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Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD- GRN , namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD- GRN -associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD- GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD- GRN and potentially other CNS disorders.

Transcatheter aortic-valve replacement (TAVR) is increasingly being used for the treatment of aortic-valve stenosis. Therefore, the total number of patients with an aortic-valve prosthesis is increasing, causing the incidence of prosthetic-valve endocarditis to increase., Methods: Between March 2016 and July 2019, ten patients underwent surgery due to prosthetic-valve endocarditis after TAVR. They were identified in our institutional database and analyzed., Results: Infective endocarditis was diagnosed 17 ± 16 month after TAVR. Mean age was 79 ± 4.4 years. Microbiological detection showed 6/10 positive blood cultures for enterococcus faecalis. Median EuroScore II was 24.64%. The mean size of the surgically replaced aortic prosthesis was 23.6 ± 1.3 and that of the TAVR was 28.4 ± 2.3 mm. The surgically implanted aortic valves had a mean gradient of 8.5 ± 2.2 mmHg. One patient died in hospital due to septic multiorgan failure. After discharge, all patients survived with a mean follow-up of 9 ± 8 month., Conclusions: With a rising number of patients after TAVR, prosthetic-valve endocarditis will increasingly occur in patients who were previously considered high or intermediate risk. Our results show that patients with TAVR infective endocarditis can be operated on with good results. Surgical therapy should not be withheld from TAVR patients with infective endocarditis.

Amyloid-β (Aβ) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, Aβ plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aβ plaques, we observed a more ramified morphology of Aβ plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aβ plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aβ targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

To analyze whether cardiac surgical residents can perform their first surgeries without compromising patients' safety or outcomes, by comparing their performance and results to those of senior surgeons. All documented CABGs conducted between 2002 and 2020 were included. Surgeries were divided according to the experience level of the main surgeon (defined by the number of CABG conducted by him/her) using the following thresholds: 1000; 150; 80 and 35. This resulted in 5 groups: senior surgeons (the reference group); attending surgeons; fellow surgeons; advanced residents and new residents. Primary endpoint was 30 day mortality. Secondary endpoints included a list of intra and post-operative parameters (including in-hospital complications). A multivariable analysis was conducted. 16,486 CABG were conducted by 66 different surgeons over a period of 18 years. Multivariable analysis did not find significant differences between both the primary and the secondary endpoints. Skin-to-skin time correlated significantly with experience level, as new residents needed almost 30% more time than senior surgeons (234 vs 180 minutes). With a suitable supervision by experienced surgeons, patient selection and sufficient resources (longer duration of surgery), surgical residents can perform CABGs with good results and without compromising the patient's outcome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background:  Mental distress is suspected to influence the morbidity of cardiac patients. Evaluating mental distress in cardiac patients is rare and the impact on surgical outcome is still not certified., Methods:  In 94 cardiac surgical patients, mental distress was assessed by the Patient Health Questionnaire-4 (PHQ-4). We defined length of stay in hospital and on intensive care unit as well as time of mechanical ventilation as outcomes on surgery. Age, physical activity, diabetes, overweight, PHQ-4, and an inflammation marker were tested for their predictive value on outcomes., Results:  Reportedly prevalence of generalized anxiety was 16.0% and depression rate was 13.8%. Length of stay in hospital was 13 ± 8 days, time of mechanical ventilation was 10 (0-1,207) hours, and length of stay on intensive care unit was 3 ± 6 days. Length of stay in hospital was significantly predicted by age ( p  = 0.048), low physical activity ( p  = 0.029), and high C-reactive protein (CRP; p  = 0.031). Furthermore, CRP was the only significant predictor of time of mechanical ventilation and length of stay on intensive care unit., Conclusion:  Outcome was not predicted by mental distress. However, inflammation marker CRP was predictive for outcome, potentially caused by higher cardiovascular risk profile. Additionally, depression was referred to be associated with inflammation. Probably, the small sample and the timing of assessment were responsible for the missing relation between mental distress and outcome. We presume a relation with low physical activity and depression. Nevertheless, further randomized studies are needed to pay more attention on patients' distress to intervene preoperatively to improve postoperative outcome., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Diabetic vasculopathy plays an important role in the pathophysiology of coronary artery disease (CAD) with oxidative stress as a strong mediator. This study aims to elucidate the underlying pathomechanisms of diabetic cardiac vasculopathy leading to coronary disease with an emphasis on the role of oxidative stress. Therefore, novel insights into antioxidant pathways might contribute to new strategies in the treatment and prevention of diabetic CAD., Methods: In 20 patients with insulin-dependent or non-insulin dependent diabetes mellitus (IDDM/NIDDM) and 39 non-diabetic (CTR) patients, myocardial markers of oxidative stress, vasoactive proteins, endothelial nitric oxide synthase (eNOS), activated phosphorylated eNOS ( p -eNOS), and antioxidant enzymes, e.g., tetrahydrobiopterin generating dihydrofolate reductase (DHFR), heme oxygenase (HO-1), as well as serum markers of inflammation, e.g., E-selectin, interleukin-6 (IL-6), and lipid metabolism, e.g., high- and low-density lipoptrotein (HDL- and LDL-cholesterol) were determined in specimens of right atrial tissue and in blood samples from type 2 diabetic and non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery., Results: IDDM/NIDDM increased markers of inflammation (e.g., E-selectin, p = 0.005 and IL-6, p = 0.051), decreased the phosphorylated myocardial p -eNOS ( p = 0.032), upregulated the myocardial stress response protein HO-1 ( p = 0.018), and enhanced the serum LDL-/HDL-cholesterol ratio ( p = 0.019). However, the oxidative stress markers in the myocardium and the expression of vasoactive proteins (eNOS, DHFR) showed only marginal adverse changes in patients with IDDM/NIDDM., Conclusion: Dyslipidemia and myocardial inflammation seem to be the major determinants of diabetic CAD complications. Dysregulation in pro-oxidative enzymes might be attributable to the severity of CAD and oxidative stress levels in all included patients undergoing CABG.

