(Circulation. 1997;96:2215-2220.)
© 1997 American Heart Association, Inc.
Articles |
Paradoxical Relationship Between N-Terminal Proatrial Natriuretic Peptide and Filling Pressure in Adults With Cyanotic Congenital Heart Disease
From the Cardiology Unit, University of Vermont College of Medicine, Burlington (W.E.H.), and Institute for Surgical Research, University of Oslo, Norway (C.H.).
Correspondence to William E. Hopkins, MD, University of Vermont College of Medicine, Cardiology Unit, McClure 1, Burlington, VT 05401. E-mail william.hopkins{at}vtmednet.org
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Abstract |
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Background Many adults with cyanotic congenital heart disease are characterized by reduced ventricular filling pressures and decreased systemic oxygen transport. Data from animals suggest that hypoxia can induce synthesis and secretion of atrial natriuretic peptide.
Methods and Results We measured plasma N-terminal (1-98) proatrial natriuretic peptide (proANP) in 26 cyanotic adults and 28 noncyanotic control subjects. Resting arterial oxygen saturation was significantly lower and hemoglobin concentration and hematocrit significantly greater in cyanotic patients than in control subjects (82±6 versus 96±3%, 19.7±2.2 versus 14.7±2.1 g/dL, and 59.0±8.5% versus 44.3±5.2%, respectively, P<.0001 in all cases). Four cyanotic patients had evidence of iron deficiency. Plasma proANP levels were elevated in cyanotic patients compared with control subjects (1828±1147 versus 689±343 pmol/L, P<.0001). Comparison of resting arterial oxygen saturation and proANP levels demonstrated an inverse linear relationship between the two measures (r=-.70, P<.0001). There was a significant linear relationship between both hemoglobin concentration and hematocrit and proANP levels as well (r=.53, P=.0003 and r=.48, P=.002, respectively). Cyanotic patients had lower mean right atrial pressures than the control subjects (4±3 versus 7±2 mm Hg, P=.005), and there were inverse logarithmic relationships between proANP levels and systemic cardiac index (r=-.82, P=.0002), systemic oxygen transport (r=-.68, P=.005), and mixed venous oxygen saturation (r=-.79, P<.0001).
Conclusions Adults with cyanotic congenital heart disease are characterized by increased levels of plasma proANP. The increased atrial natriuretic peptide most likely results in extracellular and plasma volume depletion and reduced systemic oxygen transport. Measures designed to increase ventricular filling may improve quality of life of these patients.
Key Words: atrial natriuretic peptide • hypoxia • heart defects, congenital
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Introduction |
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For most adults with cyanotic congenital heart disease, definitive repair is not feasible and transplantation is the only surgical option. Yet, lung transplant with intracardiac repair or heart-lung transplant may have a negative impact on survival.1 2 Consequently, nontransplant measures to improve quality of life should be sought. Exertional capacity in cyanotic patients is dependent in part on tissue oxygen delivery, which depends more on flow than on the oxygen content of blood.3 Although some have suggested that congestive heart failure is common,4 5 most reports of cyanotic adults with Eisenmenger syndrome, tetralogy of Fallot, or tricuspid atresia have noted that congestion is unusual.1 6 7 8 Furthermore, biventricular function is typically preserved in those patients with a nonrestrictive ventricular septal defect (Eisenmenger syndrome or tetralogy of Fallot).9 10 Our experience, based on clinical evaluation, Doppler echocardiography, and invasive hemodynamic assessment, suggests that filling pressure is actually reduced in many of these adult patients despite complex anatomic defects, hypoxemia, and systemic level right ventricular pressure.1 11
Atrial natriuretic peptide (ANP), a natriuretic and diuretic agent, is derived from a 126-amino-acid prohormone, synthesized and stored in secretory granules of atrial myocytes and released in response to atrial stretch.12 13 14 Its presence in blood tends to counteract the fluid retention characteristic of patients with congestive heart failure.14 15 16 17 It has been suggested that hypoxia can induce synthesis of ANP as well.18 19 Stockman et al19 demonstrated increased immunoreactive ANP and increased ANP mRNA in right ventricular myocardium of rats exposed to 10% oxygen for 3 weeks. Hypoxia followed by normoxia resulted in a fall of right ventricular ANP to control levels within 3 days despite persistent myocardial hypertrophy. We hypothesized that adults with cyanotic congenital heart disease would have increased levels of circulating ANP secondary to chronic hypoxemia and that the net result would be reduced ventricular filling, reduced systemic blood flow, and reduced oxygen transport.
