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BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

Diabetes, obesity and metabolism 23(12), 2814-2818 (2021). doi:10.1111/dom.14517, Published by Wiley-Blackwell, Oxford [u.a.]

Sodium-glucose cotransporter-2 inhibitors, glucose-lowering drugs that increase urinary glucose excretion, have been shown to reduce CV events in patients with type 2 diabetes (T2D), despite the fact that these agents increase blood levels of the proatherogenic low density lipoprotein cholesterol (LDL-C). It has been hypothesized that hemoconcentration due to osmotic diuresis, effects on calculated LDL particle size, or a modulation of lipoprotein subfractions may play a role in this context but to date the underlying mechanisms remain largely unexplored. Therefore, the present study examined effects of empagliflozin on LDL-C and lipoprotein subfractions including calculated LDL particle size and composition.In this placebo-controlled, randomized, double blind study, patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Composition of lipoprotein subfractions was assessed before and after 3 months of treatment. Lipoproteins were separated using a combined ultracentrifugation-precipitation method (β-quantification).Empagliflozin increased LDL-C after 3 months of treatment (from baseline: 103 ± 36 mg/dL to 112 ± 47 mg/dL; p 0.001) while no difference was recorded after day 1 or day 3 of treatment. The increase of LDL-C was paralleled by an increase of total cholesterol (baseline: 169 ± 41 mg/dL, 3 months: 185 ± 48 mg/dL; p = 0.001). Analyses of lipoprotein subfractions revealed LDL phospholipids and LDL apolipoprotein B to be increased by empagliflozin after 3 months of treatment while calculated LDL particle size was not affected. In addition empagliflozin increased free fatty acid concentrations.Empagliflozin treatment of patients with T2D increased LDL-C and LDL apolipoprotein B levels but had no effect on calculated LDL particle size.

OBJECTIVES The aim of this study was to characterize the feasibility of coronary angiography (CA) and percutaneous coronary intervention (PCI) in acute settings among patients who have undergone transcatheter aortic valve replacement (TAVR). BACKGROUND Impaired coronary access after TAVR may be challenging and particularly in acute settings could have deleterious consequences. METHODS In this international registry, data from patients with prior TAVR requiring urgent or emergent CA were retrospectively collected. A total of 449 patients from 25 sites with acute coronary syndromes (89.1%) and other acute cardiovascular situations (10.9%) were included. RESULTS Success rates were high for CA of the right coronary artery (98.3%) and left coronary artery (99.3%) and were higher among patients with short stent-frame prostheses (SFPs) than in those with long SFPs for CA of the right coronary artery (99.6% vs 95.9%; P��=��0.005) but not for CA of the left coronary artery (99.7% vs 98.7%; P��=��0.24). PCI of native coronary arteries was successful in 91.4% of cases and independent of valve type (short SFP 90.4% vs long SFP 93.4%; P��=��0.44). Guide engagement failed in 6 patients, of whom 3 underwent emergent coronary artery bypass grafting and another 3 died in the hospital. Among patients requiring revascularization of native vessels, independent predictors of 30-day all-cause mortality were prior diabetes, cardiogenic shock, and failed PCI but not valve type or success of coronary engagement. CONCLUSIONS CA or PCI after TAVR in acute settings is usually successful, but selective coronary engagement may be more challenging in the presence of long SFPs. Among patients requiring PCI, prior diabetes, cardiogenic shock, and failed PCI were predictors of early mortality.

Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of patients with severe aortic stenosis and is now standard of care for high surgical risk patients and a valid alternative strategy in intermediate risk patients. Recently, TAVR has shown excellent results in low-risk patients, indicating an imminent extension toward this population. Improvements in procedural outcomes are the result of increasing operator experience, sophisticated imaging for procedural planning but also due to the continuous evolution of transcatheter heart valves developed to minimize procedural complications. ‘Next-generation’ valves are currently available, among them the self-expanding ACURATE neo. Here, the technical details and clinical outcomes of the ACURATE neo are reviewed, comparative data with other ‘next-generation’ valves and potential advantages and disadvantages are discussed.

Objectives Computed tomography angiography (CTA) is performed routinely in the work-up for transcatheter aortic valve implantation (TAVI), and could potentially replace invasive coronary angiography (ICA) to rule out left main (LM) and proximal coronary stenosis. The objectives were to assess the diagnostic yield and accuracy of pre-TAVI CTA to detect LM and proximal coronary stenosis of ≥ 50% and ≥ 70% diameter stenosis (DS). Methods The DEPICT CTA database consists of individual patient data from four studies with a retrospective design that analyzed the diagnostic accuracy of pre-TAVI CTA to detect coronary stenosis, as compared with ICA. Pooled data were used to assess diagnostic accuracy to detect coronary stenosis in the left main and the three proximal coronary segments on a per-patient and a per-segment level. We included 1060 patients (mean age: 81.5 years, 42.7% male). Results On ICA, the prevalence of proximal stenosis was 29.0% (≥ 50% DS) and 15.7% (≥ 70% DS). Pre-TAVI CTA ruled out ≥ 50% DS in 51.6% of patients with a sensitivity of 96.4%, specificity of 71.2%, PPV of 57.7%, and NPV of 98.0%. For ≥ 70% DS, pre-TAVI CTA ruled out stenosis in 70.0% of patients with a sensitivity of 96.7%, specificity of 87.5%, PPV of 66.9%, and NPV of 99.0%. Conclusion CTA provides high diagnostic accuracy to rule out LM and proximal coronary stenosis in patients undergoing work-up for TAVI. Clinical application of CTA as a gatekeeper for ICA would reduce the need for ICA in 52% or 70% of patients, using a threshold of ≥ 50% or ≥ 70% DS, respectively. Key Points • Clinical application of CTA as a gatekeeper for ICA would reduce the need for ICA in 52% or 70% of TAVI patients, using a threshold of ≥ 50% or ≥ 70% diameter stenosis. • The diagnostic accuracy of CTA to exclude proximal coronary stenosis in these patients is high, with a sensitivity of 96.4% and NPV of 98.0% for a threshold of ≥ 50%, and a sensitivity of 96.7% and NPV of 99.0% for a threshold of ≥ 70% diameter stenosis. • Atrial fibrillation and heart rate did not significantly affect sensitivity and NPV. However, a heart rate of < 70 b/min during CTA was associated with a significantly improved specificity and PPV.

