SAFEty and efficacy of autologous bone marrow – derived mononuclear stem cell therapy in patients with severe chronic ischemic Heart Failure – rationale and design

The main aim of this study is to explore the safety and efficacy of autologous bone marrow – derived mononuclear stem cell therapy in patients with severe chronic ischemic heart failure on short to medium-term (1-3 months). The SAFE-HF trial is a prospective, single center, two-arm, controlled trial with blind evaluation of endpoints. Target population will consist of patients with heart failure due to prior extensive myocardial infarction and left ventricle ejection fraction of less than 35% – namely the population with the highest risk of adverse events and the highest mortality. All patients will be treated with the state of the art reperfusion – primary percutaneous coronary intervention and also with guidelinebased optimal medical therapy. The stem cell injection will be performed 1 to 3 months after the acute event; evolution of stem cell treated patients will be compared with matched control–cases. Comprehensive assessment of outcomes will be done at 1 and 3 months follow-up; serum biomarkers, cardiac structural and physiological parameters, functional capacity and health-related quality of life will be evaluated. This pilot study possibly will serve as a foundation for designing future trials.

Age-related clonal haemopoiesis is associated with increased epigenetic age

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations. The most prevalent ARCH mutations are in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly-used tools to measure age acceleration are epigenetic clocks. They are based on age-related methylation differences at specific CpG sites correlating chronological age accurately with epigenetic age. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in individuals with ARCH.