtz’s equation: LVSF (%) = (end-diastolic dimension – end-systolic dimension)/(end-diastolic dimension) x 100 [7]. The animals were positioned in the left lateral decubitus position, and an intravenous catheter was placed in a posterior auricular vein.
Surgical Protocol
An intravenous injection of cefazolin (20 mg/kg) was given after initiation of general endotracheal anesthesia. The left thoracic cavity was entered anterolaterally through a muscle-sparing thoracotomy incision at the fourth intercostal space. The lung was reflected laterally, and the pericardium was opened anterior to the phrenic nerve. A left atrial blood sample was obtained, and ventilator settings were adjusted accordingly to achieve standard arterial blood gas values (partial pressure of carbon dioxide, 45 mm Hg; partial pressure of oxygen, >85 mm Hg; fraction of inspired oxygen, 0.40). In the shunt group, a pulmonary artery to left atrium anastomosis was created after placement of side-biting Satinsky clamp using a 5-mm thin-walled polytetrafluoroethylene tube graft (Gore-Tex Stretch Vascular Graft Pediatric Shunt, catalog ST05020A; W.L. Gore & Assoc, Flagstaff, AZ; Fig 1). Sham animals underwent thoracotomy, pericardial dissection, and placement of side-biting clamps on the left atrium and the pulmonary artery. Subsequently, the clamps were removed and an arterial blood gas sample was obtained for analysis from the ascending aorta.
Afterward, hemostasis was achieved, the pericardium was reapproximated, and the thoracotomy incision was closed over a fully expanded lung, in layers. The piglets were extubated when awake and placed in an oxygenated incubator (oxygen flow, 4 L/min) until they were able to tolerate room air without any respiratory distress, drink water, and walk without assistance. Postoperative analgesia was achieved with a transdermal fentanyl patch (25 g/h for 48 hours), and animals were housed in the laboratory animal facility with daily monitoring and routine animal care with free access to food and water.
Tissue Harvest
On day 7 or 14, according to the respective randomly assigned group, after induction of anesthesia with ketamine (30 mg/kg) and acepromazine (1.2 mg/kg), all animals were endotracheally intubated and mechanically ventilated to standard values. General anesthesia was maintained with isoflurane (1.5%) in oxygen (40%). Left ventricular shortening fraction was again measured using transthoracic echocardiography. A left thoracotomy was performed, and an arterial blood gas sample was obtained from the descending aorta for analysis. The animals were then euthanized with intravenous pentobarbital and phenytoin (175.5 and 22.5 mg/kg, respectively). Left ventricular (LV) cardiac muscle (free wall only, excluding the septum) was immediately harvested, flash frozen in liquid nitrogen, and stored at –70°C for analysis.
Cytoplasmic Protein Extraction
Cardiac ventricles were minced and homogenized in H medium (70 mmol/L sucrose, 220 mmol/L mannitol, 2.5 mmol/L N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid], pH 7.4, and 2 mmol/L EDTA). The homogenate was centrifuged for 10 minutes at 1,500g to remove unbroken tissue and nuclei. The supernatant was centrifuged for 10 minutes at 10,000g to separate the cytosolic fraction (supernatant) from the mitochondria (pellet). Once the cytosol was isolated using differential centrifugation, cytoplasmic protein concentration was then determined using the Bradford spectrophotometric method [8, 9].
Protein Immunoblotting for Pro-Brain Natriuretic Protein
Immunoblotting was conducted with 50 µg of cytoplasmic protein using sodium dodecylsulfate-polyacrylamide gel electrophoresis (Mini-PROTEAN 3 electrophoresis system; Bio-Rad Laboratories, Hercules, CA) as previously described [8, 10]. Blots were labeled with a primary monoclonal antibody to mouse pro-BNP [13C1], peptide sequence RPTGVWKSREVATEGI, corresponding to amino acids 45 through 61 of Human pro-BNP (catalog ab13122, Abcam, Cambridge, MA) and secondarily exposed to rabbit anti-mouse immunoglobulin G (Santa Cruz Biotechnology Inc, Santa Cruz, CA). The protein signal was detected with enhanced chemiluminescence (Amersham Pharmacia Biotech, Piscataway, NJ), and density was measured using autoradiography and scanning densitometry (Molecular Imager GS-800 Calibrated Densitometer; Bio-Rad Laboratories).
