Reweighting and validation of the hospital frailty risk score using electronic health records in Germany: a retrospective observational study.

BACKGROUND: In the hospital setting, frailty is a significant risk factor, but difficult to measure in clinical practice. We propose a reweighting of an existing diagnoses-based frailty score using routine data from a tertiary care teaching hospital in southern Germany. METHODS: The dataset includes patient characteristics such as sex, age, primary and secondary diagnoses and in-hospital mortality. Based on this information, we recalculate the existing Hospital Frailty Risk Score. The cohort includes patients aged ≥ 75 and was divided into a development cohort (admission year 2011 to 2013, N = 30,525) and a validation cohort (2014, N = 11,202). A limited external validation is also conducted in a second validation cohort containing inpatient cases aged ≥ 75 in 2022 throughout Germany (N = 491,251). In the development cohort, LASSO regression analysis was used to select the most relevant variables and to generate a reweighted Frailty Score for the German setting. Discrimination is assessed using the area under the receiver operating characteristic curve (AUC). Visualization of calibration curves and decision curve analysis were carried out. Applicability of the reweighted Frailty Score in a non-elderly population was assessed using logistic regression models. RESULTS: Reweighting of the Frailty Score included only 53 out of the 109 frailty-related diagnoses and resulted in substantially better discrimination than the initial weighting of the score (AUC = 0.89 vs. AUC = 0.80, p < 0.001 in the validation cohort). Calibration curves show a good agreement between score-based predictions and actual observed mortality. Additional external validation using inpatient cases aged ≥ 75 in 2022 throughout Germany (N = 491,251) confirms the results regarding discrimination and calibration and underlines the geographic and temporal validity of the reweighted Frailty Score. Decision curve analysis indicates that the clinical usefulness of the reweighted score as a general decision support tool is superior to the initial version of the score. Assessment of the applicability of the reweighted Frailty Score in a non-elderly population (N = 198,819) shows that discrimination is superior to the initial version of the score (AUC = 0.92 vs. AUC = 0.87, p < 0.001). In addition, we observe a fairly age-stable influence of the reweighted Frailty Score on in-hospital mortality, which does not differ substantially for women and men. CONCLUSIONS: Our data indicate that the reweighted Frailty Score is superior to the original Frailty Score for identification of older, frail patients at risk for in-hospital mortality. Hence, we recommend using the reweighted Frailty Score in the German in-hospital setting.

Scalable and modular 8-channel transmit and 8-channel flexible receive coil array for 19 F MRI of large animals.

PURPOSE: To introduce an RF coil system consisting of an 8-channel transmit (Tx) and 8-channel receive (Rx) coil arrays for 19 F MRI of large animals. METHODS: The Tx efficiency and homogeneity of the 8-element loop coil array (loop size: 6 × 15 cm2 ) were simulated for two different pig models rendered from MR images. An 8-channel Rx coil array consisting of a flexible 6-channel posterior and a 2-channel planar anterior array was designed to fit on the abdomen of an average-sized pig in supine position. Measurements were performed in a grid phantom and ex vivo on a pig model with perfluoroctylbromide (PFOB)-filled tubes inserted in the thorax. RESULTS: Measured and simulated Tx efficiency and homogeneity for the 8-channel and 5-channel arrays were in good agreement: 1.87 ± 0.22µT/√kW versus 1.96 ± 0.29µT/√kW, and 2.29 ± 0.39µT/√kW versus 2.41 ± 0.37µT/√kW. An isolation of 38 ± 8 dB is achieved between the 19 F Tx and Rx elements, and over 30 dB between the 1 H and 19 F elements. The PFOB-filled vials could be clearly identified within the cadaver abdomen with an SNR of 275 ± 51 for a 3D gradient-echo sequence with 2-mm isotropic resolution and 12 averages, acquired in 9:52 min:s. Performance of the Tx array was robust against phase and amplitude mismatches at the input ports. CONCLUSIONS: A modular and scalable Tx array offers improved Tx efficiency in 19 F MRI of large animals with various sizes. Although conventional birdcage coils have superior Tx efficiency within the target region of interest, scalability of the Tx array to animal size is a major benefit. The described 19 F coil provides homogeneous excitation and high sensitivity detection in large pig models.

