What's new in transapical aortic valve implantation: clinical experience with second generation devices.

Within 10 years after transcatheter aortic valve implantation (TAVI) was first accomplished for treatment of calcified aortic stenosis, this new technology has rapidly evolved to become clinical routine. Today it may be considered standard treatment for inoperable patients with superior outcomes compared to best medical therapy. Furthermore, it represents an alternative therapeutic option compared to surgical aortic valve replacement in high-risk patients. According to current international guidelines and expert consensus statements, TAVI should be performed as a joint effort by an interdisciplinary heart team to ensure input from multiple skill sets for optimal patient outcome. Major safety concerns include neurologic complications, acute kidney injury, access site complications, procedure-related conduction disturbances, paravalvular leakage valve durability. At present, only one device for transapical TAVI is in widespread clinical use: the Edwards Sapien transcatheter valve (Edwards Lifesciences, Irvine, CA, USA). Recently, however, a number of second generation devices for transapical TAVI have been developed in order to address some of the limitations of first generation valves. In this paper, current data on second generation devices for transapical TAVI will be reviewed and ongoing trials discussed.

Transcatheter aortic valve implantation: alternative access options.

Calcific aortic valve stenosis represents the most common acquired valvular heart disease in adults. Transcatheter aortic valve implantation (TAVI) has been established as a widely accepted therapeutic option in elderly and multimorbid patients with severe aortic stenosis not amenable to conventional surgery. Retrograde transfemoral and antegrade transapical approaches are commonly used for implantation. However, there are a certain number of patients who are not candidates for either approach due to poor vascular access, severe pulmonary dysfunction or other prohibitive chest pathologies. Recently, different alternative access route options have been proposed and described. These alternative access routes include approaches via the subclavian/axillary artery, the ascending aorta, the carotid artery, and the brachiocephalic artery.

Simultaneous transcatheter aortic and mitral valve-in-valve implantation in a patient with degenerated bioprostheses and high surgical risk.

Transcatheter valve-in-valve implantation is evolving as a promising alternative to reoperative valve replacement in selected high-risk patients, considering the increasing need for redo surgery due to bioprosthetic degeneration in the future. Reoperative double valve replacements are particularly associated with an elevated surgical risk. The transapical access provides the opportunity to approach the aortic and mitral valves during one intervention. We report the case of a successful transcatheter valve-in-valve implantation in the aortic and mitral position within a single procedure.

[Treating mitral regurgitation: a surgical and interventional update]. / Therapie der Mitralklappeninsuffizienz: Chirurgische und interventionelle Neuerungen.

Surgical mitral valve repair has constantly evolved to become the standard of care for severe mitral regurgitation (MR) with superior acute and long-term results compared to valve replacement. Minimally-invasive surgical techniques have been successful in reducing operative trauma while yielding equivalent or even superior results compared to the conventional sternotomy approach. However, due to elevated operative risk a growing proportion of patients are not referred for surgery, especially elderly patients with reduced ventricular function and functional MR who often present with relevant comorbidities. It is for these patients that transcatheter-based therapies may represent an attractive option. While most interventional techniques are still in experimental or early clinical stages of development, relevant clinical experience has been gained with the MitraClip® device. For successful implementation of a patient-centered mitral valve program, integration of surgical and interventional treatment modalities within a heart center is of paramount importance. This is best accomplished by an interdisciplinary dedicated heart team consisting of cardiologists and cardiac surgeons.

Early results of a real-world series with two transapical transcatheter mitral valve replacement devices.

