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ABSTRACT: Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension.
Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage.
Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction.
The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.
Thorax 12/2011; 67(4):334-41. · 6.84 Impact Factor
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ABSTRACT: Progressive pulmonary arterial hypertension (PAH) is a rare condition with high morbidity and mortality. Paediatric PAH distinguishes itself from PAH in adults, but is still poorly characterized. Paediatric PAH presents itself with non-specific symptoms which often results in later diagnosis. Determination of the correct underlying diagnosis in paediatric PAH is complex, and must therefore take place at specialized centres. Paediatric progressive PAH is usually either idiopathic or associated with congenital heart disease. Pediatric PAH frequently co-occurs with dysmorphic abnormalities, which may point towards aetiological mechanisms. Recent reports suggest an improved survival and exercise tolerance due to treatment with new second-generation drugs for paediatric PAH. In the Netherlands, the care for children with PAH is centralised to guarantee the optimization of diagnosis and treatment in accordance with the most recent scientific insights.
Nederlands tijdschrift voor geneeskunde 01/2011; 155(49):A3901.
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ABSTRACT: Objective. To assess the impact of PPHN on mortality, morbidity, and behavioural skills. Methods. A retrospective observational study of 143 newborns with PPHN, over an 11-year period, using objective health-status data from medical records and family doctors, and subjective health status data from a standardized Child Behaviour Checklist. Results. The majority of patients were males, treated with inhaled nitric oxide had maladaptation/maldevelopment as pathophysiological mechanism and a gestational age >37 weeks. In term newborns, types of pathophysiological mechanism (P < .001) and Oxygen Index (P = .02) were independent predicting risk factors for PPHN-related mortality. Analysis of preexisting disease and outcome categories in term newborns showed only a significant correlation between the use of iNO and respiratory complaints (P = .03), not confirmed by multivariate analysis and regression analysis. Conclusions. PPHN is a serious, often fatal condition. The incidence of PPHN in preterm newborns is high. In term survivors, PPHN had no additional role in morbidity/outcome.
Pulmonary medicine. 01/2011; 2011:858154.
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ABSTRACT: In this review we discuss the new anti- Pulmonary Arterial Hypertension [PAH] drugs and the available data on their use in paediatric PAH. Treatment of patients with PAH, children and adults, is aimed at a reduction of symptoms, survival and improvement of haemodynamics as well as exercise capacity. PAH may reflect significant different disease conditions in infants and children when compared to PAH in adults. In contrast to adult PAH, characterized mainly by idiopathic PAH and PAH associated with connective tissue disease, more than half of the cases of PAH in children are associated with congenital heart disease. Therefore, efficacy of PAH drugs in these diseases can not be extrapolated from that in adults with PAH.
Paediatric Respiratory Reviews 12/2010; 11(4):240-5. · 2.77 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a serious, progressive condition, which can present idiopathically or secondary to conditions such as systemic sclerosis or congenital heart disease. The condition exists in both adult and paediatric forms, which possess several similar characteristics. Adult and paediatric PAH can, however, be distinguished based on underlying pathology and the presence of age-specific conditions, some of which are related to poor lung development in children. Improved knowledge of vascular biology has led to the development of several PAH-specific therapies, which have demonstrated clinical benefits in adults, including improved exercise capacity and prolonged survival. Treatment data in paediatric PAH are scarce. Although limited, the existing data indicate that current treatments for paediatric PAH are well tolerated and effective, at least in the short- and medium-term. Nevertheless, the current guidelines for clinicians, which recommend use of the adult treatment algorithm in paediatric patients, appear justified when judged according to the available evidence. However, further randomised, controlled trials are necessary to increase the evidence base for treatment of paediatric PAH, especially in relation to age-specific conditions. At present, early initiation of treatment and combination pharmacological therapy may offer the most promising courses of action to improve outcomes in paediatric PAH.
European Respiratory Review 12/2010; 19(118):321-30.
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M G J Duffels,
M N van der Plas,
S Surie,
M M Winter,
B Bouma,
M Groenink,
A P J van Dijk,
E Hoendermis, R M F Berger,
P Bresser,
B J M Mulder
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ABSTRACT: Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)).Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests.Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444+/-112 m to 471+/-100 m, p=0.02), and in CTEPH (376+/-152 m to 423+/-141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups.Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334-8.).
