Raila Busch

New stent surface materials: the impact of polymer-dependent interactions of human endothelial cells, smooth muscle cells, and platelets.

Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.

Site-selective immobilization of anti-CD34 antibodies to poly(l-lactide) for endovascular implant surfaces

Aiming at a speed up of the re-endothelialization process of biodegradable endovascular implants, novel approaches for the functionalization of poly(l-lactide) (PLLA) with anti-CD34 antibodies were established. We propose a three-step process involving PLLA surface activation with functional amino groups, attachment of a protein repelling peptide spacer, and covalent random or site-selective immobilization of the antibodies. Obtainable antibody surface densities and antigen binding capacities were thoroughly evaluated by means of enzyme-linked immunosorbent assay. Results indicate that a lower amount of anchoring sites on the antibody favors high coupling efficiency, while localization of the anchoring sites, facing the antigen binding moiety, strongly enhances the antigen capture capacity of the support. Besides minimization of physisorption and cell adhesion exemplarily shown with bovine serum albumin, avidin, and human umbilical vein endothelial cells, respectively, the inclusion of the protein-repelling spacer strengthened this effect, yielding antigen capture capacities exceeding values so far reported in literature. In contrast, the number of amino groups on the PLLA surfaces, which is indeed highly dependent on the applied activation procedure, does not seem to influence antibody coupling efficiency and antigen capture capacity considerably. This allows the choice of surface activation treatment, plasma or wet-chemical, regarding other processing parameters as for instance sterilizability or favored modification depth.

Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow.

Although the apelin/APJ system is abundantly expressed in vascular endothelial cells (EC), it has not yet been considered to be regulated by fluid flow. The aim of this study was to explore the influence of shear stress on the expression of apelin/APJ in human EC. Therefore, gene and protein expression were assessed after flow exposure; cell supernatants were collected for measurements of NO and apelin; APJ or apelin knockdown were performed using siRNA. Our data show that gene and protein expression of apelin and APJ are modulated by fluid flow depending on the magnitude of shear stress. Moreover, apelin-12 activated NO production via PI3K/Akt signaling in human EC. In contrast, apelin-13 additionally activated Erk1/2 phosphorylation and enhanced EC proliferation. Knockdown of APJ inhibited phosphorylation of PI3K and impaired flow-induced eNOS and PECAM-1 expression. Knockdown of apelin had no influence on flow-induced APJ and PECAM-1 expression, but derogated eNOS expression under static and flow conditions. The present study reveals a flow-mediated adjustment of the apelin/APJ system in human EC in which APJ expression is induced by shear stress independently of its ligand. Furthermore, apelin-12 signaling is an essential regulatory element in endothelial NO synthesis.

Polymers for Cardiovascular Stent Coatings

Polymers have found widespread applications in cardiology, in particular in coronary vascular intervention as stent platforms (scaffolds) and coating matrices for drug-eluting stents. Apart from permanent polymers, current research is focussing on biodegradable polymers. Since they degrade once their function is fulfilled, their use might contribute to the reduction of adverse events like in-stent restenosis, late stent-thrombosis, and hypersensitivity reactions. After reviewing current literature concerning polymers used for cardiovascular applications, this review deals with parameters of tissue and blood cell functions which should be considered to evaluate biocompatibility of stent polymers in order to enhance physiological appropriate properties. The properties of the substrate on which vascular cells are placed can have a large impact on cell morphology, differentiation, motility, and fate. Finally, methods to assess these parameters under physiological conditions will be summarized.

Biodegradable Polymers Influence the Effect of Atorvastatin on Human Coronary Artery Cells

Drug-eluting stents (DES) have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs). Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC) proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR) on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.