AIMS: Transcatheter mitral valve replacement (TMVR) with dedicated devices promises to fill the treatment gap between open-heart surgery and edge-to-edge repair for patients with severe mitral regurgitation (MR). We herein present a single-centre experience of a TMVR series with two transapical devices. METHODS AND RESULTS: A total of 11 patients were treated with the Tendyne™ (N = 7) or the Tiara™ TMVR systems (N = 4) from 2016 to 2020 either as compassionate-use procedures or as commercial implants. Clinical and echocardiographic data were collected at baseline, discharge and follow-up and are presented in accordance with the Mitral Valve Academic Research Consortium (MVARC) definitions. The study cohort [age 77 years (73, 84); 27.3% male] presented with primary (N = 4), secondary (N = 5) or mixed (N = 2) MR etiology. Patients were symptomatic (all NYHA III/IV) and at high surgical risk [logEuroSCORE II 8.1% (4.0, 17.4)]. Rates of impaired RV function (72.7%), severe pulmonary hypertension (27.3%), moderate or severe tricuspid regurgitation (63.6%) and prior aortic valve replacement (63.6%) were high. Severe mitral annulus calcification was present in two patients. Technical success was achieved in all patients. In 90.9% (N = 10) MR was completely eliminated (i.e. no or trace MR). Procedural and 30-day mortality were 0.0%. At follow-up NYHA class was I/II in the majority of patients. Overall mortality after 3 and 6 months was 10.0% and 22.2%. CONCLUSIONS: TMVR was performed successfully in these selected patients with complete elimination of MR in the majority of patients. Short-term mortality was low and most patients experienced persisting functional improvement.

Efficient nucleofection of primary human B cells and B-CLL cells induces apoptosis, which depends on the microenvironment and on the structure of transfected nucleic acids.

Accumulation of neoplastic cells in B-cell chronic lymphocytic leukemia (B-CLL) is thought to be due to intrinsic defects in the apoptotic machinery of the leukemic cells or to an altered, survival-stimulating microenvironment in vivo. Despite their long survival in vivo, B-CLL cells undergo rapid spontaneous apoptosis ex vivo. To maintain survival in vitro, we established a coculture system using the human bone marrow-derived stromal cell line HS-5. The microenvironment in these cocultures lead to B-CLL cell survival for at least several months and therefore provided a tool for valid in vitro analysis, mimicking the in vivo situation. Although primary B lymphocytes are notoriously resistant to most gene transfer techniques, we achieved high transfection efficiency and cell viability in this coculture system by using a nucleofection-based strategy. Surprisingly, the introduction of circular plasmid DNA into B cells and B-CLL cells induced rapid apoptosis, which was independent of the type of transgene used, but dependent on the DNA concentration. However, transfection of these cells with mRNA was highly efficient and resulted in sustained cell viability and potent transgene expression. The described procedure represents a new approach to study gene function in primary B cells and B-CLL cells.

Regulation of the ubiquitin proteasome system in mechanically injured human skeletal muscle.

Metabolic consequences of direct muscle trauma are insufficiently defined. Their effects on the ubiquitin-proteasome pathway (UPP) of protein degradation in human skeletal muscles are as yet unknown. Thus, we investigated whether the UPP is involved in the metabolic response evoked in directly traumatized human skeletal muscles. Biopsies were obtained from contused muscles after fractures and from normal muscles during elective implant removal (control). As estimated by western blot analyses, concentrations of free ubiquitin and ubiquitin protein conjugates were similar in extracts from injured and uninjured muscles. Ubiquitin protein ligation rates were reduced after injury (1.5+/-0.2 vs. 1.0+/-0.15 fkat/microg; p=0.04). Chymotryptic-, tryptic- and caspase-like proteasome peptidase activities (total activity minus activity in the presence of proteasome inhibitors) increased significantly after trauma (p=0.04 - 0.001). Significant increases in total chymotryptic- and caspase-like activities were attributable to proteasome activation. Our results extend the possible role of the UPP in muscle wasting to direct muscle trauma. They further suggest that the effects of direct mechanical trauma are not limited to the proteasome and imply that ubiquitin protein ligase systems are also involved. Based on the potential role of the UPP in systemic diseases, it might also be a therapeutic target to influence muscle loss in critically ill blunt trauma patients, in which large proportions of muscle are exposed to direct trauma.

Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.

Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eµ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.

The predictive value of different equations for estimation of glomerular filtration rate in patients with coronary artery disease - Results from the AtheroGene study.