Enzyme-Linked Immunosorbent Assay for Pro-Atrial Natriuretic Protein
Cytoplasmic samples of cardiac ventricles were subjected to enzyme-linked immunosorbent assay using pro-ANP–coated enzyme-linked immunosorbent assay plate kits (catalog 2892-14, Diagnostic Automation, Inc, Calabasas, CA). Optical density of the wells was measured at the recommended wavelength of 450 nm using an enzyme-linked immunosorbent assay plate reader (Synergy 2 Multi-Detection Microplate Reader; BioTek Instruments Inc, Winooski, VT).
Statistical Analysis
Data analysis proceeded in two distinct phases: a descriptive phase, in which descriptive statistics were generated for all variables in the dataset, and an inferential phase, in which five different hypotheses were tested, one for each of five outcomes described below.
Left ventricular pro-BNP and LV pro-ANP served as the two primary outcomes with three measures of cardiac function serving as secondary outcomes: hematocrit (HCT) level, arterial oxygen tension (PaO
2), and LVSF. Data were organized using a 2 x 2 (hypoxemia and time) conceptual design, and analyzed using the Kruskal-Wallis test based on nonparametric nature of the data (ie, small sample sizes, skewed distributions). For each outcome it was assumed that no statistically significant differences existed among the four treatment groups (shunted 1 week, shunted 2 weeks, sham controls 1 week, sham controls 2 weeks). Follow-up tests to statistically significant omnibus values were calculated using the Wilcoxon rank-sum test for two sets of comparisons: (1) shunted piglets versus sham controls at 1 week and (2) shunted piglets versus sham controls at 2 weeks. For outcomes in which omnibus tests were statistically significant but simple effect comparisons were not, main-effect comparisons were pursued (eg, shunted versus nonshunted piglets). All 200 transthoracic echocardiographs were evaluated by the primary author (A.R.K.) and ratings assigned, thus assuring interrater reliability across samples. To assure the highest quality rating possible, a random sample of 10 sets of transthoracic echocardiographs were evaluated and compared with the ratings of a local expert in echocardiography (M.S.C.) using a standard Spearman-rho correlation coefficient (no statistically significant difference). Alpha was not adjusted beyond the traditional 
of 0.05 level because of the exploratory nature of the study. All analyses were conducted using SPSS v14.0 (SPSS Inc, Chicago, IL).
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Results
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Natriuretic Peptides—Pro-Atrial Natriuretic Protein Enzyme-Linked Immunosorbent Assay and Pro-Brain Natriuretic Protein Western Blotting
A statistically significant difference among treatment groups was observed for LV pro-BNP (p = 0.008) but not for pro-ANP (p = 0.110). Pairwise comparisons to the statistically significant omnibus test for BNP values indicated that steady-state levels of LV pro-BNP were significantly higher for shunted piglets than for sham controls at 2 weeks (p = 0.002) but not at 1 week (p = 0.075; Figs 2, 3).
Conversely, LV pro-ANP values were significantly lower for shunted piglets than for sham controls at 1 week (p = 0.029) but not at 2 weeks (p = 0.353; Fig 4). The presence of statistically significant values for both pro-BNP and pro-ANP outcomes negated the need for follow-up comparisons at the main-effect level.
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Fig 2. Left ventricular pro-brain natriuretic protein levels at euthanasia in different animal groups; * indicates statistically significant difference. Animal groups are defined as follows: 1 week sham, white bars; 1 week shunt, horizontally striped bars; 2 week sham, black bars; 2 week shunt, diagonally striped bars.
