Ralf Kaiser - Academia.edu (original) (raw)

Papers by Ralf Kaiser

European Respiratory Journal, 2012

Introduction: The endothelin pathway is upregulated in various forms of pulmonary hypertension. I... more Introduction: The endothelin pathway is upregulated in various forms of pulmonary hypertension. Its disease promoting activity has lead to the development of endothelin receptor blockers as specific therapeutics. The highly unstable active form requires greatest care in sample preparation to acquire reproducable results. In this study we examined the role of the more stable CT-proET in pulmonary hypertension using a high precision and standardized system. Methods: We examined 36 patients retrospectively. Therapy was applied following contemporary guidelines. Samples of platelet free EDTA plasma were stored at -80°C since collection between 2000 and 2003. Biomarker levels were determined by a Kryptor compact (BRAHMS, Germany) according to vendor instructions. Results: Patients were categorized according to DanaPoint classification as class 1 (n=16), class 2 (n=1), class 3 (n=9), class 4 (n=8) and class 5 (n=2). The mean follow-up time was 4.67 years. Survivors had significantly lower...

European Respiratory Journal, 2013

Background: We aimed to assess active and passive tobacco smoke exposure in a larger PH-collectiv... more Background: We aimed to assess active and passive tobacco smoke exposure in a larger PH-collective and to compare it with epidemiological data from presumptively healthy subjects. Methods: This is an international, multicenter, case-control study including patients with differently classified precapillary PH from Germany (DE), Austria (AUT) and Switzerland (CH). All patients were asked specific questions about active and second-hand tobacco smoke exposure. Presumptively healthy controls were retrieved from the Swiss Health Survey (SHS) and the SHIP-cohort (Germany). Results: We analyzed 494 PH-patients (61.9% females) from CH (46%), DE (48%), and AUT (6%). The mean age was 57.7, BMI 26.9, and the 6 minute walking distance 372m. Patients were classified as pulmonary arterial (idiopathic (37.0%), associated (24.7%)), chronic thromboembolic (24.5%), PH in left heart disease (0.6%), miscellaneous PH (3.2%) and 8.7% had PH in chronic lung disease. Overall, tobacco smoke exposure was comm...

European Respiratory Journal, 2012

Background: Pulmonary hypertension (PH) is associated with dysfunction of pulmonary endothelium. ... more Background: Pulmonary hypertension (PH) is associated with dysfunction of pulmonary endothelium. Shearstress dependent peripheral arterial endothelial dysfunction has been found in various cardiovascular diseases and data in PH is limited. The aim of this study was to evaluate peripheral endothelial function in IPAH and CTEPH and the relation to right heart function. Methods: Flow mediated dilation (FMD) of the brachial artery was determined in 26 patients (55.5±15.5y, PAPm: 48.0±13.7mmHg, PVR: 837.6±476.8dyn*s*cm-5) with IPAH or CTEPH and 14 healthy controls. FMD was defined as the maximum change in vessel diameter after reactive hyperemia. Right ventricular function was examined by echocardiography. Results: Patients and controls were similar in terms of peripheral flow conditions and cardiovascular risk factors including Intima-media thickness (IMT) (IMT: 0.57±0.14 vs. 0.59±0.14 mm, p=0.39). Patients with PH demonstrated impaired peripheral endothelial function (FMD absolute chan...

