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Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion
Case Report
www. AJOG.org
Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion Boriana G. Jahns, MD; Werner Stein, MD; Denise Hilfiker-Kleiner, MD; Burkert Pieske, MD; Günter Emons, MD
P
eripartum cardiomyopathy (PPCM) is a rare disease of unknown etiology, characterized by an acute onset of heart failure in women in the late stage of pregnancy up to several months postpartum.1,2 The reported outcome of PPCM is variable, improves significantly when heart failure medication was given and is reported not to worsen even after discontinuation of the therapy.1-4 PPCM presents mostly with symptoms and signs of systolic heart failure.2,5,6 Early treatment of PPCM is often hampered by a delayed diagnosis due to an overlap with common symptoms of the physiological adaptation during the peripartum phase. Bromocriptine, a dopamine D(2) antagonist that inhibits prolactin secretion, implies a novel causative therapeutic option.7 Due to the common delay in diagnosis in patients with PPCM and the newly causative therapeutic option with Bromocriptine, we present this case report.
From the Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany (Drs Jahns, Stein, and Emons); Department of Obstetrics and Gynecology, Inselspital, University Hospital University of Bern, Bern, Switzerland (Dr Jahns); Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (Dr Hilfiker-Kleiner); Centre for Internal Medicine, GeorgAugust-University, Göttingen, Germany (Dr Pieske); Centre for Internal Medicine, University Hospital, Graz, Austria (Dr Pieske). Received April 10, 2008; revised May 30, 2008; accepted June 18, 2008. Reprints: Boriana Jahns, Department of Gynecology and Obstetrics, Georg-AugustUniversity, Robert-Koch-Strae 40, D-37075 Göttingen, Germany. [email protected]. 0002-9378/free © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.051
Peripartum cardiomyopathy (PPCM) is a rare disease of unclear etiology with a frequent poor outcome, despite optimal medical therapy. Recent experimental data implicate a causal role of prolactin. We report a patient with PPCM who responded well to treatment with Bromocriptine in addition to standard therapy of heart failure. Key words: bromocriptine, cathepsin D, peripartum cardiomyopathy, prolactin
C ASE R EPORT A 43-year-old primigravida with uneventful history and family history was transferred at 34 ⫹2 weeks of gestation due to preeclampsia and suspected hemolysis, elevated liver enzyme levels, low platelet count (HELLP) syndrome. The patient showed slightly elevated blood pressure (145/95 mmHg) and proteinuria (protein 100 mg/dL). Ultrasonography showed apart from oligohydramnion (amnion fluid index 4) a fetal weight estimation and Doppler measuments of fetal and maternal vessels within normal range. The patient was initially without further complaints; however, she developed a headache. Platelets dropped from 102,000 to 87,000/mm3 and haptoglobin lowered to 0.14 g/L (normal range, 0.45-2.05 g/L). Lactate-dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were within normal range. A cesarean section was performed 2 days after admission because she developed dyspnea. A male newborn—Apgar 7/8/9, umbilical artery pH 7.35, birthweight 1825 g—was delivered. Immediately after delivery the patient weaned with Cabergolin 1 mg. The dyspnea was initially thought to be a complication of a HELLP syndrome. Her clinical condition improved upon diuretic medication. She was discharged to home 7 days postoperatively in stable condition. The next day she was readmitted because of increasing dyspnea and orthopnea. The chest x-ray demonstrated a pulmonary edema. Despite appropriate therapy the left ventricular (LV) contractility deteriorated
considerably and the ejection fraction dropped to 30% within the next 4 days. The coronary angiography was normal. The myocardial biopsy revealed a histopathological picture of cardiomyopathy (Figure 1). The prolactin cleaving protease Cathepsin D gave a strong and specific signal on biopsy section (Figure 2). The patient responded very well to medically induced diuresis. She received angiotensin-converting enzyme (ACE)inhibitor, digoxin, and beta-blocker, to treat cardiac failure, and was also given Bromocriptine 2.5 mg/QD after written consent. On discharge 16 days after the second admission, the left ventricular contractility had improved with an ejection fraction of 43%. At follow-up examinations, the ejection fraction of the left ventricle had improved further (after 6 months: ejection
FIGURE 1
Myocardial biopsy from the patient
Small cardiomyocytes with big nuclei (arrow) and edematous cardiac musculature. Jahns. Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion. Am J Obstet Gynecol 2008.
OCTOBER 2008 American Journal of Obstetrics & Gynecology
e5
Case Report
www.AJOG.org
FIGURE 2
Cathepsin D expression in the myocard of the patient DAPI (blue) Cathepsin D (CY3) Neuromics G115042
A
DAPI (blue) IgG (CY3)
C
associated with dilated cardiomypathy in a patient being treated for a microprolactinoma.10 Despite this encouraging case, a randomized trial will be needed to prove the efficacy of Bromocriptine in the treatf ment of PPCM. REFERENCES
B
Cathepsin D gave a strong and specific signal on paraffin section from PPCM patient. A, Cathepson D staining (red ) on paraffin section from the patient myocard; B, A myocardiocyt with a strong Cathepsin D signal; C, IgG control. Jahns. Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion. Am J Obstet Gynecol 2008.
fraction 50%). Bromocriptine was discontinued after a 3-month period.
