Peripartum Cardiomyopathy

Transcription

1 Peripartum Cardiomyopathy Denise Hilfiker-Kleiner Kardiologie & Angiologie MHH, Hannover Nothing to disclose

2 Peri- or Postpartum Cardiomyopathy Peri- or postpartum cardiomyopathy (PPCM) is a disorder of unknown etiology in which symptoms of heart failure occur between the last month of pregnancy and 5 months postpartum. USA and Western Europa: 1: to 1:3.500 Africa: 1: 100 to 1:1.000 Haiti: 1: 300 Reimold S.& Rutherford J. N Engl J Med 2001 Sliwa K. et al. Am J Cardiol 2004 Sliwa K. et al. Lancet 2006 Mayosi Int J Cardiol Hilfiker-Kleiner et al. TCM 2008

3 Peri- or Postpartum Cardiomyopathy Rapid progression of the disease, endstage heart failure is often seen already 1 to 6 months after diagnosis At present PPCM is listed as a form of dilated cardiomyopathy and is treated according to the guidelines for dilated cardiomyopathy with no specific therapy. Reimold S., Rutherford J., Peripartum Cardiomyopathy, N Engl J Med 2001 Sliwa K. et al. Am J Cardiol 2004, Sliwa K. et al. Lancet 2006

4 Experimental data and first clinical data suggest that a cascade involving oxidative stress and cleavage of prolactin in an angiostatic subfragment initiates and drives PPCM Selle,.., Hilfiker-Kleiner Future Cardiology 2009

5 Several case reports suggest that an early treatment of acute PPCM with Bromocriptine is beneficial Hilfiker-Kleiner et al. JACC 2007 Jahns et al. Am J Obstet Gynecol 2008 Habedank et al.eur J of Heart Failure 2008 Meyer et al. JMCR 2010

6 First randomized study with 20 patients tested efficacy of bromocriptine in acute PPCM South Africa Inclusion criteria: within the first postpartal month, HIV negative. Observation periode: 6 months Standard therapy and Bromocriptine: 10 patients Standard therapy, Std: 10 patients 16 kda prolactin in PPCM patients at baseline NP Br Std Br Br Std Std IgG 23 kda 16 kda Sliwa K.,... Hilfiker-Kleiner D. Circulation 2010

7 Lower mortality and better cardiac function in the Bromocriptine group PPCM Bromocriptine, n=10: Mortality 10% PPCM Standard therapy, n=10: Mortality 40% Sliwa K.,... Hilfiker-Kleiner D. Circulation 2010

8 Blockade of prolactin by Bromocriptine seems to prevent onset of heart failure in PPCM patients with subsequent pregnancies Pilot study in South Africa and Germany with 20 patients with a subsequent pregnancy after a previous PPCM. 6 patients on standard therapy (ACE inhibitor, -blocker): control 15 patients on standard therapy (ACE inhibitor, -blocker) and Bromocriptine: BR (%) Ejection Fraction ** **P<0.01 Prepartum Postpartum Three patients in the control group died and the remaining three patients showed impaired cardiac function 4 months postpartum. All 14 patients treated with BR survived and maintained normal cardiac function. Hilfiker-Kleiner et al. Cell 2007

9 gefördert vom Förderkennzeichen 01KG1001 Prof. Dr. Denise Hilfiker-Kleiner, Hannover Study Coordiantion

10 Evidence that bromocriptine may improve cardiac function in patients with chronic PPCM (later than 6 months postpartum)

11 Late application of bromocriptine in chronic PPCM may still contribute to recovery Patient was treated 6 months treatment with HF medication without bromocriptine followed by CRT (2 months) and bromocriptine (6 months) LVEDD (mm) EF (%) BR baseline 3 months 6 months 12 months BR baseline 3 months 6 months 12 months NT-proBNP (ng/l) BR 0 baseline 3 months 6 months 12 months

12 Late application of bromocriptine in chronic PPCM may still contribute to recovery 3 additional patient with heart failure for more than 6 months without bromocriptine followed by HF medication and bromocriptine (6 months) baseline Follow up

13 Patients who fail to respond to HFA medication and bromocriptine Pregnancy may demask genetic forms of cardiomyopathy In the German PPCM register 10% patients (n=17) with positive familial history for cardiomyopathy of which n=7 were non-responsive to treatment with heart failure medication. PPCM patients with positive familial history for cardiomyopathy need genetic analysis and counseling.

