Oup Accepted Manuscript 2019

Cardiovascular Research REVIEW
doi:10.1093/cvr/cvz252
Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Peripartum cardiomyopathy: basic mechanisms
and hope for new therapies
Melanie Ricke-Hoch, Tobias J. Pfeffer, and Denise Hilfiker-Kleiner *
Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
Received 1 April 2019; revised 17 July 2019; editorial decision 23 August 2019; accepted 4 October 2019
Abstract Peripartum cardiomyopathy (PPCM) is a life-threatening cardiomyopathy characterized by acute or slow progres-
sion of left ventricular (LV) systolic dysfunction (LV ejection fraction of <45%) late in pregnancy, during delivery, or
in the first postpartum months, in women with no other identifiable causes of heart failure. PPCM patients display
variable phenotypes and risk factor profiles, pointing to involvement of multiple mechanisms in the pathogenesis of
the disease. The higher risk for PPCM in women with African ancestry, the prevalence of gene variants associated
with cardiomyopathies, and the high variability in onset and disease progression in PPCM patients also indicate mul-
tiple mechanisms at work. Experimental data have shown that different factors can induce and drive PPCM, includ-
ing inflammation and immunity, pregnancy hormone impairment, catecholamine stress, defective cAMP-PKA, and G-
protein-coupled-receptor signalling, and genetic variants. However, several of these mechanisms may merge into a
common major pathway, which includes unbalanced oxidative stress and the cleavage of the nursing hormone pro-
lactin (PRL) into an angiostatic, pro-apoptotic, and pro-inflammatory 16 kDa-PRL fragment, resulting in subsequent
vascular damage and heart failure. Based on this common pathway, potential disease-specific biomarkers and thera-
pies have emerged. Despite commonalities, the variation in aetiology and mechanisms poses challenges for the diag-
nosis, treatment, and management of the disease. This review summarizes current knowledge on the clinical presen-
tation of PPCM in the context of recent experimental research. It discusses the challenge to develop disease-
specific biomarkers in the context of rapid changing physiology in the peripartum phase, and outlines possible fu-
ture treatment and management strategies for PPCM patients.
䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏
Keywords PPCM • Prolactin • 16 kDa-PRL • Pregnancy • Heart failure • Bromocriptine
.. registry, and the Bromocriptine trial (NCT00998556).10,11 A worldwide

1. Introduction ..
.. network has emerged in which experimental researchers and clinicians
.. share their knowledge and investigate disease-causing risk factors, mech-
Peripartum or postpartum heart failure was first described by Ritchie ..
et al. from the Glasgow Royal Infirmary in 1849 and 1850 as a non-valvu- .. anisms, better diagnostic markers, and treatment for PPCM patients. The
..
lar myocardial insufficiency with onset in the puerperium and the post- .. present knowledge on PPCM with regard to epidemiology, clinical pre-
partum period.1,2 A few years later, the maternal disorder was .. sentation, and management, together with current research findings on
..
recognized as peripartum cardiomyopathy (PPCM)3,4 and a long- .. mechanisms, diagnostic markers, and treatments will be summarized in
standing debate followed as to whether PPCM was a specific disease or a .. the following chapters.
..
form of dilated cardiomyopathy (DCM) diagnosed in the peripartum ..
phase. Today, PPCM is considered an independent disease5,6 of largely .. 2. Epidemiology of PPCM
..
unknown aetiology, which has drawn increasing interest from basic sci- ..
entists. The latter has led to discovery of multiple mechanisms that initiate .. Historically, in Western societies PPCM had been considered a rare dis-
..
and drive the disease. Moreover, several national and international regis- .. ease and seemed to affect mainly African women or women of African
tries and clinical studies have been established, collecting data and bio- .. ancestry. However, in line with other forms of cardiovascular disease,
..
material from PPCM patients (Table 1) including the EURObservational .. the incidence of PPCM is steadily on the rise in Western countries being
Research Programme (http://www.eorp.org; European Society of
.. diagnosed more often also in women without African ancestry. Today,
..
Cardiology (ESC),7,8 the investigations of pregnancy-associated cardio- .. we estimate that around one in 1000 live births worldwide is affected.8,12
myopathy (IPAC) registry (NCT01085955, USA9), the German PPCM
.. The incidence of PPCM does, however, differ widely between
* Corresponding author. Tel: þ49 511 532 2531; fax: þ49 511 532 3263, E-mail: hilfiker.denise@mh-hannover.de
C The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
2 M. Ricke-Hoch et al.
Table 1 Overview of registries and clinical studies in PPCM
PPCM registries and clinical studies

..............................................................................................................................................................................................................................

EURObservational Research Programme International registry, (http://www.eorp.org; European
Society of Cardiology (ESC)7,8
Investigations of pregnancy-associated cardiomyopathy (IPAC) registry USA, NCT010859559
German PPCM registry Germany10,11
African PPCM registry South Africa67,119
Japanese nationwide survey of PPCM Japan18
A RegisTry of pEripartuM cardiomyopathy in Turkish patientS Turkey, ARTEMIS120
Nationwide cohort study from the Danish national register Denmark8,9,32,120
The addition of pentoxifylline to conventional therapy improves outcome in patients with PPCM South Africa75
Evaluation of bromocriptine in the treatment of acute severe PPCM: a Proof-of-Concept Pilot Study South Africa67
Bromocriptine for the treatment of PPCM: a multicentre randomized study Germany, NCT0099855611
Placebo-controlled study initiated in Canada Canada, NCT02590601
..
geographic regions and ethnic groups, with hotspots in Nigeria (one in .. failure occurs during pregnancy prior to the last trimester, it is not
102 live births), Haiti (one in 300 live births), China (one in 346 live .. termed PPCM according to the ESC definition.5,6 The latest definition of
..
births), and South Africa (one in 1000 live births).13–17 In contrast, the in- .. PPCM according to the ESC position paper published in 2019 views
cidence in some European or Asian countries, such as England (one in .. PPCM as ‘an idiopathic cardiomyopathy presenting with heart failure sec-
..
5000–10 000 live births), Denmark (one in 10 149 live births), or Japan .. ondary to left ventricular (LV) systolic dysfunction with an LV ejection
(one in 20 000 live births) seems to be considerably lower, although it is .. fraction (LVEF) below 45% towards the end of pregnancy or in the
..
assumed that many cases remain unreported.18–20 Other Western coun- .. months following delivery, where no other cause of heart failure is iden-
..
tries have reported an increasing incidence of PPCM, e.g. a recently pub- .. tified’, meaning PPCM is a diagnosis of exclusion.6 The definition relies
lished epidemiological study using the US Nationwide Inpatient Sample .. specifically on the status that ‘no cardiomyopathy or other cause of heart
showed that incidence of PPCM had increased from one in 1181 live
..
.. failure has been identified prior to the last month of pregnancy’, and an
births in 2004 to one in 849 live births in 2011.21,22 In Germany, the .. exclusion of other explanations for peripartum heart failure. This defini-
..
PPCM incidence is estimated to be one in 1500–2000 live births.23,24 .. tion has recently been challenged by the emerging possibilities for analy-
Possible reasons for the increasing incidence of PPCM in Western socie- .. sis offered by sequencing technologies, which, for example, have
..
ties may derive from socio-economic changes such as planning mother- .. revealed that around 15% of PPCM patients carry pathogenic mutations
hood later in life and a broader use of assisted reproductive technologies ..
.. associated with cardiomyopathies,30 which will be discussed in more de-
resulting in more twin pregnancies.25 In addition, changes in life style .. tail in the following chapter Risk factors and genetic predisposition. Thus,
leading to more adiposity, diabetes, and high blood pressure may also ..
.. PPCM appears to be more of an umbrella syndrome, which summarizes
play a role in the increasing prevalence of PPCM. In parallel, there is .. different aetiologies leading to new onset peripartum heart failure than a
growing awareness of the disease based on the multiple efforts of na- ..
.. single disease.
tional and international cardiac societies. Likewise, numerous basic sci- ..
ence studies have attracted attention to this disease. In fact, the number
..
..
of studies on PPCM increased from 383 papers published between 1980 .. 4. Risk factors and genetic
and 2006 to over 840 publications in the years 2007–19. This recent rise
..
.. predisposition
in awareness has also shown that many patients had previously remained ..
..
undiagnosed or had been diagnosed at a late stage, an aspect which may .. In recent years, several risk factors for PPCM have been identified includ-
explain the high morbidity and mortality (mortality rates up to 30%) in ..
.. ing African ancestry, familial forms of cardiomyopathy, older age at preg-
earlier studies16,26–29 and the better outcome and lower morbidity and .. nancy, multiparity and twin pregnancy, subsequent pregnancy after
mortality rates in more recent studies.9,11 Finally, the efforts of cardiac ..
.. PPCM, pregnancy-associated hypertensive disorders, in vitro fertilization,
societies to clarify the definition and diagnostic criteria for PPCM has .. smoking, use of tocolytic agents, and previous treatment with cardio-
helped to identify more patients and diagnose them at an earlier time ..
.. toxic substances.5,6,8 Some of these risk factors had been confirmed in
point, as will be outlined in the following chapters. .. multiple PPCM cohorts. For example, pregnancy-associated hyperten-
..
... sive disorders like preeclampsia, HELLP [hemolysis (H), elevated liver
.. enzymes (EL), and low platelet count (LP)] syndrome or gestational hy-
3. Definition of PPCM ..
.. pertension have been reported in European, African, and Asian PPCM
PPCM is defined as a form of heart failure occurring in the last month of .. cohorts.10,21,31–35 Moreover, several studies demonstrated a higher inci-
..
pregnancy, during delivery, or in the first six postpartum months, that .. dence of PPCM in women with high gravidity and parity.8,16,36 In this con-
can manifest acutely within hours or develop slowly over several weeks .. text, subsequent pregnancies in women with undiagnosed PPCM are
..
or months.5,6,23,24,29 It is important to note that PPCM can also occur af- .. specifically dangerous, as the risk for severe PPCM in a subsequent preg-
ter an abortion in the first or second trimester.5,6 However, if heart
.. nancy can be as high as 50%.37–39
Pathomechanism and therapy of PPCM 3

