Publications by authors named "Denise Hilfiker-Kleiner"

196 Publications

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

PLoS One 2021 4;16(8):e0255335. Epub 2021 Aug 4.

Department of Cardiology and Angiology, Hannover Medical School, Hanover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255335PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336874PMC
August 2021

Peripartum cardiomyopathy: from genetics to management.

Eur Heart J 2021 08;42(32):3094-3102

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Peripartum cardiomyopathy (PPCM) is a disease that occurs globally in all ethnic groups and should be suspected in any peripartum women presenting with symptoms and signs of heart failure, towards the end of pregnancy or in the months following delivery, with confirmed left ventricular dysfunction. After good history taking, all women should be thoroughly assessed, and alternative causes should be excluded. Urgent cardiac investigations with electrocardiogram and natriuretic peptide measurement (if available) should be performed. Echocardiography follows as the next step in investigation. Patients with abnormal cardiac investigations should be urgently referred to a cardiology team for expert management. Referral for genetic work-up should be considered if there is a family history of cardiomyopathy or sudden death. PPCM is a disease with substantial maternal and neonatal morbidity and mortality. Maternal mortality rates range widely, from 0% to 30%, depending on the ethnic background and geographic region. Just under half of women experience myocardial recovery. Remarkable advances in the comprehension of the pathogenesis and in patient management and therapy have been achieved, largely due to team efforts and close collaboration between basic scientists, cardiologists, intensive care specialists, and obstetricians. This review summarizes current knowledge of PPCM genetics, pathophysiology, diagnostic approach, management, and outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab458DOI Listing
August 2021

ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.

Circ Heart Fail 2021 07 12;14(7):e006898. Epub 2021 Jul 12.

Department of Pharmaceutical, Biomedical and Veterinary Sciences, Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium (E.F., J.V.f., Z.V., L.D., T.B., V.F.M.S., G.W.D.K.).

Background: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene is a common driving factor of PPCM.

Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific mice (, n=9) with their age-matched nonpregnant CTRLs (n=9-10).

Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; <0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; <0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, <0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, =0.07; -27±20%, <0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, <0.05) but without signs of myocardial apoptosis and inflammation.

Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006898DOI Listing
July 2021

Telemonitoring-Supported Exercise Training in Employees With Metabolic Syndrome Improves Liver Inflammation and Fibrosis.

Clin Transl Gastroenterol 2021 06 18;12(6):e00371. Epub 2021 Jun 18.

Institute of Sports Medicine, Hannover Medical School, Hannover, Germany.

Introduction: Metabolic syndrome (MetS) is a major health problem worldwide and the main risk factor for metabolic-associated fatty liver disease (MAFLD). Established treatment options are lifestyle interventions facilitating dietary change and increased physical activity. Here, we tested the effect of a telemonitoring-supported intervention on liver parameter of inflammation and fibrosis in individuals with MetS.

Methods: This was a prospective, randomized, parallel-group, and assessor-blind study performed in workers of the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed MetS were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on supervised, activity-tracker-guided exercise or to a waiting-list control group. This secondary analysis assessed the effect of the intervention on liver enzymes and MAFLD-related parameters.

Results: We screened 543 individuals between October 10, 2017, and February 27, 2018, of whom 314 were randomly assigned to the intervention group (n = 160) or control group (n = 154). Liver transaminases, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased after 6 months in the intervention group compared with the CG. Furthermore, an aspartate aminotransferase-to-platelet ratio index score as a marker for liver fibrosis significantly decreased in the intervention group. These improvements were associated with changes in obesity and exercise capacity.

Discussion: A 6-month lifestyle intervention based on exercise training with individualized telemonitoring-based supervision led to improvements of liver inflammation and fibrosis in employees with MetS. Therefore, this intervention shows therapeutic potential for individuals at high risk of MAFLD (ClinicalTrials.gov Identifier: NCT03293264).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ctg.0000000000000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216678PMC
June 2021

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

ESC Heart Fail 2021 08 17;8(4):3375-3381. Epub 2021 May 17.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

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 β-adrenergic receptor (β-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 β-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-Cre ;Stat3 ; 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 β-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 β-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 β-AR agonists should be avoided whenever possible. In cases with CS complicating PPCM, when treatment with β-AR agonists cannot be prevented, co-medication with perhexiline might help to reduce the cardiotoxic side effects of β-AR stimulation. Clinical data are necessary to further validate this therapeutic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318439PMC
August 2021

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

Circulation 2021 May 20;143(19):1852-1862. Epub 2021 Apr 20.

