Transforming Perspectives in Cardiac Cell Therapy: Hypothesis and Commentary Following Updated Results of a Pilot Study Investigating Very Long-Term Clinical Outcomes in Severe AMI Patients Following Trans-Epicardial Injection of Peripheral Blood CD34+ Cells.

Ischemic heart attack is the leading cause of death worldwide. Ten percent of cases will die within an hour. Of the survivors, around 30% will have suffered a severe infarction which will lead to the irreparable destruction of 1 to 2 billion myocardial cells, causing an irreversible secondary heart failure with a poor prognosis in the short. The heart is a totally differentiated organ with a very low capacity for self-regeneration. No current treatment can prevent this fatal outcome, but only slow it down. For these reasons, cell therapy has generated enormous hope, but achieved somewhat disappointing results, depending on the type/source of cells which were used. From the end of 2002, our group conducted a Pilot study using immuno-selected autologous peripheral-blood (PB) CD34+ cells in a small cohort of patients who had experienced a heart attack with poor prognosis. Three of these patients were immediately considered for heart transplant but lacked a readily available donor. CD34+ cells were trans-epicardially delivered at the end of a coronary artery by-pass graft (CABG) operation without reperfusing the ischemic area, which was performed on a compassionate basis. All but one patient showed a marked and sustained improvement in their cardiac function parameters from the baseline values, associated with both cardiac tissue repair and revascularization, as demonstrated by PetScan examination. The patients' outcomes have been recently updated. Six out of seven patients have survived in good enough conditions for at least 12 years after cell therapy, including those three initially recommended for heart transplant and who have avoided it. Presently, five out of seven patients are still alive with an average follow-up of 17 years (range 16-20 years), which is very unusual after CABG for patients with such a poor initially prognosis.

Long-term benefit of intracardiac delivery of autologous granulocyte-colony-stimulating factor-mobilized blood CD34+ cells containing cardiac progenitors on regional heart structure and function after myocardial infarct.

BACKGROUND AIMS: Starting from experimental data proposing hematopoietic stem cells as candidates for cardiac repair, we postulated that human peripheral blood (PB) CD34+ cells mobilized by hematopoietic growth-factor (G-CSF) would contain cell subpopulations capable of regenerating post-ischemic myocardial damages. METHODS: In a phase I clinical assay enrolling seven patients with acute myocardial infarct, we directly delivered to the injured myocardium autologous PB CD34+ cells previously mobilized by G-CSF, collected by leukapheresis and purified by immunoselection. In parallel, we looked for the eventual presence of cardiomyocytic and endothelial progenitor cells in leukapheresis products of these patients and controls, using flow cytometry, reverse transcription-quantitative (RTQ)-polymerase chain reaction (PCR), cell cultures and immunofluorescence analyzes. RESULTS: The whole clinical process was feasible and safe. All patients were alive at an average follow-up of 49 months (range 24-76 months). Improvement of heart function parameters became obvious from the third month following cell reinjection. Left ventricular ejection fraction values progressively and dramatically increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association (NYHA) grade improvement. Furthermore, we identified PB CD34+ cell subpopulations expressing characteristics of both immature and mature endothelial and cardiomyocyte progenitor cells. In vitro CD34+ cell cultures on a specific medium induced development of adherent cells featuring morphologies, gene expression and immunocytochemistry characteristics of endothelial and cardiac muscle cells. CONCLUSIONS: Mobilized CD34+ cells contain stem cells committed along endothelial and cardiac differentiation pathways, which could play a key role in a proposed two-phase mechanism of myocardial regeneration after direct intracardiac delivery, probably being responsible for the long-term clinical benefit observed.

Mitral bioprosthesis hypertrophic scaring and native aortic valve fibrosis during benfluorex therapy.

The authors describe the case of a simultaneous mitral bioprosthesis hypertrophic scaring and native aortic valve fibrosis during benfluorex therapy in a 40-year-old woman. Four years before, she underwent a mitral valve replacement after the diagnosis of mitral regurgitation during benfluorex treatment (150 mg/day). This drug was reintroduced postoperatively. She presented with exercise and sometimes resting dyspnoea. The bioprosthesis and aortic valves exhibited similar histopathological lesions. Thickening and plaque deposits made by smooth muscle alpha actin- and vimentin-positive cells in a glycosaminoglycan matrix were observed. The study discusses the putative contribution of circulating progenitor cells activated by 5-HT(2B) receptor agonists in the development of drug-induced heart disease.