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C
URRENT
O
PINION
Peripartum cardiomyopathy: update 2012
Katrin Bachelier-Walenta
a
, Denise Hilfiker-Kleiner
b
, and Karen Sliwa
c
Purpose of review
Peripartum cardiomyopathy (PPCM) is a disorder in which initial left ventricular systolic dysfunction and
symptoms of heart failure occur between the late stages of pregnancy and the early postpartum period.
Incidences vary geographically; it is common in some countries and rare in others. The acute form of
PPCM is a clinical syndrome with reduced cardiac output, tissue hypoperfusion, and increase in the
pulmonary capillary wedge pressure. Monitoring of the patient with the acute form of PPCM should be
initiated as soon as possible. The syndrome carries a high morbidity and mortality and diagnosis is often
delayed. This review focuses on new data and aspects in terms of diagnosis, causes of disease,
pharmacological therapy, and management of delivery in patients with PPCM.
Recent findings
New investigations reveal that PPCM is likely due to multiple factors. It develops based on oxidative stress
leading to cleavage of deleterious 16-kDa prolactin, which can be blocked with bromocriptine. New data
show furthermore that it is partly a two-hit vascular disease due to imbalances in angiogenic signaling
worsening the severity of the disease.
Summary
Different mechanisms have been investigated and give rise to promising therapeutic approach, which will
be developed based on the new findings.
Keywords
heart failure, peripartum cardiomyopathy, pregnancy
INTRODUCTION
Peripartum cardiomyopathy (PPCM) is a relatively
rare idiopathic disease associated with severe heart
failure and occurs toward the end of pregnancy or in
the months following delivery [1]. Incidence varies
according to race and region, 1: 22894000 life-
births in the United States [2], 1: 1000 in South
Africa [3], and 1: 299 in Haiti [4]. Maternal mortality
and normalization of left ventricular ejection frac-
tion occurs only rarely with high incidence of devel-
oping heart failure despite therapy [14]. PPCM is a
diagnosis of exclusion after ruling out other causes
of cardiac function. Clinical symptoms comply with
those typical for heart failure and are not pathogno-
monic for PPCM. Diagnosis of PPCM is often missed
at early stages of the life-threatening disease and
investigations focusing on specific diagnostic tools
such as imaging techniques and diagnostic tests
have been performed in the last few years with
promising data. Underlying mechanisms have been
and still are deeply explored. One concerns trans-
genic mice defective in STAT3, normally involved in
protection of oxidative stress inhibiting develop-
ment of PPCM [5,6]. Consecutive lack of antioxida-
tive enzymes, protective in the postnatal heart,
induces increased oxidative stress, which in turn
enhances cathepsin-Dactivity leading to proteolytic
cleavage of prolactin (PRL) into its detrimental
16kDa form producing endothelial cell apoptosis,
capillary dissociation, and vasoconstriction [5].
Inhibition of PRL with bromocriptine prevented
the formation of a PPCM in animal models [7]
and led to improvement of left ventricular function
in patients [8]. Newer data conclude that PPCM is
a two-hit vascular disease due to imbalances in
angiogenic signaling, and that antiangiogenic states
a
Klinik fu r Innere Medizin III, Kardiologie, Angiologie und Internistische
Intensivmedizin, Universita tsklinikum des Saarlandes, Homburg/Saar,
b
Department of Cardiology und Angiology, Medizinische Hochschule
Hannover, Hannover, Germany and
c
Faculty of Health Sciences, Hatter
Institute for Cardiovascular Research in Africa & IIDMM, University of
Cape Town, Cape Town, South Africa
Correspondence to Professor Karen Sliwa, MD, PhD, FESC, FACC,
DTM&H, Department of Medicine Medical School, Hatter Institute for
Cardiovascular Research in Africa, Groote Schuur Hospital and Univer-
sity of Cape Town, Anzio Road Observatory, Cape Town 7925, South
Africa. Tel: +27 21 4043333; fax: +27 21 6831363; e-mail: sliwa-
hahnlek@mdh-africa.org
Curr Opin Crit Care 2013, 19:397403
DOI:10.1097/MCC.0b013e328364d7db
1070-5295 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-criticalcare.com
REVI EW
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
worsen the severity of the disease [9
&&
]. Mice lacking
cardiac PGC-1a, a powerful regulator of angiogene-
sis, develop PPCM. This review focuses on new data
and aspects in terms of diagnosis, cause, pharmaco-
logical therapy, and management of delivery in
patients with PPCM.