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Methods |
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Patients studied
Twenty-six adults with cyanotic congenital heart defects secondary to a variety of morphological abnormalities (12 women and 14 men; mean age, 30±8 years; range, 18 to 51 years) and 28 noncyanotic control subjects (17 women and 11 men; mean age, 36±11 years; range, 20 to 70 years) were studied. No member of either group had evidence of atrial hypertension (see below). Among the patients with cyanotic congenital heart disease, 12 had Eisenmenger syndrome and 14 had anatomic obstruction to pulmonary blood flow (Table 1
). All 26 patients had either a
nonrestrictive atrial septal defect, a nonrestrictive
ventricular septal defect, or univentricular
physiology (Table 1) (Fig 1). All had a
resting upper extremity arterial oxygen saturation <90%.
Nine members of the study group and one member of the control group had
previously undergone surgical placement of one or more shunts. Two had
Potts' shunts, two had Waterston shunts, one had a Blalock-Taussig
shunt, one had bilateral Blalock-Taussig shunts and a Glenn shunt, one
had bilateral Blalock-Taussig shunts, one had a Potts' and a
Blalock-Taussig shunt, one had a Waterston and a Blalock-Taussig shunt,
and one had a Glenn shunt. Four patients had pulmonary artery
bands.
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The control group was selected so as to include noncyanotic patients
with and without hemodynamic abnormalities. Because the
majority of cyanotic patients in the study had right
ventricular pressure overload secondary to a nonrestrictive
atrial or ventricular septal defect (Table 1
: patients with
an atrial septal defect, ventricular septal defect, truncus
arteriosus, atrioventricular canal defect, or tetralogy
of Fallot), we specifically sought to include noncyanotic individuals
with hemodynamic abnormalities resulting in pressure
and/or volume load of the right heart. Specifically, the control group
consisted of nine individuals with structurally normal hearts, three
with previously repaired congenital heart defects, and 16 with
unrepaired or residual noncyanotic congenital heart defects (Table 2). Resting upper extremity oxygen
saturation was >90% in all. One subject had unrepaired tetralogy of
Fallot and a Blalock-Taussig shunt and a resting arterial
oxygen saturation of 91%. Two had a nonrestrictive patent ductus
arteriosus and secondary Eisenmenger syndrome with differential
cyanosis. The upper extremity arterial oxygen saturation,
and therefore coronary arterial saturation, was
98% in one and 93% in the other.
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All patients with repaired or unrepaired congenital heart defects were recruited from either the lung transplant or adult congenital heart disease programs at Washington University, St Louis, Mo, or from the adult congenital heart disease program at the University of Vermont, Burlington. The studies were approved by the institutional review boards of both institutions. None of the patients or control subjects had Down syndrome.
Clinical Data
Twenty-four subjects underwent invasive
hemodynamic assessment (10 cyanotic patients and 14
noncyanotic control subjects). Catheterizations were
performed as clinically indicated and not for the purpose of the study.
Oxygen consumption was either measured (polarographic method) or
assumed to be 140 mL O2 ·
min-1 · m-2.
Cardiac output was determined by the Fick method in patients with
congenital heart defects and by either the Fick method or
thermodilution method in those with a structurally normal heart.
Cardiac index is reported as L ·
min-1 · m-2
and oxygen transport as mL O2 ·
min-1 · m-2.
Cardiac output was not measured in two subjects who underwent
hemodynamic assessment. None of the patients or control
subjects had evidence of increased ventricular filling
pressures. All individuals (n=24, see above) who underwent invasive
hemodynamic assessment had a mean right atrial pressure
<10 mm Hg. In those individuals (cyanotic patients and
noncyanotic control subjects) who did not undergo invasive
hemodynamic assessment, the jugular venous pressure was
used to exclude right atrial hypertension. The jugular venous pressure
was determined by careful physical examination by one of the
investigators (W.E.H.). All individuals had a normal jugular venous
pressure; the A and V waves were <10 cm H2O in each.