Figure 1 Scheme illustrating genetic aspects possibly associated with PPCM. Ethnic-related genome-wide effects and gene variants more frequently pre-
sent in people with Africans ancestry left side (blue panels). Familial clustering of cardiomyopathies mostly associated with specific pathologic gene variants
(red panels), either on autosomal chromosomes (heterozygous, homozygous, or transheterozygous combinations) or on the X-chromosome leading to
clonal mosaics in female carriers. Abbreviations: BAG3, BCL-associated athanogene-3; BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystro-
phy, dystrophin; GNB3, guanine nucleotide-binding proteins beta-3-subunit; LAMP2, lysosome-associated membrane protein 2; LMNA, lamin A/C; MYBPC3,
cardiac myosin binding protein C; MYH6, cardiac a-myosin heavy chain; MYH7, cardiac b-myosin heavy chain; PPCM, peripartum cardiomyopathy; PSEN2,
presenilin; PTHLH, parathyroid hormone like hormone; SCN5A, Nav1.5; SNP, single nucleotide polymorphism; TNNC1, cardiac troponin C; TNNT2, cardiac
troponin T; TTN, titin.
..
There are also multiple reports suggesting that African ancestry is a .. prevalence of PPCM among patients with African ancestry, a higher num-
risk factor for PPCM since the prevalence of PPCM is higher in women .. ber of titin-truncating mutations30 and of a polymorphism (C825T) in
..
of black African ancestry, independent of their home country/continent .. the gene encoding guanine nucleotide-binding proteins beta-3-subunit
(Figure 1).21,30,40,41 Moreover, familial clustering of PPCM has been
.. (GNB3)50 was observed in black women. In both cases, the presence of
..
reported,42–45 with family histories of cardiomyopathies including PPCM, .. the pathogenic variants seems to be associated with a poorer outcome.
..
DCM, arrhythmias, sudden cardiac death and/or hypertension in first- .. This observation suggests that pathogenic variants causing PPCM may in-
degree relatives.10,46 Many PPCM patients display cardiac phenotypes .. deed be more prevalent among this ethnic group and may partly explain
..
similar to idiopathic DCM such as reduced systolic function and dilated .. the higher risk for PPCM in women with African ancestry. In a small num-
or hypertrophic heart muscle.47 Based on these information, it seems .. ber of PPCM patients, an association with the carrier state for X-linked
..
likely that specific gene variants or mutations are associated with PPCM .. forms of cardiomyopathies were found, including female carriers of
in part with ethnic specific prevalence that may in response to pregnancy .. Duchenne muscular dystrophy (DMD),30,51–55 Becker muscular dystro-
..
and/or postpartum stress lead to PPCM as a specific form of genetic car- .. phy (BMD),56 or Danon disease, the latter caused by lysosomal-
diomyopathy.47 Indeed, pathogenic genetic variants in genes responsible
.. associated membrane protein 2 (LAMP2) mutations.57,58 In 2011, a first
..
for DCM or hypertrophic cardiomyopathy (HCM), such as genes coding .. genome-wide association study (GWAS) in PPCM patients was com-
for titin, lamin A/C (LMNA), myosin heavy chain 7 (MYH7), cardiac myo-
.. pleted and a single nucleotide polymorphism (rs258415) on chromo-
..
sin binding protein 3 (MYBPC3), and sodium voltage-gated channel alpha .. some 12p11.22 at the PTHLH gene locus showed genome-wide
..
subunit 5 (SCN5A), presenilin-2 (PSEN2), BCL2 associated athanogene .. significant association with PPCM (Figure 1).59 The gene code for a mem-
3 (BAG3), and cardiac troponin T (TNNT2), have been associated with .. ber of parathyroid hormone family referred to as parathyroid hormone
..
PPCM10,30,47–49 (Figure 1). An international consortium reported a prev- .. like hormone (PTHLH) or parathyroid hormone-related protein
alence of 15% for cardiomyopathy-associated truncating gene variants in .. (PTHrP).60
..
TTN, encoding titin in PPCM patients, which was similar its prevalence in .. Although analyses of the impact of genetics on PPCM are only just
the cohort of DCM patients (17%), but significantly higher compared
.. emerging and no causal relation to PPCM has been proved for most
..
with the reference population (4.7%).30 With regard to the higher . mutations/gene variants, it is important to focus research efforts on this
aspect as it may help to develop better diagnostic tools and more per-
Table 2 Phenotypes of PPCM
sonalized treatments for patients with mutations. Along this line, it has
been observed that PPCM patients with familial cardiomyopathy and/or Method of Potential finding

cardiomyopathy-associated gene variants are similar to PPCM patients examination
......................................................................................................
not having this clinical history with regard to cardiac function at baseline
Clinical examination Hypotension up to cardiogenic shock115
but may have a lower chance for recovery at follow-up.30 Nevertheless,
Dyspnoea/tachypnea/orthopnea11
in contrast to DCM, PPCM patients with gene variants associated with
Electrocardiography Sinus tachycardia72,121
DCM can fully recover. Finally, pathologic gene variants could be trans- Sinus arrhythmia72
mitted to offspring who will also be at risk for genetic cardiomyopathies. Atrial fibrillation72
Based on the relatively high prevalence of gene variants associated with Prolonged QTc interval71
cardiomyopathy and/or positive familial history in PPCM patients, genetic Repolarization abnormalities, especially
analyses and also counselling of family members should be considered as T wave inversion71,72,121
part of treatment strategies in the future. Bundle branch block72,121,122
Taken together, among risk factors for PPCM pregnancy-associated Laboratory Elevated levels of NT-proBNP6,11
hypertensive disorders, multiparity, subsequent pregnancy, African an- diagnostics Elevated levels of cardiac enzymes (creatine
cestry, and genetics (including history of familial cardiomyopathy) kinase and TnI)10
seem to be general risk factors for PPCM and higher awareness for Increased blood lactate values/ low
the disease should be raised in patients caring one or more of these pH values115
risk factors. Echocardiography Decreased LVEF6,9,11
Mitral regurgitation95
Cardiac thrombus36,123
Cardiac magnetic Decreased LVEF6,11,124
5. Diagnosis of PPCM resonance imaging Decreased right ventricular ejection

fraction11,69
PPCM patients typically display heart failure symptoms like fatigue, dys- Elevated T2 ratio as a sign of cardiac
pnoea, cough, exercise intolerance, peripheral oedema, and orthop- oedema124
noea.5,23,61 These symptoms overlap with normal pregnancy-associated Late gadolinium enhancement as a sign of
discomfort and/or symptoms of infectious disease (flu-like symptoms), myocardial fibrosis (incongruent findings
rendering an accurate diagnosis challenging for the treating physician. in different studies124–126
Moreover, the diagnosis of PPCM relies only on an LV systolic dysfunc- Coronary Normal findings24
tion with an LVEF below 45% and the time point in relation to pregnancy angiography
as stated in the definition.5,6,62 Beyond these diagnostic parameters, the Table 2 shows the high variability of the phenotype of PPCM in connection with
phenotype of PPCM is highly variable (summarized in Table 2). For exam- the different diagnostic methods. It is important to note that some of the listed
criteria can be found in almost all PPCM patients whereas others seem to be
ple, some patients display a high degree of cardiac inflammation and peri- quite rare.
cardial effusion, where cardiac magnetic resonance imaging (MRI) can
provide additional information, for example, in cases with suspected
myocarditis.63 In severely affected patients, right ventricular (RV) dys- ..
function and/or mitral regurgitation as a consequence of LV dilatation
..
..
6. Onset, clinical course, and
may be present.64,65 Ventricular dilatation is frequent but not always dis-
..
..
prognosis of PPCM
cernible in PPCM patients.61 Furthermore, some PPCM patients have a ..
higher risk for potentially life-threatening ventricular tachycardia,66 while
.. The time of onset of the disease in relation to pregnancy varies among
.. different PPCM populations, with a large part of patients presenting late
others have apparently normal electrocardiography (ECG). As a guide ..
.. in pregnancy and during delivery in the US (IPAC study number:
for diagnosis, the Heart Failure Association (HFA) recently published a .. NCT01085955),9 while in Germany few patients are symptomatic during
diagnostic algorithm for PPCM in which clinical laboratory diagnostics is ..
.. pregnancy with the majority presenting during delivery and in the first
recommended in addition to clinical and echocardiographic investiga- .. month postpartum,10,11 and in South Africa, almost all patients present
tions, including measurements of the amino-terminal pro-B-type natri-
..
.. postpartum.10,67,68 It should be noted, however, that it is often hard to
uretic peptide (NT-proBNP), creatine kinase (CK), and cardiac troponin .. define the time point of the onset of heart failure, since the diagnosis of
..
I (TnI), ECG, together with lung ultrasound, and repeated measurements .. PPCM is often delayed.5,24 The clinical course of disease is also highly var-
of the vital signs in patients with suspected PPCM.63 Overall, the clinical ..
.. iable. While some patients develop symptoms slowly over weeks, others
diagnosis of PPCM is challenging and largely dependent on the subjective ... develop acute heart failure and cardiogenic shock within hours.24
assessment of the physician. Diagnosis should include functional assess- .. In contrast to other forms of heart failure, PPCM patients have a good
ments, full clinical laboratory workup, and the medical history of the pa-
..
.. chance for full cardiac recovery. Although there is no specific test to pre-
tient and her family. In addition, there is a significant need for biomarkers .. dict outcome, time to diagnosis, the severity of heart failure, and the
..
to help to identifying patients at risk prior to the onset of disease and for .. treatment seem important. In this regard, most studies report that early
early diagnosis. The current knowledge on potential disease-specific di- .. diagnosis and start of treatment at least with standard therapy for heart
..
agnostic markers and related challenges are detailed in the chapters .. failure are associated with a better chance for cardiac recovery, while
below.
.. patients with severely reduced LV function have a lower chance for full
..
cardiac recovery.68 In addition, affected RV function also appears to be .. A potential common pathway in PPCM: Unbalanced oxidative stress and
associated with a lower chance of cardiac recovery.65,69 In a retrospec- .. subsequent PRL cleavage and vascular impairment: Recent research has
..
tive analysis of 82 consecutive patients diagnosed with PPCM, Ekizler .. identified an impairment of the vasculature, especially endothelial dam-
..