BACKGROUND: Impaired renal function leads to dramatically increased risk for the development and progression of coronary artery disease (CAD). Therefore we aimed to assess the predictive value of different equations for estimated glomerular filtration rate (eGFR) in CAD-patients. METHODS: From the AtheroGene study 2135 patients were included. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (4MDRD) equation for serum creatinine (sCr), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for sCr and cystatin C (CysC) each alone, and in combination (CysC/sCr). eGFR was assessed regarding the combined outcome of cardiovascular death and non-fatal myocardial infarction and regarding complex CAD represented by a SYNTAX score ≥23. Median follow-up was 4.3years. RESULTS: Only the CKD-EPI equation using CysC could differentiate between eGFR >90ml/min/1.73m(2) vs. eGFR 60-90ml/min/1.73m(2) according to the occurrence of an endpoint event (log-rank test p=0.009). In the Cox regression analysis only eGFR calculated by CKD-EPI equation for CysC (Hazard ratio per 1 standard deviation (HR) 1.27 (95% CI 1.07-1.50); p=0.007) and for CysC/sCr (HR 1.22 (95% CI 1.02-1.46); p=0.026) were predictive regarding the outcome after adjustment for cardiovascular risk factors and Nt-proBNP. Furthermore, only eGFR calculated by CKD-EPI equation for CysC (odds ratio (OR) 1.57 (95% CI 1.36-1.78); p<0.001) and for CysC/sCr (OR 1.32 (95% CI 1.13-1.53); p<0.001) were significantly associated with a SYNTAX score ≥23. CONCLUSION: In patients with CAD the CKD-EPI equation for CysC and for CysC/sCr provided the best predictive value regarding the prognosis and the severity of CAD.

Symetis ACURATE TAVI: review of the technology, developments and current data with this self-expanding transcatheter heart valve.

The Symetis ACURATE TA and ACURATE neo technology is a novel transcatheter heart valve for treatment of aortic valvular stenosis. This review illustrates the implantation steps, which are designed for an easy and intuitive transapical and transfemoral TAVI procedure. The most important difference to other self-expanding platforms is the top-down deployment with minimal protrusion of the stent towards the left ventricular outflow tract. In addition, the supra-annularly placed porcine leaflets provide very low gradients and the pericardial skirt acts very effectively to seal against paravalvular leaks. This review reports about the hemodynamic features, low rates of paravalvular leaks and very low rates of pacemaker implantation, which have been observed in various registries. Meanwhile more than 3000 patients have been treated worldwide and additional registries are currently under investigation.

Mitogenic and adhesive effects of tenascin-C on human hematopoietic cells are mediated by various functional domains.

In the adult organism, the extracellular matrix molecule tenascin-C is prominently expressed in the bone marrow. Bone marrow mononuclear cells can adhere to plastic-immobilized tenascin-C, and in the present study we have used bacterial expression proteins to map the domains of tenascin-C responsible for binding of hematopoietic cells. A strong binding site was found to be located within the fibrinogen-like domain, and this binding could be inhibited by heparin, suggesting interactions with membrane-bound heparan sulfate proteoglycans. A second strong binding site was identified within the fibronectin type III-like repeats 6-8, and was also inhibitable by heparin. Adhesion to both attachment sites could not be blocked by various anti-integrin antibodies. A third hematopoietic cell binding site is located in the fibronectin type III-like repeats 1-5, which harbor an RGD sequence in the third fibronectin type III-like repeat. Binding to this domain, however, seems to be RGD-independent, since RGD-containing peptides could not inhibit cell binding; the addition of heparin also did not block adhesion to this domain. Since contradictory results had been reported on a proliferative effect of soluble tenascin-C, we also analyzed its activity on hematopoietic cells. The heterogeneous bone marrow mononuclear cells show a striking proliferative response in the presence of tenascin-C which is concentration-dependent. This result indicates a strong mitogenic activity of tenascin-C on primary hematopoietic cells. Using recombinant fragments of human tenascin-C, we identified several mitogenic domains within the tenascin-C molecule. These adhesive and mitogenic effects of tenascin-C suggest a direct functional association with proliferation and differentiation of hematopoietic cells within the bone marrow microenvironment.