Clinical symptoms
Most patients present with typical signs and symp-
toms of heart failure such as dyspnea, peripheral
edema, fatigue, and sometimes cough and abdomi-
nal discomfort [10,11]. Patients with PPCM often
admitted to the clinic with severe symptoms with
acute onset of heart failure (AHF). The presentation
with reduced cardiac output, tissue hypoperfusion,
increase in the pulmonary capillary wedge pressure,
and tissue congestion is often life-threatening and
requires urgent treatment. The diagnosis of AHF is
based on the symptoms and clinical findings in
combination with appropriate investigations such
as ECG, chest radiograph, biomarkers, for example,
brain natriuretic peptide (BNP) and echocardiogra-
phy. Systematic clinical assessment of the peripheral
circulation, venous filling, and peripheral tempera-
ture are important. Right ventricular filling in
decompensated heart failure may be evaluated from
the central jugular venous pressure.
Causes and new mechanisms
The exact cause of PPCM is still unknown. There are
data underlying the hypothesis of a multifactorial
cause. Anumber of mechanisms and many potential
causes have been proposed but not proven
[10,12,13]. These include nutritional deficiencies,
genetic disorders [14], viral or autoimmune causes,
hormonal imbalances, volume overload, alcohol,
physiologic stress of pregnancy, abnormal immune
response to pregnancy, unmasking of latent idio-
pathic dilated cardiomyopathy, inflammation, and
apoptosis [15]. PPCM from different ethnic groups
or geographic regions might have different causes
inducing PPCM [10]. This is supported by the differ-
ent prevalence of comorbidities and their impact on
outcome in our PPCM collectives. The rare inci-
dence of PPCM in some regions and the problem
to generate suitable animal models have limited
guided research and understanding of the patho-
genic mechanisms involved up to now.
Recently, Hilfiker-Kleiner et al. [5] have investi-
gated a novel and specific pathogenic mechanism in
female mice with a cardiomyocyte-specific deletion
of the transcription factor signal transducer and
activator of transcription 3 (STAT3) protein. In
these mice, the lack of STAT3 in the postpartum
heart resulted in increased oxidative stress secondary
to blunted induction of the antioxidant enzyme
manganese superoxide dismutase (MnSOD).
Increased oxidative stress promoted the expression
andproteolytic activityof cardiac cathepsinD, result-
ing in cleavage of the nursing hormone PRL into an
antiangiogenic and proapoptotic 16-kDa formwitha
detrimental effect on the myocardial microvascula-
ture leading to myocardial hypoxemia and apoptosis
and the development of PPCM. Based on these
results, a pilot study in humans showed a favorable
effect of bromocriptine, a pharmacological inhibitor
of PRL, in patients with PPCM, supporting the hypo-
thesis of this mechanism [8].
Newer investigations suggest that PPCM may be
caused by multiple factors that lead primarily to
an imbalance in angiogenic signaling. In fact, the
placenta is known to release high amounts of
antiangiogenic factors such as 16kDa PRL, sFlt1,
vasopressin, and others to generate a highly anti-
angiogenic environment potentially to prevent
extensive bleeding during delivery. It seems that
organs like the heart need to protect themselves
from these antiangiogenic effects in part by upre-
gulating pro-angiogenic factors such as vascular
endothelial growth factor (VEGF) [9
&&
]. This hypo-
thesis is supported by experimental findings show-
ing that VEGF expression is reduced in hearts of
mice with PPCM [9
&&
]. The peroxisome proliferator-
activated receptor gamma, co-activator 1 alpha
(PGC1-alpha) is known to promote VEGF expression
in the heart independent of ischemic conditions
[9
&&
]. Female mice lacking PGC1-alpha in their
hearts display reduced VEGF expression in the peri-
partum phase and invariably die after one or two
pregnancies. Like the STAT3-knockout (STAT3-KO)
mice, their hearts display marked reduction in capil-
lary density and perfusion and are highly fibrotic
[9
&&
]. Interestingly, treatment with recombinant
VEGF provided just a moderate improvement of
the condition. Further analysis showed that the
PGC1-alpha-knockout mice display also reduced
MnSOD expression indicating that not only
STAT3 but also PGC1-alpha drives the expression
of antioxidative enzymes and that therefore also
KEY POINTS
PPCM is a life-threatening disease affecting young
women of childbearing age and is associated with
morbidity and mortality.
Early diagnosis and initiation of a therapy is essential.
New mechanisms give rise to promising specific
therapeutic approach such as ablactation with
bromocriptine or pro-angiogenic therapies like
exogenous VEGF121.