Center Volumes Correlate with Likelihood of Stent Implantation in German Coronary Angiography.

Aims: Literature on percutaneous coronary intervention (PCI) stated an inverse relationship between hospital volume and mortality, but the effects on other characteristics are unclear. Methods: Using German national records, all coronary angiographies with coronary artery disease in 2017 were identified. We applied risk-adjustment to account for differences in population characteristics. Results: Of overall 528,188 patients, 55.22% received at least one stent, with on average 1.01 stents implanted in all patients. Based on those patients who received at least one stent, this corresponds to an average number of 1.82 stents. In-hospital mortality across all patients was 2.93%, length of hospital stay was 6.46 days, and mean reimbursement was €5,531. There were comparatively more emergency admissions in low volume centers and more complex cases (3-vessel disease, left main stenosis, and in-stent stenosis) in high volume centers. In multivariable regression analysis, volume and likelihood of stent implantation (p=0.003) as well as number of stents (p=0.020) were positively correlated. No relationship was seen for in-hospital mortality (p=0.105), length of stay (p=0.201), and reimbursement (p=0.108). Nonlinear influence of volume suggests a ceiling effect: In hospitals with ≤100 interventions, likelihood and number of implanted stents are lowest (∼34% and 0.6). After that, both rise steadily until a volume of 500 interventions. Finally, both remain stable in the categories of over 500 interventions (∼60% and 1.1). Conclusion: In PCI, lower volume centers contribute to emergency care. Higher volume centers treat more complex cases and show a higher likelihood of stent implantations, with a stable safety.

Impact of the COVID-19 pandemic on aortic valve replacement procedures in Germany.

BACKGROUND: COVID-19 has caused the deferral of millions of elective procedures, likely resulting in a backlog of cases. We estimate the number of postponed surgical aortic valve replacement (sAVR) and transcatheter aortic valve replacement (TAVR) procedures during the first two waves of the COVID-19 pandemic in Germany. METHODS: Using German national records, all isolated TAVR and sAVR procedures between 2007 and 2020 were identified. Using weekly TAVR and sAVR procedures between 2017 and 2019, we created a forecast for 2020 and compared it with the observed number of procedures in 2020. RESULTS: In Germany, a total of 225,398 isolated sAVR and 159,638 isolated TAVR procedures were conducted between 2007 and 2020 that were included in our analysis. The reduction in all AVR procedures (sAVR and TAVR) for the entire year 2020 was 19.07% (95%CI: 15.19-22.95%). During the first wave of the pandemic (week 12-21), the mean weekly reduction was 32.06% (23.44-40.68%) and during the second wave of the pandemic (week 41-52), the mean weekly reduction was 25.58% (14.19-36.97%). The number of sAVR procedures decreased more than the number of TAVR procedures (24.63% vs. 16.42% for the entire year 2020). CONCLUSION: The first year of the COVID-19 pandemic saw a substantial postponing of AVR procedures in Germany. Postponing was higher for sAVR than for TAVR procedures and less pronounced during the second wave of the COVID-19 pandemic.

[European guidelines on heart failure: pharmacotherapy]. / Europäische Leitlinien Herzinsuffizienz: medikamentöse Therapie.

The new 2021 guidelines of the European Society of Cardiology (ESC) have broken with the old step by step treatment of heart failure and have fundamentally revised the strategy in the pharmacotherapy setting. For patients with heart failure and reduced ejection fraction ≤ 40%, the 4 substance groups angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transporter 2 (SGLT2) inhibitors are now recommended as early as possible after diagnosis. Completing the substance groups has priority over increasing the dosage of the individual substances. This makes it necessary to rethink current clinical practice, especially as the guidelines are reluctant to give concrete instructions for implementation.

