Peripartum cardiomyopathy, an autoimmune manifestation of allograft rejection?

doi:10.1016/j.autrev.2008.12.003

Autoimmunity Reviews

Volume 8, Issue 5, March 2009, Pages 384-387

https://doi.org/10.1016/j.autrev.2008.12.003 Get rights and content

Abstract

The timing of peripartum cardiomyopathy (PPCM) in association with pregnancy is typical of autoimmune conditions. This review addresses this fact by presenting PPCM as an organ specific autoimmune response (though not necessarily as an outright autoimmune condition), akin to autoimmune responses seen with complications of allogeneic organ transplantations. Since pregnancy represents a semi-allograft (representing paternal alloantigens), pregnancy and allogeneic organ transplants can be expected to be subject to similar allograft tolerance mechanisms, and also to share potential complications of normal allograft tolerance. This review suggests that PPCM represents a cardio-toxic autoimmune component within a more general immunological malfunction of tolerance of the fetal allograft by the maternal immune system. Treatment of PPCM with therapies, proven successful in graft versus host disease and organ rejection, may, therefore, be successful. Their success would also be confirmatory of such a concept.

Introduction

Noted in the 18th century, pregnancy associated heart failure was first described in 1937 [1]. In the early 70s, at Chicago's Cook County Hospital, it was defined as peripartum cardiomyopathy (PPCM), characterized by cardiac decompensation in the last month of pregnancy or up to five months postpartum [2]. This definition has not much changed [3], [4], though PPCM is now believed also to occur earlier in pregnancy [5]. With “unknown” etiology, PPCM's current definition still includes absence of obviously determinable causes [3], [4].

Diagnoses are still frequently delayed and/or overlooked, as symptoms may mimic normal physiologic findings of pregnancy or be mistaken for preeclampsia/eclampsia [3]. Both conditions may present with congestive heart failure and/or pulmonary edema, but preeclampsia/eclampsia, in contrast to PPCM, is usually not characterized by left ventricular systolic dysfunction [6].

Section snippets

Etiology and pathophysiology

PPCM is amongst only a small number of conditions, characterized by first occurrence and recurrence in association with pregnancy. Amongst those, where an etiology is known, all are considered autoimmune conditions, and this kind of occurrence pattern has, therefore, been characterized as autoimmune [7]. It, therefore, does not surprise that PPCM has been suggested to represent an autoimmune disease [8], [9], [10], [11].

We, however, in subtle contrast, consider PPCM one (amongst many possible)

Autoimmunity in non-pregnancy associated cardiomyopathy

Outside of pregnancy, chronic myocarditis [22], [23] and especially idiopathic dilated cardiomyopathy [24], [25], [26], [27], [28], [29] have been associated with anti-cardiac autoimmune responses. As in cardiac transplantation, autoantibodies appear polyclonal, associated with cytokine abnormalities [27], [28] and can be organ-specific or not [29]. Some heart-specific autoantibodies are poorly defined [24], but most are anti-myosin antibodies [25], [26] and some exert functional effects on

PPCM's other characteristics of autoimmune conditions

Abnormal autoimmunity is familial and one autoimmune condition in an individual predisposes to the development of others [32]. Whether this applies to PPCM is unknown. PPCM, however, demonstrate a dramatically higher prevalence in African than Caucasians women [3], [4], suggesting a genetic component to risk, and in this sense behaves like an autoimmune condition.

After pregnancy, autoimmune diseases may go into remission, only to clinically resurface later. In contrast, autoimmune phenomena,

What speaks against it and why it matter?

Recent reports, implying that the hormone prolactin mediates PPCM [35], and that inhibition of prolaction may enhance recovery from PPCM [36] have been suggested to be contradictory to an autoimmune etiology for the condition. Such an opinion, however, ignores that elevated prolactin levels have been associated with abnormal autoimmune function in general [37], [38], specific autoimmune conditions, such as systemic lupus erythematousus, rheumatoid arthritis and thyroid disease and that

Take-home messages

•
There is convincing circumstantial evidence in support of abnormal autoimmune function as an underlying pathophysiologic mechanism in the development of PPCM.
•
It is, however, tempting to speculate further that these observed autoimmune responses are not representative of an autoimmune condition, but reflect the typically observed autoimmune components of malfunctions in allograft (in this case pregnancy-) tolerance.
•
Building on this concept, pharmaceutical interventions, which have been proven

