Direct secretion from left atrium and pulmonary extraction of human atrial natriuretic peptide To evaluate direct secretion from the left atrium and pulmonary extraction of human atrial natriuretic peptide (hANP), we measured plasma hANP levels in the pulmonary artery, pulmonary vein, and left atrium in patients with either mitral stenosis or atrial septal defect. Left atrial pressure in patients with mitral stenosis was significantly higher than that in patients with atrial septal defect (7.5 + 1.0 mm Hg vs 3.1 + 0.5 mm Hg, p < 0.01). The significant increase in the hANP level in the left atrium was recognized only in patients with mitral stenosis (149 + 33 pglml in the left atrium vs 130 + 28 pglml in the pulmonary vein, p < 0.05). The plasma hANP level in the pulmonary vein was significantly lower than that in the pulmonary artery in both patients with mitral stenosis and those with atrial septal defect, which suggests that hANP is extracted in the lung. We conclude that hANP is secreted not only through the coronary sinus but also directly from the left atrium, stimulated by high left atrial pressure, and that circulating hANP is partially extracted in the pulmonary circulation. (AM HEART J 1992;123:984.)
Masashi Akaike, MD, Fuminobu Ishikura, MD, Seiki Nagata, MD, Kohji Kimura,a MD, and Kunio Miyatake, MD. OS&Z, Japan.
Human atria1 natriuretic peptide (hANP) is a 28amino acid polypeptide with potent natriuretic and vasodilatory effects, which is produced mainly in atria1 myocytes.‘W3 Assessment of plasma hANP levels in various blood vessels has showed that hANP is secreted into the right atria1 cavity through the coronary sinus4 and that a gignificant amount of hANP is extracted from the circulation in the kidney.5 Recently several reports have suggested that hANP may be secreted directly into the left atria1 cavity and that circulating hANP may also be extracted in the pulmonary circulation. 6-g However, it is not known whether left atria1 secretion and pulmonary extraction are modulated by the nature of the underlying heart disease or by hemodynamic parameters. In this study we measured plasma hANP levels in the pulmonary artery, pulmonary vein, and left atrium in patients with either mitral stenosis or atria1 septal defect to investigate the direct secretion from the left
From the Division of Cardiology, National Cardiovascular Center.
Departments
of Medicine
and %adiology,
Supported in part by a Grant for Cardiovascular Research (C-1-5) from the Ministry of Health and Welfare, and a Grant-in-Aid (No. 63870040) from the Ministry of Education, Science, and Culture, Tokyo, Japan. Received
for publication
Reprint requests: Fuminobu cine, National Cardiovascular Japan. 411135411
984
June
14, 1991; Ishikura, Center,
accepted
Sept.
MD, Cardiology 5-7-l Fujishiro-dai,
23, 1991. Division Suita,
of MediOsaka 565,
atrium and pulmonary extraction. In patients with mitral stenosis, stenotic mitral valves result in left atria1 overload, whereas in patients with atria1 septal defect, the left-to-right shunt or pulmonary hypertension causes overloading of the right side of the heart. In addition, the pulmonary blood flow in patients with atria1 septal defect is greater than that in patients with mitral stenosis. The present study was designed to clarify the relationship between the hemodynamic state and left atria1 secretion or pulmonary extraction of hANP by comparing the two study groups. METHODS Subjects. Two specific groupsof patients were studied: 11 with mitral stenosis, who were undergoing percutaneous transvenous mitral commissurotomy (PTMC), and 12 with atria1 septal defect. The group with mitral stenosis included four men and seven women, ranging in age from 29 to 62 years (mean 49 years). Five patients were in sinus rhythm and six had atria1 fibrillation. None of the 11 patients had severe mitral regurgitation or severe tricuspid regurgitation. The group with atria1 septal defect included four men and eight women, ranging in age from 38 to 60 years (mean 44 years). All of these patients were in sinus rhythm. Eleven patients had a left-to-right shunt, and the remaining patient, who had a significant right-to-left shunt, was excluded from evaluation of the plasma hANP level in the left atrium. Cardiac catheterization and PTMC. Right- and leftsided heart catheterization was performed via the femoral approach in all patients. Heart rate and pressures in the
Volume Number
123
Left atria1 secretion
4, Part 1
Table I. Hemodynamic
data
II Study
Hemodynamic
parameters
Heart rate (beats/min) Cardiac index (L/min/m?
Mean aortic pressure (mm Hd Mean pulmonary arterial pressure (mm Hg) Mean right atria1 pressure (mm Hg) Mean left atria1 pressure (mm Hg) Pulmonary vascular resistance (dynes/sec/cmm5m’)
p < 0.01
of ANP
985
p < 0.05
group
MS
ASD
74.2 + 4.8 2.50 _t 0.2 88.3 k 3.5
72.6 f 4.3 2.70 k 0.2 90.9 + 4.4
15.1 _t 1.1
23.1 k 5.6
1.5 k 0.4
3.8 + 0.7*
7.5 * LO?
