Long-term outcome of combined (percutaneous intramyocardial and intracoronary) application of autologous bone marrow mononuclear cells post myocardial infarction: the 5-year MYSTAR study

OBJECTIVE: The long-term (5-year) outcome of early (3-6 weeks after acute myocardial infarction [AMI], BM-MNC Early group) and late (3-4 months after AMI, BM-MNC Late group) combined (percutaneous intramyocardial and intracoronary) delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30-45% post-AMI. METHODS: Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome. RESULTS: Five-year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control (from baseline to 5-year: 5.3%, 95% CI:0.5-10.1, and 5.7%, 95% CI:1.7-9.6, p<0.05 in the Early and Late groups, respectively), with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up (Early group: 5.4%, 95% CI:1.0-9.6; and Late group: 8.4%, 95% CI:4.5-12.3). Lower baseline levels of myocardial viability of the treated cardiac area (6.3+/-2.4 vs 8.2+/-3.0 mV, p<0.05) were associated with incidence of MACCE. CONCLUSIONS: Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI (Clinicaltrials.gov NCT01395212)

Secondary end points of patients with LV functional studies (n = 51) 5 years after cardiac bone-marrow mononuclear cell (BM-MNC) therapy.

<p>Secondary end points of patients with LV functional studies (n = 51) 5 years after cardiac bone-marrow mononuclear cell (BM-MNC) therapy.</p

Schematic display of the segmental transmurality and NOGA electromechanical mapping-derived parameter.

<p>(A) Schematic display of the segmental transmurality using MathLab software, showing a decrease in infarct transmurality over 5 years in patients with acute myocardial infarction who were treated with combined delivery of cells. Summed data from 26 patients. (B) NOGA electromechanical mapping-derived parameter in patients with or without major adverse events during the 5-year follow-up. *<i>p</i><0.05.</p

Primary end point: occurrence of adverse events during the 5-year follow-up.

<p>In patients with multiple events during the 5-year FUP, the most serious major adverse event was entered as MACCE and the composite of all adverse events (one/patient) for each patient.</p

Gated ⁹⁹m-Sestamibi myocardial scintigraphy of a patient with cardiac bone marrow mononuclear cell (BM-MNC) treatment.

<p>(A) and (B) Before combined cardiac delivery of autologous BM-MNC treatment; 3-dimensional calculation of LV volume (A) and polar map of infarct size (B). (C) and (D) At the 1-year follow-up, 3-dimensional calculation of LV volume (C) and polar map for infarct size (D). (E) and (F) At the 5-year follow-up, 3-dimensional calculation of LV volume (E) and polar map for infarct size (F).</p

Segmental infarct transmurality determined by cardiac magnetic resonance imaging (n = 26).

<p>Segmental infarct transmurality determined by cardiac magnetic resonance imaging (n = 26).</p

Left and right ventricular function in subgroup of patients.

<p>underwent single photon emission computed tomography (SPECT) and cardiac magnetic resonance imaging (cMRI) 5 years after cardiac bone-marrow mononuclear cell (BM-MNC) therapy.</p

Left ventricular function and infarct size of patients randomized to Early or Late cell-therapy during the 5-year follow-up.

<p><b>Patients were treated with combined delivery of autologous BM-MNC.</b> Global left ventricular (LV) ejection fraction, wall motion score index (measured by echocardiography), and infarct size (by single photon emission computed tomography) of patients in the Early and Late groups before receiving cardiac BMMNCs therapy and 1 and 5 years post cell therapy. No differences between the Early and Late group were observed.</p