Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BRD4 (bromodomain-containing protein 4), a member of the BET (bromodomain and ...extra-terminal motif) family, has been identified as a critical epigenetic driver for cardiovascular diseases.
To explore the therapeutic potential in PAH of RVX208, a clinically available BET inhibitor.
Microvascular endothelial cells, smooth muscle cells isolated from distal pulmonary arteries of patients with PAH, rats with Sugen5416 + hypoxia- or monocrotaline + shunt-induced PAH, and rats with RV pressure overload induced by pulmonary artery banding were treated with RVX208 in three independent laboratories.
BRD4 is upregulated in the remodeled pulmonary vasculature of patients with PAH, where it regulates FoxM1 and PLK1, proteins implicated in the DNA damage response. RVX208 normalized the hyperproliferative, apoptosis-resistant, and inflammatory phenotype of microvascular endothelial cells and smooth muscle cells isolated from patients with PAH. Oral treatment with RVX208 reversed vascular remodeling and improved pulmonary hemodynamics in two independent trials in Sugen5416 + hypoxia-PAH and in monocrotaline + shunt-PAH. RVX208 could be combined safely with contemporary PAH standard of care. RVX208 treatment also supported the pressure-loaded RV in pulmonary artery banding rats.
RVX208, a clinically available BET inhibitor, modulates proproliferative, prosurvival, and proinflammatory pathways, potentially through interactions with FoxM1 and PLK1. This reversed the PAH phenotype in isolated PAH microvascular endothelial cells and smooth muscle cells
, and in diverse PAH rat models. RVX208 also supported the pressure-loaded RV
. Together, these data support the establishment of a clinical trial with RVX208 in patients with PAH.
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis ...and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.
A study started in 1988 in the Netherlands to get more information on concerns about AIDS among the non-infected population and on the general practitioner's role in providing advice and health ...education about AIDS is discussed. General practitioners can play an important role in reassuring their concerned patients providing that they can translate the general information about AIDS/HIV to the needs of the individual patients.
Objective. The present study was conducted in order to determine the change of frequency and type of hormone replacement therapy (HRT) regimen newly prescribed by Dutch GPs. Methods. A comparison was ...made of two data sets (multi-stage random samples) collected in 1987/88 and from 1995 to 1998 concerning women 40 years and older who were newly prescribed HRT. Results. Compared with 1987/88, 50% more patients were newly prescribed HRT in 1998 (2.0 in 1987/88 and 3.0 in 1998 per 1000 registered women, P < 0.01). The age distribution remained about the same, with a peak between 50 and 54 years in each year of registration. Unopposed oestrogens (including plasters) were prescribed less frequently (1.3‰ in 1987/88 versus 0.7‰ in 1998, P < 0.001), and combinations of oestrogen and progestogen more frequently in 1998 (0.2‰ in 1987/88 versus 1.8‰ in 1998, P < 0.01). Sequential therapy was prescribed slightly more frequently than continuous therapy (65% sequential therapy in 1995; 55% in 1998). The most frequent reason for starting HRT in 1995–1998 was climacteric symptoms (89–98%), followed by osteoporosis prevention (16–28%) and early menopause (13–25%). Rarely were preventive goals the only reason (6%) for prescribing HRT. Conclusions. The number of HRT prescriptions increased by 50% over the last decade of the millennium. The age distribution remained the same. There was a tendency to shift from prescribing unopposed oestrogens to combinations of oestrogens and progestogens. Alleviation of climacteric symptoms was the main reason for prescribing HRT throughout the registration period. Prescription of HRT for prevention of osteoporosis and/or cardiovascular disease has so far not been adopted on a large scale by Dutch GPs.
Therapeutic bacteriophages (phages) are primarily chosen based on their in vitro bacteriolytic activity. Although anti-phage antibodies are known to inhibit phage infection, the influence of other ...immune system components is less well known. An important anti-bacterial and anti-viral innate immune system that may interact with phages is the complement system, a cascade of proteases that recognizes and targets invading microorganisms. In this research, we aimed to study the effects of serum components such as complement on the infectivity of different phages targeting
. We used a fluorescence-based assay to monitor the killing of
by phages of different morphotypes in the presence of human serum. Our results reveal that several myophages are inhibited by serum in a concentration-dependent way, while the activity of four podophages and one siphophage tested in this study is not affected by serum. By using specific nanobodies blocking different components of the complement cascade, we showed that activation of the classical complement pathway is a driver of phage inhibition. To determine the mechanism of inhibition, we produced bioorthogonally labeled fluorescent phages to study their binding by means of microscopy and flow cytometry. We show that phage adsorption is hampered in the presence of active complement. Our results indicate that interactions with complement may affect the in vivo activity of therapeutically administered phages. A better understanding of this phenomenon is essential to optimize the design and application of therapeutic phage cocktails.
