Peripartum Cardiomyopathy .BOARD scheme for the therapy of patients with acute PPCM.

Magdy El-Masry
Prof. of Cardiology
Tanta University
 Identify
 Treat
 Prevent
PPCM:

Today’s talk will include:
 Historical Context
 Definition
 Epidemiology
 Risk Factors
 Patho-physiology & Novel Therapies
 Clinical Presentation & Differential Diagnosis
 Diagnostic Workup
 Treatment & Breast feeding
 Prognosis
 Counseling / Subsequent Pregnancy
 Contraception
 Knowledge Gap
How to see the big picture is not as easy as you'd think.

The first description of idiopathic myocardial failure with onset in the
puerperium has been attributed to Ritchie in 1849.
Ritchie C. Edinb Med Surg J. 1849;2:333–342.
Clinical contribution to the pathology, diagnosis, and treatment of
certain chronic diseases of the heart.

The 19th
(nineteenth)
century
The 20th
(twentieth)
century
The 21st
(twenty first)
century
Ritchie C
(1849)
Gouley BA et al
(1937)
&
Hull E and
Hafkesbring E
(1937)
There is a crisis in
academic publishing (Too
much academic research
is being published)
PPCM

" K e y R e f e r e n c e s "
2018
2019
2018

Definition of peripartum cardiomyopathy
1. Heart failure secondary to left ventricular
systolic dysfunction with a LVEF < 45%
2. Occurrence towards the end of pregnancy or in
the months following delivery (mostly in the month
following delivery)
3. No other identifiable cause of heart failure
Diagnosis is often always by exclusion

Worldwide variation in incidence of PPCM
Incidence seems to be highest in
Nigeria (one in 100 live births) and Haiti (one in 300 live births)
Haiti Nigeria

*The unit of population differs among studies depending on the population representing all births, live births (excluding stillbirth), deliveries,
hospitalizations, and women. †Although there are several reports from the United States, the report by Kolte, et al was selected because it
includes the most recent data.(Isogai, et al. Int Heart J May 2019)
Maternal mortality rate and incidence of PPCM in various countries
Significant Geographical Variations
The incidence of PPCM and the maternal mortality rate were well correlated

CONCLUSION
Yes, we can prevent peripartum cardiomyopathy, but
such a challenge involves changing the way of life of millions
of people and effectively fighting poverty.
SL Clinical and Experimental Cardiology. 2019; 2(1):117
Yes, we can prevent peripartum cardiomyopathy, but…

Risk Factors for the Development of PPCM
Risk factors for the development of PPCM have been classified as probable (twin pregnancy, high parity/gravidity,
extreme reproductive age and prolonged tocolysis);proposed (smoking, hypertension, malnutrition, cocaine use,
African ancestry and socioeconomic status); and emerging (genetics, pre-eclampsia and obesity).

Pathophysiology
& Novel therapies

Etio-pathogenesis (etiology and pathophysiology ) of PPCM : ???
Hemodynamic stress
Viral myocarditis—coxsackievirus, echovirus, parvovirus B19
Microchimerism—myocyte engraftment with immune dysfunction
Genetic factors—mutations of cardiac genes—TTNC1, TTN, STAT3
Antiangiogenic factors—sFlt-1 inhibition of VEGF
Prolactin—increased cathepsin D peptidase
Possible Causes or Triggering Events for PPCM
Proposed
pathogenesis :
a “two-hit
hypothesis.”
Environmental
Factors
Vasculohormonal
(pregnancy)
Genetic
Factors
Titin-truncating
Variants (TTNtv)Affected
PPCM is likely caused by a complex interaction of
genetic and environmental factors

The Pathophsiology of PPCM is uncertain.
Current thinking favors a “two hit” model of PPCM pathogenesis
How do vasculo-hormonal insults interact with underlying genetic susceptibility
to produce PPCM ?
First hit
Genetic predisposition
 Gene mutations : e.g. TTN gene
Second hit
Antivascular or hormonal effects
 ↑Prolactin (PRL)→16-kDa (vasoinhibin)
 ↑Soluble fms-like tyrosine kinase receptor 1
(sFlt-1):Angiogenic Imbalance
Pituitary
Placenta