Cardiovascular system
398 www.co-criticalcare.com Volume 19 Number 5 October 2013
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PGC1-alpha-knockout mice will produce increased
16kDa PRL in the heart. In fact, bromocriptine
together with recombinant VEGF provided a com-
plete rescue in the PGC1-alpha mice supporting
the idea that in this mouse model, two independent
mechanisms are driving the disease [9
&&
]. Hilfiker-
Kleiner and coworkers went on to dissect the
downstream effects of 16kDa PRL in PPCM. They
discovered that 16kDa PRL, which is not signaling
throughthe PRL receptors, induces the expressionof
microRNA-146a (miR-146a) inendothelial cells [16].
This microRNAmediates most of the antiangiogenic
effects of 16kDa PRL in endothelial cells. Further-
more, it is transmitted via exosomes into cardio-
myocytes where it impairs epidermal growth factor
receptor (ErbB) signaling and subsequently meta-
bolic activity and function. Pharmacological inhi-
bition of miR-146a was able to largely prevent onset
of PPCM in STAT3-KO mice without disturbing the
nursing ability of these mice indicating that with
this approach 16kDa PRL effects could be specifi-
cally eliminated while the beneficial effects of the
nursing hormone PRL could be maintained [16].
Finally, in serum probes of PPCM patients, the
miR-146a was highly specifically elevated compared
with healthy postpartum women or with patients
with dilated cardiomyopathy of other causes [16].
This observation suggests that miR-146a could be
the first specific biomarker for PPCM and may be
used for early diagnosis [16].
This matter of fact, that PPCM is obviously a
vascular disease, could be strengthened by a recent
work on vascular damage measuring endothelial
microparticles (EMPs) in PPCM [15]. It was demon-
strated that EMPs were significantly increased in
acute PPCM reflecting vascular damage due to
apoptosis with subsequent impaired microcircula-
tion. Patients treated with bromocriptine showed a
significant decrease of EMPs [15]. Beyond this,
measurements of inflammation markers such as
leukocyte-derived and monocyte-derived micropar-
ticles reflected inflammation in the acute onset of
PPCM.
However, none of these mechanisms have been
confirmed in more detailed investigations or in
prospective studies [11,17].
Associated conditions and risk factors
Recently, several studies reported that PPCM
occurred in patients who had a positive family
history of cardiomyopathies suggesting that the
pregnancy/peripartum stress may have demasked
a genetic form of cardiomyopathy [17,18], for
example, a syncope caused by long-QT-syndrome
with torsades de pointes due to a KCNH2 mutation,
a gene encoding cardiac ion channels [19]. Recently,
a genome-wide association was discovered and
replicated for rs258415 at chromosome 12p11.22
near PTHLH with PPCM [20].
Numerous risk factors have been summarized
recently [17], but only few have been confirmed in
epidemiological studies. Several authors have
suggested that multiparity [11], multifetal pregnan-
cies [21], older maternal age [22,23], pregnancy-
induced hypertension or preeclampsia [2], and pro-
longed use of tocolysis [24] may be risk factors for
PPCM. A study reported from Elkayam et al. [22]
does not support the theory of multiparity within
their cohort in the United States because almost
40% of the cases occurred in association with a first
pregnancy and more than 50% within the first two
pregnancies. PPCMis a diagnosis of exclusion with a
large differential diagnosis. However, there is no
agreement on the exclusion of preeclampsia [1].
Unfortunately, the inclusion of patients with vary-
ing degrees of gestational hypertension, in index as
well as prior pregnancies, has contributed greatly to
the discrepancy in reported characteristics of PPCM.
This may also formthe basis for the difference in the
time of presentation. A study in the United States
comprising greater proportions of patients with pre-
eclampsia, and of greater severity, tends to have a far
greater frequency of PPCM cases presenting in the
last month of pregnancy [22]. In turn, studies in
Japan [25] and in Europe observe no such corre-
lation and find onset of PPCM in patients with
preeclampsia mainly during or after delivery. In
contrast, studies that have attempted to minimize
the inclusionof patients withpreeclampsia and only
including milder forms of hypertension showa clear
postpartum peak in the presentation of PPCM, with
reported onset of symptoms most commonly being
262 days postpartum [4,10,26
&&
,27].
A recently published experimental study
included patients with PPCM and a documented
episode of preeclampsia suggesting a link between
those conditions based on an extremely antiangio-
genic environment [9
&&
]. Recently, Blauwet et al.
[26
&&
] showed in a large series of patients fromSouth
Africa that increased left ventricular end-systolic
diameter (LVESD), lower BMI, and lower serum
cholesterol at baseline, possibly as a marker of
increased immune activation, may be independent
predictors of poor outcome in patients with PPCM,
whereas older age and smaller LVESD at baseline
appear to be independently associated with a higher
chance of left ventricular recovery.