Background Transcatheter aortic valve implantation (TAVI) has become standard treatment for elderly patients with symptomatic severe aortic valve stenosis. The ACURATE neo AS study evaluates 30-day and 1-year clinical and hemodynamic outcomes in patients treated with the ACURATE neo2 valve. Methods The primary endpoint of this single-arm multicenter study is 30-day all-cause mortality. Other key endpoints include device performance, echocardiographic measures assessed by an independent core laboratory, and VARC-2 clinical efficacy and safety endpoints through 12 months. Results The study enrolled 120 patients (mean age 82.1 ± 4.0 years; 67.5% female, mean baseline STS score 4.8 ± 3.8%). The VARC-2 composite safety endpoint at 30 days occurred in 13.3% of patients. All-cause mortality was 3.3% at 30 days and 11.9% at 1 year. The 30-day stroke rate was 2.5% (disabling stroke 1.7%); there were no new strokes between 30 days and 12 months. The rate of permanent pacemaker implantation was 15.0% (18/120) at 30 days and 17.8% (21/120) at 1 year. No patients required re-intervention for valve-related dysfunction and there were no cases of valve thrombosis or endocarditis. Patients demonstrated significant improvement in mean aortic valve gradient (baseline 38.9 ± 13.1 mmHg, 1 year 7.8 ± 3.5 mmHg; P Conclusions One-year outcomes from the ACURATE neo AS study support the safety and performance of TAVI with the ACURATE neo2 valve. Graphic Abstract

Rationale: Increased myocardial activity of CaMKII (Ca/calmodulin-dependent kinase II) leads to heart failure and arrhythmias. In Drosophila neurons, interaction of CaMKII with CASK (Ca/CaM-dependent serine protein kinase) has been shown to inhibit CaMKII activity, but the consequences of this regulation for heart failure and ventricular arrhythmias are unknown. Objective: We hypothesize that CASK associates with CaMKII in human and mouse hearts thereby limiting CaMKII activity and that altering CASK expression in mice changes CaMKII activity accordingly, with functional consequences for contractile function and arrhythmias. Methods and Results: Immunoprecipitation revealed that CASK associates with CaMKII in human hearts. CASK expression is unaltered in heart failure but increased in patients with aortic stenosis. In mice, cardiomyocyte-specific knockout of CASK increased CaMKII-autophosphorylation at the stimulatory T287 site, but reduced phosphorylation at the inhibitory T305/306 site. Knockout of CASK mice showed increased CaMKII-dependent sarcoplasmic reticulum Ca leak, reduced sarcoplasmic reticulum Ca content, increased susceptibility to ventricular arrhythmias, greater loss of ejection fraction, and increased mortality after transverse aortic constriction. Intriguingly, stimulation of the cardiac glucagon-like peptide 1 receptor with exenatide increased CASK expression resulting in increased inhibitory CaMKII T305 phosphorylation, reduced CaMKII activity, and reduced sarcoplasmic reticulum Ca leak in wild type but not CASK-KO. Conclusions: CASK associates with CaMKII in the human heart. Knockout of CASK in mice increases CaMKII activity, leading to contractile dysfunction and arrhythmias. Increasing CASK expression reduces CaMKII activity, improves Ca handling and contractile function.

Background In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted. Study Design The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke. Conclusions The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.

OBJECTIVES Chronic kidney disease (CKD) is a key risk factor in patients undergoing transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). We analysed the impact of estimated glomerular filtration rate (eGFR) and CKD stages on their mid-term survival. METHODS Data from 29 893 patients enrolled in the German Aortic Valve registry from January 2011 to December 2015 receiving TAVI (n = 12 834) or SAVR (n = 17 059) at 88 sites were included. The impact of renal impairment, as measured by eGFR and CKD stages, was investigated. The primary end-point was 1-year cumulative all-cause mortality. RESULTS Higher CKD stages were significantly associated to lower in-hospital, 30-day- and 1-year survival rates. Both TAVI- and SAVR-treated patients in CKD 3a, 3b, 4 and 5 stages showed significant and gradually increasing HR values for 1-year all-cause mortality. The same trend persisted in multivariable analysis, although HR values for CKD 3a and 5 did not reach significance in TAVI patients, whereas CKD 4 + 5 did not reach statistical significance in SAVR. Likewise, eGFR as a continuous variable was a significant predictor for 1-year mortality, with the best cut-off points being 47.4 ml/min/1.73 m2 for TAVI and 59.8 ml/min/1.73 m2 for SAVR. Significant 8.6% and 9.0% increases in 1-year mortality were observed for every 5-ml reduction in eGFR for TAVI and SAVR, respectively. CONCLUSIONS CKD ≥3b and CKD ≥3a are the independent major risk factors for mortality in patients undergoing TAVI and SAVR, respectively. In the overall population of patients with severe aortic stenosis, an appropriate stratification based on CKD substage may contribute to a better selection of patients suitable for such therapies.

Interpretation biases are suggested to be transdiagnostic phenomena, but have rarely been compared across different disorders and current concerns. We investigated explicit, decision-based, and more implicit, reaction time-based interpretation bias in individuals with body dysmorphic disorder (BDD; N = 29), social anxiety disorder (SAD; N = 36), generalized anxiety disorder (GAD; N = 22), and non-clinical controls (NC; N = 32), using an adapted Word Sentence Association Paradigm (WSAP). Results indicated that interpretation bias occurred transdiagnostically, while content-specific bias patterns varied meaningfully across groups. BDD and SAD shared explicit and, more inconsistently, implicit interpretation biases for appearance-related and social situations. The GAD group exhibited an explicit and implicit negative interpretation bias for general situations, and an additional implicit lack of positive bias. Mechanistic Wiener diffusion model analyses revealed that interpretation bias patterns were mainly driven by speeded information uptake, potentially mirroring disorder-specific associative memory organization. These findings have important implications for understanding interpretation biases as both etiological and treatment factors., Projekt DEAL

Both surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) are established options to treat aortic valve stenosis. We present the outcome of the complete cohort of all patients undergoing SAVR or TAVI in Germany during the calendar year 2019. Data concerning all isolated aortic valve procedures performed in Germany in 2019 were retrieved from the mandatory nationwide quality control program: 22,973 transvascular (TV)-TAVI procedures, 7905 isolated SAVR (iSAVR), and 1413 transapical (TA)-TAVI. Data was complete in 99.9% (n = 32,156). In-hospital mortality after TV-TAVI (2.3%) was significantly lower when compared with iSAVR (2.8%, p = 0.007) or TA-TAVI (6.3%; p

The elderly patient with acute coronary syndrome (ACS) is often not treated on an evidence based basis due to age, previous illnesses and also an increased risk of bleeding. This applies to both drug and interventional therapy. However, valid data clearly show that elderly patients in particular benefit from guideline-adherent therapy, especially interventional revascularisation.

