Prevalence of HSPB6 gene variants in peripartum cardiomyopathy: Data from the German PPCM registry.

BACKGROUND: Heat shock protein family B (small) member 6 (HSPB6) mediates cardioprotective effects against stress-induced injury. In humans two gene variants of HSPB6 have been identified with a prevalence of 1% in patients with dilated cardiomyopathy (DCM). Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease of unknown etiology in previously healthy women of whom 16-20% of PPCM carry gene variants associated with cardiomyopathy. This study was designed to analyze the prevalence of pathogenic HSPB6 gene variants in PPCM. METHODS AND RESULTS: Whole-exome sequencing was performed in whole blood samples of PPCM patients (n = 65 PPCM patients from the German PPCM registry) and screened subsequently for HSPB6 gene variants. In this PPCM cohort one PPCM patient carries a HSPB6 gene variant of uncertain significance (VUS), which was not associated with changes in the amino acid sequence and no likely pathogenic or pathogenic variants were detected. CONCLUSION: HSPB6 gene variants did not occur more frequently in a cohort of PPCM patients from the German PPCM registry, compared to DCM patients. Genetic analyses in larger cohorts and in cohorts of different ethiologies of PPCM patients are needed to address the role of the genetic background in the pathogenesis of PPCM.

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.

Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy.

AIMS: Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart-healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16 kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)-146a-dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. METHODS AND RESULTS: Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (αMHC-Cretg/+ ; Stat3fl/fl ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5 mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum-matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5 ± 9.4% vs. CKO: 22.1 ± 9%, P < 0.05] and prevented the development of cardiac hypertrophy, fibrosis, and inflammation as effective as bromocriptine therapy (FS: CKO Br: 33.4 ± 5.6%). The myocardial up-regulation of the PPCM biomarkers plasminogen inhibitor activator 1 (PAI-1) and miR-146a were prevented by both cabergoline and bromocriptine therapy. A small cohort of three PPCM patients from the German PPCM Registry was treated with cabergoline (1 mg per week for 2 weeks, followed by 0.5 mg per week for another 6 weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26 ± 2%). However, at 6 months of follow-up, LV function (LVEF: 56 ± 2%) fully recovered in all three PPCM patients, and no adverse events were detected. CONCLUSIONS: In the experimental PPCM mouse model, the selective D2R agonist cabergoline prevents the onset of postpartum HF similar to bromocriptine. In PPCM patients, cabergoline treatment was safe and effective as all patients fully recovered. Cabergoline might serve as a promising alternative to bromocriptine. However, these findings are based on experimental data and a small case series and thus have to be interpreted with caution and should be validated in a larger clinical trial.

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.

Acute echocardiographic and electrocardiographic effects of triggered left ventricular pacing.

Cardiac resynchronization therapy (CRT) is an essential pillar in the therapy of heart failure patients with reduced ejection fraction (HFrEF) presenting with broad left bundle branch block (LBBB) or pacemaker dependency. To achieve beneficial effects, CRT requires high bi-ventricular (BiV) pacing rates. Therefore, device-manufacturers designed pacing algorithms which maintain high BiV pacing rates by a left ventricular (LV) pacing stimulus immediately following a right ventricular sensed beat. However, data on clinical impact of these algorithms are sparse. We studied 17 patients implanted with a CRT device providing triggered left ventricular pacing (tLVp) in case of atrioventricular nodal conduction. Assessment of LV dyssynchrony was performed using echocardiographic and electrocardiographic examination while CRT-devices were set to three different settings: 1. Optimized bi-ventricular-stimulation (BiV); 2. Physiological AV nodal conduction (tLVp-off); 3. Physiological AV nodal conduction and tLVp-algorithm turned on (tLVp-on). QRS duration increased when the CRT-device was set to tLVp-off compared to BiV-Stim, while QRS duration was comparable to BiV-Stim with the tLVp-on setting. Echocardiographic analysis revealed higher dyssynchrony during tLVp-off compared to BiV-Stim. TLVp-on did not improve LV dyssynchrony compared to tLVp-off. QRS duration significantly decreased using tLVp-algorithms compared to physiological AV nodal conduction. However, echocardiographic examination could not show functional benefit from tLVp-algorithms, suggesting that these algorithms are inferior to regular biventricular pacing regarding cardiac resynchronization. Therefore, medical treatment and ablation procedures should be preferred, when biventricular pacing rates have to be increased. TLVp-algorithms can be used in addition to these treatment options.