3.1 t 0.5
256 ?z 35
326 k 193
5oa I-
+
mean
f SE
4oc I A F \ u) n
300 I -
9 AZ I-
ASD, Atria1 septal defect; MS, mitral Values are mean f SD for comparisons
stenosis. between
the two study
groups.
*p < 0.05. tp < 0.01.
E 3 a
*Oa
100 I -
right atrium, left atrium, pulmonary artery, and aorta were measured. Cardiac index and pulmonary blood flow were determined by the thermodilution method in patients with mitral stenosis and by the Fick oxygen method in those with atria1 septal defect. Pulmonary vascular resistance was calculated by standard formulas. In patients with mitral stenosis, PTMC was performed with the Inoue balloon catheter as previously reported.‘O The Inoue balloon catheter was passed into the left atrium by the transseptal Brockenbrough method and entered the pulmonary vein. Hemodynamic parameters were measured 30 minutes after balloon inflation. In patients with atrial septal defect, a balloon wedge pressure catheter was passed into the left atrium and the pulmonary vein through the atria1 septal defect. Blood sampling and radioimmunoassay for hANP. In patients with mitral stenosis, blood samples were simultaneously drawn from the pulmonary artery through a Swan-Ganz catheter and from the left atrium and the pulmonary vein through the Inoue balloon catheter 30 minutes after balloon inflation. In patients with atrial septal defect, blood samples were drawn simultaneously from the pulmonary artery, pulmonary vein, and left atrium through a balloon wedge pressure catheter. Blood samples were collected into tubes containing ethylenediamine tetraacetic acid and aprotinin in the same manner as reported previ0us1y.‘~ Plasma hANP levels were determined by specific radioimmunoassay after extraction with octadecylsilane cartridges (Sep-Pak, C18, Waters Chromatography Division, Millipore, Milford, Mass.) as previously described.12 Calculations. We calculated the amount of hANP extracted in the lung by the product of the pulmonary plasma flow index and the difference in plasma hANP levels between the pulmonary artery and the pulmonary vein.g To determine the pulmonary extraction ratio of hANP, the
0l-
I
IWmonary
Artery
Pulmonary Vein
Left Atrium
Fig. 1. PlasmahANP levels in pulmonary artery, pulmonary vein, and left atrium in 11 patients with mitral stenosis. Each line showsan individual patient. PlasmahANP level in pulmonary vein wassignificantly lower than that in pulmonary artery. Significant increase in plasma hANP level from pulmonary vein to left atrium was recognized.
difference in plasmahANP levels betweenthe pulmonary artery and the pulmonary vein was divided by the plasma hANP level in the pulmonary artery. For the left atria1 secretion ratio, wedivided the difference in the plasmahANP levels between the left atrium and the pulmonary vein by the plasmahANP levels in the pulmonary vein. Statistical analysis. Data were expressed as mean * standard error. Linear regressionanalysiswasobtained by the least-squaresmethod. Statistical significance of hANP levels wasassessed with analysis of variance for multiple comparisons(Fisher test). A probability value of Fig. 4. Correlation between amount of hANP extracted in lung and the pulmonary blood flow (Qp). PTMC, as well as in patients with atria1 septal defect. PTMC is a new minimally invasive procedure developed for treatment of mitral stenosis by balloon inflation at the mitral orifice. Balloon inflation in this procedure may cause a transitory elevation of left atria1 pressure and may stimulate hANP secretion from the left atrium. However, we previously reported that the left atria1 pressure and the plasma hANP level decreased rapidly and stabilized 30 minutes after balloon inflation with no changes in other hemodynamic parameters.i6 Because balloon inflation time was within a few seconds in PTMC with the Inoue balloon catheter, the stimulus for hANP se-
cretion by this procedure was expected ‘to disappear at the time of blood sampling 30 minutes after inflation. Direct secretion from the left atrium. hANP is mainly secreted into the right atria1 cavity through the coronary sinus, stimulated by an increase in right or left atrial pressure and atria1 distention.17y ls Recently several reports have suggested that hANP might also be released directly into circulating blood at the level of the left atrium, probably via the thebesian veins, which entered directly into all four cardiac chambers, becausethe plasma hANP level in the aorta or the left atrium was higher than that in the pulmonary capil-
988
Akaike
et al.