Aims During the COVID-19 pandemic, hospital admissions for cardiac care have declined. However, effects on mortality are unclear. Thus, we sought to evaluate the impact of the lockdown period in central Germany on overall and cardiovascular deaths. Simultaneously we looked at catheterization activities in the same region. Methods and results Data from 22 of 24 public health-authorities in central Germany were aggregated during the pandemic related lockdown period and compared to the same time period in 2019. Information on the total number of deaths and causes of death, including cardiovascular mortality, were collected. Additionally, we compared rates of hospitalization (n = 5178) for chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and out of hospital cardiac arrest (OHCA) in 26 hospitals in this area. Data on 5,984 deaths occurring between March 23, 2020 and April 26, 2020 were evaluated. In comparison to the reference non-pandemic period in 2019 (deaths: n = 5832), there was a non-significant increase in all-cause mortality of 2.6% [incidence rate ratio (IRR) 1.03, 95% confidence interval (CI) 0.99–1.06; p = 0.16]. Cardiovascular and cardiac mortality increased significantly by 7.6% (IRR 1.08, 95%-CI 1.01–1.14; p = 0.02) and by 11.8% (IRR 1.12, 95%-CI 1.05–1.19; p Conclusion During the COVID-19-related lockdown a significant increase in cardiovascular mortality was observed in central Germany, whereas catherization activities were reduced. The mechanisms underlying both of these observations should be investigated further in order to better understand the effects of a pandemic-related lockdown and social-distancing restrictions on cardiovascular care and mortality. Graphic abstract

Objectives This study sought to compare patient characteristics, procedural outcomes, and valve hemodynamics of surgical aortic valve replacement (SAVR) with current-generation rapid-deplo...

Background: The rate of intracranial haemorrhage after an acute coronary syndrome has been studied in detail in the era of thrombolysis; however, in the contemporary era of percutaneous coronary intervention, most of the data have been derived from clinical trials. With this background, we aim to analyse the incidence, timing, predictors and prognostic impact of post-discharge intracranial haemorrhage in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Methods: We analysed data from the BleeMACS registry (patients discharged for acute coronary syndrome and undergoing percutaneous coronary intervention from Europe, Asia and America, 2003–2014). Analyses were conducted using a competing risk framework. Uni and multivariate predictors of intracranial haemorrhage were assessed using the Fine–Gray proportional hazards regression analysis. The endpoint was 1-year post-discharge intracranial haemorrhage. Results: Of 11,136 patients, 30 presented with intracranial haemorrhage during the first year (0.27%). The median time to intracranial haemorrhage was 150 days (interquartile range 55.7–319.5). The fatality rate of intracranial haemorrhage was very high (30%). After multivariate analysis, only age (subhazard ratio 1.05, 95% confidence interval 1.01–1.07) and prior stroke/transient ischaemic attack (hazard ratio 3.29, 95% confidence interval 1.36–8.00) were independently associated with a higher risk of intracranial haemorrhage. Hypertension showed a trend to associate with higher intracranial haemorrhage rate. The combination of older age (⩾75 years), prior stroke/transient ischaemic attack, and/or hypertension allowed us to identify most of the patients with intracranial haemorrhage (86.7%). The annual rate of intracranial haemorrhage was 0.1% in patients with no risk factors, 0.2% in those with one factor, 0.6% in those with two factors and 1.3% in those with three factors. Conclusion: The incidence of intracranial haemorrhage in the first year after an acute coronary syndrome treated with percutaneous coronary intervention is low. Advanced age, previous stroke/transient ischaemic attack, and hypertension are the main predictors of increased intracranial haemorrhage risk.

The aim of this study was to compare outcomes of transcatheter and surgical aortic valve implantation in chronic dialysis patients with aortic valve stenosis (AS). Chronic dialysis patients undergoing heart valve surgery are at higher risk for morbidity and mortality. Whether interventional techniques can reduce this risk is unclear because dialysis patients have thus far been excluded from randomized trials. Chronic dialysis patients with AS enrolled in the German Aortic Valve Registry (GARY) between 2012 and 2015 were analyzed to compare transcatheter aortic valve implantation (TAVI n = 661) with surgical aortic valve replacement (SAVR n = 457). Propensity scores for inverse probability of treatment weighting (IPTW) were used to adjust the comparison of the two treatment groups for potential confounders. TAVI patients were older (78 ± 7.3 vs. 69 ± 10.2 years, p

Aortic valve calcification (AVC) determined by computed tomography has emerged as a complementary measure of aortic stenosis (AS) severity and as a predictor of adverse events. Thus, AVC can guide further treatment decisions in patients with low-gradient AS (LG-AS). We compared the symptomatic and prognostic outcome of patients with low vs. high AVC after transcatheter aortic valve implantation (TAVI). Patients with an aortic valve area index ≤ 0.6 cm2/m2 and a mean pressure gradient (MPG) 35 ml/m2, LVEF ≥ 50%, n = 244); patients with MPG ≥ 40 mmHg (n = 1142) served as controls. Patients were further categorized according to published AVC thresholds. Demographic characteristics and cardiovascular risk were not different between patients with high vs. low AVC in any of the subgroups. Patients with low AVC had a lower MPG. Symptom improvement at 30 days was observed in the majority of patients but was less pronounced in LFLG-AS patients with low vs. those with high AVC. Kaplan-Meier 1-year survival curves were identical between patients with low and high AVC in all three LG-AS groups. The severity of LG-AS based on AVC has no impact on 1-year prognosis once TAVI has been performed. • Aortic valve calcification (AVC) determined by computed tomography has emerged as a complementary measure of aortic stenosis (AS) severity and is of prognostic value in selected patients. • Patients with inconsistent echocardiographic measures can be classified as having severe or nonsevere AS by the computed tomography–derived AVC score. • The prognostic value of AVC in patients with low-gradient AS is abrogated after correction of afterload by TAVI.

