Pulmonary veno-occlusive disease (PVOD) is a rare condition of pulmonary arterial hypertension (PAH), in which post-capillary veins are affected. Since the therapeutic approach in PVOD differs from other forms of PAH, it is crucial to establish the diagnosis. Due to the fact that affected patients are often hemodynamically unstable, minimal invasive procedures are necessary for the diagnostic work-up. Chronic alveolar haemorrhage has been observed during bronchoalveolar lavage in PVOD cases. This study therefore investigates whether signs of alveolar haemorrhage can also be found in the sputum of these patients.
Methods and Results
Six patients suffering from PVOD were included in this analysis. As controls, patients with idiopathic PAH (n = 11), chronic thromboembolic PH (n = 9) and with sclerodermia-associated PH (n = 10) were assessed. Sputum from every patient was obtained by a non-invasive manner. The amount of haemosiderin-laden macrophages was determined using the Golde score. There were statistically significant more haemosiderin-laden macrophages in the sputum of patients suffering from PVOD as compared to the other groups (P<0.05). Assuming a cut-off of 200 on the Golde score, all of the 6 PVOD patients surpassed this value compared with only 1 out of the 30 cases with precapillary PH. Thus, sensitivity and specificity with respect to the diagnosis of PVOD was 100% and 97%, respectively.
The content of haemosiderin-laden macrophages in the sputum of patients suffering from PVOD is significantly higher as compared to other forms of PH and may be useful in the non-invasive diagnostic work-up of these patients.
Data on exercise pulmonary hemodynamics in healthy people and patients with pulmonary hypertension (PH) are rare. We analyzed exercise right heart catheterization (RHC) data in a symptomatic collective referred with suspected PH to characterize the differential response by diagnostic groups, to correlate resting with exercise hemodynamics, and to evaluate safety.
This is a retrospective single-center study reviewing data from patients in whom an exercise RHC was performed between January 2006 and January 2013. Patients with follow-up RHC under PH -therapy were excluded.
Data from 101 patients were analyzed, none of them had an adverse event. In 35% we detected a resting PH (27.8% precapillary, 6.9% postcapillary). Exercise PH (mean pulmonary arterial pressure (mPAP) >30 mmHg at exercise) was found in 38.6%, whereas in 25.7% PH was excluded. We found a remarkable number of exercise PH in scleroderma patients, the majority being postcapillary. 83% of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH. Patients with resting PH had worse hemodynamics and were older compared with exercise PH ones.
In this real-life experience in symptomatic patients undergoing exercise RHC for suspected PH, we found that exercise RHC is safe. The facts that the vast majority of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH and the older age of patients with resting PH may indicate that exercise PH is a precursor of resting PH. Whether earlier treatment start in patients with exercise PH would stabilize the disease should be addressed in future studies.
Exercise; Pulmonary arterial hypertension; Pulmonary hypertension; Right heart catheterization
Pulmonary hypertension is an “umbrella term” used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.
This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.
Pulmonary hypertension; Inflammation; Immune cells; Experimental models; Cytokines; microRNAs
Introduction Despite new treatment options targeted at its three main pathogenic pathways, prognosis of idiopathic pulmonary arterial hypertension has remained dismal, with 3-year survival rates around 70 %. Antiproliferative agents have emerged as a new therapeutic concept. However, they may exert their effects only after a prolonged period of time. Case description Herein we present a patient who, despite being on a triple targeted drug therapy including high-dose intravenous prostanoids, still had severe pulmonary hypertension. After 4 years treatment with the tyrosine kinase inhibitor imatinib, the patient could be weaned from intravenous prostanoids and attained a persistent hemodynamic normalization. Conclusions Antiproliferative agents might be a promising new class of drugs in pulmonary arterial hypertension. However, the occurrence of unexpected side effects like the increased incidence of subdural hematomas, has led to the recommendation that at present such an off-label use is strongly discouraged, and that further studies elucidating the risk/benefit ratio of tyrosine kinase inhibitors are clearly needed.
