Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study

Abstract

Objectives: This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM).

Background: PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology.

Methods: In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months.

Results: Mean age was 30 ± 6 years, with a baseline of LVEF 0.35 ± 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004).

Conclusions: In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955).

Keywords: cardiomyopathy; heart failure; hormones; pregnancy and post-partum.

Figure 1. Biomarker levels by days post-partum (quartiles)

A. Relaxin-2 levels (pg/ml) were significantly higher in women presenting in the first quartile (0 to 11 days) compared to subjects presenting in the latter three (12 to 95 days). (p=0.0043). B. Prolactin levels (ng/ml) were significantly higher in women presenting in the first quartile compared to subjects presenting in the latter three (p<0.00001). C. sFlt1 levels pg/ml were significantly higher in women presenting in the first quartile compared to subjects presenting in the latter three (p<0.003). D. VEGF levels (pg/ml) were not significantly different by days post-partum (p=0.73). Boxplots: box represents the interquartile range from1st to 3rd quartile. Median represented by a thick black line across the interquartile range. Error bars represent 1.5 times the interquartile range.

Figure 2. LVEF over time by tertiles of relaxin-2 level at entry

A. Entire cohort (n=98). White bars=lowest tertile, gray bars= intermediate tertile, and red bars=highest tertile. Early myocardial recovery (LVEF at 2 months) best in the highest relaxin tertile (p=0.01) B. Subjects enrolled in the first quartile of days post-partum (0–11 days, n=25): White bars=lowest tertile, gray bars=intermediate tertile, red bars=highest tertile. Early myocardial recovery (LVEF at 2 months) again greatest in the highest relaxin tertile (p=0.02)

Figure 3. Soluble Flt1 levels by NYHA class

Boxplots with red box representing the interquartile range from 1st to 3rd quartile. Median represented by a thick black line across the interquartile range. Error bars represent 1.5 times the interquartile range. Higher progressive sFlt1 levels with increasing NYHA class (p=0.01)

Figure 4. Event Free survival by sFlt1 tertiles

Event free survival was defined as free of death, cardiac transplantation, or LVAD implantation. Kaplan Meier log rank analysis comparing subjects in the highest tertile of soluble Flt1 levels with subjects in the lower two tertiles. Poorer event free survival was evident for subjects with higher sFlt1 level (p=0.004)