Representative diagram of titin’s position in myocyte architecture.
Titin extends from the Z-disk of the sarcomere (N-terminus) to the M-band (C-terminus).
The central part of the protein contains I-band region (I) and A-band region (A).
Titin-truncating mutations :
Titin-truncating variants (TTNtv)→Sarcomere insufficiency →DCM /PPCM

Secretion of prolactin by the anterior pituitary gland, upregulation of endothelial microRNA-146a
(miRNA-146a), and placental secretion of soluble fms-like tyrosine kinase receptor 1 (sFlt-1)
lead to endothelial dysfunction and cardiomyocyte death
Pathophsiology of PPCM : a vascular/hormonal hypothesis
sFlt-1
inhibition of VEGF
(Antiangiogenic)
(PRL fragment:
vasoinhibin)
a

One of the new strategies for treating PPCM is based on this knowledge :
Prolactin inhibition.
Blocking PRL completely by use of bromocriptine eliminates
pathophysiological 16K PRL, but also nursing ability.
Class IIb
Recommendation

Emerging treatments :
Antisense therapy against microRNA-146a
Use of anti-miR-146a in less severely affected patients may
improve PPCM recovery, while keeping normal nursing functions.
Note: MicroRNA-146a is a therapeutic target and biomarker for PPCM
? Investigational

Clinical
Presentation
& Differential Diagnosis

PPCM : a diagnostic challenge
Since no specific test to confirm PPCM exists,
it remains a diagnosis of exclusion, and differential diagnoses
need to be considered.

Is it PPCM or normal pregnancy ?
 Shortness of breath
 Fatigue
 Leg swelling
 Tachycardia
The major symptoms of PPCM are those of heart failure and include fatigue, shortness of
breath, tachycardia ,and fluid retention.
Because there is a significant overlap between symptoms related to pregnancy, especially
toward the end of the third trimester or after delivery, and heart failure , the diagnosis
may be initially missed or delayed.

Signs and
symptoms in
PPCM vs normal
pregnancy
normal

Is it PPCM or Preeclampsia ?
 Pre‐existing or new‐onset
hypertension, proteinuria
 During second trimester of pregnancy
 LVH, diastolic dysfunction
 No known cardiac disease, no HF signs
and/or symptoms prior pregnancy
 Towards the end of pregnancy and the
months following delivery
 LVEF < 45%
Overlapping Diseases of Pregnancy

Differential diagnoses of peripartum cardiomyopathy
Myocarditis
Pre‐existing idiopathic/ familial dilated or acquired cardiomyopathy
Takotsubo syndrome
Pregnancy‐associated myocardial infarction
Pulmonary embolism
Amniotic fluid embolism
Hypertensive heart disease/severe pre‐eclampsia
Hypertrophic cardiomyopathy
HIV/AIDS cardiomyopathy
Pre‐existing (unknown) congenital heart disease
Pre‐existing valvular heart disease