lary wedge position in humans.6-8 In the present study the significant increase in the plasma hANP level from the pulmonary vein to the left atrium in patients with mitral stenosis indicates the existence of direct secretion at the level of the left atrium in humans. On the other hand, there was no significant increase in the plasma hANP level in the left atrium in patients with atria1 septal defect. Right atria1 pressure was higher whereas left atria1 pressure was lower in patients with atria1 septal defect compared with mitral stenosis. These differences between the two study groups indicate that direct secretion from the left atrium is stimulated by left atria1 pressure not right atria1 pressure. Indeed the left atria1 secretion ratio correlated significantly with the mean left atria1 pressure. Pulmonary extraction of hANP. hANP secreted into the right atria1 cavity through the coronary sinus would first pass through the lung. In rats a considerable amount of ANP was shown to exist in the lung, suggesting that the lung was one of the possible target organs for ANP and that ANP could be extracted in the pulmonary circulation.lg Results of a receptor binding study of lung tissue showed that the vasculature and alveoli in the lung were labeled with 1251ANP and that there were specific receptors for ANP in the lung.20 This finding suggested that hANP was taken up from the circulation in the lung by receptor binding and that may have exerted biological actions on the pulmonary circulation. Indeed ANP-like bioactivity was reduced 26% and 14 % after passage through isolated guinea pig lungs,8 and the pulmonary ANP extraction ratio was 19.3 % in dogs undergoing blood sampling from the pulmonary artery and vein.7 In humans, several investigators have been unable to clarify pulmonary extraction of hANP when they sampled blood from the left ventricle,13 the aorta,i4 or the femoral arteryI rather than the pulmonary vein. In these reports direct secretion from the left atrium might have obscured the decrease in the plasma hANP level in the pulmonary circulation. Hollister et a1.7 reported a pulmonary extraction ratio of 24% when blood samples were obtained from the pulmonary artery and the pulmonary capillary wedge position.7 In the present study human pulmonary extraction ratios were 25.1% in mitral stenosis and 19.4% in atria1 septal defect, which were similar to those in previous reports. These findings suggest that the pulmonary extraction ratio was independent of underlying heart disease. On the other hand, the amount of hANP extracted in the lung was significantly correlated with the pulmonary blood flow in our study. Because ANP reduces pulmonary vascular tone by a vasodilatory effect21
American
April 1992 Heart Journal
and has a protective effect on chemically induced edema in the guinea pig lung,22 pulmonary extraction of hANP may prevent pulmonary hypertension or pulmonary edema in conditions of high pulmonary blood pressure. Obata et a1.gdemonstrated that the amount of hANP extracted in the lung correlated significantly with mean pulmonary arterial pressure or pulmonary capillary wedge pressure in patients with mitral stenosis and in normal control subjects. However, in our study groups, which included patients with atria1 septal defect, the amount of hANP extracted in the lung did not correlate significantly with these hemodynamic parameters. Further examination in each patient subgroup is needed to clarify the relationship between pulmonary extraction of hANP and hemodynamic parameters. Conclusions. hANP is secreted not only through the coronary sinus but also directly into circulating blood from the left atrium in conditions of high left atria1 pressure. Circulating hANP is partially extracted in the pulmonary circulation and may have some biological effects on the lung. We thank Dr. Yukio Hirata for supplying the hANP antibody and Drs. Shiro Saito and Masakazu Yamagishi for helpful advice. REFERENCES
4.
5.
6.
7.
8.
9.
10.
11.
Kisch B. Electron microscopy of the heart. I. Guinea pig. Exp Med Surg 1956;14:99-112. de Bold AJ. Atria1 natriuretic factor: a hormone produced by the heart. Science 1985;230:767-70. Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atria1 natriuretic polypeptide (alpha-hANP). Biochem Biophys Res Commun 1984;118:131-9. Sugawara A, Nakao K, Morii N, Sakamoto M, Suda M, Shimokura M, Kiso Y, Kihara M, Yamori Y, Nishimura K, Soneda J, Ban T, Imura H. Alpha-human atria1 natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun 1985;129:439-46. Sato F. Kamoi K. Wakiva Y. Ozawa T. Arai 0. Ishibashi M. Yamaji T. Relationship between plasma atria1 natriuretic peptide levels and atria1 pressure in man. J Clin Endocrinol Metab 1986;63:823-7. Rodeheffer RJ, Tanaka I, Imada T, Hollister AS, Robertson D, Inagaki T. Atria1 pressure and secretion of atria1 natriuretic factor into the human central circulation. J Am Co11 Cardiol 1986;8:18-26. Hollister AS, Rodeheffer RJ, White FJ, Potte JR, Imada T, Inagaki T. Clearance of atria1 natriuretic factor by lung, liver, and kidney in human subjects and the dog. J Clin Invest 1989;83:623-8. Weselcouch EO, Humphrey WR, Aiken JW. Effect of pulmonary and renal circulations on activity of atria1 natriuretic factor. Am J Physiol 1985;249:R595-602. Obata K, Yasue H, Okumura K, Matsumoto K, Ogawa H, Kurose M, Saito Y, Nakao K, Imura H, Nobuyoshi M. Atria1 natriuretic polypeptide is removed by the lungs and released into the left atrium as well as the right atrium in humans. J Am Co11 Cardiol’l990;15:1537-43. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984;87:394402. Kojima T, Hirata Y, Fukuda Y, Iwase S, Kobayashi Y. Plasma
Volume Number
123 4, Part 1
Left atria1 secretion of ANP
atria1 natriuretic peptide and spontaneous diuresis in sick neonates. Arch Dis Child 1987;62:667-70. 12. Yoshimi H, Inoue I, Hirata Y, Kojima S, Kuramochi M, Ito K, Sakakibara H. Atria1 natriuretic peptide secretion in mitral stenosis. Am J Cardiol 1987;60:396-7. 13. Bates ER, Shenker Y, Grekin RJ. The relationship between plasma levels of immunoreactive atrial natriuretic hormone and hemodynamic function in man. Circulation 1986;73:115561.