Imatinib; Pulmonary arterial hypertension; Treatment
The six-minute walk test (6MWT) is a simple, low tech, safe and well established, self-paced assessment tool to quantify functional exercise capacity in adults. The definition of normal 6MWT in children is especially demanding since not only parameters like height, weight and ethnical background influence the measurement, but may be as crucial as age and the developmental stage. The aim of this study is establishing reference values for the 6MWT in healthy children and adolescents in Switzerland and to investigate the influence of age, anthropometrics, heart rate, blood pressure and physical activity on the distance walked.
Children and adolescents between 5–17 years performed a 6MWT. Short questionnaire assessments about their health state and physical activities. anthropometrics and vitals were measured before and after a 6-minute walk test and were previously defined as secondary outcomes.
Age, height, weight and the heart rate after the 6MWT all predicted the distance walked according to different regression models: age was the best single predictor and mostly influenced walk distance in younger age, anthropometrics were more important in adolescents and females. Heart rate after the 6MWT was an important distance predictor in addition to age and outreached anthropometrics in the majority of subgroups assessed.
The 6MWT in children and adolescents is feasible and practical. The 6MWT distance depends mainly on age; however, heart rate after the 6MWT, height and weight significantly add information and should be taken into account mainly in adolescents. Reference equations allow predicting 6-minute walk test distance and may help to better assess and compare outcomes in young patients with cardiovascular and respiratory diseases and are highly warranted for different populations.
6-minute walk test; Healthy children; Exercise physiology; Exercise testing; Predicted equation; Reference value
Individuals with precapillary pulmonary hypertension (PH) experience severely impaired quality of life. A disease-specific outcome measure for PH, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was developed and validated in the UK and subsequently adapted for use in additional countries. The aim of this study was to translate and assess the reliability and validity of the CAMPHOR for German-speaking populations.
Three main adaptation stages involved; translation (employing bilingual and lay panels), cognitive debriefing interviews with patients and validation (assessment of the adaptation’s psychometric properties). The psychometric evaluation included 107 patients with precapillary PH (60 females; age mean (standard deviation) 60 (15) years) from 3 centres in Austria, Germany and Switzerland.
No major problems were found with the translation process with most items easily rendered into acceptable German. Participants in the cognitive debriefing interviews found the questionnaires relevant, comprehensive and easy to complete. Psychometric analyses showed that the adaptation was successful. The three CAMPHOR scales (symptoms, activity limitations and quality of life) had excellent test-retest reliability correlations (Symptoms = 0.91; Activity limitations = 0.91; QoL = 0.90) and internal consistency (Symptoms = 0.94; Activity limitations = 0.93; QoL = 0.94). Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of the CAMPHOR scales. The CAMPHOR adaptation also showed known group validity in its ability to distinguish between participants based on perceived general health, perceived disease severity, oxygen use and NYHA classification.
The CAMPHOR has been shown to be valid and reliable in the German population and is recommend for use in clinical practice.
Pulmonary hypertension; Pulmonary arterial hypertension; Chronic thromboembolic pulmonary hypertension; Quality of life; Patient reported outcome; German adaptation
A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH).
pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression.
206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status.
We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.
Chronic thromboembolic pulmonary hypertension; Heart rate; Prognosis; Pulmonary hypertension; Pulmonary arterial hypertension
Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders.
In this case–control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls.
Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls.
This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.
Pulmonary hypertension; Echocardiography; Martorell ulcer
An association between pulmonary arterial hypertension (PAH) and various immune disorders is well established. Recently, the role of an intact immune system in protecting against pulmonary angioproliferation was shown in an animal model.
To elucidate the role of T cells in human PAH, we comparatively studied T cell subclasses with emphasis on regulatory T cells (Treg) in the peripheral blood of patients with idiopathic pulmonary arterial hypertension (IPAH) and healthy controls.