According to the Valve Academic Resortium, underweight is one parameter in the definition of frailty, which is associated with increased mortality after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Aims of our study were (1) to examine the impact of underweight on mortality after TAVI and SAVR and (2) to determine the effect of intervention mode (TAVI vs SAVR) on mortality in underweight patients from the German Aortic Valve Registry. Overall, 35,109 patients treated with TAVI or SAVR were studied. Outcomes of underweight (body mass index [BMI]

The aim of the present study was to analyze the size of the preoperatively calculated defect volume of MRONJ patients (medication-related osteonecrosis of the jaw) and to develop a computer-aided tool based on techniques of AI (artificial intelligence) that facilitates diagnostics of MRONJ. For this purpose, on the basis of 3D (three-dimensional) data sets of 175 MRONJ patients, the outline of the necrosis was marked with the software iPlan 3.0.5 (BrainLAB AG) thus determining the respective volume. The correlation of this volume with other 31 collected parameters was analyzed retrospectively. There was a significant correlation between the defect volume on the one hand, and the MRONJ stage, the number of performed operations, and the therapy invasiveness on the other hand. Furthermore, it could be shown that in one third of the cases no defects could be recognized in the 2D imaging by panoramic radiograph, while in the 3D data sets defects already had been demarcated. On the basis of these data, a computer-aided tool based on the principles of AI was developed and validated, which might allow the automated calculation of the 3D defect extension and classification of the MRONJ cases into a ranking system. In conclusion, preparation of a 3D image can be recommended for reliably making the diagnosis “MRONJ.” Moreover, knowledge of the exact defect volume serves as a decision-making aid with regard to the choice of therapy, ensures intraoperative certitude, and allows an assessment of the prognosis.

Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Malignant niches frequently go along with inflammatory responses, but their impact on cancerogenesis often remains unexplored. Here, we uncovered an aberrant production of inflammatory cytokines in untreated AML bone marrow that was proved to promote the proliferation of leukemia cells. This inflammatory response induced an activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in AML blasts as well as bone marrow stromal cells that also fostered leukemia proliferation. Inhibition of JAK/STAT signaling using the selective JAK1/2 inhibitor ruxolitinib resulted in significant antileukemic activity in AML in vitro which is mediated through both cell-autonomous and microenvironment-mediated mechanisms. However, in a xenograft transplantation model, monotherapy with ruxolitinib did not achieve substantial antileukemic activity, possibly suggesting a complementary function of JAK1/2 inhibition in AML.

The coronavirus disease 2019 (COVID-19) pandemic poses an unprecedented challenge to healthcare worldwide. The infection can be life threatening and require intensive care treatment. The transmission of the disease poses a risk to both patients and healthcare workers. The number of patients requiring hospital admission and intensive care may overwhelm health systems and negatively affect standard care for patients presenting with conditions needing emergency interventions. This position statements aims to assist cardiologists in the invasive management of acute coronary syndrome (ACS) patients in the context of the COVID-19 pandemic. To that end, we assembled a panel of interventional cardiologists and acute cardiac care specialists appointed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and from the Acute Cardiovascular Care Association (ACVC) and included the experience from the first and worst affected areas in Europe. Modified diagnostic and treatment algorithms are proposed to adapt evidence-based protocols for this unprecedented challenge. Various clinical scenarios, as well as management algorithms for patients with a diagnosed or suspected COVID-19 infection, presenting with ST- and non-ST-segment elevation ACS are described. In addition, we address the need for re-organization of ACS networks, with redistribution of hub and spoke hospitals, as well as for in-hospital reorganization of emergency rooms and cardiac units, with examples coming from multiple European countries. Furthermore, we provide a guidance to reorganization of catheterization laboratories and, importantly, measures for protection of healthcare providers involved with invasive procedures.

Practical and applied knowledge of local fishers can help to improve our understanding of target species ecology and fisheries management decisions. In the Western Baltic Sea (WBS), the spatio-temporal distribution of cod is still largely unknown despite decades of research. We studied changes in cod distribution by obtaining information on temporal depth and habitat use of cod from commercial gillnet fishers using semi-directed interviews supplemented by at-sea observer data. Linear and non-linear regression analyses revealed significant relationships between depth use of cod and sea surface temperature (SST) as well as thermal stratification. Moreover, habitat use was related to SST and residence depth of cod. Areas deeper than 15 m were favoured from late December until March during low SST and a mixed water column (spawning) and also from July until August during high SST and strong thermal stratification (summer aestivation). Shallower areas were favoured during the rest of the year. The depth and habitat use displayed distinct seasonal up- and downslope movements of cod. This study highlights the importance of shallow-water and structured habitats for cod in the WBS and the value of local knowledge held by fishers for a better understanding of the distributional dynamics of important marine resource populations.

The ACURATE neo aortic valve system is a self-expanding transcatheter device that was granted CE mark in 2014 and has since been widely adopted in the treatment of patients with severe aortic stenosis. The ACURATE neo can be used in a wide clinical spectrum, but there are some specific indications and anatomies where this device is particularly suitable. Recently, it was shown that, with appropriate patient screening, size selection, and optimised positioning, results can be improved substantially. This review provides an overview of existing data and compiles a standardised manual of best practice for the implantation of this device based on both evidence and individual experience.

Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML). AML infiltration induces a significant release of inflammatory cytokines in the human bone marrow niche which accelerates leukemogenesis. As the transmembrane glycoprotein CD38 has been shown to regulate cytokine release, we assessed the anti-leukemic potential of CD38 inhibition in AML. CD38 expression in AML cells proved to depend on microenvironmental cues and could be significantly enforced through addition of tretinoin. In fact, the anti-CD38 antibody daratumumab showed significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, but with modest cell-autonomous cytotoxic activity and independent of CD38 expression level. In line with a predominantly microenvironment-mediated activity of daratumumab in AML, CD38 inhibition significantly induced antibody-dependent phagocytosis and showed interference with AML cell trafficking in vivo in a xenograft transplantation model, but overall lacked robust anti-leukemic effects.

Background The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. Methods In this mul...