14 Patients may fail to respond to low dose bromocriptine because of elevated prolactin systems due to medication or prolactinoma Case of a 30 year old patient with PPCM after delivery of first child Developed cardiac decompensation during delivery. Intensive care with sedation and respiratory support Obtained heart failure medication and bromocriptine Stabilized and slightly improved in the first 7 days Developed fever 8 days after delivery, conditioned worsened within a few hours. Transport with ECMO to large University Hospital (on Weekend) Condition worsened over the weekend. Prolactin on Monday: 260ng/ml (normal <25ng/ml) despite 5 mg bromocriptine Assist device on Thuesday, bromocriptine 20 mg/day to suppress prolactin Fever continued to raise, patient needed constant cooling Gynecologists discoverd placenta rest, curtage on Friday and addition of cortison. The conditioned stabilized over the weekend, patient rapidly improved. Patients obtained HFA medication and bromocriptine for 2 months and completely recovered cardiac function, planed weaning of assist device in 4 months

15 Opioids and opioid analogs can increase serum prolactin levels in humans and animals Higher levels of Bromocriptine seem to be necessary to suppress opiod induced prolactin secretion!

16 Identification of factors predisposing to PPCM and corresponding biomarkers may help to identify women at risk for PPCM and may lead to earlier diagnosis

17 Chematherapy emerges as a risk factor for later development of PPCM and vice versa

18 German PPCM Registry Report of more then 170 patients with symptoms of PPCM from over 60 hospitals (from 2006 to 2011)

19 Risk factor profile in Germany PPCM collection 32% Overall frequency in pregnant women in Germany Gynecological risk profile: Cesarean section 66% % Preeclampsia 59% 3 5 % Pregnancy induced hypertension 8% 6 8 % Cardiovascular risk profile: Gestational diabetes 10 % 5 % Smoking 51 % % Obesity 58 % -- ECG abnormalities 45% --

20 Preeclampsia

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23 Preeclampsia

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25 Women with complicated pregnancies, i.e. preeclampsia have a higher risk for developing cardiovasculare diseases later in life

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27 Total prolactin levels in urine and serum are elevated and correlates with disease severity in patients with preeclampsia

28 16kDa prolactin levels in urine correlates with disease severity in patients with preeclampsia

29 Experimental data explain how preeclampsia may induce predisposition for PPCM Yamac, Bultmann and Hilfiker-Kleiner, Heart 2010

30 16 kda Prolactin promotes shedding of mir-146a containing exosomes from endothelial cells in vitro and in vivo Circulation in revision

31 Exososmes/microvesicles constitute a way of cell to cell communication

32 mir-146a relative level Endothelial exosomes containing mir-146a are absorbed by cardiomyocytes a-actinin/exosomes/dapi a-actinin exosomes a-actinin * mir-146a expression in CM ** Ctrl 146a * * Ctrl 146a Ctrl 146a Ctrl 146a Circulation in revision Exosomes Exosomes + Anti-miR 146a Anti-miR Pre-miR

33 mir-146a containing exosomes reduce metabolic activity and decrease ErbB4 receptor expression in cardiomyocytes Circulation in revision

34 Inactivation of NRG-1/ErbB signaling in the heart leads to heart failure Lemmens, K. et al. Circulation 2007;116: Copyright 2007 American Heart Association

35 Mice with PPCM display up-regulated mir-146a levels and decrease ErbB4 expression in cardiac tissue Circulation in revision

36 mir-146a levels are increased and ErbB4 levels are reduced in left ventricular tissue of PPCM PPCM mir-146a ErbB4 mrna *p< % 120% 100% 80% 60% *p< % 1 20% 0 NF DCM PPCM 0% NF PPCM Circulation in revision

37 Systemic effects from endothelial cells triggered by 16kDa Prolactin and mediated by mir-146a decrease the cardioprotective Nrg- 1/ErbB4 signaling. This could make the heart more susceptible to stress induced damage during birth and postpartum. ErbB Signaling Cooperation of the Struman and Hilfiker-Kleiner Lab

38 Summary and Conclusion PPCM patients display increased oxidative stress, Cathepsin D and 16 kda Prolactin suggesting a causative role of this pathway for the development of PPCM. Preliminary results in PPCM patients with Bromocriptine are promising even in patient with chronic PPCM. Controlled randomized trials are in progress. Opioid derivatives may increase prolactin in sedated PPCM patients requiring higher bromocriptine doses A novel circuit involving 16kDa Prolactin and mir-146a may downregulate cardioprotective mechanisms during preeclampsia thereby predisposing the maternal heart to PPCM.

39 Hannover Clinic for Cardiology & Angiology J. Bauersachs E. Podewski A. Haghikia G. Klein A. Schaefer S. Labidi M. Hoch B.Stapel S. Gutzke S.Erschow B.Brandt PPCM hotline Johannesburg, SA K. Sliwa Liège, B I. Struman Homburg M. Böhm K. Walenta HTTG Surgery, LEBAO A. Hilfiker M. Strueber We thank all centers who contributed data for the German PPCM registry!