Cathepsin-D and outcomes in peripartum cardiomyopathy: Results from IPAC

Abstract

Objective: Evaluate the relationship of cathepsin-D (CD) on disease severity and clinical outcomes for women with peripartum cardiomyopathy.

Background: Cathepsin-D is a protease released during oxidative stress that cleaves prolactin (PRL) generating a 16 kDa fragment that is pro-apoptotic, anti-angiogenic, and has been implicated in the pathogenesis of peripartum cardiomyopathy (PPCM).

Methods: In 99 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy (IPAC) study, CD levels were assessed by ELISA from serum obtained at study entry. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6, and 12-months. CD levels were compared to healthy PP and non-PP controls. Survival free from major cardiovascular events (death, transplantation, or left ventricular assist device) was determined up to 12 months post-partum (PP).

Results: Mean age was 30 ± 6 years, with a baseline LVEF of 34 % ± 10. Cathepsin-D levels were higher in PPCM women (278 ± 114 ng/ml) than in healthy PP (190 ± 74, p = 0.02) and healthy non-PP controls (136 ± 79, p < 0.001). There was no association of CD with age, breastfeeding status, or time from delivery to the presentation. Cathepsin-D levels were higher in women with higher New York Heart Association (NYHA) functional class (p = 0.001). Higher tertiles of CD levels were associated with lower event-free survival (p = 0.008).

Conclusions: In this prospective cohort of women with PPCM, higher CD levels at the time of diagnosis were associated with worse symptoms, less recovery of LVEF, and worse clinical outcomes. Circulating CD may contribute to the development of PPCM and influence disease severity, myocardial recovery, and clinical outcomes.

Keywords: Cardiomyopathies; Heart failure; Peripartum cardiomyopathy; Pregnancy.

Fig. 1

Cathepsin-D by NYHA functional class at study enrollment – Boxplots represent the interquartile range from the first to the third quartile. Median represented by a thick black line across the interquartile range, and error bars represent 1.5 times the interquartile range. Cathepsin-D levels were significantly higher in women with a higher NYHA functional class at study enrollment, p = 0.001 (NYHA = New York Heart Association).

Fig. 2

LVEF by cathepsin-D tertile at enrollment, 6, and 12 months post-partum – Boxplots represent the interquartile range from the first to the third quartile. Median represented by a thick black line across the interquartile range, and error bars represent 1.5 times the interquartile range. LVEF is shown in the lowest, middle, and highest tertiles of cathepsin-D at enrollment, 6, and 12 months PP to show the role of cathepsin-D in myocardial recovery. There is no difference in LVEF among tertile groups at enrollment or six-months, however, at there is a significantly higher LVEF for women in the lowest CD tertile at 12 months (overall p = 0.03). Post hoc analysis demonstrated a significant higher LVEF for women in the lowest CD tertile compared to the middle tertile (p = 0.027) while the other pairwise comparisons were not significant. LVEF = left ventricular ejection fraction; PP = post-partum.

Fig. 3

Number of women with full or partial recovery compared to death, transplant, LVAD, or persistent cardiomyopathy at 12 months PP in each cathepsin-D tertile – Bar graph represents the number of women in each cathepsin-D tertile at 12-months of follow up. The outcome is a comparison of women who experienced an event defined as: death, cardiac transplantation, LVAD implantation, or persistent cardiomyopathy (LVEF ≤35 %), to those who experienced a full or partial recovery. All women in the lowest cathepsin-D tertile group experienced full or partial recovery, and incrementally more women experienced events in the higher cathepsin-D tertile groups, p = 0.01. (LVAD = left ventricular assist device; PP = post-partum; LVEF = left ventricular ejection fraction).

Fig. 4

LVAD or transplant-free survival post-partum by cathepsin-D tertile. Event-free survival was defined as survival free of death, cardiac transplantation, or LVAD implantation. Kaplan-Meier log-rank analysis comparing subjects in the lowest, middle, and highest tertiles of cathepsin-D. Poorer event-free survival was evident for subjects with higher cathepsin-D, p = 0.008. (LVAD = left ventricular assist device).