Charlotte U. Andersen

Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test.

BACKGROUND Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients. METHODS 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed. RESULTS 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure ≥ 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non-PH patients (difference ± SEM: 58 ± 22 m, p = 0.01). CONCLUSIONS PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH.

Apelin and pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by pulmonary vasoconstriction, pulmonary arterial remodeling, abnormal angiogenesis and impaired right ventricular function. Despite progress in pharmacological therapy, there is still no cure for PAH. The peptide apelin and the G-protein coupled apelin receptor (APLNR) are expressed in several tissues throughout the organism. Apelin is localized in vascular endothelial cells while the APLNR is localized in both endothelial and smooth muscle cells in vessels and in the heart. Apelin is regulated by hypoxia inducible factor-1α and bone morphogenetic protein receptor-2. Patients with PAH have lower levels of plasma-apelin, and decreased apelin expression in pulmonary endothelial cells. Apelin has therefore been proposed as a potential biomarker for PAH. Furthermore, apelin plays a role in angiogenesis and regulates endothelial and smooth muscle cell apoptosis and proliferation complementary and opposite to vascular endothelial growth factor. In the systemic circulation, apelin modulates endothelial nitric oxide synthase (eNOS) expression, induces eNOS-dependent vasodilatation, counteracts angiotensin-II mediated vasoconstriction, and has positive inotropic and cardioprotective effects. Apelin attenuates vasoconstriction in isolated rat pulmonary arteries, and chronic treatment with apelin attenuates the development of pulmonary hypertension in animal models. The existing literature thus renders APLNR an interesting potential new therapeutic target for PH.

Phyto-oestrogens in herbage and milk from cows grazing white clover, red clover, lucerne or chicory-rich pastures.

A grazing experiment was carried out to study the concentration of phyto-oestrogens in herbage for cattle and in milk during two periods (May and June). Forty-eight Danish Holstein cows were divided into four groups with four treatment diets; white clover, red clover, lucerne and chicory-rich pastures. Each experimental period lasted 15 days. Herbage samples from the first day and individual milk samples from the last day of the experimental period were analysed for phyto-oestrogens using LC-MS technique. The total concentration of phyto-oestrogens was 21 399 mg/kg dry matter (DM) for red clover and 238 to 466 mg/kg DM for the other three herbages mainly due to a much higher concentration of biochanin A, formononetin and glycitein in red clover. In the milk, the total concentration of phyto-oestrogens was 253 to 397 μg/l for red clover milk and 56 to 91 μg/l in the milk from the other three treatments. This was especially due to a higher concentration of equol, daidzein and formononetin in the red clover milk. The concentration of biochanin A was significantly higher in milk from the red clover treatment in May while no differences were observed in June. Enterodiol was similar across treatments while the concentration of enterolactone was significantly lower for red clover milk compared with the other treatments. Of the tested pastures, red clover appears to have the highest concentration and to be the best source of phyto-oestrogens, especially equol, in bovine milk.

Pulmonary apelin levels and effects in rats with hypoxic pulmonary hypertension.

BACKGROUND The peptide apelin is localised in the vascular endothelium and highly expressed in pulmonary tissue. The aim of this study was to investigate whether apelin could be a potential lung-derived plasma marker for pulmonary hypertension, and study the effect of apelin in pulmonary arteries. METHODS Apelin protein levels were measured in the lung, right ventricle, and plasma from normoxic and chronic hypoxic rats with pulmonary hypertension. Isolated intrapulmonary arteries were mounted in microvascular myographs and the effect of apelin investigated. Finally, the distribution of apelin receptors in pulmonary tissue was visualised by immunohistochemistry. RESULTS Total pulmonary apelin content was not changed by hypoxia. Right ventricular apelin concentrations and content were lower than in the lung, but increased substantially in hypoxia in correlation with right ventricular pressure. Plasma apelin did not reflect pulmonary or right ventricular apelin levels. In pulmonary arteries from normoxic rats, apelin inhibited vasoconstriction to endothelin-1 and angiotensin-II. However, in arteries from hypoxic rats, apelin failed to inhibit contraction to angiotensin-II and endothelin-1. No difference in immunoreaction for apelin receptors was found in lung sections and arteries from normoxic versus chronic hypoxic rats. CONCLUSIONS Apelin changes in the right ventricle seem more specific for pulmonary hypertension than do changes in pulmonary tissue, which does not speak in favour of apelin as a lung-derived marker for this disease. During normoxic conditions, apelin has a modulating effect on vasoconstriction which is lost in chronic hypoxia. This may reflect alterations in the signal transduction downstream of the apelin receptor.

