Search

Zusammenfassung Hintergrund Aufgrund der neuen Leitlinien der European Society of Cardiology (ESC) zur Diagnostik und Behandlung der akuten und chronischen Herzinsuffizienz (McDonagh et al. 2021) kann Vericiguat (Verquvo®) zur Behandlung von erwachsenen Patienten mit symptomatischer, chronischer Herzinsuffizienz und reduzierter Ejektionsfraktion, die trotz Standardtherapie nach einem kürzlich aufgetretenen Dekompensationsereignis mit erforderlicher intravenöser (i.v.) Therapie stabilisiert wurden, mit in die Therapie aufgenommen werden. Ziel der Arbeit Die vorliegende Übersichtsarbeit fasst die Entwicklung von Vericiguat, einem löslichen Guanylatzyklase-Stimulator (sGC-Stimulator), als konsequente Umsetzung eines neuartigen pharmakologischen Therapieansatzes zur Behandlung der Herzinsuffizienz zusammen und bietet über die Charakterisierung dieses erstmalig untersuchten Patientenkollektivs wertvolle Ansätze für die praktische Verwendung. Ergebnisse Die beiden wesentlichen Studien in der klinischen Entwicklung von Vericiguat – SOCRATES-Reduced und VICTORIA – haben die Wirksamkeit und Sicherheit von Vericiguat eindrucksvoll belegt. Der primäre Wirksamkeitsendpunkt der VICTORIA-Studie „kardiovaskulärer Tod oder Herzinsuffizienz-bedingte Hospitalisierung“ wurde im Vericiguat-Arm signifikant im Vergleich zu Placebo reduziert. Relevante Subgruppenanalysen sowie Sicherheitsdaten bestätigen dieses Ergebnis und unterstützen die sichere Anwendung in diesem Hochrisikokollektiv. Diskussion Die vorliegenden Daten lassen die Schlussfolgerung zu, dass Vericiguat effektiv und sicher zu einer bestehenden Therapie mit den empfohlenen Herzinsuffizienzmedikamenten hinzugefügt werden kann. Es ist zu erwarten, dass im Praxisalltag die Zieldosis von 10 mg verlässlich erreicht und gehalten werden kann. Vericiguat stellt daher eine neuartige, einfache und sichere Therapieoption in einem vulnerablen Patientenkollektiv dar, für das es bisher kaum medikamentöse Behandlungsoptionen gab.

Background Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure. Methods Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry. Results Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content. Conclusions These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.

Nicht-Vitamin-K-abhangige orale Antikoagulanzien (NOAK) werden zur Schlaganfallprophylaxe bei Vorhofflimmern mit entsprechendem Risikoscore sowie zur Therapie venoser thromboembolischer Ereignisse (wie tiefe Beinvenenthrombose und Lungenembolie) und deren Prophylaxe bei rezidivierenden Ereignissen eingesetzt. Die in Studien uberwiegend an nierengesunden Patienten erhobenen Daten sind jedoch nicht immer auf Patienten mit chronischer Niereninsuffizienz ubertragbar. NOAK sind bei hohergradiger Niereninsuffizienz nicht empfohlen bzw. kontraindiziert.

Die Praeklampsie ist eine haufige schwangerschaftsbedingte Erkrankung mit hoher mutterlicher und kindlicher Morbiditat und Mortalitat. Sowohl die Definition als auch unser pathophysiologisches Verstandnis haben sich in den letzten Jahren geandert. Es sind immunologische und antiangiogenetische Dysbalancen fur das Entstehen einer Praeklampsie entscheidend. Wahrend neue Studien den angestrebten Zielblutdruck in Frage stellen, werden innovative Therapien in klinischen Studien getestet. Patientinnen nach Praeklampsie zeigen auch nach 2 Jahren strukturelle Herzveranderungen (diastolische Dysfunktion). Dies kann das deutlich erhohte kardiovaskulare Risiko dieser Patientinnen im weiteren Lebensverlauf miterklaren.

