Update on mechanisms of peripartum cardiomyopathy: New Heart Failure Association working group position statement

Transcription

1 Update on mechanisms of peripartum cardiomyopathy: New Heart Failure Association working group position statement Denise Hilfiker-Kleiner Kardiologie & Angiologie MHH, Hannover I have nothing to declare.

2 Study Group on Peripartum Cardiomyopathy Prof. K. Sliwa (Cape Town, South Africa) Prof. B. Pieske (Graz, AT) D Hilfiker-Kleiner (Hannover, DE) J McMurray (Glasgow, GB) A Mebazaa (Paris, FR) M Petrie (Glasgow, GB) V Regitz-Zagrosek (Berlin, DE) M Schaufelberger (Gothenburg, SE) P Seferovic (Belgrade, RS) A Shah (London, GB) L Tavazzi (Cotignola, IT) D van Veldhuisen (Groningen, NL) K van Spaendonck-Zwart (Haren, NL) U Elkayam (Los Angeles, US) F Mouquet (Lille, FR) Katrin Walenta ( Homburg, GE) Affilate members: Amam Mbakwem ( Nigeria) Aims To establish a platform where current knowledge on peripartum cardiomyopathy based on experimental and clinical studies is summarized and regularly up-dated. To raise awareness of this uncommon but devastating problem by promoting sessions at congresses and publishing articles. To coordinate the collection and analysis of data internationally for better understanding of the condition. To meet regularly to discuss and update management strategies with a focus on novel diagnostic and therapeutic approaches. Provide information and contact addresses on our webpage for physicians and patients concerned about PPCM. To initiate and be advocates for the PPCM Registry

3 Study Group on Peripartum Cardiomyopathy

4 Definition and diagnostic criteria of PPCM Definition: Non-familial, non-genetic form of dilated cardiomyopathy in the last month of pregnancy or within the first months post-partum (later onset in nursing mothers possible) in absence of recongnizable heart disease prior the last month of pregnancy. Main diagnostic criteria: 1. An aquired form of cardiomyopathy with an LV systolic dysfunction of an EF <45% or FS <30%. 2. Dilatation of the LV is often but not always present. Sliwa, Hilfiker-Kleiner et al. European Journal of Heart Failure 2010

5 ESC HFA PPCM Registry Start April 2012, N=1000 patients, European Society of Cardiology Members Countries Access: via the EURObservational Research Program or via a link though the Heart Failure Association (HFA) of the ESC website: The front page contains the mandatory key questions qualifying a patient as potential PPCM Peripartum stage Signs and/or symptoms of heart failure Ejection fraction <45% This will ensure that mainly patients with suspected PPCM will be entered. Link to the Pregnancy in cardiac disease registry Download CRF as pdf for local ethical committees

6 Flyer on Information on PPCM Registry

7 Aims of Registry: Information on incidence of PPCM in Europe Blauwet L, Cooper L, Heart 2011 Data from European countries on incidence are not available and information will hopefully obtained by the PPCM registry

8 Aims of European Registry Information on ethiology Information on risk factors Information on treatment strategies and management Information on prognosis Information on comorbiditis (preeclampsia, diabetes, adipositas etc) Information on biomarkers

9 Data from the first European PPCM registry performed in Germany Prof. Dr. Denise Hilfiker-Kleiner, Hannover Study Coordiantion

10 From 2004 to potential PPCM cases were reported to our study center in Hannover, Germany Diagnosis confirmed in 92 patients No. of patients (n) Mean EF of 27% (range from 9% to 45%)

11 Patients (%) Time of diagnosis in Patients with confirmed PPCM 40 32% Time point of diagnosis Month Delivery + 1 Month 1-3 Months 4-8 Months Pre-partal Post-partal

12 Markers for cardiac injury are within normal range in the majority of PPCM patients! CRP and NT-proBNP are almost always elevated No. of patients (n) % % normal elevated % 9 % Tropopnin T CK NT-proBNP CRP

