Circulation

EDITORIAL

Natriuretic Peptide Receptor 1, a Novel

Player in Peripartum Heart Failure

Article, see p 571 Denise Hilfiker-Kleiner,

PhD

P
eripartum cardiomyopathy (PPCM) is a potentially life-threatening form of Tobias König, MD
heart failure with reduced left ventricular ejection fraction in the last month Johann Bauersachs, MD
of pregnancy or in the months after delivery in women without previous car-
diomyopathies or another identifiable cause of heart failure.1,2 PPCM appears to
be rather a clinical syndrome resulting from different pathomechanisms initiating
and driving the disease than a unique entity. There is high variability with regard to
onset and cardiac phenotype of patients with PPCM.1–3 In addition, the discovery
of frequent cardiomyopathy-causing mutations in a multinational PPCM cohort
suggests overlap with dilated cardiomyopathy.2,4 Epidemiological observations
show that the risk for PPCM is higher in women with African ancestry, and wom-
en with hypertensive disorders of pregnancy or multiparity, history of cardiotoxic
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treatment, and older age.1–3 Different experimental models leading to peripartum

heart failure enable mechanistic studies of PPCM. Among the pathomechanisms
potentially involved in PPCM are inflammation and immunity, disturbed prolac-
tin metabolism, angiogenic and metabolic imbalance, catecholamine stress, and
defective cAMP-proteinkinase A– and G-protein–coupled receptor signaling, as
well as cardiomyopathy-causing mutations.2,4 Moreover, experimental and clinical
data suggest that PPCM is associated with a systemic angiogenic imbalance, which
can be superimposed to preexisting or pregnancy-induced hypertension involving
deregulated vascular endothelial growth factor signaling and increased levels of
circulating soluble FMS-like tyrosine kinase 1.1,2,4,5 Additional new data reveal that
breastfeeding elevates the activity of the immune system in PPCM.6
Several of these mechanisms seem to merge into a common major pathway
that includes unbalanced oxidative stress and the nursing hormone prolactin. Clini-
cal data are not conclusive yet, but several studies support this idea.2,7–9 In the IPAC
study (Investigations of Pregnancy-Associated Cardiomyopathy) in patients with
PPCM patients with more moderate heart failure, breastfeeding was associated
This article is part of the Science Goes
with an activated immune system but not with adverse effects on recovery.6
Red™ collection. Science Goes Red™
In the present issue of Circulation, Otani et al10 observed that mice with a defi- is an initiative of Go Red for Women®,
ciency of natriuretic peptide (NP) receptor 1 (Npr1), the common receptor of ANP the American Heart Association’s global
movement to end heart disease and
(atrial natriuretic peptide) and BNP (B-type natriuretic peptide), develop PPCM. The
stroke in women.
study by Otani et al10 indicates that the Npr1 in cardiomyocytes and in endothelial
The opinions expressed in this article are
cells is important for protecting the maternal heart from lactation-induced cardiac not necessarily those of the editors or
hypertrophy. In addition, the authors show that in Npr1-/- mice, peripartum cardiac of the American Heart Association.
remodeling and inflammatory responses are mainly triggered by lactation and me- Key Words: Editorials
diated through aldosterone-induced mineralocorticoid receptor (MR) activation in
© 2020 American Heart Association, Inc.
neurons, as well as interleukin-6–dependent pathways. Like in several other PPCM
models, blocking prolactin with bromocriptine moderately improved PPCM in https://www.ahajournals.org/journal/circ

Circulation. 2020;141:589–591. DOI: 10.1161/CIRCULATIONAHA.119.043957 February 18, 2020 589