14. Crazier IG, Nicholls MG, Ikram H, Espiner EA, Yandle TG, Jan S. Atria1 natriuretic peptide in humans. Production and clearance by various tissues. Hypertension 1986;8(suppl II):II11-5.
15. Schutten HJ, Henriksen JH, Warberg J. Organ extraction of atria1 natriuretic peptide (ANP) in man. Significance of sampling site. Clin Physiol 1987;7:125-32. 16. Ishikura F, Nagata S, Hirata Y, Kimura K, Nakatani S, Tamai J, Yamagishi M, Ohmori F, Beppu S, Takamiya M, Miyatake K, Nimura Y. Rapid reduction of plasma atria1 natriuretic peptide levels during percutaneous transvenous mitral commissurotomy in patients with mitral stenosis. Circulation 1989;79:47-50.
17. Ledsome J, Wilson RN, Courneya CA, Rankin AJ. Release of atria1 natriuretic peptide by atria1 distension. Can J Physiol Pharmacol 1985;63:739-42. 18. Metzler CH, Lee M, Thrasher TN, Ramsay DJ. Increased right or left atria1 pressure stimulates release of atrial natriuretic peptides in conscious dogs. Endocrinology 1986;119:2396-8. 19. Sakamoto M, Nakao K, Morii N, Sugawara A, Yamada T, Itoh H, Shiono S, Saito Y, Imura H. The lung as a possible target organ for atria1 natriuretic polypeptide secreted from the heart. Biochem Biophys Res Commun 1986;135:515-20. 20. Bianchi K, Gutkowska J, Thibault G, Garcia R, Genest J, Cartin M. Radioautographic localization of lz51-atria1 natriuretic factor (ANF) in rat tissues. Histochemistry 1985;82:44152. 21.
22.
Faison EP, Siegl PKS, Morgan G, Winquist RJ. Regional vasorelaxant selectivity of atria1 natriuretic factor in isolated rabbit vessels. Life Sci 1985;37:1073-9. Inomata N, Ohnuma N, Furuya M. Alpha-human atria1 natriuretic peptide prevents pulmonary edema induced by arachindonic acid treatment in isolated perfused lung from guinea pig. Jpn J Pharmacol 1987;44:211-4.
Heart rate variations during isoproterenol infusion in congestive heart failure: Relationships to cardiac mortality A marked derangement of heart rate modulation in patients with severe cardiac heart failure (CHF) has been reported. The purpose of the study was to correlate the variations of sinus cycle length (SCL) during infusion of 4 pglmin of isoproterenol with the prognosis of 83 patients with CHF (mean left ventricular ejection fraction 28 + 9%). During a mean follow-up of 28 f 9 months, nine patients died from CHF (group I), nine died suddenly (group II), and 65 are alive (group Ill). Compared with groups II and Ill, a significantly weaker ejection fraction (20 k 8% versus 29.5 r 11% and 28 + 9%), a smaller control state SCL (571 + 65 versus 722 + 200 and 747 + 195), and a smaller percentage of SCL shortening during isoproterenol infusion (11.5 + 7% versus 36 f 16% and 33 t 13%) were noted in group I. The sensitivity and specificity of a percentage of SCL shortening during isoproterenol infusion ~15% for predicting death from CHF were 89% and 93%, respectively. Therefore the injection of small doses of isoproterenol (4 pglmin) may be proposed to evaluate the prognosis of patients with CHF; a weak increase in heart rate during this infusion is a sign of bad prognosis with a high risk of cardiac death as a result of CHF. (AM HEART J 1992;123:989.)
Beatrice Brembilla-Perrot,
MD. Vundoeuvre Les Nancy, France
Patients with long-standing congestive heart failure (CHF) have a high mortality irrespective of treatment. Some prognostic indicators can be identified. From Received
Cardiology
Reprint requests: 54500 Vandoeuvre 4/l/35357
A and B, CHU
for publication
April
of Brabois. 29, 1991;
B. Brembilla-Perrot, Les Nancy, France.
accepted MD,
Sept.