Transcatheter aortic valve implantation (TAVI) is emerging as the standard of care for patients with severe aortic stenosis. Recent results have been favourable even for patients with low periprocedural risk. We analysed the number of procedures, complications, and in-hospital mortality rates of all patients undergoing isolated aortic valve replacement in 2017 in Germany, focussing especially on transvascular (TV) TAVI. Patients were stratified according the German Aortic Valve Score (AKL) into the risk classes low, intermediate, high and very high (≥ 10%). A total of 17,956 TV-TAVI and 9011 isolated surgical aortic valve replacements (iSAVR) were performed in Germany in 2017. Although the total rate of intraprocedural complications after TV-TAVI was the same as in 2016 (both 7.4%), fewer patients experienced an arterial vascular complication in 2017 (2017: 6.0%; 2016: 7.1%; p

Background The ACURATE neo prosthesis is commonly implanted using introducer sheaths with inner diameters of up to 20 French. The use of only the expandable mesh component of the transGlide introducer system (Meshonly) would substantially decrease the inner diameter to 13 French. We sought to assess the feasibility and safety of using Meshonly for femoral access of the ACURATE neo device and to compare outcomes with patients in whom standard sheaths were used. Methods and results We retrospectively analyzed a total of 551 patients with severe aortic stenosis from 4 high volume centers in Germany and Switzerland undergoing transfemoral TAVI between February 2016 and February 2018 with implantation of the ACURATE neo device. The median age was 81.7 [78.3–85.2], 67.0% were female, the STS score was 4.2% [2.8–6.5]. The use of the Meshonly was feasible in all attempted cases (n = 272); in all other patients, a standard sheath was used. Major vascular complications at the main access-site (VARC-2) were less frequent in the Meshonly group than in the standard sheath group (1.5% vs. 7.9%; p Conclusions Transfemoral implantation of the ACURATE neo device using the Meshonly was associated with a lower rate of major access-related complications when compared to the standard of care.

Objectives This study sought to examine whether the prognosis of patients with severe aortic stenosis (AS) having high versus low transvalvular mean pressure gradients (MPGs) is intrinsically different after transcatheter aortic valve replacement (TAVR), even after strict matching of baseline parameters. Background Patients with low MPG are characterized by higher cardiovascular risk and more comorbidities than other AS patients are. Methods In this retrospective, single-center study involving 2,282 patients, 3 groups were derived according to the following criteria: 1) high-gradient AS (HG-AS) (MPG ≥40 mm Hg); 2) low-flow, low-gradient AS (LFLG-AS) (MPG Results A total of 136 patients with HG-AS or LFLG-AS were identified. Kaplan-Meier survival curves were significantly different (p = 0.039), with death occurring in 11 versus 21 patients (hazard ratio: 2.12; 95% confidence interval: 1.02 to 4.39; p = 0.044), respectively. A total of 226 patients with HG-AS or pLFLG-AS were identified and here the curves were identical (p = 0.468), with death occurring in 18 versus 21 patients (hazard ratio: 1.26; 95% confidence interval: 0.67 to 2.38; p = 0.469). Conclusions This is the first study comparing survival after TAVR of patients with high versus low MPG in matched study populations. Mortality in patients with LFLG-AS was twice that of HG-AS patients. However, it appears that patients with pLFLG-AS might benefit from TAVR to the same extent as patients with HG-AS. There must be still unmasked factors that influence mortality of patients with LFLG-AS.

Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy metabolism. In particular, IFN-γ as well as IL-10-activated CBMΦ completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis. MTOR inhibition by rapamycin equalizes cytokine production in CBMΦ and PBMΦ. Finally, incubation of PBMΦ with cord blood serum or S100A8/A9, which is highly expressed in neonates, suppresses mTOR activation, prevents glycolysis and the expression of an PBMΦ phenotype. Thus, a metabolic alteration is apparent in CBMΦ, which might be dependent on S100A8/A9 expression., Neonatal immune responses are known to differ to those of an adult immune response. Here Dreschers and colleagues, compare macrophage populations derived from cord blood or adult peripheral blood and show a metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis.

Patients presenting with severe aortic stenosis and large aortic annuli are challenging to treat because of the size limitations of available transcatheter heart valves. In this study, we aimed to determine clinical and hemodynamic outcomes in patients presenting with large aortic annuli who underwent transcatheter aortic valve implantation (TAVI). Patients from the German Aortic Valve Registry who underwent TAVI either with the Edwards Sapien (ES) or Medtronic CoreValve (MCV) systems from 2011 to 2017 were included. They were further stratified into a large (aortic annulus diameter 26 to 29 mm for ES; 26 to 30 mm for MCV) and extra-large (aortic annulus diameter >29 mm for ES; >30 mm for MCV) group and analyzed using propensity score adjustment. Extra-large was set beyond the sizing limitations according to the manufacturer's instructions for use. Patients in the large (n = 5,628) and extra-large (n = 509) groups were predominantly male (large: 92.6% vs extra-large: 91.9%). The 30-day mortality was comparable (large: 3.9% vs extra-large: 5.0%, p = 0.458). Procedure duration (large: 78.9 minutes ± 0.82 vs extra-large: 86.4 minutes ± 1.9, p

Aims Paravalvular leakage (PVL) after transcatheter aortic valve replacement (TAVR) is a common complication in patients with bicuspid aortic valve (BAV). However, predictors and mechanisms of PVL are not well understood in this subset. The aim of this study was to analyse determinants and mechanisms of PVL in BAV and tricuspid aortic valve (TAV). Methods and results Of the 2394 consecutive patients undergoing transfemoral TAVR using new-generation valves at our centre, we identified 242 cases with BAV. To adjust for baseline differences, we performed 3 : 1 propensity score matching (TAVPS n = 726). We analysed the aortic root anatomy and calcification as well as the number, circumferential distribution, and predilection sites of PVL using pre-procedural multidetector computed tomography and post-TAVR echocardiography. In the matched cohort, the incidence of PVL ≥mild (BAV 51.9% vs. TAVPS 51.7%; P = 0.955) and PVL ≥moderate (BAV 5.0% vs. TAVPS 3.7%; P = 0.393), the circumferential distribution, and independent predictors were similar between BAV and TAVPS. Both the presence of peri-annular calcium chunks or LVOT calcification were highly associated with PVL in BAV and TAVPS patients, whereas in BAV patients neither the presence of a calcium bridge nor the volume of its calcification was related to PVL. Notably, the spatial localization of these lesions did not necessarily match the circumferential leak position. Conclusion The incidence, circumferential distribution, predilection sites, and predictors of PVL were similar in matched population of BAV and TAVPS patients undergoing transfemoral TAVR using new-generation devices. These novel findings suggest a common underlying mechanism of PVL in both entities.