Objectives: Coronary artery bypass grafting or supra-arterial myotomy is now suggested as a better therapeutic option in myocardial bridging (MB) when medical treatment fails to control symptoms. For left anterior descending (LAD) MB, minimally invasive coronary artery bypass via a lower ministernotomy can be offered., Methods: Forty-four consecutive patients who underwent elective minimally invasive coronary artery bypass surgery from 2005 to 2014 via an inferior sternotomy using the left internal mammary artery as a bypass graft for LAD MB were evaluated retrospectively., Results: The mean age was 59.1 ± 13.1 years with 26 (59%) men and 18 (41%) women. The mean body mass index was 27.2 ± 3.9 and the mean EuroSCORE II was 1.6 ± 1.8. Routine coronary multislice computed tomography angiography on the 6th postoperative day revealed 97.7% graft patency. During the initial hospital stay, 1 patient (2.3%) underwent a reoperation for early graft failure. Forty patients (91%) could be followed up for a mean period of 64.4 ± 24.5 months after the procedure, during which 2 patients (4.5%) died of non-cardiac causes and 9 patients (20.5%) underwent postoperative coronary angiography with confirmed graft occlusion in only 1 case (2.3%). The improvement in the distribution of patients in the Canadian Cardiovascular Society class 0 was from 4 patients (9%) preoperatively to 37 patients (84%) at the end of the follow-up period (P-value 0.001)., Conclusions: Minimally invasive coronary artery bypass surgery via a lower ministernotomy may be safe and efficient for treating LAD artery MB with acceptable complication rates, cosmetic benefits and patency rates., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background Brain-derived neurotrophic factor (BDNF) is expressed in neuronal and nonneuronal cells and may affect vascular functions via its receptor, tropomyosin-related kinase B (TrkB). In this study, we determined the expression of BDNF in different perivascular adipose tissue (PVAT) depots of patients with established coronary atherosclerosis. Methods and Results Serum, vascular tissue, and PVAT surrounding the proximal aorta (C-PVAT) or internal mammary artery (IMA-PVAT) was obtained from 24 patients (79% men; mean age, 71.7±9.7 years; median body mass index, 27.4±4.8 kg/m 2 ) with coronary atherosclerosis undergoing elective coronary artery bypass surgery. BDNF protein levels were significantly higher in C-PVAT compared with IMA-PVAT, independent of obesity, metabolic syndrome, or systemic biomarkers of inflammation. mRNA transcripts of TrkB, the BDNF receptor, were significantly reduced in aorta compared with IMA. Vessel wall TrkB immunosignals colocalized with cells expressing smooth muscle cell markers, and confocal microscopy and flow cytometry confirmed BDNF receptor expression in human aortic smooth muscle cells. Significantly elevated levels of protein tyrosine phosphatase 1B, a negative regulator of TrkB signaling in the brain, were also observed in C-PVAT. In vitro, inhibition of protein tyrosine phosphatase 1B blunted the effects of BDNF on smooth muscle cell proliferation, migration, differentiation, and collagen production, possibly by upregulation of low-affinity p75 neurotrophin receptors. Expression of nerve growth factor or its receptor tropomyosin-related kinase A did not differ between C-PVAT and IMA-PVAT. Conclusions Elevated expression of BDNF in parallel with local upregulation of negative regulators of neurotrophin signaling in perivascular fat and lower TrkB expression suggest that vascular BDNF signaling is reduced or lost in patients with coronary atherosclerosis.

Background: Obesity is related to coronary artery disease (CAD) and worse outcomes in coronary artery bypass graft (CABG) patients. Adipose tissue itself is an endocrine organ that secretes many humoral mediators, such as adipokines, which can induce or reduce inflammation and oxidative stress., Objectives: We investigate the relationship between the body mass index (BMI), inflammation, and oxidative stress by measuring serum levels of leptin, interleukin-6, and 3-nitrotyrosine in CABG patients and correlate their levels to the cardiovascular and operative risk profiles., Methods and Results: 45 men (<75 years) with a median BMI of 29 (21-51) kg/m 2 , who were diagnosed with CAD and scheduled for elective CABG, were included after applying the following exclusion criteria: prior myocardial infarction, reoperation, female gender, and smoking. Patients' blood samples were taken preoperatively. Several markers were measured. We found significant correlations between leptin and BMI ( p < 0.0001) as well as between leptin and 3-nitrotyrosine ( p = 0.006). Interleukin-6 was correlated with C-reactive protein ( p < 0.0001) and with the incidence of insulin-dependent diabetes mellitus ( p = 0.036), arterial hypertension ( p = 0.044), reduced left ventricular function ( p = 0.003), and severe coronary calcification ( p = 0.015). It was also associated with significantly longer extracorporeal bypass time ( p = 0.009). Postoperative deep sternal wound infections could be predicted by a higher BMI ( p = 0.003) and leptin level ( p = 0.001)., Conclusions: There seems to be a correlation between inflammatory processes and cardiovascular morbidity in our cohort. Further, the incidence of deep sternal wound infections is related to a higher BMI and leptin serum level., Competing Interests: The authors have no conflict of interest., (Copyright © 2020 Katja Buschmann et al.)