B54. CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION, 2009

European Heart Journal, 2011

To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarcti... more To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarction (AMI) and in cardiogenic shock (CS). Methods and results In patients with uncomplicated AMI (n ¼ 20), CS (n ¼ 30) and in age-matched healthy controls (HC; n ¼ 20), TLR2 expression on monocytes was assessed by flow cytometry. Tumour necrosis factor alpha (TNFa) and interleukin-6 (IL6) expression in monocytes was analysed by intracellular cytokine staining. TLR2 expression was increased in patients with AMI compared with HC [mean fluorescence intensity (MFI) 111.1 + 8.2 vs. 66.9 + 1.5, P , 0.001]. In patients with CS, TLR2 expression was further increased (132.8 + 5.6 MFI, P ¼ 0.009 vs. AMI). This was accompanied by an increased expression of the proinflammatory cytokines TNFa (4.3 + 1.6% in AMI vs. 20.5 + 5.9% in CS, P ¼ 0.004) and IL6 (6.3 + 1.6% in AMI vs. 20.6 + 6.2% in CS, P ¼ 0.032). Furthermore, in all patients with myocardial infarction (AMI + CS; n ¼ 50), a strong correlation between the monocytic TLR2 expression and the symptom to reperfusion time (r 2 ¼ 0.706, P , 0.001) was found, implying tissue hypoxia dependency. Symptom to reperfusion time is a main factor to influence TLR2 expression but not the presence of CS. TLR2 expression of mononuclear cells exposed in vitro to hypoxia was assessed by flow cytometry and western blot. In vitro measurements showed a hypoxia-mediated monocytic TLR2 expression up-regulation. Conclusion We demonstrate TLR2 up-regulation and increased proinflammatory cytokine expression in circulating monocytes in AMI/CS depending on disease severity, implying an important role of TLR2 expression in ischaemic injury.

Thrombosis Research, 2014

Introduction: Elevated plasma viscosity (PV) is observed in patients with vascular risk factors, ... more Introduction: Elevated plasma viscosity (PV) is observed in patients with vascular risk factors, such as diabetes mellitus or arterial hypertension. In this study we investigated the association of plasma viscosity and the different clinical and radiological entities of cerebral ischemia. Methods: PV of 465 consecutively admitted patients with clinical symptoms of acute cerebral ischemia without radiological signs of bleeding was measured. Data is expressed as median [range] unless stated otherwise. p b 0.05 was considered statistically significant. Results: Patients with acute cerebral ischemia (TIA or Stroke) showed increased PV (TIA 1.27mPas [1.07-1.53], stroke 1.27mPas [1.07-1.56]) compared to patients without cerebral ischemia (Mimics) (1.23mPas [1.06-1.42]). The group with radiologically proven small vessel disease (SVD) had a significantly higher mean values of PV (1.29mPas [1.06-1.54]) compared to those with signs of large vessel disease or cardioembolic events (1.22mPas [1.07-1.56], p b 0.001). Patients with chronic heart failure (p = 0.007), arterial hypertension (p b 0.001) and diabetes mellitus (p = 0.002) had higher PV compared to patients without these cardiovascular risk factors. Hyperlipidemia or nicotine abuse showed no relation to PV. Conclusion: Elevated PV is not only associated TIA and Stroke but is also found in patients with radiological signs of cerebral SVD. High levels of PV could be an underestimated risk for TIA and Stroke and participate in the complex pathophysiology of SVD. Prospective observational and interventional studies are warranted for further evaluation of PV in neurological ischemic diseases.

Artificial Organs, 2021

Members of the study group are listed in the appendix.

European Respiratory Journal, 2016

Introduction: Extracorporeal CO 2 removal (ECCO 2 R) is increasingly used as a therapeutic strate... more Introduction: Extracorporeal CO 2 removal (ECCO 2 R) is increasingly used as a therapeutic strategy in hypercapnic lung failure in order to avoid intubation, to allow lung protective ventilator settings, or to facilitate weaning from invasive ventilation. Here, we report on the Homburg Lung, a novel minimal-invasive mid-flow ECCO 2 R system which was established and successfully used at our ICU. The Homburg Lung is a pump-driven (Maquet Rotaflow) system for veno-venous ECCO 2 R with ¼” tubing and a 0.8 m 2 surface oxygenator (Maquet Quadrox-I pediatric). Vascular access is usually established via a 19F/21cm bilumen cannula in the right internal jugular vein. Methods: To analyse efficacy and safety of the Homburg Lung, we screened our patient registry for ECCO 2 R procedures since 2013. Patients who underwent ECMO prior to ECCO 2 R were excluded. Patients who underwent ECCO 2 R more than one time since 2013 were only included once. Results: A total of 19 patients (age 52.3 ± 12.86 years, 42.1% female) was analysed. Ventilatory failure occurred due to COPD (47.4%), cystic fibrosis (21 %), and other origins (31.6%). The system generated a blood flow of 1.23 ± 0.29 lpm. Gas flow was 5.37 ± 2.98 lpm. Within 4 h, pCO 2 could be reduced from 74.03 ± 17.51 mmHg to 55.53 ± 10.85 mmHg. Cannulation-associated complications were transient arrhythmia (1/19 patients), pneumothorax (1/19), and air embolism (1/19). Fatal complications were not registered. Conclusion: The Homburg Lung provides effective CO 2 removal in hypercapnic lung failure. The cannulation is a safe procedure with complication rates comparable to those in central venous catheter implantation.