Expression of novel surface antigens on early hematopoietic cells.

The purpose of this report is to demonstrate the expression of very recently identified surface antigens on CD34+ and AC133+ bone marrow (BM) cells. Coexpression analysis of AC133 and defined antigens on CD34+ BM cells revealed that the majority of the CD164+, CD135+, CD117+, CD38low, CD33+, and CD71low cells resides in the AC133+ population. In contrast, most of the CD10+ and CD19+ B cell progenitors and a fraction of the CD71high population are AC133-, indicating that CD34+AC133+ cells are enriched in primitive and myeloid progenitor cells, whereas CD34+AC133- cells mainly consist of B cell and late erythroid progenitors. This corresponds to the highly reduced percentage of CD10+ B cells and the absence of CD71high erythroid progenitors on AC133+ selected BM cells. A portion of 0.2-0.7% of the AC133+ selected cells do not coexpress CD34. These cells are very small and define a uniform CD71-, CD117-, CD10-, CD38low, CD135+, HLA-DRhigh, CD45+ population with unknown delineation. Four color analysis on CD34+CD38- BM cells revealed that virtually all of these primitive cells express AC133. Using an improved liposome-enhanced labeling technique for the staining of weakly expressed antigens, subsets of this population could be identified which express the angiopoietin receptors TIE (67.6%) and TEK (36.8%), the vascular endothelial growth factor receptors FLT1 (7%), FLT4 (3.2%), and KDR (10.4%), or the receptor tyrosine kinases HER-2 (15.4%) and FLT3 (CD135; 77.6%). Our results suggest that the CD34+CD38- population is heterogeneous with respect to the expression of the analyzed receptor tyrosine kinases.

Hystero-salpingo scintigraphy: a routine investigation in sterile women?

Based on the spontaneous migration of radioactive tracer from the posterior vaginal fornix to the ovaries and peritoneal cavity, several attempts were made to assess hystero-salpingo scintigraphy (HSS). The low acceptance rate by sterile women of routine investigation of tubal function may be due to a fear of radiation exposure and unpleasant examination procedures. Our protocol for HSS adopts a low dose of radioactive tracer (0.2-0.3 mCi), a defined mode of application (between the external and internal os of the cervical canal) and a short imaging time (60 min). From 1990 to 1992, we investigated 60 fallopian tubes in 32 sterile women by HSS, hystero-salpingography (HSG) and/or chromopertubation during laparoscopy (LPSC). The results of HSG and HSS corresponded in 15 of 49 fallopian tubes, LPSC and HSS in 9 of 24. None of the 32 patients had become pregnant naturally during the average observation period of 17 months. Two patients became pregnant after in-vitro fertilization. HSS, performed according to our protocol, causes less pain and results in a lower dose of radiation than HSG (about 50%). It is well accepted by patients and is easy to perform. As an investigation of tubal function, HSS may serve as an additional examination technique in cases of presumed tubal sterility.

Effect of dietary (n-3) highly unsaturated fatty acids on growth and survival of fat snook (Centropomus parallelus, Pisces: Centropomidae) larvae during first feeding.

