Circulating T-Cell Subsets, Monocytes, and Natural Killer Cells in Peripartum Cardiomyopathy: Results From the Multicenter IPAC Study

Abstract

Objective The aim of this work was to evaluate the hypothesis that the distribution of circulating immune cell subsets, or their activation state, is significantly different between peripartum cardiomyopathy (PPCM) and healthy postpartum (HP) women. Background PPCM is a major cause of maternal morbidity and mortality, and an immune-mediated etiology has been hypothesized. Cellular immunity, altered in pregnancy and the peripartum period, has been proposed to play a role in PPCM pathogenesis. Methods The Investigation of Pregnancy-Associated Cardiomyopathy (IPAC) study enrolled 100 women presenting with a left ventricular ejection fraction of <0.45 within 2 months of delivery. Peripheral T-cell subsets, natural killer (NK) cells, and cellular activation markers were assessed by flow cytometry in PPCM women early (<6 wk), 2 months, and 6 months postpartum and compared with those of HP women and women with non–pregnancy-associated recent-onset cardiomyopathy (ROCM). Results Entry NK cell levels (CD3−CD56+CD16+; reported as % of CD3− cells) were significantly (P < .0003) reduced in PPCM (6.6 ± 4.9% of CD3− cells) compared to HP (11.9 ± 5%). Of T-cell subtypes, CD3+CD4−CD8−CD38+ cells differed significantly (P < .004) between PPCM (24.5 ± 12.5% of CD3+CD4−CD8− cells) and HP (12.5 ± 6.4%). PPCM patients demonstrated a rapid recovery of NK and CD3+CD4−CD8−CD38+ cell levels. However, black women had a delayed recovery of NK cells. A similar reduction of NK cells was observed in women with ROCM. Conclusions Compared with HP control women, early postpartum PPCM women show significantly reduced NK cells, and higher CD3+CD4−CD8−CD38+ cells, which both normalize over time postpartum. The mechanistic role of NK cells and “double negative” (CD4−CD8−) T regulatory cells in PPCM requires further investigation.

Breastfeeding, Cellular Immune Activation, and Myocardial Recovery in Peripartum Cardiomyopathy

“…Our data do not support a significant role for cytotoxic T cells in the pathogenesis of PPCM or subsequent recovery. Recently, we reported that a decrease in natural killer cells was evident in patients with PPCM compared with healthy postpartum control subjects, but in contrast, circulating cytotoxic T cell and T helper cell levels were not significantly different between the 2 cohorts (11). The present study found higher circulating cytotoxic T cells in patients with PPCM who breastfed than those who did not.…”

“…A prior analysis (11) comparing circulating immune cells from women with PPCM in the IPAC cohort with healthy postpartum women revealed a significant reduction in natural killer cells (CD3 − CD56 + CD16 + ) and an increase in CD3 + CD4 − CD8 − double-negative T-cells in patients with PPCM. There was no observed difference in the percentage of either natural killer cells or double-negative T cells between the NBF and BF subsets in the present analysis.…”

“…The diagnosis of PPCM is made in late antepartum or early postpartum at a time when the adaptive down-regulation of maternal cellular immunity allowing fetal tolerance is ending and maternal cellular immunity is being restored. Prior studies have found differences in peripheral circulating subsets of T cell populations in women with PPCM compared with healthy postpartum women (11). One preliminary study found that patients with PPCM had marked reductions of CD4 + CD25 lo+ T regulatory cells during the third trimester compared with normal healthy pregnant patients, which persisted for more than 1 month postpartum (6).…”

“…Cell “activation” status was assessed by expression of CD25, CD38, or human leukocyte antigen DR isotype. Antigen-specific and compensation antibodies used in flow cytometry were previously published (11). Flow cytometry data were acquired using a BD FACS ARIA 1 and analyzed using FACSDiva version 6.1.3 software (BD Biosciences, Ashland, Oregon).…”

Deficiency in CD4 T Cells Leads to Enhanced Postpartum Internal Carotid Artery Vasoconstriction in Mice: The Role of Nitric Oxide

“…Further, understanding how this interaction signals or generates risk of subsequent cardiovascular disease, including hypertension during pregnancy is of great importance to maternal health. Some diseases of pregnancy have a unique PP phenotype both from a vascular and immune standpoint and our understanding of the PP immune system in health and in the context of specific PP disease is still evolving ( Young et al, 2014 ; Lima et al, 2017 ; Aghaeepour et al, 2018 ; McTiernan et al, 2018 ; Brien et al, 2019 ; Coss et al, 2020 ; Osborne et al, 2020 ). The multiple layers of complexity inherent in the PP interaction between maternal immune and vascular systems is an area that is still ripe for examination in humans and animal models; the outcome of successful study will likely delineate specific mechanisms that can be utilized for diagnosis, management, and assessment of long term risk.…”