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ABSTRACT: Die peripartale Kardiomyopathie (PPCM) ist eine seltene, potenziell lebensbedrohliche Herzerkrankung unklarer Genese, die
zu einer plötzlich einsetzenden Herzinsuffizienz innerhalb der letzten Schwangerschaftswochen bis 6Monate nach der Geburt
führt. Die Prognose der PPCM ist schlecht. Die Diagnose wird oft spät gestellt, da Symptome wie Abgeschlagenheit, Luftnot
und Husten fehlinterpretiert werden können. Das klinische Bild der PPCM entspricht dem einer dilatativen Kardiomyopathie und
wird primär nach den Leitlinien zur Herzinsuffizienztherapie behandelt. Der Pathomechanismus beinhaltet erhöhten oxidativen
Stress und eine darüber induzierte Spaltung des Stillhormons Prolaktin in ein 16-kDa-Fragment. Dies bewirkt eine Störung der
Mikrozirkulation und metabolische Veränderungen der Herzmuskelzelle. Ein neuer Therapieansatz mit Bromocriptin als Prolaktinblocker
zusätzlich zur Standardtherapie zeigt erste vielversprechende Ergebnisse, und eine randomisierte Studie zur Therapie mit Bromocriptin
läuft in Deutschland an. Insgesamt scheint ein interdisziplinäres Management insbesondere zwischen Gynäkologen und Kardiologen
Diagnosestellung und Heilungschancen der PPCM positiv zu beeinflussen.
Peripartum cardiomyopathy (PPCM) is a rare and potentially life-threatening heart disease of unknown etiology that is restricted
to the last month of pregnancy and up to 6 months postpartum. The morphology similates that of idiopathic dilated cardiomyopathy
with a rapid progression to end-stage heart failure and is associated with a high morbidity and mortality rate. PPCM is treated
with standard therapy for heart failure in accordance with the current guidelines. New findings suggest that elevated oxidative
stress in the postpartum phase promotes cleavage of the nursing hormone prolactin into a toxic 16-kDa fragment that affects
microcirculation and cardiomyocyte metabolism. Thus prolactin blocking using bromocriptine as a more specific therapy option
showed promising early clinical results and is currently being tested in larger randomized trials. Frequent symptoms such
as general fatigue, dyspnea and dry cough are often misinterpreted as pregnancy-related disturbances, and diagnosis is therefore
often late. Interdisciplinary management, early diagnosis and more disease-specific therapy options appear to promote cardiac
recovery in PPCM patients.
Der Kardiologe 04/2012; 3(2):137-145.
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ABSTRACT: Heart disease is present in 0.5-1% of all pregnancies. It is the leading non-obstetric cause of maternal mortality accounting for about 10-15% of all maternal death. Over the last decades the underlying cardiac disease has changed. Also new therapeutic options have been developed. In western industrial countries the incidence of acquired rheumatic heart disease has declined. In contrast, as a result of neonatal corrective or palliative surgery, congenital heart disease has become an increasing and challenging problem. Maternal older age and the increase in women's smoking habits amplify the likelihood of coronary artery disease. Multiple therapeutic options including percutaneous interventions are available and novel therapeutic concepts are emerging i.e. for peripartum cardiomyopathy. Management of pregnancy, labor and delivery requires accurate diagnosis of the underlying cardiac disorder. Hemodynamic changes physiologically occurring during pregnancy have a different impact depending on the type and severity of cardiac anomalies. Management of these patients requires teamwork of obstetricians, neonatologists, cardiologists, anesthetists and sometimes cardiac surgeons.
Der Internist 07/2008; 49(7):805-10. · 0.30 Impact Factor
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ABSTRACT: IL-6-type cytokines bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 that is ubiquitously expressed in most tissues including the heart. The two major signalling cascades activated by the gp130 receptor, SHP2/ERK and STAT pathways, have been demonstrated to play important roles in cardiac development, hypertrophy, protection and remodelling in response to physiological and pathophysiological stimuli. Experimental data, both in vivo and in vitro, imply beneficial effects of gp130 signalling on cardiomyocytes in terms of growth and survival. In contrast, it has been reported that elevated serum levels of IL-6 cytokines and gp130 proteins are strong prognostic markers for morbidity and mortality in patients with heart failure or after myocardial infarction. Moreover, it has been shown that the local gp130 receptor system is altered in failing human hearts. In the present review, we summarize the basic principles of gp130 signalling, which requires simultaneous activation of STAT and ERK pathways under the tight control of positive and negative intracellular signalling modulators to provide a balanced biological outcome. Furthermore, we highlight the key role of the gp130 receptor and its major downstream effectors in the heart in terms of development and regeneration and in response to various physiological and pathophysiological stress situations. Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system.
