Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.

Ventilation heterogeneity is frequent in bronchial asthma and can be assessed using multiple breath wash-out testing (MBW). Most data is available in paediatric patients and using nitrogen as a tracer gas. We aimed to evaluate sulphur hexafluoride (SF6) MBW in adult asthmatics. Spirometry, whole-body plethysmography, impulse oscillometry and SF6-MBW were prospectively performed. MBW parameters reflecting global (lung clearance index, LCI), acinar (S-acin) and conductive (S-cond) ventilation heterogeneity were derived from three consecutive wash-outs. LCI was calculated for the traditional 2.5% and an earlier 5% stopping point that has the potential to reduce wash-out times. 91 asthmatics (66%) and 47 non-asthmatic controls (34%) were included in final analysis. LCI2.5 and LCI5 were higher in asthmatics (p<0.001). Likewise, S-acin and S-cond were elevated (p<0.001 and p<0.01). Coefficient of variation was 3.4% for LCI2.5 and 3.5% for LCI5 in asthmatics. Forty-one asthmatic patients had normal spirometry. ROC analysis revealed an AUC of 0.906 for the differentiation from non-asthmatic controls exceeding diagnostic performance of individual and conventional parameters (AUC=0.819, p<0.05). SF6-MBW is feasible and reproducible in adult asthmatics. Ventilation heterogeneity is increased as compared to non-asthmatic controls persisting in asthmatic patients with normal spirometry. Diagnostic performance is not affected using an earlier LCI stopping point while reducing wash-out duration considerably.

Background: SAD is common in patients with COPD. Occurring early in the course of the disease, it is frequently missed by currently used diagnostic tests. Multiple breath washout (MBW) testing detects ventilation heterogeneity (VH) while oscillometry (OS) assesses peripheral obstruction, both associated with SAD. We therefore set out to evaluate the presence and symptoms of SAD in patients with early COPD. Methods: We prospectively evaluated 26 patients (FEV1 77±19% pred., 88% GOLD I/II). In an 8-week cross-over design, the effect of dual bronchodilatation (tiotropium/olodaterol, T/O) on lung function and symptoms (CAT) was compared to monotherapy (formoterol). Lung function was assessed by spirometry, OS and SF6-MBW. Results: Patients with a high CAT dyspnoea item (≥3) had increased frequency dependence of resistance (D5-20, p<0.01) in OS and increased acinar VH (Sacin, p<0.0001) in MBW. No relevant differences were seen for FEV1 (p=0.05) or MEF25 (p=0.24, Figure 1A, mean±SEM). Patients with a high CAT cough item (≥3) had lower FEV1 (p<0.0001) and MEF25 (p<0.01) as well as higher D5-20 (p<0.001) and Sacin (p<0.05, Figure 1B). Although not being statistically significant, T/O was more effective especially in SAD parameters. Conclusions: SAD is present even in early COPD stages and associated with respiratory symptoms. These can be addressed with dual bronchodilatation exceeding the effect of monotherapy.

Background: Ventilation heterogeneity is frequent in obstructive lung disease and linked to small airway dysfunction. It can be potentially revealed using multiple breath washout (MBW) testing while being missed by commonly used tests. Lung clearance index (LCI) is the most commonly used MBW outcome parameter but normative data is scarce. We therefore set out to provide LCI reference values in pulmonary healthy adults. Methods: We prospectively evaluated 104 pulmonary healthy non-smokers and smokers (mean age 51±20, range 20-88 years). LCI was derived from triplicate MBW measurements based on Sulphur hexafluoride (SF6). We used the 2.5% (LCI2.5) and 5% (LCI5) stopping points and defined upper limit of normal (ULN) as the 95th percentile. Results: LCI2.5 increases from a mean 6.3 to 8.8 in subjects between 20 and 90 years. Upper limits of normal were calculated as of 7.4 to 9.9 (Figure). LCI5 correspondingly yielded lower mean values between 4.9 and 6.9 with ULN of 5.7 and 7.7, respectively. Age was the only meaningful parameter influencing LCI explaining 47% of its variance. Conclusions: LCI showed an age-dependent increase from early adulthood to senectitude. No influence of height, weight and gender was seen. Reference values can now be provided over the whole age range and for two different stopping points.