 Hilfiker-Kleiner et al
Npr1-/- mice, suggesting that also in this PPCM model,
the prolactin-suppressing drug bromocriptine has bene-
ficial effects, but additional mechanisms are involved. In
EDITORIAL
this regard, the model presented by Otani et al10 differs
slightly from other experimental pregnancy models as
well as from the condition in pregnant women because
neither wild-type nor Npr1-/- mice displayed cardiac hy-
pertrophy in late pregnancy. In fact, Otani et al10 report
that hypertrophy was only observed postpartum dur-
ing the lactation period. This observation is surprising
because the mechanical load on the heart in mid- and
end pregnancy is high and usually leads to substantial
eccentric hypertrophy in animals and humans.11 More-
over, although fibrosis and cardiomyocyte hypertrophy
were found in postpartum Npr1-/-, no alterations in an-
giogenesis was observed, a feature that contrasts with
other PPCM models.4
In turn, it is interesting that nullipara Npr1-/- mice
exhibit an increased blood pressure, a feature that is
frequently present in patients with PPCM either already
before pregnancy or as a pregnancy-induced complica-
tion.1–3 Although so far evidence is lacking that Npr1
signaling is disturbed in patients with PPCM, high
levels of NT-proBNP (N-terminal pro-B-type natriuretic
peptide)/BNP are frequently present in patients with
PPCM,1,2 suggesting that this pathway may belong to
an endogenous protection mechanism in PPCM. NPs
have been demonstrated to enhance diuresis, increase
sodium excretion, reduce left ventricular afterload, and
Downloaded from http://ahajournals.org by on January 10, 2024
counteract sympathetic activity in heart failure. The
neprilysin inhibitor sacubitril increases NP levels, and
recent studies demonstrated that the combination of
sacubitril and valsartan has significant beneficial ef-
fects in patients with heart failure with reduced left
ventricular ejection fraction and was recently approved
by the US Food and Drug Administration for this indi-
cation.12 Based on the protective effect of NPs on the
postpartum maternal hearts via ANP/BNP–NPR1 signal-
ing in mice, the effect of sacubitril or the sacubitril and
valsartan should be explored in patients with PPCM.
Of note, because during pregnancy and lactation the
use of sacubitril/valsartan is not recommended, the
treatment may therefore only be used in postpartum
patients with PPCM who stopped nursing.1
A novel aspect in the PPCM pathophysiology dis-
covered in the study by Otani et al10 is the potential in-
volvement of aldosterone/MR signaling as pharmaco-
logical MR antagonists (MRA) significantly ameliorated
cardiac hypertrophy in lactating Npr1-/- mice. MRAs
(either spironolactone or eplerenone) reduce heart fail-
ure hospitalizations and death in patients with heart
failure13 and are recommended by European Society
of Cardiology and American College of Cardiology
Foundation/American Heart Association guidelines in
patients with symptomatic heart failure and left ven-
tricular ejection fraction ≤35%.13
590 February 18, 2020
Npr1, a Novel Player in PPCM
Additionally, MRAs (preferably eplerenone because
of less hormonal side effects and less blood pressure re-
duction) are recommended in postpartum patients with
PPCM with a left ventricular ejection fraction <40% at
diagnosis (based on expert consensus).1 Currently, ap-
proximately 50% of patients with PPCM are treated
with MRA according to the EURObservational Research
Programme registry on peripartum cardiomyopathy,14
and its efficacy in PPCM should be systematically ex-
plored in future studies. Mechanistically, cell-specific
ablation of the MR in mouse heart failure models re-
vealed beneficial effects of interrupted MR signaling in
cardiomyocytes, smooth muscle, and endothelial cells.
In the present study, Otani et al10 discovered a novel role
of neuronal MR signaling for adverse cardiac remodel-
ing during lactation, which is suppressed by NP signal-
ing. Inflammatory cytokines and especially interleukin-6
seem to contribute to PPCM in Npr1-/- mice because the
treatment with anti–interleukin-6 antibody showed a
slight reduction in their peripartum cardiac hypertrophy.
The study by Otani et al10 emphasizes adverse effects
of lactation in PPCM with impaired NRP1-/- and aldoste-
rone/MR, thereby suggesting the use of MRA which,
however, is contraindicated in pregnant and nursing
mothers. In this regard, this study adds to the criti-
cal discussions of whether or not women with PPCM
should breastfeed. Although nursing per se is benefi-
cial for mother and infant, long-term sequelae of heart
failure drugs on infants’ health are largely unknown.15
Therefore, and also because of the slight benefit of bro-
mocriptine in the present PPCM model, it should be dis-
cussed whether sacubitril/valsartan or MR antagonists
may be combined with bromocriptine.
Finally, by adding an additional pathomechanism to
the already described ones, the study by Otani et al10
further supports the diversity of pathologies in the syn-
drome of peripartum heart failure and emphasizes that
personalized medicine should be applied to design the
optimal treatment for each individual patient with PPCM.
ARTICLE INFORMATION
Correspondence
Denise Hilfiker-Kleiner, PhD, Molecular Cardiology, Department of Cardiology
and Angiology, Hannover Medical School, Carl-Neuberg Str 1, 30625 Han-