Die ambulante 24-h-Blutdruckmessung (ABDM) ist ein unverzichtbarer Pfeiler in der Hypertoniediagnostik und Therapieuberwachung. Es besteht kein Zweifel, dass die ABDM entscheidend dazu beitragt, eine Unter- bzw. Uberschatzung (Praxisnormotonie/Praxishypertonie) des Blutdruckniveaus zu vermeiden. Dies gilt auch fur Kinder und Jugendliche, bei denen bis zu 20% Hypertoniker trotz Selbst- und Praxisblutdruckmessung ubersehen werden wurden. Mit der ABDM ist auch die Beurteilung des nachtlichen Blutdruckverhaltens moglich. Der diagnostische und prognostische Wert der ABDM als nichtinvasives Verfahren zur Blutdruckmessung ist abgesichert. Voraussetzungen sind neben der Benutzung eines validierten Systems (z. B. International Protocol 2 der European Society of Hypertension [ESH] oder Prufsiegel der Deutschen Hochdruckliga [DHL]) die richtige Indikationsstellung, eine ordnungsgemase Programmierung und Durchfuhrung der Messung sowie die korrekte Klassifikation des Blutdruckniveaus nach DHL-Kriterien. Die Einteilung des Blutdruckniveaus erfolgt in die 6 Klassen „optimal“ bis „Hypertonie Schweregrad 3“. Es erscheint sinnvoll, diese Analogwerte fur die individuelle kardiovaskulare Risikostratifizierung zu benutzen, da sich das kardiovaskulare Risiko mit steigenden ABDM-Werten erhoht und die ABDM das kardiovaskulare Risiko deutlich besser abbildet als die Praxisblutdruckmessung. Neben der computertechnischen Auswertung ist eine schriftliche Beurteilung der Blutdruckwerte und des Blutdruckprofils mit Feststellung des Schweregrads durch den untersuchenden Arzt obligat. An computergenerierten standardisierten Befundberichten mittels entsprechender Software wird derzeit von mehreren Fachgesellschaften und Herstellern gearbeitet. Wunschenswert ware die Darstellung aller wichtigen Parameter und einer graphischen Darstellung auf einer Seite.

The adipokines adiponectin and leptin may contribute to preeclampsia; however, the reports are conflicting. We explored the issue further. We studied 25 pregnant women with normal pregnancy infirst, 25 in second, and 30 in third trimesters, 15 healthy nonpregnant women, and 32 women with preeclampsia. We used enzyme-linked immunosorbent assay to measure human plasma adiponectin (ng/mL) and leptin (ng/mL) concentrations. We also investigated adiponectin and leptin expression by quantitative messenger RNA in fat, decidua, and placenta tissues in a second study. Prepregnancy body mass index was not different in preeclamptic and nonpreeclamptic women. Plasma adiponectin concentrations increased throughout normal pregnancy, compared to nonpregnant women. The values increased in every trimester but were invariably lower in women with preeclampsia. Adiponectin nonetheless correlated inversely with prepregnancy body mass index. Such correlations were not found in women with preeclampsia. Plasma leptin in contrast decreased during pregnancy in every trimester. Leptin values were much higher in preeclamptic than in nonpreeclamptic women. Leptin expression was increased in the uteroplacental unit and in fat tissue of preeclamptic, compared to nonpree-clamptic women, while no differences in adiponectin expression were found. Adiponectin increases in normal pregnancy but remains correlated with prepregnancy body mass index. Plasma leptin decreases in normal pregnancy. In preeclamptic women, the normal adipokine responses are perturbed and this could be of pathophysiological significance.

Preeclampsia is the major cause of maternal and fetal morbidity and mortality, involving 15% to 20% of pregnancies in developed countries and even more in less developed parts of the world. Superficial placentation driven by immune maladaptation, with subsequently reduced concentrations of angiogenic growth factors and increased placental debris in the maternal circulation, are likely responsible. Recent advances suggest that antiangiogenic factors (soluble fms-like tyrosine receptor kinase and soluble endoglin), altered relaxin-mediated mechanisms leading to impaired nitric oxide production through asymmetrical dimethylarginine production, and activating antibodies directed at the angiotensin II type 1 receptor may be responsible. The field of preeclampsia research is enjoying a well-deserved blossoming of novel ideas and approaches. We hope the activity will lead to much earlier diagnostic capacities and novel prophylactic treatments. The prize will go to the affected women and their afflicted children. For the investigators in the area, such a prize would be welcome.

