Peripartum cardiomyopathy

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Classification according to ICD-10
O90.3 Cardiomyopathy in the puerperium
ICD-10 online (WHO version 2019)

The peri or postpartum cardiomyopathy , abbreviated PPCM (for the English name Peripartum cardiomyopathy ) is a rare, life-threatening heart disease in previously healthy women that occurs in the last weeks of pregnancy to six months after birth. The disease manifests itself through sudden onset of heart failure with cough, leg edema, general exhaustion and palpitations and can lead to death within a few weeks. The exact cause and the way in which the disease developed are still unknown.

Spread and Risk Factors

The incidence of the disease is estimated at 1: 3500 to 1: 1400 in Europe and the United States, 1: 1000 in South Africa, and 1: 299 in Haiti. That would correspond to around 300 new cases per year in Germany, but in fact 17 new cases were registered at the Hannover Medical School alone in 2007, which indicates a higher incidence of PPCM. The higher rate of diseases in South Africa and Haiti can be explained by a genetic predisposition . Smoking, preeclampsia , high blood pressure, the use of tocolytic drugs, twin pregnancies, teenage pregnancies, and pregnancies in older women are also risk factors that increase the likelihood of developing PPCM. However, a quarter to a third of all sick people are young, healthy, primeval women without any previous burden.

Molecular mechanism of formation

The exact causes of the disease are still unknown. A possible process that leads to the development of the disease was discovered in 2007. Based on experimental studies on mice, it was possible to show that a lack of anti-oxidative enzymes in the peri / postpartum heart leads to increased formation of oxygen radicals and thus to increased oxidative stress . This in turn has the consequence that prolactin is split into a pro-apoptotic and anti-angiogenic 16 kDa subform. Prolactin is a hormone that is produced in large quantities by the anterior pituitary gland at certain intervals during pregnancy and breastfeeding . It stimulates the production of milk, the growth of the mammary glands and the regression of the uterus after birth. Its 16-kDa sub-form has a number of harmful effects on the heart: It has massive damaging effects on the endothelium , on the microcirculation in the myocardium and reduces the metabolic activity of the myocardial cells. Ultimately, this leads to severe heart damage with the typical symptoms of PPCM. In the further course of the experiment - based on the knowledge gained - it was tested whether PPMC can be prevented by bromocriptine because bromocriptine inhibits the release of prolactin and thus prevents the formation of the subform. The result of this test was positive.

Parallels to this animal experiment were found in blood tests on women suffering from PPCM: the amount of certain indicators of oxidative stress and of 16 kDa prolactin (in three out of five sick women, but not in any healthy woman) in the blood was increased . Because of these parallels, a pilot study was carried out in Africa to investigate whether treatment with bromocriptine also had beneficial effects on the course of the disease in humans. That was the case.

The theory that PPCM is mainly a disease of the vascular system or a malfunction in angiogenesis was confirmed again in 2012 by further experiments on mice; other factors that may play a role in the development of PPCM were discovered. It turned out that PPCM develops in mice which on the one hand lack PGC-1α ( Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha ) and on the other hand have an increased amount of VEGF ( vascular endothelial growth factor ) inhibitors such as sFLT1 ( soluble fms-like tyrosine kinase-1 ). PGC-1α is a powerful regulator of angiogenesis in the body. VEGF inhibitors, in turn, are produced by the placenta later in pregnancy. The placenta forms more increased amounts of this substance in twins or in multiple pregnancies . That would also explain why women pregnant with twins are at greater risk of developing PPCM. In addition, sick women have abnormally high levels of sFLT1 in their blood, which supports these results.

Finally, in 2013, the understanding of the molecular mechanism on which PPCM is based was expanded once again. Denise Hilfiker-Kleiner and others have found that 16-kDa prolactin induces the expression of microRNA-146a, which reduces angiogenesis by downregulating NRAS ( neuroblastoma RAS viral (v-ras) oncogene homologous ). The microRNA-146a attacks the endothelial cells of the heart and thus leads to damage to the heart's blood vessels. In addition, there is also an increased release of microRNA-146a in the endothelial cells, which is stored in exosomes and taken up by the myocytes of the heart. This in turn leads to a reduction in metabolic activity and a reduction in the expression of Erbb4 , Notch1 , NRAS and Irak1 - genes that are important for the survival of myocytes. The microRNA-146a can, however , be blocked with microRNA antagonists or with LNA without interrupting the entire prolactin chain at the same time, as is the case with treatment with bromocriptine. In this way, the mother's ability to breastfeed is retained. In animal experiments with mice, treatment with these agents led to a weakening of the PPCM.