University of Pittsburgh Medical Center, PA (D.M.M.).

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM.

Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated.

Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected [*]=1.2×10). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, *=7.0×10), DSP (odds ratio=14.9, *=1.0×10), and BAG3 (odds ratio=53.1, *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, =2.5×10), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery.

Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113098PMC
May 2021

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Eur J Heart Fail 2021 04 17;23(4):527-540. Epub 2021 Mar 17.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.2133DOI Listing
April 2021

[Cardiology: overcome boundaries, discover new worlds].

Herz 2021 Mar 29;46(2):105-106. Epub 2021 Jan 29.

Klinik für Innere Medizin/Kardiologie, Herzzentrum Leipzig - Universität Leipzig, Strümpellstr. 39, 04289, Leipzig, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00059-021-05026-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844774PMC
March 2021

Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL.

Blood 2021 05;137(19):2657-2661

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation.

Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008544DOI Listing
May 2021

[Cardiovascular diseases and COVID-19 : Pathophysiology, complications and treatment].

Herz 2021 Mar 4;46(2):107-114. Epub 2021 Jan 4.

Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

The coronavirus disease 2019 (COVID-19) pandemic is a challenge for our healthcare system but at the same time is one of the excellent catalyzers and promoters of successful translational research. The COVID-19 is not only a simple viral infection of the bronchial system but is also a pandemic hyperinflammatory multiorgan disease. The cardiovascular system plays a causal role in this context, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades host cells via the angiotensin-converting enzyme 2 (ACE-2), an enzyme in the renin-angiotensin system. Furthermore, cardiovascular comorbidities and risk factors, such as hypertension, diabetes and obesity play an important role in the severity of the course of the disease. Additional risk factors, such as gender, age, genetics and air pollution modulate both the severity of the SARS-CoV‑2 infection as well as cardiovascular diseases. As sequelae of COVID-19, increased thrombosis, myocardial infarction, myocardial inflammation and vasculitis occur, which directly damage the cardiovascular system and substantially contribute to the high morbidity and mortality. Knowledge gained from many studies on the course of the disease in patients infected with SARS-CoV‑2 has led to improved treatment possibilities, which now in the second wave are partly standardized and were, and are, in particular adapted to complications of the cardiovascular system. In this review we provide a short overview on the pathophysiology of the SARS-CoV‑2 in general and also specifically on the cardiovascular system. Furthermore, we summarize the current treatment approaches and their pathophysiological principles (status November 2020).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00059-020-05013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780218PMC
March 2021

Increased prostaglandin-D2 in male STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation.

PLoS Biol 2020 12 28;18(12):e3000739. Epub 2020 Dec 28.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency conditional knockout (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study, isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased prostaglandin D2 (PGD2) secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen receptor (AR)-signaling due to loss of its cofactor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated stem cell antigen-1 (SCA-1)+ cardiac progenitor cells (CPC) from young male CKO-mice compared with the adipocyte differentiation of male wild-type (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with up-regulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared with WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared with male WT-CPC, whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2, thereby up-regulating ZFP423 expression and promoting white adipocyte differentiation. The treatment of young male CKO mice with the COX inhibitor Ibuprofen or the PGD2 receptor (DP)2 receptor antagonist BAY-u 3405 in vivo increased EZH2 expression and reduced ZFP423 expression and adipocyte differentiation in CKO-CPC. Thus, cardiomyocyte STAT3 deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG-degrading enzyme HPGD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.3000739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793290PMC
December 2020

Human iPSC-Derived Cardiomyocytes of Peripartum Patients With Cardiomyopathy Reveal Aberrant Regulation of Lipid Metabolism.

Circulation 2020 12 7;142(23):2288-2291. Epub 2020 Dec 7.

Department of Cardiology (M.F.H., N.B., K.F.A.G., P.v.d.M.), University Medical Center Groningen, University of Groningen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846285PMC
December 2020

Neuraminidase-1 promotes heart failure after ischemia/reperfusion injury by affecting cardiomyocytes and invading monocytes/macrophages.

Basic Res Cardiol 2020 09 25;115(6):62. Epub 2020 Sep 25.

Molecular Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.