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks ("middle-aged") were compared to tissue or cells from mice aged 16 weeks ("adult"). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Members of the genus Bartonella are fastidious Gram-negative facultative intracellular bacteria that are typically transmitted by arthropod vectors. Several Bartonella spp. have been found to cause culture-negative endocarditis in humans. Here, we report the case of a 75-year-old German woman with prosthetic valve endocarditis due to Bartonella washoensis The infecting agent was characterized by sequencing of six housekeeping genes (16S rRNA, ftsZ , gltA , groEL , ribC , and rpoB ), applying a multilocus sequence typing (MLST) approach. The 5,097 bp of the concatenated housekeeping gene sequence from the patient were 99.0% identical to a sequence from a B. washoensis strain isolated from a red squirrel ( Sciurus vulgaris orientis ) from China. A total of 39% (24/62) of red squirrel ( S. vulgaris ) samples from the Netherlands were positive for the B. washoensis gltA gene variant detected in the patient. This suggests that the red squirrel is the reservoir host for human infection in Europe., (Copyright © 2019 American Society for Microbiology.)

Purpose: Ivabradine has emerged as a new antiarrhythmic agent that could compete with the traditional ones, such as beta -blockers. This experimental study aims to ascertain whether ivabradine directly interferes with the myocardial contractility in an in vitro environment., Methods: Myocardial tissues from the right atrial appendages of patients undergoing cardiac surgery were dissected to obtain 40 specimens from 20 patients (length: 3 mm), which were exposed to electrical impulses at a frequency of 75 bpm for 30 min to reach a steady state. Specimens were then categorised into four groups (each including five patients). The first group was the control, whereas the second, third, and fourth were treated with 60 nM, 200 nM, and 2  μ M ivabradine, respectively. We assessed five different contraction parameters before and after a 15 min treatment and calculated their relative changes, which were then compared to the control group., Results: Ivabradine has affected the force of contraction significantly in vitro ( p =0.009). However, force of contraction decreased in both the control group (93.5 ± 4.7%) and the second group (94.1 ± 4.5%, p =0.8) and force of contraction remained unchanged in the third group (101.0 ± 4.1%, p =0.24) and increased significantly in the fourth group (108.9 ± 11.6%, p =0.008). There was no change in other contraction parameters, such as passive tension force (97.1 ± 5.1%, p =0.368), duration of contraction (99.1 ± 4.3%, p =0.816), time to peak (96.6 ± 3.0%, p =0.536), and time to relaxation (101.2 ± 7.0%, p =0.564)., Conclusions: Ivabradine did not interfere with the contractile behaviour of human atrial tissue when it was used in therapeutic dosages in vitro . However, it increased the contractility slightly, when it was used in supratherapeutic dosage., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Ryan Chaban et al.)

Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression.

Leptin, a hormone produced by adipose tissue, has been linked to many regulatory pathways. Its role in the complex relationship between obesity and CVD is not yet clear. The aim of the present study was to evaluate whether leptin interferes directly with cardiac function regulation, altering its contractile force character, and hence contributing to different pathological processes. Muscle samples were obtained from human atrial myocardium. Each trial included two samples from the same patient. They were simultaneously electrically stimulated under sustained perfusion to perform isometric contractions. One sample was treated with a high concentration of human recombinant leptin (1 µg/ml). The other was treated with placebo and served as a control. The exhibited contraction forces (CF) and the contraction duration (CD) after 20 min of treatment were normalised by dividing them by the values before the treatment and reported as a percentage. A total of ten successful trials were conducted. Exposure to leptin did not yield a statistically significant variation in both CF and CF. In the treatment group, CF% measured 108 (95 % CI 91, 125) % and CD% measured 95 (95 % CI 90, 101) % after 20 min. In the control group, CF% measured 105 (90 % CI 84, 126) % and CD% measured 92 (95 % CI 80, 105) % after 20 min. We concluded that leptin does not alter the contractile character of human atrial tissues, even in supraphysiological dosage. These results suggest that leptin does not play a role in short-term cardiac regulation.

Background: Lactococcus garvieae (LG) is a gram-positive coccus known to be a major pathogen in aqua farming, which is responsible for severe outbreaks. Its incidence in humans is extremely rare. Prior to 1985, all bacteria in the genus Lactococcus were included in the Streptococcus genus. The first human infection was documented in 1991, and since then, the relevance and clinical significance in humans has increased., Case Description: We present the clinical course of an LG endocarditis in a 78-year-old man who had a history of exertional dyspnea. The patient's blood tests showed increased inflammation values, and a transesophageal ultrasound (TEE) showed a stenosis of the prosthetic aortic valve. Blood cultures were positive for LG, leading to a diagnosis of infective endocarditis. After 6 weeks of intravenous antibiotics and a prosthetic aortic valve replacement, the patient made a good recovery., Review of the Literature: After the first documented case in 1991 to 2018, 25 cases of LG endocarditis have been described in PubMed and MEDLINE. We reviewed all reported cases of LG endocarditis, commenting on predisposing risk factors, the course and outcome of the disease., Conclusion: LG endocarditis is a rare disease. Consumption of raw fish, abnormalities of the digestive tract, immune deficiency, and underlying cardiac conditions appear to be risk factors for an infective endocarditis due to LG. Improved determination techniques are likely to lead to a better and faster identification of the bacterium. This identification allows a faster and individualized therapy, which in turn affects the outcome.

