The CONCERT‐HF trial: a sweet and sour symphony

This article refers to ‘A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, patients with ischaemic heart failure: the CCTRN CONCERT-HF trial’ by R. Bolli et al., published this issue on pages 661–674. ‘Research is see what everybody else has seen, think nobody thought.’ Albert Szent-Györgyi 1893–1986. The current Journal reports final conclusions (Combination Of meseNchymal c-kit+ Cardiac stEm as Regenerative Therapy for Heart Failure) trial.1 a phase II, randomized, placebo-controlled clinical trial designed assess feasibility, safety, effect bone marrow-derived stem (MSCs) (CPCs), compared placebo (cell-free PlasmaLyte-A medium) when administered transendocardial injection cardiomyopathy. Participants had tissue samples collected from their marrow prepare cell-based products. main indicate that CPCs are safe, promising, yet not incontrovertible, efficacy effects terms reduction primary endpoint. long bumpy journey. Its scientific foundation rooted work Anversa, Director Harvard Medical School laboratory regenerative medicine 2007 2015. In 2007, Anversa colleagues reported adult hearts contain express haematological cell marker c-kit, clonogenic, multipotent, capable self-renewal (i.e. genuine cells).2 generated such burst enthusiasm I using was launched same team. SCIPIO (Cardiac Stem Cell Infusion Patients Ischemic CardiOmyopathy) trial, Lancet 2011, recruited 16 myocardial infarction; 14 them, ejection fraction increased ∼8% only 4 months after coronary delivery.3 demonstrated were safe provided encouraging hints at efficacy. logical next step design trial. official start date October 2015 ClinicalTrials.gov. Anversa's findings soon questioned several investigators who failed reproduce them. Recent lineage tracking multiple laboratories complementary techniques established endogenous do generate cardiomyocytes. It now been few transplanted engraft beyond days, function bona fide cells; they likely stimulate immunomodulatory trophic repair already identified other types, though these have firmly confirmed.4 With accumulating contradictory evidence, 2014, an investigation concluded 15 2018 recommendation retract 31 papers lab pioneering because validity data could be confirmed certainty. posted expression concern 2014,5 retraction manuscript 2019 following note: ‘Although we any reservations about Louisville used preparations good faith, lack reliability regarding means retracting paper’.6 All turmoil finally impacted progress funded National Heart, Lung, Blood Institute (NHLBI). NHLBI sought guidance CONCERT-HF's Data Safety Monitoring Board (DSMB) and, based recommendation, paused 29 2018. After thorough investigation, DSMB basis rationale sound, products met criteria use, there no concerns related participant safety. On 8 March 2019, actionable safety recommended continue, but allowing administration participants enrolled production products.7 Accordingly, out estimated sample size 144 required enough power detect differences between groups, 119 underwent harvest procedures, 110 whom received product injection. Relative authors found significant across treatment groups respect incidence adverse events 12 treatment. Nevertheless, it remarkable that, visit, nine randomized did receive Furthermore, some meet minimum dose studied MSCs + CPCs, scheduled product, 90 assigned product. diminishing follow-up data, examined treated arm. proportion major (HF-MACE) significantly different (P = 0.049). However, none components HF-MACE themselves; death, hospitalization worsening failure, exacerbation failure P-values 0.767, 0.092, 0.48, respectively.1 closing symphony bygone era, orchestra Titanic. Despite confirmatory indications here, III pivotal hard endpoints conducted, will stop now. end human search holy grail rejuvenation. earthquake shattered research field, number lessons learned,8 new generation scientists proposing interesting audacious approaches engineered tissues,9, 10 cell-derived (e.g. extracellular vesicles mitochondria),11, transcriptomics microRNA non-coding RNA),13, genetically reprogrammed cells.15 Scientific rigor must exquisite, field cannot afford let things get hand once again. Conflict interest: declared.