13 CRP is unspecifically up-regulated in peripartal women while NT-proBNP, ADMA and Cathepsin D are mainly elevated in PPCM patients Log NT-proBNP (pmol/l) ADMA (mmol/l) P<0.001 P<0.001 Control PPCM Control PPCM Cathepsin D (Ul/l) CRP (mg/l) P<0.001 P=0.494 Control PPCM Control PPCM

14 Baseline characteristica of PPCM patients who improved (IMP) or failed to improve cardiac function within 6 to 12 months after diagnosis No difference in age, parity, body mass index, smoking, pregnancy associated hypertensive conditions, blood pressure, heart rate No difference in TnT, ADMA, HB, total cholesterol, CRP etc

15 Blockade of Prolactin, a potential pathophysiolocal factor in PPCM, was successful in experimental models. Clinical testing of Bromocriptine treatment Hilfiker-Kleiner et al. Future Cardiology 2009

16 Small pilot trial in South Africa: 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

17 Patients obtaining Bromocriptine (BR-group, BR for 6 to 8 weeks) display significantly better recovery compared to the NO BR-group Patients (%) A significantly (p=0.015) higher percentage of patients classified as IMP and a lower percentage classified as NIMP were present in the BR-group compared to the non-br-group % 67% BR-Therapy No BR-Therapy 40 33% No. of Patients % 2% 4% 6% 17% 0% 4% IMP NIMP LVAD HTX Death BR-Therapy, n= No BR-Therapy, n=

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

19 Ongoing quest to identify underlying pathophysiology of PPCM 1. To discover pathophysiological mechanisms that trigger PPCM. 2. To more specifically eliminate the pathological pathway of Prolactin signaling. 3. To find diagnostic markers for early diagnosis. 4. To define biomarker profiles to distinguish PPCM from other forms of heart failure for early diagnosis and better risk stratification.

20 Patients with PPCM and positive familial history for cardiomyopathy have a higher risk for poor outcome A positive family history of cardiomyopathy (PPCM, DCM, sudden death, arrhythmias in first degree relatives) was reported in 15% (14 of 92). DNA analysis in a small subset of cases found pathogenic or putatively pathogenic mutations in DCM related genes in 3 patients (van Spaendonck-Zwarts, personal communication). 21% (3 of 14) of patients with a positive familial history of cardiomyopathy needed a heart transplantation compared to 6% (4 of 64) of patients with no reported familial history of cardiomyopathies. Among the patients with putative pathogenic mutation in a DCM related gene we had two who did not respond to heart failure therapy and Bromocriptine, one obtained an LVAD and one an heart transplantation.

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22 Endothelial microparticle, i.e. exososmes/microvesicles constitute a way of cell to cell communication

23 16 kda Prolactin promotes shedding exosomes from endothelial cells in vitro and in vivo filled with specific factors such as mir-146a 16kDa induces the expression of mir-146a in endothelial cells leading to accumulation of mir146a in shedded endothelial exosomes Strumann and Hilfiker-Kleiner, JCI in revision

24 In endothelial cells mir-146a mediate by downregulating NRAS anti-angiogenic effects of 16kDa Prolactin Strumann and Hilfiker-Kleiner, JCI in revision

25 Endothelial exosomes containing mir-146a are absorbed by cardiomyocytes leading to marked increase in intracellular mir-146a levels mir-146a relative level a-actinin/exosomes/dapi a-actinin exosomes a-actinin * mir-146a expression in CM ** Ctrl 146a Exosomes * * Ctrl 146a Exosomes + Anti-miR 146a Ctrl 146a Anti-miR Ctrl Pre-miR 146a

26 In cardiomyocytes mir-146a from endothelial exosomes reduce metabolic activity via downregulation of Nrg-1/ErbB signaling MTT-Assay ErbB4 mrna ErbB4 protein *P<0.05, #P<0.05 antimir-146a vs antimir control Strumann and Hilfiker-Kleiner, JCI in revision

27 Mice with PPCM display up-regulated mir-146a levels and decreased ErbB4 and NRAS expression in cardiac tissue Strumann and Hilfiker-Kleiner, JCI in revision