History Onset Biomarkers Echo/cardiac MRI Differentiation from PPCM
PPCM No known cardiac disease,
no HF signs and/or
symptoms prior pregnancy
Towards the end of
pregnancy and the months
following delivery
Elevated natriuretic
peptides
Reduced systolic LV
function, LVEF < 45%
–
Myocarditis Prior viral infection (e.g.
respiratory)
Acute or subacute onset
after viral infection
Elevated troponin, elevated
CRP
Normal or reduced systolic
LV function, typical
myocardial late gadolinium
enhancement pattern,
pericardial effusion
Cardiac MRI (LE pattern),
myocardial biopsy
Pre‐existing idiopathic/
familial dilated or acquired
cardiomyopathy
HF signs and/or symptoms
and/or known heart disease
prior pregnancy
During second trimester of
pregnancy
peptides
Reduced systolic LV
function, RV dysfunction
possible, typical myocardial
LE pattern (DCM)
History, echocardiography,
cardiac MRI (LE pattern)
Takotsubo syndrome Chest pain, very stressful
delivery or emergency due
to foetal complications
Acute onset, during delivery
or immediately after
delivery
peptides
Regional wall motion
abnormalities with typical
anatomical patterns
History, echocardiography
Pregnancy‐associated
myocardial infarction
Chest pain, epigastric pain Acute onset, during
pregnancy or immediately
after delivery
Elevated troponin Regional wall motion
abnormalities, ischaemic
myocardial scar
History, ECG, coronary
angiography, cardiac MRI
(LE pattern)
Pulmonary embolism Chest pain, unilateral leg
swelling, acute dyspnoea
Acute onset during
pregnancy or after delivery
peptides and/or troponin,
elevated D‐dimer
RV dysfunction, RV
dilatation, LV function
usually normal
Computed tomography, VQ
scan
Amniotic fluid embolism Chest pain
during/immediately after
delivery, acute dyspnoea
Acute onset during delivery
or immediately after
delivery
peptides possible
Reduced RV systolic
function, RV dilatation
Hypertensive heart
disease/severe
pre‐eclampsia
Pre‐existing or new‐onset
hypertension, proteinuria
pregnancy
peptides
LV hypertrophy, diastolic
dysfunction, transient LV
dysfunction
Hypertrophic
cardiomyopathy
Familial predisposition During second trimester of
pregnancy
peptides
LV hypertrophy, typical
myocardial late
enhancement pattern,
LVOTO (HOCM)
History, echocardiography,
cardiac MRI (LE pattern)
HIV/AIDS cardiomyopathy HIV infection, AIDS During second trimester of
pregnancy
peptides
Reduced systolic LV
function, LV/RV often not
dilated
HIV serology/test
Pre‐existing (unknown)
congenital heart disease
prior pregnancy, known
heart disease, prior cardiac
surgery
pregnancy
peptides
(Corrected) congenital
heart defects, cardiac
shunts
Pre‐existing valvular heart
disease
prior pregnancy, known
heart disease
pregnancy
peptides
Valvular stenosis or
regurgitation, prosthetic
heart valves

Circulating Biomarkers of PPCM
Overview of diagnosis and prognosis biomarkers in peripartum cardiomyopathy
Current Heart Failure Reports . October 2018, Volume 15, pp 297–306
Abbreviations: 16KDa-PRL, 16-kDa prolactin hormone; Apo1, apoptosis antigen 1; BNP, brain natriuretic
peptide; cTnT, cardiac troponin I; IFN-ϒ, interferon-ϒ; IL, interleukin; MMP-2, matrix metalloproteinase 2; MR-
proADM, mid-regional pro-adrenomedullin; NT-proBNP, N-terminal pro-brain natriuretic peptide; OxLDL, oxidized
low-density lipoprotein; PLGF, placental growth factor; PRL, prolactin hormone; sFlt1, soluble fms-like tyrosine
kinase-1; sST2, soluble ST2; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α

PPCM presentation may vary from subtle signs and symptoms
to severe acute heart failure, pulmonary oedema
and/or cardiogenic shock.
Subacute HF
Hemodynamic stability
Acute HF
Respiratory insufficiency
Cardiogenic shock
Hemodynamic instability
Mild PPCM
Moderate PPCM
Severe PPCM

Pragmatic evaluation scheme for suspected acute PPCM during the end of pregnancy or the
months after delivery. Measurement of natriuretic peptides and echo are recommended to
quickly strengthen or rule out the diagnosis of PPCM.
Symptoms during end of pregnancy or
months following delivery: dyspnoea,
orthopnoea, peripheral oedema, chest
pain, dizziness, palpitations, fatigue,
depression, cough

PPCM : a therapeutic challenge
To consider both the health of the mother and the foetus or baby

It is important to exclude drugs that may have a harmful effect on the
developing foetus or those that are contraindicated during breastfeeding
[ACEI, ARB , ARNI, k-sparing diuretics, warfarin, and ivabradine]
Acute heart
failure/cardiogenc shock
Stabilized/chronic heart
failure
According to the latest guidelines of the ESC 2018, the treatment of PPCM does
not deviate from the recommendations used in acute HF, cardiogenic shock, or
chronic HF of a different aetiology.

