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What can a peripartum cardiomyopathy (PPCM) subject
do to reduce the risks of relapse of heart failure in a subsequent pregnancy?
James D. Fett, MD.
the post-PPCM pregnancy:
1)Adequate treatment of first episode to help reach
left ventricular ejection fraction (LVEF) of 55 % (anything higher considered a
“variant of normal”).
2)Be sure that “contractile reserve” is adequate;
defined as increase of LVEF by at least 15 % from resting heart rate to target
exercise heart rate on exercise stress echocardiogram (example: from LVEF 55 % to 63 %).
3)Maintain normal heart function (LVEF 55 %) after
phase-out of medication that would not be safe during conception/pregnancy;
such as ACE-Inhibitor or ARB (angiotensin receptor blocker).
4)”Full recovery” confers lower risk, and means
a)No diastolic dysfunction; if that exists
more Rx indicated.
b)No LGE (late Gadolinium enhancement) on
c) Size of left ventricle < 6 cm or
< 3.5 cm/M2 BSA.
the post-PPCM pregnancy:
1)Establish base-line serum BNP (B-type Natriuretic
Peptide) and monitor serum BNP level each trimester. Look for levels that are rising and/or above “cut-off”
level for your lab’s test.
The NT-ProBNP test is recommended because it appears to be the least
affected by pregnancy alone.
2)Monitor LVEF by echocardiography each trimester and
more often if serum BNP is rising and/or above “cut-off” value.
3)Rising serum BNP above “cut-off” is an indication
to consider starting a treatment (first choice: beta-blocker) because that comes before any fall in
4)Monitor the “self-test” monthly for recognition of
signs and symptoms of heart failure during pregnancy.
5)Watch for further developments of this research
--serum soluble FLT1 >100 pg/ml
--ratio of sFLT1 to Placenta Growth Factor (PlGF)
> 50 @ 24 weeks gestation.
This may be predictive of trouble @ 32 weeks gestation.
What about the new medication,
We are learning about this new medication, FDA approved for use in treatment of heart failure with reduced EF. I have heard from 14 PPCM subject users of Entresto. 5 of those 14 have just begun and no new echo yet, so don't yet know response. Of the 9 remaining, 7 (78 %) had response of gain EF of 20 points or more; 1 had no change; 1 had to stop due to side-effects. Some of those 7 "improvers" had "plateaued" for some months, so that response is encouraging, seemingly an advantage over previous treatment. You may want to discuss this with your cardiologist.
Clinical Obstetrics, Gynecology and Reproductive Medicine
Teamwork in diagnosing and treating peripartum
James D Fett*
Peripartum Cardiomyopathy Projects, 2331 Mt. Hood Ct. SE, Lacey, WA 98503, USA
When the diagnosis of peripartum cardiomyopathy (PPCM) can
be made very early in its course the systolic heart function will be better
preserved . When the echocardiographic left ventricular ejection
fraction (LVEF) is better, recovery outcomes will also be better .
Earlier diagnosis depends upon earlier recognition of symptoms that
may be very similar to normal term pregnancy symptoms. When all
of those involved in the care of new mothers, including the subjects
themselves, are aware of a possibility for the development of pregnancy-
associated heart failure in someone who has previously had perfectly
normal heart function, then earlier diagnosis can easily be confirmed
PPCM is still one of the leading causes of maternal mortality [3-5].
Unrecognized, it progresses at variable rates into severe heart failure
threatening the life of both mother and unborn child or neonate. While
not a common condition, it is also not rare. In the USA, incidence varies
from approximately 1 case per 1500 live births in those mothers with
African heritage to 1 case per 3000 in mothers without African heritage.
Delay in diagnosis may lead to maternal mortality, newborn fatality, or
survival of a mother with chronic cardiomyopathy and varying severity
of heart failure for the rest of her life. Nevertheless, PPCM is a form
of dilated cardiomyopathy with the greatest potential for full recovery,
particularly when diagnosed early and treated appropriately, following
evidence-based guidelines [2,6].
How can an earlier diagnosis of PPCM be made?