[Peripartum Cardiomyopathy]. / Peripartale Kardiomyopathie.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening heart disease, with onset in the last month of pregnancy or in the first months after delivery in previously heart-healthy women. PPCM patients typically present with heart failure due to left ventricular (LV) dysfunction with an LV ejection fraction (EF) < 45 %. In the last years clinical and experimental studies contributed to a better understanding of the pathophysiology and the clinical course of PPCM. In the context of oxidative stress, the nursing hormone prolactin is cleaved into a smaller antiangiogenic and proapoptotic 16k Da form, leading to myocardial dysfunction. In an animal model this can be prevented by treatment with the dopamine agonist bromocriptine, which suppresses prolactin release. This therapeutic approach was confirmed in several clinical studies. Therefore, the current guidelines recommend a treatment consisting of a heart failure treatment according to current guidelines in combination with the dopamine agonist bromocriptine. If the diagnosis is made early and the treatment is started immediately, the prognosis is good compared to other forms of cardiomyopathies, as LV function recovers in most cases.In the acute phase the severity of heart failure differs among PPCM patients. Some patients present with mild forms, whereas some PPCM patients display severely reduced LV function and cardiogenic shock. Especially the latter cases are still challenging, as treatment with ß1-adrenergic receptor agonists is associated with progression of heart failure and a worse cardiac outcome. Therefore, patients with cardiogenic shock complicating PPCM should be treated in centers experienced in mechanical circulatory support in combination with bromocriptine treatment.

Echocardiographic Parameters to Predict Atrial Fibrillation in Clinical Routine-The EAHsy-AF Risk Score.

Background: Echocardiographic parameters representing impaired left atrial (LA) function and remodeling are of high value to predict atrial fibrillation (AF). This study aimed to develop a prediction model for AF easily to apply in clinical routine containing echocardiographic parameters associated with LA remodeling and-function. Methods and Results: This monocentric, semi-blinded, controlled analysis included 235 patients to derive a prediction model. This prediction model was tested in a validation cohort encompassing 290 cardiovascular inpatients. The derivation and validation cohort included 54 (23%) and 66 (23%) patients with AF, respectively. Transthoracic echocardiography, comprising parameters indicating left atrial remodeling [septal/lateral total atrial conduction time (s/l PA-TDI)] and left atrial volume indexed to a' (LAVI/a') was performed in each patient. Based on multivariable regressions analysis, four variables were enclosed into the EAHsy (Echocardiography, Age, Hypertension)-AF risk score for AF prediction: Hypertension, Age, LAVI/a' and septal PA-TDI. In the validation cohort discrimination was strong (C-statistic 0.987, 95%CI 0.974-0.991) with an adequately performed calibration. The EAHsy-AF risk score was associated with a more precise prediction of AF in comparison to commonly used AF-scores (CHADS2-, ATLAS-, ARIC-, CHARGE-AF score). Conclusion: The EAHsy-AF-Score containing age, hypertension and echocardiographic parameters of atrial dysfunction and remodeling precisely predicts the incidence of AF in a general population of patients with cardiovascular disease. The EAHsy-AF risk score may enable more selective rhythm monitoring in specific patients at high risk for AF.

Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease.

The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.

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.

ECG and arrhythmias in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare but life-threatening heart disease, with onset in the last month of pregnancy or in the first months after delivery. Extensive studies on the burden of supraventricular and ventricular arrhythmias are lacking. Patients with PPCM present with electrocardiographic findings typical in acute heart failure. Management of arrhythmias in PPCM depends on the severity and the onset (during pregnancy or after delivery). Studies on the use of the wearable cardioverter-defibrillator in patients with PPCM show a substantial burden of ventricular tachyarrhythmias and sudden death in patients with severely reduced left ventricular function. The aim of the present article is to summarize actual knowledge on electrocardiogram findings, arrhythmias, and sudden cardiac death in patients with PPCM.

Assessment of major mental disorders in a German peripartum cardiomyopathy cohort.