Neuraminidase (NEU)1 forms a multienzyme complex with beta-galactosidase (β-GAL) and protective-protein/cathepsin (PPC) A, which cleaves sialic-acids from cell surface glycoconjugates. We investigated the role of NEU1 in the myocardium after ischemia/reperfusion (I/R). Three days after inducing I/R, left ventricles (LV) of male mice (3 months-old) displayed upregulated neuraminidase activity and increased NEU1, β-GAL and PPCA expression. Mice hypomorphic for neu1 (hNEU1) had less neuraminidase activity, fewer pro-inflammatory (LinCD11bF4/80Ly-6C), and more anti-inflammatory macrophages (LinCD11bF4/80Ly-6C) 3 days after I/R, and less LV dysfunction 14 days after I/R. WT mice transplanted with hNEU1-bone marrow (BM) and hNEU1 mice with WT-BM showed significantly better LV function 14 days after I/R compared with WT mice with WT-BM. Mice with a cardiomyocyte-specific NEU1 overexpression displayed no difference in inflammation 3 days after I/R, but showed increased cardiomyocyte hypertrophy, reduced expression and mislocalization of Connexin-43 in gap junctions, and LV dysfunction despite a similar infarct scar size to WT mice 14 days after I/R. The upregulation of NEU1 after I/R contributes to heart failure by promoting inflammation in invading monocytes/macrophages, enhancing cardiomyocyte hypertrophy, and impairing gap junction function, suggesting that systemic NEU1 inhibition may reduce heart failure after I/R.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00395-020-00821-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519006PMC
September 2020

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

ESC Heart Fail 2020 Sep 10. Epub 2020 Sep 10.

Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754901PMC
September 2020

Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry.

Eur Heart J 2020 10;41(39):3787-3797

Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany.

Aims: We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally.

Methods And Results: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P < 0.001). Follow-up was available for 598 (81%) women. Six-month mortality was 6% overall, lowest in Europe (4%), and highest in the Middle East (10%). Most deaths were due to heart failure (42%) or sudden (30%). Re-admission for any reason occurred in 10% (with just over half of these for heart failure) and thromboembolic events in 7%. Myocardial recovery (LVEF > 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%).

Conclusion: Peripartum cardiomyopathy is a global disease, but clinical presentation and outcomes vary by region. Just under half of women experience myocardial recovery. Peripartum cardiomyopathy is a disease with substantial maternal and neonatal morbidity and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846090PMC
October 2020

Employers With Metabolic Syndrome and Increased Depression/Anxiety Severity Profit Most From Structured Exercise Intervention for Work Ability and Quality of Life.

Front Psychiatry 2020 18;11:562. Epub 2020 Jun 18.

Institute of Sports Medicine, Hannover Medical School, Hannover, Germany.

Background: Major depressive disorder and anxiety disorders are associated with less productivity, earlier retirement, and more sick-days at the workplace. These associations also exist for patients with metabolic syndrome. For both, exercise is a generally recommended part of multimodal treatments. However, for individuals with metabolic syndrome, in which depression and anxiety is more prevalent and severe, evidence for the efficacy of exercise interventions is limited.

Methods: Company employees with diagnosed metabolic syndrome (n=314, age: 48 ± 8 yrs) were randomized to a 6-month exercise intervention (150 min per week) or wait-list control. Participants received individual recommendations for exercise activities by personal meetings, telephone, or a smartphone app. Physical activities were supervised and adapted using activity monitor data transferred to a central database. Work ability (work ability index), depression severity and anxiety severity [hospital anxiety and depression scale (HADS)], and health-related quality of live [short form 36 (SF-36)] were assessed.

Results: We included 314 subjects from which 287 finished the intervention. Total work ability, depression- and anxiety severity, and the mental component score of the SF-36 improved after 6 months exercise compared to controls. After baseline stratification for normal (HADS scores 0-7) and increased depression- and anxiety scores (HADS scores 8-21) individuals with increased severity scores had similar age, body composition, blood lipids, and cardiorespiratory fitness compared to those with normal scores, but lower total work ability and component sum scores of health-related quality of life. After 6 months total work ability increased in the exercise group compared to controls with the magnitude of the observed increase being significantly greater for subjects with increased depression- and anxiety severity at baseline compared to those with normal severity scores.