British Journal of Pharmacology 04/2008; 153 Suppl 1:S414-27. · 4.41 Impact Factor
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ABSTRACT: Circulating levels of interleukin (IL)-6 and related cytokines are elevated in patients with congestive heart failure and after myocardial infarction. Serum IL-6 concentrations are related to decreasing functional status of these patients and provide important prognostic information.Moreover, in the failing human heart, multiple components of the IL-6- glycoprotein (gp)130 receptor system are impaired, implicating an important role of this system in cardiac pathophysiology.Experimental studies have shown that the common receptor subunit of IL-6 cytokines is phosphorylated in response to pressure overload and myocardial infarction and that it subsequently activates at least three different downstream signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3), the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, and the PI3K-Akt system. Gp130 receptor mediated signaling promotes cardiomyocyte survival, induces hypertrophy, modulates cardiac extracellular matrix and cardiac function. In this regard, the gp130 receptor system and its main downstream mediator STAT3 play a key role in cardioprotection. This review summarizes the current knowledge of IL-6 cytokines, gp130 receptor and STAT3 signaling in the heart exposed to physiological (aging, pregnancy) and pathophysiological stress (ischemia, pressure overload, inflammation and cardiotoxic agents) with a special focus on the potential role of individual IL-6 cytokines.
Archiv für Kreislaufforschung 08/2007; 102(4):279-97. · 7.35 Impact Factor
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AHA Scientific Sessions, Chicago, IL, USA; 11/2006
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World Congress of Cardiology (The unique meeting of the European Society of Cardiology Congress 2006 and the World Heart Federation's XVth World Congress of Cardiology, Barcelona, Spain; 09/2006
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72. Jahrestagung der Deutschen Gesellschaft für Kardiologie, Herz- und Kreislaufforschung, Mannheim, Germany; 04/2006
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72. Jahrestagung der Deutschen Gesellschaft für Kardiologie, Herz- und Kreislaufforschung, Mannheim, Germany; 04/2006
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AHA Scientific Sessions, Dallas, Texas, USA; 11/2005
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AHA Scientific Sessions, Dallas, Texas, USA; 11/2005
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ABSTRACT: Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O(2)(-)) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O(2)(-) anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT(1)) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O(2)(-) anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O(2)(-) anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1alpha/ss, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47(phox), a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 micromol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O(2)(-) anions generated by the NAD(P)H oxidase system, and O(2)(-) anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O(2)(-) anions generated by the NAD(P)H oxidase system.
Circulation Research 01/2001; 87(12):1195-201. · 9.49 Impact Factor
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ABSTRACT: Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease.
Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT(1)) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT(1) receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells.
Ang II, AT(1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT(1) receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.
Circulation 04/2000; 101(12):1372-8. · 14.74 Impact Factor
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ABSTRACT: In the common housefly, the presence or absence of a male-determining factor, M, is responsible for sex determination. In different strains, M has been found on the Y, on the X, or on any of the five autosomes. By analyzing a Y-autosomal translocation and a ring-shaped, truncated Y chromosome, we could show that M on the Y consists of at least two regions with M activity: One of them can be assigned to the short arm of the Y chromosome (MYS), which is largely C-banding negative, the other region lies on the C-banding positive long arm of the Y, including the centromeric part (MYL). Each region alone behaves as a hypomorphic M factor, causing many carriers to develop as intersexes of the mosaic type instead of as males. When introduced into the female germ line by transplantation of progenitor germ cells (pole cells), the MYS shows an almost complete maternal effect that predetermines 96% of the genotypic female (NoM) animals to develop as males. In contrast, the MYL has largely lost its maternal effect, and most of the NoM animals develop as females. Increasing the amount of product made by either of the two hypomorphic M factors (by combining the MYS and MYL or two MYS) leads to complete male development in almost every case. We thus assume that the Y chromosome carries at least two copies of M, and that these are functionally equivalent.