Background: Cardiac catheterization is a frequently performed diagnostic procedure, but the associated exposure to ionizing radiation is a general healthcare concern. This study was designed to assess the level and development of radiation dose for diagnostic cardiac catheterizations (DCC). Methods: In the PROcedural radiaTion dose Exposure in diagnostic Cardiac catheterizaTION (PROTECTION VII) study all DCC procedures reported to a nation-wide quality insurance program in Germany between 2008 and 2018 were included. The dose-area product (DAP) and radiation time were analyzed. Multivariate linear regression analysis was performed to identify predictors associated with radiation dose. Findings: We enrolled 5 401 525 patients undergoing DCC (median age 70 years, 40% female). The most frequent indication was the evaluation of suspected coronary artery disease in 43% of patients. The DAP of all DCC was 1 856 (IQR 990 - 3 290) cGy*cm2 and median radiation time was 3.0 (IQR 1.7 - 5.5) min. During the ten years of observation, median DAP significantly decreased by 47% (p < 0.001) resulting in 1 229 cGy*cm2 in 2018 (effective dose estimate 2.7 mSv). A 11.9-fold variability in median dose exposure was observed between catheterization laboratories in 2008, which was reduced to 4.5-fold in 2018 (both p < 0.001). Male gender, increased age, history of coronary-artery-bypass-graft surgery, heart failure and the respective indication were identified as independent predictors for increased radiation dose (all p < 0.001). Interpretation: This large radiation dose survey demonstrates a considerable reduction in radiation exposure in DCC within the last decade. However, the inter-site variability underlines the need for further site-specific training and standardized implementation of low-dose protocols. Funding: The PROTECTION VII study received no funding. Declaration of Interest: JH received speaker honoraria and research support from and serves as consultant for Abbott Vascular and Edwards Lifesciences. The other authors declare no conflict of interest. Ethical Approval: The PROTECTION VII study has been approved by the Federal Joint Committee (GBA), which is the highest decision-making body of the joint self-government of physicians in Germany (application number 2019-19/06).

Cardiovascular diabetology 20(1), 6 (2021). doi:10.1186/s12933-020-01175-5, Published by BioMed Central, London

OBJECTIVES To determine the 5-year outcome in patients treated by isolated transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (sAVR)—a prospective observational cohort study. METHODS A total of 18 010 patients were included (n = 8942 TAVI and n = 9068 sAVR) in the German Aortic Valve Registry (GARY) who were treated in 2011 and 2012 at 92 sites in central Germany. Eligible patients with TAVI and sAVR were matched using propensity scores in a nearest-neighbour approach. Patients with repeat procedures or unequivocal indication for one treatment option (e.g. frailty) were excluded (n = 4785 for TAVI and n = 2 for sAVR). This led to 13 223 patients (4157 TAVI and 9066 sAVR) as an unmatched subcohort. The main outcome measure was the 5-year all-cause mortality. RESULTS TAVI patients were significantly older (80.9 ± 6.1 vs 68.5 ± 11.1 years, P CONCLUSIONS The 5-year follow-up data show that TAVI patients were significantly older and had a higher STS score than sAVR patients. After propensity score matching, TAVI with early-generation prosthesis was associated with significantly higher 5-year all-cause mortality than sAVR.

Background Rising life expectancy in the western population is increasing the prevalence of heart valve diseases (HVD). Hypothesis The level of awareness and initial screening for HVD should be sufficient. The potential impact of HVD on the daily activities of the elderly population in Europe might affect our society. Methods and Results A survey was conducted, including a total of 12 832 people aged ≥ 60 years in 11 European countries. Of all the people surveyed, 5.6% could correctly describe aortic valve stenosis. Most participants (75.0%) claimed they regularly do activities like sports or social activities, 29.2% provide care for a family member, friend or acquaintance. The majority (69.2%) would be prevented from doing these activities by symptoms such as chest pain, fatigue or shortness of breath. Having chest pain (76.5%) and shortness of breath (57.8%) were reasons for most people to arrange an appointment with their GP, whereas only 26.2% would visit a GP for fatigue. 67.6% of respondents claimed to be checked with a stethoscope by their GP occasionally, never, or only when they ask. The preferred treatment option for HVD is a keyhole procedure (45.8%), whereas open heart surgery would only be preferred by 7.0%. Conclusion Knowledge about HVD is still low. Neither appointments with a GP driven by symptoms nor regular use of a stethoscope are a reliable guarantee for early diagnosis. With the over 60s in Europe playing an active role in social life, awareness campaigns and regular heart health checks may guarantee early diagnosis and treatment of HVD.

Background: Rates of permanent pacemaker implantation (PPI) have been low using the self‐expanding ACURATE neo device, but data regarding risk factors of PPI for this specific device are scarce. Methods: The study cohort consisted of patients (n = 1000) with severe aortic stenosis undergoing transfemoral transcatheter aortic valve implantation (TAVI) using the ACURATE neo prosthesis in our center between May 2012 and December 2019. For the present analysis, we excluded patients with previous permanent pacemaker (n = 110), high‐grade AV block prior to TAVI (n = 3), and patients requiring conversion to surgical valve replacement (n = 4) or the implantation of a second prosthesis as valve‐in‐valve (n = 15). Preexisting conduction abnormalities were determined, and the implantation depth of the prosthesis was measured on final angiography. Differences across quartiles based on the original consecutive cohort were analyzed with respect to implantation depth and PPI rate. Predictors of PPI were identified using logistic regression. Results: The PPI rate was 10%. Preexisting AV block I°, right bundle branch block (RBBB), and the implantation depth were independent predictors of PPI. Across quartiles, the implantation depth differed significantly with lowest values in the last quartile, whereas differences of PPI rates across quartiles were not statistically significant, but showed a notable decrease in the last quartile. Conclusion: Preexisting RBBB, AV block I°, and low implantation depth were independent predictors of PPI following TAVI using the ACURATE neo device. Instead of deliberately aiming at a high position, avoidance of a low implantation depth may represent a reasonable compromise to reduce the rate of PPI without increasing the risk of malpositioning.