Standard treatment strategy
Treatment of patients with PPCM is similar to
that for patients with heart failure due to other
causes. Standard therapy includes diuretic agents,
Peri partum cardiomyopathy: update 2012 Bachelier-Walenta et al.
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angiotensin-converting enzyme-inhibitors (ACE-Is)
or angiotensin receptor antagonists (ARBs), b-block-
ers, aldosterone antagonists, intravenous and oral
vasodilatators, and intravenous inotropes. Pharma-
cological treatment must be used with caution and
should follow the recent guideline recommen-
dations [28] as many drugs have potential detrimen-
tal effects on the fetus or lactating infant. Due
to pregnancy-induced hypercoagulability, PPCM
patients have often thrombotic complications
[29], especially development of a left ventricular
thrombus. Anticoagulation is not recommended
for all patients with PPCM, but should be considered
in patients with an impaired left ventricular func-
tion less than35%.
Monitoring of the patient presenting with AHF
should be initiated as soon as possible. The extent
and means by which to monitor for any individual
patient vary widely depending on the severity of the
cardiac decompensation and the response to initial
therapy. However, it has been observed that due to
their young age, PPCM patients often appear rela-
tively well at first glance despite low cardiac output
and marked tachycardia. Many women request
inappropriate early discharge due to social pressures
that include caring for their new-born or infant
child, which may lead to rapid readmission or
even death.
Ventricular arrhythmias have been reported in
up to 20% of patients with PPCM [30], but up to
now no recommendations regarding advice therapy
with implantable cardioverter defibrillator (ICD) or
cardiac resynchronization therapy exist. Delaying
implantation is particularly important in patients
with PPCM, as many will experience an improve-
ment in left ventricular function under maximum
standard heart failure therapy within the following
months after delivery. Temporary use of a wearable
defibrillator should be considered until final
decision is made [31].
Patients presenting with cardiogenic shock
might need temporary circulatory support such as
an intraaortic balloon counterpulsation pump
(IABP) or extracoroporal membrane oxygenation
(ECMO), implantation of a left ventricular assist
device [32], or even heart transplantation [33,34].
A recent published study showed that rejection and
graft failure were more likely in PPCM compared
with other transplant recipients [35]. A treatment
algorithm for acute PPCM is shown in Fig. 1.
New insights into pharmacological treatment
Bromocriptine, a PRL-blocker, has recently emerged
as a very promising therapeutic approach for the
treatment of patients with PPCM [8,36], based on
the concept of enhanced cleavage of the nursing
hormone PRL into a deleterious, antiangiogenic,
and proapoptotic form [5]. A proof-of-concept pilot
study with 20 African patients with PPCM showed
that mortality was reduced in patients treated with
bromocriptine in contrast to patients receiving
placebo [8]. Even though this agent is auspicious,
potential complications to the mother [37] have led
to withdrawal of its approval and further multi-
centric and randomized studies are essential for
clarifying the benefit and safety of bromocriptine.
Moreover, first evidence suggests that it is quite
specific to patients with PPCM and may be used
to develop specific biomarkers for diagnostic but
also prognostic purpose in women with peripartum
heart failure [38
&&
].
Drugs that block the renninangiotensin sys-
tem, such as ACE-Is and ARBs, have few side-effects,
which are often prescribed to women of reproduc-
tive age [39]. It is well known that fetal exposure to
betablockers carries the risk for relevant neonatal
and long-term complications. A systematic review
showed that ARBs have the worst outcome [40].
Leading complications were oligohydramnios, renal
failure, death, miscarriage or uterine fetal death, and
respiratory distress syndrome.
There is contradictory evidence concerning the
consequences of b-blocker treatment during preg-
nancy. Meidahl Petersen et al. [41
&
] explored the
effects of b-blocker exposure during pregnancy in
a Danish birth cohort comprising all births in
Denmark between 1995 and 2008. In addition, they
compared risks associated with exposure to labetalol
with that associated with exposure to other b-block-
ers and showed that redeeming prescriptions of
b-blockers were significantly associated with
increased risk of being born small for gestational
age, preterm birth, and perinatal mortality. Com-
parable risk profiles were demonstrated in labetalol-
exposed pregnancies and in pregnancies exposed to
any other b-blocker.
Labor, delivery, and anesthetic management
Timing and mode of delivery ina patient withPPCM
is constrained on clinical status of mother and the
unborn child. Early delivery is usually not indicated
in stable patients and pregnancy can be continued
with frequent monitoring enabling fetal maturity.