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 09/2009; 17(9):334-8. · 1.44 Impact Factor
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Heart (British Cardiac Society) 01/2009; 94(12):1653; author reply 1653-4. · 4.22 Impact Factor
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Pacing and Clinical Electrophysiology 03/2008; 31 Suppl 1:S1. · 1.35 Impact Factor
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ABSTRACT: Erythropoietin (EPO) mobilises endothelial progenitor cells and promotes neovascularisation in heart failure. The present authors studied the effects of EPO on pulmonary vascular and cardiac remodelling in a model for flow-associated pulmonary arterial hypertension (PAH). PAH was induced in adult male Wistar rats by the injection of monocrotaline combined with an abdominal aortocaval shunt 1 week later (PAH or experimental group). Immediately afterwards, rats were randomised into those who received treatment with EPO (PAH+EPO group) and controls. Pulmonary and systemic haemodynamics, and right ventricular and pulmonary vascular remodelling were evaluated 3 weeks later. Vascular occlusion of the intra-acinar pulmonary vessels (13.4+/-0.7 versus 16.7+/-1.3% in PAH+EPO and PAH, respectively) and medial wall thickness of the pre-acinar arteries (wall-to-lumen ratio 0.13+/-0.01 versus 0.17+/-0.01 in PAH+EPO and PAH, respectively) decreased after treatment with EPO. Moreover, right ventricular capillary density was increased by therapy (2,322+/-61 versus 2,100+/-63 capillaries x mm(-2) in PAH+EPO and PAH, respectively). Increased mean pulmonary arterial pressure and decreased right ventricular contractility in the model were not altered by EPO treatment. In this rat model of flow-associated pulmonary arterial hypertension, erythropoietin treatment beneficially affected pulmonary vascular and cardiac remodelling. These histopathological effects were not accompanied by significantly improved haemodynamics.
European Respiratory Journal 02/2008; 31(1):126-34. · 5.89 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) associated with congenital heart disease is usually the result of a large systemic-to-pulmonary shunt, and often leads to right ventricular failure and early death. The purpose of this study was to determine the prevalence of PAH among adult patients included in a national registry of congenital heart disease and to assess the relation between patient characteristics and PAH.
Patients with PAH associated with a septal defect were identified from the registry. Gender, age, underlying diagnosis, previous closure, age at repair and NYHA classification were recorded. PAH was defined as a systolic pulmonary arterial pressure (sPAP) greater than 40 mm Hg, estimated by means of echocardiographical evaluation.
The prevalence of PAH among all 5970 registered adult patients with congenital heart disease was 4.2%. Of 1824 patients with a septal defect in the registry, 112 patients (6.1%) had PAH. Median age of these patients was 38 years (range 18-81 years) and 40% were male. Of these patients, 58% had the Eisenmenger syndrome. Among the patients with a previously closed septal defect, 30 had PAH (3%). Ventricular septal defect (VSD) was the most frequent underlying defect (42%) among patients with PAH and a septal defect. Female sex (Odds ratio=1.5, p=0.001) and sPAP (Odds ratio=0.04, p<0.001) were independently associated with a decreased functional class.
PAH is common in adult patients with congenital heart disease. In our registry the prevalence of PAH in septal defects is around 6%. More than half of these patients have the Eisenmenger syndrome, which accounts for 1% of the total population in the CONCOR registry. Whether the prevalence of PAH will decrease in the future as a result of early detection and intervention remains to be awaited.
International journal of cardiology 08/2007; 120(2):198-204. · 7.08 Impact Factor
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ABSTRACT: Chronic increased pulmonary blood flow is considered a pre-requisite for the induction of advanced vascular lesions in pulmonary arterial hypertension in congenital heart defects. The aim of the present study was to characterise the effects of increased pulmonary flow induced by an aortocaval shunt in the monocrotaline rat model for pulmonary hypertension in terms of survival, haemodynamics, pathology and histology. Male Wistar rats were injected with monocrotaline followed by the creation of an abdominal aortocaval shunt. Animals were sacrificed when displaying symptoms of weight loss or dyspnoea, 4-5 weeks after the creation of the shunt. Echocardiography identified increased ventricular dimensions in shunted rats and right ventricular hypertrophy in monocrotaline-treated rats. At similar pulmonary artery pressures, shunted monocrotaline rats displayed higher morbidity and mortality, increased pulmonary-to-systemic artery pressure ratios and increased right ventricular hypertrophy compared with nonshunted monocrotaline rats. Histological assessment demonstrated increased number and diameter of pre-acinar pulmonary arteries. Intra-acinar vessel remodelling and occlusion occurred to a similar extent in shunted and nonshunted monocrotaline rats. In conclusion, increased pulmonary blood flow in monocrotaline-induced pulmonary hypertension is associated with increased morbidity, mortality, and unfavourable haemodynamic and cardiac effects. These effects could be attributed to more pronounced right heart failure rather than to altered intra-acinar pulmonary vessel remodelling.
European Respiratory Journal 10/2005; 26(3):487-93. · 5.89 Impact Factor
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