Increased cancer prevalence in peripartum cardiomyopathy

Objectives This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM). Background PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease. Methods Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer. Results The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes. Conclusions Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response–related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients

In peripartum cardiomyopathy plasminogen activator inhibitor-1 is a potential new biomarker with controversial roles

Aims Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-kappa B-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. Methods and results In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 +/- 10 ng/mL), but significantly elevated (64 +/- 38 ng/mL, P <0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23 +/- 8%). At 6-month follow-up (n = 23), PAI-1 levels decreased (36 +/- 14 ng/mL, P <0.01 vs. BL) and LVEF (49 +/- 11%) improved. Increased N-terminal pro-brain natriuretic peptide and Troponin T did not correlate with PAI-1. C-reactive protein, interleukin (IL)-6 and IL-1 beta did not differ between PPCM patients and PP-Ctrl. MiR-146a was 3.6-fold (P <0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16 kDa-PRL coprecipitated with PAI-1, which was associated with higher (P <0.05) uPAR-mediated NF-kappa B activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (P <0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wild-type controls, whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality. Conclusion In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-kappa B/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-kappa B-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised

Extending the performance of FcRn and FcγRIIIa affinity liquid chromatography for protein biopharmaceuticals

Affinity liquid chromatography using FcRn and FcγRIIIa columns can provide important information on the drug effector functions and the unique PK/PD properties of therapeutic mAbs. In this study, we propose a unique strategy to improve the performance of affinity chromatography by applying pH-gradient programs that incorporate multi-isocratic and negative gradient segments. These alternative gradient programs are known to greatly improve the separation of large solutes that follow a “bind-and-elute” type retention behavior. First, judicious optimization of the mobile phase compositions was performed to obtain a linear pH response. Then, with the developed strategy using multi-isocratic analysis conditions, the FcRn affinity separation selectivity for the analysis of oxidized mAb species was greatly improved. Furthermore, the introduction of negative gradient segments after each eluted peak improved the resolution between multiple glycosylated mAb species on the FcγRIIIa column. Therefore, this work provides a new strategy to improve the performance of affinity chromatography with mAb species, and could assist in the development of more accurate binding assays for important critical quality attributes related to FcRn and FcγRIIIa binding.</p

Long-term follow-up in peripartum cardiomyopathy patients with contemporary treatment: low mortality, high cardiac recovery, but significant cardiovascular co-morbidities

Aims Peripartum cardiomyopathy (PPCM) establishes late in pregnancy or in the first postpartum months. Many patients recover well within the first year, but long-term outcome studies on morbidity and mortality are rare. Here, we present 5-year follow-up data of a German PPCM cohort. Methods and results Five-year follow-up data were available for 66 PPCM patients (mean age 34 +/- 5 years) with a mean left ventricular ejection fraction (LVEF) of 26 +/- 9% at diagnosis. Ninety-eight percent initially received standard heart failure therapy (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and/or mineralocorticoid receptor antagonists), and 86% were additionally treated with dopamine D2 receptor agonists (mainly bromocriptine) and anticoagulation. After 1 year, mean LVEF had improved to 50 +/- 11% (n = 48) and further increased to 54 +/- 7% at 5-year follow-up with 72% of patients having achieved full cardiac recovery (LVEF >50%). At 5-year follow-up, only three patients (5%) displayed no recovery, of whom one had died. However, 20% had arterial hypertension and 17% arrhythmias, including paroxysmal supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation. Moreover, 70% were still on at least one heart failure drug. Subsequent pregnancy occurred in 16 patients with two abortions and 14 uneventful pregnancies. Mean LVEF was 55 +/- 7% at 5-year follow-up in these patients. Conclusion Our PPCM collective treated with standard therapy for heart failure, dopamine D2 receptor agonists, and anticoagulation displays a high and stable long-term recovery rate with low mortality at 5-year follow-up. However, long-term use of cardiovascular medication, persisting or de novo hypertension and arrhythmias were frequent

Outcome in German and South African peripartum cardiomyopathy cohorts associates with medical therapy and fibrosis markers

Aims This study aims to compare the clinical course of peripartum cardiomyopathy (PPCM) cohorts from Germany (G‐PPCM) and South Africa (SA‐PPCM) with fibrosis‐related markers to get insights into novel pathomechanisms of PPCM. Methods and results G‐PPCM (n = 79) and SA‐PPCM (n = 72) patients and healthy pregnancy‐matched women from Germany (n = 56) and South Africa (n = 40) were enrolled. Circulating levels of procollagen type‐I (PINP) and type‐III (PIIINP) N‐terminal propeptides, soluble ST2, galectin‐3, and full‐length and cleaved osteopontin (OPN) were measured at diagnosis (baseline) and 6 months of follow‐up. Both cohorts received standard heart failure therapy while anticoagulation therapy was applied in 100% of G‐PPCM but only in 7% of SA‐PPCM patients. In G‐PPCM patients, baseline left ventricular ejection fraction (LVEF) was lower, and outcome was better (baseline LVEF, 24 ± 8%, full recovery: 52%, mortality: 0%) compared with SA‐PPCM patients (baseline LVEF: 30 ± 9%, full recovery: 32%, mortality: 11%; P < 0.05). At baseline, PINP/PIIINP ratio was lower in SA‐PPCM and higher in G‐PPCM compared with respective controls, whereas total OPN was elevated in both collectives. Cleaved OPN, which increases PIIINP levels, is generated by thrombin and was reduced in patients receiving anticoagulation therapy. High baseline galectin‐3, soluble ST2, and OPN levels were associated with poor outcome in all PPCM patients. Conclusions SA‐PPCM patients displayed a more profibrotic biomarker profile, which was associated with a less favourable outcome despite better cardiac function at baseline, compared with G‐PPCM patients. Use of bromocriptine and anticoagulation therapy in G‐PPCM may counteract fibrosis and may in part be responsible for their better outcome