Evolving trends in the surgical therapy of patients with endometrial cancer in Germany: analysis of a nationwide registry with special emphasis on perioperative outcomes.

PURPOSE: Endometrial cancer (EC) is the most common gynecological malignancy in women, with increasing incidence in the last decades. Surgical therapy is the mainstay of the initial management. The present study analyzed the evolving trends of surgical therapy in Germany in patients diagnosed with EC recorded in a nationwide registry. METHODS: All patients with the diagnosis of EC undergoing open surgery, laparoscopic surgery, and robotic-assisted laparoscopic surgery between 2007 and 2018 were identified by international classification of diseases (ICD) or specific operational codes (OPS) within the database of the German federal bureau of statistics. RESULTS: A total of 85,204 patients underwent surgical therapy for EC. Beginning with 2013, minimal-invasive surgical therapy was the leading approach for patients with EC. Open surgery was associated with a higher risk of in-hospital mortality (1.3% vs. 0.2%, p < 0.001), of prolonged mechanical ventilation (1.3% vs. 0.2%, p < 0.001), and of prolonged hospital stay (13.7 ± 10.2 days vs. 7.2 ± 5.3 days, p < 0.001) compared to laparoscopic surgery. A total of 1551 (0.04%) patients undergoing laparoscopic surgery were converted to laparotomy. Procedure costs were highest for laparotomy, followed by robotic-assisted laparoscopy and laparoscopy (8286 ± 7533€ vs. 7083 ± 3893€ vs. 6047 ± 3509€, p < 0.001). CONCLUSION: The present study revealed that minimal-invasive surgery has increasingly become the standard surgical procedure for patients with EC in Germany. Furthermore, minimal-invasive surgery had superior in-hospital outcomes compared to laparotomy. Moreover, the use of robotic-assisted laparoscopic surgery is increasing, with a comparable in-hospital safety profile to conventional laparoscopy.

Weakness of lower limb muscle in symptomatic peripheral artery disease with media sclerosis detected by ultrasound shear wave elastography.

Background: Symptomatic peripheral arterial disease (PAD) is difficult to non-invasively diagnose in the presence of calcified, media sclerotic arteries that are incompressible by blood pressure cuffs. Standard ankle-brachial index (ABI) measurements in these PAD patients are very often not helpful. Shear wave elastography (SWE) is a modern ultrasound technique to detect peripheral muscle stiffness changes i.e. muscle weakness during exercise. In a pilot study, we examined whether SWE could be a reproducible tool for diagnosing ischemic loss of muscle stiffness in patients with PAD and concomitant arterial media sclerosis. Patients and methods: N=13 consecutive patients with peripheral artery disease and media sclerosis were enrolled in the pilot study. All 13 patients were symptomatic in different stages of their PAD due to hemodynamically relevant arterial stenosis or occlusions of limb arteries as confirmed by oscillography, color-coded duplex sonography or angiography. Results: ABI measurements were invalid in all 13 patients. Mean SWE measurements of medial gastrocnemius muscles showed a significant transient muscle stiffness loss (weakness) at maximum exercise (active dorsal flexion of the foot, 103.4±25.9 kPa on the asymptomatic vs. 62.5±21.9 kPa on the symptomatic limb (p<0.001). Conclusions: SWE can reproducibly detect peripheral muscle weakness during exercise in the symptomatic leg of media sclerotic PAD patients. SWE of lower limb muscles may help to identify symptomatic PAD in patients presenting with invalid ABI measurements and unclear vascular status.

P2Y12-dependent activation of hematopoietic stem and progenitor cells promotes emergency hematopoiesis after myocardial infarction.

Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y12-mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y12. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y12 in LSK, implicating a direct effect of ADP on LSK via P2Y12 signaling. P2Y12 knockout and P2Y12 inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y12 inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y12-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y12 antagonists beyond inhibition of platelet-mediated atherothrombosis.

Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice.

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.

Annual hospital procedural volume and outcome in extracorporeal membrane oxygenation for respiratory failure.

BACKGROUND: The hospital mortality of patients suffering from pulmonary failure requiring venovenous extracorporeal membrane oxygenation (V-V ECMO) or extracorporeal carbon dioxide removal (ECCO2 R) is high. It is unclear whether outcome correlates with a hospital's annual procedural volume. METHODS: Data on all V-V ECMO and ECCO2 R cases treated from 2007 to 2019 were retrieved from the German Institute for Medical Documentation and Information. Comorbidities and outcomes were assessed by DRG, OPS, and ICD codes. The study population was divided into 5 groups depending on annual hospital V-V ECMO and ECCO2 R volumes (<10 cases; 10-19 cases; 20-29 cases; 30-49 cases; ≥50 cases). Primary outcome was hospital mortality. RESULTS: A total of 25 096 V-V ECMO and 3607 ECCO2 R cases were analyzed. V-V ECMO hospitals increased from 89 in 2007 to 214 in 2019. Hospitals handling <10 cases annually increased especially (64 in 2007 to 149 in 2019). V-V ECMO cases rose from 807 in 2007 to 2597 in 2019. Over 50% of cases were treated in hospitals handling ≥30 cases annually. Hospital mortality was independent of the annual hospital procedural volume (55.3%; 61.3%; 59.8%; 60.2%; 56.3%, respectively, p = 0.287). We detected no differences when comparing hospitals handling <30 cases to those with ≥30 annually (p = 0.659). The numbers of ECCO2 R hospitals and cases has dropped since 2011 (287 in 2007 to 48 in 2019). No correlation between annual hospital procedural volume and hospital mortality was identified (p = 0.914). CONCLUSION: The number of hospitals treating patients requiring V-V ECMO and V-V ECMO cases rose from 2007 to 2019, while ECCO2 R hospitals and their case numbers decreased. We detected no correlation between annual hospital V-V ECMO or ECCO2 R volume and hospital mortality.

Impact of Procedure Volume on the Outcomes of Surgical Aortic Valve Replacement.

BACKGROUND: Literature demonstrated that procedure volumes affect outcomes of patients undergoing transcatheter aortic valve implantation. We evaluated the outcomes of surgical aortic valve replacement. METHODS: All isolated surgical aortic valve replacement procedures in Germany in 2017 were identified. Hospitals were divided into five groups from ≤25 (very low volume) until >100 (very high volume) annual procedures. RESULTS: In 2017, 5,533 patients underwent isolated surgical aortic valve replacement. All groups were of comparable risk (logistic EuroSCORE, 5.12-4.80%) and age (66.6-68.1 years). In-hospital mortality and complication rates were lowest in the very high-volume group. Multivariable logistic regression analyses showed no significant volume-outcome relationship for in-hospital mortality, stroke, postoperative delirium, and mechanical ventilation > 48 hours. Regarding acute kidney injury, patients in the very high-volume group were at lower risk than those in the very low volume group (odds ratio [OR] = 0.53, p = 0.04). Risk factors for in-hospital mortality were previous cardiac surgery (OR = 5.75, p < 0.001), high-grade renal disease (glomerular filtration rate < 15 mL/min, OR = 5.61, p = 0.002), surgery in emergency cases (OR = 2.71, p = 0.002), and higher grade heart failure (NYHA [New York Heart Association] III/IV; OR = 1.80, p = 0.02). Risk factors for all four complication rates were atrial fibrillation and diabetes mellitus. CONCLUSION: Patients treated in very low volume centers (≤25 operations/year) had a similar risk regarding in-hospital mortality and most complications compared with very high-volume centers (>100 operations/year). Only in the case of acute kidney injury, very high-volume centers showed better outcomes than very low volume centers. Therefore, surgical aortic valve replacement can be performed safely independent of case volume.