Respiratory Research, 2016

Background: The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased ... more Background: The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased shear stress and hypoxia. Both conditions are prevalent in pulmonary hypertension (PH). TSP-1 damages the local microcirculation by disrupting pathways, which are essential for specific medical therapeutics. Furthermore, TSP-1 induces excessive fibrosis and smooth muscle proliferation-a common finding in advanced PH-via TGF-ß and might promote disease progression. The prognostic impact of circulating TSP-1, influence on hemodynamic parameters and interaction with other biomarkers in patients with PH is incompletely understood. This study examines prospectively circulating TSP-1 in association with hemodynamic parameters, clinical variables and mortality. Methods: Circulating TSP-1 was measured prospectively in 93 patients with precapillary PH undergoing right heart catheterization and in 19 subjects without PH. TSP-1 levels were determined by ELISA and examined in the context of hemodynamic variables. For evaluation of survival, patients were monitored for adverse events on a 3-monthly basis and contacted at the end of the study after 5 years. In addition, levels of big-endothelin and humoral cofactors of TSP-1 release were measured. Results: Patients with PH had significantly increased TSP-1 levels compared to controls without PH (1114 ± 136 ng/mL vs. 82.1 ± 15.8 ng/mL, p < 0.05). Levels were correlated with mean pulmonary artery pressure (PAPm, r = −0.58, p < 0.001) and pulmonary vascular resistance (PVR, r = 0.33, p = 0.002). Survivors had lower TSP-levels as non-survivors and all cause mortality associated with TSP-1 plasma levels above 2051 ng/mL (p = 0.0002, HR 1.49). Conclusions: High plasma levels of TSP-1 are associated with increased PAPm, increased PVR and decreased survival. Due to its interaction with therapeutic pathways, studies are warranted to clarify the impact of TSP-1 on of specific medications for PH.

European Respiratory Journal, 2015

Background: Left ventricular torsion is directly related to muscle fibre orientation. The occurre... more Background: Left ventricular torsion is directly related to muscle fibre orientation. The occurrence of a flattened intraventricular septum and paradoxical movement are associated with precapillary pulmonary hypertension (PH). This study examines changes in left ventricular torsion due to this deformation. Methods: 50 patients with PH and 15 healthy controls received echocardiography including parameters of right ventricular function and optimized short axis views, suitable for speckle tracking analysis. Raw data was obtained and F-test was used for pointwise inference by eccentricity index. Results: With increasing eccentricity of the LV, decreased and delayed systolic torsion became apparent. Moreover, systolic torsion rate decreased reflecting decreased systolic function. While a trend to decreased diastolic torsion and torsion rate was observed, none of this reached significance. ![Figure][1] Discussion: Septal deformation has been observed in PH and used for prognosis previously. The effect on LV mechanics is described in this study for the first time. We observed a decrease in LV torsion not only dependent from pressure increase in the pulmonary circulation, but RV and LV geometry. This might lead to hypotension in patients with PH and serve as both novel prognostic parameter as well as the basis for treatment options in CTEPH scheduled for pulmonary thrombendarterectomy. [1]: pending:yes