Cardiologie
12, 1991. A, CHU
Brabois,
The major predisposing factors for total mortality and sudden death are the severity of left ventricular impairment,’ a high plasma norepinephrine concentration2 the etiology of CHF,3 and the presence of ventricular arrhythmias. 4, 5 Recently a marked derangement of heart rate modulation in patients with severe CHF was reported$ a reduced standard deviation of normal R-R intervals over a 24-hour period is associated with increased mortality. The frequency
Masashi Akaike, MD, Fuminobu Ishikura, MD, Seiki Nagata, MD, Kohji Kimura,a MD, and Kunio Miyatake, MD. OS&Z, Japan.
Human atria1 natriuretic peptide (hANP) is a 28amino acid polypeptide with potent natriuretic and vasodilatory effects, which is produced mainly in atria1 myocytes.‘W3 Assessment of plasma hANP levels in various blood vessels has showed that hANP is secreted into the right atria1 cavity through the coronary sinus4 and that a gignificant amount of hANP is extracted from the circulation in the kidney.5 Recently several reports have suggested that hANP may be secreted directly into the left atria1 cavity and that circulating hANP may also be extracted in the pulmonary circulation. 6-g However, it is not known whether left atria1 secretion and pulmonary extraction are modulated by the nature of the underlying heart disease or by hemodynamic parameters. In this study we measured plasma hANP levels in the pulmonary artery, pulmonary vein, and left atrium in patients with either mitral stenosis or atria1 septal defect to investigate the direct secretion from the left
From the Division of Cardiology, National Cardiovascular Center.
Departments
of Medicine
and %adiology,
Supported in part by a Grant for Cardiovascular Research (C-1-5) from the Ministry of Health and Welfare, and a Grant-in-Aid (No. 63870040) from the Ministry of Education, Science, and Culture, Tokyo, Japan. Received
for publication
Reprint requests: Fuminobu cine, National Cardiovascular Japan. 411135411
984
June
14, 1991; Ishikura, Center,
accepted
Sept.
MD, Cardiology 5-7-l Fujishiro-dai,
23, 1991. Division Suita,
of MediOsaka 565,
atrium and pulmonary extraction. In patients with mitral stenosis, stenotic mitral valves result in left atria1 overload, whereas in patients with atria1 septal defect, the left-to-right shunt or pulmonary hypertension causes overloading of the right side of the heart. In addition, the pulmonary blood flow in patients with atria1 septal defect is greater than that in patients with mitral stenosis. The present study was designed to clarify the relationship between the hemodynamic state and left atria1 secretion or pulmonary extraction of hANP by comparing the two study groups. METHODS Subjects. Two specific groupsof patients were studied: 11 with mitral stenosis, who were undergoing percutaneous transvenous mitral commissurotomy (PTMC), and 12 with atria1 septal defect. The group with mitral stenosis included four men and seven women, ranging in age from 29 to 62 years (mean 49 years). Five patients were in sinus rhythm and six had atria1 fibrillation. None of the 11 patients had severe mitral regurgitation or severe tricuspid regurgitation. The group with atria1 septal defect included four men and eight women, ranging in age from 38 to 60 years (mean 44 years). All of these patients were in sinus rhythm. Eleven patients had a left-to-right shunt, and the remaining patient, who had a significant right-to-left shunt, was excluded from evaluation of the plasma hANP level in the left atrium. Cardiac catheterization and PTMC. Right- and leftsided heart catheterization was performed via the femoral approach in all patients. Heart rate and pressures in the
Volume Number
123
Left atria1 secretion
4, Part 1
Table I. Hemodynamic
data
II Study
Hemodynamic
parameters
Heart rate (beats/min) Cardiac index (L/min/m?
Mean aortic pressure (mm Hd Mean pulmonary arterial pressure (mm Hg) Mean right atria1 pressure (mm Hg) Mean left atria1 pressure (mm Hg) Pulmonary vascular resistance (dynes/sec/cmm5m’)
p < 0.01
of ANP
985
p < 0.05
group
MS
ASD
74.2 + 4.8 2.50 _t 0.2 88.3 k 3.5
72.6 f 4.3 2.70 k 0.2 90.9 + 4.4
15.1 _t 1.1
23.1 k 5.6
1.5 k 0.4
3.8 + 0.7*
7.5 * LO?
3.1 t 0.5
256 ?z 35
326 k 193
5oa I-
+
mean
f SE
4oc I A F \ u) n
300 I -
9 AZ I-
ASD, Atria1 septal defect; MS, mitral Values are mean f SD for comparisons
stenosis. between
the two study
groups.
*p < 0.05. tp < 0.01.