Effect of forage on the content of phyto-oestrogens in bovine milk

Phyto-oestrogens are believed to have a range of beneficial effects on predominant Western diseases. A few studies on phyto-oestrogens in milk exist and show that the composition can be affected by feeding. Therefore, the aim was to study how feeding of lucerne and grass/clover silages (GCSs) affects the concentration of phyto-oestrogens in bovine milk. Sixteen Danish Holstein cows were assigned to a 4 × 4 latin square design with four cows per treatment per period of 3 weeks. The four treatment diets were lucerne silage (LS), 2/3 lucerne silage and 1/3 maize silage (2/3LS), 1/3 lucerne silage and 2/3 maize silage (1/3LS) and GCS. Milk was collected at the end of each period and feed samples on day 6, 13 and 20 in each experimental period. Milk and pooled feed samples were analysed for the concentration of isoflavones, coumestans and lignans. The content of isoflavones was higher and the content of coumestrol lower in the GCS diet than in LS, 2/3LS and 1/3LS diets. For the LS, 2/3LS and 1/3LS diets, the concentration of coumestrol and secoisolariciresinol increased with the proportion of lucerne while the concentration of isoflavones was similar across the diets. The concentrations of the formononetin, daidzein and equol in the milk were significantly higher for the GCS diet than for the LS, 2/3LS and 1/3LS diets. In particular, the concentration of equol was 62-291 times higher for GCS. The concentration of coumestrol was significantly lower for the GCS diet compared to the LS, 2/3LS and 1/3LS diets. No pattern for the concentration of lignans was observed. In conclusion, a high concentration of isoflavones, particularly equol, and a low concentration of coumestrol were measured in the milk from the GCS diet. In contrast, a low concentration of isoflavones and a high concentration of coumestrol were measured in the milk from the LS, 2/3LS and 1/3LS diets. However, the concentration of phyto-oestrogens in bovine milk is low compared to food sources rich in phyto-oestrogens but the high concentration of equol could possibly be of therapeutic importance.

Opioids: an unexplored option for treatment of dyspnea in IPF

Background Idiopathic pulmonary fibrosis (IPF) is the most common among the idiopathic interstitial pneumonias and has the worst prognosis, with a median survival of 3–5 years. The most common symptom in IPF is dyspnea, impacting on the patients quality of life and life expectancy. Morphine in the treatment of dyspnea has been investigated but with conflicting results. This review aims to clarify the role of opioids in the treatment of dyspnea in patients with IPF. Methods A literature search was performed using the MeSH and PubMed databases. As only very few studies included patients with IPF, studies conducted primarily with patients with chronic obstructive pulmonary disease were also included. In total, 14 articles were found. Results Seven studies reported use of systemic morphine and seven studies of inhaled morphine. Five of the seven studies investigating systemic administration detected an improvement in either dyspnea or exercise capacity, whereas no beneficial effect on dyspnea was detected in any study using inhaled morphine. No severe adverse effects such as respiratory depression were reported in any study, although constipation was reported as a notable adverse effect. Conclusions Results were inconsistent, but in some studies systemic morphine administration showed a significant improvement in the dyspnea score on a visual analog scale without observation of severe side effects. Nebulized morphine had no effect on dyspnea.

Pulmonary hypertension in chronic obstructive and interstitial lung diseases

The purpose of the present review is to summarize the current knowledge on PH in relation to COPD and ILD from a clinical perspective with emphasis on diagnosis, biomarkers, prevalence, impact, treatment, and practical implications. PH in COPD and ILD is associated with a poor prognosis, and is considered one of the most frequent types of PH. However, the prevalence of PH among patients with COPD and ILD is not clear. The diagnosis of PH in chronic lung disease is often established by echocardiographic screening, but definitive diagnosis requires right heart catheterization, which is not systematically performed in clinical practice. Given the large number of patients with chronic lung disease, biomarkers to preclude or increase suspicion of PH are needed. NT-proBNP may be used as a rule-out test, but biomarkers with a high specificity for PH are still required. It is not known whether specific treatment with existent drugs effective in pulmonary arterial hypertension (PAH) is beneficial in lung disease related PH. Studies investigating existing PAH drugs in animal models of lung disease related PH have indicated a positive effect, and so have case reports and open label studies. However, treatment with systemically administered pulmonary vasodilators implies the risk of worsening the ventilation-perfusion mismatch in patients with lung disease. Inhaled vasodilators may be better suited for PH in lung disease, but new treatment modalities are also required.