Statins are related to impaired exercise capacity in males but not females

Background Exercise and statins reduce cardiovascular disease (CVD). Exercise capacity may be assessed using cardiopulmonary exercise testing (CPET). Whether statin medication is associated with CPET parameters is unclear. We investigated if statins are related with exercise capacity during CPET in the general population. Methods Cross-sectional data of two independent cohorts of the Study of Health in Pomerania (SHIP) were merged (n = 3,500; 50% males). Oxygen consumption (VO2) at peak exercise (VO2peak) and anaerobic threshold (VO2@AT) was assessed during symptom-limited CPET. Two linear regression models related VO2peak with statin usage were calculated. Model 1 adjusted for age, sex, previous myocardial infarction, and physical inactivity and model 2 additionally for body mass index, smoking, hypertension, diabetes and estimated glomerular filtration rate. Propensity score matching was used for validation. Results Statin usage was associated with lower VO2peak (no statin: 2336; 95%-confidence interval [CI]: 2287–2,385 vs. statin 2090; 95%-CI: 2,031–2149 ml/min; P < .0001) and VO2@AT (no statin: 1,172; 95%-CI: 1,142–1,202 vs. statin: 1,111; 95%-CI: 1,075–1,147 ml/min; P = .0061) in males but not females (VO2peak: no statin: 1,467; 95%-CI: 1,417–1,517 vs. statin: 1,503; 95%-CI: 1,426–1,579 ml/min; P = 1.00 and VO2@AT: no statin: 854; 95%-CI: 824–885 vs. statin 864; 95%-CI: 817–911 ml/min; P = 1.00). Model 2 revealed similar results. Propensity scores analysis confirmed the results. Conclusion In the general population present statin medication was related with impaired exercise capacity in males but not females. Sex specific effects of statins on cardiopulmonary exercise capacity deserve further research.

Riociguat and cinaciguat exert no direct effects on contractility and relaxation of cardiac myocytes from normal rats

Clinical background In the clinical setting, administration of organic nitrates and nitric oxide (NO) donors has serious limitations such as resistance to NO and organic nitrates due to insufficient biometabolism and development of tolerance following prolonged administration of NO soluble guanylate cyclase (sGC) to NO [1,2]. This circumstance has led to development of heme-dependent sGC stimulators and heme-independent sGC activators. The sGC stimulator riociguat and the sGC activator cinaciguat have been shown to induce various beneficial effects in both experimental and clinical research. Any direct dosedependent effects of these compounds on cell contraction and relaxation of isolated cardiac myocytes, however, remain to be elucidated [3].

The apelin receptor influences biomechanical and morphological properties of endothelial cells

The adaption of endothelial cells to local flow conditions is a multifunctional process which leads to distinct alterations in cell shape, the subcellular distribution of structural proteins, and cellular function. G‐protein‐coupled receptors (GPCRs) have been identified to be fundamentally involved in such processes. Recently, we and others have shown that the expression of the endothelial GPCR apelin receptor (APJ) is regulated by fluid flow and that activation of APJ participates in signaling pathways which are related to processes of mechanotransduction. The present study aims to illuminate these findings by further visualization of APJ function. We show that APJ is located to the cellular junctions and might thus be associated with platelet endothelial cell adhesion molecule‐1 (PECAM‐1) in human umbilical vein endothelial cells (HUVEC). Furthermore, siRNA‐mediated silencing of APJ expression influences the shear‐induced adaption of HUVEC in terms of cytoskeletal remodeling, cellular elasticity, cellular motility, attachment, and distribution of adhesion complexes. Taken together, our results demonstrate that APJ is crucial for complemented endothelial adaption to local flow conditions.

Impact of atrial fibrillation detected by extended monitoring—A population‐based cohort study

The clinical relevance of extended monitoring of AF in the general population is unclear. The study evaluated the detection of AF using transtelephonic electrocardiography and the clinical relevance of additional AF findings, especially with regard to stroke risk and mortality.

Polymers in Cardiology

Polymers have found widespread applications in cardiology, in particular in coronary vascular intervention as stent platforms, coating matrices for drug-eluting stents (DES) and drug-coated balloons (DCB) and for transcatheter valve therapy. Besides permanent polymers, biodegradable polymers came in focus of current research and development for medical applications, as they degrade once their function is fulfilled, which might efficiently reduce observed hypersensitivity reactions. After reviewing polymers used for cardiovascular applications, the book chapter deals with possible surface modification reactions of the polymers including the provision with a local drug delivery function and/or biofunctionalization in order to selectively control cell-implant interactions. These functionalizations can be furthermore designed to enhance bio- and hemo-compatibility, which is of special interest for cardiovascular implants and devices. A general discussion of bio- and hemo-compatibility of polymers for cardiovascular applications and corresponding evaluation methods is additionally given. With our own published data, we finally highlight exemplary polymer applications in cardiology as polymer-based biodegradable stent platforms, biodegradable polymeric coatings for DES and hydrogel-based coatings for DCB. Moreover, developed biofunctionalization strategies of polymers are discussed with regard to their application in cardiology.