Because mean right and left atrial pressures tend to be equal in
patients with cyanotic congenital heart disease in view of the presence
of either a nonrestrictive atrial septal defect, a nonrestrictive
ventricular septal defect, or single
ventricular physiology, the absence of right atrial
hypertension was thought to exclude left atrial hypertension as
well.20 21 The exception to this is patients with an
intact atrial septum and significant mitral
regurgitation. Two of our cyanotic patients did have
significant (at least moderate) atrioventricular valve
regurgitation. One had a complete
atrioventricular canal and therefore equal right and
left atrial pressures, and the other had right isomerism with a single
ventricle and single atrium. Neither had right atrial hypertension at
the time of invasive hemodynamic assessment.
All patients and control subjects were in normal sinus rhythm. One patient with tetralogy of Fallot and pulmonary atresia had 2:1 heart block. Another with a single ventricle and Eisenmenger syndrome had complete heart block and harbored a dual-chamber pacemaker. Resting arterial oxygen saturation was determined by upper extremity pulse oximetry or reflective oximetry and reported as percentage saturation. A measure of arterial oxygen saturation was not obtained in one individual (cyanotic group). Hemoglobin concentration was reported as g/dL and hematocrit as percent. Hematologic values were not available in 12 individuals (11 from the control group and one from the cyanotic group). Four cyanotic patients had evidence of iron deficiency (mean corpuscular volume <80). One of the study patients with an ostium secundum atrial septal defect and Eisenmenger syndrome was taking diuretics at the time of evaluation (furosemide 20 mg/d). Hemodynamic assessment before and after initiation of the diuretic demonstrated a mean right atrial pressure of 2 mm Hg.
Assay of ANP
Because of its prolonged half-life and in vitro stability
relative to active ANP (99-126), we measured concentrations of the
N-terminal (1-98) fragment of the ANP prohormone called proANP. Close
correlations between blood levels of ANP (99-126) and proANP and
between proANP and hemodynamic indexes have been
demonstrated.22 23 24 Samples for proANP were obtained by
direct venipuncture with the subject at rest. Plasma was
separated and stored frozen. The samples were batched and shipped
frozen to Norway, where determination of plasma proANP was performed
with a specific radioimmunoassay as described
previously.17 25 The assay uses a polyclonal antibody from
rabbits immunized with rat ANP (1-30). ProANP results are reported as
pmol/L.
Statistical Analysis
Continuous variables are expressed as mean±SD. Two-tailed,
unpaired Student's t tests were used to compare results. In
all cases, a value of P<.05 was considered significant. The
relationship between variables was determined by
univariate regression analysis. In all cases, a
value of P<.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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ProANP and Hypoxemia
Resting arterial oxygen saturation was significantly lower and hemoglobin concentration and hematocrit significantly greater in cyanotic patients than in the control subjects (82±6 versus 96±3%, P<.0001; 19.7±2.2 versus 14.7±2.1 g/dL, P<.0001; and 59.0±8.5 versus 44.3±5.2%, P<.0001, respectively). Plasma proANP levels were significantly greater in cyanotic patients than in the control subjects (1828±1147 versus 689±343 pmol/L, P<.0001) (Fig 2
). Regression analysis of the
entire group demonstrated a significant inverse linear relationship
between resting arterial oxygen saturation and proANP
levels (r=-.70, P<.0001) (Fig 3A). There was a significant linear
relationship between both hemoglobin concentration and hematocrit and
proANP levels as well (r=.53, P=.0003 and
r=.48, P=.002, respectively) (Fig 3B). There was
no relationship between proANP levels and age in the cyanotic patients,
the control subjects, or the groups combined.
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ProANP and Hemodynamics
Mean right atrial pressure, determined by invasive
hemodynamic assessment, was significantly lower in
patients with cyanotic congenital heart disease than in control
subjects (4±3 versus 7±2 mm Hg, P=.005) (Fig 4A). In addition, a highly significant
inverse logarithmic relationship existed between proANP levels and both
systemic cardiac index (r=-.82, P=.0002) (Fig 4B) and systemic oxygen transport (r=-.68,
P=.005) (Fig 4C). The relationship between proANP levels and
mixed venous oxygen saturation, a measure that reflects both systemic
cardiac output and arterial oxygen saturation, was inverse
and highly significant as well (r=-.79,
P<.0001) (Fig 4D).
