Praetorian-covid

2020

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:

  1. ARBs block excessive angiotensin-mediated activation of the AT1R.
  2. 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.

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RACE 9

2020
Until recently the standard approach of patients with recent-onset atrial fibrillation (AF) involved early cardioversion. In the latest ESC AF guidelines, a delayed cardioversion approach within 48 hours has been added to the recommendations. However, given the self-terminating and recurrent nature of AF, cardioversion may not always be necessary, and rate control medication could suffice to manage symptoms until spontaneous conversion to sinus rhythm occurs. The Research Continuous heart rhythm monitoring elucidated the recurrent and transient nature of recent-onset atrial fibrillation (AF). In the RACE7 we showed that a wait-and-see approach (WAS) in patients with recent-onset AF (rate control for symptom relief followed by delayed cardioversion if needed <48h) allows spontaneous conversion to sinus rhythm in 69% of patients, obviating active cardioversion. Recurrences within one month were seen in 30% of patients in both groups, i.e. the initially chosen strategy did not affect the recurrence pattern. Considering the latter, it remains unclear whether cardioversion is needed at all, especially since cardioversion strategy does not seem to affect behaviour of the arrhythmia over time. Instead of cardioversion a watchful-waiting rate control strategy may be appropriate as initial strategy. Therefore, we intend to perform a multi-center clinical randomized controlled trial to show non-inferiority of watchful-waiting with rate control versus the WAS approach in terms of prevalence of sinus rhythm at 4 weeks follow-up, using a novel telemonitoring infrastructure to guide rate and rhythm control during follow-up. This novel telemonitoring infrastructure may facilitate the watchful-waiting strategy and obviate the need for cardioversion and reduce costs compared to the delayed rhythm control WAS strategy. The study will be conducted across multiple centers in the Netherlands, including UMC Groningen, Radboud UMC, Amsterdam UMC, Alrijne Hospital, VieCuri Medical Centre, Zuyderland Medical Centre, Elisabeth-TweeSteden Hospital, Rijnstate Hospital, Martini Hospital, St. Antonius Hospital, Antonius Hospital, Noordwest Hospitalgroup, Medisch Spectrum Twente, and Maastricht University Medical Center. Origin This project is funded within the Innovative Medical Devices Initiative (IMDI) program 'Heart for Sustainable Care'. The focus of this program is the development of medical technology for the earlier detection, monitoring, and better treatment of cardiovascular diseases to ensure accessible healthcare and sufficient staffing. The program has been developed en funded by the Dutch Heart Foundation, ZonMw and NWO, who collaborate within the Dutch CardioVascular Alliance.
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EMBRACE

2023
Atrial fibrillation (AF) is not benign. It commonly progresses from paroxysmal AF (PAF) to permanent AF. AF progression is associated with major adverse cardiovascular/cerebral events (MACCE). Cardiovascular risk factors and comorbidities (CVR) are present long before the first AF episode, causing a progressive atrial cardiomyopathy (ACM). The mechanisms of ACM vary between patients hindering effective AF management. The EmbRACE network now aims to unravel the diversity of mechanisms underlying ACM, identify simple diagnostic tools to identify them, and develop a therapeutic approach to prevent ACM progression. The Research Early rhythm-control therapy is one promising intervention to potentially interfere with ACM progression next to CVR management. For a sustained impact we aim to develop care pathways to prevent ACM and AF progression and MACCE. Therefore, we will identify and validate relevant cellular and molecular determinants of ACM and AF and their clinical surrogate parameters; develop an in-silico platform to simulate identified mechanisms of ACM and AF and their effects on AF progression and, based on these data, make suggestions for future refinement of ACM therapy; explore the variety of temporal patterns of PAF as markers of ACM subtypes, demonstrate their prognostic relevance and identify surrogate markers available in clinical practice, based on AI and machine learning; test in a randomized trial stratified for sex the hypothesis that early AF ablation and optimal CVR management in AF patients with ACM delays ACM progression and reduces MACCE; explore whether lifestyle management reduces ACM progression, whereas with only rate control ACM progresses; validate the RACE V AF progression score in real life cohorts and translate this and other knowledge into novel care pathways for AF. The origin Atrial fibrillation is the most common cardiac arrhythmia and can lead to a variety of complications, such as stroke. Currently, there are limited treatment options for this cardiac arrhythmia. Moreover, the disease is often noticed late, which makes proper treatment even more difficult. Therefore, the Dutch Heart Foundation funded the RACE V consortium. Afterwards, the Dutch Heart Foundation guided an exploration to form a national consortium as a follow-up around this theme. This led to the EmbRACE consortium, which is a national network of six university medical centers, UMC Groningen, Maastricht UMC+, UMC Utrecht, Amsterdam UMC and LUMC and Erasmus MC, and hospitals in Arnhem and Eindhoven. The Dutch Heart Foundation funds the research.
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