AIMS: Peripartum cardiomyopathy (PPCM) is a heart disease affecting women during the last month of pregnancy or in the first months after delivery. The impact of the disease on mental health is largely unknown. METHODS AND RESULTS: Major mental disorders were assessed by a structured clinical interview in 40 patients with a confirmed PPCM diagnosis, and the data were compared with published prevalence in postpartum women. Circulating biomarkers associated with mental health, such as kynurenine, serotonin, and microRNA (miR)-30e, were evaluated in PPCM and compared with matched healthy pregnancy-matched postpartum controls (PP-Ctrl). Major mental disorders were diagnosed in 65% (26/40) of the PPCM cohort. The prevalence for major depressive disorders was 4-fold, for post-traumatic stress disorder 14-fold, and for panic disorder 6-fold higher in PPCM patients compared with postpartum women without a PPCM diagnosis. Compared with PP-Ctrl, PPCM patients displayed elevated levels of serum kynurenine (P < 0.01), reduced levels of serum serotonin (P < 0.05), and elevated levels of plasma miR-30e (P < 0.05). CONCLUSIONS: The majority of PPCM patients in the present cohort displayed mental disorders with a higher prevalence of major depressive disorders, post-traumatic stress disorder (PTBS), and panic disorder, compared with postpartum women without a PPCM diagnosis. This higher prevalence was associated with an impaired tryptophan metabolism and elevated levels of the depression-associated miR-30e, suggesting a potential predisposition for mental disorders at the time of PPCM diagnosis. Consequently, physicians should be aware of the increased risk for mental disorders in PPCM patients, and psychiatric assessment should be included in the diagnosis and management of PPCM patients.

Autophagy alleviates amiodarone-induced hepatotoxicity.

Amiodarone is a widely used antiarrhythmic drug that can cause the development of steatohepatitis as well as liver fibrosis and cirrhosis. The molecular mechanisms of amiodarone-mediated liver injury remain largely unknown. We therefore analyzed amiodarone-mediated hepatocellular injury in patients with chronic heart failure, in primary hepatocytes and HepG2 cells. We found that amiodarone-treated patients with chronic heart failure revealed significantly higher serum levels of caspase-cleaved keratin-18, an apoptosis biomarker, compared to healthy individuals or patients not receiving amiodarone. Furthermore, amiodarone treatment of hepatocytes resulted in apoptosis associated with lipid accumulation and ER-stress induction. Liver cell steatosis was accompanied by enhanced de novo lipogenesis which, after reaching peak levels, declined together with decreased activation of ER stress. The decline of amiodarone-mediated lipotoxicity was associated with protective autophagy induction. In contrast, in hepatocytes treated with the autophagy inhibitor chloroquine as well as in autophagy gene (ATG5 or ATG7)-deficient hepatocytes, amiodarone-triggered toxicity was increased. In conclusion, we demonstrate that amiodarone induces lipid accumulation associated with ER stress and apoptosis in hepatocytes, which is mirrored by increased keratin-18 fragment serum levels in amiodarone-treated patients. Autophagy reduces amiodarone-mediated lipotoxicity and could provide a therapeutic strategy for protection from drug-induced liver injury.

Common genetic predisposition for heart failure and cancer.

Cardiovascular diseases and cancer are major causes of mortality in industrialized societies. They share common risk factors (e.g., genetics, lifestyle, age, infection, toxins, and pollution) and might also mutually promote the onset of the respective other disease. Cancer can affect cardiac function directly while antitumor therapies may have acute- and/or late-onset cardiotoxic effects. Recent studies suggest that heart failure might promote tumorigenesis and tumor progression. In both cancer and cardiovascular diseases, genetic predisposition is implicated in the disease onset and development. In this regard, genetic variants classically associated with cardiomyopathies increase the risk for toxic side effects on the cardiovascular system. Genetic variants associated with increased cancer risk are frequent in patients with peripartum cardiomyopathy complicated by cancer, pointing to a common genetic predisposition for both diseases. Common risk factors, cardiotoxic antitumor treatment, genetic variants (associated with cardiomyopathies and/or cancer), and increased cardiac stress lead us to propose the "multi-hit hypothesis" linking cancer and cardiovascular diseases. In the present review, we summarize the current knowledge on potential connecting factors between cancer and cardiovascular diseases with a major focus on the role of genetic predisposition and its implication for individual therapeutic strategies and risk assessment in the novel field of oncocardiology.

Mechanical circulatory support in refractory cardiogenic shock due to influenza virus-related myocarditis.