Clinical manifestations

In terms of clinical appearance, PPCM is similar to dilated cardiomyopathy and is therefore characterized by severe, rapidly progressing heart failure , which can necessitate a heart transplant . The symptoms are roughly: cough, leg edema and general exhaustion, but also peripheral arterial thrombosis and palpitations. However, these symptoms are very general and can occur during normal pregnancy; therefore a diagnosis is often made late. Due to the PPCM, mitral regurgitation can still occur. The risk of left ventricular and peripheral arterial thrombi, cardiac arrhythmias and sudden cardiac death is increased.

Investigation methods

If PPCM is suspected (typical symptoms appear), an echocardiogram and blood test for the N-terminal propeptide BNP are performed. This is used to identify the typical signs of dilated cardiomyopathy such as systolic dysfunction with a left ventricular ejection fraction (EF) of <45% and with an enlarged ventricle. An increased BNP level in the blood is not a specific marker for PPCM, but is generally typical for heart failure. The difference to other forms of dilated cardiomyopathy lies in the speed with which the PPCM progresses and can develop within a few days in previously apparently completely healthy women without previous illnesses. Chest X-rays and EKGs are of limited diagnostic use .

A diagnosis of PPCM is often made very late. There are several reasons for this: On the one hand, women who used to have a completely healthy heart do not think of a cardiac problem. On the other hand, the symptoms are very unspecific and are often interpreted as normal side effects of pregnancy or as pneumonia / infection . This applies in particular to shortness of breath and coughing, which, according to the authors of the Ärzteblatt, are often the first symptoms of the disease. Other clinical manifestations, such as an increase in the number of drawings in the X-ray image in the decompensation phase , leg edema or peripheral embolisms are not assigned to PPCM, but rather to the postpartum conversion phase . According to the experience of the authors, in 30% of all cases several weeks or even months pass before the correct diagnosis. The recently discovered marker MicroRNA-146a could make a decisive contribution to an earlier diagnosis as it is specific for this disease.

treatment

The treatment of peripartum cardiomyopathy is based primarily on conventional heart failure therapy according to the guidelines of the German Society for Cardiology , whereby the health of the fetus must also be taken into account (certain medications cannot then be used). Thus, ACE inhibitors or angiotensin II receptor antagonists and aldosterone antagonists are used only after pregnancy because of fetal damage. Instead, hydralazine and / or nitrates can be used. Beta blockers are also available if the woman is hemodynamically stable and digitalis . The exact dose of digitalis must be strictly observed, as women are more sensitive to this active ingredient.

If the left ventricular ejection fraction is less than 35%, the administration of anticoagulants ( heparin before and warfarin after birth) is indicated as otherwise there is an increased risk of left ventricular thrombosis (blood clots). Calcium channel blockers (such as amlodipine ) may also be indicated to lower blood pressure, but in most cases these drugs can not be used because of their poor inotropic properties. In severe heart failure, the heart must be mechanically supported or a heart transplant performed.

Because of the likely pathological effects of prolactin in this context, women who have recently given birth should stop breastfeeding immediately or should not even start breastfeeding. At the same time, this prevents the transfer of medication from the mother to the child. The more specific treatment with bromocriptine is under discussion and has already been tested in various smaller studies in Africa and Haiti, but is not yet approved in Germany. A newer therapeutic approach can also result from the knowledge gained with regard to the microRNA-146a by blocking the microRNA-146a with microRNA antagonists or with LNA . This would not affect the prolactin per se and breastfeeding would be possible for the mothers.

Prospect of healing

The mortality rate for peripartum cardiomyopathy is around 15% according to a study with 100 women in Africa and a further longer study over five years in Haiti. Another study that looked mainly (67%) in white women found a mortality rate of 9%. The first study in Africa found that the left ventricular values ​​normalized in 23% of the women affected, the second study in Haiti found this to be 31-35% and the last 54%. Normalization is more likely if the left ventricular ejection fraction was over 30% at diagnosis.

Other, but not more recent, studies show far more favorable results: They only come to mortality rates of 0 to 7%.