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Fatal accelerated rejection with a prominent natural killer cell infiltrate in a heart transplant recipient with peripartum cardiomyopathy
2018, Transplant Immunology
Citation Excerpt :
Ischemia/reperfusion injury and viral pathogens can activate innate immunity, but no evidence supports either mechanism in this case. NK cells could mediate antibody-dependent cellular cytotoxicity in response to CD16-FcRγIIIA ligation [11] potentially triggered by alloantibodies and/or autoantibodies secondary to PPCM [17,18]. Interestingly, recipient genotyping of the killer Ig receptors (KIR) revealed the presence of activating KIR (2DS2, and 2DS3 of KIR B haplotypes), and 2DS4 with its cognate HLA-C1 and C2 ligands in the donor (Table 1).
Accelerated rejection is uncommon after cardiac transplantation. The mechanism is hypothesized to be mediated by cytotoxic T cells and anti-HLA antibodies resulting from a memory response to the donor allograft in sensitized patients. A role for Natural Killer (NK) cell in cellular rejection has also been suggested. We report a case of fulminant accelerated rejection in a heart transplant recipient, with a history of peripartum cardiomyopathy (PPMC). The patient had no pre-transplant donor specific antibody and flow cytometric T and B cell crossmatches were negative. Autopsy revealed left ventricular subendocardial and intramyocardial hemorrhage with diffuse lymphocytic infiltrates and myocyte damage (Grade 3R rejection). Immunohistochemistry revealed a large proportion (50–70%) of mature CD16 + NK cells with cytotoxic potential in the interstitium and the intra capillary compartments. This case highlights the need for evaluating the potential role of NK cells in accelerated rejection in heart transplant recipients.
Editorial: How do genetic components play a role in peripartum cardiomyopathy?
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Clinical Outcomes for Peripartum Cardiomyopathy in North America: Results of the IPAC Study (Investigations of Pregnancy-Associated Cardiomyopathy)
2015, Journal of the American College of Cardiology
Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality.
This study sought to prospectively evaluate recovery of the left ventricular ejection fraction (LVEF) and clinical outcomes in the multicenter IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study.
We enrolled and followed 100 women with PPCM through 1 year post-partum. The LVEF was assessed by echocardiography at baseline and at 2, 6, and 12 months post-partum. Survival free from major cardiovascular events (death, transplantation, or left ventricular [LV] assist device) was determined. Predictors of outcome, particularly race, parameters of LV dysfunction (LVEF), and remodeling (left ventricular end-diastolic diameter [LVEDD]) at presentation, were assessed by univariate and multivariate analyses.
The cohort was 30% black, 65% white, 5% other; the mean patient age was 30 ± 6 years; and 88% were receiving beta-blockers and 81% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The LVEF at study entry was 0.35 ± 0.10, 0.51 ± 0.11 at 6 months, and 0.53 ± 0.10 at 12 months. By 1 year, 13% had experienced major events or had persistent severe cardiomyopathy with an LVEF <0.35, and 72% achieved an LVEF ≥0.50. An initial LVEF <0.30 (p = 0.001), an LVEDD ≥6.0 cm (p < 0.001), black race (p = 0.001), and presentation after 6 weeks post-partum (p = 0.02) were associated with a lower LVEF at 12 months. No subjects with both a baseline LVEF <0.30 and an LVEDD ≥6.0 cm recovered by 1 year post-partum, whereas 91% with both a baseline LVEF ≥0.30 and an LVEDD <6.0 cm recovered (p < 0.00001).
In a prospective cohort with PPCM, most women recovered; however, 13% had major events or persistent severe cardiomyopathy. Black women had more LV dysfunction at presentation and at 6 and 12 months post-partum. Severe LV dysfunction and greater remodeling at study entry were associated with less recovery. (Investigations of Pregnancy Associated Cardiomyopathy [IPAC]; NCT01085955)
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How a passively transferred SSA/Ro–SSB/La autoantibody-mediated immune response would cause such divergent tissue damage is somewhat difficult to imagine and has not been replicated in animal models. Autoimmune abnormalities, including autoantibody abnormalities, are fairly typically associated with allogeneic graft rejection and GVHD [34]. In solid allogeneic organ transplantation complications they, however, do not usually reflect causation.
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Peripartum cardiomyopathy, an autoimmune manifestation of allograft rejection?

Abstract

Introduction

Section snippets

Etiology and pathophysiology

Autoimmunity in non-pregnancy associated cardiomyopathy

PPCM's other characteristics of autoimmune conditions

What speaks against it and why it matter?

Take-home messages

Lancet

Int J Cardiol

Autoimmun Rev

Autoimmun Rev

Ann Cardiol Angeiol (Paris)

Int J Cardiol

Am J Obstet Gynecol

J Heart Lung Transplant

Transpl Immunol

J Am Coll Cardiol

Int J Cardiol

Am J Cardiol

Biochem Biophys Res Commun

Am Heart J

Am J Cardiol

Cell

J Am Coll Cardiol

Autoimmune Rev

Biomed Pharmacother

Am J Obstet Gynecol