E 3 a
*Oa
100 I -
right atrium, left atrium, pulmonary artery, and aorta were measured. Cardiac index and pulmonary blood flow were determined by the thermodilution method in patients with mitral stenosis and by the Fick oxygen method in those with atria1 septal defect. Pulmonary vascular resistance was calculated by standard formulas. In patients with mitral stenosis, PTMC was performed with the Inoue balloon catheter as previously reported.‘O The Inoue balloon catheter was passed into the left atrium by the transseptal Brockenbrough method and entered the pulmonary vein. Hemodynamic parameters were measured 30 minutes after balloon inflation. In patients with atrial septal defect, a balloon wedge pressure catheter was passed into the left atrium and the pulmonary vein through the atria1 septal defect. Blood sampling and radioimmunoassay for hANP. In patients with mitral stenosis, blood samples were simultaneously drawn from the pulmonary artery through a Swan-Ganz catheter and from the left atrium and the pulmonary vein through the Inoue balloon catheter 30 minutes after balloon inflation. In patients with atrial septal defect, blood samples were drawn simultaneously from the pulmonary artery, pulmonary vein, and left atrium through a balloon wedge pressure catheter. Blood samples were collected into tubes containing ethylenediamine tetraacetic acid and aprotinin in the same manner as reported previ0us1y.‘~ Plasma hANP levels were determined by specific radioimmunoassay after extraction with octadecylsilane cartridges (Sep-Pak, C18, Waters Chromatography Division, Millipore, Milford, Mass.) as previously described.12 Calculations. We calculated the amount of hANP extracted in the lung by the product of the pulmonary plasma flow index and the difference in plasma hANP levels between the pulmonary artery and the pulmonary vein.g To determine the pulmonary extraction ratio of hANP, the
0l-
I
IWmonary
Artery
Pulmonary Vein
Left Atrium
Fig. 1. PlasmahANP levels in pulmonary artery, pulmonary vein, and left atrium in 11 patients with mitral stenosis. Each line showsan individual patient. PlasmahANP level in pulmonary vein wassignificantly lower than that in pulmonary artery. Significant increase in plasma hANP level from pulmonary vein to left atrium was recognized.
difference in plasmahANP levels betweenthe pulmonary artery and the pulmonary vein was divided by the plasma hANP level in the pulmonary artery. For the left atria1 secretion ratio, wedivided the difference in the plasmahANP levels between the left atrium and the pulmonary vein by the plasmahANP levels in the pulmonary vein. Statistical analysis. Data were expressed as mean * standard error. Linear regressionanalysiswasobtained by the least-squaresmethod. Statistical significance of hANP levels wasassessed with analysis of variance for multiple comparisons(Fisher test). A probability value of Fig. 4. Correlation between amount of hANP extracted in lung and the pulmonary blood flow (Qp). PTMC, as well as in patients with atria1 septal defect. PTMC is a new minimally invasive procedure developed for treatment of mitral stenosis by balloon inflation at the mitral orifice. Balloon inflation in this procedure may cause a transitory elevation of left atria1 pressure and may stimulate hANP secretion from the left atrium. However, we previously reported that the left atria1 pressure and the plasma hANP level decreased rapidly and stabilized 30 minutes after balloon inflation with no changes in other hemodynamic parameters.i6 Because balloon inflation time was within a few seconds in PTMC with the Inoue balloon catheter, the stimulus for hANP se-
cretion by this procedure was expected ‘to disappear at the time of blood sampling 30 minutes after inflation. Direct secretion from the left atrium. hANP is mainly secreted into the right atria1 cavity through the coronary sinus, stimulated by an increase in right or left atrial pressure and atria1 distention.17y ls Recently several reports have suggested that hANP might also be released directly into circulating blood at the level of the left atrium, probably via the thebesian veins, which entered directly into all four cardiac chambers, becausethe plasma hANP level in the aorta or the left atrium was higher than that in the pulmonary capil-
988
Akaike
et al.