The effect of rotifers, Brachionus rotundiformis (S-type), fed three different diets: A (rotifer fed Nannochloropsis oculata), B (rotifer fed N. oculata and baker's yeast, 1:1), and C (rotifer fed N. oculata and baker's yeast, 1:1, and enriched with Selcoregister mark or target), was evaluated based on the survival, growth and swim bladder inflation rate of fat snook larvae. Rotifers of treatment A had higher levels (4.58 mg/g dry weight) of eicosapentaenoic acid (EPA) than B (1.81 mg/g dry weight), and similar levels (0.04 and 0.06 mg/g dry weight, respectively) of docosahexaenoic acid (DHA). Rotifers of treatment C had the highest levels of EPA (13.2 mg/g dry weight) and DHA (6.08 mg/g dry weight). Fat snook eggs were obtained by spawning induction with human chorionic gonadotropin. Thirty hours after hatching, 30 larvae/liter were stocked in black cylindric-conical tanks (36-liter capacity). After 14 days of culture, there were no significant differences among treatments. Mean standard length was 3.13 mm for treatment A, 3.17 mm for B, and 3.39 mm for C. Mean survival rates were very low (2.7% for treatment A, 2.3% for B, and 1.8% for C). Swim bladder inflation rates were 34.7% for treatment A, 27.1% for B, and 11.9% for C. The lack of differences in growth and survival among treatments showed that the improvement of the dietary value of rotifer may not have been sufficient to solve the problem of larval rearing. Some other factor, probably pertaining to the quality of the larvae, may have negatively influenced survival.

Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton.

Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search for novel drugs that target CLL cells in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A secondary metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A (ChA), a member of the cytochalasan family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by ChA, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation. To provide insight into its mechanism of action, we showed that ChA targets filamentous actin in CLL cells and thereby induces cell-cycle arrest and inhibits membrane ruffling and cell migration. Our data further revealed that ChA prevents CLL cell activation and sensitizes them for treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.

Mid-term prognostic value of coronary artery disease in patients undergoing transcatheter aortic valve implantation: a meta-analysis of adjusted observational results.

AIMS: Coronary artery disease (CAD) negatively affects prognosis in patients undergoing surgical aortic valve replacement, being currently evaluated in the most common used risk score. Our meta-analysis aims to clarify the prognostic role of CAD on mid-term survival in patients undergoing TAVI. METHODS AND RESULTS: Studies reporting multivariate predictors of adverse outcomes in patients undergoing TAVI were systematically searched for and pooled, when appropriate, using a random-effect method. 960 citations were first screened and finally 7 studies (2472 patients) were included. Diagnosis of CAD was reported in 52%(42-65) of patients and 1169 Edwards SAPIEN and 1303 CoreValve prostheses were implanted. After a median follow up of 452 days (357-585) 24% of patients (19-33) died, and 23 (14-32) for cardiovascular death. At pooled analysis of multivariate approach, diagnosis of coronary artery disease did not increase risk of death (OR 1.0, 95% CI, confidence interval, 0.67-1.50 I(2) 0%). CONCLUSION: CAD does not affect mid-term TAVI outcome: this finding should be weighted to accurately evaluate risk and strategies for patients with severe aortic stenosis.

Minimally invasive resection of a right atrial mass in a cardiac transplant recipient: a case report.

Intracardiac thrombus formation usually occurs in the left-sided cavities of the heart, most frequently in the presence of atrial fibrillation or cardiomyopathy. We report the case of an initially unclear mass developing in the right atrium (RA) of a heart transplant recipient, which was subsequently resected via a minimally invasive surgical approach. Access via right anterior minithoracotomy using videoscopic assistance allowed for uncomplicated RA thrombectomy in the presented case, avoiding reentry sternotomy with the potential risk of cardiac injury and without aortic cross-clamping or cardioplegic arrest. The patient is doing fine with excellent graft function at the latest follow-up 4 months after minimally invasive thrombectomy and 30 months after cardiac transplantation. To the best of our knowledge, this is the first report describing minimally invasive resection of a right atrial thrombus in a heart transplant recipient.

Transcatheter aortic valve implantation in a heart transplant recipient: a case report.

Transcatheter aortic valve implantation (TAVI) has evolved into a feasible therapeutic option for the management of selected patients with severe aortic stenosis and high or prohibitive risk for standard surgery. Symptomatic severe aortic stenosis occasionally occurs in the allograft long after heart transplantation. Because of specific characteristics and comorbidities of heart transplant recipients, these patients may be considered candidates for this less invasive approach. We report a first case of successful transapical TAVI in a heart transplant recipient with symptomatic severe calcific aortic valvular disease and relevant comorbidities long after heart transplantation.