Isolated peripheral blood mononuclear cells from 36 patients diagnosed with IPAH and 33 healthy controls were stained with fluorescently labeled monoclonal antibodies against superficial T cell markers (CD3, CD4, CD8, CD25) and FoxP3, the intracellular marker of Treg cells. The relative cell distribution was analyzed by flow cytometry. The functionality of patient and control Treg cells was assessed by coculture of Treg with nonregulatory T cells from the same individual.
Significantly less CD8+ T cells (p = 0.02) and more CD25hi+ and FoxP3+CD4+ T cells were found in the peripheral blood of patients compared with controls (p = 0.009 and p < 0.001, respectively). The percentage of FoxP3+ cells within the CD25hi+CD4+ Treg cells was similar. Treg cell functionality was equal in patients and controls.
Our findings of decreased CD8+ T cells and increased Treg cells in the peripheral blood of patients with IPAH are novel and may have implications for directing future research in the field to elucidate the differential role of T cells and the immune system in IPAH.
CD4; CD8; CD25; FoxP3; Idiopathic pulmonary arterial hypertension; Regulatory T cells
While infectious peritonitis is a common occurrence in patients with liver cirrhosis, Mycoplasma is rarely identified as a causative agent.
We report the case of a 43-year-old Caucasian woman presenting with an extensive abdominal conglomerate tumor mimicking malignancy. A histologic specimen showed a xanthogranulomatous inflammation. Subsequently, Mycoplasma hominis was identified as the specific causative infectious agent using a broad-range (eubacterial) polymerase chain reaction. To the best of our knowledge, this is the first reported case of an intra-abdominal Mycoplasma infection presenting as a conglomerate tumor.
An unusual presentation of an inflammatory process in the abdomen or an insufficient response to conventional therapy should prompt clinicians to consider atypical infectious agents in the differential diagnosis. This case illustrates the potential of newer diagnostic methods, since certain fastidious microorganisms may not be diagnosed and treated appropriately using conventional means.
Pulmonary arterial hypertension is a complication of systemic lupus erythematosus. Mortality in pregnant patients with pulmonary arterial hypertension related to connective tissue disease is as high as 56%. The authors report the first case of a successful maternal-fetal outcome in a pregnant patient with systemic lupus erythematosus-associated pulmonary arterial hypertension treated with sildenafil and inhaled iloprost during pregnancy and until several weeks after caesarean section.
The case presented is of a 29-year-old woman with systemic lupus erythematosus and associated severe pulmonary arterial hypertension. Vasodilator therapy with bosentan and sildenafil, immunosuppressive therapy with prednisone, hydroxychloroquine and azathioprine and oral anticoagulation (phenprocoumon) had normalized her right ventricular over right atrial pressure when she was diagnosed in her 5th week of pregnancy. The teratogenic drugs bosentan and phenprocoumon were stopped, the latter replaced by low molecular weight heparin. During the 35th week, a slight increase in pulmonary pressure was found. Therapy with inhaled iloprost was established. A caesarean section was performed in the 37th week and a healthy baby was delivered. The patient remained stable until 11 weeks after delivery, when an increase in right ventricular over right atrial pressure was noted. Bosentan was reintroduced and prednisone and azathioprine doses were increased. The patient has remained stable until the present time.
Pulmonary arterial hypertension has been considered a contraindication for pregnancy. Novel vasodilator therapy, combined with immunosuppressants in this patient with systemic lupus erythematosus, may "cure" pulmonary arterial hypertension and permit pregnancy with successful outcome. However, postpartum exacerbation of systemic lupus erythematosus and pulmonary arterial hypertension have to be considered.
Low bone mineral density (BMD) is common in chronic lung diseases and associated with reduced quality of life. Little is known about BMD in pulmonary hypertension (PH).
Steroid-naïve patients with PH (n=34; 19 idiopathic, 15 chronic thromboembolic) had BMD measured by DXA at the time of diagnostic right heart catheterization. Exercise capacity, quality of life and various parameters related to PH severity and bone metabolism were also assessed. 24 patients with left heart failure (LHF) were similarly assessed as controls.