European Respiratory Journal, 2012

Introduction: The endothelin pathway is upregulated in various forms of pulmonary hypertension. I... more Introduction: The endothelin pathway is upregulated in various forms of pulmonary hypertension. Its disease promoting activity has lead to the development of endothelin receptor blockers as specific therapeutics. The highly unstable active form requires greatest care in sample preparation to acquire reproducable results. In this study we examined the role of the more stable CT-proET in pulmonary hypertension using a high precision and standardized system. Methods: We examined 36 patients retrospectively. Therapy was applied following contemporary guidelines. Samples of platelet free EDTA plasma were stored at -80°C since collection between 2000 and 2003. Biomarker levels were determined by a Kryptor compact (BRAHMS, Germany) according to vendor instructions. Results: Patients were categorized according to DanaPoint classification as class 1 (n=16), class 2 (n=1), class 3 (n=9), class 4 (n=8) and class 5 (n=2). The mean follow-up time was 4.67 years. Survivors had significantly lower...

European Respiratory Journal, 2013

Background: We aimed to assess active and passive tobacco smoke exposure in a larger PH-collectiv... more Background: We aimed to assess active and passive tobacco smoke exposure in a larger PH-collective and to compare it with epidemiological data from presumptively healthy subjects. Methods: This is an international, multicenter, case-control study including patients with differently classified precapillary PH from Germany (DE), Austria (AUT) and Switzerland (CH). All patients were asked specific questions about active and second-hand tobacco smoke exposure. Presumptively healthy controls were retrieved from the Swiss Health Survey (SHS) and the SHIP-cohort (Germany). Results: We analyzed 494 PH-patients (61.9% females) from CH (46%), DE (48%), and AUT (6%). The mean age was 57.7, BMI 26.9, and the 6 minute walking distance 372m. Patients were classified as pulmonary arterial (idiopathic (37.0%), associated (24.7%)), chronic thromboembolic (24.5%), PH in left heart disease (0.6%), miscellaneous PH (3.2%) and 8.7% had PH in chronic lung disease. Overall, tobacco smoke exposure was comm...

European Respiratory Journal, 2012

Background: Pulmonary hypertension (PH) is associated with dysfunction of pulmonary endothelium. ... more Background: Pulmonary hypertension (PH) is associated with dysfunction of pulmonary endothelium. Shearstress dependent peripheral arterial endothelial dysfunction has been found in various cardiovascular diseases and data in PH is limited. The aim of this study was to evaluate peripheral endothelial function in IPAH and CTEPH and the relation to right heart function. Methods: Flow mediated dilation (FMD) of the brachial artery was determined in 26 patients (55.5±15.5y, PAPm: 48.0±13.7mmHg, PVR: 837.6±476.8dyn*s*cm-5) with IPAH or CTEPH and 14 healthy controls. FMD was defined as the maximum change in vessel diameter after reactive hyperemia. Right ventricular function was examined by echocardiography. Results: Patients and controls were similar in terms of peripheral flow conditions and cardiovascular risk factors including Intima-media thickness (IMT) (IMT: 0.57±0.14 vs. 0.59±0.14 mm, p=0.39). Patients with PH demonstrated impaired peripheral endothelial function (FMD absolute chan...