et al.70 demonstrated that the prognostic value of positive T wave in lead .. age and dysfunction, as a major factor inducing and driving PPCM
aVR (TaVR) could be used as a feasible ECG marker for adverse out- .. (Figure 2).10,24,80,81 During pregnancy, physiologically rising oxidative
come, like persistent LV systolic dysfunction, arrhythmic events, and
.. stress leads to the enhanced generation of reactive oxygen species
..
death. Moreover, a prolonged QTc and sinus tachycardia in the 12-lead .. (ROS).82 This is normally compensated by an increasing total antioxidant
ECG at baseline were independent predictors of poor outcome in
.. capacity (TAC) mediated by an up-regulated expression of mitochon-
..
PPCM patients (N = 66) at 6 months and 1 year follow-up.71 A recently .. drial superoxide dismutase 2 (SOD2).82 In the postpartum maternal
.. heart, SOD2 is up-regulated by STAT3 and the peroxisome proliferator-
published study using the IPAC patient cohort (N = 88) reported that ..
half of PPCM patients had an abnormal ECG, as they present with atrial .. activated receptor gamma coactivator-1 (PGC-1a) (Figure 2).80,83 The
.. importance of these three factors, STAT3, PGC-1a, and SOD2, for the
abnormality, ventricular hypertrophy, ST-segment deviation, and/or bun- ..
dle branch block.72 PPCM patients with left atrial abnormality had a .. development of PPCM is illustrated in experimental mouse models,
.. where transgenic mice with cardiomyocyte-specific deficiency of STAT3
lower chance for cardiac recovery.72 However, with regard to recovery ..
prediction, few parameters have been validated in more than a single
.. (STAT3-KO) or PGC-1a (PGC-1a-KO), as well as mice hemizygous for
.. Sod2, develop PPCM phenotypes (Figure 2).80,83 So far, there is no evi-
study population to date. Low baseline LV function and African ancestry ..
.. dence for genetic factors leading to reduced cardiac STAT3 or PGC-1a
have been established as parameters associated with lower recovery .. expression in PPCM patients. However, extensive bleeding or a hyperos-
rates.9,11,14,26,73 Conversely, several studies report that PPCM patients ..
.. molar stress might lead to reduced cardiac STAT3 in the peripartum
with pregnancy-associated hypertension seem to have a better chance .. phase.81,84
for recovery.10,18 Whether the higher frequency of PPCM with adverse ..
.. The enhanced oxidative stress in the above mentioned PPCM mouse
outcome in patients with African ancestry can be attributed to a different ..
.. models promotes activation of proteases, such as cathepsin D and metal-
genetic background or differences in health care systems is currently not .. loproteinases (MMP), which subsequently cleave the nursing hormone
known. Likewise, the reason for a better outcome among PPCM patients ..
.. PRL into the anti-angiogenic N-terminal PRL metabolite 16 kDa-PRL
with hypertensive disorders is also not known but might relate to re- .. (Figure 2).23,80,81 The 16 kDa-PRL subsequently impacts on endothelial
duced loading conditions postpartum upon lowering or resolution of hy- ..
.. cells, where it induces apoptosis and prevents proliferation and migra-
pertension. Therefore, prognostic markers validated in large .. tion (for detailed description see80,85–89). Further analyses revealed that
international registries to predict and monitor stable and sustained re- ..
.. 16 kDa-PRL attenuates vasorelaxation and angiogenesis via inhibition of
covery vs. persisting cardiovascular impairment are needed. .. the Ca2þ-related activation of endothelial nitric oxide synthase
..
.. (eNOS).90,91 It is also associated with elevated asymmetric dimethylargi-
.. nine (ADMA) levels.10,92 Moreover, the 16 kDa-PRL induces expression
7. Pathophysiology of PPCM ..
.. of microRNA-146a (miR-146a) via activation of nuclear factor kappa-
.. light-chain-enhancer of activated B cells (NF- jB) in endothelial cells,
Although the aetiology of PPCM is still largely unknown, clinical and ex- ..
perimental studies have discovered several underlying mechanisms,
.. which mediates detrimental effects of 16 kDa-PRL in the heart
.. (Figure 2).89 MiR-146a is largely responsible for the endothelium-
which are discussed below and summarized in Figure 2. ..
The impact of inflammation and autoimmune reactions: Inflammation and
.. damaging, pro-apoptotic, and anti-angiogenic properties of 16 kDa-PRL
.. and exerts adverse effects on the heart via exosomal transfer of miR-
autoimmune reactions have been discussed as potential factors inducing ..
.. 146a to cardiomyocytes. In the cardiomyocyte, miR-146a alters the me-
and driving PPCM.74 In this context, elevated levels of various circulating ..
.. tabolism and reduces the Erb-B2 receptor tyrosine kinase 4 (ErbB4) re-
cytokines including interleukin-6 (IL-6), tumour necrosis factor-a
.. ceptor system (Figure 2).89 Additionally, a STAT3-dependent
(TNFa), C-reactive protein (CRP), and interferon gamma (IFNc) were .. upregulation of miR-199a-5p independent of pregnancy contributes fur-
found in PPCM patients that positively correlated with severity of cardiac ..
.. ther to the downregulation of ErbB4 (Figure 2).84 As activation of the
failure.67,75,76 There is evidence that pentoxifylline, a xanthine-derived .. neuregulin (NRG)/ErbB4 system is also cardioprotective during physio-
agent known to inhibit the release of TNFa, when administered along
..
.. logical ventricular remodelling in pregnancy,93 the miRNA-mediated
with other heart failure medications has been shown to improve the out- ..
.. downregulation of NRG/ErbB4 in postpartum hearts further contributes
come of PPCM patients in an African cohort.75 Additionally, several sin- .. to heart failure (Figure 2). Moreover, in the context of PPCM and ele-
gle studies have reported elevated levels of autoantibodies (AABs) that ..
.. vated circulating IFNc levels possibly due to infection, the full-length PRL
might be involved in the pathogenesis of the disease. Data from the .. also seems to become an adverse factor in the postpartum heart, since it
German PPCM registry demonstrated the presence of AABs against car- ..
.. promotes upregulation of chemokine C–C motif chemokine ligand
diac troponin I (TnI) and myosin heavy chain 7 in particular in PPCM .. (CCL2) and cardiac inflammation (Figure 2).76 The importance of the
patients with more severe LV dysfunction.74 A small sample size study
..
.. role of PRL, both full length and the cleaved 16 kDa-PRL form, for the
(N = 37) reported elevated levels of AABs against b1-adrenergic recep- .. pathophysiology of PPCM was demonstrated in the positive effects of
tors (b1 R) and the M2-muscarinic receptor (M2-R), which positively
..
.. PRL blockade by the dopamine 2D receptor agonist bromocriptine in
correlated with LV dimensions and cardiac function.77 Likewise, a recent .. the STAT3-KO and PGC-1a-KO PPCM mouse models (Figure 2).80,81 In
..
study showed that PPCM patients who did not have the above AABs .. addition, adding PRL blockers to standard heart failure therapy has been
had a favourable outcome.78 There are a few case reports where plas- .. associated with good recovery in several case reports and in several clini-
..
mapheresis was used in PPCM patients to deplete AABs,79 but so far it is .. cal studies and trials with PPCM patients,8,11,62,94–96 thereby supporting
not clear whether the AABs are contributing to the pathogenesis of .. the concept of oxidative stress and (cleaved) PRL as a major common
..
PPCM or are a consequence of the disease. . mechanism in PPCM.

Figure 2 Scheme illustrating mechanisms (red lines) predisposing, inducing, and/or driving PPCM, potential protective pathways (black lines) as well as
clinical tested therapies (green lines). Abbreviations: ACE, angiotensin-converting-enzyme; AR, adrenergic receptors; angiotensin II (Ang II) type 1 receptor
(AT1); CD, cathepsin D; CCL2, C–C motif chemokine ligand; eNOS, endothelial nitric oxide synthase; ErbB4, erb-B2 receptor tyrosine kinase 4; IFNc, inter-
feron gamma; GPCR, G-protein-coupled receptors; Gq, G-protein q; MMP, matrix metallopeptidase; NFjB, nuclear factor kappa B; NRAS, neuroblastoma
ras viral oncogene homologue; PAI-1, plasminogen activator inhibitor-1; PGC-1a, peroxisome proliferator-activated receptor gamma coactivator 1 alpha;
PPCM, peripartum cardiomyopathy; PRL, prolactin; sFtl-1, soluble fms-like tyrosine kinase-1; SOD, superoxide dismutase; STAT, signal transducer and acti-
vator of transcription; VEGF, vascular endothelial growth factor.
Potential role of additional pregnancy-associated factors in PPCM: Recent .. diagnosed early after delivery, treatment with recombinant Relaxin-2
..
studies analysed the role of other pregnancy hormones in PPCM, such as .. (Serelaxin) was tested in the STAT3-KO mouse model. This experimen-
Relaxin-2, a hormone that is produced in the first phase of pregnancy
.. tal approach showed a mild positive effect on physiological hypertrophy
..
and shortly before birth by the corpus luteum. It causes a transformation .. with Serelaxin, but no effect on preventing the development of postpar-
of the extracellular matrix of the cervical canal and acts pro-angiogenic
.. tum heart failure in STAT3-KO mice.98 Consequently, treatment with
..
and as a vasodilator.97 Relaxin-2 serum levels are elevated in pregnancy .. the vasoprotective Serelaxin had no substantial protective effect and will
..
and decline in the first days postpartum, thereafter, rapidly returning to .. not be pursued further. Since cardiomyocyte-specific deletion of STAT3
non-pregnant levels in healthy women.98 Several studies showed that ... and/or PGC-1a expression reduce the expression of pro-angiogenic fac-
higher serum Relaxin-2 levels soon after birth were associated with bet- .. tors, e.g. vascular endothelial growth factor (VEGF), they also reduce the
..
ter myocardial recovery after 2 months in PPCM patients who were di- .. ability of the heart to regenerate its vasculature (Figure 2).80,81 Moreover,
agnosed between 0 and 11 days postpartum, but showed no correlation .. systemic or local upregulation of additional anti-angiogenic factors such
..
with better myocardial function after 6 and 12 months.98,99 PPCM .. as the receptor soluble fms-like tyrosine kinase-1 (sFlt-1) promote both
patients diagnosed later than the first week postpartum showed no dif- .. local and systemic vascular dysfunction (Figure 2).81,100 In this regard, ad-
..
ference in Relaxin-2 levels compared with postpartum-matched healthy .. dition of recombinant VEGF and the prolactin blocker bromocriptine to
controls.98 Based on the reduced Relaxin-2 levels in PPCM patients
.. the PGC-1a-KO PPCM mouse model provided a better rescue than
..
bromocriptine alone indicating that placenta-released anti-angiogenic .. stress.103 However, cardiac-specific overexpression of AKT (AKTtg) per
factors such as sFlt-1 also contribute to PPCM (Figure 2). .. se or in combination with low STAT3 expression (STAT3-KO; AKTtg)
..
Potential role of catecholamines and impaired cAMP-PKA signalling: Recent .. promotes postpartum heart failure in mice with massive cardiac hyper-
.. trophy and diminished capillary density (Figure 2).76 These findings sug-