Hemodynamic monitoring prior to labor and deliv-
ery is very important in terms of optimization of the
hemodynamic status. Spontaneous labor and vagi-
nal delivery are generally tolerable in stable patients
and aggressive pain management is pivotal for con-
trolling heart rate and systemic vascular resistance
[42]. Nevertheless, an elective cesarean section is
Cardiovascular system
400 www.co-criticalcare.com Volume 19 Number 5 October 2013
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preferable avoiding hemodynamic fluctuations,
larger blood loss, pain and respiratory or thrombem-
bolic complications [43].
Uniform recommendations for anesthetic
management in parturients with PPCM do not
exist, although several options have been reported
concerning general anesthesia with inhalational
agents [44] or remifentanil [45], epidural [46] or
spinal [47] and combined epidural-spinal [48]. Main
goals during management of anesthesia in patients
with PPCM are avoidance of drug-induced myo-
cardial depression, maintenance of normovolemia,
and prevention of increased ventricular afterload
[49].
Prognosis
Published data regarding recovery of left ventricular
function differ widely. Looking at four presented
studies, 2354%of patients with PPCMrecover [17].
Patients of the United States even have a reported
recovery ranging from 45 to 78% [11] within differ-
ent time periods. Patients in Utah recovered within
9 months [50], whereas indigent patients after
54 months [51], which might be due to race and
ethnicity as almost 90% were AfricanAmericans.
Elkayam and coworkers [52
&
] compared left ventric-
ular recovery in AfricanAmericans and whites
showing that whites improved their left ventricular
function in 61% versus 40% in AfricanAmericans
having a poorer outcome. In a recent study in 176
patients from South Africa, the 6-month full recov-
ery rate was only 23%with a mortality of 13%[26
&&
].
In Turkey, a single tertiary center reported a
mortality rate of 30%over 4 years of follow-up [53
&
].
Echocardiography is the most important diag-
nostic tool in PPCM and provides significant prog-
nostic information with regard to recovery of
cardiac function [4]. A fractional shortening value
less than 20% and a left ventricular end-diastolic
dimension more than 60mm at the time of diag-
nosis is associated with a more than three-fold
higher risk for persistent left ventricular dysfunction
[54].
Compared to other forms of cardiomyopathy,
patients with PPCM demonstrate better survival
[55]. Mortality rates have been reported to range
from 1.4 to 30% [2,23,27,55]. In a study from Haiti,
Acute severe PPCM with EF 45%
Peripartum
Hemodynamic unstable
Cardiogenic shock
Optimized HF-Therapy:
- Diuretics
-ACE-Is or ARBs
- -blockers
-Aldosterone antagonists
Oxygenation
Postpartum up to 6 months
Ablactation with bromocriptine
+
Response No Response
-Inotropica
-Intubation
-IABP/ ECMO
-LVAD
bridge to complete recovery
bridge to transplant
HF-Therapy until complete
recovery
+/-
No Response
Transplantation
Stable
Optimized HF-Therapy:
- Hydrochlothiazide
- Hydralazine
-Aldosterone antagonists
Immediate delivery
Maturation of the fetus lung
+/-
Cesarean section
No Response
-Digoxin
-Intubation
-IABP/ ECMO
FIGURE 1. Therapeutic algorithm for acute severe peripartum cardiomyopathy patients. Shown is the strategy for treatment
choices for patients peripartum and postpartum. EF, ejection fraction; PPCM, peripartum cardiomyopathy.
Peri partum cardiomyopathy: update 2012 Bachelier-Walenta et al.
1070-5295 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-criticalcare.com 401
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the ratio of PPCM deaths for the 5-year period was
47.1 per 100000 live-births, and the mortality rate
15.3% during a mean follow-up period of 2.2 years.
Only 28% of patients who were observed for at least
6 months regained normal left ventricular function
[26
&&
].
CONCLUSION
PPCM is a life-threatening disease affecting young
women of childbearing age defined as a disorder of
unknown pathogenesis, in which left ventricular
dysfunction and symptoms of heart failure occur
between the last month of pregnancy and the first
5 months postpartum. New investigations reveal
that PPCM is likely due to multiple factors. It devel-
ops based on oxidative stress with cleavage of
deleterious 16-kDa PRL, which can be blocked with
bromocriptine. Newdata showfurthermore that it is
partly a two-hit vascular disease due to imbalances
in angiogenic signaling, worsening the severity of
the disease. Definitely, more investigations analyz-
ing pathophysiology, genetics, and treatment
options are essential in order to establish standar-
dized treatment recommendations.
Acknowledgements
None
Conflicts of interest
None declared.
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