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Right Atrial Stretch and Right Ventricular Hypertrophy
A significant number of noncyanotic control subjects had pressure
and/or volume overload of the right heart. To exclude right atrial
stretch and/or right ventricular stretch or
hypertrophy as the primary cause of elevated proANP levels
in our patients, we compared these individuals (n=15) with the other
control subjects (n=13, Table 2). Six of the 15 had right atrial and
right ventricular dilatation secondary to a nonrestrictive
atrial septal defect (normal pulmonary artery pressure), 3 had
marked dilatation and dysfunction of the right ventricle secondary to a
nonrestrictive atrial septal defect and systemic level
pulmonary artery hypertension, 2 had systemic level right
ventricular pressure and Eisenmenger syndrome secondary to
a nonrestrictive patent ductus arteriosus, 2 had moderate to severe
right ventricular hypertension secondary to supravalvar
pulmonic stenosis in one case and conduit (right ventricle to
pulmonary artery) obstruction in the other, 1 had systemic
level right ventricular pressure secondary to tetralogy of
Fallot and a Blalock-Taussig shunt, and 1 had moderate valvar pulmonic
stenosis (Table 2 and Fig 5). All
15 had an upper extremity arterial oxygen saturation of
>90% (mean, 96±3%; range, 91% to 100%). Despite marked
hemodynamic abnormalities in all 15, proANP levels did
not differ from those in the control subjects with normal
hemodynamics (789±404 versus 573±217 pmol/L,
P=.10).
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Discussion |
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Exertional capacity is related, in part, to systemic oxygen transport in cyanotic patients. Although systemic oxygen transport is dependent on both the oxygen content of blood and systemic cardiac output, flow is the major determinant. In a study of children with congenital heart defects, Berman et al3 found a close linear relationship between systemic oxygen transport and cardiac output. Volume depletion results in decreased ventricular filling and therefore reduced systemic blood flow. Data derived from invasive hemodynamic assessment and from Doppler echocardiography suggest that ventricular filling may be reduced in many adults with cyanotic congenital heart defects.1 7 11 26 In a study of 100 adults with severe pulmonary artery hypertension, those with Eisenmenger syndrome had a mean right atrial pressure of only 5 mm Hg, compared with 12 mm Hg in those patients with primary pulmonary hypertension.1 Hu et al7 reported a mean right atrial pressure of 7 mm Hg in 30 adults 40 to 60 years old with unrepaired tetralogy of Fallot. Saha et al26 reported on 201 children and adults with Eisenmenger syndrome. Mean right atrial pressure for the group was 7 mm Hg. Although left atrial pressure was not reported in any of these studies, it is important to note that the individuals in these studies had either a nonrestrictive communication at the atrial and/or ventricular level or univentricular physiology. Right and left atrial pressures tend to be equal in such patients.20 21
Data derived from Doppler echocardiographic assessment are consistent with those derived from invasive hemodynamic assessment. Transmitral flow velocity profiles, measured with pulse Doppler in 25 cyanotic adults with nonrestrictive ventricular septal defects, yielded results consistent with reduced preload in these patients. The cyanotic patients, despite normal systolic right and left ventricular function, were characterized by significantly reduced E-to-A ratios and prolonged deceleration and isovolumic relaxation times compared with age- and sex-matched control subjects. Interestingly, a significant inverse relationship between resting arterial oxygen saturation and both mitral deceleration time and isovolumic relaxation time was noted in the study.11
Although contrary to the accepted fact that ANP is secreted in response to atrial stretch, the observation in animals that hypoxia induces synthesis and secretion of ANP led us to hypothesize that there may be an inverse relationship between ANP levels and ventricular filling pressure in adults with cyanotic congenital heart defects. This was indeed the case. We evaluated cyanotic adults with a variety of morphological defects and found that plasma proANP was significantly greater than that in control subjects. We found a significant inverse linear relationship between proANP and resting arterial oxygen saturation. Although invasive hemodynamic assessment was performed only in a subset of subjects, highly significant inverse relationships were present between proANP concentrations and both systemic cardiac index and systemic oxygen transport. Whether the relationship between mixed venous oxygen saturation and proANP levels simply reflects the relationship between proANP and cardiac output or whether decreased mixed venous oxygen content stimulates myocardial ANP production cannot yet be determined. Of interest, Nootens et al27 found a similar relationship between mixed venous oxygen saturation and ANP levels in their study of patients with primary pulmonary hypertension. In addition to reduced cardiac output, chronic volume depletion is likely to result in increased blood viscosity secondary to hemoconcentration. In support of this, we found a significant linear relationship between both hemoglobin concentration and hematocrit and plasma proANP levels. This was true despite evidence of iron deficiency in a subset of cyanotic patients.