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Fig 4. Left ventricular pro-atrial natriuretic protein levels at euthanasia in different animal groups; * = statistically significant difference. Animal groups are defined as follows: 1 week sham, white bars; 1 week shunt, horizontally striped bars; 2 week sham, black bars; 2 week shunt, diagonally striped bars.
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Partial Pressure of Arterial Oxygen and Hematocrit
Baseline PaO
2 and HCT were similar among all four groups. One week and 2 weeks after the procedure, respectively, shunt piglets had a significant lower PaO
2 (41 ± 8 mm Hg and 44 ± 8 mm Hg; p < 0.001) and higher HCT (28% ± 4% and 30% ± 2%, p < 0.001) compared with sham controls (PaO
2 149 ± 33 mm Hg and 144 ± 24 mm Hg; HCT 21% ± 3% and 24% ± 2%; Figs 5, 6).
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Fig 5. Arterial oxygen tension (PaO
2) at euthanasia in different animal groups; * = statistically significant difference. Animal groups are defined as follows: 1 week sham, white bars; 1 week shunt, horizontally striped bars; 2 week sham, black bars; 2 week shunt, diagonally striped bars.
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Fig 6. Hematocrit (HCT) at euthanasia in different animal groups; * = statistically significant difference. Animal groups are defined as follows: 1 week sham, white bars; 1 week shunt, horizontally striped bars; 2 week sham, black bars; 2 week shunt, diagonally striped bars.
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Left Ventricular Shortening Fraction
Left ventricular shortening fraction was determined independently by two observers (A.R.K. and M.S.C.). Interobserver variability was 2.9% ± 0.04% (p = 0.16). Left ventricular shortening fraction was similar between both groups of shunt piglets and both groups of sham-operated controls at baseline. One week and 2 weeks after the procedure, respectively, LVSF was 32% ± 6% and 30% ± 6% in shunt piglets and 32% ± 4% and 31% ± 4% in sham-operated controls. There was no statistically significant difference between postprocedure LVSF and baseline LVSF among all animal groups (p = 0.638; Fig 7).
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Fig 7. Left ventricular shortening fraction (LVSF) at euthanasia in different animal groups; no statistically significant difference noted. Animal groups are defined as follows: 1 week sham, white bars; 1 week shunt, horizontally striped bars; 2 week sham, black bars; 2 week shunt, diagonally striped bars.
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Cardiac Function—Partial Pressure of Arterial Oxygen, Hematocrit, and Left Ventricular Shortening Fraction
A statistically significant difference among the four treatment groups was observed for HCT level (p < 0.001) and PaO
2 (p < 0.001) but not for LVSF (p = 0.638). Consequently, follow-up comparisons for the two significant omnibus values also revealed statistically significant differences between shunted and sham controls at both 1-week and 2-week times for both HCT (p < 0.001) and PaO
2 (p < 0.001). Similar to the presence of statistically significant values for the natriuretic peptides, the presence of statistically significant HCT and PaO
2 outcomes negated the need for follow-up comparisons at the main-effect level. In addition, the lack of a statistically significant omnibus value for LVSF negated the need for follow-up tests.
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Comment
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There is an increasing trend for use of circulating BNP levels to aid in the clinical assessment and treatment of patients with congestive heart failure, including those with cyanotic CHD. This is based on a significant correlation between the degree of right ventricular overload and BNP levels in the plasma of children with different types of CHD [11, 12]. However, cyanotic CHD may stimulate BNP production through several mechanisms: myocardial stretch (transmural stress secondary to pressure or volume overload caused by outflow tract obstruction or shunts), neurohumoral activation, and hypoxia. The fact that hypoxemia alone may elevate BNP may complicate its use as a marker of ventricular dysfunction in patients with cyanotic disorders.