lary wedge position in humans.6-8 In the present study the significant increase in the plasma hANP level from the pulmonary vein to the left atrium in patients with mitral stenosis indicates the existence of direct secretion at the level of the left atrium in humans. On the other hand, there was no significant increase in the plasma hANP level in the left atrium in patients with atria1 septal defect. Right atria1 pressure was higher whereas left atria1 pressure was lower in patients with atria1 septal defect compared with mitral stenosis. These differences between the two study groups indicate that direct secretion from the left atrium is stimulated by left atria1 pressure not right atria1 pressure. Indeed the left atria1 secretion ratio correlated significantly with the mean left atria1 pressure. Pulmonary extraction of hANP. hANP secreted into the right atria1 cavity through the coronary sinus would first pass through the lung. In rats a considerable amount of ANP was shown to exist in the lung, suggesting that the lung was one of the possible target organs for ANP and that ANP could be extracted in the pulmonary circulation.lg Results of a receptor binding study of lung tissue showed that the vasculature and alveoli in the lung were labeled with 1251ANP and that there were specific receptors for ANP in the lung.20 This finding suggested that hANP was taken up from the circulation in the lung by receptor binding and that may have exerted biological actions on the pulmonary circulation. Indeed ANP-like bioactivity was reduced 26% and 14 % after passage through isolated guinea pig lungs,8 and the pulmonary ANP extraction ratio was 19.3 % in dogs undergoing blood sampling from the pulmonary artery and vein.7 In humans, several investigators have been unable to clarify pulmonary extraction of hANP when they sampled blood from the left ventricle,13 the aorta,i4 or the femoral arteryI rather than the pulmonary vein. In these reports direct secretion from the left atrium might have obscured the decrease in the plasma hANP level in the pulmonary circulation. Hollister et a1.7 reported a pulmonary extraction ratio of 24% when blood samples were obtained from the pulmonary artery and the pulmonary capillary wedge position.7 In the present study human pulmonary extraction ratios were 25.1% in mitral stenosis and 19.4% in atria1 septal defect, which were similar to those in previous reports. These findings suggest that the pulmonary extraction ratio was independent of underlying heart disease. On the other hand, the amount of hANP extracted in the lung was significantly correlated with the pulmonary blood flow in our study. Because ANP reduces pulmonary vascular tone by a vasodilatory effect21
American
April 1992 Heart Journal
and has a protective effect on chemically induced edema in the guinea pig lung,22 pulmonary extraction of hANP may prevent pulmonary hypertension or pulmonary edema in conditions of high pulmonary blood pressure. Obata et a1.gdemonstrated that the amount of hANP extracted in the lung correlated significantly with mean pulmonary arterial pressure or pulmonary capillary wedge pressure in patients with mitral stenosis and in normal control subjects. However, in our study groups, which included patients with atria1 septal defect, the amount of hANP extracted in the lung did not correlate significantly with these hemodynamic parameters. Further examination in each patient subgroup is needed to clarify the relationship between pulmonary extraction of hANP and hemodynamic parameters. Conclusions. hANP is secreted not only through the coronary sinus but also directly into circulating blood from the left atrium in conditions of high left atria1 pressure. Circulating hANP is partially extracted in the pulmonary circulation and may have some biological effects on the lung. We thank Dr. Yukio Hirata for supplying the hANP antibody and Drs. Shiro Saito and Masakazu Yamagishi for helpful advice. REFERENCES
4.
5.
6.
7.
8.
9.
10.
11.
Kisch B. Electron microscopy of the heart. I. Guinea pig. Exp Med Surg 1956;14:99-112. de Bold AJ. Atria1 natriuretic factor: a hormone produced by the heart. Science 1985;230:767-70. Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atria1 natriuretic polypeptide (alpha-hANP). Biochem Biophys Res Commun 1984;118:131-9. Sugawara A, Nakao K, Morii N, Sakamoto M, Suda M, Shimokura M, Kiso Y, Kihara M, Yamori Y, Nishimura K, Soneda J, Ban T, Imura H. Alpha-human atria1 natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun 1985;129:439-46. Sato F. Kamoi K. Wakiva Y. Ozawa T. Arai 0. Ishibashi M. Yamaji T. Relationship between plasma atria1 natriuretic peptide levels and atria1 pressure in man. J Clin Endocrinol Metab 1986;63:823-7. Rodeheffer RJ, Tanaka I, Imada T, Hollister AS, Robertson D, Inagaki T. Atria1 pressure and secretion of atria1 natriuretic factor into the human central circulation. J Am Co11 Cardiol 1986;8:18-26. Hollister AS, Rodeheffer RJ, White FJ, Potte JR, Imada T, Inagaki T. Clearance of atria1 natriuretic factor by lung, liver, and kidney in human subjects and the dog. J Clin Invest 1989;83:623-8. Weselcouch EO, Humphrey WR, Aiken JW. Effect of pulmonary and renal circulations on activity of atria1 natriuretic factor. Am J Physiol 1985;249:R595-602. Obata K, Yasue H, Okumura K, Matsumoto K, Ogawa H, Kurose M, Saito Y, Nakao K, Imura H, Nobuyoshi M. Atria1 natriuretic polypeptide is removed by the lungs and released into the left atrium as well as the right atrium in humans. J Am Co11 Cardiol’l990;15:1537-43. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984;87:394402. Kojima T, Hirata Y, Fukuda Y, Iwase S, Kobayashi Y. Plasma
Volume Number
123 4, Part 1
Left atria1 secretion of ANP
atria1 natriuretic peptide and spontaneous diuresis in sick neonates. Arch Dis Child 1987;62:667-70. 12. Yoshimi H, Inoue I, Hirata Y, Kojima S, Kuramochi M, Ito K, Sakakibara H. Atria1 natriuretic peptide secretion in mitral stenosis. Am J Cardiol 1987;60:396-7. 13. Bates ER, Shenker Y, Grekin RJ. The relationship between plasma levels of immunoreactive atrial natriuretic hormone and hemodynamic function in man. Circulation 1986;73:115561.