Conclusions: A 6-month exercise intervention for company employees with metabolic syndrome showed strongest effects on self-perceived work ability in individuals with mild to severe depression- and anxiety severity. This suggests exercise programs offered to workers with metabolic syndrome not only reduces individual disease risk but may also reduce healthcare and employers costs arising from metabolic syndrome and mental disease conditions.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03293264.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2020.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314973PMC
June 2020

Common genetic predisposition for heart failure and cancer.

Herz 2020 Nov;45(7):632-636

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00059-020-04953-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581596PMC
November 2020

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology.

Clin Res Cardiol 2020 Oct 13;109(10):1197-1222. Epub 2020 May 13.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

The acute and long-lasting side effects of modern multimodal tumour therapy significantly impair quality of life and survival of patients afflicted with malignancies. The key components of this therapy include radiotherapy, conventional chemotherapy, immunotherapy and targeted therapies. In addition to established tumour therapy strategies, up to 30 new therapies are approved each year with only incompletely characterised side effects. This consensus paper discusses the risk factors that contribute to the development of a potentially adverse reaction to tumour therapy and, in addition, defines specific side effect profiles for different treatment groups. The focus is on novel therapeutics and recommendations for the surveillance and treatment of specific patient groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-020-01636-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515958PMC
October 2020

Effects of six month personalized endurance training on work ability in middle-aged sedentary women: a secondary analysis of a randomized controlled trial.

J Occup Med Toxicol 2020 6;15. Epub 2020 May 6.

1Institute of Sports Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Background: To test the effects of guided endurance training on work ability in middle-aged female hospital workers of various occupations.

Methods: We randomized 265 healthy, sedentary, middle-aged women (45-65 years) to an endurance training group (EG 210 min/week) or a wait-list control group (CG). At baseline and at 6-month follow-up, we assessed work ability (Work Ability Index [WAI]), physical activity (Freiburger activity questionnaire) and peak oxygen uptake (VO) by cardiopulmonary exercise testing. To examine the influence of baseline work ability, participants were divided into poor-moderate (WAI 1, 7-36 points,  = 83), good (WAI 2, 37-43 points,  = 136) and excellent (WAI 3, 44-49 points,  = 46) WAI subgroups.

Results: Cardiorespiratory fitness improved significantly after 6 months in the EG but not in the CG. The WAI total score increased significantly in the EG (38.3 ± 5.0 to 39.8 ± 4.9 points) but not in the CG (39.4 ± 4.7 to 39.3 ± 4.9 points), with a significant difference between groups ( < 0.01). In the EG, only the poor-moderate subgroup (WAI 1, 33.0 ± 2.9 to 36.6 ± 4.8 points,  < 0.05) increased the WAI total score, with this increase being significantly higher compared to the good (WAI 2, 40.2 ± 2.1 to, 40.4 ± 3.7 points) and excellent (WAI 3, 45.6 ± 1.5 to 45.7 ± 1.8 points) subgroup.

Conclusions: A 6-month guided exercise training intervention significantly increases cardiorespiratory fitness with concomitant improvements in work ability in middle-aged previously sedentary hospital employees. Women with low baseline work ability seem to particularly benefit from the intervention, which implies that similar interventions may be particularly beneficial for this group of individuals.

Trial Registration: German Clinical Trails Register Identifier: DRKS00005159. Registered 25 September 2013.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12995-020-00261-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201966PMC
May 2020

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

J Clin Med 2020 Apr 14;9(4). Epub 2020 Apr 14.

Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.

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 ( = 21 and = 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, = 0.048), miR-21 (r = -0.277, = 0.012), miR-29a (r = -0.269, = 0.015), miR-146b (r = -0.319, = 0.004) and miR-328 (r = -0.296, = 0.008). In particular, NT-proBNP showed a strong correlation with echocardiographic markers of LA remodelling and dysfunction (septal PA-TDI: r = 0.444, < 0.001, LAVI/a': r = 0.457, = 0.001, SRa: r = 0.581, < 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, = 0.009; NT-proBNP: HR 1.002 95%CI 1.001-1.004, = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9041118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230176PMC
April 2020

Natriuretic Peptide Receptor 1, a Novel Player in Peripartum Heart Failure.

Circulation 2020 02 17;141(7):589-591. Epub 2020 Feb 17.

Department of Cardiology and Angiology, Hannover Medical School, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043957DOI Listing
February 2020

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

ESC Heart Fail 2020 04 17;7(2):512-522. Epub 2020 Feb 17.