A newborn with hypoplastic left heart underwent a Norwood operation. Obstruction of the Blalock–Thomas–Taussig shunt was treated with a stent. During resuscitation, this was compressed, which ...contributed to a fatal outcome.
From 1996 to 1999, the incidence of gastroenteritis in general practices and the role of a broad range of pathogens in the Netherlands were studied. All patients with gastroenteritis who had visited ...a general practitioner were reported. All patients who had visited a general practitioner for gastroenteritis (cases) and an equal number of patients visiting for nongastrointestinal symptoms (controls) were invited to participate in a case-control study. The incidence of gastroenteritis was 79.7 per 10,000 person years. Campylobacter was detected most frequently (10% of cases), followed by Giardia lamblia (5%), rotavirus (5%), Norwalk-like viruses (5%) and Salmonella (4%). Our study found that in the Netherlands (population 15.6 million), an estimated 128,000 persons each year consult their general practitioner for gastroenteritis, slightly less than in a comparable study in 1992 to 1993. A pathogen could be detected in almost 40% of patients (bacteria 16%, viruses 15%, parasites 8%).
Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a ...young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT-proBNP (N-terminal pro-B-type natriuretic peptide), GDF-15 (growth differentiation factor 15), Gal-3 (galectin-3), ST2 (suppression of tumorigenicity 2), DLK-1 (protein delta homolog 1), FABP-4 (fatty acid-binding protein 4), IGFBP-1 (insulin-like growth factor-binding protein 1), IGFBP-7, MMP-2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1-12.1) years after Fontan completion. After this baseline study measurement, follow-up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4-15.9) years, median age at Fontan 3.2 (2.5-3.9) years. After a median follow-up of 6.2 (4.9-6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT-proBNP was associated with (all) events during follow-up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32-2.68). The severe event-free survival was better in patients with low levels of GDF-15 (
=0.005) and vWF (
=0.008) and high levels of DLK-1 (
=0.041). There was a positive correlation (β=0.33,
=0.003) between DLK-1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT-proBNP, GDF-15, vWF, DLK-1, ST-2 FABP-4, and IGFBP-7 levels relate to long-term outcome in young patients who have undergone the Fontan procedure.
Cellular senescence is recognized as a crucial contributor to the pathobiology of various degenerative and cardiovascular diseases, such as idiopathic pulmonary fibrosis and atherosclerosis. We ...describe the potential link between cellular senescence and the degenerative character of neointimal pulmonary vascular disease in pulmonary arterial hypertension (PAH). Senescence markers have been described in remodeled pulmonary arteries, and PAH and senescence share common triggers and pathogenic pathways, such as transforming growth factor-β/bone morphogenetic protein and TNF-α. In addition, interventions that target a senescence phenotype also target pulmonary vascular remodeling
. These data provide a basis for further exploration of the role of senescence in the pathobiology of PAH and for preclinical trials with a senolytic class of drugs.
Right ventricular (RV) failure due to pressure load is an important determinant of clinical outcome in pulmonary hypertension, congenital heart disease and left ventricular failure. The last decades ...it has become clear that metabolic dysregulation is associated with the development of RV-failure. However, underlying mechanisms remain to be unraveled. Recently, disruption of intracardiac lipid content has been suggested as potential inducer of RV failure. In the present study, we used a rat model of RV-dysfunction and aimed to obtain insight in temporal changes in RV-function, -remodelling and -metabolism and relate this to RV lipid content.
Male Wistar WU rats were subjected to pulmonary artery banding (n = 25) or sham surgery (n = 14) and cellular, hemodynamic and metabolic assessments took place after 2, 5 and 12 weeks. In this model RV dysfunction and remodelling occurred, including early upregulation of oxidative stress markers. After 12 weeks of pressure load, lipidomics revealed significant decreases of myocardial diglycerides and cardiolipins, driven by (poly-)unsaturated forms. The decrease of cardiolipins was driven by its most abundant form, tetralinoleoylcardiolipin. Mitochondrial capacity for fatty acid oxidation preserved, while the capacity for glucose oxidation increased.
RV dysfunction due to pressure load, is associated with decreased intracardiac unsaturated lipids, especially tetralinoleoylcardiolipin. This was accompanied with preserved mitochondrial capacity regarding fatty acids oxidation, with increased capacity for glucose oxidation, and early activation of oxidative stress. We suggest that early interventions should be directed towards preservation of lipid availability as possible mean in order to prevent RV failure.
•Right ventricular (RV) pressure load induces early RV dysfunction.•Altered lipid composition accompanies RV dysfunction.•Lipid decreases in RV pressure load are driven by poly-unsaturated fatty acids.•Decrease of cardiolipins and diglycerides precede mitochondrial dysfunction.•RV dysfunction is associated with early upregulation of oxidative stress markers.
PDF
