Rationale and design of a prospective, randomised study of retrograde application of bone marrow aspirate concentrate (BMAC) through coronary sinus in patients with congestive heart failure of ischemic etiology (the RETRO study)

Abstract

BackgroundHeart failure (HF) is a major chronic illness and results in high morbidity and mortality. The most frequent cause of HF with reduced ejection fraction (HFREF) is coronary artery disease (CAD). Although revascularisation of ischemic myocardium lead to improvements in myocardial contractility and systolic function, it cannnot restore the viability of the already necrotic myocardium.Methods/designThe aim of our prospective randomised study is to assess the efficacy of the retrograde application of non-selected bone marrow autologous cells concentrate (BMAC) in patients with HFREF of ischemic aetiology. The evaluated preparation is concentrated BMAC, obtained using Harvest SmartPReP2 (Harvest Technologies, Plymouth, MA, USA). The study population will be a total of 40 patients with established CAD, systolic dysfunction with LV EF of ≤40% and HF in the NYHA class 3. Patients have been on standard HF therapy for 3 months and in a stabilised state for at least 1 month, before enrolling in the clinical study. Patients will be randomised 1:1 to either retrograde BMAC administration via coronary sinus or standard HF therapy. The primary end-points (left ventricular end-systolic and end-diastolic diameters [LVESd/EDd] and volumes [LVESV/EDV] and left ventricular ejection fraction [LV EF]) will be assessed by magnetic resonance imaging. The follow-up period will be 12 month.DiscussionThe application of bone marrow stem cells into affected areas of the myocardium seems to be a promising treatment of ischemic cardiomyopathy.The Harvest BMAC contains the entire population of nuclear cells from bone marrow aspirates together with platelets. The presence of both platelets and additional granulocytes can have a positive effect on the neovascularisation potential of the resulting concentrate. Our assumption is that retrograde administration on non-selected BMAC via coronary sinus, due to the content of platelets and growth factors, might improve left ventricular function and parameters compared to standard HF therapy. Furthermore, it will be associated with improved exercise tolerance in the six-minute corridor walk test and an improvement in the life quality of patients without increasing the incidence of severe ventricular arrythmias.Trial registration(ClinicalTrials.gov; https://clinicaltrials.gov; NCT03372954).

The effect of stem cells in congenital heart disease

“…Not only did they want to test the idea that MSCs preserved right ventricle function but also to attenuate ventricular remodeling. They did this by using a neonatal swine model of right ventricle (RV) pressure overload [3]. Stem cell therapy mechanisms in these animal models have yielded important insights of stem cell therapy in congenital heart defects in humans since there are a small, but growing amount of clinical trials for those patient's [7].…”

“…Stem cell research is an exciting field with great potential for heart regeneration [2]. The use of stem cells to allow cardiovascular diseases has rapidly progressed by proposing the idea of moderate improvement in heart function by reversing the myocardial injuries [3]. Transplanting stem cells can be achieved through several routes of delivery to the heart including intracoronary, intramyocardial, intravenous, and epicardial [4].…”

“…Transplanting stem cells can be achieved through several routes of delivery to the heart including intracoronary, intramyocardial, intravenous, and epicardial [4]. Each delivery has its own advantages and disadvantages with several factors to consider [3]. In the review by Sheng et al, [5] they present their belief that cell delivery methods should be personalized based on the case rather than its overall success.…”

“…When selecting a cell delivery method, intracoronary may not be the most favorable solution regardless of its overall effectiveness in other cases. This reveals that there may not be an overall preferred method of delivery but there are preferred deliveries based on each case individually [3]. Although cell delivery modalities are important, the cell type, dose, and timing of administration are also important to discuss for cardiac regeneration.…”