Ventral calcification in the common femoral artery: A risk factor for major transcatheter aortic valve intervention access site complications.

OBJECTIVES: We aimed to identify risk factors for major transcatheter aortic valve intervention (TAVI) access site complications based on detailed analysis of the preprocedural computed tomography angiogram (CTA). BACKGROUND: Transfemoral TAVI has become the treatment of choice for severe aortic stenosis in elderly patients, especially with increased perioperative risk. Frailty, however, favors complications at the vascular access site due to the large bore vascular sheath devices necessary for valve deployment. METHODS: In this monocentric study, we retrospectively analyzed the preprocedural CTA of 417 consecutive patients that received transfemoral TAVI between 2015 and 2019 to quantify vessel diameter, calcification volume and calcified plaque location in detail within 10 cm proximal to the femoral bifurcation. RESULTS: The mean age of the study cohort was 81.4 ± 6.5 years with a STS of 8 ± 5.2 representing a population at increased periprocedural risk. 54.4% of patients were female. Major vascular access site complications occurred in 8.2% of patients. Major vascular complications correlated statistically with a sheath-to-vessel diameter (SFAR) when measured 1 cm proximal to the femoral bifurcation using a line-derived diameter and ventral calcification within the first 5 cm proximal to the bifurcation. In contrast, overall calcification volume had no influence. CONCLUSIONS: Transfemoral TAVI harbors a considerable risk for vascular access site complications especially if vessel diameter is too small to comfortably host the sheath diameter at the area of the femoral bifurcation. For preprocedural TAVI planning and risk assessment, location of calcification, especially if located ventrally, seems to be more relevant than consideration of overall calcification alone.

Incidence and predictors of delirium on the intensive care unit after acute myocardial infarction, insight from a retrospective registry.

OBJECTIVES: This study aimed to identify the incidence and potential risk factors for delirium after myocardial infarction (MI). BACKGROUND: Delirium is a common complication on intensive care units. Data on incidence and especially on predictors of delirium in patients after acute MI are rare. METHODS: In this retrospective study, all patients hospitalized for MI treated with coronary angiography in an university hospital in 2018 were included and analyzed. Onset of delirium within the first 5 days after MI was attributed to the MI and was defined by a Nursing Delirium screening scale (NuDesc) ≥2. This score is taken as part of daily care in every patient on intensive care unit three times a day by especially trained nurses. RESULTS: A total of 624 patients with MI (age 68.5 ± 13.2 years, ST-elevation MI 41.6%, hospital mortality 3.2%) were included in the study. Delirium was detected in 10.9% of all patients. In the subgroup of patients with a stay on the intensive care unit (ICU) for more than 24 hr (n = 229), delirium was detected in 29.7%. Hospital and ICU stay were significantly longer in patients with delirium (p < .001). Delirium was an independent predictor of prolonged ICU-stay. Independent predictors of delirium were age, dementia, alcohol abuse, cardiac arrest, hypotension, and leucocytosis. Infarct size or presentation with ST-elevation were not associated with incidence of delirium. CONCLUSION: Development of delirium is frequent after acute MI and prolongs hospitalization. Incidence of delirium is associated with clinical instability, preexisting comorbidity, and age rather than MI type or size.

Impact of Preprocedural Aortic Valve Calcification on Conduction Disturbances after Transfemoral Aortic Valve Replacement.