Background: Obesity is one of the major cardiovascular risk factors and is associated with oxidative stress and myocardial dysfunction. We hypothesized that obesity affects cardiac function and morbidity by causing alterations in enzymatic redox patterns., Methods: Sixty-one patients undergoing coronary artery bypass grafting (CABG) were included in the study. Excessive right atrial myocardial tissue emerging from the operative connection to the extracorporeal circulation was harvested. Patients were assigned to control ( n = 19, body mass index (BMI): <25 kg/m 2 ), overweight ( n = 25, 25 kg/m 2  < BMI < 30 kg/m 2 ), or obese ( n = 17, BMI: >30 kg/m 2 ) groups. Oxidative enzyme systems were studied directly in the cardiac muscles of patients undergoing CABG who were grouped according to BMI. Molecular biological methods and high-performance liquid chromatography were used to detect the expression and activity of oxidative enzymes and the formation of reactive oxygen species (ROS)., Results: We found increased levels of ROS and increased expression of ROS-producing enzymes (i.e., p47phox, xanthine oxidase) and decreased antioxidant defense mechanisms (mitochondrial aldehyde dehydrogenase, heme oxygenase-1, and eNOS) in line with elevated inflammatory markers (vascular cell adhesion molecule-1) in the right atrial myocardial tissue and by trend also in serum (sVCAM-1 and CCL5/RANTES)., Conclusion: Increasing BMI in patients undergoing CABG is related to altered myocardial redox patterns, which indicates increased oxidative stress with inadequate antioxidant compensation. These changes suggest that the myocardium of obese patients suffering from coronary artery disease is more susceptible to cardiomyopathy and possible damage by ischemia and reperfusion, for example, during cardiac surgery.

Objectives: Acute pulmonary embolism can be a life-threatening condition with a high mortality. The treatment choice is a matter of debate. The early and late outcomes of patients treated with surgical pulmonary embolectomy for acute pulmonary embolism in a single center were analyzed., Methods: All consecutive patients operated on for pulmonary embolism between January 2002 and March 2017 were reviewed. Patient demographics and pre- and postoperative clinical data were retrieved from our patient registry, and risk factors for in-hospital and long-term mortality were identified., Results: In total, 175 patients (mean age 59±3 years, 50% male) were operated on for acute pulmonary embolism. In-hospital mortality was 19% (34/175). No differences were found when comparing surgery utilizing a beating heart or cardioplegic arrest. Risk factors for in-hospital mortality were age >70 years [odds ratio (OR) 4.8, confidence interval (CI) 1.7-13.1, p=0.002], body surface area <2 m 2 (OR 4.7, CI 1.6-13.7, p=0.004), preoperative resuscitation (OR 14.1, CI 4.9-40.8, p<0.001), and the absence of deep vein thrombosis (OR 9.6, CI 2.5-37.6, p<0.001). Follow-up was 100% complete with a 10-year survival rate of 66.4% in 141/175 patients surviving to discharge. Once discharged from hospital, none of the risk factors identified for in-hospital mortality were relevant for long-term survival except the absence of deep vein thrombosis (OR 3.2, CI 1.2-8.2, p=0.019). The presence of malignancy was a relevant risk factor for long-term mortality (OR 4.3, CI 1.8-10.3, p=0.001)., Conclusion: Surgical pulmonary embolectomy as a therapy for acute pulmonary embolism demonstrates excellent short- and long-term results in patients with an otherwise life-threatening disease, especially in younger patients with a body surface area >2 m 2 and pulmonary embolism caused by deep vein thrombosis. Pulmonary embolectomy should therefore not be reserved as a treatment of last resort for clinically desperate circumstances., (©2018 Dohle K., et al., published by De Gruyter, Berlin/Boston.)

Background: Our study aimed to evaluate changes in the contractile behavior of human myocardium after exposure to caffeine and taurine, the main active ingredients of energy drinks (EDs), and to evaluate whether taurine exhibits any inotropic effect at all in the dosages commonly used in EDs., Methods: Myocardial tissue was removed from the right atrial appendages of patients undergoing cardiac surgery and prepared to obtain specimens measuring 4 mm in length. A total of 92 specimens were exposed to electrical impulses at a frequency of 75 bpm for at least 40 min to elicit their maximum contractile force before measuring the isometric contractile force (ICF) and duration of contraction (CD). Following this, each specimen was treated with either taurine (group 1, n = 29), or caffeine (group 2, n = 31) or both (group 3, n = 32). After exposure, ICF and CD measuring were repeated. Post-treatment values were compared with pre-treatments values and indicated as percentages., Results: Exposure to taurine did not alter the contraction behavior of the specimens. Exposure to caffeine, in contrast, led to a significant increase in ICF (118 ± 03%, p < 0.01) und a marginal decrease in CD (95 ± 1.6%, p < 0.01). Exposure to a combination of caffeine and taurine also induced a statistically significant increase in ICF (124 ± 4%, p < 0.01) and a subtle reduction in CD (92 ± 1.4%, p < 0.01). The increase in ICF achieved by administration of caffeine was similar to that achieved by a combination of both caffeine and taurine (p = 0.2). The relative ICF levels achieved by administration of caffeine and a combination of taurine and caffeine, respectively, were both significantly higher (p < 0.01) than the ICF resulting from exposure to taurine only., Conclusion: While caffeine altered the contraction behavior of the specimen significantly in our in-vitro model, taurine did not exhibit a significant effect. Adding taurine to caffeine did not significantly enhance or reduce the effect of caffeine.

