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Elevated B-type natriuretic peptide levels after anthracycline administration
Elevated B-type natriuretic peptide levels after anthracycline administration Toru Suzuki, MD, Doubun Hayashi, MD, Tsutomu Yamazaki, MD, Takehiko Mizuno, MD, Yoshinobu Kanda, MD, Issei Komuro, MD, Masahiko Kurabayashi, MD, Kazuhide Yamaoki, MD, Kinuko Mitani, MD, Hisamaru Hirai, MD, Ryozo Nagai, MD, and Yoshio Yazaki, MD Tokyo, Japan
Background Cardiotoxicity leading to congestive heart failure is a complication of the anthracyclines. Biochemical methods to diagnose and monitor cardiac function after anthracycline administration would be most useful. We examined the diagnostic role of Btype natriuretic peptide (BNP), a potent biochemical marker of left ventricular dysfunction, in patients administered anthracyclines.
Methods Twenty-seven consecutive patients receiving anthracyclines were investigated by serial measurements of BNP levels and other cardiac neurohormones (A-type natriuretic peptide, renin, aldosterone, angiotensin II, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain). Echocardiography was done to assess systolic (ejection fraction) and diastolic (mitral inflow A/E ratio) functions.
Results Of the examined cardiac biochemical markers, BNP levels alone showed marked elevations to abnormal levels after anthracycline administration. Most patients showed transient increases (peak at 3 to 7 days). Patients with persistent elevations showed a poor prognosis. A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest that raised BNP levels are reflective of induced diastolic dysfunction.
Conclusions Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Serial BNP profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction. (Am Heart J 1998;136:362-3.)
The anthracycline antineoplastic agents are widely used chemotherapeutic agents, yet cardiotoxic side effects leading to heart failure are a limitation in their use.1,2 Biochemical means as a noninvasive method to diagnose and monitor cardiac function after anthracycline administration would be beneficial both for cardiologists and noncardiologists. B-type natriuretic peptide (BNP) is a potent biochemical marker of left ventricular (LV) dysfunction with diagnostic, therapeutic, and prognostic implications.3-5 We reasoned that BNP could be a promising marker for use in biochemical assessment of cardiac function after anthracycline administration and examined BNP levels in patients who were administered anthracyclines.
From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo. Submitted Nov. 26, 1997; accepted Feb. 19, 1998. Reprint requests: Toru Suzuki, MD, The Third Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail:[email protected] Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89908
Methods Twenty-seven consenting consecutive patients (13 men and 14 women, 47.9 ± 8.7 and 53.2 ± 4.6 years, mean ± SE; not significant) undergoing anthracycline administration for hematologic malignancies were investigated by serial measurements. Patients with renal failure, hypertension, myocardial hypertrophy, or ischemia were excluded because of the possibility of concomitant elevations in BNP levels. The cumulative anthracycline dosage at entry was 221.4 ± 53.7 mg/m2.
Results Basal BNP levels were raised and showed further marked elevations after anthracycline administration (basal levels 31.1 ± 7.16; after chemotherapy 58.1 ± 12.8 pg/ml [normal reference <19 pg/ml]). Basal and postchemotherapy levels of circulating levels of other cardiac neurohormones (atrial natriuretic peptide, renin, aldosterone, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain), with the exception of circulating angiotensin II levels, were within the normal range. Although atrial natriuretic peptide did show significant elevations with chemotherapy, they were nondiagnostic changes. None of
American Heart Journal Volume 136, Number 2
Suzuki et al. 363
Table I. Serial changes in biochemical parameters Before chemotherapy Circulating levels BNP ANP Norepinephrine Epinephrine Aldosterone Angiotensin II Renin (resting supine) CK-MB Myosin light chain Serial changes in biochemical and echocardiographic parameters Ejection fraction E/A ratio
After chemotherapy
31.1 ± 7.16 14.1 ± 2.21 0.21 ± 0.07 0.052 ± 0.002 77.17 ± 26.2 20.3 ± 5.57 1.78 ± 0.92 1.36 ± 0.16 1.26 ± 0.24
58.1 ± 12.8* 29.2 ± 6.94* 0.094 ± 0.016 0.050 ± 0.001 50.3 ± 8.58 24.5 ± 16.1 3.48 ± 2.23 1.46 ± 0.27 1.68 ± 0.40
56.0 ± 3.45 1.30 ± 0.11
58.0 ± 2.49 1.13 ± 0.08
Reference values <19 pg/ml <43 pg/ml 0.07 to 0.31 ng/ml <0.10 ng/ml 30 to 160 pg/ml <20 pg/ml 0.47 to 4.72 ng/ml/hr <7.4 ng/ml <2.5 ng/ml 65.0% ± 10.0%
BNP, B-type natriuretic peptide; ANP, atrial natriuretic peptide; CK-MB, creatine kinase-MB. *p < .05 for prechemotherapeutic versus postchemotherapeutic values.
