Impact of route of access and stenosis subtype on outcome after transcatheter aortic valve replacement.

Introduction: Previous analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR. Methods: A total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22-4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically. Results: The operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54-5.48), p = 0.001] and patients with LFLG AS [OR: 2.27 (1.13-4.56), p = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35-12.62), p < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p = 0.016) and TA HG patients (6.36%, p = 0.024). Conclusions: HG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible.

Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

Trib1 Deficiency Promotes Hyperlipidemia, Inflammation, and Atherosclerosis in LDL Receptor Knockout Mice.

BACKGROUND: Genetic variants at the TRIB1 gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. Here, we analyzed the consequences of Trib1 deficiency on lipid metabolism and atherosclerotic lesion formation in atherosclerosis-susceptible Ldlr-/- mice. METHODS: Trib1-/- mice were crossed onto the Ldlr-/- background to generate double-knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol and 4.3% fat) until 20 weeks of age. RESULTS: Trib1-/-Ldlr-/- mice had profoundly larger (5.8-fold) and more advanced atherosclerotic lesions at the aortic root as compared with Trib1+/+Ldlr-/- controls. Further, we observed significantly elevated plasma total cholesterol and triglyceride levels in Trib1-/-Ldlr-/- mice, resulting from higher VLDL (very-low-density lipoprotein) secretion. Lipidomics analysis revealed that loss of Trib1 altered hepatic lipid composition, including the accumulation of cholesterol and proinflammatory ceramide species, which was accompanied by signs of hepatic inflammation and injury. Concomitantly, we detected higher plasma levels of IL (interleukin)-6 and LCN2 (lipocalin 2), suggesting increased systemic inflammation in Trib1-/-Ldlr-/- mice. Hepatic transcriptome analysis demonstrated significant upregulation of key genes controlling lipid metabolism and inflammation in Trib1-/-Ldlr-/- mice. Further experiments suggested that these effects may be mediated through pathways involving a C/EPB (CCAAT/enhancer binding protein)-PPARγ (peroxisome proliferator-activated receptor γ) axis and JNK (c-Jun N-terminal kinase) signaling. CONCLUSIONS: We provide experimental evidence that Trib1 deficiency promotes atherosclerotic lesion formation in a complex manner that includes the modulation of lipid metabolism and inflammation.

Biodegradable Poly(D-L-lactide-co-glycolide) (PLGA)-Infiltrated Bioactive Glass (CAR12N) Scaffolds Maintain Mesenchymal Stem Cell Chondrogenesis for Cartilage Tissue Engineering.

Regeneration of articular cartilage remains challenging. The aim of this study was to increase the stability of pure bioactive glass (BG) scaffolds by means of solvent phase polymer infiltration and to maintain cell adherence on the glass struts. Therefore, BG scaffolds either pure or enhanced with three different amounts of poly(D-L-lactide-co-glycolide) (PLGA) were characterized in detail. Scaffolds were seeded with primary porcine articular chondrocytes (pACs) and human mesenchymal stem cells (hMSCs) in a dynamic long-term culture (35 days). Light microscopy evaluations showed that PLGA was detectable in every region of the scaffold. Porosity was greater than 70%. The biomechanical stability was increased by polymer infiltration. PLGA infiltration did not result in a decrease in viability of both cell types, but increased DNA and sulfated glycosaminoglycan (sGAG) contents of hMSCs-colonized scaffolds. Successful chondrogenesis of hMSC-colonized scaffolds was demonstrated by immunocytochemical staining of collagen type II, cartilage proteoglycans and the transcription factor SOX9. PLGA-infiltrated scaffolds showed a higher relative expression of cartilage related genes not only of pAC-, but also of hMSC-colonized scaffolds in comparison to the pure BG. Based on the novel data, our recommendation is BG scaffolds with single infiltrated PLGA for cartilage tissue engineering.

The Spectrum of Caseous Mitral Annulus Calcifications.