14. Crazier IG, Nicholls MG, Ikram H, Espiner EA, Yandle TG, Jan S. Atria1 natriuretic peptide in humans. Production and clearance by various tissues. Hypertension 1986;8(suppl II):II11-5.
15. Schutten HJ, Henriksen JH, Warberg J. Organ extraction of atria1 natriuretic peptide (ANP) in man. Significance of sampling site. Clin Physiol 1987;7:125-32. 16. Ishikura F, Nagata S, Hirata Y, Kimura K, Nakatani S, Tamai J, Yamagishi M, Ohmori F, Beppu S, Takamiya M, Miyatake K, Nimura Y. Rapid reduction of plasma atria1 natriuretic peptide levels during percutaneous transvenous mitral commissurotomy in patients with mitral stenosis. Circulation 1989;79:47-50.
17. Ledsome J, Wilson RN, Courneya CA, Rankin AJ. Release of atria1 natriuretic peptide by atria1 distension. Can J Physiol Pharmacol 1985;63:739-42. 18. Metzler CH, Lee M, Thrasher TN, Ramsay DJ. Increased right or left atria1 pressure stimulates release of atrial natriuretic peptides in conscious dogs. Endocrinology 1986;119:2396-8. 19. Sakamoto M, Nakao K, Morii N, Sugawara A, Yamada T, Itoh H, Shiono S, Saito Y, Imura H. The lung as a possible target organ for atria1 natriuretic polypeptide secreted from the heart. Biochem Biophys Res Commun 1986;135:515-20. 20. Bianchi K, Gutkowska J, Thibault G, Garcia R, Genest J, Cartin M. Radioautographic localization of lz51-atria1 natriuretic factor (ANF) in rat tissues. Histochemistry 1985;82:44152. 21.
22.
Faison EP, Siegl PKS, Morgan G, Winquist RJ. Regional vasorelaxant selectivity of atria1 natriuretic factor in isolated rabbit vessels. Life Sci 1985;37:1073-9. Inomata N, Ohnuma N, Furuya M. Alpha-human atria1 natriuretic peptide prevents pulmonary edema induced by arachindonic acid treatment in isolated perfused lung from guinea pig. Jpn J Pharmacol 1987;44:211-4.
Heart rate variations during isoproterenol infusion in congestive heart failure: Relationships to cardiac mortality A marked derangement of heart rate modulation in patients with severe cardiac heart failure (CHF) has been reported. The purpose of the study was to correlate the variations of sinus cycle length (SCL) during infusion of 4 pglmin of isoproterenol with the prognosis of 83 patients with CHF (mean left ventricular ejection fraction 28 + 9%). During a mean follow-up of 28 f 9 months, nine patients died from CHF (group I), nine died suddenly (group II), and 65 are alive (group Ill). Compared with groups II and Ill, a significantly weaker ejection fraction (20 k 8% versus 29.5 r 11% and 28 + 9%), a smaller control state SCL (571 + 65 versus 722 + 200 and 747 + 195), and a smaller percentage of SCL shortening during isoproterenol infusion (11.5 + 7% versus 36 f 16% and 33 t 13%) were noted in group I. The sensitivity and specificity of a percentage of SCL shortening during isoproterenol infusion ~15% for predicting death from CHF were 89% and 93%, respectively. Therefore the injection of small doses of isoproterenol (4 pglmin) may be proposed to evaluate the prognosis of patients with CHF; a weak increase in heart rate during this infusion is a sign of bad prognosis with a high risk of cardiac death as a result of CHF. (AM HEART J 1992;123:989.)
Beatrice Brembilla-Perrot,
MD. Vundoeuvre Les Nancy, France
Patients with long-standing congestive heart failure (CHF) have a high mortality irrespective of treatment. Some prognostic indicators can be identified. From Received
Cardiology
Reprint requests: 54500 Vandoeuvre 4/l/35357
A and B, CHU
for publication
April
of Brabois. 29, 1991;
B. Brembilla-Perrot, Les Nancy, France.
accepted MD,
Sept.
Cardiologie
12, 1991. A, CHU
Brabois,
The major predisposing factors for total mortality and sudden death are the severity of left ventricular impairment,’ a high plasma norepinephrine concentration2 the etiology of CHF,3 and the presence of ventricular arrhythmias. 4, 5 Recently a marked derangement of heart rate modulation in patients with severe CHF was reported$ a reduced standard deviation of normal R-R intervals over a 24-hour period is associated with increased mortality. The frequency