B54. CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION, 2009

European Heart Journal, 2011

To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarcti... more To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarction (AMI) and in cardiogenic shock (CS). Methods and results In patients with uncomplicated AMI (n ¼ 20), CS (n ¼ 30) and in age-matched healthy controls (HC; n ¼ 20), TLR2 expression on monocytes was assessed by flow cytometry. Tumour necrosis factor alpha (TNFa) and interleukin-6 (IL6) expression in monocytes was analysed by intracellular cytokine staining. TLR2 expression was increased in patients with AMI compared with HC [mean fluorescence intensity (MFI) 111.1 + 8.2 vs. 66.9 + 1.5, P , 0.001]. In patients with CS, TLR2 expression was further increased (132.8 + 5.6 MFI, P ¼ 0.009 vs. AMI). This was accompanied by an increased expression of the proinflammatory cytokines TNFa (4.3 + 1.6% in AMI vs. 20.5 + 5.9% in CS, P ¼ 0.004) and IL6 (6.3 + 1.6% in AMI vs. 20.6 + 6.2% in CS, P ¼ 0.032). Furthermore, in all patients with myocardial infarction (AMI + CS; n ¼ 50), a strong correlation between the monocytic TLR2 expression and the symptom to reperfusion time (r 2 ¼ 0.706, P , 0.001) was found, implying tissue hypoxia dependency. Symptom to reperfusion time is a main factor to influence TLR2 expression but not the presence of CS. TLR2 expression of mononuclear cells exposed in vitro to hypoxia was assessed by flow cytometry and western blot. In vitro measurements showed a hypoxia-mediated monocytic TLR2 expression up-regulation. Conclusion We demonstrate TLR2 up-regulation and increased proinflammatory cytokine expression in circulating monocytes in AMI/CS depending on disease severity, implying an important role of TLR2 expression in ischaemic injury.

Thrombosis Research, 2014

Introduction: Elevated plasma viscosity (PV) is observed in patients with vascular risk factors, ... more Introduction: Elevated plasma viscosity (PV) is observed in patients with vascular risk factors, such as diabetes mellitus or arterial hypertension. In this study we investigated the association of plasma viscosity and the different clinical and radiological entities of cerebral ischemia. Methods: PV of 465 consecutively admitted patients with clinical symptoms of acute cerebral ischemia without radiological signs of bleeding was measured. Data is expressed as median [range] unless stated otherwise. p b 0.05 was considered statistically significant. Results: Patients with acute cerebral ischemia (TIA or Stroke) showed increased PV (TIA 1.27mPas [1.07-1.53], stroke 1.27mPas [1.07-1.56]) compared to patients without cerebral ischemia (Mimics) (1.23mPas [1.06-1.42]). The group with radiologically proven small vessel disease (SVD) had a significantly higher mean values of PV (1.29mPas [1.06-1.54]) compared to those with signs of large vessel disease or cardioembolic events (1.22mPas [1.07-1.56], p b 0.001). Patients with chronic heart failure (p = 0.007), arterial hypertension (p b 0.001) and diabetes mellitus (p = 0.002) had higher PV compared to patients without these cardiovascular risk factors. Hyperlipidemia or nicotine abuse showed no relation to PV. Conclusion: Elevated PV is not only associated TIA and Stroke but is also found in patients with radiological signs of cerebral SVD. High levels of PV could be an underestimated risk for TIA and Stroke and participate in the complex pathophysiology of SVD. Prospective observational and interventional studies are warranted for further evaluation of PV in neurological ischemic diseases.

Artificial Organs, 2021

Members of the study group are listed in the appendix.

European Respiratory Journal, 2016

Introduction: Extracorporeal CO 2 removal (ECCO 2 R) is increasingly used as a therapeutic strate... more Introduction: Extracorporeal CO 2 removal (ECCO 2 R) is increasingly used as a therapeutic strategy in hypercapnic lung failure in order to avoid intubation, to allow lung protective ventilator settings, or to facilitate weaning from invasive ventilation. Here, we report on the Homburg Lung, a novel minimal-invasive mid-flow ECCO 2 R system which was established and successfully used at our ICU. The Homburg Lung is a pump-driven (Maquet Rotaflow) system for veno-venous ECCO 2 R with ¼” tubing and a 0.8 m 2 surface oxygenator (Maquet Quadrox-I pediatric). Vascular access is usually established via a 19F/21cm bilumen cannula in the right internal jugular vein. Methods: To analyse efficacy and safety of the Homburg Lung, we screened our patient registry for ECCO 2 R procedures since 2013. Patients who underwent ECMO prior to ECCO 2 R were excluded. Patients who underwent ECCO 2 R more than one time since 2013 were only included once. Results: A total of 19 patients (age 52.3 ± 12.86 years, 42.1% female) was analysed. Ventilatory failure occurred due to COPD (47.4%), cystic fibrosis (21 %), and other origins (31.6%). The system generated a blood flow of 1.23 ± 0.29 lpm. Gas flow was 5.37 ± 2.98 lpm. Within 4 h, pCO 2 could be reduced from 74.03 ± 17.51 mmHg to 55.53 ± 10.85 mmHg. Cannulation-associated complications were transient arrhythmia (1/19 patients), pneumothorax (1/19), and air embolism (1/19). Fatal complications were not registered. Conclusion: The Homburg Lung provides effective CO 2 removal in hypercapnic lung failure. The cannulation is a safe procedure with complication rates comparable to those in central venous catheter implantation.