Mitral annular calcification (MAC) is a chronic, degenerative condition of the fibrous mitral annulus, which may transform to liquefaction necrosis MAC, a rare variant of caseous MAC. We present a series of experiences, showing the varying manifestations of caseous MAC according to multimodal imaging. (Level of Difficulty: Intermediate.).

Secreted Factors from Adipose Tissue Reprogram Tumor Lipid Metabolism and Induce Motility by Modulating PPARα/ANGPTL4 and FAK.

Recent studies indicate that adipose tissue in obesity promotes breast cancer progression by secreting protumorigenic chemokines, growth factors, and fatty acids. However, the detailed mechanisms by which hypertrophic adipose tissue influences breast cancer cells are still not well understood. Here we show that co-culture with adipose tissue from high-fat diet induced obese C57BL/6 mice alters transcriptome profiles in triple-negative breast cancer (TNBC) cells, leading to upregulation of genes involved in inflammation and lipid metabolism, such as IL1B, PLIN2, and ANGPTL4. Similar results were obtained by treating TNBC cells with adipose tissue conditioned media (ACM) generated from fat tissue of obese female patients. Many of the upregulated genes were activated by PPAR nuclear receptors, as shown by pathway analyses and gene expression experiments using PPAR agonists and antagonists. Metabolic analysis revealed that TNBC cells cultivated with ACM had significantly higher levels of ß-oxidation. Furthermore, ACM-treated TNBC cells displayed a pronounced aggressive cell phenotype, with enhanced wound healing, proliferation, and invasion capabilities. ACM-induced invasion was dependent on the PPAR-target ANGPTL4 and activated FAK signaling, as shown by ANGPTL4 depletion and FAK inhibition. Together, our data suggest that factors released by adipose tissue change PPAR-regulated gene expression and lipid metabolism and induce a more aggressive TNBC cell phenotype. These effects are, at least in parts, mediated by fatty acids provided by the adipose tissue. IMPLICATIONS: Adipose tissue provides factors for increased progression of TNBC cells, identifying PPAR- and FAK-signaling as potential novel targets for treatment of TNBC, especially in obese women.

Prophylactic Ligature of AV Fistula Prevents High Output Heart Failure after Kidney Transplantation.

BACKGROUND: Arteriovenous (AV) fistulas are considered the gold standard for ensuring safe and long-term vascular access in patients with haemodialysis-dependent end-stage renal disease. However, previous studies demonstrated that high-flow AV fistulas might add additional cardiovascular burden in the post-transplant setting, leading to frequent fistula closure in this population. Currently, there is no consensus regarding management of high-flow fistulas in post-transplant patients with stable kidney function. The present randomized controlled trial examines the effect of prophylactic AV fistula closure on high-output heart failure. METHODS: Twenty-eight kidney transplant patients with stable graft function, absence of pre-existing severe cardiac failure, and brachial arterial flow rate of at least 1,500 mL/min were recruited and randomized in a 1:1 ratio to an intervention and control group, respectively. The intervention group was subject to immediate fistula ligature. Patients within the control group were referred to fistula ligature only if the main study endpoint high-output heart failure was reached. The latter was defined by the presence of at least 1 clinical sign (i.e., worsening NYHA score) and at least 2 of the following echocardiographic parameters: diameter of right atrium (major) >53 mm, right atrium (minor) >44 mm, inferior vena cava ≥21 mm, right pulmonary artery >20 mm, TAPSE <16 mm, systolic pulmonal artery pressure >40 mm Hg, and/or left ventricular eccentricity index <1. During a 24-month follow-up period, quarterly measurements of kidney function, NT-proBNP, and lactate dehydrogenase as well as a biannual echocardiographic check-up were performed. RESULTS: High-output heart failure attributable to high-flow fistula was reported in 5 of 13 control patients (38.5%), whereas no patient in the intervention group presented with clinical and echocardiographic signs of high-output heart failure during the follow-up period. Thus, prophylactic ligature of high-flow fistulas avoided high-output heart failure in our patient population (p = 0.013). Three patients in the control group, however, had to undergo fistula ligature due to aneurysm formation (n = 2) and steal phenomenon (n = 1). Median NT-proBNP levels decreased from 317 ng/L pre-ligature to 223 ng/L post-ligature (p = 0.003). Serum creatinine levels did not significantly differ before and after AV fistula ligature (1.69 vs. 1.60 mg/dL, respectively, p = 0.059). Improvement of echocardiographic findings (e.g., a decrease in systolic pulmonary arterial pressure) was found in 7 of 8 ligature patients but did not reach statistical significance. CONCLUSION: Prophylactic ligature of high-flow AV fistulas after kidney transplantation can avoid high-output heart failure, and a more liberal approach to close AV fistulas might be justified.

