PERFECT-FIT

The successful treatment of congenital heart disease (ConHD) has greatly increased the survival of children with this condition. Many of these defects require surgical or catheter interventions immediately after birth. However, complete restoration of the defect is often unachievable, a high risk of developing heart failure, arrhythmias, sudden cardiac death or blood vessel dilatation or stenosis relatively early in life. Currently, there is a lack of personalized risk predictors and optimal clinical decision tools, highlighting an unmet need to develop new effective strategies for treating and preventing ventricular failure, arrhythmias, and large vessel diseases. The Focus The OUTREACH consortium focuses on specific types of congenital heart diseases (ConHD) related to outflow tract defects, such as transposition of the great arteries, congenital aortic stenosis, and tetralogy of Fallot, which collectively account for over half of all ConHD cases. The goal of OUTREACH is to reduce the risk of mortality and morbidity and improve the quality of life for these patients (both children and adults) by improving follow-up practices based on outcomes, implementing personalized risk assessment tools, and advancing therapeutic strategies. The Research The OUTREACH consortium integrates expertise in preclinical research, developmental biology, disease modeling, and clinical research from academic centers specializing in pediatric and adult congenital cardiology and surgery. Its objectives are: identifying better parameters for risk assessment and early detection of heart failure or ventricular arrhythmias in ConHD patients with outflow tract defects. Exploring efficient treatments to enhance adaptation and prevent heart failure and vascular damage in at-risk ConHD patients. This consortium conducts extensive research involving a large cohort of ConHD patients to unravel the underlying causes and mechanisms of cardiac adaptations following surgical interventions. It investigates the molecular mechanisms responsible for outflow tract defects and evaluates whether stimulating heart regeneration in ConHD models can mitigate adverse remodeling and heart failure. Additionally, the consortium explores new non-invasive imaging techniques and blood-derived biomarkers to develop innovative risk analysis tools for clinical decision-making. In OUTREACH a nationwide registry is created for all patients (children and adults) with ConHD in the Netherlands by harmonizing existing registries KinCor and ConCor. This is an important step towards optimizing the quality of care for the ConHD population and fostering scientific research on ConHD. Origin The Dutch Heart Foundation and Stichting Hartekind, who collaborate within the Dutch CardioVascular Alliance, initiated an invitational grant to start and fund large-scale research aimed at earlier detection and better treatment of the consequences of congenital heart defects.

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.