Background: This study analyzes the myocardial force-generating capacity in infective endocarditis (IE) using an experimental model of isolated human atrial myocardium. In vivo , it is difficult to decide whether or not alterations in myocardial contractile behavior are due to secondary effects associated with infection such as an altered heart rate, alterations of preload and afterload resulting from valvular defects, and altered humoral processes. Our in vitro model using isolated human myocardium, in contrast, guarantees exactly defined experimental conditions with respect to preload, afterload, and contraction frequency, thus not only preventing confounding by in vivo determinants of contractility but also excluding effects of other factors associated with sepsis, hemodynamics, humoral influences, temperature, and medical treatment., Methods: We analyzed right atrial trabeculae (diameter 0.3-0.5 mm, initial length 5 mm) from 32 patients undergoing aortic and/or mitral valve replacement for acute valve incompetence caused by IE and 65 controls receiving aortic and/or mitral valve replacement for nonendocarditic valve incompetence. Isometric force amplitudes and passive resting force values measured at optimal length in the two groups were compared using Student's t-test., Results: There were no significant differences between the groups in terms of the passive resting force. The isometric force amplitude in the endocarditis group, however, was significantly lower than in the nonendocarditis group (p=0.001). In the endocarditis group, the calculated active force, defined as the isometric force amplitude minus the resting force, was significantly lower (p<0.0001) and the resting force/active force ratio was significantly higher (p<0.0001). Using linear regression to describe the function between resting force and active force, we identified a significant difference in slope (p<0.0001), with lower values found in the endocarditis group., Conclusion: Our data suggest that the force-generating capacity of atrial myocardium is significantly reduced in patients with IE. In these patients, an elevated resting force is required to achieve a given force amplitude. It remains unclear, however, whether this is due to calcium desensitization of the contractile apparatus, presence of myocardial edema, fibrotic remodeling, disruption of contractile units, or other mechanisms., (©2017 Buschmann K., et al., published by De Gruyter, Berlin/Boston.)

Although fish oil-based and olive oil-based lipid emulsions have been shown to exert anti-inflammatory functions, the immunomodulating properties of lipids are still controversial. Therefore, we investigated the anti-inflammatory effect of three different parenterally administered lipid emulsions in vivo: olive oil-based Clinoleic, fish oil-based Smoflipid, and soybean oil-based Lipofundin. We observed leukocyte recruitment in inflamed murine cremaster muscle using intravital microscopy and survival in a murine model of LPS-induced systemic inflammation and analyzed expression of leukocyte and endothelial adhesion molecules. Olive oil-based Clinoleic and fish oil-based Smoflipid profoundly inhibited leukocyte adhesion compared to Lipofundin during LPS-induced inflammation of the murine cremaster muscle. In the trauma model of cremaster muscle inflammation, Lipofundin was the only lipid emulsion that even augmented leukocyte adhesion. In contrast to Smoflipid and Lipofundin, Clinoleic effectively blocked leukocyte recruitment and increased survival during lethal endotoxemia. Flow chamber experiments and analysis of adhesion molecule expression suggest that both endothelial and leukocyte driven mechanisms might contribute to anti-inflammatory effects of Clinoleic. We conclude that the anti-inflammatory properties of Clinoleic are superior to those of Smoflipid and Lipofundin even during systemic inflammation. Thus, these results should stimulate further studies investigating parenteral lipids as an anti-inflammatory strategy in critically ill patients.

Background: Insufficient leukocyte recruitment may be one reason for the high incidence of life-threatening infections in preterm infants. Since the receptor of advanced glycation end products (RAGE) is a known leukocyte adhesion molecule and highly expressed during early development, we asked whether RAGE plays a role for leukocyte recruitment in preterm and term infants., Methods: Leukocyte adhesion was analyzed in dynamic flow chamber experiments using isolated leukocytes of cord blood from extremely premature (<30 weeks of gestation), moderately premature (30-35 weeks of gestation) and mature neonates (>35 weeks of gestation) and compared to the results of adults. For fluorescent microscopy leukocytes were labeled with rhodamine 6G. In the respective age groups we also measured the plasma concentration of soluble RAGE (sRAGE) by ELISA and Mac-1 and LFA-1 expression on neutrophils by flow cytometry., Results: The adhesive functions of fetal leukocytes significantly increase with gestational age. In all age groups, leukocyte adhesion was crucially dependent on RAGE. In particular, RAGE was equally effective to mediate leukocyte adhesion when compared to ICAM-1. The plasma levels of sRAGE were high in extremely premature infants and decreased with increasing gestational age. In contrast, expression of β2-Integrins Mac-1 and LFA-1 which are known ligands for RAGE and ICAM-1 did not change during fetal development., Conclusion: We conclude that RAGE is a crucial leukocyte adhesion molecule in both preterm and term infants.

