FORSEE

The IN-CONTROL II consortium builds upon the success of IN-CONTROL I, which highlighted the pivotal role of the microbiome in low-grade inflammation associated with atherosclerotic cardiovascular diseases (CVD) and related risk factors such as lipid levels and microbiome-derived metabolites. These insights are crucial for addressing the rising rates of CVD-related mortality, particularly in aging and overweight populations. The Focus The objectives of IN-CONTROL II are to: Investigate the mechanisms underlying trained immunity in CVD patients, considering factors like senescence, age, sex, and obesity. Elucidate the interactions between microbiome-derived signals (aromatic amino acids, metabolites, bile acids) and immune senescence in obesity-related cardio-metabolic diseases. Identify novel therapeutic targets and develop pharmacological and microbiome-based therapies to counteract inappropriate induction of trained immunity and inflammation in cardiovascular disease. The Research The consortium aims to shift from association to causality, from population-based cohorts to patient groups with atherosclerotic cardiovascular disease (CVD) and from observation to intervention. In this transition, it will also take advantage of recent developments in the network of the consortium, delineating cellular senescence as a druggable target for the broad spectrum of age-related chronic diseases, including cardiovascular diseases, and identification of components of the bile acid-signaling system for this purpose. Another recent development of the recognition of innate immune memory (‘trained immunity’) as pathophysiological mechanism in atherosclerotic CVD. The consortium will conduct proof-of-principle trials in specific patient cohorts, employing advanced experimental techniques such as systems biology, single cell sequencing, innovative animal models, and metabolic flux quantification (fluxomics). A talent program will facilitate knowledge transfer and skill development for young researchers within the consortium, emphasizing rapid translation of research findings into clinical applications. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To validate these findings, a prospective, randomized, placebo-controlled trial is required to redefine the role of digoxin in modern HF treatment. The Focus The primary objective of this study is to investigate whether low-level digoxin (targeting serum concentrations of 0.5-0.9 ng/mL), compared to a placebo, reduces (repeated) HF hospitalizations, (repeated) urgent HF hospital visits, and cardiovascular mortality when added to standard guideline-recommended therapies in chronic HF patients with reduced or mid-range ejection fractions (LVEF ≤50%). The Research This proposed trial is a national, multicenter, randomized, double-blind, placebo-controlled clinical trial involving 982 chronic HF patients aged ≥18 years, classified as NYHA II to ambulatory IV, LVEF ≤50%, and specific serum NT-proBNP concentrations based on rhythm and recent HF hospitalization status. Patients must also be on guideline-recommended therapies. The study population includes at least one-third with atrial fibrillation (AF) and one-third women to represent the real-life HF population. Patients were randomized to receive either a low-level digoxin or a placebo in a double-blinded manner. Digoxin Teva will be administered orally, starting at doses of 0.2mg or 0.1mg (based on age, renal function, and concomitant medication). No loading dose is given to the placebo group. After 4 weeks of evaluating medication (digoxin or placebo), concentrations will be measured. Dose adjustments will be made if needed to reach the target serum digoxin concentration range of 0.5-0.9ng/mL. The outcomes in reducing adverse cardiovascular events in patients with chronic heart failure of low-dose digoxin will be compared to the outcomes of the placebo. The origin This study was funded as part of the Dutch Heart Foundation's collaboration with the ZonMw GGG program on Good Use of Medicines (Goed Gebruik Geneesmiddelen) for better treatment of heart failure and atrial fibrillation, which was one of the 5 priority's that the Dutch Heart Foundation set in 2014. The DECISION study involves 38 hospitals and is led by cardiologists from UMC Groningen and the WCN.