RACE 9

In the Netherlands, there are 250,000 patients with heart failure. Half of these patients die within five years. The best treatment: a donor heart. But: there is a great shortage of these. The Holland Hybrid Heart consortium is therefore working on an alternative: a robot heart, made of soft materials. The research We envision the treatment of patients with heart failure (HF) in such a way that the survival and quality of life of HF patients drastically increases. We aim to achieve this by developing a unique bioinspired total artificial heart that integrates soft robotics and tissue engineering (TE). In the long term, we foresee that this pioneering technology allows us to develop and bring to the clinic a full set of artificial motile organs and tissues that seamlessly integrate with the human body. This will be possible as the novel and exciting technologies underlying the artificial heart developed in this project - soft robotics and in situ TE - can be used to generate a broad range of artificial motile organs such as muscle structures (e.g., limbs), bowels or lungs: The motility and flexibility in shape and size of soft robots make them suitable for mimicking motile organs. Actuators can be embedded within the elastomeric matrix of these robots without compromising their malleable properties. In addition, embodied intelligence provides direct feedback on shape and force, enabling natural behaviour. Biocompatibility of these artificial organs is provided by TE inside the body (in situ) using biodegradable coatings or scaffolds. Such TE scaffolds are cell-free synthetic bio-resorbable implants or linings that can recruit or interact with cells from the bloodstream, leading to gradual replacement of the scaffold by fully endogenous, and thus biocompatible, tissue. Importantly, the cell-free and thus off-the-shelf availability of these scaffolds avoids the high costs and complex logistics inherent to pre-implantation in vitro TE. The Holland Hybrid Heart (HHH) consortium will push the development of these newly emerging technologies forward and combines soft robotics and in situ TE to generate the first biocompatible, soft actuated heart. This project will deliver Proof-of-Principle for full in vivo cardiac functionality of the artificial HHH in large animals. If successful, the HHH will be available for translation to the clinic as an effective treatment for advanced HF in patients and a valid alternative for moderately effective current HF therapies. This is a quantum leap forward in the treatment of HF. Origin A photo in the newspaper inspired Rotterdam heart specialist Jolanda Kluin to develop a robot heart. Kluin immediately contacted the interviewee in the article, Bas Overvelde, head of the Soft Robotic Matter group at Amolf, which develops soft robots. Could he perhaps also make a heart using soft robot techniques? Overvelde believed in it and a collaboration was born. Five years ago, they received a European subsidy of more than 3 million euros. This grant started the previous EU consortium, the EU Hybrid Heart. Last December (2023), Kluin received another 11 million euros from the Dutch government to continue the Holland hybrid heart project. The Holland Hybrid Heart has pivoted to meet the demands of that new grant and now only contains 15 Dutch consortium partners. The consortium is funded by NWA-ORC and the Dutch Heart Foundation. In-kind contributions are also provided by the DCVA, the Dutch Heart Foundation, TrailBlazers, SBMC, EVOS and EE-Labels. The executing academic partners are Erasmus MC, Amolf, TU Eindhoven, University of Twente, TU Delft and Saxion Applied University. This research is driven by patient needs and the Harteraad and Stichting Pulmonale Hypertensie will provide the connections to these patients.

The SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the acute respiratory distress syndrome (ARDS). The reninangiotensin-system (RAS) plays an important role in the development of ARDS, with ACE2 (angiotensin-converting enzyme 2) being a key enzyme within this. The virus's spike protein binds to ACE2, facillitating cellular internalization. Downregulation of ACE2 results in the excessive accumulation of angiotensin II, which in turn increases pulmonary vascular permeability through stimulation of the angiotensin II type 1a receptor (AT1R), thereby exacerbating lung pathology associated with decreased ACE2 activity. Currently available AT1R blockers (ARBs) such as valsartan, have shown potential to block this pathological process mediated by angiotensin II. The Focus The primary aim of the PRAETORIAN-COVID trial is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death of COVID-19 patients. The Research Participants receiving active treatment are administered valsartan at a dosage titrated to blood pressure, with a maximum of 160 mg twice daily. Participants receiving placebo are provided with a matching placebo. The treatment duration was 14 days or until reaching the primary endpoint, or until hospital discharge, if applicable within 14 days.Two complementary mechanisms underpin the potential efficacy of angiotensin II type 1 receptor blockers (ARBs) in preventing acute respiratory distress syndrome (ARDS) and reducing morbidity and mortality: ARBs block excessive angiotensin-mediated activation of the AT1R. ARBs upregulate ACE2 expression, leading to reduced angiotensin II levels and increased production of the protective vasodilator angiotensin 1–7. Given these mechanisms, ARBs show promise in preventing ARDS development, potentially reducing the need for intensive care unit (ICU) admission and mechanical ventilation, and ultimately lowering mortality rates associated with SARS-CoV-2 infection.