Department of Cardiology and Angiology, MHH, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.12553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160487PMC
April 2020

Glucose stimulates microRNA-199 expression in murine pancreatic β-cells.

J Biol Chem 2020 01 27;295(5):1261-1270. Epub 2019 Dec 27.

Division of Endocrinology, Diabetes, and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136

MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of diabetic patients. Here we investigated how miR-199 expression is regulated in β-cells by assessing expression of miR-199 precursors (primiR-199a1, primiR-199a2, and primiR-199b) and mature miR-199 (miR-199-3p and miR-199-5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma cells (MIN6) under different stimuli. We found that mouse islets equally express miR-199-3p and miR-199-5p. However, the primiRNA expression levels differed; although primiR-199a1 expression was about 30% greater than that of primiR-199a2, primiR-199b is barely detected in islets. We observed a 2-fold increase in primiR-199a1 and primiR-199a2 mRNA levels in mouse islets cultured in 10 mm glucose compared with 5.5 mm glucose. Similar responses to glucose were observed in MIN6 cells. Exposure to 30 mm KCl to induce membrane depolarization and calcium influx increased expression of primiR-199a2 but not of primiR-199a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 cells also revealed that primiR-199a2 promoter activity was enhanced by glucose and reduced by 2-deoxy-D-glucose-induced starvation. KCl and the potassium channel blocker tolbutamide also stimulated primiR-199a2 promoter activity. Calcium channel blockade by nifedipine reduced primiR-199a2 promoter activity in MIN6 cells, and diazoxide-mediated calcium influx inhibition blunted glucose up-regulation of miR-199-3p in islets. In conclusion, we uncover that glucose acutely up-regulates miR-199 family expression in β-cells. Glucose metabolism and calcium influx are involved in primiR-199a2 expression but not primiR-199a1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA119.010356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996880PMC
January 2020

Increased Cancer Prevalence in Peripartum Cardiomyopathy.

JACC CardioOncol 2019 Dec 17;1(2):196-205. Epub 2019 Dec 17.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccao.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352111PMC
December 2019

Stable depletion of RUNX1-ETO in Kasumi-1 cells induces expression and enhanced proteolytic activity of Cathepsin G and Neutrophil Elastase.

PLoS One 2019 11;14(12):e0225977. Epub 2019 Dec 11.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

The oncogenic fusion protein RUNX1-ETO is a product of the t(8;21) translocation and consists of the hematopoietic transcriptional master regulator RUNX1 and the repressor ETO. RUNX1-ETO is found in 10-15% of acute myeloid leukemia and interferes with the expression of genes that are essential for myeloid differentiation. The neutrophil serine protease Cathepsin G is one of the genes suppressed by RUNX1-ETO, but little is known about its impact on the regulation of other lysosomal proteases. By lentiviral transduction of the t(8;21) positive cell line Kasumi-1 with an RUNX1-ETO specific shRNA, we analyzed long-term effects of stable RUNX1-ETO silencing on cellular phenotypes and target gene expression. Stable anti RUNX1-ETO RNAi reduces both proliferation and apoptosis in Kasumi-1 cells. In addition, long-term knockdown of RUNX1-ETO leads to an upregulation of proteolytic activity in Kasumi-1 cells, which may be released in vitro upon cell lysis leading to massive degradation of cellular proteins. We therefore propose that protein expression data of RUNX1-ETO-silenced Kasumi-1 cells must be analyzed with caution, as cell lysis conditions can heavily influence the results of studies on protein expression. Next, a mass spectrometry-based approach was used to identify protease cleavage patterns in RUNX1-ETO-depleted Kasumi-1 cells and Neutrophil Elastase has been identified as a RUNX1-ETO candidate target. Finally, proteolytic activity of Neutrophil Elastase and Cathepsin G was functionally confirmed by si/shRNA-mediated knockdown in Kasumi-1 cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905530PMC
March 2020

Sex differences in heart failure.

Eur Heart J 2019 12;40(47):3859-3868c

University Medical Centre Groningen, Hanzeplein 1, GZ Groningen, The Netherlands.

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz835DOI Listing
December 2019

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

Eur J Heart Fail 2019 12 13;21(12):1534-1542. Epub 2019 Nov 13.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1624DOI Listing
December 2019

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

Cardiovasc Res 2020 09;116(11):1875-1886

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.

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-1β 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvz300DOI Listing
September 2020
-->