28 ErbB4 is up-regulated in the maternal heart during pregnancy and postpartum. Inhibition of Nrg-1/ErbB4 signaling with Lapatinib peripartum promotes heart failure and leads to increased mortality

29 Stimulating with ErbB signaling with Nrg-1 or blocking mir-146a attenuates systolic dysfunction and LV dilatation in the PPCM mouse model STAT3-KO PPCM with LNA Control STAT3-KO PPCM with LNA mir146a 4.5 mm 3.7 mm 4.1 mm 2.06 mm Control %FS Nrg Control LNA Strumann and Hilfiker-Kleiner, JCI in revision %FS LNA mir-146a

30 Blocking mir-146a attenuates adverse 16kDa effects but allows normal Prolactin signaling as indicated by the ability of treated PPCM STAT3-KO mice to raise offspring Number of weaned offspring 0 not treated control-lna mir-146a-lna Strumann and Hilfiker-Kleiner, JCI in revision

31 mir-146a levels are increased in serum from PPCM patients compared to controls and normalize after Bromocriptine treatment mir-146a in Serum mir-146a in Heart ErbB4 in Heart p=0.05 p=0.05 p=0.05 Strumann and Hilfiker-Kleiner, JCI in revision

32 16 kda Prolactin impairs the communication of the endothelium with the cardiomyocytes by transferring micrornas via exosomes. Blocking mir-146a eliminates adverse effects of 16kDa Prolactin and leaves normal prolactin signaling intact. mir-146a is elevated in PPCM but not in DCM and may serve as a novel specific biomarker for PPCM

33 Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany

34 The end of pregnancy represents a strongly antiangiogenic environment where the placenta produces massive amounts of angiostatic factors and the heart? Organ protection requires for example up-regulation of VEFG to neutralize angiostatic sflt-1. Parikh and Karumanchi Nat Med 2008;

35 sflt-1 is up-regulated in serum of PPCM patients compared to healthy control. This is independent of pre-existing preeclampsia sflt-1 may be new potential biomarker with pathophysiological potential Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany

36 Disturbing the balance in VEGF and sflt-1 by overexpression of sflt-1 is sufficient to induce heart failure in non-pregnant PGC-1α k.o. mice Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany

37 Combined therapy with Bromocriptine and VEGF prevented PPCM in PGC-1α (HKO) mouse suggesting that both systems are involved Some patients who do not respond well to BR may need a therapeutic approach to neutralize sflt-1. Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany

38 Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany 1. PPCM appears primarily to be an endothelial disease. 2. STAT3, PGC1a/PPAR and Nrg/ErbB signaling systems emerged as key players in the pathophysiology of PPCM. 3. Targeting 16kDa Prolactin, its downstream mediator mir-146a and sflt1 may be novel specific therapeutic options for PPCM. 4. Serum levels of mir-146a and the ratio of VEGF/sFlt1 may serve as specific diagnostic biomarkers which together with NT-proBNP may help to get early diagnosis and better risk stratification in PPCM patients.

39 Hannover Clinic for Cardiology & Angiology H. Drexler ( ) J. Bauersachs M. Hoch E. Podewski A. Haghikia S. Labidi O. Sorokin B. Stapel S. Gutzke S. Erschow B. Brandt HTTG Surgery, LEBAO A. Hilfiker, I. Tudorache PPCM hotline Johannesburg, SA K. Sliwa Liège, B I. Struman Boston, USA Z. Arany We thank all centers who contributed data for the German PPCM registry!

40 Accidental cleavage of the nursing hormone prolactin seems to be a major factor in the pathophysiology of PPCM 16 kda prolactin acts as a potent inhibitor of angiogenesis Linda Schuler; Corbacho A.M. et al., J Endocrinol 2002

41 PGC-1α is important for the up-regulation of VEGF in cardiomyocytes independent of hypoxia for example in maternal hearts 5 4 VEGF mrna: PGC-1α: HIF-1β + HIF-1β -

42 Mice with a cardiac specific knockout of PGC-1α (HKO) develop PPCM with massive capillary loss Nature 2012, Corresponding authors: Hilfiker-Kleiner, Arany

43 Characteristics - Screen 1