Aims: The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C., Methods and Results: We analyzed the effect of protein C on leukocyte adhesion and transmigration in WT- and RAGE-deficient mice using intravital microscopy of cremaster muscle venules during trauma- and TNFα-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 µg/kg/h) treatment significantly inhibited leukocyte adhesion in WT mice in these inflammation models. The impaired leukocyte adhesion after trauma-induced inflammation in RAGE knockout mice could not be further reduced by PC and aPC. After TNFα-stimulation, however, aPC but not PC treatment effectively blocked leukocyte adhesion in these mice. Consequently, we asked whether RAGE is involved in PC activation. Since RAGE-deficient mice and endothelial cells showed insufficient PC activation, and since thrombomodulin (TM) and endothelial protein C receptor (EPCR) are reduced on the mRNA and protein level in RAGE deficient endothelial cells, an involvement of RAGE in TM-EPCR-dependent PC activation is likely. Moreover, TNFα-induced activation of MAPK and upregulation of ICAM-1 and VCAM-1 are reduced both in response to aPC treatment and in the absence of RAGE. Thus, there seems to be interplay of the RAGE and the PC pathway in inflammation., Conclusion: RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.

By binding β 2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNF α ). In contrast to WT and Icam-1(-/-) mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE(-/-) mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC.

As nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) seem to be critical mediators in the inflammatory response, we studied the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on (a) the activation of NF-κB and MAPKs and (b) the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) with or without the specific inhibitors of these intracellular signal transduction pathways in neonatal cord and adult blood. TNF-α and IL-6 concentrations showed a sharp increase in the supernatants of cord and adult whole blood after stimulation. TNF-α concentrations were significantly higher, whereas IL-6 concentrations were tendentially lower in adult blood after stimulation. Stimulation with LPS or LTA resulted in a significantly decreased activation of p38 MAPK in neonatal compared with adult blood. Although LTA failed to induce additional ERK1/2 phosphorylation, LPS stimulation mediated the moderately increased levels of activated ERK1/2 in neonatal monocytes. The addition of the p38 MAPK inhibitor SB202190 significantly decreased IL-6 and TNF-α production upon LPS or LTA stimulation. Furthermore, the inhibition of ERK1/2 was able to reduce LPS-stimulated TNF-α production in neonatal blood. We conclude that p38 MAPK as well as ERK1/2 phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood.

It is well acknowledged that proinflammatory stimulation during acute hyperglycemia is able to aggravate inflammatory diseases. However, the mechanisms of proinflammatory effects of glucose are controversially discussed. We investigated leukocyte recruitment after intravenous injection of glucose in different inflammatory models using intravital microscopy. Flow chamber experiments, expression analysis, functional depletion, and knockout of key adhesion molecules gave mechanistic insight in involved pathways. We demonstrated that a single injection of glucose rapidly increased blood glucose levels in a dose-dependent manner. Notably, during tumor necrosis factor (TNF) α-induced inflammation leukocyte recruitment was not further enhanced by glucose administration, whereas glucose injection profoundly augmented leukocyte adhesion and transmigration into inflamed tissue in the trauma model, indicating that proinflammatory properties of glucose are stimulus dependent. Experiments with functional or genetic inhibition of the chemokine receptor CXCR2, intercellular adhesion molecule 1 (ICAM1), and lymphocyte function antigen 1 (LFA1) suggest that keratino-derived-chemokine CXCL1-triggered interactions of ICAM1 and LFA1 are crucially involved in the trauma model of inflammation. The lacking effect of glucose on β(2) integrin expression and on leukocyte adhesion in dynamic flow chamber experiments argues against leukocyte-driven underlying mechanisms and favours an endothelial pathway since endothelial ICAM1 expression was significantly upregulated in response to glucose.