analyses on cardiac biopsies obtained from PPCM patients showed
..
remodelling and contractile impairments at the myofilament level, includ- .. gest that AKT seems to be protective during pregnancy but enhanced
ing increased compliant titin, reduced phosphorylation of titin at .. AKT activation postpartum may be detrimental. Similar to STAT3-KO,
..
Ser4010, and impaired myofilament length-dependent activation.101 .. STAT3-KO; AKTtg and AKTtg postpartum mice showed enhanced acti-
Moreover, myofilaments from PPCM patients hearts have a reduced .. vation of p66 Src homology 2 domain containing protein (p66SHC) and
..
cAMP-PKA activation and display an increased in calcium (Ca)2þ-sensi- .. forkhead box O3 (FoxO3A), and reduced SOD2 expression, indicative
tivity, which was restored after incubation with exogenous PKA.101 .. for increased oxidative stress and cell death (Figure 2). Moreover, in-
..
Additionally, PPCM biopsies showed a lack of EH-myomesin re-expres- .. creased cardiac cathepsin D activation and elevated cardiac miR-146a
sion, which may contribute to the increase in passive force and could be .. levels, involved in generation of 16 kDa-PRL, were observed in postpar-
..
a reason for the fast deterioration of some PPCM patients into terminal .. tum STAT3-KO; AKTtg and AKTtg mice.76 Enhanced cardiac AKT activa-
heart failure.101 Based on this data, one would assume that activation of
..
.. tion specifically in the absence of STAT3 in the postpartum heart also
cAMP-PKA signalling by catecholamines, i.e. b1-adrenergic receptors .. promoted pro-inflammatory and pro-fibrotic effects of the full-length
(b1-AR) agonists, would improve heart failure in PPCM patients.
..
.. PRL (Figure 2).76 While these data show that simply activating AKT in a
However, the contrary seems to be the case; data from the German .. PPCM heart might be detrimental, treatment with bromocriptine was
PPCM registry demonstrated that treatment with the b1-AR agonist
..
.. able to a large extent prevent PPCM in STAT3-KO; AKTtg and AKTtg
dobutamine in PPCM patients with cardiogenic shock is associated with .. mice, supporting the idea of a common downstream pathway that
an adverse cardiac outcome.84 Findings from the experimental STAT3-
..
.. involves oxidative stress and prolactin.76
KO PPCM model confirmed the adverse effects of b-AR agonist treat- ..
..
ment in PPCM leading to acute heart failure associated with high mortal- ..
ity.84 Impaired fatty acid and glucose uptake, the generation of a .. 8. Search for biomarkers for PPCM
..
metabolic deficit, oxidative stress-mediated dysfunction, cardiomyocyte .. in the context of mechanisms and
loss, and high degree of fibrosis and inflammation were identified as ..
..
mechanisms responsible for the detrimental effects of b-AR agonists in .. pregnancy-specific physiology
PPCM.84 These data demonstrate that b-AR agonists may irreversibly ..
.. In recent years, the increasing knowledge on mechanisms in PPCM has
damage the heart and could explain why dobutamine is associated with ..
higher levels of terminal heart failure in PPCM patients. Based on this evi- .. helped to identify a panel of potential diagnostic and prognostic bio-
.. markers.24 Their relevance and potential usefulness are discussed here.
dence from basic and clinical research, new treatment guidelines for ..
PPCM patients recommend avoiding dobutamine in favour of mechanical .. Diagnostic biomarkers: So far, only the rather unspecific natriuretic pep-
.. tides (i.e. BNP and NT-proBNP)107 have been established as valid bio-
support systems in critically ill PPCM patients.6,102 ..
Potential role of impaired hypertrophy and survival pathways: Pregnancy .. markers for PPCM diagnosis.107 Novel, more specific biomarkers include
.. miR-146a, the major mediator of 16 kDa-PRL effects, which was found
requires adaptation of the heart to an increased volume load resulting in ..
a process of physiological hypertrophy.103 Activation of G-protein-cou- .. to be elevated in PPCM patients compared with healthy postpartum
.. women and healthy non-pregnant women.10,89 Moreover, miR-146a is
pled receptors plays an important role for cardiomyocyte hypertrophy ..
and survival. The G-protein Gq couples several cell surface receptors
.. also packaged in endothelial exosomes, and circulating elevated endo-
..
(i.e. a and b-ARs, angiotensin II type 1 receptor, endothelin-1 receptor) .. thelial and monocyte microparticles are indicators for PPCM.108
involved in cardiomyocyte hypertrophy to intracellular signalling path-
.. However, in our experience, miR-146a in blood samples, even if pack-
..
ways (Figure 2). It has been shown that overexpression of the Gaq subu- .. aged in exosomes, is quite unstable. It needs high standards in blood sam-
nit promotes a form of PPCM that is associated with peripartum
.. pling and storage conditions, which may be difficult to maintain for a
..
hypertrophy and high cardiomyocyte apoptosis,104 features that are in .. broadly used biomarker. The PRL cleaving protease cathepsin D and
part similar to the observed PPCM phenotype in STAT3-KO mice stimu-
.. ADMA, a marker for endothelial dysfunction, can also be considered as
..
lated with b-AR agonists.84 Recently a point mutation in HSPB6 gene, .. potential biomarkers connected to the 16 kDa-PRL pathophysiology.10
.. Although both markers are significantly higher in PPCM patients, a high
encoding hear shock protein family member 6, also known as Hsp20, ..
was identified in 0.85% of patients with DCM.105 Subsequent studies in .. overlap in their values has been observed with values from postpartum
.. healthy control women, making it difficult to define a cut-off value.10
mice showed that overexpression of the S10F mutation induced peripar- ..
tum heart failure.106 Further analyses revealed that S10F-overexpressing .. Recent research showed that 16 kDa-PRL does not signal via the PRL
.. receptor, but instead needs to form a complex with the plasminogen ac-
females displayed enhanced cardiomyocyte apoptosis after multiple de- ..
liveries, which was associated with decreased levels of B-cell lymphoma .. tivator inhibitor-1 (PAI-1) protein and the urokinase-type plasminogen
..
2 (Bcl-2)/Bcl-2-associated X protein (Bax) and reduced protein kinase B .. activator receptor (uPAR) to signal into endothelial cells and mediate
(AKT) phosphorylation. The findings suggest that the S10F mutant .. anti-angiogenic properties.109 There is emerging evidence that postpar-
..
HSPB6, similar to Gaq104 overexpression, acts through dysregulation of .. tum upregulation of PAI-1 is specifically present in PPCM patients and
cell survival signalling in the postpartum heart.106 AKT has been shown .. not in healthy postpartum women and may thus serve as a diagnostic
..
to be important for pregnancy-induced hypertrophy,103 but seems to be .. biomarker.110 Additional blood markers associated with PPCM include
reduced in the healthy postpartum heart compared with non-pregnant .. Relaxin-2, Placental Growth Factor (PIGF) and sFlt-1. For Relaxin-2, re-
..
hearts.80 Estrogen is known to induce cardioprotective signalling path- .. duced serum levels have been described by Mebazaa et al.111 In the same
ways, e.g. proto-oncogene tyrosine-protein kinase (c-Src)-AKT, which is
.. study, PPCM patients diagnosed in the early postpartum phase showed
..
activated during pregnancy to protect the heart from pregnancy-induced . elevated levels of the pro-angiogenic PIGF.111 Furthermore, PPCM
..
patients with severe forms of heart failure at diagnosis showed increased .. Besides the beneficial effects of the BOARD concept, subgroups of
sFlt-1 levels.99 Although these markers are statistically different in PPCM .. PPCM patients, i.e. those with pathogenic mutations, inflammatory disor-
..
patients and pregnancy-matched healthy controls early after delivery, all .. ders or specific pathologies in pregnancy (hypertension) may exhibit
.. highly individual pathologies, which need to be targeted specifically. For

three biomarkers have a rapid and highly specific kinetic in relation to ..
pregnancy and delivery and it will be difficult to define clear threshold .. example, the high degree of inflammation observed in African PPCM
values for them in the peripartum phase. .. patients suggests that these patients may benefit from additional anti-
..
Prognostic biomarkers: Prognostic biomarkers would be very helpful in .. inflammatory treatment, such as pentoxifylline.75 In turn, the role of au-
the management of PPCM. In this regard, a small retrospective study in
.. toimmunity and AABs with regard to treatment is controversial, as it is
..
African PPCM patients reported that the failure to decrease oxidized .. not clear if AABs are primarily disease causing or rather a consequence
low-density lipoprotein (oxLDL), IFNc, and PRL was associated with a
.. of heart failure, and so far no breakthrough study has been published on
..
poor outcome within the first 6 months after diagnosis.112 Likewise, .. the elimination of AABs in PPCM patients.79 Other disease-specific ther-
..
monocyte-to-high density lipoprotein (HDL) cholesterol ratio (MHR) .. apies, such as targeting miR-146a, have proved successful in mouse mod-
was reported as a significant predictor of persistent LV systolic dysfunc- .. els of PPCM.10,89 However, miR-146a has multiple targets and regulates
..
tion in a further African PPCM cohort.113 More recent evidence suggests .. a multitude of biological mechanisms, raising safety issues for its targeting
that prognostic biomarkers for fibrosis, i.e. serum levels of procollagen .. in human PPCM patients. Similarly, the combination of bromocriptine
..
type I (PINP) and type III (PIIINP) N-terminal propeptide, soluble ST-2 .. with a VEGF analogue to improve angiogenesis was effective in treating
(sST-2) and plasma levels of Galectin 3 (Gal-3), differ between African
.. PPCM in PGC-1a-KO.81 However, due to a corresponding increased
..
and non-African PPCM patients with regard to baseline values as well as .. cancer risk, VEGF analogues are not suitable for use in human PPCM
prognosis.114
.. patients. The above mentioned potential adverse effects of (b1-AR) ago-
..
In contrast to other cardiovascular disease types, identification of diag- .. nists in PPCM patients84 emphasizes that more detailed investigations
..
nostic biomarkers for PPCM needs to consider substantial hormonal .. into medication that may harm PPCM patients and prevent them from
alterations in the peripartum phase, which may make it difficult to define .. recovery are also needed.
..
performance characteristics of the biomarker of interest, especially in ..
patients with symptoms around the time of delivery. In addition, diagnos- ..
..
tic and prognostic biomarker profiles may differ according to ethnic and/ .. 10. Conclusion
or genetic background, respectively and differing causes of PPCM. The
..
.. PPCM is a rare multi-factorial, life-threatening heart disease with the
large international registries with associated biobanks, i.e. the ..
EURObservational Research Programme (http://www.eorp.org; ESC)7,8
.. chance for full recovery upon early diagnosis and optimal treatment.
.. Clinical and experimental research has shown that multiple mechanisms
and the IPAC registry (USA)9 offer an optimal platform for mining for ..
.. pertain to the pathogenesis of PPCM, whose diagnosis is confirmed
biomarkers based on the above considerations and in particular regard- .. upon exclusion of other forms of heart failure. It is likely that PPCM
ing specificity for PPCM, pregnancy-related kinetics, and high storage ..
.. patients differ in the initiating pathologies but share common down-
stability. .. stream mechanisms, such as increased oxidative stress and disease-
..
.. driving PRL and PRL metabolites, which might explain the broad positive
..
9. Current and future treatment .. effect of the BOARD treatment concept in PPCM patients.116 At the
.. same time, the heterogeneity of pathologies in PPCM patients require
concepts for PPCM ..
.. specific diagnostic and prognostic biomarker profiles to ensure early di-
.. agnosis and initiation of optimal therapy. The relatively high presence of
Optimized heart failure medication and the availability of mechanical sup- ..
port systems are associated with better survival rates in PPCM cohorts
.. pathogenic mutations and the recent advances in genome-wide analyses
.. indicate that family genetic counselling, cascade phenotypic screening,
in the USA and in Germany.9,10,115 In addition, the discovery of a poten- ..
tial common mechanism, oxidative stress and PRL/16 kDa-PRL cardio-
.. and clinical genetic testing should be considered in PPCM management
.. with the overall aim of developing tailored therapies towards fast and
vascular toxicity, led to a novel disease-specific treatment called the ..
.. sustained recovery for these young patients.
BOARD concept (Bromocriptine, Oral heart failure therapies, ..
Anticoagulants, vasoRelaxing agents, and Diuretics) where, in addition to ..
..
standard heart failure therapy, the PRL blocker bromocriptine and anti- .. Acknowledgement
coagulation is added.106,107 The BOARD concept was introduced in the ..
.. We thank Nina McGuiness for helpful comments and proofreading.
2018 guidelines of the ESC to treat heart failure in pregnancy and may ..
benefit a large number of PPCM patients.116,117
..
.. Conflict of interest: none declared.
It is often debated whether blocking PRL by bromocriptine is ethically ..
correct, since it prevents the mother from nursing and the baby from
..
..
getting breast milk. In addition, potential beneficial effects of the full- .. Funding
..
length PRL are lost as PRL has pro-angiogenic effects and fosters bonding .. This study was supported by the MHH research funds (Clinical Scientist pro-
between mother and child. However, it seems that in the context of .. gramme) and by the German Research Foundation (DFG, HI 842/4-3), and
..
PPCM, full-length PRL may also act as an adverse factor, as it promotes .. the DFG Clinical Research Group (KFO 311, HI 842/10-1, RI 2531/2-1).
cardiac inflammation.76 Moreover, PPCM patients often need high doses ..
..
of heart failure medications, which are mostly transmitted to breast milk ..
and there is to date no clear evidence that the presence of heart failure .. References
.. 1. Melvin JP Jr. Post-partal heart disease. Ann Intern Med 1947;27:596–609.
medication in breast milk is safe for the nursing infant.118 . 2. Meadows WR. Postpartum heart disease. Am J Cardiol 1960;6:788–802.
3. Seftel H, Susser M. Maternity and myocardial failure in African women. Br Heart J