C OMMENT A 16 kDa prolactin derivate promotes endothelial cell apoptosis, disrupts capillary structures, and impairs cardiomyocyte metabolism and contractility.7-9 Recent experimental data implicate a causal role of the cleaved 16 kDa prolactin for the development of PPCM in mice with a cardiac restricted deletion of the signal transducer and activator of transcription-3 (STAT-3).7 Suppression of prolactin secretion with Bromocriptine averts PPCM in
e6
these mice. Most importantly, Bromocriptine prevented the expected deterioration of LV dimensions and systolic function in a clinical pilot study when given in addition to standard heart failure therapy to patients with a subsequent pregnancy after a known PPCM.7 Here, we report that Bromocriptine in addition to standard therapy improved the symptoms of PPCM. Based on experimental and initial clinical findings, Bromocriptine may serve as a causative therapeutic option. Side effects of Bromocriptine are rare but include nausea, vomiting, and orthostatic dysregulation. Bromocriptine has recently also been
American Journal of Obstetrics & Gynecology OCTOBER 2008
1. Reimold SC, Rutherford JD. Peripartum cardiomyopathy. N Engl J Med 2001;344: 1629-30. 2. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368:687-93. 3. Brar SS, Khan SS, Sandhu GK, et al. Incidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol 2007; 100:302-4. 4. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006;152:509-13. 5. Fett JD. Peripartum cardiomyopathy. Insights from Haiti regarding a disease of unknown etiology. Minn Med 2002;85:46-8. 6. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: Analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/ APO-1. J Am Coll Cardiol 2000;35:701-5. 7. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589-600. 8. Corbacho AM, Martinez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. J Endocrinol 2002;173:219-38. 9. Tabruyn SP, Sorlet CM, Rentier-Delrue F, et al. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB. Mol Endocrinol. 2003; 7:1815-23. 10. Kaushik P, Vatsavai SR, Banda VR, Sanghi PK, Ahmad M, Kaushik R. Acute onset of severe dilated cardiomyopathy during bromocriptine therapy. Ann Pharmacother 2004;38: 1219-21.
www. AJOG.org
Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion Boriana G. Jahns, MD; Werner Stein, MD; Denise Hilfiker-Kleiner, MD; Burkert Pieske, MD; Günter Emons, MD
P
eripartum cardiomyopathy (PPCM) is a rare disease of unknown etiology, characterized by an acute onset of heart failure in women in the late stage of pregnancy up to several months postpartum.1,2 The reported outcome of PPCM is variable, improves significantly when heart failure medication was given and is reported not to worsen even after discontinuation of the therapy.1-4 PPCM presents mostly with symptoms and signs of systolic heart failure.2,5,6 Early treatment of PPCM is often hampered by a delayed diagnosis due to an overlap with common symptoms of the physiological adaptation during the peripartum phase. Bromocriptine, a dopamine D(2) antagonist that inhibits prolactin secretion, implies a novel causative therapeutic option.7 Due to the common delay in diagnosis in patients with PPCM and the newly causative therapeutic option with Bromocriptine, we present this case report.