Anti-inflammatory properties of protein C (PC) concentrate are poorly studied compared to activated protein C, although PC is suggested to be safer in clinical use. We investigated how PC interferes with the leukocyte recruitment cascade during acute inflammation and its efficacy during murine endotoxemia. We found that similar to activated protein infusion, intravenous PC application reduced leukocyte recruitment in inflamed tissues in a dose- and time-dependent manner. During both tumor necrosis factor-α induced and trauma-induced inflammation of the cremaster muscle, intravital microscopy revealed that leukocyte adhesion and transmigration, but not rolling, were profoundly inhibited by 100 U/kg PC. Moreover, PC blocked leukocyte emigration into the bronchoalveolar space during lipopolysaccharide (LPS) induced acute lung injury. PC was efficiently activated in a murine endotoxemia model, which reduced leukocyte infiltration of organs and strongly improved survival (75% versus 25% of control mice). Dependent on the inflammatory model, PC provoked a significant inhibition of leukocyte recruitment as early as 1 hour after administration. PC-induced inhibition of leukocyte recruitment during acute inflammation critically involves thrombomodulin-mediated PC activation, subsequent endothelial PC receptor and protease-activated receptor-1-dependent signaling, and down-regulation of intercellular adhesion molecule 1 leading to reduced endothelial inflammatory response. We conclude that during acute inflammation and sepsis, PC is a fast acting and effective therapeutic approach to block leukocyte recruitment and improve survival., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The receptor for advanced glycation endproducts, RAGE, is involved in the pathogenesis of many inflammatory conditions, which is mostly related to its strong activation of NF-κB but also due to its function as ligand for the β2-integrin Mac-1. To further dissect the stimulus-dependent role of RAGE on leukocyte recruitment during inflammation, we investigated β2-integrin-dependent leukocyte adhesion in RAGE-/- and Icam1-/- mice in different cremaster muscle models of inflammation using intravital microscopy., Results: We demonstrate that RAGE, but not ICAM-1 substantially contributes to N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukocyte adhesion in TNF-α-pretreated cremaster muscle venules in a Mac-1-dependent manner. In contrast, fMLP-stimulated leukocyte adhesion in unstimulated cremaster muscle venules is independent of RAGE, but dependent on ICAM-1 and its interaction with LFA-1. Furthermore, chemokine CXCL1-stimulated leukocyte adhesion in surgically prepared cremaster muscle venules was independent of RAGE but strongly dependent on ICAM-1 and LFA-1 suggesting a differential and stimulus-dependent regulation of leukocyte adhesion during inflammation in vivo., Conclusion: Our results demonstrate that RAGE and ICAM-1 differentially regulate leukocyte adhesion in vivo in a stimulus-dependent manner.

The receptor for advanced glycation end products (RAGE) contributes to the inflammatory response in many acute and chronic diseases. In this context, RAGE has been identified as a ligand for the beta(2)-integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds beta(2)-integrins, we studied RAGE(-/-), Icam1(-/-), and RAGE(-/-) Icam1(-/-) mice to define the relative contribution of each ligand for leukocyte adhesion in vivo. We show that trauma-induced leukocyte adhesion in cremaster muscle venules is strongly dependent on RAGE and ICAM-1 acting together in an overlapping fashion. Additional in vivo experiments in chimeric mice lacking endothelium-expressed RAGE and ICAM-1 located the adhesion defect to the endothelial compartment. Using microflow chambers coated with P-selectin, CXCL1, and soluble RAGE (sRAGE) demonstrated that sRAGE supports leukocyte adhesion under flow conditions in a Mac-1- but not LFA-1-dependent fashion. A static adhesion assay revealed that wild-type and RAGE(-/-) neutrophil adhesion and spreading were similar on immobilized sRAGE or fibrinogen. These observations indicate a crucial role of endothelium-expressed RAGE as Mac-1 ligand and uncover RAGE and ICAM-1 as a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute trauma-induced inflammatory response in vivo.

Acute lung injury (ALI) still poses a major challenge in critical care medicine. Neutrophils, platelets, and chemokines are all considered key components in the development of ALI. The Duffy antigen receptor for chemokines (DARC) is thought to be involved in scavenging, transendothelial transport, and presentation of neutrophil-specific chemokines. DARC is expressed on endothelial cells and erythrocytes but not on leukocytes. Here, we show that DARC is crucial for chemokine-mediated leukocyte recruitment in vivo. However, we also demonstrate that changes in chemokine and chemokine receptor homeostasis, associated with Darc gene deficiency, exert strong anti-inflammatory effects. Neutrophils from Darc gene-deficient (Darc(-/-)) mice display a more prolonged downregulation of CXCR2 during severe inflammation than neutrophils from wild-type mice. In a CXCR2-dependent model of acid-induced ALI, Darc gene deficiency prevents ALI. Darc(-/-) mice demonstrate fully preserved oxygenation, only a small increase in vascular permeability, and a complete lack of pulmonary neutrophil recruitment. Further analysis reveals that only neutrophils but neither endothelial cells nor erythrocytes from Darc(-/-) mice confer protection from ALI. The protection appears to be due to abolished pulmonary recruitment of neutrophils from Darc(-/-) mice. The generation of neutrophil-platelet aggregates, a key mechanism in both pulmonary neutrophil recruitment and thrombus formation, is also affected by altered CXCR2 homeostasis in Darc(-/-) mice. CXCR2 blockade enhances the formation of platelet-neutrophil aggregates and thereby corrects a formerly unknown bleeding defect in Darc(-/-) mice. In summary, our study suggests that chemokine/chemokine receptor homeostasis plays a previously unrecognized and crucial role in severe ALI.

Background: In order to prepare for the introduction of a universal newborn hearing screening program on a larger scale, TEOAE and ABR were recorded on automated screening instruments from both ears of 501 newborns at the University Hospital Heidelberg over a period of 13 months. The parents of children in whom OAE and ABR could not be detected in both ears, were requested to allow a complete exploration of the auditory status of the children at the department of pediatric audiology., Subjects and Methods: Internally available data networks were used for the acquisition and evaluation of data and for the organization of tracking and follow-up. Of the children 35% exhibited risk factors for congenital hearing impairment., Results: The pass rate was 98.7% for the exclusion of binaural and 91.6% for monaural hearing disorders (TEOAE or ABR detectable). On the basis of the data it can be shown how pass rates can be optimized by selecting a suitable moment for the examination and by prescribing a minimum number of test repetitions (3 for TEOAE and 2 for AABR)., Conclusion: Quality control of screening programs should include these parameters and, in particular the number of repetitions of test measurements in all screening steps.