Dataset on the prognostic value of cardiac biomarkers used in clinical routine in patients with severe aortic stenosis undergoing valve replacement.

Hereby, the supplemental data of the research article "Long-Term Prognostic Value of High-Sensitivity Troponin T added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels before Valve Replacement for Severe Aortic Stenosis" are presented [1]. It offers enhanced input on the predictive value of these biomarkers considering the influence of the presence of concomitant coronary artery disease (CAD) in various severities as well as an additional cox proportional hazard model on cardiovascular mortality. Furthermore, the receiver operating characteristic (ROC) curves are shown as figures. The material described increases therefore the understanding of the predictive value of these already routinely available biomarkers and reduces the risk of potential bias due to possible confounding factors. It also underlines the urge for a multi-factorial approach in diagnostics to detect the optimal point for referral to valve replacement other than just symptomatic status, an observed reduction in left ventricular ejection fraction or the presence of CAD with the necessity for coronary artery bypass grafting (CABG) [2]. The data of the 3595 patients were gathered retrospectively at a consortium of four university hospital centers in Austria and combined with prospectively collected data on cardiovascular and all-cause mortality.

Infective endocarditis and neurologic events: indications and timing for surgical interventions.

A therapeutic dilemma arises when infective endocarditis (IE) is complicated by a neurologic event. Postponement of surgery up to 4 weeks is recommended by the guidelines, however, this negatively impacts outcomes in many patients with an urgent indication for surgery due to uncontrolled infection, disease progression, or haemodynamic deterioration. The current literature is ambiguous regarding the safety of cardiopulmonary bypass in patients with recent neurologic injury. Nevertheless, most publications demonstrate a lower risk for secondary haemorrhagic conversion of uncomplicated ischaemic lesions than the risk for recurrent embolism under antibiotic treatment. Here, we discuss the current literature regarding neurologic stroke complicating IE with an indication for surgery.

A case report on the successful interventional treatment of a rare cause of left heart failure in a 69-year-old woman.

BACKGROUND: Dyspnoea is very common in elderly patients and can be caused by a variety of different diseases. However, the initial diagnosis of patent ductus arteriosus (PDA) as a cause of left heart failure is very rare in this patient population. CASE SUMMARY: A 69-year-old physically active woman with known hypertension presented with worsening exertional dyspnoea. Echocardiography showed a dilated left ventricle with moderately reduced left ventricular ejection fraction, and evidence for PDA. The PDA was confirmed by computed tomography angiography and successfully closed by implantation of an Amplatzer PDA occluder II 06-06 mm. As a result, the heart failure symptoms receded completely. DISCUSSION: Congenital heart diseases should be considered as heart failure causes even in older adults. In addition to the standard medical therapy, there may be effective interventional treatment options to reverse the symptoms of heart failure in such patients.

Baseline LV ejection fraction by cardiac magnetic resonance and 2D echocardiography after ST-elevation myocardial infarction - influence of infarct location and prognostic impact.

