[Prevalence of Pulmonary Hypertension in Dialysis Patients with End-stage Renal Disease]. / Prävalenz der pulmonalen Hypertonie bei Dialysepatienten mit terminaler Niereninsuffizienz.

BACKGROUND: In patients with end-stage renal disease (ESRD), pulmonary hypertension (PH) is a frequent complication with different etiologies and a 17 - 56 % prevalence rate. We evaluated the impact of fluid retention measured by bioimpedance on the prevalence of PH in this patient cohort. METHODS: All patients with ESRD at the dialysis center of the Medical Clinic II of the University Hospital Gießen were invited to participate in the study and undergo non-invasive PH screening. If the screening suggested PH, patients underwent bioimpedance spectroscopy for measurement of fluid retention followed by adjustment of fluid levels to normovolemia as far as possible. Thereafter a second non-invasive screening was performed in this patient cohort after reaching normovolemia. If signs for PH persisted, patients underwent right heart catheterization for further assessment. RESULTS: 52 patients agreed to participate in the study. After the first noninvasive screening, PH was suspected in 12 patients (23 %). After adjustment of fluid levels to reach normovolemia, PH was suspected only in 4 patients (7.7 %) with confirmation in 2 patients by right heart catheterization (3.8 %). DISCUSSION: In patients with ESRD, PH is frequently associated with fluid retention as shown by bioimpedance spectroscopy. After adjustment of fluid to normal levels, PH was confirmed by invasive test in nearly 4 % of cases.

Airway-centered interstitial fibrosis - an under-recognized subtype of diffuse parenchymal lung diseases.

Airway centered interstitial fibrosis (ACIF) has been recently suggesed as a rare histological pattern of interstitial lung disease of variable etiology and outcome. It is characterized by fibrosis of the respiratory bronchioles and the peribronchiolar interstitium. We describe the clinical features of 13 patients (7 female, mean age 55 years) with histologically proven ACIF in 12 cases and long-term follow up. In ten patients, exogenous agents could be detected (mould n=5, wood n=2, leather exposure n=1, occupational exposure n=2). Two patients had rheumatoid arthritis and 1 patient suffered from recurrent aspiration. In three patients no associated exposure could be detected. Eight patients were never-smokers, while five were ex- smokers. At time of diagnosis patients presented with a moderate restrictive ventilation impairment and sever reduction in diffusion capacity (VC 61%, TLC 66%, DLCOc-SB 38% pred.). All patients were started on immunosuppressive therapy with steroids which were combined with azathioprine in seven and with mycophenolate mofetil in one patient. Median time of follow up was 52 months (2-127 months). Patients with ACIF due to exogenous agents or associated with RA were stable with immunosuppressive therapy. One patient with idiopathic ACIF showed a progressive deterioration within 29 months despite immunosuppression and died while on a waiting-list for lung transplantation. In our experience ACIF is a rare finding, which is relatively frequently observed in the context of hypersensitivity pneumonitis, aspiration and rheumatoid arthritis, while idiopathic ACIF was a minority. In the majority of patients, ACIF showed a favorable long-term outcome with immunosuppressive therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 218-229).

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Shunt volume dynamics in stroke patients with patent foramen ovale.

A variation in right atrial and pulmonary arterial pressure might result in a shunt dynamic across a patent foramen ovale (PFO). In the present study we tested if peak exercise facilitates a restoration of right to left shunt (RLS) in stroke patients who demonstrated a functional PFO closure (no evidence of RLS across an initially demonstrated PFO). In stroke patients with PFO demonstrating a functional closure, the RLS was reassessed on peak exercise using contrast-enhanced transcranial Doppler sonography. The exercise procedure consisted of a cardiopulmonary exercise test with supplementary stress echocardiography for assessment of pulmonary circulation. Four stroke patients with initially PFO curtain pattern and a subsequent functional PFO closure (no evidence for RLS) underwent the procedure. In all four patients a RLS could be resurrected during peak physical exercise after a Valsalva strain. While in two patients peak exercise led to an RLS in a countable range of microembolic signals, in two patients a curtain pattern was obtained. One patient showed evidence for reoccurrence of RLS on peak exercise without a Valsalva strain. The patients with curtain pattern had a better peak exercise performance. Although the systolic pulmonary arterial pressure increased during exercise in all patients, there was no direct correlation with the detected RLS. After a functional PFO closure peak exercise combined with a Valsalva strain facilitates the reoccurrence of RLS in stroke patients.

[Dynamic hyperinflation in pulmonary arterial hypertension: "hyperinflator" and "non-hyperinflator"]. / Dynamische Hyperinflation bei der pulmonal arteriellen Hypertonie: "Hyperinflator" und "Non-Hyperinflator".