The prevalence of osteopenia was high both in PH (80%) and in controls with LHF (75%). Low BMD was associated with lean body mass, age, lower BMI, impaired exercise capacity and in PH with higher pulmonary vascular resistance. Serum parathyroid hormone (PTH) was elevated and considerably higher in PH than in LHF (above normal, in 55 vs 29%). Secondary hyperparathyroidism was not related to impaired renal function but possibly to low vitamin D status.
Osteopenia is common in PH and in chronically ill patients with LHF. Osteopenia is associated with known risk factors but in PH also with disease severity. Preventive measures in an increasingly chronic ill PH population should be considered. Secondary hyperparathyroidism is highly prevalent in PH and might contribute to bone and possibly pulmonary vascular disease. Whether adequate vitamin D substitution could prevent low BMD in PH remains to be determined.
Pulmonary hypertension; chronic thromboembolic pulmonary hypertension; hyperparathyroidism; osteopenia; osteoporosis; left heart failure.
Caveolin-1 is a regulator of both intracellular calcium homeostasis and endothelial nitric oxide synthase and may play a pathogenetic role in pulmonary hypertension. In the present study, we aimed to investigate the correlations between pulmonary hemodynamics and vessel morphology including the expression of Caveolin-1 in pulmonary arterioles from patients with chronic obstructive pulmonary disease (COPD) who underwent lung-volume reduction surgery. Staining and subsequent analysis was performed on paraffin-embedded lung tissue from COPD patients (n = 12). Pulmonary arteries with an external diameter of 100-500µm were analysed. Immunhistochemistry with antibodies against caveolin-1 was performed and intensity was assessed. Morphometric data were obtained by using computer-assisted imaging software. The findings were quantified and correlated to hemodynamic data obtained by right-heart catheterization. In COPD patients with pulmonary hypertension (n = 5), the expression of caveolin-1 within the medial smooth muscle cell layer was found to be increased, whereas the intimal caveolin-1 was more prominently expressed in COPD patients with normal pulmonary pressures (n = 7). The ratio between these expression patterns was positively correlated to the mean pulmonary artery pressure. Similar findings were observed for the ratio between intimal and medial thickness as well as for the expression of smooth muscle actin (SMA).
Taken together, the expression of caveolin-1 within medial smooth muscle cells of pulmonary arteries in patients with COPD is associated with pulmonary hypertension. Our results thus emphasize a potential novel player in the pathogenesis of COPD-associated pulmonary hypertension.
Caveolin-1; chronic obstructive pulmonary disease (COPD); morphometry; pulmonary hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and still incurable disease. Research of IPAH-pathogenesis is complicated by the lack of a direct access to the involved tissue, the human pulmonary vasculature. Various auto-antibodies have been described in the blood of patients with IPAH. The purpose of the present work was therefore to comparatively analyze peripheral blood B lymphocyte RNA expression characteristics in IPAH and healthy controls.
Patients were diagnosed having IPAH according to WHO (mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary occlusion pressure ≤ 15 mmHg, absence of another explaining disease). Peripheral blood B-lymphocytes of patients and controls were immediately separated by density gradient centrifugation and magnetic beads for CD19. RNA was thereafter extracted and analyzed by the use of a high sensitivity gene chip (Affymetrix HG-U133-Plus2) able to analyze 47000 transcripts and variants of human genes. The array data were analyzed by two different softwares, and up-and down-regulations were defined as at least 1.3 fold with standard deviations smaller than fold-changes.
Highly purified B-cells of 5 patients with IPAH (mean pulmonary artery pressure 51 ± 13 mmHg) and 5 controls were analyzed. Using the two different analyzing methods we found 225 respectively 128 transcripts which were up-regulated (1.3–30.7 fold) in IPAH compared with healthy controls. Combining both methods, there were 33 overlapping up-regulated transcripts and no down-regulated B-cell transcripts.
Patients with IPAH have a distinct RNA expression profile of their peripheral blood B-lymphocytes compared to healthy controls with some clearly up-regulated genes. Our finding suggests that in IPAH patients B cells are activated.