Safety of drugs for PPCM during pregnancy and lactation
Drug Use during pregnancy Potential adverse effects Use during lactation†
Loop diuretics
Compatible (most experience with
furosemide)
Maternal hypovolemia and
hypotension, resulting in
uterine hypoperfusion
Compatible
(overdiuresis may
decrease breast milk
production)
β blockers Compatible
Fetal bradycardia, fetal
hypoglycemia
Compatible
ACE inhibitors and ARBs Incompatible
Renal agenesis,
oligohydramnios,
malformations, fetal demise
Compatible (captopril,
enalapril, quinapril,
benazepril)
Mineralocorticoid receptor
antagonists
Incompatible Undervirilization of the fetus Compatible
Sacubitril-valsartan Incompatible
Same as ACE
inhibitors/ARBs
Unknown (lack of
data)
Hydralazine/nitrates Compatible
Maternal hypotension,
resulting in uterine
hypoperfusion
Compatible
Ivabradine
Not recommended (worrying results in
animal studies, no studies in humans)
Unknown
Unknown (lack of
data)
Digoxin Compatible Low birth weight Compatible
Heparin (unfractionated and
low molecular weight)
Compatible Does not cross placenta Compatible
Warfarin
Avoid if possible owing to
teratogenicity
Warfarin embryopathy
(skeletal deformities),
intracranial hemorrhage,
spontaneous abortion,
stillbirth
Compatible
Direct-acting oral
anticoagulants (eg,
rivaroxaban, apixaban,
edoxaban, dabigatran)
Incompatible
Limited data suggest
possible malformations,
growth restriction
Currently discouraged
owing to lack of data

Subacute HF
Acute HF
Cardiogenic shock
Hemodynamic instability
Mild PPCM
Moderate PPCM
Severe PPCM
Normal ward, ambulatory
treatment in selected patients
possible
Intermediate care (IMC), HF unit
(HFU)
Intensive care unit (ICU)
 Oral HF drugs
 Oral diuretics in case
of fluid overload
 Consider
bromocriptine for 1
week
– Diuretics i.v.
– Consider vasorelaxants if SBP
>110 mmHg
– Supplemental O2 , non-invasive
ventilation if necessary
– Avoid inotropes/catecholamines
– Consider bromocriptine for 8
weeks if LVEF <25%
- Oral HF drugs
– Diuretics i.v.
– Inotropes/catecholamines if
needed
– Invasive ventilation
– Mechanical circulatory support
(Impella and/or ECMO)
– Consider bromocriptine for 8
weeks , uptitration depending on
prolactin levels
– Oral HF drugs after stabilization
Overview of different clinical scenarios in patients with PPCM.

The wearable
cardioverter-defibrillator (WCD)
The implantable
cardioverter defibrillator (ICD)
Because LV recovery is common in PPCM, the decision to insert an ICD
in a patient who initially presents with an LVEF <35% could be delayed,
and a WCD could be considered instead.
 The WCD could be used as ‘bridging therapy’ until the LVEF is re-evaluated at follow up.
 ICDs are best reserved for patients with PPCM without LV recovery after 6 months.
LVEF <35%

If a patient cannot be
stabilised
haemodynamically,
urgent delivery by
caesarean section is
necessary.
Vaginal delivery is preferred in
haemodynamically stable
patients.
Delivery