BackgroundIn the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that early hemodynamic effects may play a role, potentially mediated by direct diuretic effects of the drug. In this study we examined immediate and more delayed effects of empagliflozin on urinary volume excretion, left ventricular filling pressure and function in addition to hemodynamic parameters.MethodsIn this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Urinary volume excretion, echocardiographic and hemodynamic parameters were assessed after 1 day, 3 days and 3 months of treatment.ResultsBaseline characteristics were comparable in the empagliflozin (n = 20) and placebo (n = 22) group. Empagliflozin led to a significant increase of urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 hrs; day 1: 48.4 ± 34.7 g/24 hrs; p

Introduction and objectives The incidence of permanent pacemaker implantation (PPI) and new conduction abnormalities (CA) with the ACURATE neo (Symetis S.A., Eclubens, Switzerland) has not been studied in detail. We aimed to analyze their predictors, evaluating patient- and device-related factors, including implantation depth and device-to-annulus ratio (DAR). Methods Two analyses of a multicenter population were performed: new PPI in pacemaker-naive patients (n = 283), and PPI/new-CA in patients without prior CA or pacemaker (n = 232). Results A new PPI was required in 9.9% of patients, who had a higher body mass index, higher rate of right bundle branch block and bradycardia. Neither implantation depth nor DAR differed in patients with PPI compared with those without. In the multivariable analysis neither DAR (OR, 1.010; 95%CI, 0.967-1.055; P = .7) nor implantation depth (OR, 0.972; 95%CI, 0.743-1.272; P = .8) predicted PPI. Only high body mass index, bradycardia and right bundle branch block persisted as independent predictors. PPI/new-onset CA occurred in 22.8% of patients and was associated with a higher logistic EuroSCORE. Neither implantation depth nor DAR differed in patients with PPI/new-CA vs those without (7.3 ± 1.9 vs 7.1 ± 1.5mm; P = .6 and 41.0 ± 7.9 vs 42.2 ± 10.1%; P = .4). The only predictor of PPI/new-CA was a higher logistic EuroSCORE (OR, 1.039; 95%CI, [1.008-1.071]; P = .013). Conclusions New PPI and new-onset CA rates were low with the ACURATE neo. These were mainly influenced by patient characteristics and not by device-depending factors.

Objectives The aim of this study was to evaluate very long-term results after unrestricted everolimus-eluting bioresorbable scaffolds (BRS) implantation. Background Previous randomized studies mainly included selected patients differing from those seen during daily routine and long-term data from all-comers registries are sparse. Methods Consecutive patients undergoing BRS implantation were included in this observational, single center study. Clinical follow-up was conducted up to 5 years. Endpoint of interest was the composite of target lesion failure (TLF), including target-vessel myocardial infarction and target lesion revascularization and cardiac death. Furthermore, ARC-defined scaffold thrombosis (ScT) were assessed. Results A total of 176 patients with a median age of 64 (55 - 72) years were analyzed, of which 59.6% presented an acute coronary syndrome. A total of 183 mainly complex lesions (55.8%) were treated. At 5 years, the rate for TLF was 21.6%. Definite or probable ScT rate was 4.1%. The rate of ScT within the first year was 2.8% and afterwards 1.2%. Notably, no ScT was seen later than 2 years. Conclusions Although this real-world registry displays high rates of clinical events during long-term follow-up, no ScT was seen after 2 years.

Introduction 3–4% of pregnant women present with a fetal breech position at term. National societies regard vaginal breech delivery as a safe option, but only for a specific and thoroughly counseled group of patients. To avoid adverse outcome, many practitioners recommend elective cesarean section once their patients go past the estimated due date. Since encompassing evidence is missing, the evaluation on this common clinical practice is needed. Objective This study compares the short-term maternal and fetal outcome in intended vaginally breech deliveries before the estimated due date (until 40 0/7 weeks of gestation) to the outcome of deliveries carried out past the estimated due date (later than 40 0/7 weeks of gestation). Methods This prospective cohort study includes 827 women who presented for an intended vaginal breech delivery of a singleton at our perinatal center between January 2010 and December 2016. Results 447 patients (54%) delivered before or at their estimated due date, 380 (46%) of pregnancies continued after the estimated due date. Comparing both groups, no significant difference in maternal and neonatal short-term mortality and morbidity was found. The rate of caesarian sections was increased in the group of patients, who delivered later than 40 1/7 weeks of gestation. Here, the likelihood for delivery maneuvers was also increased. Conclusion This study provides evidence, that an elective cesarean section for breech presentations at term is not obligatory when the estimated due date has passed in singleton pregnancy.

Background: Transcatheter aortic valve replacement (TAVR) is increasingly being used for treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement (SAVR). Currently, real-world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated TAVR with those undergoing SAVR are scarce. Methods: We compared clinical characteristics and outcomes of patients with intermediate surgical risk (Society of Thoracic Surgeons score 4%–8%) who underwent isolated TAVR or conventional SAVR within the prospective, all-comers German Aortic Valve Registry. Results: A total of 7613 patients at intermediate surgical risk underwent isolated TAVR (n=6469) or SAVR (n=1144) at 92 sites in Germany between 2012 and 2014. Patients treated by TAVR were significantly older (82.5±5.0 versus 76.6±6.7 years, P P P P P =0.976), whereas unadjusted 1-year mortality was significantly higher in patients after TAVR (17.5% versus 10.8%, P P =0.59). Conclusions: Patients at intermediate risk undergoing TAVR differ significantly from those treated with SAVR with regard to age and baseline characteristics. Isolated TAVR and SAVR were associated with an in-hospital mortality rate of 3.6%. In the propensity score analysis, there was no significant difference in 1-year mortality between patients with TAVR and SAVR.

Aims Transcatheter aortic valve implantation (TAVI) has become the standard treatment for patients with severe aortic valve stenosis at high surgical risk and may be considered for patients with intermediate risk. During the last few years, an increasing number of patients with low surgical risk have been treated with TAVI. In this study, low-risk patients undergoing isolated TAVI or surgical aortic valve replacement (SAVR) were analysed using data from the German Aortic Valve Registry (GARY). Methods and results All patients with a Society of Thoracic Surgeons Score of Conclusion In this first GARY analysis of low-risk patients, weighted comparison showed similar 1-year survival for TAVI and SAVR and higher in-hospital survival for TAVI patients.

