Peripartum Cardiomyopathy

Denise Hilfiker-Kleiner
Kardiologie & Angiologie
MHH, Hannover

Nothing to disclose

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:

Africa:
Haiti:
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. 2008
Hilfiker-Kleiner et al. TCM 2008

1: 1.400 to 1:3.500
1: 100 to 1:1.000
1: 300

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

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

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

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

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

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.

Ejection Fraction
(%) 80
70

**

60

6 patients on standard therapy (ACE

inhibitor, -blocker): control

50

**P<0.01

40

15 patients on standard therapy (ACE

inhibitor, -blocker) and Bromocriptine: BR

30
20
10

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

gefrdert vom

Frderkennzeichen 01KG1001

Prof. Dr. Denise Hilfiker-Kleiner, Hannover Study Coordiantion

Evidence that bromocriptine may

improve cardiac function in patients
with chronic PPCM (later than 6

months postpartum)

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)
80
70
60
50
40
30
20
10
0

EF (%)
50

BR

40
30
20

BR

10
0

baseline

3 months

6 months

12 months

NT-proBNP (ng/L)
4000
3000
2000

BR

1000
0
baseline

3 months

6 months

12 months

baseline

3 months

6 months

12 months

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).

50

40

30
20

10

0
baseline

Follow up

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.

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

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!

Identification of factors
predisposing to PPCM and
corresponding biomarkers may help

to identify women at risk for PPCM

and may lead to earlier diagnosis

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

vice versa

German PPCM Registry

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

Risk factor profile in Germany

PPCM collection
32%

Overall frequency in
pregnant women in Germany

Gynecological risk profile:

Cesarean section

66%

2530 %

Preeclampsia

59%

35 %

Pregnancy induced hypertension

8%

68 %

Cardiovascular risk profile:

Gestational diabetes

10 %

5%

Smoking

51 %

2530 %

Obesity

58 %

--

ECG abnormalities

45%

--

Preeclampsia

Preeclampsia

Women with complicated pregnancies, i.e.

preeclampsia have a higher risk for developing
cardiovasculare diseases later in life

Total prolactin levels in urine and serum are

elevated and correlates with disease severity in
patients with preeclampsia

16kDa prolactin levels in urine correlates with

disease severity in patients with preeclampsia

Experimental data explain how

preeclampsia may induce predisposition
for PPCM

Yamac, Bultmann and Hilfiker-Kleiner, Heart 2010

16 kDa Prolactin promotes shedding of miR-146a

containing exosomes from endothelial cells in vitro
and in vivo

Circulation in revision

Exososmes/microvesicles constitute a way of cell to

cell communication

Endothelial exosomes containing miR-146a are absorbed

by cardiomyocytes
a-Actinin/exosomes/DAPI

a-Actinin

miR-146a relative level

40000
40000

a-Actinin

exosomes

miR-146a expression in CM

**

30000
30000
20000
20000

10000
10000
10000
5050
0
-50
-50

-150
-150
-250
-250
Ctrl

Circulation in revision

146a

Exosomes

*
Ctrl

*
146a

Exosomes +
Anti-miR 146a

Ctrl

146a

Anti-miR

Ctrl

146a

Pre-miR

miR-146a containing exosomes reduce metabolic

activity and decrease ErbB4 receptor expression in
cardiomyocytes

Circulation in revision

Inactivation of NRG-1/ErbB signaling in the heart leads

to heart failure

Lemmens, K. et al. Circulation 2007;116:954-960

Copyright 2007 American Heart Association

Mice with PPCM display up-regulated miR-146a levels

and decrease ErbB4 expression in cardiac tissue

Circulation in revision

miR-146a levels are increased and ErbB4 levels are

reduced in left ventricular tissue of PPCM PPCM

ErbB4 mRNA

miR-146a
8

*p<0.05

140%
120%

100%

*p<0.05

5
80%

60%

40%

20%

0
NF

DCM

PPCM

Circulation in revision

0%
NF

PPCM

Systemic effects from endothelial cells triggered by 16kDa Prolactin

and mediated by miR-146a decrease the cardioprotective Nrg1/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

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.

Johannesburg, SA
Hannover
Clinic for Cardiology & Angiology

J. Bauersachs
E. Podewski
A. Haghikia
G. Klein
A. Schaefer
S. Labidi

PPCM hotline
PPCM@mh-hannover.de

K. Sliwa
Lige, B
I. Struman

Homburg
M. Bhm

M. Hoch
B.Stapel
S. Gutzke
S.Erschow
B.Brandt
HTTG Surgery, LEBAO
A. Hilfiker
M. Strueber

K. Walenta

We thank all centers who contributed

data for the German PPCM registry!