the other biochemical markers, including angiotensin II, showed significant changes after chemotherapy (see Table I for values). Analysis showed correlation of basal BNP levels with age (r = 0.46, p < 0.05), which were stronger with elevations induced by anthracycline administration (r = 0.66, p < 0.01) independent of dosage. A marginal increase in the A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest raised BNP levels to be reflective of induced diastolic dysfunction.
Discussion BNP levels were raised in patients receiving anthracyclines. Most patients showed transient increases with peak levels within 3 to 7 days after administration that returned to baseline within 2 weeks. However, two of three patients with persistently elevated BNP levels subsequently died from circulatory failure, which may suggest a possible prognostic role for BNP measurements as well.5 Secondary causes resulting in elevated BNP levels were unlikely in these patients, nor were marked hemodynamic changes seen in the asymptomatic stages. Elevated atrial natriuretic peptide and angiotensin II level changes are supportive of cardiac dysfunction; they are also augmented in cardiac decompensatory states. However, the importance of this finding will require further clarification given the absence of marked changes. Collectively, we have shown BNP plasma levels to be elevated in patients receiving anthracyclines, with raised basal levels further elevated by anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Increased BNP
secretion is the most reasonable physiologic response (vasodilatory and natriuretic). Age-related effects on basal and induced responses are suggested (i.e., augmented basal and induced response in older patients). BNP serial profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying LV dysfunction.6 Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. Studies in larger cohorts should clarify the therapeutic and prognostic use of BNP measurements.
References 1. Doroshow, JH. Doxorubicin-induced cardiac toxicity. N Engl J Med 1991;324:843-5. 2. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996;125:47-58. 3. Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M, Mukoyama M, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464-9. 4. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90:195-203. 5. Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Circulation 1996;93:1963-9. 6. Matsumoto A, Hirata Y, Momomura S, Suzuki E, Yokoyama I, Sata M, et al. Effects of exercise on plasma level of brain natriuretic peptide in congestive heart failure with and without left ventricular dysfunction. Am Heart J 1995;129:139-45.
Background Cardiotoxicity leading to congestive heart failure is a complication of the anthracyclines. Biochemical methods to diagnose and monitor cardiac function after anthracycline administration would be most useful. We examined the diagnostic role of Btype natriuretic peptide (BNP), a potent biochemical marker of left ventricular dysfunction, in patients administered anthracyclines.
Methods Twenty-seven consecutive patients receiving anthracyclines were investigated by serial measurements of BNP levels and other cardiac neurohormones (A-type natriuretic peptide, renin, aldosterone, angiotensin II, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain). Echocardiography was done to assess systolic (ejection fraction) and diastolic (mitral inflow A/E ratio) functions.
Results Of the examined cardiac biochemical markers, BNP levels alone showed marked elevations to abnormal levels after anthracycline administration. Most patients showed transient increases (peak at 3 to 7 days). Patients with persistent elevations showed a poor prognosis. A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest that raised BNP levels are reflective of induced diastolic dysfunction.
Conclusions Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Serial BNP profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction. (Am Heart J 1998;136:362-3.)
The anthracycline antineoplastic agents are widely used chemotherapeutic agents, yet cardiotoxic side effects leading to heart failure are a limitation in their use.1,2 Biochemical means as a noninvasive method to diagnose and monitor cardiac function after anthracycline administration would be beneficial both for cardiologists and noncardiologists. B-type natriuretic peptide (BNP) is a potent biochemical marker of left ventricular (LV) dysfunction with diagnostic, therapeutic, and prognostic implications.3-5 We reasoned that BNP could be a promising marker for use in biochemical assessment of cardiac function after anthracycline administration and examined BNP levels in patients who were administered anthracyclines.
From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo. Submitted Nov. 26, 1997; accepted Feb. 19, 1998. Reprint requests: Toru Suzuki, MD, The Third Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail:[email protected] Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89908
Methods Twenty-seven consenting consecutive patients (13 men and 14 women, 47.9 ± 8.7 and 53.2 ± 4.6 years, mean ± SE; not significant) undergoing anthracycline administration for hematologic malignancies were investigated by serial measurements. Patients with renal failure, hypertension, myocardial hypertrophy, or ischemia were excluded because of the possibility of concomitant elevations in BNP levels. The cumulative anthracycline dosage at entry was 221.4 ± 53.7 mg/m2.
