Editor's Note: Commentary based on Ersbøll AS, Goetze JP, Johansen M, et al. Biomarkers and their relation to cardiac function late after peripartum cardiomyopathy. J Card Fail 2021;27:168-75.¹

Introduction
Peripartum cardiomyopathy (PPCM) is the acute onset of heart failure late in pregnancy or in the early post-partum period.² Although many women have a full recovery of the left ventricular systolic function, others experience poor outcomes ranging from persistent myocardial dysfunction to death.³

Several biomarkers have previously been implicated in the pathogenesis of PPCM, including soluble Fms-like tyrosine kinase 1 (sFlt-1), which reduces angiogenesis via antagonism of vascular endothelial growth factor (VEGF); it also increases cathepsin D, which produces a pro-apoptotic prolactin fragment.^4,5 However, the long-term angiogenic imbalance factors and the correlation with cardiac recovery have not been established. A recent study examined long-term differences in biomarkers between women with PPCM and those without as well as any correlation between biomarker levels and cardiac dysfunction.

Methods
Participants with PPCM were selected from a nationwide Danish cohort and controls were selected from a population-based Danish obstetric database. The study protocol included non-fasting venous blood samples (for biomarker measurement), maximum cardiopulmonary exercise testing (defined by peak oxygen consumption), and cardiac magnetic resonance imaging (CMR), analyzed using semi-automated software to evaluate cardiac volumes and function.

Results
The recent study included 84 participants, 28 women with PPCM from a 10-year (2005-2014) Danish cohort, and age-matched controls with a history of severe preeclampsia (PE group, n=28) or uncomplicated pregnancies (UCP group, n=28) from a Danish obstetric database. Baseline demographic and clinical characteristics between the two groups were only statistically significantly different for pre-pregnancy body mass index (BMI) [PPCM 28.3 kg/m³ (6.4), PE 22.8 kg/m³ (3.2), UCP 21.3 kg/m³ (1.8), p <0.0001], parity (PPCM 43% 0, PE 86% 0, UCP 43% 0, p 0.007), and concomitant pre-eclampsia (PPCM 39%, PE 100%, UCP 0%, p <0.0001). The PPCM group had a median follow-up of 91 months (range 27-137 months) after delivery.

For the PPCM group, the mean left ventricular ejection faction (LVEF) at diagnosis was 27%, with four of the women (14%) suffering a major adverse event. Though a majority of PPCM patients reported no symptoms at follow-up (86%), they showed a significant (p <0.0001) lower exercise capacity and LVEF (29.6±7.2 mL/kg/min; 62±6%) compared with the PE (43.2±11.1 mL/kg/min; 69±4%) and UCP groups (45.4±10.2 mL/kg/min, 67±5%).

Women in the PPCM group also demonstrated CMR signs of diastolic dysfunction with significantly lower left ventricular peak filling rate (LVPFR), left atrial passive emptying volume (LAPEV) and left atrial passive emptying fraction (LAPEF) compared to the two other groups. Out of the 84 women, five did not undergo exercise testing and five did not undergo CMR for various reasons.

Women in the PPCM group had significantly higher median levels of NT-proBNP, copeptin and PIGF compared to the PE and UCP groups. Additionally, median sFlt-1 was significantly higher in the PPCM group compared to the UCP group (but not the PE group). Furthermore, the PPCM group had more detectable CD activity (68%) compared to PE group (29%) and UCP group (36%) (p=0.0073). After adjustment for BMI, PIGF and copeptin were still significantly higher in the PPCM group.

In any participant with diastolic dysfunction in any group, NT-proBNP was the only marker found to be significantly higher. Ultimately, sFlt-1 and PIGF were both inversely correlated with LAPEV and copeptin was inversely correlated with LAPEF, both markers of diastolic dysfunction. NT-proBNP was positively correlated with LV end-systolic volume. PIGF level and copeptin were inversely correlated with peak VO₂.

Discussion
This study demonstrated that women with PPCM had significantly higher levels of NT-proBNP, copeptin, sFlt-1, PIGF, and CD as compared to women with history of severe preeclampsia or previous uncomplicated pregnancies. Elevated levels of these biomarkers were associated with long-term diminished maximal exercise capacity as well as systolic and/or diastolic dysfunction measured by CMR. This suggests that both persistent angiogenic imbalance and increased CD activity are associated with residual cardiac dysfunction.

Future Directions

• Angiogenic factor biomarkers may be used in the future to diagnose, prognosticate, monitor, and serve as treatment targets for PPCM patients.
• PIGF may be useful in the diagnosis of PPCM because of its relatively low levels in pre-eclampsia and high levels PPCM.
• The marked long-term persistence of CD in women with PPCM suggests potential ongoing damage that could serve as a starting point for interventions both in the acute phase of PPCM and in patients with persistent heart failure.
• Limitations of this study include a small patient population, confounding risk factors, retrospective analysis, and lack of serologic, imaging, and exercise tolerance data prior to pregnancy.
• Larger trials will be required to investigate these biomarkers at baseline, throughout pregnancy, and in the postpartum period in women with and without PPCM to better understand the diagnosis, treatment, and prognosis of this disease. Future prospective studies will also be needed to establish causality between these biomarker levels and cardiac function parameters to elucidate targets for therapies. 

References

1. Ersbøll AS, Goetze JP, Johansen M, et al. Biomarkers and their relation to cardiac function late after peripartum cardiomyopathy. J Card Fail 2021;27:168-75.
2. Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U. Peripartum cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:207-21.
3. McNamara DM, Elkayam U, Alharethi R, et al. Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC Study (Investigations of Pregnancy-Associated Cardiomyopathy). J Am Coll Cardiol 2015;66:905–14.
4. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589–600.
5. Damp J, Givertz MM, Semigran M, et al. Relaxin-2 and soluble Flt1 levels in peripartum cardiomyopathy: results of the multicenter IPAC study. JACC Heart Fail 2016;4:380–8.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Magnetic Resonance Imaging

Keywords: Dyslipidemias, Cathepsin D, Vascular Endothelial Growth Factor A, Exercise Test, Pre-Eclampsia, Vascular Endothelial Growth Factor Receptor-1, Body Mass Index, Prolactin, Cardiac Volume, Peripartum Period, Angiogenesis Inducing Agents, Follow-Up Studies, Exercise Tolerance, Cardiomyopathies, Heart Failure, Magnetic Resonance Imaging, Biomarkers, Oxygen Consumption

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