Greater awareness is already having an impact, leading to
improving outcomes. Increasing attention must be given to enhance
this awareness among all subjects with pregnancy as well as all their
medical caregivers, including birthing center personnel, obstetrical
nurses and aides, primary care physicians, emergency room physicians,
obstetricians and cardiologists.
A self-test for heart failure in pregnancy is available for
quantification of common symptoms . Scores of 5 and higher
continue to be validated as indicating the need for carrying out
additional testing, including serum B-type Natriuretic Peptide (BNP)
and/or echocardiography. It is important to work quickly in this
assessment because, once triggered, the PPCM process may move very
rapidly; in which case the LVEF falls to levels that risk the subject’s
susceptibility to ventricular tachyarrhythmias and sudden cardiac
arrest. Once recognized, early treatment reverses the cardiomyopathic
process and gives the greatest potential for avoiding those dangerous
levels of systolic dysfunction, providing the greatest potential for
subsequently returning to normal heart function.
What is the treatment of PPCM?
Evidence-based “Guidelines” for the initial treatment of heart failure
with reduced LVEF include diuretics, beta-blockers (BB) and ACE-
inhibitors or angiotensin receptor blockers (ACEI/ARB) in tolerable
dosages as “Class I (“should use”) recommendations . Usually,
ACEI are started first followed by BB when there is hemodynamic
stability; however, reverse order has been used and is also effective.
The combination of ACEI + BB seems to have a synergistic effect that
We do not yet know if the new dual angiotensin receptor blocker
(ARB) and neprilysin inhibitor (ARNI) will be more effective than an
ACEI; but it does show promise of benefit for some . We do know
that newer intervention trials are needed to help those who currently
are the most resistant to full recovery; namely, those who at diagnosis
have LVEF < 0.30 and left ventricular end-diastolic diameter (LVEDD)
≥ 6 cm .
Thus far, inhibition of the lactating hormone, prolactin, with
the use of bromocriptine has neutral or disappointing results; and
continuation of breastfeeding has not been shown to be detrimental to
recovery [2,10,11]. More work needs to be done on the prolactin theory
of causation to be sure that findings on the mouse model can indeed
translate to the human model, in which there may be more resistance to
cleavage of normal prolactin into a cardiotoxic metabolite (genetically
First priority is to initiate the recovery phase. The issue
of safety for subsequent pregnancies can be considered
It is helpful to indicate to the new mother that the safety of future
pregnancies depends upon achieving full recovery of heart function.
We now know that most women who experience full recovery are
indeed able to safely have a subsequent pregnancy [8,14,15]. We are
still learning about the risks for relapse of heart failure in subsequent
pregnancies. This type of relapse is still a possibility in some of those
Correspondence to: James D. Fett, MD, Peripartum Cardiomyopathy
Projects, 2331 Mt. Hood Ct. SE, Lacey, WA 98503, USA; Co-Director and
Steering Committee, Peripartum Cardiomyopathy Network (PCN), IPAC
=Investigations in Pregnancy-Associated Cardiomyopathy, (Principal
Investigator and Co-Director, Dennis McNamara, MD), Tel: 360-438-5270;
Received: November 06, 2015; Accepted: December 07, 2015; Published:
December 10, 2015
Clin Obstet Gynecol Reprod Med, 2015 doi: 10.15761/COGRM.1000127
A new era
This is a new era for PPCM.
progress. Working together as a team we are now in a much better
position to help every PPCM mother fully recover.
Fett JD (2013) Earlier detection can help avoid many serious complications of
peripartum cardiomyopathy. Future Cardiol 9: 809-816. [Crossref]
McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, et al. (2015) Clinical
Outcomes for Peripartum Cardiomyopathy in North America: Results of the IPAC
Study (Investigations of Pregnancy-Associated Cardiomyopathy). J Am Coll Cardiol
66: 905-914. [Crossref]
James D Fett (2014) Peripartum cardiomyopathy: A puzzle closer to solution. World J
Cardiol 6: 87-99. [Crossref]
Elkayam U (2011) Clinical characteristics of peripartum cardiomyopathy in the
United States: diagnosis, prognosis, and management. J Am Coll Cardiol 58: 659-670.