.. 23. Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardio-
..
1961;23:43–52. .. myopathy. Nat Rev Cardiol 2014;11:364–370.
4. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy. Circulation 1971;44: .. 24. Hilfiker-Kleiner D, Haghikia A, Nonhoff J, Bauersachs J. Peripartum cardiomyopathy:
964–968. .. current management and future perspectives. Eur Heart J 2015;36:1090–1097.
..

5. Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, Regitz- 25. Hilfiker-Kleiner D. ‘Social freezing’ of women’s eggs. Eur Heart J 2015;36:773.
Zagrosek V, Schaufelberger M, Tavazzi L, van Veldhuisen DJ, Watkins H, Shah AJ, .. 26. Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United
Seferovic PM, Elkayam U, Pankuweit S, Papp Z, Mouquet F, McMurray JJ. Current
.. States: diagnosis, prognosis, and management. J Am Coll Cardiol 2011;58:659–670.
.. 27. Fett JD. Peripartum cardiomyopathy. Insights from Haiti regarding a disease of un-
state of knowledge on aetiology, diagnosis, management, and therapy of peripartum ..
cardiomyopathy: a position statement from the Heart Failure Association of the .. known etiology. Minn Med 2002;85:46–48.
European Society of Cardiology Working Group on peripartum cardiomyopathy. .. 28. Fett JD. Earlier detection can help avoid many serious complications of peripartum
Eur J Heart Fail 2010;12:767–778. .. cardiomyopathy. Future Cardiol 2013;9:809–816.
6. Bauersachs J, König T, Meer P, Petrie MC, Hilfiker-Kleiner D, Mbakwem A, Hamdan .. 29. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368:687–693.
R, Jackson AM, Forsyth P, Boer RA, Mueller C, Lyon AR, Lund LH, Piepoli MF, .. 30. Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner
Heymans S, Chioncel O, Anker SD, Ponikowski P, Seferovic PM, Johnson MR,
.. D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-
.. Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J,
Mebazaa A, Sliwa K. Pathophysiology, diagnosis and management of peripartum car- ..
diomyopathy: a position statement from the Heart Failure Association of the .. Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu
European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J .. P, Gorcsan J, McNamara DM, Seidman CE, Seidman JG, Arany Z. Shared genetic
Heart Fail 2019;21:827. .. predisposition in peripartum and dilated cardiomyopathies. N Engl J Med 2016;374:
7. Sliwa K, Hilfiker-Kleiner D, Mebazaa A, Petrie MC, Maggioni AP, Regitz-Zagrosek V, .. 233–241.
Schaufelberger M, Tavazzi L, van Veldhuisen DJ, Roos-Hesslink JW, Shah AJ,
.. 31. Wu VC, Chen TH, Yeh JK, Wu M, Lu CH, Chen SW, Wu KP, Cheng CW, Chang
.. CH, Hung KC, Chern MS, Lin FC, Wen MS. Clinical outcomes of peripartum car-
Seferovic PM, Elkayam U, van Spaendonck-Zwarts K, Bachelier-Walenta K, .. diomyopathy: a 15-year nationwide population-based study in Asia. Medicine
Mouquet F, Kraigher-Krainer E, Hall R, Ponikowski P, McMurray JJ, Pieske B. .. (Baltimore) 2017;96:e8374.
EURObservational Research Programme: a worldwide registry on peripartum car- ..
diomyopathy (PPCM) in conjunction with the Heart Failure Association of the .. 32. Behrens I, Basit S, Lykke JA, Ranthe MF, Wohlfahrt J, Bundgaard H, Melbye M, Boyd
European Society of Cardiology Working Group on PPCM. Eur J Heart Fail 2014;16: .. HA. Hypertensive disorders of pregnancy and peripartum cardiomyopathy: a na-
583–591. .. tionwide cohort study. PLoS One 2019;14:e0211857.
8. Sliwa K, Mebazaa A, Hilfiker-Kleiner D, Petrie MC, Maggioni AP, Laroche C, Regitz-
.. 33. Ntusi NB, Badri M, Gumedze F, Sliwa K, Mayosi BM. Pregnancy-associated heart fail-
.. ure: a comparison of clinical presentation and outcome between hypertensive heart
Zagrosek V, Schaufelberger M, Tavazzi L, van der Meer P, Roos-Hesselink JW, .. failure of pregnancy and idiopathic peripartum cardiomyopathy. PLoS One 2015;10:
Seferovic P, van Spandonck-Zwarts K, Mbakwem A, Böhm M, Mouquet F, Pieske B, .. e0133466.
Hall R, Ponikowski P, Bauersachs J. Clinical characteristics of patients from the ..
worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational .. 34. Lindley KJ, Conner SN, Cahill AG, Novak E, Mann DL. Impact of preeclampsia on
Research Programme in conjunction with the Heart Failure Association of the .. clinical and functional outcomes in women with peripartum cardiomyopathy. Circ
European Society of Cardiology Study Group on PPCM. Eur J Heart Fail 2017;19:
.. Heart Fail 2017;10. pii: e003797. doi: 10.1161/CIRCHEARTFAILURE.116.003797.
.. 35. Bello N, Rendon IS, Arany Z. The relationship between pre-eclampsia and peripar-
1131–1141. .. tum cardiomyopathy: a systematic review and meta-analysis. J Am Coll Cardiol 2013;
9. McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G, Modi K, Alexis .. 62:1715–1723.
JD, Ramani GV, Semigran MJ, Haythe J, Markham DW, Marek J, Gorcsan J, Wu W- .. 36. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardio-
C, Lin Y, Halder I, Pisarcik J, Cooper LT, Fett JD, Investigators I. Clinical outcomes .. myopathy: analysis of clinical outcome, left ventricular function, plasma levels of
for peripartum cardiomyopathy in North America: results of the IPAC study ..
(Investigations of Pregnancy-Associated Cardiomyopathy). J Am Coll Cardiol 2015;66: .. cytokines and Fas/APO-1. J Am Coll Cardiol 2000;35:701–705.
905–914.
.. 37. Elkayam U. Risk of subsequent pregnancy in women with a history of peripartum
.. cardiomyopathy. J Am Coll Cardiol 2014;64:1629–1636.
10. Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, Tsikas D, .. 38. Elkayam U, Tummala PP, Rao K, Akhter MW, Karaalp IS, Wani OR, Hameed A,
Jordan J, Lichtinghagen R, Kaisenberg CS, Struman I, Bovy N, Sliwa K, Bauersachs J, .. Gviazda I, Shotan A. Maternal and fetal outcomes of subsequent pregnancies in
Hilfiker-Kleiner D. Phenotyping and outcome on contemporary management in a .. women with peripartum cardiomyopathy. N Engl J Med 2001;344:1567–1571.
German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 2013; .. 39. Hilfiker-Kleiner D, Haghikia A, Masuko D, Nonhoff J, Held D, Libhaber E, Petrie
108:366. ..
11. Hilfiker-Kleiner D, Haghikia A, Berliner D, Vogel-Claussen J, Schwab J, Franke A, .. MC, Walker NL, Podewski E, Berliner D, Bauersachs J, Sliwa K. Outcome of subse-
Schwarzkopf M, Ehlermann P, Pfister R, Michels G, Westenfeld R, Stangl V,

.. quent pregnancies in patients with a history of peripartum cardiomyopathy. Eur J
.. Heart Fail 2017;19:1723.
Kindermann I, Kühl U, Angermann CE, Schlitt A, Fischer D, Podewski E, Böhm M, .. 40. Kao DP, Hsich E, Lindenfeld J. Characteristics, adverse events, and racial differences
Sliwa K, Bauersachs J. Bromocriptine for the treatment of peripartum cardiomyopa- .. among delivering mothers with peripartum cardiomyopathy. JACC Heart Fail 2013;1:
thy: a multicentre randomized study. Eur Heart J 2017;38:2671–2679. .. 409–416.
12. Sliwa K, Bohm M. Incidence and prevalence of pregnancy-related heart disease. .. 41. Krishnamoorthy P, Garg J, Palaniswamy C, Pandey A, Ahmad H, Frishman WH,
Cardiovasc Res 2014;101:554–560. ..
13. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experiences at King .. Lanier G. Epidemiology and outcomes of peripartum cardiomyopathy in the United
Edward VIII Hospital, Durban, South Africa and a review of the literature. Trop Doct
.. States: findings from the nationwide inpatient sample. J Cardiovasc Med (Hagerstown)
.. 2016;17:756–761.
1995;25:118–123. .. 42. Pierce JA, Price BO, Joyce JW. Familial occurrence of postpartal heart failure. Arch
14. Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in .. Intern Med 1963;111:651–655.
Africa. Circulation 2005;112:3577–3583. .. 43. Ntusi NB, Wonkam A, Shaboodien G, Badri M, Mayosi BM. Frequency and clinical
15. Isezuo SA, Abubakar SA. Epidemiologic profile of peripartum cardiomyopathy in a .. genetics of familial dilated cardiomyopathy in Cape Town: implications for the eval-
tertiary care hospital. Ethn Dis 2007;17:228–233. .. uation of patients with unexplained cardiomyopathy. S Afr Med J 2011;101:394–398.
16. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the
..
.. 44. Massad LS, Reiss CK, Mutch DG, Haskel EJ. Familial peripartum cardiomyopathy af-
incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo .. ter molar pregnancy. Obstet Gynecol 1993;81:886–888.
Clin Proc 2005;80:1602–1606. .. 45. Pearl W. Familial occurrence of peripartum cardiomyopathy. Am Heart J 1995;129:
17. Huang GY, Zhang LY, Long-Le MA, Wang LX. Clinical characteristics and risk fac- .. 421–422.
tors for peripartum cardiomyopathy. Afr Health Sci 2012;12:26–31. .. 46. Christiansen MN, Køber L, Torp-Pedersen C, Smith JG, Gustafsson F, Vejlstrup NG,
18. Kamiya CA, Kitakaze M, Ishibashi-Ueda H, Nakatani S, Murohara T, Tomoike H, .. Damm P, Johansen M, Andersson C, Ersbøll AS. Prevalence of heart failure and
Ikeda T. Different characteristics of peripartum cardiomyopathy between patients .. other risk factors among first-degree relatives of women with peripartum cardiomy-
complicated with and without hypertensive disorders. Results from the Japanese
..
.. opathy. Heart 2019;105:1057.
Nationwide survey of peripartum cardiomyopathy. Circ J 2011;75:1975–1981. .. 47. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R,
19. Ersboll AS, Johansen M, Damm P, Rasmussen S, Vejlstrup NG, Gustafsson F. .. Jongbloed JD, Paulus WJ, Dooijes D, van den Berg MP. Peripartum cardiomyopathy
Peripartum cardiomyopathy in Denmark: a retrospective, population-based study of .. as a part of familial dilated cardiomyopathy. Circulation 2010;121:2169–2175.
incidence, management and outcome. Eur J Heart Fail 2017;19:1712–1720. .. 48. van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker-Kleiner D,
20. Patel PA, Roy A, Javid R, Dalton JA. A contemporary review of peripartum cardio- .. Bollen IA, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ,
myopathy. Clin Med 2017;17:316–321. .. van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JD. Titin gene muta-
21. Kolte D, Khera S, Aronow WS, Palaniswamy C, Mujib M, Ahn C, Jain D, Gass A,
.. tions are common in families with both peripartum cardiomyopathy and dilated car-
..
Ahmed A, Panza JA, Fonarow GC. Temporal trends in incidence and outcomes of .. diomyopathy. Eur Heart J 2014;35:2165–2173.
peripartum cardiomyopathy in the United States: a nationwide population-based .. 49. Morales A, Painter T, Li R, Siegfried JD, Li D, Norton N, Hershberger RE. Rare vari-
study. J Am Heart Assoc 2014;3:e001056. .. ant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation
22. Honigberg MC, Givertz MM. Peripartum cardiomyopathy. BMJ 2019;364:k5287. . 2010;121:2176–2182.
50. Sheppard R, Hsich E, Damp J, Elkayam U, Kealey A, Ramani G, Zucker M, Alexis JD, .. Hilfiker-Kleiner D, Bauersachs J. Bromocriptine treatment in patients with peripar-
Horne BD, Hanley-Yanez K, Pisarcik J, Halder I, Fett JD, McNamara DM,
.. tum cardiomyopathy and right ventricular dysfunction. Clin Res Cardiol 2019;108:
..
Investigators I. GNB3 C825T polymorphism and myocardial recovery in peripartum .. 290–297.
cardiomyopathy. Circ Heart Fail 2016;9:e002683. .. 70. Ekizler FA, Cay S, Kafes H, Ozeke O, Ozcan F, Topaloglu S, Temizhan A, Aras D.
..

51. Soltanzadeh P, Friez MJ, Dunn D, von Niederhausern A, Gurvich OL, Swoboda KJ, The prognostic value of positive T wave in lead aVR: a novel marker of adverse car-
Sampson JB, Pestronk A, Connolly AM, Florence JM, Finkel RS, Bonnemann CG, .. diac outcomes in peripartum cardiomyopathy. Ann Noninvasive Electrocardiol 2019;
Medne L, Mendell JR, Mathews KD, Wong BL, Sussman MD, Zonana J, Kovak K, .. 24:e12631.
Gospe SM Jr, Gappmaier E, Taylor LE, Howard MT, Weiss RB, Flanigan KM. Clinical .. 71. Hoevelmann J, Viljoen CA, Manning K, Baard J, Hahnle L, Ntsekhe M, Bauersachs J,
and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul
.. Sliwa K. The prognostic significance of the 12-lead ECG in peripartum cardiomyopa-
..
Disord 2010;20:499–504. .. thy. Int J Cardiol 2019;276:177–184.
52. Ahmed A, Spinty S, Murday V, Longman C, Khand A. A de-novo deletion of dystro- .. 72. Honigberg MC, Elkayam U, Rajagopalan N, Modi K, Briller JE, Drazner MH, Wells
phin provoking severe ‘peri-partum cardiomyopathy’: the importance of genetic .. GL, McNamara DM, Givertz MM, Investigators I. Electrocardiographic findings in
testing in peripartum cardiomyopathy to uncover female carriers. Int J Cardiol 2016; .. peripartum cardiomyopathy. Clin Cardiol 2019;42:524–529.
203:1084–1085. .. 73. Pillarisetti J, Kondur A, Alani A, Reddy M, Reddy M, Vacek J, Weiner CP, Ellerbeck
53. Cheng VE, Prior DL. Peripartum cardiomyopathy in a previously asymptomatic car- .. E, Schreiber T, Lakkireddy D. Peripartum cardiomyopathy: predictors of recovery
rier of Duchenne muscular dystrophy. Heart Lung Circ 2013;22:677–681. .. and current state of implantable cardioverter-defibrillator use. J Am Coll Cardiol
54. Davies JE, Winokur TS, Aaron MF, Benza RL, Foley BA, Holman WL.
.. 2014;63:2831–2839.
..
Cardiomyopathy in a carrier of Duchenne’s muscular dystrophy. J Heart Lung .. 74. Haghikia A, Kaya Z, Schwab J, Westenfeld R, Ehlermann P, Bachelier K, Oettl R, von
Transplant 2001;20:781–784. .. Kaisenberg CS, Katus HA, Bauersachs J, Hilfiker-Kleiner D. Evidence of autoantibod-
55. Giliberto F, Radic CP, Luce L, Ferreiro V, de Brasi C, Szijan I. Symptomatic female .. ies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy.
carriers of Duchenne muscular dystrophy (DMD): genetic and clinical characteriza- .. Basic Res Cardiol 2015;110:60.
tion. J Neurol Sci 2014;336:36–41. .. 75. Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of
56. Politano L, Nigro V, Nigro G, Petretta VR, Passamano L, Papparella S, Di Somma S, .. pentoxifylline to conventional therapy improves outcome in patients with peripar-
Comi LI. Development of cardiomyopathy in female carriers of Duchenne and
.. tum cardiomyopathy. Eur J Heart Fail 2002;4:305–309.
..
Becker muscular dystrophies. JAMA 1996;275:1335–1338. .. 76. Ricke-Hoch M, Bultmann I, Stapel B, Condorelli G, Rinas U, Sliwa K, Scherr M,