Mutations in the gene encoding dysferlin cause limb-girdle muscular dystrophy 2B (LGMD2B), a disorder that is believed to spare the heart. We observed dilated cardiomyopathy in two out of seven LGMD2B patients and cardiac abnormalities in three others. Cardiac biopsies showed that dysferlin was completely absent from the sarcolemma and appeared to be trapped within the cardiomyocytes. SJL/J mice (33-week-old) had diminished end-systolic pressure and reduced dP/dt; however, the hearts were histologically normal. Gene expression profiles of cardiac tissue were obtained and later confirmed by quantitative RT-PCR. Dysferlin-deficient and control mice had different gene expression patterns in terms of cardiomyocyte Z-disc and signal transduction proteins. CapZ, LIM-domain-binding protein 3 (LDB3, MLP), cypher (ZASP), desmin, and the cardiac ankyrin-repeated protein (CARP) were differentially expressed, compared to controls. Mechanical stress induced by the nonselective beta-adrenergic agonist isoproterenol (5 mg/kg body weight) given daily for 10 days resulted in reduced fractional shortening and increased cardiac fibrosis in SJL/J mice as compared to controls. Isoproterenol also caused metalloproteinase-2 upregulation in SJL/J mice. In A/J mice, the effect of isoproterenol injection was even more dramatic and lead to premature death as well as marked sarcolemmal injury as demonstrated by Evans blue dye penetration. Our data suggest that disturbances in dysferlin as well as Z-line proteins and transcription factors particularly under mechanical stress cause cardiomyopathy.

Hypertension with left ventricular hypertrophy is a major cause of diastolic heart failure (DHF). Due to its high prevalence and high rate of mortality, DHF represents a major challenge in today's cardiovascular medicine; with limited therapeutic options. Soluble guanylate cyclase (sGC) stimulation is emerging as a promising treatment option in DHF, and is currently under investigation in preclinical and clinical studies. The present study investigates the effect of the sGC stimulator BAY 41-8543 in a transgenic rat model of hypertension-induced heart failure. We used 4 week-old male double transgenic rats expression both human renin and angiotensinogen genes (dTGRs). At 7 weeks of age, dTGRs exhibit striking cardiac hypertrophy with fibrosis and inflammation, ventricular arrhythmias and heart failure, which is accompanied with high mortality. We compared vehicle-treated dTGR (receiving 10% transcutol, 20% cremophor, 70% water) to those receiving 3 mg/kg/d BAY 41-8543, and vehicle-treated SD control rats (single oral dose per day for 3 weeks). We performed in vivo echocardiography, hemodynamic monitoring, cardiac electrophysiology studies and blood pressure measurements. Endothelial function was measured in isolated mesenteric arteries. Transcriptional analyses in cardiac tissue were performed using qRT-PCR and gene-microarray. Cardiac tissue was analyzed using histology. Treatment of dTGRs with BAY 41-8543 resulted in 100% survival at week 7, whereas only 24% of vehicle-treated dTGRs survived. Mean arterial pressure in dTGRs was significantly by BAY 41-8543 reduced (197 ± 11 mmHg vehicle vs 133 ± 4 mmHg BAY 41-8543). In addition, BAY 41-8543 significantly decreased in vivo total peripheral resistance and improved endothelium-dependent vasorelaxation of isolated mesenteric arteries. Furthermore BAY 41-8543 prevented fibrosis and inflammation of cardiac tissue. Echocardiography and invasive hemodynamic monitoring revealed BAY 41-8543 significantly increased ejection fraction and cardiac output in dTGR, whereas vehicle-treated had preserved systolic function but reduced diastolic function. In addition, diastolic compliance was significantly enhanced by BAY 41-8543, as shown by myocardial strain analysis and end-diastolic pressure volume relationship (EDPVR); indicative of an improved diastolic function. In vivo programmed electrical stimulation revealed a high ventricular tachycardia induction rate in vehicle-treated dTGRs (46%), which was significantly reduced in BAY 41-8543-treated dTGR (11%). Myocardial gene-microarray analysis showed a reversal of dysregulated genes in dTGR by BAY 41-8543 treatment. Our data demonstrate that BAY 41-8543 improves survival and cardiac performance in a transgenic rat model of hypertension-induced DHF. We postulate that treatment of DHF with sGC stimulators offers a novel therapeutic potential for humans.

