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.

Keywords: Cardiomyopathies; cellular immunity; flow cytometry; peripartum period.

Fig. 1

CD3−CD56+CD16+ and CD3+CD4−CD8−CD38+ cell presence in peripartum cardiomyopathy (PPCM) and healthy postpartum (HP) samples matched by postpartum day. Flow cytometry determination of the percentage of (A) Natural killer (NK; CD3−CD56+CD16+) and (B) CD38+ “double negative” (DN; CD3+CD4−CD8−CD38+) cells in HP (white; n = 10) and PPCM (black; n = 52) samples matched by postpartum day (PPCM 49.6 ± 10.6 days; HP 48.8 ± 11.2 days) and presented as box plot. *Significant by Mann-Whitney U test.

Fig. 2

Changes in NK (%CD3−CD56+CD16+) cell subsets over time, comparison by race. (A) Percentage of NK cells in PPCM patients who had samples collected at each time point (n = 42; 35 white, 5 black, 2 other). (B) Percentage of NK cells in white PPCM patients with samples collected at each time point (n = 42). (C) Percentage of NK cells in black PPCM patients with samples collected at each time point (n = 5). (D) Percentage of NK cells in all available patients at each time point (early, 2 mo, 6 mo, respectively: white n = 50, 48, and 53; black n = 14, 22, and 21). Abbreviations as in Fig. 1. *P < .05 vs 2 months; †P < .05 vs 6 months; ‡P < .05 black vs white, same time point.

Fig. 3

Changes in CD38+ DN (%CD3+CD4−CD8−CD38+) cell subsets over time, comparison by race. (A) Percentage of CD38+ DN cells in PPCM patients who had samples collected at each time point (n = 41; 34 white, 5 black, 2 other). (B) Percentage of CD38+ DN cells in white PPCM patients with samples collected at each time point (n = 41). (C) Percentage of CD38+ DN cells in black PPCM patients with samples collected at each time point (n = 5). (D) Percentage of CD38+ DN cells in all available patients at each time point (early, 2 mo, 6 mo, respectively: white n = 50, 47, and 53; black n = 13, 22, and 21). Abbreviations as in Fig. 1.