Background: Functional diagnosis of COPD is primarily based on central obstruction in spirometry. Impulse oscillometry (IOS) and multiple breath washout (MBW) can additionally detect peripheral obstruction or ventilation heterogeneity (VH). We aimed to evaluate IOS and MBW for a refined phenotyping and therapeutic implications. Methods: We performed body plethysmography, IOS and MBW (SF6) in 66 COPD patients (74% men, 70% GOLD I/II) in a prospective, cross-sectional protocol. In an 8-week cross-over design, the effect of dual bronchodilator therapy (tiotropium/olodaterol, TO) was compared to monotherapy (formoterol, F) in 12 patients. Results: IOS showed an abnormal frequency dependence of resistance (D5-20, 55±45%) and reactance area (Ax, 1.65±1.60). Global VH (lung clearance index, LCI) was elevated to 10.3±2.0. An increase of 0.34±0.21 L-1 in acinar phase-III slopes (Sacin) resembles local VH. Clusters corresponding to components of conventional lung function testing, peripheral resistance and VH were identified (Figure). SGRQ improvement following TO was predicted by changes in small airways during F (D5-20, Sacin) affected early in COPD pathogenesis. Signs of central obstruction and emphysema (TLCO, FEV1, LCI) assessed prior to therapy added predictive value. Conclusion: IOS and MBW add information to current diagnostic concepts in COPD. Initial phenotyping is improved and consequences for differential therapy can be derived.

Background: Ventilation heterogeneity is frequent in obstructive lung disease and can be assessed using multiple breath washout testing (MBW). In bronchial asthma, most data is available in pediatric collectives and using N2 as tracer gas suffering from several technical issues. We therefore aimed to evaluate the feasibility of MBW using sulfur hexafluoride (SF6) in adult asthmatic patients. Methods: MBW parameters reflecting global (lung clearance index, LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from SF6-MBW. Results: 91 asthmatic patients (66%) and 47 controls (34%) were included. LCI was significantly higher in asthmatic patients than in healthy controls (p<0.001). Likewise, Sacin and Scond were significantly elevated (p<0.001 and p<0.01). Coefficient of variation was 3.4±2.4% for LCI in patients with asthma and 3.0±1.9% (p=0.28) in controls. Sacin and Scond showed larger variation. Forty-one asthma patients had normal spirometry. ROC analysis revealed an AUC of 0.886 for the differentiation from healthy controls using a regularized generalized linear model including MBW parameters. This exceeded diagnostic performance of the individual parameters and a model based on parameters of conventional lung function testing only (AUC=0.819, p<0.05). Conclusion: SF6-MBW is feasible and reproducible in adults with bronchial asthma. Global and local ventilation heterogeneity is increased as compared to pulmonary healthy controls. Differences persist in asthmatic patients with normal spirometry. MBW parameters therefore may contain additional information that can be used to identify asthmatic patients missed by current tests.

Airways obstruction is frequent in patients with pulmonary hypertension (PH). Small airway disease (SAD) was identified as a major contributor to resistance and symptoms. However, it is easily missed using current diagnostic approaches. We aimed to evaluate more elaborate diagnostic tests such as impulse oscillometry (IOS) and SF6-multiple-breath-washout (MBW) for the assessment of SAD in PH. Twenty-five PH patients undergoing body-plethysmography, IOS and MBW testing were prospectively included and equally matched to pulmonary healthy and non-healthy controls. Lung clearance index (LCI) and acinar ventilation heterogeneity (Sacin) differed significantly between PH, healthy and non-healthy controls. Likewise, differences were found for all IOS parameters between PH and healthy, but not non-healthy controls. Transfer factor corrected for ventilated alveolar volume (TLCO/VA), frequency dependency of resistance (D5-20), resonance frequency (Fres) and Sacin allowed complete differentiation between PH and healthy controls (AUC (area under the curve) = 1.0). Likewise, PH patients were separated from non-healthy controls (AUC 0.762) by D5-20, LCI and conductive ventilation heterogeneity (Scond). Maximal expiratory flow (MEF) values were not associated with additional diagnostic values. MBW and IOS are feasible in PH patients both providing additional information. This can be used to discriminate PH from healthy and non-healthy controls. Therefore, further research targeting SAD in PH and evaluation of therapeutic implications is justified.