Goland S, Modi K, Bitar F, Janmohamed M, Mirocha JM, et al. (2009) Clinical profile
and predictors of complications in peripartum cardiomyopathy. J Card Fail 15: 645-
Sabe MA, Jacob MS, Taylor DO (2015) A new class of drugs for systolic heart failure:
The PARADIGM-HF study. Cleve Clin J Med 82: 693-701. [Crossref]
Safirstein JG, Ro AS, Grandhi S, Wang L, Fett JD, et al. (2012) Predictors of left
ventricular recovery in a cohort of peripartum cardiomyopathy patients recruited via
the internet. Int J Cardiol 154: 27-31. [Crossref]
Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, et al. (2013) Phenotyping
and outcome on contemporary management in a German cohort of patients with
peripartum cardiomyopathy. Basic Res Cardiol 108: 366. [Crossref]
Patten IS, Rana S, Shahul S, Rowe GC, Jang C, et al. (2012) Cardiac angiogenic
imbalance leads to peripartum cardiomyopathy. Nature 485: 333-338. [Crossref]
Piwnica D, Touraine P, Struman I, Tabruyn S, Bolbach G, et al. (2004) Cathepsin D
processes human prolactin into multiple 16K-like N-terminal fragments: study of their
antiangiogenic properties and physiological relevance. Mol Endocrinol 18: 2522-2542.
Fett JD, Fristoe KL, Welsh SN (2010) Risk of heart failure relapse in subsequent
pregnancy among peripartum cardiomyopathy mothers. Int J Gynaecol Obstet 109:
Elkayam U, Tummala PP, Rao K, Akhter MW, Karaalp IS, et al. (2001) Maternal and
fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy.
N Engl J Med 344: 1567-1571. [Crossref]
Fett JD (2015) Teamwork in diagnosing and treating peripartum cardiomyopathy
Copyright: ©2015 Fett JD. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Clin Obstet Gynecol Reprod Med, 2015 doi: 10.15761/COGRM.1000127
Another new study from IPAC:
JACC Heart Fail.
2016 May;4(5):380-8. doi: 10.1016/j.jchf.2016.01.004. Epub 2016 Mar 9.
Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study.
, Givertz MM2
, Semigran M3
, Alharethi R4
, Ewald G5
, Felker GM6
, Bozkurt B7
, Boehmer J8
, Haythe J9
, Skopicki H10
, Hanley-Yanez K11
, Pisarcik J11
, Halder I11
, Gorcsan J 3rd11
, Rana S12
, Arany Z13
, Fett JD11
, McNamara DM11
; IPAC Investigators
This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM).
PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology.
In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months.
Mean age was 30 ± 6 years, with a baseline of LVEF 0.35 ± 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004).
In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955).
Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
cardiomyopathy; heart failure; hormones; pregnancy and post-partum
N Engl J Med.
2016 Jan 21;374(3):233-41. doi: 10.1056/NEJMoa1505517. Epub 2016 Jan 6.
Circ Heart Fail.
2016 Mar;9(3):e002683. doi: 10.1161/CIRCHEARTFAILURE.115.002683.
GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.
Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins β-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM.
METHODS AND RESULTS:
A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04).
The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.
© 2016 American Heart Association, Inc.
cardiomyopathy; heart failure; peripartum period; polymorphism genetics; pregnancy
Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.
, Li J
, Mazaika E
, Yasso CM
, DeSouza T
, Cappola TP
, Tsai EJ
, Hilfiker-Kleiner 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
, Ramani G
, Safirstein J
, Boehmer J
, Pauly DF
, Wittstein IS
, Thohan V
, Zucker MJ
, Liu P
, Gorcsan J 3rd
, McNamara DM
, Seidman CE
, Seidman JG
, Arany Z
; IMAC-2 and IPAC Investigators
Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.
08-18-2015: IPAC OUTCOME REPORT: