Ralf Ewert

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUNDnOriginally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions.nnnMETHODSnProspective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18-65 years) and elderly (>65 years) patients with newly diagnosed IPAH (incident cases only) were compared.nnnRESULTSnA total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n=209; median age, 54 [16] years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n=378; median age, 75 [8] years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance>400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p=0.006 by log-rank analysis).nnnCONCLUSIONSnIn countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required.nnnCLINICAL TRIALS REGISTRATIONnNCT01347216.

Anticoagulation and Survival in Pulmonary Arterial Hypertension Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216.BACKGROUND: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). nMETHODS AND RESULTS: We analyzed data from COMPERA, an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1,283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year-survival (p=0.006) in patients on anticoagulation compared to patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (p=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio 0.79, 95% confidence interval 0.66 to 0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. nCONCLUSIONS: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. nCLINICAL TRIALS REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifier: NCT01347216.

Effects of Iloprost Inhalation on Exercise Capacity and Ventilatory Efficiency in Patients With Primary Pulmonary Hypertension

BACKGROUNDnThe continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH.nnnMETHODS AND RESULTSnIn 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 microgram of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne. s(-1). cm(-5), P<0.05). Arterial blood gases remained unchanged (PaO(2) 69.3 versus 66.8 mm Hg; PaCO(2) 29.6 versus 28.8 mm Hg). Iloprost significantly (P<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL. kg(-1). min(-1)), VE-versus-V CO(2) slope (58 versus 51.4).nnnCONCLUSIONSnThe present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.

Peripheral airway obstruction in primary pulmonary hypertension

Background: As there is controversy about changes in lung function in primary pulmonary hypertension (PPH), lung mechanics were assessed with a focus on expiratory airflow in relation to pulmonary haemodynamics. Methods: A cross sectional study was performed in 64 controls and 171 patients with PPH (117 women) of mean (SD) age 45 (13) years, pulmonary artery pressure (PAPmean) 57 (15) mm Hg, and pulmonary vascular resistance 1371 (644) dyne.s/cm5. Results: Mean (SD) total lung capacity was similar in patients with PPH and controls (98 (12)% predicted v 102 (17)% predicted, mean difference –4 (95% confidence interval (CI) –7.89 to –0.11); residual volume (RV) was increased (118 (24)% predicted v 109 (27)% predicted, mean difference 9 (95% CI 1.86 to 16.14); and vital capacity (VC) was decreased (91 (16)% predicted v 102 (10)% predicted, mean difference –11 (95% CI 15.19 to –6.80). RV/TLC was increased (117 (27)% predicted v 97 (29)% predicted, mean difference 20 (95% CI 12.3 to 27.8)) and correlated with PAPmean (r=0.31, p<0.001). In patients with PAPmean above the median of 56 mm Hg, RV/TLC was further increased (125 (32)% predicted v 111 (22)% predicted, mean difference –14 (95% CI –22.2 to –5.8)). Expiratory flow-volume curves were reduced and curvilinear in patients with PPH. Conclusions: Peripheral airway obstruction is common in PPH and is more pronounced in severe disease. This may contribute to symptoms. Reversibility of bronchodilation and relation to exercise capacity need further evaluation.

Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis

Pulmonary hypertension is a relevant interceding morbidity in patients with pulmonary fibrosis that has significant impact on exercise tolerance and outcome. The aim of this study was to further characterize the exercise intolerance, dyspnoea and ventilatory inefficiency of patients with pulmonary fibrosis in the presence or absence of pulmonary hypertension via cardiopulmonary exercise testing. Thirty-four patients underwent pulmonary function testing, symptom-limited exercise testing on a bicycle and dyspnoea evaluation according to the BORG scale. Pulmonary hypertension was assessed by echocardiography and in a subset of patients right heart catheterization. Sixteen of 34 patients with pulmonary fibrosis revealed pulmonary hypertension. While all study patients did not differ in lung functions and demographic characteristics, patients suffering from pulmonary hypertension showed a significantly impaired exercise tolerance and worsened ventilatory inefficiency. The extent of pulmonary artery pressure elevation impacted significantly on ventilatory inefficiency. In addition, the increased ventilatory requirements significantly influenced the extent of dyspnoea in patients with pulmonary hypertension. We conclude that pulmonary hypertension has a significant impact on exercise capacity and dyspnoea in patients with interstitial lung disease (ILD). The further impairment of exercise capacity as well as the extent of dyspnoea in patients with interceding PHT is attributable to a significantly impaired ventilatory inefficiency.

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (Removab) (anti-EpCAM x Anti-CD3): results of a phase 1/2 study.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcγ receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200u2009μg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomabs mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.

Late acute rejection in long-term renal allograft recipients. Diagnostic and predictive value of circulating activated T cells.

Episodes of acute rejection can occur in functional renal grafts even at a very late stage after transplantation. They are not necessarily due to patient non-compliance. The incidence of late acute rejection is commonly underestimated because the diagnosis generally requires histopathology in order to rule out other origins of declining graft function, even more so, as the typical signs of acute rejection as seen in the early posttransplantation period (sudden and rapid increase of creatinine serum level, inflammatory signs) are missing. Histology revealed acute rejection in 157 of 412 renal allograft recipients suffering from progressive graft deterioration between the 2nd and 18th year after Tx. Late acute rejection was clearly associated with elevated levels of activated HLA-DR+ T cells in the peripheral blood. These cells were characterized by flow cytometry to be postmitotic activated effector-T cells belonging to the CD4+ and CD8+ “memory” T cell pool. The high sensitivity (97%) and specificity (88%) of flow cytometric analysis allows for the discrimination between late acute rejection and other causes of deteriorating graft function (infection, toxicity, arteriopathy, chronic rejection). Additionally, this immune monitoring can predict the success of antirejection therapy as early as a few days after initiation of treatment while conventional parameters do not reflect the therapeutic result until 1–3 weeks later. In addition to this, peripheral T cell activation also seems to identify a subgroup of patients with chronic rejection who would respond, at least partially, to steroid bolus therapy. As a result, this parameter is very useful for the clinical management of patients suffering from late deterioration of renal graft function.

Measurement of Anti-Human Cytomegalovirus T Cell Reactivity in Transplant Recipients and Its Potential Clinical Use: A Mini-Review

By allowing direct determination of the frequencies of antigen-specific memory T cells in peripheral blood, novel techniques based on flow cytometry provide new diagnostic opportunities in various clinical settings, including organ transplantation. While the importance of the T cell compartment for the anti-human cytomegalovirus (HCMV) immune response is undisputed, efficient monitoring of this response was previously impossible because the conventional methods for measuring CD4+ and CD8+ T cell responses are too time-consuming and cost-intensive. We analyzed how the rapid induction of anti-HCMV CD4+ and CD8+ memory T cells by HCMV viral lysate or HCMV-derived peptides, respectively, followed by a flow-cytometric detection step, may be used to monitor HCMV-specific CD4+ and CD8+ memory T cells in solid-organ recipients. We also discuss a number of preconditions for integrating such testing into the clinical routine.