Introduction To prospectively evaluate the feasibility of single contrast bolus high-pitch CT pulmonary angiography (CTPA) subsequently followed by low-dose retrospectively ECG-gated cardiac CT (4D-cCT) in patients with suspected pulmonary embolism (PE) to accurately evaluate right ventricular (RV) function. Materials and Methods 62 patients (33 female, age 65.1 ± 17.5 years) underwent high-pitch CTPA examination with 80cc of iodinated contrast material. 5 s after the end of the high-pitch CTPA study, a low-dose retrospectively ECG-gated cardiac CT examination was automatically started. The volume CT dose index (CTDI vol) and dose length product (DLP) were recorded in all patients and the effective dose was calculated. For the assessment of image quality, attenuation was measured as Hounsfield units (HUs) within various regions of interest (ROIs). These ROIs were used to calculate the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Subjective image quality was assessed using a five-point Likert scale. On 4D-cCT, the ejection fraction of both ventricles (RVEF, LVEF) as well as the ratio of RVEF and LVEF (RVEF/LVEF) was assessed. The statistical difference of all parameters between the PE and non-PE group was calculated. Results The mean effective radiation dose was 4.22 ± 2.05 mSv. Attenuation measurements on CTPA showed the highest attenuation values in the main pulmonary artery (442.01 ± 187.64). On 4D-cCT attenuation values were highest in the descending aorta (560.59 ± 208.81). The CNR and SNR values on CTPA were highest within the main pulmonary artery (CNR = 12.43 ± 4.57; SNR = 15.14 ± 4.90). On 4D-cCT images, the highest SNR and CNR could be measured in the descending aorta (CNR = 10.26 ± 5.57; SNR = 10.86 ± 5.17). The mean LVEF was 60.73 %± 14.65 %, and the mean RVEF was 44.90 %± 9.54 %. The mean RVEF/LVEF was 0.79 ± 0.29. There was no significant difference between the PE and non-PE group for either of the parameters. Conclusion The investigated combined CTPA and 4D-cCT protocol is feasible using a single contrast bolus and allows the evaluation of RV function in patients with suspected PE. Further studies have to evaluate the additional value of this protocol regarding risk stratification in patients with PE. Key Points: Citation Format

BACKGROUND:Hantavirus disease belongs to the emerging infections. The clinical picture and severity of infections differ between hantavirus species and may even vary between hantavirus genotypes. The mechanisms that lead to the broad variance of severity in infected patients are not completely understood. Host- and virus-specific factors are considered.CASE PRESENTATION:We analyzed severe cases of hantavirus disease in two young women. The first case was caused by Puumala virus (PUUV) infection in Germany; the second case describes the infection with Dobrava-Belgrade virus (DOBV) in Russia. Symptoms, laboratory parameters and cytokine levels were analyzed and compared between the two patients. Serological and sequence analysis revealed that PUUV was the infecting agent for the German patient and the infection of the Russian patient was caused by Dobrava-Belgrade virus genotype Sochi (DOBV-Sochi). The symptoms in the initial phase of the diseases did not differ noticeably between both patients. However, deterioration of laboratory parameter values was prolonged and stronger in DOBV-Sochi than in PUUV infection. Circulating endothelial progenitor cells (cEPCs), known to be responsible for endothelial repair, were mobilized in both infections. Striking differences were observed in the temporal course and level of cytokine upregulation. Levels of angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and stromal derived factor-1 (SDF-1α) were increased in both infections; but, sustained and more pronounced elevation was observed in DOBV-Sochi infection.CONCLUSIONS:Severe hantavirus disease caused by different hantavirus species did not differ in the general symptoms and clinical characteristics. However, we observed a prolonged clinical course and a late and enhanced mobilization of cytokines in DOBV-Sochi infection. The differences in cytokine deregulation may contribute to the observed variation in the clinical course.

Decreased physical activity (PA) is both a consequence and a risk factor for progressive functional impairment in COPD. However, methodological approaches for its accelerometric quantification in patients are heterogeneous. The present study examined the correlation between measurements by two common accelerometers in COPD. Accelerometric data were collected in COPD patients from the German COSYCONET study over 6 full days by a Bodymedia SenseWear MF armband, worn at the upper arm all the time, and an ActiGraph GT3X device, worn at the hip (day) or wrist (night). Additionally, patients recorded their daily routine in an activity diary. Only days with a weartime>22h for both devices were evaluated. Minutes spent in the common activity levels, sedentary (SPA), light (LPA), and moderate-to-vigorous (MVPA) activity, as well as number of steps were determined per day and the correlation between both devices was examined using Spearman9s rank correlation coefficient. 18 patients were examined (10 females; mean age 69.4y) and a total number of 86 valid days were included in the analysis. Patients spent a median of 237 min/day in LPA and 83 min/day in MVPA. Over subject-specific activity means, correlation coefficients were 0.34 for SPA, 0.16 for LPA, 0.38 for MVPA, and 0.95 for number of steps per day (p<0.01 for number of steps). Correlations between PA measures by both devices were low to moderate for activity levels and markedly better for number of steps per day. For comparative analyses of daily activity in studies which use the examined devices a primary focus on the number of steps appears to be most appropriate. Funded by the BMBF FKZ 01GI0881 and 01GI0882.

We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.