High prevalence of reduced fertility and use of assisted reproductive technology in a German cohort of patients with peripartum cardiomyopathy.

BACKGROUND: Over the past decades the use of assisted reproduction technology (ART) increased worldwide. ARTs are associated with an elevated risk for cardiovascular complications. However, a potential relation between subfertility/ARTs and the heart disease peripartum cardiomyopathy (PPCM) has not been systematically analyzed yet. METHODS: A retrospective cohort study was carried out, including n = 111 PPCM patients from the German PPCM registry. Data from PPCM patients were compared to those from postpartum women in the German general population. RESULTS: The prevalence of reported subfertility was high among PPCM patients (30%; 33/111). Most of the subfertile PPCM patients (55%; 18/33) obtained vitro fertilizations (IVF) or intracytoplasmic sperm injections (ICSI). PPCM patients were older (p < 0.0001), the percentage of born infants conceived by IVF/ICSI was higher (p < 0.0001) with a higher multiple birth (p < 0.0001), C-section (p < 0.0001) and preeclampsia rate (p < 0.0001), compared to postpartum women. The cardiac outcome was comparable between subfertile and fertile PPCM patients. Whole exome sequencing in a subset of n = 15 subfertile PPCM patients revealed that 33% (5/15) carried pathogenic or likely pathogenic gene variants associated with cardiomyopathies and/or cancer predisposition syndrome. CONCLUSIONS: Subfertility occurred frequently among PPCM patients and was associated with increased age, hormonal disorders, higher twin pregnancy rate and high prevalence of pathogenic gene variants suggesting a causal relationship between subfertility and PPCM. Although this study found no evidence that the ART treatment per se increases the risk for PPCM or the risk for an adverse outcome, women with subfertility should be closely monitored for signs of peripartum heart failure.

Clinical characteristics and long-term outcomes in patients with peripartum cardiomyopathy (PPCM) receiving left ventricular assist devices (LVAD).

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure (HF), presenting with left ventricular (LV) systolic dysfunction either at the end of pregnancy or in the months following delivery. In rare cases, PPCM leads to severe impairment of LV function, refractory cardiogenic shock or advanced HF. LV assist devices (LVAD) have been shown to be a feasible treatment option in advanced HF. However, little is known about long-term outcomes and prognosis of PPCM patients undergoing LVAD implantation. METHODS: A retrospective analysis of data from PPCM patients undergoing LVAD implantation in two tertiary centers with respect to long-term outcomes was performed. RESULTS: Twelve patients of median age 30 (18-39) years were included. Eight patients were experiencing cardiogenic shock (INTERMACS 1) at implantation. Seven patients were implanted within 1 month of their PPCM diagnosis. Median duration of LVAD support was 19 (2-92) months with median follow up of 67 (18-136) months (100% complete). In-hospital and 1-year mortality were 0% and 8.3%, respectively. Two patients died on LVAD support, four patients were successfully bridged to transplantation, two patients are still on LVAD, and four were successfully weaned due to sufficient LV recovery (one died after LV function deteriorated again). CONCLUSION: LVAD treatment of decompensated end-stage PPCM is feasible. Early LVAD provision led to hemodynamic stabilization in our cohort and facilitated safe LV recovery in one third of these young female patients.

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.

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.

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.

Bromocriptine treatment in patients with peripartum cardiomyopathy and right ventricular dysfunction.

BACKGROUND: Right ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement. METHODS: In this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF < 45%). We examined the effect of short-term (1W: bromocriptine, 2.5 mg, 7 days, n = 10) compared with long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for another 6 weeks, n = 14) in addition to guideline-based heart failure therapy in patients with an initial RVEF < 45% on the following outcomes: (1) change from baseline (Δ delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF ≥ 50%) and (4) rate of patients with full RV recovery (RVEF ≥ 55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging. RESULTS: Reduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up (patients with RV dysfunction: 58% vs. patients with normal RV function: 81%; p = 0.027). RVEF increased from 38 ± 7 to 53 ± 11% with a delta-RVEF of + 15 ± 12% in the 1W group, and from 35 ± 9 to 58 ± 7% with a Δ RVEF of + 23 ± 10% in the 8W group (Δ RVEF 1W vs 8W: p = 0.118). LVEF increased from 25 ± 8 to 46 ± 12% with a Δ LVEF of + 21 ± 11% in the 1W group, and from 22 ± 6 to 49 ± 10% with a Δ LVEF of + 27 ± 9% in the 8W group (Δ LVEF 1W vs 8W: p = 0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p = 0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p = 0.092). CONCLUSIONS: Despite overall worse outcome in patients with RV dysfunction at baseline, bromocriptine treatment in PPCM patients with RV involvement was associated with a high rate of full RV and LV recovery, although no significant differences were observed between the short-term and long-term bromocriptine treatment regime. These findings suggest that bromocriptine in addition to standard heart failure therapy may be also effective in PPCM patients with biventricular impairment.