Several studies have theorized the existence of cellular adaptive mechanisms during hypoxemia to preserve homeostasis and limit injury secondary to decreased oxygen tension [13–16]. Alterations in natriuretic peptides may be one such mechanism. We tested this hypothesis by using a porcine model of hypoxemia resulting from the creation of a pulmonary artery to left atrium shunt.
In the present study, creation of a pulmonary artery to left atrium shunt resulted in a significant decrease in PaO
2 in the hypoxemic groups of animals. The decrease in arterial oxygen content caused an increase in HCT. This shift is often associated with changes seen in humans with cyanotic CHD. The results of this study revealed a significant increase in LV cytoplasmic levels of BNP with time, independent of LVSF. Upregulation of myocardial BNP may be an adaptive mechanism during hypoxemia allowing for the preservation of homeostasis and cardiac function. However, LV levels of cytoplasmic ANP were significantly decreased during hypoxemia, possibly secondary to increased secretion into the circulation [4]. The eventual increase of LV cytoplasmic levels of ANP could represent the "catching up" of the transcriptional mechanisms of cellular natriuretic peptide synthesis.
Numerous models mimicking hypoxemia exist and are used experimentally [13–16]. Our model is a well-accepted model of hypoxemia and is advantageous to other models of hypoxemia because right ventricular pressure and volume states are not altered [16]. In addition, cardiac index and LV function are preserved. Thus, hypoxemia alone, in the absence of wall stretch, may be sufficient to increase natriuretic peptide levels in patients with cyanotic CHD. The elevation of BNP secondary to hypoxic stimulation is in line with previous studies, which have shown the presence of a hypoxia-responsive element in the promoter region of the BNP gene [4, 17, 18]. Results from this study revealed that LVSF and, indirectly, cardiac function are unchanged during early adaptation to hypoxemia. These findings support the description of maintenance of preischemic cardiac performance as a compensatory mechanism in the cyanotic heart [13, 14, 19].
Limitations
An obvious limitation of this study is that the hypoxemia model was surgically created in the postnatal period as opposed to the prenatal presence of hypoxemia in cyanotic CHD in humans. Secondly, there was a relatively short follow-up period of 2 weeks. A longer follow-up (greater than 1 month) may have better elucidated the long-term response of the natriuretic peptides. Another limitation of the study was the determination of cardiac function through the use of echocardiography. The technique is subjective and technician- and preload-dependent. Echocardiography is an indirect method to measure LVSF and to infer cardiac performance. A more effective and true measurement of heart contractility and function would have been a more invasive pressure-volume evaluation. However, echocardiography remains a noninvasive and repeatable method for evaluation of cardiac performance and in this study was corroborated by two independent observers. Finally, this study did not include data on either the plasma protein concentrations or cellular messenger ribonucleic acid levels of both ANP and BNP. It would have been helpful to have the plasma concentration data to correlate the systemic to the cytoplasmic response of natriuretic peptide levels, as the plasma levels are easiest to measure in the clinical setting. The ribonucleic acid data would have allowed further clarification of the response of the cellular machinery to hypoxemia in relation to the more immediate cytoplasmic response.
Conclusions
Creation of a pulmonary artery to left atrium shunt resulted in a relatively chronic decrease in PaO
2. This is associated with an increase in LV pro-BNP despite preserved cardiac function. These findings indicate that hypoxemia alone may be sufficient to increase steady-state levels of pro-BNP protein. Such changes may be adaptive, preserving cardiomyocyte function during hypoxemia, and this finding may have implications for the use of BNP levels to assess clinical status of patients with cyanotic CHD. Further studies should be directed toward the determination of the clinical utility of BNP in the setting of cyanotic cardiac disease.
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Acknowledgments
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Supported in part by the Alice Langdon Warner and Daniel M. Tabas Endowed Chairs in Pediatric Cardiothoracic Surgery at The Children’s Hospital of Philadelphia.
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Abstract
Introduction