BACKGROUND: There is scarce evidence for mechanical circulatory support (MCS) in patients with influenza-related myocarditis complicated by refractory cardiogenic shock (rCS). We sought to investigate the impact of MCS using combined veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and micro-axial flow pumps (the ECMELLA concept) in influenza-related myocarditis complicated by rCS. METHODS: This is a prospective, observational analysis from the single centre HAnnover Cardiac Unloading REgistry (HACURE) from two recent epidemic influenza seasons. We analysed patients with verified influenza-associated myocarditis complicated by rCS who were admitted to our intensive care unit (ICU) on MCS. Subsequently, we performed a propensity score (PS) matched analysis to patients with acute myocardial infarction (AMI) complicated by rCS and non-ischaemic cardiomyopathy (DCM) related rCS. RESULTS: We describe a series of seven patients with rCS-complicated influenza-related myocarditis (mean age 56±10 years, 58% male, influenza A (n=2)/influenza B (n=5)). No patient had been vaccinated prior to the influenza season. MCS was provided using combined VA-ECMO and Impella micro-axial flow pump. In two patients with out-of-hospital cardiac arrest, VA-ECMO had been implanted for extracorporeal cardiopulmonary resuscitation. All patients died within 18 days of hospital admission. By PS-based comparison to patients with AMI- or DCM-related rCS and combined MCS, 30-day mortality was significantly higher in influenza-related rCS. CONCLUSION: Despite initial stabilisation with combined MCS in patients with rCS-complicated influenza-related myocarditis, the detrimental course of shock could not be stopped and all patients died. Influenza virus infection potentially critically affects other organs besides the heart, leading to irreversible end-organ damage that MCS cannot compensate for and, therefore, results in a devastating outcome.

miR-21 and NT-proBNP Correlate with Echocardiographic Parameters of Atrial Dysfunction and Predict Atrial Fibrillation.

This study aimed to investigate the association of circulating biomarkers with echocardiographic parameters of atrial remodelling and their potential for predicting atrial fibrillation (AF). In patients with and without AF (n = 21 and n = 60) the following serum biomarkers were determined: soluble ST2 (sST2), Galectin-3 (Gal-3), N-terminal pro-brain natriuretic peptide (NT-proBNP), microRNA (miR)-21, -29a, -133a, -146b and -328. Comprehensive transthoracic echocardiography was performed in all participants. Biomarkers were significantly altered in patients with AF. The echocardiographic parameter septal PA-TDI, indicating left atrial (LA) remodelling, correlated with concentrations of sST2 (r = 0.249, p = 0.048), miR-21 (r = -0.277, p = 0.012), miR-29a (r = -0.269, p = 0.015), miR-146b (r = -0.319, p = 0.004) and miR-328 (r = -0.296, p = 0.008). In particular, NT-proBNP showed a strong correlation with echocardiographic markers of LA remodelling and dysfunction (septal PA-TDI: r = 0.444, p < 0.001, LAVI/a': r = 0.457, p = 0.001, SRa: r = 0.581, p < 0.001). Multivariate Cox regressions analysis highlighted miR-21 and NT-proBNP as predictive markers for AF (miR-21: hazard ratio (HR) 0.16; 95% confidence interval (CI) 0.04-0.7, p = 0.009; NT-proBNP: HR 1.002 95%CI 1.001-1.004, p = 0.006). Combination of NT-proBNP and miR-21 had the best accuracy to discriminate patients with AF from those without AF (area under the curve (AUC)= 0.843). Our findings indicate that miR-21 and NT-proBNP correlate with echocardiographic parameters of atrial remodeling and predict AF, in particular if combined.

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.

Peripartum cardiomyopathy: basic mechanisms and hope for new therapies.

Peripartum cardiomyopathy (PPCM) is a life-threatening cardiomyopathy characterized by acute or slow progression of left ventricular (LV) systolic dysfunction (LV ejection fraction of <45%) late in pregnancy, during delivery, or in the first postpartum months, in women with no other identifiable causes of heart failure. PPCM patients display variable phenotypes and risk factor profiles, pointing to involvement of multiple mechanisms in the pathogenesis of the disease. The higher risk for PPCM in women with African ancestry, the prevalence of gene variants associated with cardiomyopathies, and the high variability in onset and disease progression in PPCM patients also indicate multiple mechanisms at work. Experimental data have shown that different factors can induce and drive PPCM, including inflammation and immunity, pregnancy hormone impairment, catecholamine stress, defective cAMP-PKA, and G-protein-coupled-receptor signalling, and genetic variants. However, several of these mechanisms may merge into a common major pathway, which includes unbalanced oxidative stress and the cleavage of the nursing hormone prolactin (PRL) into an angiostatic, pro-apoptotic, and pro-inflammatory 16 kDa-PRL fragment, resulting in subsequent vascular damage and heart failure. Based on this common pathway, potential disease-specific biomarkers and therapies have emerged. Despite commonalities, the variation in aetiology and mechanisms poses challenges for the diagnosis, treatment, and management of the disease. This review summarizes current knowledge on the clinical presentation of PPCM in the context of recent experimental research. It discusses the challenge to develop disease-specific biomarkers in the context of rapid changing physiology in the peripartum phase, and outlines possible future treatment and management strategies for 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-κB-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-1ß 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-κB 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-κB/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-κB-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.