Breastfeeding : Breastfeeding in patients with PPCM is controversial
JACC 2019
LevelClassRecommendations
BIIbDue to the high metabolic demands of lactation and
breastfeeding, preventing lactation may be considered in
patients with severe HF
BIIbIn patients with PPCM, bromocriptine treatment may be
considered to stop lactation and enhance recovery (LV function).
CIIaBromocriptine treatment should be accompanied by prophylactic
(or therapeutic) anticoagulation
2018 ESC Guidelines for the management of CVDs during pregnancy

The treatment of PPCM, should consists of Bromocriptine, Oral heart failure therapies, Anticoagulation, vasoRelaxing
agents, and Diuretics. Non-invasive ventilation should be added in patients with pulmonary congestion.
BOARD scheme for the therapy of patients with acute PPCM.
Of note, this scheme addresses patients after delivery who do not breastfeed.

ICU = intensive care unit; LVEF = left ventricular ejection fraction; MCS, mechanical circulatory support (e.g. extracorporeal membrane
oxygenation, percutaneous microaxial pump); RV = right ventricle.
Scheme for Bromocriptine Treatment of Acute PPCM
Cardiac Failure Review 2018;4(1):46–9
If bromocriptine treatment is considered (class IIb recommendation),
different regimens are recommended according to disease severity.

Up to 72% of women with PPCM have
improvement in LVEF ,
but increased LV remodeling (LVEDD ≥6.0 cm)
, black race , and initial LVEF
< 30 % are poor prognostic factors
72% achieved an
LVEF ≥ 50 %
(J Am Coll Cardiol 2015;66:905–14)
Poor Predictors of outcome ( poorer recovery )
 Race : black women
 LV dysfunction (LVEF) : < 30%
 LV remodeling (LVEDD): ≥6.0 cm

Worse NYHA functional class
LVEF ≤ 25%
Black race
Multiparity
Age more than 35 years
Risk factors
for increased
mortality in PPCM
"Rest In
Peace"
Maternal mortality
The mortality rate varies
from <2% to 50%.

Counseling/
Subsequent
Pregnancies

Counselling of women with PPCM regarding subsequent pregnancy and a guide to management.
↖
↖

Risks in Subsequent Pregnancies in PPCM

Recommended schedule of screening echo for women
with a history of PPCM and subsequent pregnancy.

It should be remembered that the right form of
contraception is the key to prevent the recurrence of PPCM.
What is the right birth control for me?

1 A condition for which there is no restriction to use
2 A condition for which the advantages of use outweigh the theoretical or proven risks
3 A condition for which the theoretical or proven risks outweigh the advantages
4 A condition for which the method should not be used
The 2016 CDC-MEC (Centers for Disease Control and Prevention Medical Eligibility Criteria)
Simplified schema for contraceptive choices in PPCM and DCM
Current Heart Failure Reports (2018) 15:161–170
CHC = combined hormonal
contraceptive
PC = progestin-only
contraceptive
IUD = intrauterine
device
EC = emergency
contraception

"Research Gap" or "Knowledge Gap"
Knowledge gaps in PPCM research :
Pathogenesis
Diagnosis
Management

Another key unanswered question about the management of
PPCM is the optimal treatment of women with recovered LVEF,
who make up the majority of cases.
Length of treatment for patients with PPCM with recovered LVEF
 Treatment is recommended for at least 12 months after recovery
of both the left ventricular EF and dimensions.
 A period of time without medication and with recurrent
echocardiograms is ideal for confirming that the EF does not
deteriorate before a decision regarding a new pregnancy
HF reduced EF HF recovered EF

What do you do when doctors fail to properly treat or
misdiagnose PPCM ? See you in court
PPCM-related malpractice lawsuits

Peripartum Cardiomyopathy .BOARD scheme for the therapy of patients with acute PPCM.

Peripartum Cardiomyopathy .BOARD scheme for the therapy of patients with acute PPCM.

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Peripartum Cardiomyopathy .BOARD scheme for the therapy of patients with acute PPCM.

Notes de l'éditeur