AIM: The present study analyzes in depth the impact of different calcification patterns on disturbances of the conduction system in transcatheter aortic valve replacement (TAVR) patients. METHODS AND RESULTS: A total of 169 preprocedural TAVR multislice computed tomography scans from consecutive transfemoral (TF) TAVRs performed between 2014 and 2017 using either Edwards SAPIEN or Medtronic Evolut R valves were retrospectively evaluated. The volume, distribution, and orientation of annular and valvular aortic valve calcification were measured and their impact on postoperative conduction disturbances was determined using linear and logistic regression analyses. The total volume of calcification and distribution at the aortic annulus or valve did not influence the conduction system. Oval calcification of the left aortic cusp was independently associated with an elevated risk for an increase in atrioventricular block degree (+0.6, p = 0.03). Moreover, orthogonal calcifications at the level of the aortic annulus were associated with an increased risk for QRS prolongation (+26 ms, p = 0.004) and an increased risk for permanent pacemaker implantation (OR 4.3, p = 0.03) after TF TAVR. This was more pronounced in patients undergoing TF TAVR using a balloon-expandable Edwards SAPIEN 3 valve (QRS +38.195 ms, p < 0.001; OR permanent pacemaker 15.48, p = 0.013). CONCLUSION: Orthogonal annular calcification confers an increased risk for conduction disturbances after TAVR. This is even more pronounced after implantation of balloon-expandable valves.

[Coronary physiology in the catheter laboratory]. / Koronarphysiologie im Herzkatheterlabor.

The regulation of coronary flow is mainly located in the resistance vessels of the microcirculation, so that the functional relevance of a coronary stenosis arises from the interaction between the epicardial stenosis and the downstream microcirculation. These complex interactions are precisely detectable by physiological measurements, such as the instantaneous wave-free ratio (iwFR) or the fractional flow reserve (FFR). In contrast, the purely visual assessment of the coronary anatomy could lead to misinterpretation and possibly to incorrect revascularization decisions. Consequently, in the current guidelines on myocardial revascularization of the European Society of Cardiology (ESC) the measurement of iwFR and FFR has a class IA indication in intermediate stenoses with unclear hemodynamic relevance. Despite this clear recommendation, physiological measurements are not yet regularly used in the clinical routine. Besides the purely hemodynamic assessment, novel methods such as co-registration and coronary mapping can be used for virtual planning of percutaneous coronary interventions, especially in vessels with diffuse lesions and serial stenoses. Furthermore, invasive flow measurements are also helpful for risk stratification between conservative and interventional treatment of patients with acute coronary syndrome, where additional factors of flow limitation, such as coronary spasm, thrombus and acute disturbance of the microcirculation play an important role.

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.

Analysis of accelerated 4D flow MRI in the murine aorta by radial acquisition and compressed sensing reconstruction.

Preclinical 4D flow MRI remains challenging and is restricted for parallel imaging acceleration due to the limited number of available receive channels. A radial acquisition with combined parallel imaging and temporal compressed sensing reconstruction was implemented to achieve accelerated preclinical 4D flow MRI. In order to increase the accuracy of the measured velocities, a quantitative evaluation of different temporal regularization weights for the compressed sensing reconstruction based on velocity instead of magnitude data is performed. A 3D radial retrospectively triggered phase contrast sequence with a combined parallel imaging and compressed sensing reconstruction with temporal regularization was developed. It was validated in a phantom and in vivo (C57BL/6 J mice), against an established fully sampled Cartesian sequence. Different undersampling factors (USFs [12, 15, 20, 30, 60]) were evaluated, and the effect of undersampling was analyzed in detail for magnitude and velocity data. Temporal regularization weights λ were evaluated for different USFs. Acceleration factors of up to 20 compared with full Nyquist sampling were achieved. The peak flow differences compared with the Cartesian measurement were the following: USF 12, 3.38%; USF 15, 4.68%; USF 20, 0.95%. The combination of 3D radial center-out trajectories and compressed sensing reconstruction is robust against motion and flow artifacts and can significantly reduce measurement time to 30 min at a resolution of 180 µm3 . Concisely, radial acquisition with combined compressed sensing and parallel imaging proved to be an excellent method for analyzing complex flow patterns in mice.