Objective: Acute renal failure remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of acute renal failure. Although the Duffy antigen receptor for chemokines (DARC) is present in several tissues and a highly specific ligand for various chemokines, its exact role in vivo remains unclear., Design: Prospective, controlled experimental study., Setting: University-based research laboratory., Subjects: C57BL/6 wild-type and DARC gene-deficient mice (DARC-/-)., Interventions: To unravel the functional relevance of DARC in vivo, we compared wild-type and DARC-/- using neutrophil-dependent models of acute renal failure, induced by either local (renal ischemia-reperfusion) or systemic (endotoxemia, lipopolysaccharide) injury., Measurements and Main Results: Plasma creatinine and blood urea nitrogen concentrations served as indicators of renal function or dysfunction. Enzyme-linked immunosorbent assays were used to measure tissue and plasma chemokine concentrations. We also performed immunostaining to localize chemokine expression and flow cytometry to evaluate neutrophil recruitment into the kidney. Following renal injury, wild-type mice developed moderate renal ischemia-reperfusion(lipopolysaccharide, 300% increase in plasma creatinine concentrations) to severe acute renal failure (renal ischemia-reperfusion, 40% mortality) as well as extensive renal neutrophil recruitment. DARC-/- mice exhibited no renal dysfunction (renal ischemia-reperfusion) or only very mild renal dysfunction (lipopolysaccharide, 20% increase in serum creatinine concentrations). DARC-/- mice showed no postischemic neutrophil infiltration. Although DARC-/- and wild-type mice exhibited similar global renal neutrophil-recruitment during endotoxemia, DARC-/- mice showed significantly impaired neutrophil extravasation. Total renal concentrations of the chemokine macrophage inflammatory protein 2, which has been shown to bind to DARC and to be crucial in postischemic acute renal failure, were either identical (lipopolysaccharide) or only moderately different (renal ischemia-reperfusion) between wild-type and DARC-/- mice. Immunostaining revealed an absence of macrophage inflammatory protein-2 in renal endothelial cells of DARC-/- mice., Conclusions: We suggest that DARC predominantly exerts its effects by controlling spatial chemokine distribution, which in turn regulates neutrophil recruitment and subsequent acute renal failure.

Chronic headache and facial pain cannot be categorized as purely organic or purely psychological; therefore, treatment should be both medical and psychotherapeutic. An interdisciplinary approach optimises treatment results and significantly reduces the intensity and frequency of the pain. This article illustrates a cognitive behavioural treatment strategy that has shown a clear reduction in patient impairment. With extensive education and training in pain management techniques, patients are enabled to exert influence over their pain, preventing and easing it and dealing with it strategically. The results are improved self-control, improved quality of life, and a possible reduction in the consumption of pain-killing drugs.

Our objective was to characterize monoclonal antiphospholipid antibodies (APL) and identify disease-associated antigens in patients with the antiphospholipid syndrome (APS). We used the monoclonal antibody HL-5B, derived from a patient with APS suffering from multiple ischemic events, to screen a 12-mer peptide phage display library (New England Biolabs, London, England). The identified phage clones were sequenced and the derived consensus peptide was synthesized. The peptide was used to perform competitive inhibition experiments for their ability to inhibit the binding of the monoclonal antibody and of serum antibodies to cardiolipin and phosphatidylserine. Additionally patients and control sera were screened for their binding reactivities to this peptide. Using this 12-mer phage display library the peptide APHKHKASLSIY as consensus peptide for the monoclonal antiphospholipid antibody HL-5B could be identified. In competitive inhibition studies we showed that this peptide is able to inhibit the binding of HL-5B to cardiolipin and phosphatidylserine and furthermore another antiphospholipid antibody used as control was also inhibited in its binding to phospholipids. Using 21 sera from APS patients 67% showed a binding to the peptide in a specific ELISA above the cutoff level, generated with sera from 20 healthy controls. Out of the reactive patients' sera we used two exemplarily to perform inhibition studies. Both sera could be inhibited more than 40% in their binding to cardiolipin in a commercially available antiphospholipid antibody assay (Aescu.diagnostics, Wendelsheim, Germany). The identified peptide APHKHKASLSIY simulates the antigenic structure recognized from a subpopulation of serum antiphospholipid antibodies. This might indicate that the diversity of the antiphospholipid antibodies is limited and only few epitopes or few common structures are responsible for the development of those antibodies. Tests using these epitopes will strongly improve laboratory diagnosis of the APS.

Since formerly only the diastolic phase of the curve of the mitral valve was in the centre of interest for diagnosing the mitral stenosis, nowadays the systolic area is more taken into consideration, the changes of which apart from the hypertrophies of the heart walls increasingly gains significance for the diagnostics of the idiopathic hypertrophic cardiomyopathies, the floppy valve syndrome, the aneurysm of the heart wall, the atrial septum defect as well as for systolic murmurs of different genesis. The registration of the movement of the posterior wall and the septum give the possibility of determination of the volume. Thus mean values of the stroke volume, the minute volume of the heart and the cardiac index showed a conspicuously good correspondence in persons with healthy heart compared with former determinations by dye dilution technique. As formerly (dye examinations) we found significant differences between normals and values of patients with mitral stenosis in stroke volume, ejection fraction, cardiac output and cardiac index, when we used the echocardiographic technique.