Genetics 11/1998; 150(2):651-61. · 4.01 Impact Factor
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ABSTRACT: Sex-lethal (Sxl) is the master switch gene for somatic sex determination in Drosophila melanogaster. In XX animals, Sxl becomes activated and imposes female development; in X(Y) animals, Sxl remains inactive and male development ensues. A switch gene for sex determination, called F, has also been identified in the housefly, Musca domestica. An active F dictates female development, while male development ensues when F is inactive. To test if the switch functions of Sxl and F are founded on a common molecular basis, we isolated the homologous Sxl gene in the housefly. Though highly conserved in sequence, Musca-Sxl is not sex-specifically regulated: the same transcripts and protein isoforms are expressed in both male and female animals throughout development. Musca-Sxl is apparently not controlled by the primary sex-determining signal and, thus, is unlikely to correspond to the F gene. Ectopic expression of Musca-SXL protein in Drosophila does not exert any noticeable effects on the known target genes of endogenous Sxl. Instead, forced overexpression of the transgene eventually results in lethality of both XY and XX animals and in developmental abnormalities in some escaper XY animals. Similar results were obtained with the Sxl homologue of Ceratitis capitata (Saccone, G., Peluso, I., Artiaco, D. , Giodano, E., Bopp, D. and Polito, L. C. (1998) Development 125, 1495-1500) suggesting that, in these non-drosophilid species, Sxl performs a function different from that in sex determination.
Development 04/1998; 125(8):1487-94. · 6.60 Impact Factor
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ABSTRACT: Dosage compensation is a regulatory process that insures that males and females have equal amounts of X-chromosome gene products. In Drosophila, this is achieved by a 2-fold enhancement of X-linked gene transcription in males, relative to females. The enhancement of transcription is mediated by the activity of a group of regulatory genes characterized by the male-specific lethality of their loss-of-function alleles. The products of these genes form a complex that is preferentially associated with numerous sites on the X chromosome in somatic cells of males but not of females. Binding of the dosage compensation complex is correlated with a significant increase in the presence of a specific histone isoform, histone 4 acetylated at Lys16, on this chromosome. Experimental results and sequence analysis suggest that an additional gene, males-absent on the first (mof), encodes a putative acetyl transferase that plays a direct role in the specific histone acetylation associated with dosage compensation. The predicted amino acid sequence of MOF exhibits a significant level of similarity to several other proteins, including the human HIV-1 Tat interactive protein Tip60, the human monocytic leukemia zinc finger protein MOZ and the yeast silencing proteins SAS3 and SAS2.
The EMBO Journal 05/1997; 16(8):2054-60. · 9.20 Impact Factor
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ABSTRACT: In Musca domestica, sex in the soma is cell autonomously determined by the male-determiner M, or by the female-determiner FD. Transplanted pole cells (precursors of the germ line) show that sex determination of germ cells is non-autonomous genotypically male pole cells form functional eggs in female hosts, and genotypically female pole cells form functional sperm in male hosts. When M/+ cells undergo oogenesis, a male-determining maternal effect predetermines offspring without M, i.e. of female genotype, to develop as fertile males. FD is epistatic to M in the female germ line, as it is in the soma, overruling the masculinizing effect of M. The results suggest that maternal F product is needed for activation of the zygotic F gene.
Development 10/1994; 120(9):2531-8. · 6.60 Impact Factor
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ABSTRACT: In the housefly, Musca domestica, a single dominant factor, M, determines maleness. Animals hemi-or heterozygous for M are males, whereas those without M develop as females. In certain strains, however, both sexes are homozygous for M, and an epistatic dominant factor, FD, dictates female development. The requirement for these factors was analyzed by producing, with mitotic recombination, mosaic animals consisting of genetically male and female cells. Removal of FD from an M/M;FD/+ cell at any time of larval development, even in the last larval instar, resulted in sex-reversal, i.e., in the development of a male clone in an otherwise female fly. In contrast, when M was removed from M/+ cells, the resulting clones remained male despite their female genotype, even when the removal of M happened at embryonic stages. The occurrence of spontaneous gynandromorphs, however, shows that the loss of M in individual nuclei prior to blastoderm formation causes the affected cells to adopt the female pathway. These results are consistent with the hypothesis that M is the primary sex-determining signal which sets the state of activity of the key gene F at around the blastoderm stage. Parallels and differences to the sex-determining system of Drosophila are discussed.
Genetics 09/1993; 134(4):1187-94. · 4.01 Impact Factor