57. Toib A, Grange DK, Kozel BA, Ewald GA, White FV, Canter CE. Distinct clinical .. Hilfiker-Kleiner D. Opposing roles of Akt and STAT3 in the protection of the ma-
and histopathological presentations of Danon cardiomyopathy in young women. J .. ternal heart from peripartum stress. Cardiovasc Res 2014;101:587–596.
Am Coll Cardiol 2010;55:408–410. .. 77. Liu J, Wang Y, Chen M, Zhao W, Wang X, Wang H, Zhang Z, Zhang J, Xu L, Chen
58. Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med 2011; .. J, Yang X, Zhang L. The correlation between peripartum cardiomyopathy and auto-
13:563–568. .. antibodies against cardiovascular receptors. PLoS One 2014;9:e86770.
59. Horne BD, Rasmusson KD, Alharethi R, Budge D, Brunisholz KD, Metz T, Carlquist .. 78. Ma G, Wang Y, Hou D, Liu J, Zhang J, Xu L, Wang H, Zhao W, Zhang Y, Zhang L.
JF, Connolly JJ, Porter TF, Lappe DL, Muhlestein JB, Silver R, Stehlik J, Park JJ, May
.. Association of autoantibodies against the M2-muscarinic receptor with long-term
..
HT, Bair TL, Anderson JL, Renlund DG, Kfoury AG. Genome-wide significance and .. outcomes in peripartum cardiomyopathy patients: a 5-year prospective study.
replication of the chromosome 12p11.22 locus near the PTHLH gene for peripar- .. J Cardiol 2019 74:251–257.
tum cardiomyopathy. Circ Cardiovasc Genet 2011;4:359–366. .. 79. Wang TL, Hung HF, Shyu KG, Yeh JH, Chiu HC. Successful treatment of peripartum
60. Maioli E, Fortino V, Pacini A. Parathyroid hormone-related protein in preeclampsia: .. cardiomyopathy with plasmapheresis. Acta Cardiol Sin 2013;29:471–474.
a linkage between maternal and fetal failures. Biol Reprod 2004;71:1779–1784. .. 80. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, Forster
61. Sliwa K, Petrie MC, Hilfiker-Kleiner D, Mebazaa A, Jackson A, Johnson MR, van der .. O, Quint A, Landmesser U, Doerries C, Luchtefeld M, Poli V, Schneider MD,
Meer P, Mbakwem A, Bauersachs J. Long-term prognosis, subsequent pregnancy,
.. Balligand JL, Desjardins F, Ansari A, Struman I, Nguyen NQ, Zschemisch NH, Klein
..
contraception and overall management of peripartum cardiomyopathy: practical .. G, Heusch G, Schulz R, Hilfiker A, Drexler H. A cathepsin D-cleaved 16 kDa form
guidance paper from the Heart Failure Association of the European Society of .. of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589–600.
Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail 2018;20: .. 81. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, Hacker MR, Rhee JS, Mitchell J,
951–962. .. Mahmood F, Hess P, Farrell C, Koulisis N, Khankin EV, Burke SD, Tudorache I,
62. Haghikia A, Schwab J, Vogel-Claussen J, Berliner D, Pfeffer T, Konig T, Zwadlo C, .. Bauersachs J, del Monte F, Hilfiker-Kleiner D, Karumanchi SA, Arany Z. Cardiac an-
Moulig VA, Franke A, Schwarzkopf M, Ehlermann P, Pfister R, Michels G, .. giogenic imbalance leads to peripartum cardiomyopathy. Nature 2012;485:333–338.
Westenfeld R, Stangl V, Kuhl U, Podewski E, Kindermann I, Bohm M, Sliwa K,
.. 82. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F. Oxidative stress and normal
Hilfiker-Kleiner D, Bauersachs J. Bromocriptine treatment in patients with peripar-
.. pregnancy. Clin Endocrinol (Oxf) 2002;57:609–613.
..
tum cardiomyopathy and right ventricular dysfunction. Clin Res Cardiol 2019;108: .. 83. Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, Osugi T, Izumi
290–297. .. M, Oshima Y, Nakaoka Y, Hirota H, Kishimoto T, Yamauchi-Takihara K. Activation
63. Bauersachs J, Arrigo M, Hilfiker-Kleiner D, Veltmann C, Coats AJ, Crespo-Leiro .. of signal transducer and activator of transcription 3 protects cardiomyocytes from
MG, De Boer RA, van der Meer P, Maack C, Mouquet F, Petrie MC, Piepoli MF, .. hypoxia/reoxygenation-induced oxidative stress through the upregulation of manga-
Regitz-Zagrosek V, Schaufelberger M, Seferovic P, Tavazzi L, Ruschitzka F, Mebazaa .. nese superoxide dismutase. Circulation 2001;104:979–981.
A, Sliwa K. Current management of patients with severe acute peripartum cardio- .. 84. Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, Silvola JM,
myopathy: practical guidance from the Heart Failure Association of the European
.. Roivainen A, Saraste A, Nickel AG, Saar JA, Sieve I, Pietzsch S, Muller M, Bogeski I,
..
Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail .. Kappl R, Jauhiainen M, Thackeray JT, Scherr M, Bengel FM, Hagl C, Tudorache I,
2016;18:1096–1105. .. Bauersachs J, Maack C, Hilfiker-Kleiner D. Low STAT3 expression sensitizes to
64. Kane A, Dia AA, Diouf A, Dia D, Diop IB, Moreau JC, Faye EO, Sarr M, Ba SA, .. toxic effects of beta-adrenergic receptor stimulation in peripartum cardiomyopathy.
Diadhiou F, Diouf SM. Peripartum idiopathic myocardiopathy: prospective echocar- .. Eur Heart J 2017;38:349–361.
diographic study. Ann Cardiol Angeiol (Paris) 2001;50:305–311 (in French). .. 85. Martini JF, Piot C, Humeau LM, Struman I, Martial JA, Weiner RI. The antiangiogenic
65. Haghikia A, Rontgen P, Vogel-Claussen J, Schwab J, Westenfeld R, Ehlermann P, .. factor 16K PRL induces programmed cell death in endothelial cells by caspase acti-
Berliner D, Podewski E, Hilfiker-Kleiner D, Bauersachs J. Prognostic implication of
.. vation. Mol Endocrinol 2000;14:1536–1549.
..
right ventricular involvement in peripartum cardiomyopathy: a cardiovascular mag- .. 86. Lee SH, Kunz J, Lin SH, Yu-Lee LY. 16-kDa prolactin inhibits endothelial cell migra-
netic resonance study. ESC Heart Fail 2015;2:139–149. .. tion by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway. Cancer Res
66. Duncker D, Westenfeld R, Konrad T, Pfeffer T, Correia de Freitas CA, Pfister R, .. 2007;67:11045–11053.
Thomas D, Furnkranz A, Andrie RP, Napp A, Schmitt J, Karolyi L, Wakili R, Hilfiker- .. 87. Tabruyn SP, Nguyen NQ, Cornet AM, Martial JA, Struman I. The antiangiogenic fac-
Kleiner D, Bauersachs J, Veltmann C. Risk for life-threatening arrhythmia in newly .. tor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both
diagnosed peripartum cardiomyopathy with low ejection fraction: a German multi- .. the G0-G1 and the G2-M phases. Mol Endocrinol 2005;19:1932–1942.
centre analysis. Clin Res Cardiol 2017;106:582–589. .. 88. Tabruyn SP, Sorlet CM, Rentier-Delrue F, Bours V, Weiner RI, Martial JA, Struman
67. Sliwa K, Forster O, Libhaber E, Fett JD, Sundstrom JB, Hilfiker-Kleiner D, Ansari
.. I. The antiangiogenic factor 16K human prolactin induces caspase-dependent apo-
..
AA. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in .. ptosis by a mechanism that requires activation of nuclear factor-kappaB. Mol
100 prospectively studied patients. Eur Heart J 2006;27:441–446. .. Endocrinol 2003;17:1815–1823.
68. Elkayam U, Akhter MW, Singh H, Khan S, Bitar F, Hameed A, Shotan A. Pregnancy- .. 89. Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M,
associated cardiomyopathy: clinical characteristics and a comparison between early .. Castermans K, Malvaux L, Lambert V, Thiry M, Sliwa K, Noel A, Martial JA, Hilfiker-
and late presentation. Circulation 2005;111:2050–2055. .. Kleiner D, Struman I. MicroRNA-146a is a therapeutic target and biomarker for
69. Haghikia A, Schwab J, Vogel-Claussen J, Berliner D, Pfeffer T, Konig T, Zwadlo C, .. peripartum cardiomyopathy. J Clin Invest 2013;123:2143–2154.
Moulig VA, Franke A, Schwarzkopf M, Ehlermann P, Pfister R, Michels G,
.. 90. Gonzalez C, Corbacho AM, Eiserich JP, Garcia C, Lopez-Barrera F, Morales-Tlalpan
Westenfeld R, Stangl V, Kuhl U, Podewski E, Kindermann I, Bohm M, Sliwa K,
.. V, Barajas-Espinosa A, Diaz-Mu~ noz M, Rubio R, Lin S-H, Martinez de la Escalera G,
Clapp C. 16K-prolactin inhibits activation of endothelial nitric oxide synthase, intra-