From the Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany (Drs Jahns, Stein, and Emons); Department of Obstetrics and Gynecology, Inselspital, University Hospital University of Bern, Bern, Switzerland (Dr Jahns); Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (Dr Hilfiker-Kleiner); Centre for Internal Medicine, GeorgAugust-University, Göttingen, Germany (Dr Pieske); Centre for Internal Medicine, University Hospital, Graz, Austria (Dr Pieske). Received April 10, 2008; revised May 30, 2008; accepted June 18, 2008. Reprints: Boriana Jahns, Department of Gynecology and Obstetrics, Georg-AugustUniversity, Robert-Koch-Strae 40, D-37075 Göttingen, Germany. [email protected]. 0002-9378/free © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.051
Peripartum cardiomyopathy (PPCM) is a rare disease of unclear etiology with a frequent poor outcome, despite optimal medical therapy. Recent experimental data implicate a causal role of prolactin. We report a patient with PPCM who responded well to treatment with Bromocriptine in addition to standard therapy of heart failure. Key words: bromocriptine, cathepsin D, peripartum cardiomyopathy, prolactin
C ASE R EPORT A 43-year-old primigravida with uneventful history and family history was transferred at 34 ⫹2 weeks of gestation due to preeclampsia and suspected hemolysis, elevated liver enzyme levels, low platelet count (HELLP) syndrome. The patient showed slightly elevated blood pressure (145/95 mmHg) and proteinuria (protein 100 mg/dL). Ultrasonography showed apart from oligohydramnion (amnion fluid index 4) a fetal weight estimation and Doppler measuments of fetal and maternal vessels within normal range. The patient was initially without further complaints; however, she developed a headache. Platelets dropped from 102,000 to 87,000/mm3 and haptoglobin lowered to 0.14 g/L (normal range, 0.45-2.05 g/L). Lactate-dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were within normal range. A cesarean section was performed 2 days after admission because she developed dyspnea. A male newborn—Apgar 7/8/9, umbilical artery pH 7.35, birthweight 1825 g—was delivered. Immediately after delivery the patient weaned with Cabergolin 1 mg. The dyspnea was initially thought to be a complication of a HELLP syndrome. Her clinical condition improved upon diuretic medication. She was discharged to home 7 days postoperatively in stable condition. The next day she was readmitted because of increasing dyspnea and orthopnea. The chest x-ray demonstrated a pulmonary edema. Despite appropriate therapy the left ventricular (LV) contractility deteriorated
considerably and the ejection fraction dropped to 30% within the next 4 days. The coronary angiography was normal. The myocardial biopsy revealed a histopathological picture of cardiomyopathy (Figure 1). The prolactin cleaving protease Cathepsin D gave a strong and specific signal on biopsy section (Figure 2). The patient responded very well to medically induced diuresis. She received angiotensin-converting enzyme (ACE)inhibitor, digoxin, and beta-blocker, to treat cardiac failure, and was also given Bromocriptine 2.5 mg/QD after written consent. On discharge 16 days after the second admission, the left ventricular contractility had improved with an ejection fraction of 43%. At follow-up examinations, the ejection fraction of the left ventricle had improved further (after 6 months: ejection
FIGURE 1
Myocardial biopsy from the patient
Small cardiomyocytes with big nuclei (arrow) and edematous cardiac musculature. Jahns. Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion. Am J Obstet Gynecol 2008.
OCTOBER 2008 American Journal of Obstetrics & Gynecology
e5
Case Report
www.AJOG.org
FIGURE 2
Cathepsin D expression in the myocard of the patient DAPI (blue) Cathepsin D (CY3) Neuromics G115042
A
DAPI (blue) IgG (CY3)
C
associated with dilated cardiomypathy in a patient being treated for a microprolactinoma.10 Despite this encouraging case, a randomized trial will be needed to prove the efficacy of Bromocriptine in the treatf ment of PPCM. REFERENCES
B
Cathepsin D gave a strong and specific signal on paraffin section from PPCM patient. A, Cathepson D staining (red ) on paraffin section from the patient myocard; B, A myocardiocyt with a strong Cathepsin D signal; C, IgG control. Jahns. Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion. Am J Obstet Gynecol 2008.
fraction 50%). Bromocriptine was discontinued after a 3-month period.
C OMMENT A 16 kDa prolactin derivate promotes endothelial cell apoptosis, disrupts capillary structures, and impairs cardiomyocyte metabolism and contractility.7-9 Recent experimental data implicate a causal role of the cleaved 16 kDa prolactin for the development of PPCM in mice with a cardiac restricted deletion of the signal transducer and activator of transcription-3 (STAT-3).7 Suppression of prolactin secretion with Bromocriptine averts PPCM in
e6
these mice. Most importantly, Bromocriptine prevented the expected deterioration of LV dimensions and systolic function in a clinical pilot study when given in addition to standard heart failure therapy to patients with a subsequent pregnancy after a known PPCM.7 Here, we report that Bromocriptine in addition to standard therapy improved the symptoms of PPCM. Based on experimental and initial clinical findings, Bromocriptine may serve as a causative therapeutic option. Side effects of Bromocriptine are rare but include nausea, vomiting, and orthostatic dysregulation. Bromocriptine has recently also been
American Journal of Obstetrics & Gynecology OCTOBER 2008
1. Reimold SC, Rutherford JD. Peripartum cardiomyopathy. N Engl J Med 2001;344: 1629-30. 2. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368:687-93. 3. Brar SS, Khan SS, Sandhu GK, et al. Incidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol 2007; 100:302-4. 4. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006;152:509-13. 5. Fett JD. Peripartum cardiomyopathy. Insights from Haiti regarding a disease of unknown etiology. Minn Med 2002;85:46-8. 6. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: Analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/ APO-1. J Am Coll Cardiol 2000;35:701-5. 7. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589-600. 8. Corbacho AM, Martinez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. J Endocrinol 2002;173:219-38. 9. Tabruyn SP, Sorlet CM, Rentier-Delrue F, et al. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB. Mol Endocrinol. 2003; 7:1815-23. 10. Kaushik P, Vatsavai SR, Banda VR, Sanghi PK, Ahmad M, Kaushik R. Acute onset of severe dilated cardiomyopathy during bromocriptine therapy. Ann Pharmacother 2004;38: 1219-21.