Respiratory Research, 2016

Background: The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased ... more Background: The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased shear stress and hypoxia. Both conditions are prevalent in pulmonary hypertension (PH). TSP-1 damages the local microcirculation by disrupting pathways, which are essential for specific medical therapeutics. Furthermore, TSP-1 induces excessive fibrosis and smooth muscle proliferation-a common finding in advanced PH-via TGF-ß and might promote disease progression. The prognostic impact of circulating TSP-1, influence on hemodynamic parameters and interaction with other biomarkers in patients with PH is incompletely understood. This study examines prospectively circulating TSP-1 in association with hemodynamic parameters, clinical variables and mortality. Methods: Circulating TSP-1 was measured prospectively in 93 patients with precapillary PH undergoing right heart catheterization and in 19 subjects without PH. TSP-1 levels were determined by ELISA and examined in the context of hemodynamic variables. For evaluation of survival, patients were monitored for adverse events on a 3-monthly basis and contacted at the end of the study after 5 years. In addition, levels of big-endothelin and humoral cofactors of TSP-1 release were measured. Results: Patients with PH had significantly increased TSP-1 levels compared to controls without PH (1114 ± 136 ng/mL vs. 82.1 ± 15.8 ng/mL, p < 0.05). Levels were correlated with mean pulmonary artery pressure (PAPm, r = −0.58, p < 0.001) and pulmonary vascular resistance (PVR, r = 0.33, p = 0.002). Survivors had lower TSP-levels as non-survivors and all cause mortality associated with TSP-1 plasma levels above 2051 ng/mL (p = 0.0002, HR 1.49). Conclusions: High plasma levels of TSP-1 are associated with increased PAPm, increased PVR and decreased survival. Due to its interaction with therapeutic pathways, studies are warranted to clarify the impact of TSP-1 on of specific medications for PH.

European Respiratory Journal, 2015

Background: Left ventricular torsion is directly related to muscle fibre orientation. The occurre... more Background: Left ventricular torsion is directly related to muscle fibre orientation. The occurrence of a flattened intraventricular septum and paradoxical movement are associated with precapillary pulmonary hypertension (PH). This study examines changes in left ventricular torsion due to this deformation. Methods: 50 patients with PH and 15 healthy controls received echocardiography including parameters of right ventricular function and optimized short axis views, suitable for speckle tracking analysis. Raw data was obtained and F-test was used for pointwise inference by eccentricity index. Results: With increasing eccentricity of the LV, decreased and delayed systolic torsion became apparent. Moreover, systolic torsion rate decreased reflecting decreased systolic function. While a trend to decreased diastolic torsion and torsion rate was observed, none of this reached significance. ![Figure][1] Discussion: Septal deformation has been observed in PH and used for prognosis previously. The effect on LV mechanics is described in this study for the first time. We observed a decrease in LV torsion not only dependent from pressure increase in the pulmonary circulation, but RV and LV geometry. This might lead to hypotension in patients with PH and serve as both novel prognostic parameter as well as the basis for treatment options in CTEPH scheduled for pulmonary thrombendarterectomy. [1]: pending:yes