nover, Germany. Email hilfiker.denise@mh-hannover.de
Affiliation
Department of Cardiology and Angiology, Hannover Medical School, Germany.
Disclosures
None.
REFERENCES
1. Bauersachs J, König T, van der Meer P, Petrie MC, Hilfiker-Kleiner D,
Mbakwem A, Hamdan R, Jackson AM, Forsyth P, de Boer RA, et al.
Circulation. 2020;141:589–591. DOI: 10.1161/CIRCULATIONAHA.119.043957
 Hilfiker-Kleiner et al
Pathophysiology, diagnosis and management of peripartum cardiomyopa-
thy: a position statement from the Heart Failure Association of the Euro-
pean Society of Cardiology Study Group on peripartum cardiomyopathy.
Eur J Heart Fail. 2019;21:827–843. doi: 10.1002/ejhf.1493
2. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC,
Francis GS, Lenihan D, Lewis EF, McNamara DM, et al; American Heart As-
sociation Committee on Heart Failure and Transplantation of the Council
on Clinical Cardiology; Council on Cardiovascular Disease in the Young;
Council on Cardiovascular and Stroke Nursing; Council on Epidemiology
and Prevention; and Council on Quality of Care and Outcomes Research.
Current diagnostic and treatment strategies for specific dilated cardiomy-
opathies: a scientific statement from the American Heart Association. Cir-
culation. 2016;134:e579–e646. doi: 10.1161/CIR.0000000000000455
3. McNamara DM, Elkayam U, Alharethi R, Damp J, Hsich E, Ewald G,
Modi K, Alexis JD, Ramani GV, Semigran MJ, et al; IPAC Investigators.
Clinical outcomes for peripartum cardiomyopathy in North America: re-
sults of the IPAC Study (Investigations of Pregnancy-Associated Cardio-
myopathy). J Am Coll Cardiol. 2015;66:905–914. doi: 10.1016/j.jacc.
2015.06.1309
4. Ricke-Hoch M, Pfeffer TJ, Hilfiker-Kleiner D. Peripartum cardiomyopa-
thy: basic mechanisms and hope for new therapies. Cardiovasc Res.
2019:cvz252. doi: 10.1093/cvr/cvz252 [epub ahead of print].
5. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, Hacker MR,
Rhee JS, Mitchell J, Mahmood F, et al. Cardiac angiogenic imbalance
leads to peripartum cardiomyopathy. Nature. 2012;485:333–338. doi:
10.1038/nature11040
6. Koczo A, Marino A, Jeyabalan A, Elkayam U, Cooper LT, Fett J, Briller J,
Hsich E, Blauwet L, McTiernan C, et al; IPAC Investigators. Breastfeed-
ing, cellular immune activation, and myocardial recovery in peripar-
tum cardiomyopathy. JACC Basic Transl Sci. 2019;4:291–300. doi:
10.1016/j.jacbts.2019.01.010
7. Biteker M, Özlek B, Özlek E, Çil C, Çelik O, Doğan V, Başaran Ö. Predictors
of early and delayed recovery in peripartum cardiomyopathy: a prospec-
tive study of 52 patients. J Matern Fetal Neonatal Med. 2020;33:390–
397. doi: 10.1080/14767058.2018.1494146
8. Hilfiker-Kleiner D, Haghikia A, Berliner D, Vogel-Claussen J, Schwab
J, Franke A, Schwarzkopf M, Ehlermann P, Pfister R, Michels G, et al.
Bromocriptine for the treatment of peripartum cardiomyopathy: a
Downloaded from http://ahajournals.org by on January 10, 2024
Circulation. 2020;141:589–591. DOI: 10.1161/CIRCULATIONAHA.119.043957
Npr1, a Novel Player in PPCM
multicentre randomized study. Eur Heart J. 2017;38:2671–2679. doi:
10.1093/eurheartj/ehx355
9. Tremblay-Gravel M, Marquis-Gravel G, Avram R, Desplantie O, Ducharme A,
Bibas L, Pacheco C, Couture E, Simard F, Poulin A, et al; BRO-HF Investiga-
EDITORIAL
tors. The effect of bromocriptine on left ventricular functional recovery
in peripartum cardiomyopathy: insights from the BRO-HF retrospective
cohort study. ESC Heart Fail. 2019;6:27–36. doi: 10.1002/ehf2.12376
10. Otani K, Tokudome T, Kamiya CA, Mao Y, Nishimura H, Hasegawa T,
Arai Y, Kaneko M, Shioi G, Ishida J, Fukamizu A, et al. Deficiency of car-
diac natriuretic peptide signaling promotes peripartum cardiomyopathy-
like remodeling in the mouse heart. Circulation. 2020;141:571-588. doi:
10.1161/CIRCULATIONAHA.119.039761
11. Gibb AA, Hill BG. Metabolic coordination of physiological and patho-
logical cardiac remodeling. Circ Res. 2018;123:107–128. doi: 10.1161/
CIRCRESAHA.118.312017
12. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR,
Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al; PARADIGM-HF
Investigators and Committees. Angiotensin-neprilysin inhibition ver-
sus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi:
10.1056/NEJMoa1409077
13. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS,
Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, et al; ESC Scien-
tific Document Group. 2016 ESC Guidelines for the diagnosis and treat-
ment of acute and chronic heart failure: The Task Force for the diagnosis
and treatment of acute and chronic heart failure of the European Society
of Cardiology (ESC) developed with the special contribution of the Heart
Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
doi: 10.1093/eurheartj/ehw128
14. Sliwa K, Mebazaa A, Hilfiker-Kleiner D, Petrie MC, Maggioni AP, Laroche C,
Regitz-Zagrosek V, Schaufelberger M, Tavazzi L, van der Meer P, et al.
Clinical characteristics of patients from the worldwide registry on peripar-
tum cardiomyopathy (PPCM): EURObservational Research Programme in
conjunction with the Heart Failure Association of the European Society of
Cardiology Study Group on PPCM. Eur J Heart Fail. 2017;19:1131–1141.
doi: 10.1002/ejhf.780
15. Byrne JJ, Spong CY. “Is it safe?” - the many unanswered questions about
medications and breast-feeding. N Engl J Med. 2019;380:1296–1297.
doi: 10.1056/NEJMp1817420
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