Results Basal BNP levels were raised and showed further marked elevations after anthracycline administration (basal levels 31.1 ± 7.16; after chemotherapy 58.1 ± 12.8 pg/ml [normal reference <19 pg/ml]). Basal and postchemotherapy levels of circulating levels of other cardiac neurohormones (atrial natriuretic peptide, renin, aldosterone, norepinephrine, and epinephrine) and myocardial markers (creatine kinase-MB and myosin light chain), with the exception of circulating angiotensin II levels, were within the normal range. Although atrial natriuretic peptide did show significant elevations with chemotherapy, they were nondiagnostic changes. None of
American Heart Journal Volume 136, Number 2
Suzuki et al. 363
Table I. Serial changes in biochemical parameters Before chemotherapy Circulating levels BNP ANP Norepinephrine Epinephrine Aldosterone Angiotensin II Renin (resting supine) CK-MB Myosin light chain Serial changes in biochemical and echocardiographic parameters Ejection fraction E/A ratio
After chemotherapy
31.1 ± 7.16 14.1 ± 2.21 0.21 ± 0.07 0.052 ± 0.002 77.17 ± 26.2 20.3 ± 5.57 1.78 ± 0.92 1.36 ± 0.16 1.26 ± 0.24
58.1 ± 12.8* 29.2 ± 6.94* 0.094 ± 0.016 0.050 ± 0.001 50.3 ± 8.58 24.5 ± 16.1 3.48 ± 2.23 1.46 ± 0.27 1.68 ± 0.40
56.0 ± 3.45 1.30 ± 0.11
58.0 ± 2.49 1.13 ± 0.08
Reference values <19 pg/ml <43 pg/ml 0.07 to 0.31 ng/ml <0.10 ng/ml 30 to 160 pg/ml <20 pg/ml 0.47 to 4.72 ng/ml/hr <7.4 ng/ml <2.5 ng/ml 65.0% ± 10.0%
BNP, B-type natriuretic peptide; ANP, atrial natriuretic peptide; CK-MB, creatine kinase-MB. *p < .05 for prechemotherapeutic versus postchemotherapeutic values.
the other biochemical markers, including angiotensin II, showed significant changes after chemotherapy (see Table I for values). Analysis showed correlation of basal BNP levels with age (r = 0.46, p < 0.05), which were stronger with elevations induced by anthracycline administration (r = 0.66, p < 0.01) independent of dosage. A marginal increase in the A/E ratio also correlated with increases in BNP levels in selected patients, which may suggest raised BNP levels to be reflective of induced diastolic dysfunction.
Discussion BNP levels were raised in patients receiving anthracyclines. Most patients showed transient increases with peak levels within 3 to 7 days after administration that returned to baseline within 2 weeks. However, two of three patients with persistently elevated BNP levels subsequently died from circulatory failure, which may suggest a possible prognostic role for BNP measurements as well.5 Secondary causes resulting in elevated BNP levels were unlikely in these patients, nor were marked hemodynamic changes seen in the asymptomatic stages. Elevated atrial natriuretic peptide and angiotensin II level changes are supportive of cardiac dysfunction; they are also augmented in cardiac decompensatory states. However, the importance of this finding will require further clarification given the absence of marked changes. Collectively, we have shown BNP plasma levels to be elevated in patients receiving anthracyclines, with raised basal levels further elevated by anthracycline administration. BNP levels most likely reflect cardiac tolerance to the cardiotoxic agent. Increased BNP
secretion is the most reasonable physiologic response (vasodilatory and natriuretic). Age-related effects on basal and induced responses are suggested (i.e., augmented basal and induced response in older patients). BNP serial profiles also suggest persistent elevations to be associated with potentially decompensatory states in contrast to tolerable transient increases. Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying LV dysfunction.6 Our studies suggest the possible use of BNP levels to assess the cardiac state after anthracycline administration. Studies in larger cohorts should clarify the therapeutic and prognostic use of BNP measurements.
References 1. Doroshow, JH. Doxorubicin-induced cardiac toxicity. N Engl J Med 1991;324:843-5. 2. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996;125:47-58. 3. Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M, Mukoyama M, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464-9. 4. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90:195-203. 5. Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Circulation 1996;93:1963-9. 6. Matsumoto A, Hirata Y, Momomura S, Suzuki E, Yokoyama I, Sata M, et al. Effects of exercise on plasma level of brain natriuretic peptide in congestive heart failure with and without left ventricular dysfunction. Am Heart J 1995;129:139-45.