Individual evidence

  1. ↑ a b c Karen Sliwa, James Fett and Uri Elkayam: Peripartum cardiomyopathy Archived from the original on March 4, 2016. Information: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: The Lancet . 368, 2006, pp. 687-693. PMID 16920474 . Retrieved July 27, 2015. @1@ 2Template: Webachiv / IABot / www.med.upenn.edu
  2. ↑ a b c d e f g Denise Hilfiker-Kleiner, Elisabeth Schieffer, Gerd Peter Meyer, Edith Podewski and Helmut Drexler: Postpartum cardiomyopathy: a cardiological emergency for gynecologists, general practitioners, internists, pulmonologists and cardiologists . In: Deutsches Ärzteblatt . 105, No. 44, 2008, pp. 751-756. doi : 10.3238 / arztebl.2008.0751 .
  3. ↑ Denise Hilfiker-Kleiner, K. Kaminski, E. Podewski, T. Bonda, A. Schaefer, K. Sliwa, O. Forster, A. Quint, U. Landmesser, C. Doerries, M. Luchtefeld, V. Poli, Schneider, JL Balligand, F. Desjardins, A. Ansari, I. Struman, NQ Nguyen, NH Zschemisch, G. Klein, G. Heusch, R. Schulz, A. Hilfiker and H. Drexler: A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. . In: Cell . 128, No. 3, February 2007, pp. 589-600. PMID 17289576 .
  4. ↑ Ian S. Patten, Sarosh Rana, Sajid Shahul, Glenn C. Rowe, Cholsoon Jang, Laura Liu, Michele R. Hacker, Julie S. Rhee, John Mitchell, Feroze Mahmood, Philip Hess, Caitlin Farrell, Nicole Koulisis, Eliyahu V Khankin, Suzanne D. Burke, Igor Tudorache, Johann Bauersachs , Federica del Monte, Denise Hilfiker-Kleiner, S. Ananth Karumanchi, Zoltan Arany: Cardiac angiogenic imbalance leads to peripartum cardiomyopathy . In: Nature . 485, May 2012, ISSN  0028-0836 , pp. 333-338. doi : 10.1038 / nature11040 .
  5. ↑ a b Julie Halkein, Sebastien P. Tabruyn, Melanie Ricke-Hoch, Arash Haghikia, Ngoc-Quynh-Nhu Nguyen, Michaela Scherr, Karolien Castermans, Ludovic Malvaux, Vincent Lambert, Marc Thiry, Karen Sliwa, Agnes Noel, Joseph A. Martial, Denise Hilfiker-Kleiner and Ingrid Struman: MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy . In: The Journal of Clinical Investigation . 123, No. 5, May 2013, pp. 2143-2154. doi : 10.1172 / JCI64365 . PMID 23619365 .
  6. ↑ a b Hannover Medical School: MHH researchers discover new diagnostic options for heart failure in pregnant women . April 25, 2013. Archived from the original on October 9, 2015. Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved on July 31, 2015. (Press release from MHH). @1@ 2Template: Webachiv / IABot / www.mh-hannover.de
  7. ↑ Peripartum Cardiomyopathy (PPCM) , Hannover Medical School, accessed on August 1, 2015.
  8. ^ H. Stepan, T. Walther and D. Pfeiffer: Peripartum cardiomyopathy-the (un) known obstetricalcardiologic emergency situation . In: Journal of Cardiology . 92, No. 10, October 2003, pp. 811-816. PMID 14579044 .
  9. ^ Diagnosis for cardiac insufficiency in pregnant women , In: Ärztezeitung , May 3, 2013, accessed on July 31, 2015.
  10. ↑ a b Therapy of periparal cardiomyopathy . In: The medicament letter . 46, No. 29, 2012.
  11. ↑ Gail D. Pearson, Jean-Claude Veille, Shahbudin Rahimtoola, Judith Hsia, Celia M. Oakley, Jeffrey D. Hosenpud, Aftab Ansari, Kenneth L. Baughman: Peripartum Cardiomyopathy National Heart, Lung, and Blood Institute and Office of Rare Diseases ( National Institutes of Health) Workshop Recommendations and Review . In: Journal of the American Medical Association . 283, No. 9, March 2000, pp. 1183-1188. doi : 10.1001 / jama.283.9.1183 . PMID 10703781 .
  12. ↑ U. Elkayam, MW Akhter, H. Singh, S. Khan, F. Bitar, A. Hameed, A. Shotan: Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation . In: Circulation . 111, No. 16, April 2005, pp. 2050-2055. PMID 15851613 .
  13. ↑ G. Michael Felker, Christopher J. Jaeger, Elizabeth Klodas, David R. Thiemann, Joshua M. Hare, Ralph H. Hruban, Edward K. Kasper and Kenneth L. Baughman: Myocarditis and long-term survival in peripartum cardiomyopathy . In: American Heart Journal . 140, No. 5, November 2000, pp. 785-791. doi : 10.1067 / mhj.2000.110091 . PMID 11054626 .
  14. ↑ Ankie M. Amos, Wissam A. Jaber and Stuart D. Russell: Improved outcome in peripartum cardiomyopathie with contemporary . In: American Heart Journal . 152, No. 3, September 2006, pp. 509-513. doi : 10.1016 / y.ahj.2006.02.008 . PMID 16923422 .