OBJECTIVES: The comparability of left ventricular ejection fraction (LVEF) measurements by cardiac magnetic resonance (CMR) and 2D echocardiography (2DE) early after ST-elevation myocardial infarction (STEMI) remains unclear. METHODS: In this study, LVEF measured by CMR and 2DE (Simpson's method) were compared in 221 patients after STEMI treated by primary percutaneous coronary intervention. 2DE image quality was systematically assessed and studies reported by an accredited examiner. Intermodality agreement was assessed by the Bland-Altman method. Major adverse cardiac events (MACE) were defined as the composite of death, myocardial infarction or hospitalisation for heart failure. Patients were followed up for a median of 40.9 months (IQR 28.1-56). RESULTS: After non-anterior STEMI, LVEF measurements by 2DE (single and biplane) were consistently underestimated in comparison to CMR (CMR 55.7 ± 9.5% vs. 2DE-4CV 49 ± 8.2% (p = 0.06), 2DE-2CV 52 ± 8% (p < 0.001), 2DE-biplane 53.5 ± 7.1% (p = 0.01)). After anterior STEMI, there was no significant difference in LVEF measurements by 2DE and CMR with acceptable limits of agreement (CMR 49 ± 11% vs. 2DE-4CV 49 ± 8.2% (p = 0.8), 2DE-2CV 49 ± 9.2% (p = 0.9), 2DE-biplane 49.6 ± 8% (p = 0.5)). In total, 15% of patients experienced a MACE during follow-up. In multivariate Cox regression analysis, reduced LVEF (< 52%) as assessed by either 2DE or CMR was predictive of MACE (2DE HR = 2.57 (95% CI 1.1-6.2), p = 0.036; CMR HR = 2.51 (95% CI 1.1-5.7), p = 0.028). CONCLUSIONS: At baseline after non-anterior STEMI, 2D echocardiography significantly underestimated LVEF in comparison to CMR, whereas after anterior infarction, measurements were within acceptable limits of agreement. Both imaging modalities offered similar prognostic values when a reduced LVEF < 52% was applied. KEY POINTS: • After non-anterior STEMI, 2D-echocardiography significantly underestimated LVEF compared with cardiac MRI • An ejection fraction of < 52% in the acute post-infarct period by both 2D echocardiography and CMR offered similar prognostic values.

Impact of posteromedial papillary muscle infarction on mitral regurgitation during ST-segment elevation myocardial infarction.

The exact role of papillary muscle infarction (PMI) during the acute phase of acute ST-segment elevation myocardial infarction (STEMI) is not well understood, as existing data on the impact of PMI location is conflicting. We hypothesized that infarction of the posteromedial papillary muscle (PM-PMI) as determined by cardiac magnetic resonance imaging might be associated with an increased incidence of mitral valve regurgitation in the first week after STEMI. 242 patients with first STEMI underwent a late-enhancement (LGE-) cardiac magnetic resonance imaging within a median of 2 (IQR 2-5) days and echocardiography within 3 (IQR 2-5) days after primary angioplasty for the index event. PMI was scored based on short axis slices (AL-PMI: anterolateral PMI, PM-PMI, AL/PM-PMI: AL- and PM-PMI). Patients with PM-PMI had significantly higher odds (OR 2.62, p < 0.01) for the occurrence of mitral regurgitation than patients with no-PMI, AL-PMI or AL/PM-PMI. Furthermore, advanced age, non-anterior infarct location and longer pain-to-balloon time were identified as risk factors for the occurrence of mitral regurgitation. Binary logistic regression analysis revealed that PM-PMI is a predictor of mitral regurgitation independent of infarct location and age (OR 2.229, CI 1.078-4.903, p = 0.031). PM-PMI as determined by cardiac magnetic resonance imaging is an independent predictor of mitral regurgitation in the setting of acute STEMI. Our data might improve our understanding of the dynamic nature of functional mitral regurgitation.

Long-Term Prognostic Value of High-Sensitivity Troponin T Added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels Before Valve Replacement for Severe Aortic Stenosis.