Die Blockade des Renin-Angiotensin-Systems hat im Rahmen der medikamentosen Behandlung des Bluthochdrucks ihren Nutzen bewiesen. ACE-Hemmer und Angiotensinrezeptorblocker senken als Antihypertensiva der 1. Wahl effektiv den Blutdruck, verhindern die Progression bzw. bewirken die Regression von Endorganschaden und vermindern die kardiovaskulare Morbiditat und Mortalitat. Die neue Strategie der direkten Renininhibition scheint in diesem Zusammenhang ein Erfolg versprechender therapeutischer Ansatz zu sein, da auf diese Art und Weise der erste und geschwindigkeitsbestimmende Schritt des Renin-Angiotensin-Systems gehemmt wird. Im Sinn einer optimalen kardiovaskularen Protektion sollte bei Patienten mit arterieller Hypertonie ein „Niedrig-Reninaktivitat-“ und „Niedrig-Angiotensin-Zustand“ angestrebt werden. Auch aus diesem Grund ist das Konzept der direkten Renininhibition vielversprechend. Die bisher vorliegenden Daten weisen Aliskiren als ein potentes Antihypertensivum mit geringem Nebenwirkungsprofil aus. Seine Anwendung in der Hochdrucktherapie scheint sowohl in der Mono- als auch in der Kombinationstherapie mit anderen Antihypertensiva indiziert zu sein. Ob es in der Behandlung kardiovaskularer Endorganschaden und der Primar- oder Sekundarpravention kardiovaskularer Erkrankungen erfolgreich ist, wird sich herausstellen.

Immune mechanisms and circulating mediators may be important in the pathogenesis of preeclampsia. We review our findings on agonistic antibodies against the angiotensin II (Ang II) receptor (AT1-AA) and their possible role in the pathogenesis of this disorder. AT1-AA appear in the course of preeclampsia and are largely gone by 6 weeks after delivery. AT1-AA detection relies on a bioassay using spontaneously beating neonatal rat cardiomyocytes. Their specificity has been documented by other methods, including Western blotting, co-localization, and co-immunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including transcription factor activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proved with certainty. However, we believe the findings are compelling and warrant further study.

Background In the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease. Results As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection. Conclusions These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking. peerReviewed

Seit einigen Jahren erlebt die Hypertonietherapie eine Renaissance der Fixkombinationen. Neben zahlreichen Zweifachkombinationen stehen nun auch wieder fixe Dreifachkombinationen zur Verfugung. Diese konnen bei geeigneten Patienten die Hochdrucktherapie erleichtern, durfen aber nicht unkritisch eingesetzt werden.

The proto-oncoprotein Bcl-3 is a member of the IkappaB family and is present predominantly in the nucleus. To gain insight into specific nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identified four novel binding partners of Bcl-3 in addition to NF-kappaB p50 and p52, previously known to associate with Bcl-3. The novel Bcl-3 interactors Jab1, Pirin, Tip60 and Bard1 are nuclear proteins which also bind to other transcription factors including c-Jun, nuclear factor I (NFI), HIV-1 Tat or the tumor suppressor and PolII holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kappaB DNA binding sites, whereas Jab1 enhances p50-Bcl-3-DNA complex formation. Furthermore, the histone acetylase Tip60 enhances Bcl-3-p50 activated transcription through an NF-kappaB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kappaB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kappaB p50/p52 and other transcription regulators and suggest that its gene activation function may at least in part be due to recruitment of the Tip60 histone actetylase.

B-Myb belongs to a family of related transcription factors which share a unique DNA binding domain. B-Myb plays an important role in regulation of the cell cycle. Its expression is upregulated by the human papilloma virus HPV16 E7 oncoprotein. Overexpression of B-Myb can bypass p53-mediated cell cycle arrest. The founding member of the myb gene family, c-Myb, and A-Myb are involved in hematopoiesis and neurogenesis, respectively, and are both activators of gene transcription. Whether B-Myb is a transactivator or a repressor, however, has remained a matter of discussion. We reviewed the transactivation potential of B-Myb in yeast, taking advantage of the fact that inducible gene activation is an evolutionarily conserved process. By mutational analysis we localized a conserved activation domain in B-Myb. In vertebrate cells the transactivation potential of B-Myb is concealed by the C-terminal part of the protein. We show that the cell cycle regulators cyclin A and cyclin E activate B-Myb by eradicating the inhibition mediated by its carboxy-terminus. Our data suggest that in vertebrates the trans-activating function of B-Myb is regulated during the cell cycle and link Myb functions to cell cycle progression.

Two recent studies—one in humans by Levine et al. in 2004 and one in mice by Venkatesha et al. in 2006—have shown an important role for placental-derived soluble antiangiogenic factors as mediators of the pathologies associated with preeclampsia. These findings may have profound implications for the diagnosis, treatment and prevention of this devastating condition.