BACKGROUND: Compromised renal function is a major risk factor that is strongly associated with poor outcome in patients with mitral regurgitation (MR) and heart failure. Cystatin C, a cysteine protease inhibitor, has been used as a specific and sensitive biomarker of renal function. Neutrophil gelatinase‐associated lipocalin (NGAL) is another sensitive biomarker that specifically indicates functional and structural kidney damage. The aim of the present study was to determine the predictive value of serum cystatin C and urinary NGAL as indicators of mortality in patients undergoing percutaneous mitral valve repair (PMVR). METHODS: A total of 120 consecutive patients (age: 77.3 years [±11.2]) undergoing PMVR using the MitraClip system were included in this study. Venous blood and urinary samples were collected for biomarker analysis prior to PMVR. Physiological parameters, medication use, safety events, and all‐cause mortality were assessed 12 months after the procedure. RESULTS: Twelve months after PMVR, there was a significant reduction in the severity of MR (P < 0.001), and an improvement in the New York Heart Association class (P < 0.01) was documented. Baseline levels of serum cystatin C (nonsurvivors: 2.4 mg/L [interquartile, IQR: 1.7;3.1] vs survivors: 1.7 mg/L [IQR: 1,3;2.1], P < 0.001) and urinary NGAL (nonsurvivors: 242.0 ng/mL [IQR: 154.5;281.5] vs survivors: 132.0 ng/mL [IQR:107.0;177.3], P < 0.001) were significantly higher in patients who died during the 12‐month follow‐up period. CONCLUSION: Cystatin C and urinary NGAL were found to be predictors of long‐term mortality in high‐risk patients undergoing PMVR. Thus, cystatin C and NGAL assessment may be helpful in risk stratification in patients undergoing PMVR.

Transcatheter aortic valve implantation (TAVI) is increasingly performed in patients with severe aortic stenosis. The efficacy and safety have been demonstrated in large randomized trials in patients with high- or intermediate operative risk. With latest-generation transcatheter heart valve (THV) systems, growing operator experience and improved patient selection, clinical outcome has significantly improved with a decline of TAVI-related complications. In this review, the Edwards SAPIEN 3 THV is discussed in terms of technology, procedural advances and complication trends and future developments.

Objectives The aim of this study was to perform a comprehensive analysis of factors that affect procedural outcomes of transcatheter aortic valve replacement using the ACURATE neo prosthesis (Symetis/Boston, Ecublens, Switzerland). Background Predictors of procedural outcomes using the ACURATE neo prosthesis are poorly understood. Methods A total of 500 patients underwent transfemoral aortic valve replacement with the ACURATE neo prosthesis. Device landing zone calcification was stratified as severe, moderate, or mild. Anatomic and procedural predictors of second-degree or greater paravalvular leakage and permanent pacemaker implantation were assessed. Results Post-procedural second-degree or greater paravalvular leakage was more frequent with increasing device landing zone calcification (mild 0.8% vs. moderate 5.0% vs. severe 13.0%; p Conclusions Successful transcatheter aortic valve replacement using the ACURATE neo device predominantly depends on careful patient selection with appropriate oversizing and taking into account the individual anatomy and calcium distribution of the aortic root.

Background The extent of aortic valve calcification is an important determinant of procedural success in transcatheter aortic valve implantation (TAVI). We sought to validate device landing zone calcium volume (DLZ-CV) measurements on contrast-enhanced multidetector computed tomography (MDCT) with non-contrast-enhanced scans as reference. Methods We determined DLZ-CV in 141 patients undergoing transfemoral TAVI. Non-contrast-enhanced images were analyzed using a threshold of 130 HU as reference (DLZ-CV130). For contrast-enhanced scans, we applied various thresholds including 450 HU (DLZ-CV450), 850 HU (DLZ-CV850), mean aortic attenuation (AttenAo) + 2 SD (DLZ-CV2SD), AttenAo + 4 SD (DLZ-CV4SD), AttenAo + 4 SD + 5 mm3 volume filter (DLZ-CV4SD+), and based on visual estimation (DLZ-CVvis). We compared DLZ-CV values between patients with versus without paravalvular leak (PVL), and between patients with versus without post-dilatation stratified by the type of prosthesis. Results All DLZ-CV measurements on contrast-enhanced scans significantly differed from DLZ-CV130 (p Conclusion Measurement of DLZ-CV using contrast-enhanced scans with unadjusted thresholds results in incorrect estimation of the calcium volume. The use of a scan-specific individual HU threshold including a volume filter (DLZ-CV4SD+) provides the best approximation to the reference and allows for discrimination of PVL ≥ 1° in patients receiving the Acurate neo prosthesis.

The 2015 Heart Valve Disease Awareness Survey showed a low knowledge and awareness about heart valve disease in the general population despite its high prevalence and morbidity. The 2017 survey was conducted to re-evaluate concern and knowledge about heart valve disease after 2 years of rapidly increasing patient numbers presenting with heart valve disease. A total of 12,820 people aged 60 years or older in 11 European countries took part in the survey. While the number of people concerned most about heart valve disease increased significantly (2015:1.7% vs. 2017:2.1%; p

Onset of progression even during therapy with novel drugs remains an issue in chronic lymphocytic leukemia (CLL). Thus, there is ongoing demand for novel agents. Approaches targeting cyclin-dependent kinases (CDK) have reached the clinical trial stage. CDK9 mediating RNA transcriptional elongation is the evolving pivotal CLL CDK inhibitor target. However, more CDK9 selective compounds are desirable. Here, we describe the CDK9 inhibitor LDC526 displaying a low nanomolar biochemical activity against CDK9 and an at least 50-fold selectivity against other CDKs. After demonstrating in vitro MEC-1 cell line and primary human CLL cell cytotoxicity we evaluated the LDC526 in vivo effect on human CLL cells transplanted into NOD/scid/ γcⁿull (NSG) mice. LDC526 administration (75 mg/kg) for 5 days resulted in a 77% reduction of human CLL cells in NSG spleens compared to carrier control treatment. Next, we longitudinally studied the LDC526 impact on circulating CLL cells in the TCL1 transgenic mouse model. LDC526 (50 mg/kg) administration for two days led to a 16-fold reduction of blood CLL cell numbers. Remarkably, residual CLL cells exhibited significantly increased intracellular BCL-2 levels. However, the LDC526 cytotoxic effect was not restricted to CLL cells as also declining numbers of normal B and T lymphocytes were observed in LDC526 treated TCL1 mice. Taken together, our in vivo data provide a strong rational for continued LDC526 development in CLL therapy and argue for the combination with BCL-2 inhibitors. CA Göthert