Nationwide outcomes of aortic valve replacement for pure aortic regurgitation in Germany 2008-2015.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is routinely used in patients with severe aortic stenosis at increased operative risk. Due to potential technical difficulties, TAVR is not recommended for pure aortic regurgitation (AR). Smaller studies reported its use in AR, but data from big registries are lacking. The present study analyzes the nationwide use of surgical aortic valve replacement (SAVR) and TAVR in patients with AR from 2008 until 2015. METHODS: We identified 138,237 cases of aortic valve replacement in Germany based on ICD and OPS codes. RESULTS: Of 13.2% SAVR-cases and 1.3% of TAVR cases were performed in AR. AR patients undergoing SAVR were younger with lower logistic EuroSCORE (stenosis: 6.1 ± 5.6; AR: 4.5 ± 4.9). Nevertheless, stroke rates, bleedings, prolonged mechanical ventilation, and in-hospital mortality were higher (mortality: stenosis 2.6%, AR: 4.7%). In the TAVR group, patients with AR were at higher operative risk (logistic EuroSCORE: transfemoral (TF)-TAVR: stenosis: 14.3 ± 10.4; AR: 17.3 ± 13.3. Transapical (TA)-TAVR: stenosis: 16.1 ± 11.4; AR: 15.7 ± 12.2). Stroke rates were lower, but bleedings and prolonged ventilation occurred more frequently after TF-TAVR in AR compared to stenosis. The mortality varied markedly (TF-TAVR: 15.2% in 2011; 2.8% in 2015; TA-TAVR: 17.7% in 2012 and 0% in 2014). CONCLUSION: TAVR is off-label used in AR in clinical practice. TAVR seems to be a safe option for AR with regard to in-hospital outcomes. However, further research evaluating long-term outcomes is required to establish the feasibility of TAVR in pure AR.

Inflammatory Pathways Regulated by Tumor Necrosis Receptor-Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity.

RATIONALE: The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. OBJECTIVE: We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor-associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-α, IL (interleukin)-1ß, and TLRs (toll-like receptors). METHODS AND RESULTS: Mice deficient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1-/- mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance-an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1-enabled thermogenesis. TRAF-1-dependent catabolic and proinflammatory cues were synergistically driven by ß3-adrenergic and inflammatory signaling and required the presence of both TRAF-1-deficient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated. CONCLUSIONS: Enhancing TRAF-1-dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These findings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.

Prone positioning in severe ARDS requiring extracorporeal membrane oxygenation.

BACKGROUND: Prone positioning (PP) has shown to improve survival in patients with severe acute respiratory distress syndrome (ARDS). To this point, it is unclear if PP is also beneficial for ARDS patients treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) support. METHODS: We report retrospective data of a single-centre registry of patients with severe ARDS requiring VV ECMO support between October 2010 and May 2018. Patients were allocated to the PP group if PP was performed during VV ECMO treatment or the supine positioning group. VV ECMO weaning success and hospital survival were analysed before and after propensity score matching. RESULTS: A total of 158 patients could be analysed, and 38 patients (24.1%) received PP. There were no significant differences in VV ECMO weaning rate (47.4% vs. 46.7%, p = 0.94) and hospital survival (36.8% vs. 36.7%, p = 0.98) between the prone and supine groups, respectively. The analysis of 38 propensity score matched pairs also showed no difference in hospital survival (36.8% vs. 36.8%, p = 1.0) or VV ECMO weaning rate (47.4% vs. 44.7%, p = 0.82). Hospital survival was superior in the subgroup of patients treated with early PP (cutoff < 17 h via Youden's Index) as compared to late or no PP (81.8% vs. 33.3%, p = 0.02). CONCLUSION: In this propensity score matched cohort of severe ARDS patients requiring VV ECMO support, prone positioning at any time was not associated with improved weaning or survival. However, early initiation of prone positioning was linked to a significant reduction of hospital mortality.