.. failure of the European Society of Cardiology (ESC). Developed with the special
..
cellular calcium mobilization, and endothelium-dependent vasorelaxation. .. contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail
Endocrinology 2004;145:5714–5722. .. 2016;18:891–975.
91. Gonzalez C, Parra A, Ramirez-Peredo J, Garcia C, Rivera JC, Macotela Y, Aranda J, .. 108. Walenta K, Schwarz V, Schirmer SH, Kindermann I, Friedrich EB, Solomayer EF,
..

Lemini M, Arias J, Ibarguengoitia F, de la Escalera GM, Clapp C. Elevated vasoinhi- Sliwa K, Labidi S, Hilfiker-Kleiner D, Bohm M. Circulating microparticles as indica-
bins may contribute to endothelial cell dysfunction and low birth weight in pre- .. tors of peripartum cardiomyopathy. Eur Heart J 2012;33:1469–1479.
eclampsia. Lab Invest 2007;87:1009–1017. .. 109. Bajou K, Herkenne S, Thijssen VL, D’Amico S, Nguyen NQ, Bouche A, Tabruyn S,
92. Haghikia A, Missol-Kolka E, Tsikas D, Venturini L, Brundiers S, Castoldi M,
.. Srahna M, Carabin JY, Nivelles O, Paques C, Cornelissen I, Lion M, Noel A, Gils A,
..
Muckenthaler MU, Eder M, Stapel B, Thum T, Haghikia A, Petrasch-Parwez E, .. Vinckier S, Declerck PJ, Griffioen AW, Dewerchin M, Martial JA, Carmeliet P,
Drexler H, Hilfiker-Kleiner D, Scherr M. Signal transducer and activator of tran- .. Struman I. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K pro-
scription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial .. lactin. Nat Med 2014;20:741–747.
cell function in the heart: a key role for ubiquitin-conjugating enzymes. Eur Heart J .. 110. Ricke-Hoch M, Hoes M, Pfeffer T, Schlothauer S, Nonhoff J, Haidari S, Scherr M,
2011;32:1287–1297. .. Stapel B, Stelling E, Kiyan Y, Falk C, Bauersachs J, Haghikia A, van der Meer P,
93. Lemmens K, Doggen K, De Keulenaer GW. Activation of the neuregulin/ErbB sys- .. Hilfiker-Kleiner D. Plasminogen activator-1 links peripartum cardiomyopathy to the
tem during physiological ventricular remodeling in pregnancy. Am J Physiol Heart Circ
.. coagulation system. Clin Res Cardiol 2019;108(Suppl 1).
..
Physiol 2011;300:H931–H942. .. 111. Mebazaa A, Seronde MF, Gayat E, Tibazarwa K, Anumba DOC, Akrout N, Sadoune
94. Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema J-P, Becker A, McMurray J, .. M, Sarb J, Arrigo M, Motiejunaite J, Laribi S, Legrand M, Deschamps L, Fazal L,
Yamac H, Labidi S, Struman I, Struhman I, Hilfiker-Kleiner D. Evaluation of bromo- .. Bouadma L, Collet C, Manivet P, Solal AC, Launay JM, Samuel JL, Sliwa K.
criptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of- .. Imbalanced angiogenesis in peripartum cardiomyopathy—diagnostic value of pla-
concept pilot study. Circulation 2010;121:1465–1473. .. centa growth factor. Circ J 2017;81:1654–1661.
95. Tremblay-Gravel M, Marquis-Gravel G, Avram R, Desplantie O, Ducharme A, Bibas .. 112. Forster O, Hilfiker-Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W,
L, Pacheco C, Couture E, Simard F, Poulin A, Malhame I, Tran D, Rey E, Tournoux
.. Becker A, Yip A, Klein G, Sliwa K. Reversal of IFN-gamma, oxLDL and prolactin se-
..
F, Harvey L, Senechal M, Belisle P, Descarries L, Farand P, Pranno N, Diaz A, Afilalo .. rum levels correlate with clinical improvement in patients with peripartum cardio-
J, Ly HQ, Fortier A, Jolicoeur EM, Investigators B-H. The effect of bromocriptine on .. myopathy. Eur J Heart Fail 2008;10:861–868.
left ventricular functional recovery in peripartum cardiomyopathy: insights from the .. 113. Ekizler FA, Cay S. A novel marker of persistent left ventricular systolic dysfunction
BRO-HF retrospective cohort study. ESC Heart Fail 2019;6:27–36. .. in patients with peripartum cardiomyopathy: monocyte count- to- HDL cholesterol
96. Haghikia A, Podewski E, Berliner D, Sonnenschein K, Fischer D, Angermann CE, .. ratio. BMC Cardiovasc Disord 2019;19:114.
Bohm M, Rontgen P, Bauersachs J, Hilfiker-Kleiner D. Rationale and design of a ran- .. 114. Pfeffer T, Azibani F, Ricke-Hoch M, Schlothauer S, Stelling E, Kasten M, Berliner D,
domized, controlled multicentre clinical trial to evaluate the effect of bromocriptine
.. Koenig T, Bauersachs J, Sliwa J, Hilfiker-Kleiner D. Different outcome and fibrosis
..
on left ventricular function in women with peripartum cardiomyopathy. Clin Res .. marker profiles suggest different pathomechanisms for peripartum cardiomyopathy
Cardiol 2015;104:911–917. .. in German and South African patients. Clin Res Cardiol 2018;107 (Suppl 1).
97. Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J .. 115. Sieweke JT, Pfeffer TJ, Berliner D, Konig T, Hallbaum M, Napp LC, Tongers J, Kuhn
Physiol Regul Integr Comp Physiol 2011;301:R267–R275. .. C, Schmitto JD, Hilfiker-Kleiner D, Schafer A, Bauersachs J. Cardiogenic shock com-
98. Nonhoff J, Ricke-Hoch M, Mueller M, Stapel B, Pfeffer T, Kasten M, Scherr M, von .. plicating peripartum cardiomyopathy: importance of early left ventricular unloading
Kaisenberg C, Bauersachs J, Haghikia A, Hilfiker-Kleiner D. Serelaxin treatment pro- .. and bromocriptine therapy. Eur Heart J Acute Cardiovasc Care 2018;doi:
motes adaptive hypertrophy but does not prevent heart failure in experimental
.. 10.1177/2048872618777876 [Epub ahead of print].
..
peripartum cardiomyopathy. Cardiovasc Res 2017;113:598–608. .. 116. Arrigo M, Blet A, Mebazaa A. Bromocriptine for the treatment of peripartum car-
99. Damp J, Givertz MM, Semigran M, Alharethi R, Ewald G, Felker GM, Bozkurt B, .. diomyopathy: welcome on BOARD. Eur Heart J 2017;38:2680–2682.
Boehmer J, Haythe J, Skopicki H, Hanley-Yanez K, Pisarcik J, Halder I, Gorcsan J 3rd, .. 117. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomström-Lundqvist C,
Rana S, Arany Z, Fett JD, McNamara DM, Investigators I. Relaxin-2 and soluble Flt1 .. Cı́fková R, De Bonis M, Iung B, Johnson MR, Kintscher U, Kranke P, Lang IM, Morais
levels in peripartum cardiomyopathy: results of the multicenter IPAC study. JACC .. J, Pieper PG, Presbitero P, Price S, Rosano GMC, Seeland U, Simoncini T, Swan L,
Heart Fail 2016 4:380–388. ... Warnes CA, Deaton C, Simpson IA, Aboyans V, Agewall S, Barbato E, Calda P,
100. Hilfiker-Kleiner D, Arany Z. Focus on pregnancy-mediated heart and vascular dis- .. Coca A, Coman IM, De Backer J, Delgado V, Di Salvo G, Fitzsimmons S, Fitzsimons
ease. Cardiovasc Res 2014;101:543–544. .. D, Garbi M, Gevaert S, Hindricks G, Jondeau G, Kluin J, Lionis C, McDonagh TA,
101. Bollen IAE, Ehler E, Fleischanderl K, Bouwman F, Kempers L, Ricke-Hoch M, .. Meier P, Moons P, Pantazis A, Piepoli MF, Rocca B, Roffi M, Rosenkranz S, Sarkozy
Hilfiker-Kleiner D, Dos Remedios CG, Kruger M, Vink A, Asselbergs FW, van
.. A, Shlyakhto E, Silversides CK, Sliwa K, Sousa-Uva M, Tamargo J, Thorne S, Van de
..
Spaendonck-Zwarts KY, Pinto YM, Kuster DWD, van der Velden J. Myofilament .. Velde M, Williams B, Zamorano JL, Windecker S, Aboyans V, Agewall S, Barbato E,
remodeling and function is more impaired in peripartum cardiomyopathy compared .. Bueno H, Coca A, Collet J-P, Coman IM, Dean V, Delgado V, Fitzsimons D,
with dilated cardiomyopathy and ischemic heart disease. Am J Pathol 2017;187: .. Gaemperli O, Hindricks G, Iung B, Jüni P, Katus HA, Knuuti J, Lancellotti P, Leclercq
2645–2658. .. C, McDonagh TA, Piepoli MF, Ponikowski P, Richter DJ, Roffi M, Shlyakhto E,
102. Haghikia A, Tongers J, Berliner D, Konig T, Schafer A, Brehm M, Bohm M, Hilfiker- .. Simpson IA, Sousa-Uva M, Zamorano JL, Hammoudi N, Piruzyan A, Mascherbauer J,
Kleiner D, Bauersachs J. Early ivabradine treatment in patients with acute peripar- .. Samadov F, Prystrom A, Pasquet A, Caluk J, Gotcheva N, Skoric B, Heracleous H,
tum cardiomyopathy: subanalysis of the German PPCM registry. Int J Cardiol 2016;
.. Vejlstrup N, Maser M, Kaaja RJ, Srbinovska-Kostovska E, Mounier-Vehier C,
..
216:165–167. .. Vakhtangadze T, Rybak K, Giannakoulas G, Kiss RG, Thrainsdottir IS, Erwin RJ,
103. Eghbali M, Deva R, Alioua A, Minosyan TY, Ruan H, Wang Y, Toro L, Stefani E. .. Porter A, Geraci G, Ibrahimi P, Lunegova O, Mintale I, Kadri Z, Benlamin H,
Molecular and functional signature of heart hypertrophy during pregnancy. Circ Res .. Barysiene J, Banu CA, Caruana M, Gratii C, Haddour L, Bouma BJ, Estensen M-E,
2005;96:1208–1216. .. Hoffman P, Petris AO, Moiseeva O, Bertelli L, Tesic BV, Dubrava J, Kozelj M,
104. Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW 2nd, Armstrong .. Prieto-Arévalo R, Furenäs E, Schwerzmann M, Mourali MS, Ozer N, Mitchenko O,
RC, Kitsis RN. Inhibition of cardiac myocyte apoptosis improves cardiac function .. Nelson-Piercy C. 2018 ESC guidelines for the management of cardiovascular dis-
and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic
.. eases during pregnancy. Eur Heart J 2018;39:3165–3241.
..
mice. Circulation 2003;108:3036–3041. .. 118. Byrne JJ, Spong CY. ‘Is it safe?’—the many unanswered questions about medications
105. Liu GS, Zhu H, Cai WF, Wang X, Jiang M, Essandoh K, Vafiadaki E, Haghighi K, Lam .. and breast-feeding. N Engl J Med 2019;380:1296–1297.
CK, Gardner G, Adly G, Nicolaou P, Sanoudou D, Liang Q, Rubinstein J, Fan GC, .. 119. Blauwet LA, Libhaber E, Forster O, Tibazarwa K, Mebazaa A, Hilfiker-Kleiner D,
Kranias EG. Regulation of BECN1-mediated autophagy by HSPB6: insights from a .. Sliwa K. Predictors of outcome in 176 South African patients with peripartum car-
human HSPB6(S10F) mutant. Autophagy 2018;14:80–97. .. diomyopathy. Heart 2013;99:308–313.
106. Liu GS, Gardner G, Adly G, Jiang M, Cai WF, Lam CK, Alogaili F, Robbins N, .. 120. Kayıkçıoglu M, Tokgözoglu L, Mutluer FO, Ural D, Biteker M. The rationale and de-
Rubinstein J, Kranias EG. A novel human S10F-Hsp20 mutation induces lethal peri-
.. sign of the national peripartum cardiomyopathy registries in Turkey: the ARTEMIS-I
..
partum cardiomyopathy. J Cell Mol Med 2018;doi: 10.1111/jcmm.13665 [Epub ahead .. and ARTEMIS-II studies. Turk Kardiyol Dern Ars 2018;46:39–46.
of print]. .. 121. Tibazarwa K, Lee G, Mayosi B, Carrington M, Stewart S, Sliwa K. The 12-lead ECG
107. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, .. in peripartum cardiomyopathy. Cardiovasc J Afr 2012;23:1–8.
Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, .. 122. Labidi S, Hilfiker-Kleiner D, Klein G. Left bundle branch block during pregnancy as a
Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, .. sign of imminent peripartum cardiomyopathy. Eur Heart J 2011;9:1076.
Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R. .. 123. Meyer GP, Labidi S, Podewski E, Sliwa K, Drexler H, Hilfiker-Kleiner D.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
.. Bromocriptine treatment associated with recovery from peripartum cardiomyopa-
failure: the Task Force for the diagnosis and treatment of acute and chronic heart
.. thy in siblings: two case reports. J Med Case Rep 2010;4:80.
..
124. Arora NP, Mohamad T, Mahajan N, Danrad R, Kottam A, Li T, Afonso LC. Cardiac .. 126. Schelbert EB, Elkayam U, Cooper LT, Givertz MM, Alexis JD, Briller J, Felker GM,
magnetic resonance imaging in peripartum cardiomyopathy. Am J Med Sci 2014;347: .. Chaparro S, Kealey A, Pisarcik J, Fett JD, McNamara DM. Investigations of preg-
112–117. .. nancy associated cardiomyopathy I. myocardial damage detected by late gadolinium
125. Mouquet F, Lions C, de Groote P, Bouabdallaoui N, Willoteaux S, Dagorn J, .. enhancement cardiac magnetic resonance is uncommon in peripartum cardiomyop-
..

Deruelle P, Lamblin N, Bauters C, Beregi JP. Characterisation of peripartum cardio- athy. J Am Heart Assoc 2017;6. pii: e005472. doi: 10.1161/JAHA.117.005472.
myopathy by cardiac magnetic resonance imaging. Eur Radiol 2008;18:2765–2769. ..

Oup Accepted Manuscript 2019

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Oup Accepted Manuscript 2019

Uploaded by

Copyright:

Available Formats

Cardiovascular Research REVIEW

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Keywords PPCM • Prolactin • 16 kDa-PRL • Pregnancy • Heart failure • Bromocriptine

.. registry, and the Bromocriptine trial (NCT00998556).10,11 A worldwide

Table 1 Overview of registries and clinical studies in PPCM

PPCM registries and clinical studies

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

5. Diagnosis of PPCM resonance imaging Decreased right ventricular ejection

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

3. Seftel H, Susser M. Maternity and myocardial failure in African women. Br Heart J

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Schwarzkopf M, Ehlermann P, Pfister R, Michels G, Westenfeld R, Stangl V,

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Clapp C. 16K-prolactin inhibits activation of endothelial nitric oxide synthase, intra-

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

Downloaded from https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvz252/5586231 by Stockholm University Library user on 14 October 2019

You might also like