Echocardiographic Screening for Pulmonary Hypertension in Stable COPD Out-Patients and NT-proBNP as a Rule-Out Test

Abstract Pulmonary hypertension (PH) worsens the prognosis in chronic obstructive pulmonary disease (COPD). The diagnosis of PH is established by right heart catheterisation (RHC), while echocardiography can be used for screening. We aimed to asses the outcome of echocardiographic screening for PH in a group of stable COPD out-patients, and to evaluate NT-proBNP as a first line screening tool. Criteria for PH on echocardiography were a tricuspid regurgitation pressure gradient > 40 mmHg, a tricuspid annular plane systolic excursion < 1.8 cm or right ventricular dilatation. Positively screened patients were asked to undergo RHC. Results (Mean ± SEM): 16 of 117 patients (14%) had PH on echocardiography. They had a higher mortality (hazard ratio for death: 2.7 ± 1.3, p = 0.037) and lower six minute walk test (224 ± 33 vs. 339 ± 15, p = 0.006). NT-proBNP below 95 ng/l excluded PH on echocardiography with a negative predictive value of 100 (95% CI: 89–100%). RHC was obtained in six patients screened positive. In three of these, PH was not confirmed. Conclusions: Signs of PH on echocardiography as defined here was found in 14% and had prognostic significance in COPD. A value of NT-proBNP less than 95 ng/l may be used to exclude signs of PH.

Cardiovascular Effects of Current and Future Anti-Obesity Drugs

The prevalence of obesity increases and is associated with increases in co-morbidities e.g. type 2 diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, several forms of cancer, depression, and may result in reduction of expected remaining lifespan. We have reviewed the adverse effects on the cardiovascular system of anti-obesity drugs now retracted from the market as well as the cardiovascular profile of current drugs and potential pathways which are considered for treatment of obesity. Fenfluramine, and sibutramine were withdrawn due to increased cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol remains unexplored. Pathways with anti-obesity potential include sirtuin activation, blockade of transient receptor potential (TRPV1) channels, acetyl-CoA carboxylase 1 and 2 inhibitors, uncoupling protein activators, bile acids, crotonins, CB1 antagonists, but the cardiovascular profile remains to be investigated. For type 2 diabetes, new drug classes with possible advantageous cardiovascular profiles, e.g. GLP-1 analogues and sodium-glucose co-transport type 2 inhibitors, are associated with weight loss and are currently being evaluated as anti-obesity drugs.

Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis

To the Editors: Voriconazole is a broad-spectrum antifungal agent that is effective against moulds such as Aspergillus fumigatus . It inhibits the cytochrome P450-dependent 14-α–lanosterol demethylase, preventing the conversion of lanosterol to ergosterol. This results in the accumulation of toxic methylsterols in the fungal wall and the inhibition of fungal growth [1]. Voriconazole is available as an intravenous infusion solution containing a cyclodextrin molecule (Captisol®; Ligand Pharmaceuticals Inc., La Jolla, CA, USA) to increase its solubility in water [2]. Adverse effects, such as gastrointestinal disorders, visual disturbances and elevated transaminase levels, complicate the use of voriconazole if used systemically. The therapeutic concentration range of voriconazole is from 1 to 5.5 μg·mL−1 and, although higher concentrations (>5.5 μg·mL−1) are associated with better clinical outcomes, they are also associated with more severe and less common side-effects, including encephalopathy and hallucinations [1]. Inhaled voriconazole reduces histological manifestations of invasive aspergillosis in rodents [3] and it has been proposed that a favourable lung tissue to plasma concentration ratio is obtained through this route of administration [4]. Consequently, inhaled voriconazole may provide higher concentrations at the site of infection without increasing the risk of systemic side-effects. We present three cases in which life-threatening invasive aspergillosis was treated with systemic voriconazole, but due to unacceptable adverse effects, the treatment had to be withdrawn. With no other conventional treatment options, inhaled voriconazole was administered. In September 2009, a 66-yr-old, otherwise healthy male was admitted to our Dept of Infectious Diseases due to symptomatic pneumonia that had lasted for 4 weeks. The patient was a previous smoker (40 pack-yrs) and due to brain surgery for an incidental meningioma, he was treated with steroids. Due to complications, he was treated with methylprednisolone (100 mg) for >1 …