BACKGROUND: The dynamic decrease in inspiratory capacity (IC) during exercise with restriction of tidal volume (VT) is known as dynamic hyperinflation (DH) and is described mostly in patients with COPD differentiating between a "hyperinflator" and a "non-hyperinflator". Recent studies have revealed DH in patients with idiopathic pulmonary arterial hypertension (iPAH), but the influence of the DH on the reduced exercise capacity with exertional dyspnoae is still being debated. METHODS: We analysed flow-volume curves during cardiopulmonary exercise testing (CPET) in idiopathic PAH (n = 19), in COPD (n = 17), in idiopathic pulmonary fibrosis (IPF) (n = 19) and a control group (n = 30). We measured IC at rest and during maximal exercise and furthermore ventilation, VT and oxygen uptake (VO2 peak). In iPAH a right heart catheter test and a 6-minute walk test (6MWT) were performed, also the B-type naturetic peptide (BNP) and the NYHA/WHO functional class were determined. RESULTS: The IC decreased significantly in 11 PAH "hyperinflators" (PAH-H) (Δ IC: - 0.34 ± 0.14 L, p < 0.001) compared to 8 PAH "non-hyperinflators" (PAH-NH) (Δ IC: 0.08 ± 0.2 L). COPD patients exhibited a characteristic hyperinflation pattern with a decrease in IC throughout exercise (Δ IC: - 0.61 ± 0.3 L, p < 0.001), while patients with IPF (Δ IC: 0.03 ± 0.15 L) and the control group responsed to exercise with a non-hyperinflator pattern (Δ IC: 0.1 ± 0.2 L). Both PAH collectives showed a reduced IC/TLC, while VT/IC was elevated with a decreased peak VO2 and max. performance compared to the control group. Correlations of the IC rest/max (L) were shown in PAH-H and PAH-NH with the VO2 peak, max. performance and VT. CONCLUSION: The analysis of flow-volume curves during CPET can indentify DH in a subgroup of patients with iPAH. The DH contributes significantly but slightly to the development of exertional limitations and dyspnoe in a subgroup of iPAH. Further studies with a larger sample size will be required to definitively measure the impact of the DH seen in these patients.

Diagnosis of CTEPH versus IPAH using capillary to end-tidal carbon dioxide gradients.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents an important differential diagnosis to idiopathic pulmonary arterial hypertension (IPAH). We hypothesised that the capillary to end-tidal carbon dioxide gradient at rest and during exercise might help differentiate CTEPH from IPAH. Patients who presented with unequivocal IPAH or CTEPH according to ventilation/perfusion scanning, pulmonary angiography, computed tomography and right heart catheterisation were included in this retrospective study and compared with healthy controls. 21 IPAH patients and 16 CTEPH patients fulfilled the inclusion criteria. Haemodynamics and peak oxygen uptake were comparable, but respiratory rates at rest and during exercise were significantly higher in CTEPH than in IPAH. End-tidal carbon dioxide was significantly lower in CTEPH versus IPAH at rest and during exercise, while capillary carbon dioxide values were similar. Correspondingly, capillary to end-tidal carbon dioxide gradients were significantly increased in CTEPH versus IPAH at rest and during exercise (median (range) 8.6 (3.0-13.7) versus 4.4 (0.9-9.0) (p<0.001) and 9.3 (3.3-13.1) versus 4.1 (0.0-8.8) mmHg (p<0.001), respectively). Although these values were closer to normal in IPAH they were still significantly elevated compared with healthy controls (2.3 (-4.8-8.1) and -1.9 (-5.7-6.2) mmHg, respectively). Capillary to end-tidal carbon dioxide gradients may help to distinguish CTEPH from IPAH based on resting and exercise values.

[Pulmonary arterial hypertension]. / Pulmonalarterielle Hypertonie.

Pulmonary arterial hypertension is a chronic disorder of the pulmonary circulation characterized by an increased pulmonary artery pressure and an impaired cardiac function. It can present as idiopathic form or associated with several systemic diseases. Typical symptoms include progressive dyspnoea and exercise intolerance. When pulmonary arterial hypertension is suspected, echocardiography is the key investigation for noninvasive assessment of the disease. The diagnosis requires an invasive measurement of pulmonary hemodynamics by right heart catheterization. Treatment is based on general measures and application of pulmonary vasoactive compounds, such as prostanoids, endothelin receptor blockers and phosphodiesterase 5 inhibitors. These treatment options can be combined at progression of the disease. Lung transplantation might be an option in patients refractory to medical therapy.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen: Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Pulmonary hypertension in hereditary haemorrhagic teleangiectasia]. / Pulmonalvaskuläre Beteiligung bei Morbus Osler.