Natriuretic peptide plasma levels help to manage patients with severe aortic stenosis (AS). The role of troponin plasma levels in this patient cohort remains speculative. A consortium of 4 university hospital centers in Austria analyzed retrospectively 3,595 patients admitted for valve replacement because of severe AS since 2007. The aim was to compare the additive preprocedural value of high-sensitivity troponin T (hsTnT) to N-terminal pro brain natriuretic peptide (NT-proBNP) plasma levels in predicting postoperative long-term survival in a large cohort undergoing either surgical (57.8%) or transcatheter (42.2%) aortic valve replacement. During a median follow-up of 2.93 (1.91 to 4.92) years, 919 patients (25.6%) died, in them 556 (15.5%) due to cardiovascular causes. Both normal hsTnT (<14 ng/l) and NT-proBNP (within age- and sex-corrected normal range) plasma levels were found in 481 patients (14.3%, group 1). Normal hsTnT but elevated NT-proBNP plasma levels were found in 748 patients (22.3%, group 2). Elevated hsTnT but normal NT-proBNP plasma levels were found in 258 patients (7.7%, group 3). Both elevated hsTnT and elevated NT-proBNP plasma levels were found in 1,869 patients (55.7%, group 4). Using Log Rank tests for comparison there was a highly significant difference in both cardiovascular mortality (p <0.0001) and all-cause mortality (p <0.0001). All-cause mortality rates after 1, 3, and 5 years were 2.1%, 5.4%, 7.7% in group 1; 4.0%, 7.5%, 11.5% in group 2; 5.8%, 8.9%, 14.0% in group 3; and 12.3%, 22.6%, 28.4% in group 4. In conclusion, hsTnT adds additional impact to NT-proBNP as a routinely available biomarker for risk stratification concerning postoperative survival in patients with severe AS admitted for valve replacement. The present study supports the concept to integrate hsTnT plasma levels in the management of severe AS.

Crotoxin from Crotalus durissus terrificus venom: In vitro cytotoxic activity of a heterodimeric phospholipase A2 on human cancer-derived cell lines.

Crotoxin (CTX), a heterodimeric phospholipase present in venom of snakes of the genus Crotalus, has demonstrated a broad spectrum of pharmacological properties, such as antimicrobial, hemostatic, and antitumoral. However, the precise mechanism of its cytotoxicity and antitumoral properties remains to be determined. Therefore, in the present study, we isolated crotoxin (F1 CTX) through two steps DEAE-Sepharose and Heparin-Sepharose FF chromatography. The C-terminal sequence of the A- and B-chain protein fragment was determined by LC-MS/MS mass spectrometry, which showed 100% identity to crotoxin structure. In order to investigate its cytotoxic effects, we demonstrated that the F1 CTX fraction at 0-30 µg/mL concentrations for 72 h presented a heterogeneous response profile on nine human cancer-derived cell lines from four tumor types (pancreatic, esophagus, cervical cancer, and glioma). The glioma (GAMG and HCB151) and pancreatic (PSN-1 and PANC-1) cancer cells showed a higher sensitivity with IC50 of <0.5, 4.1, 0.7 and < 0.5 µg/mL, respectively. Conversely, F1 CTX does not reduce the viability of normal cells. On the other hand, cervical (SiHa) and esophagus (KYSE270) cancer cell lines presented higher resistance, with IC50 higher than 30.2 and 8.7 µg/mL, respectively. Moreover, F1 CTX did not affect cell cycle distribution under the conditions evaluated and seems to be more cytotoxic than cytostatic. The pro-apoptotic effect of F1 CTX treatment was demonstrated in glioma (HCB151) cell line. In addition, crotoxin revealed a potential to initiate cell responses such as DNA damage in glioma (HCB151) and pancreatic cancer by H2AX activity induction. Conversely, F1 CTX does not reduce the viability of normal cells. Importantly, the comparison of F1 CTX effect with standard chemotherapeutic agents demonstrated a greater cytotoxic potential in the majority of tumor types (glioma, pancreatic, and cervical cancer). On the other hand, F1 CTX was less cytotoxic in esophageal cell lines compared to the gemcitabine agent used in clinical practice. Therefore, this work showed that F1 CTX has a cytotoxic activity and pro-apoptotic potential, contributing to the knowledge about the F1 crotoxin properties as well as its possible use in cancer research, particularly in glioma and pancreatic cancer cell lines.