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.

Perhexiline treatment improves toxic effects of ß-adrenergic receptor stimulation in experimental peripartum cardiomyopathy.

AIMS: Peripartum cardiomyopathy (PPCM) is a pregnancy-associated cardiomyopathy that occurs in previously heart-healthy women towards the end of pregnancy or in the first months after delivery and is characterized by heart failure due to systolic dysfunction. The clinical course of PPCM differs between mild symptoms and severe forms with acute heart failure complicated by cardiogenic shock (CS). Treatment of CS complicating PPCM is challenging, as ß-adrenergic receptor (ß-AR) stimulation seems to be associated with progression of heart failure and adverse outcome. This experimental study aims to examine whether postpartum treatment with the glucose uptake-promoting drug perhexiline alone or as co-treatment with ß-AR stimulation prevents heart failure in the experimental PPCM mouse model. METHODS AND RESULTS: Postpartum (PP) female PPCM-prone mice with a cardiomyocyte-restricted STAT3-deficiency (αMHC-Cretg/+ ;Stat3fl/fl ; CKO) were treated with perhexiline over two to three pregnancies and nursing periods (2/3PP) or were co-treated with perhexiline after one pregnancy (1PP) under chronic ß-AR stimulation using isoproterenol (Iso) infusion. Perhexiline was not able to prevent onset of PPCM in CKO mice (FS: CKO Pexsig-2/3PP: 25 ± 12% vs. CKO Ctrl-2/3PP: 24 ± 9%, n.s.) but attenuated worsening of left ventricular function in response to treatment with the ß-AR agonist Iso (FS: CKO Pexsig-Iso-1PP: 19 ± 4% vs. CKO Ctrl-Iso-1PP: 11 ± 5%, P < 0.05). CONCLUSIONS: Treatment of PPCM patients with ß-AR agonists should be avoided whenever possible. In cases with CS complicating PPCM, when treatment with ß-AR agonists cannot be prevented, co-medication with perhexiline might help to reduce the cardiotoxic side effects of ß-AR stimulation. Clinical data are necessary to further validate this therapeutic approach.

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.