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)

Geographical miss during intracoronary irradiation: impact on restenosis and determination of required safety margin length

AbstractObjectivesThe goal of this study was to evaluate the incidence and effects of underdosage of injured segments during intracoronary irradiation and to define the minimal length of safety margin required to avoid mismatched source placement.BackgroundUnderdosage of injured segments due to misplacement of active source has been suggested as the underlying mechanism for the occurrence of edge restenosis.MethodsBaseline angiograms of 112 vessels in 109 patients with in-stent restenosis undergoing coronary reintervention followed by intracoronary irradiation (192Ir: Checkmate, Cordis, Miami, Florida; 32P: Gallileo, Guidant, Houston, Texas; 90Sr/Y: Beta-Cath, Novoste, Norcross, Georgia) were analyzed. The distances between the outermost injury and outermost end of “reference isodose length” (RIL), defined as a segment with ≥90% of reference dose at 1 mm vessel wall depth, were measured. “Safety margin” was defined as the distance between the outermost injury and outermost end of the RIL, “geographical miss” (GM) as a complete injured segment not being covered by the RIL, and “restenosis” as the percent diameter stenosis >50%.ResultsBaseline angiographic analysis was performed for 224 edges in 112 vessels. Geographical miss was found in 46 (20.6%) edges. The incidence of target lesion restenosis within the 78 vessels with available follow-up was 43.3% for patients with GM versus 14.9% for patients with no GM (p = 0.005). Analysis of various injured segments exposed highest restenosis rates in injured segments with negligible irradiation (27.8%) in comparison with injured segments with dose fall-off (16.7%) or injured segments with full-dose irradiation (7.7%) (p = 0.006). Receiver operating curve analysis revealed a safety margin of 10 mm required per vessel (i.e., 5-mm safety margin/edge) to achieve 95% specificity of GM.ConclusionsGeographical miss is associated with a higher incidence of restenosis at the corresponding edges. Restenosis was more pronounced in injured segments with negligible irradiation than in injured segments at the dose fall-off zones. We recommend a safety margin of 10 mm per vessel to minimize GM

Preclinical randomised safety, efficacy and physiologic study of the silicon dioxide inert-coated Axetis and bare metal stent: Short-, mid- and long-term outcome

Aims: To evaluate the short-, mid- and long-term safety, efficacy and vascular physiology of Axetis silicon dioxide (SiO2, abrading the micropores) inert-coated stent implantation in a randomised preclinical setting. Methods and results: Coronary arteries of domestic pigs were randomised to receive either Axetis or BMS (same design) stents with one-, three- and six-month follow-up (FUP), controlled by coronary angiography, optical coherence tomography (OCT), intravascular ultrasound (IVUS) and histology (n=32). The time-dependent vasomotor reaction of coronary arteries to stenting was measured using modified myography (n=12). Complete endothelialisation of the Axetis stent was confirmed by OCT, IVUS and histology at one-month FUP. Histopathology revealed continuous healing of the vessel wall with a gradual reduction of inflammation and fibrin score during the six-month FUP in both stent types. Significantly smaller neointimal area and %area stenosis were measured in Axetis stents compared with BMS at each FUP time point. Vascular reactivity measurements showed significantly better endothelium-dependent vasodilation of stented arteries with Axetis implantation. Conclusions: Implantation of the Axetis SiO2-coated stent resulted in a significantly better safety, efficacy and vessel physiology profile compared with BMS of the same design with a continuous decrease in vessel inflammation during the six-month FUP

Multimarker Approach to Identify Patients with Coronary Artery Disease at High Risk for Subsequent Cardiac Adverse Events: The Multi-Biomarker Study

In our prospective non-randomized, single-center cohort study (n = 161), we have evaluated a multimarker approach including S100 calcium binding protein A12 (S100A1), interleukin 1 like-receptor-4 (IL1R4), adrenomedullin, copeptin, neutrophil gelatinase-associated lipocalin (NGAL), soluble urokinase plasminogen activator receptor (suPAR), and ischemia modified albumin (IMA) in prediction of subsequent cardiac adverse events (AE) during 1-year follow-up in patients with coronary artery disease. The primary endpoint was to assess the combined discriminatory predictive value of the selected 7 biomarkers in prediction of AE (myocardial infarction, coronary revascularization, death, stroke, and hospitalization) by canonical discriminant function analysis. The main secondary endpoints were the levels of the 7 biomarkers in the groups with/without AE; comparison of the calculated discriminant score of the biomarkers with traditional logistic regression and C-statistics. The canonical correlation coefficient was 0.642, with a Wilk&rsquo;s lambda value of 0.78 and p &lt; 0.001. By using the calculated discriminant equation with the weighted mean discriminant score (centroid), the sensitivity and specificity of our model were 79.4% and 74.3% in prediction of AE. These values were higher than that of the calculated C-statistics if traditional risk factors with/without biomarkers were used for AE prediction. In conclusion, canonical discriminant analysis of the multimarker approach is able to define the risk threshold at the individual patient level for personalized medicine

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

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

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