Soluble ST2 in end-stage heart failure, before and after support with a left ventricular assist device.

BACKGROUND: The interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) pathway is suggested to play an important role in fibrosis, remodelling and the progression of heart failure (HF). Increased soluble (sST2) levels are associated with adverse outcome in the average HF population. Less is known about sST2 levels in end-stage HF. Therefore, we studied sST2 levels in end-stage HF and the effect of unloading by left ventricular assist device (LVAD) support on sST2 levels. METHOD AND RESULTS: Serial plasma measurements of sST2 were performed pre-implantation and 1, 3 and 6 months after (LVAD) implantation in 38 patients. sST2 levels were elevated in end-stage HF just prior to LVAD implantation (74.2 ng/mL [IQR 54.7-116.9]; normal <35 ng/mL) and decreased substantially during LVAD support, to 29.5 ng/mL [IQR 24.7-46.6](P < .001). Patients with INTERMACS profile I had significantly higher sST2 levels compared to patients in profile II and profile III. A moderate correlation was found between sST2 and C-reactive protein (r = .580, P < .010). CONCLUSION: Levels of sST2 are elevated in end-stage HF patients with variability that suggests multiple inputs to a pro-inflammatory and pro-fibrotic pathway. Cardiogenic shock and increased C-reactive protein levels are associated with higher sST2 levels. LVAD support results in a significant drop in sST2 levels with normalization within 3 months postimplantation. This suggests that LVAD support leads to lessening of fibrosis and inflammation, which might eventually be used to target medical policy: explantation of the LVAD versus permanent use or cardiac transplantation.

The Interleukin-33/ST2 Pathway Is Expressed in the Failing Human Heart and Associated with Pro-fibrotic Remodeling of the Myocardium.

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway is a potential pathophysiological mediator of cardiac fibrosis. Soluble ST2 (sST2) is one of the main isoforms of ST2 with strong prognostic value in cardiac disease. The exact role of sST2 in cardiac fibrosis is unknown. The aim of this study was (1) to investigate myocardial expression of the IL-33/ST2 pathway in relation to myocardial fibrosis in end-stage heart failure patients and (2) to study whether plasma sST2 is associated with histologically determined cardiac fibrosis. In 38 patients undergoing left ventricular assist device implantation, mRNA expression of sST2, total ST2, and IL-33 was measured in cardiac tissue obtained during the implantation. In the same tissue, histological fibrosis was digitally quantified and mRNA expression of pro-fibrotic signaling molecules, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGFß1), was measured. In addition, plasma levels of sST2 were determined. Expression levels of IL-33/ST2 pathway factors in myocardial tissue were significantly associated with cardiac fibrosis and the expression levels of CTGF and TGFß1. Plasma levels of sST2 did not correlate with tissue expression of ST2, the amount of fibrosis or myocardial expression of pro-fibrotic signaling proteins. The interleukin-33/ST2 pathway is expressed in the failing human heart and its expression is associated with cardiac fibrosis and pro-fibrotic signaling proteins, suggesting a role in pro-fibrotic myocardial remodeling. Soluble ST2 levels in the circulation did not correlate with the amount of cardiac fibrosis or myocardial ST2 expression, however. Therefore, other pathophysiological processes such as inflammation might also substantially affect sST2 plasma levels.

MRI Visualization of Injectable Ureidopyrimidinone Hydrogelators by Supramolecular Contrast Agent Labeling.

Information about the in vivo location, shape, degradation, or erosion rate of injected in situ gelating hydrogels can be obtained with magnetic resonance imaging (MRI). Herein, an injectable supramolecular ureidopyrimidinone-based hydrogel (UPy-PEG) is functionalized with a modified Gadolinium(III)-DOTA complex (UPy-Gd) for contrast enhanced MRI. The contrast agent is designed to supramolecularly interact with the hydrogel network to enable high-quality imaging of this hydrogel. The applicability of the approach is demonstrated with successful visualization of the Gd-labeled UPy-PEG hydrogel after targeted intramyocardial catheter injection in a pig heart.

Transplantation of Allogeneic PW1pos/Pax7neg Interstitial Cells Enhance Endogenous Repair of Injured Porcine Skeletal Muscle.

Skeletal muscle-derived PW1pos/Pax7neg interstitial cells (PICs) express and secrete a multitude of proregenerative growth factors and cytokines. Utilizing a porcine preclinical skeletal muscle injury model, delivery of allogeneic porcine PICs (pPICs) significantly improved and accelerated myofiber regeneration and neocapillarization, compared with saline vehicle control-treated muscles. Allogeneic pPICs did not contribute to new myofibers or capillaries and were eliminated by the host immune system. In conclusion, allogeneic pPIC transplantation stimulated the endogenous stem cell pool to bring about enhanced autologous skeletal muscle repair and regeneration. This allogeneic cell approach is considered a cost-effective, easy to apply, and readily available regenerative therapeutic strategy.

Advanced Strategies for End-Stage Heart Failure: Combining Regenerative Approaches with LVAD, a New Horizon?

Despite the improved treatment of cardiovascular diseases, the population with end-stage heart failure (HF) is progressively growing. The scarcity of the gold standard therapy, heart transplantation, demands novel therapeutic approaches. For patients awaiting transplantation, ventricular-assist devices have been of great benefit on survival. To allow explantation of the assist device and obviate heart transplantation, sufficient and durable myocardial recovery is necessary. However, explant rates so far are low. Combining mechanical circulatory support with regenerative therapies such as cell (-based) therapy and biomaterials might give rise to improved long-term results. Although synergistic effects are suggested with mechanical support and stem cell therapy, evidence in both preclinical and clinical setting is lacking. This review focuses on advanced and innovative strategies for the treatment of end-stage HF and furthermore appraises clinical experience with combined strategies.

An Injectable and Drug-loaded Supramolecular Hydrogel for Local Catheter Injection into the Pig Heart.

Regeneration of lost myocardium is an important goal for future therapies because of the increasing occurrence of chronic ischemic heart failure and the limited access to donor hearts. An example of a treatment to recover the function of the heart consists of the local delivery of drugs and bioactives from a hydrogel. In this paper a method is introduced to formulate and inject a drug-loaded hydrogel non-invasively and side-specific into the pig heart using a long, flexible catheter. The use of 3-D electromechanical mapping and injection via a catheter allows side-specific treatment of the myocardium. To provide a hydrogel compatible with this catheter, a supramolecular hydrogel is used because of the convenient switching from a gel to a solution state using environmental triggers. At basic pH this ureido-pyrimidinone modified poly(ethylene glycol) acts as a Newtonian fluid which can be easily injected, but at physiological pH the solution rapidly switches into a gel. These mild switching conditions allow for the incorporation of bioactive drugs and bioactive species, such as growth factors and exosomes as we present here in both in vitro and in vivo experiments. The in vitro experiments give an on forehand indication of the gel stability and drug release, which allows for tuning of the gel and release properties before the subsequent application in vivo. This combination allows for the optimal tuning of the gel to the used bioactive compounds and species, and the injection system.