It is important to emphasize that the elevated plasma proANP levels in our cyanotic patient group do not appear to be primarily due to dilatation or hypertrophy of the right heart. It has been shown that patients with nonrestrictive atrial septal defects are characterized by volume load of the right heart with subsequent dilatation of both the right atrium and right ventricle.28 Those with unrepaired atrial septal defects and severe pulmonary hypertension are characterized by marked right ventricular dilatation and severe right ventricular dysfunction.9 A subset of our control group had unrepaired atrial septal defects with or without pulmonary hypertension. Another subset had significant right ventricular hypertension due to either outflow obstruction or Eisenmenger physiology (nonrestrictive patent ductus arteriosus). Despite the significant hemodynamic abnormalities noted in these patients, plasma proANP was not elevated relative to the other members of the control group.
On the basis of the results of this study, hypoxemia appears to stimulate the release of ANP, although the mechanism is unknown. Recent work suggests that blood volume expansion leads to increased circulating ANP through a complex set of mechanisms involving vascular and cardiac baroreceptors, the brain, and the heart.29 In animals, blood volume expansion results in distension of baroreceptors in the atria, the carotid and aortic sinuses, and the kidney. Afferent impulses from the baroreceptors activate the locus ceruleus in the brain. After a complex set of connections, neurons in the hypothalamus are ultimately activated and stimulated to release ANP. Some of the ANP neurons appear to terminate in the neurohypophysis and stimulate the release of oxytocin. It has been proposed that oxytocin is the major effector of cardiac ANP secretion. In a classic endocrine sense, oxytocin circulates to the heart and stimulates the release of cardiac ANP.29 It could be that hypoxemia activates vascular or cardiac baroreceptors, leading to the cascade outlined above. Alternatively, hypoxemia may act at a specific site in the central nervous system, ultimately effecting the release of oxytocin and ANP.
It is of interest to note that during pregnancy, plasma volume increases on average by 50%.30 One would speculate that the above axis is "turned off" or inhibited in some way during pregnancy, thus allowing for the volume expansion. It is well documented that the risk of pregnancy is high in women with Eisenmenger syndrome. Despite systemic right ventricular pressure and the possibility of right heart failure secondary to the volume load, which peaks well before term, pregnant women with Eisenmenger syndrome seem especially vulnerable in the immediate postpartum period. Elkayam notes that death often occurs in the first few days after delivery and is preceded by desaturation and hemodynamic decompensation.30 This is the time when oxytocin is increased in the mother and a marked diuresis ensues. Rather than the volume load, these individuals seem more vulnerable to the rapid loss of volume and the subsequent fall in cardiac output.
Although this study does not prove that hypoxia induces ANP secretion or that ANP is the cause of the volume depletion, it does suggest a novel stimulus for ANP secretion that appears to be independent of atrial stretch. Further studies will be needed to clearly establish a causal link between hypoxia, ANP, and volume depletion. In addition, we have not shown that active ANP (99-126) is increased in our patient group. However, a significant correlation between both active ANP and proANP and hemodynamic indices has been described in patients with heart failure. The authors concluded that active ANP and proANP were equally good indicators of atrial distension.22 It is also unclear whether the increased circulating ANP in cyanotic adults is beneficial in any way. Most importantly, the results of the study suggest that many cyanotic adults have reduced ventricular filling secondary to elevated proANP levels. Efforts to increase ventricular filling may result in increased cardiac output, increased systemic oxygen transport, and decreased blood viscosity in these patients. Improvement of the quality of life of adults with cyanotic congenital heart disease may be possible.
Conclusions
Adults with cyanotic congenital heart disease are characterized by
increased levels of circulating ANP. The increased ANP may cause
extracellular and plasma volume depletion and reduced systemic oxygen
transport. Thus, measures designed to increase ventricular
filling may improve quality of life.
Received January 9, 1997; revision received May 12, 1997; accepted May 20, 1997.
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