BACKGROUND: In hereditary haemorrhagic teleangiectasia (HHT) can be accompanied by pulmonary arteriovenous vascular malformations (PAVM). Pulmonary hypertension (PH) is regarded as a rare pulmonary manifestation. METHODS AND PATIENTS: We non-invasively assessed the pulmonary circulation in 20 patients with HHT using standard resting echocardiography including contrast studies. In 14 patients a mutation in the endoglin gene was present. The other 6 patients carried a mutation in the Alk-1 gene. RESULTS: We identified 4 patients with manifest PH, among them 2 patients (both with endoglin mutations) with concurrent thromboembolism, and 2 patients (both with Alk-1 mutations) with hepatic manifestations of HHT. Two patients required specific pulmonary vasoactive therapy with sildenafil and bosentan, respectively. Another patient received embolisation therapy for hypercirculatory PH due to hepatic arteriovenous malformations. Pulmonary arteriovenous malformations were found in 8 patients (7 with endoglin, and 1 with Alk-1 mutations), among them were 2 patients with PH. CONCLUSIONS: Patients with HHT should undergo echocardiographic screening for PAVM as well as PH. When PH is detected, other conditions such as hepatic or thromboembolic diseases should be considered, regardless of the underlying genetic defect.

[Therapy of pulmonary arterial hypertension]. / Therapie der pulmonalarteriellen Hypertonie.

Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.

Noninvasive detection of early pulmonary vascular dysfunction in scleroderma.

BACKGROUND: Pulmonary arterial hypertension is a serious complication in scleroderma and early diagnosis is warranted. PATIENTS AND METHODS: 33 Scleroderma patients (mean age 54 [SD 11] years) with normal systolic pulmonary artery pressure (sPAP), right and left ventricular parameters at rest were enrolled in this study. They were investigated by echocardiography during physical exercise and hypoxia. A hypertensive pulmonary vascular reaction was diagnosed when sPAP inappropriately increased during exercise compared to individual exercise tolerance, or if sPAP was >40mm Hg during hypoxia exposure, respectively. RESULTS: In 17 patients there was a normal increase of sPAP at exercise of 34 [8]mm Hg (mean VO2 max 70 [17]% predicted), and 29 [5]mm Hg during hypoxia. Sixteen patients developed a hypertensive pulmonary vascular response with a sPAP of 47 [9]mm Hg during exercise (VO2max 64 [15]% pred.), and 54 [7]mm Hgmm Hg during hypoxia, respectively. The sPAP/VO2 max ratio was higher in patients with a hypertensive response (0.76 [0.17] vs. 0.49 [0.12] p<0.0001). There was no difference in scleroderma subtype, duration of disease, gender or age between groups. During a 3-year follow up one patient with a hypertensive response developed manifest pulmonary arterial hypertension. CONCLUSION: Non-invasive assessment of pulmonary circulation during physical exercise and/or hypoxia enables screening for pulmonary vascular dysfunction in scleroderma.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

[Obstructive sleep apnoea and metabolic syndrome]. / Obstruktive Schlaf-Apnoe und metabolisches Syndrom.

Metabolic syndrome, i. e., the combined occurrence of obesity, arterial hypertension, insulin resistance and dyslipidaemia (increased triglycerides, reduced HDL cholesterol), is associated with a marked increase in cardiovascular risk. The prevalence of metabolic syndrome in patients with obstructive sleep apnoea (OSA) is very high. Obesity is the main risk factor for OSA and OSA itself is now considered to be the most frequent cause of secondary arterial hypertension. Due to the confounding influence of obesity, the causal connection between OSA and metabolic disturbances is less well established, however, epidemiological data are at least in favour of an independent link between OSA and insulin resistance. It is known that CPAP therapy can ameliorate OSA-associated hypertension. In contrast, the effects of CPAP treatment on insulin resistance and dyslipidaemia have to be further elucidated by large, randomised interventional trials.

Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension.

For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean +/- sem age 62 +/- 11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863 +/- 38 dyn.s.cm(-5)) and a 6-min walking distance of 310 +/- 11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months' treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759 +/- 62 dyn.s.cm(-5). The 6-min walking distance increased significantly to 361 +/- 15 m after 3 months' treatment, and to 366 +/- 18 m after 12 months' treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long-term outcome of therapy.

Effects of nebulised iloprost on pulmonary function and gas exchange in severe pulmonary hypertension.

Nebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140 micro g iloprost/24h via an ultrasonic nebuliser. Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423+/-98 to 415+/-98) and percutaneous oxygen saturation increased in mean by 0.7% (90+/-6 to 91+/-5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction. Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV(1), FVC, TLC, residual volume nor in diffusions capacity, SO(2) at rest and during 6 min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6 min walking distance (6 MWD) after 3 months (246+/-113 to 294+/-115 m, P<0.05). In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients.