Transcoronary stem cell transfer and evolution of infarct-related artery atherosclerosis: evaluation with conventional and novel imaging techniques including Quantitative Virtual Histology (qVH).

Introduction: It has been suggested that infarct-related artery (IRA) atherosclerosis progression after stem cell transcoronary administration might represent a stem-cell mediated adverse effect. Aim: To evaluate, using conventional (quantitative coronary angiography, QCA, intravascular ultrasound - IVUS) and novel (quantitative virtual histology - qVH) tools, evolution of IRA atherosclerosis following transcoronary stem cell transfer. Material and methods: QCA, IVUS, VH-IVUS and qVH were performed in 22 consecutive patients (4 women) aged 59 years (data provided as median) undergoing a distal-to-stent infusion of 2.21 × 106 CD34+CXCR4+ autologous bone marrow cells via a cell delivery-dedicated perfusion catheter at anterior AMI day 7. Imaging was repeated at 12 months. This was a substudy of Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial (NCT00316381). Results: 18.2% subjects showed absence of distal-to-stent angiographic/IVUS atherosclerotic lesion(s) at baseline and no new lesion(s) at 12-months. In the remaining cohort, there were 28 lesions by QCA (32 by IVUS) at baseline and no new lesion(s) at follow-up. Three fibroatheromas evolved (2 to calcified fibroatheroma and 1 to a fibrocalcific lesion); other plaques maintained their stable (low-risk) phenotypes. Diameter stenosis of QCA-identified lesions was 29.5 vs. 26.5% (p = 0.012, baseline vs. 12-months). Gray-scale IVUS showed reduction in area stenosis (33.8 vs. 31.0%, p = 0.004) and plaque burden (66.27 vs. 64.56%, p = 0.009) at 12-months. Peak fibrotic plaque content increased from 70.41% to 75.0% (p = 0.004). qVH peak confluent necrotic core area and minimal fibrous cap thickness remained stable (0.64 vs. 0.59 mm2, p = 0.290, and 0.15 vs. 0.16 mm, p = 0.646). Conclusions: This study, using a range of classic and novel imaging techniques, indicates lack of any stimulatory effect of transcoronary stem cell transfer on coronary atherosclerosis. Whether, and to what extent, a moderate reduction in plaque burden and stenosis severity at 12-months results from optimized pharmacotherapy and/or stem cell transfer requires further elucidation.

Infarct size and long-term left ventricular remodelling in acute myocardial infarction patients subjected to transcoronary delivery of progenitor cells.

Introduction: Infarct size (IS) is a fundamental determinant of left-ventricular (LV) remodelling (end-systolic and end-diastolic volume change, ΔESV, ΔEDV) and adverse clinical outcomes after myocardial infarction (MI). Our prior work found that myocardial uptake of transcoronary-delivered progenitor cells is governed by IS. Aim: To evaluate the relationship between IS, stem cell uptake, and the magnitude of LV remodelling in patients receiving transcoronary administration of progenitor cells shortly after MI. Material and methods: Thirty-one subjects (age 36-69 years) with primary percutaneous coronary intervention (pPCI)-treated anterior ST-elevation MI (peak CK-MB 584 [181-962] U/l, median [range]) and sustained left ventricle ejection fraction (LVEF) ≤ 45% were studied. On day 10 (median) 4.3 × 106 (median) autologous CD34+ cells (50% labelled with 99mTc-extametazime) were administered via the infarct-related artery (left anterior descending). ΔESV, ΔEDV, and mid circumferential myocardial strain (mCS) were evaluated at 24 months. Results: Infarct mass (cMRI) was 57 [11-112] g. Cell label myocardial uptake (whole-body γ-scans) was proportional to IS (r = 0.62), with a median 2.9% uptake in IS 1st tercile (≤ 45 g), 5.2% in 2nd (46-76 g), and 6.7% in 3rd (> 76 g) (p = 0.0006). Cell uptake in proportion to IS attenuated the IS-ΔESV (p = 0.41) and IS-ΔEDV (p = 0.09) relationship. At 24 months, mCS improved in IS 2nd tercile (p = 0.028) while it showed no significant change in smaller (p = 0.87) or larger infarcts (p = 0.58). Conclusions: This largest human study with labelled CD34+ cell transplantation shortly after MI suggests that cell uptake (proportional to IS) may attenuate the effect of IS on LV adverse remodelling. To boost this effect, further strategies should involve cell types and delivery techniques to maximize myocardial uptake.

Misclassification of carotid stenosis severity with area stenosis-based evaluation by computed tomography angiography: impact on erroneous indication to revascularization or patient (lesion) migration to a higher guideline recommendation class as per ESC/ESVS/ESO/SVS and CMS-FDA thresholds.

Intoduction: Despite a growing understanding of the role played by plaque morphology, the degree of carotid lumen reduction remains the principle parameter in decisions on revascularization in symptomatic and asymptomatic patients. Computed tomography angiography (CTA) is a widely used guideline-approved imaging modality, with "percent stenosis" commonly calculated as %area reduction (area stenosis - AS). Aim: We evaluated the impact of the non-linear relationship between diameter stenosis (DS) and AS (area = π • (diameter/2)2, so that in concentric lesions 51%AS is 30%DS and 75%AS is 50%DS) on stenosis severity misclassification using calculation of area reduction. Material and methods: CTA and catheter quantitative angiography (cQA) were performed in 300 consecutive patients referred to a tertiary vascular centre for potential carotid revascularization (age: 47-83 years, 33.7% symptomatic, 36% female; referral stenosis of ≥ "50%"). CTA-AS was determined by agreement of 2 experienced radiologists; cQA-DS (pivotal trials standard reference, NASCET method) was calculated by agreement of 2 corelab analysts. Results: For symptomatic lesion thresholds, CTA-AS-based calculation reclassified 76% of "< 50%" cQA-DS measurements to the "50-69%" group, and 58% of "50-69%" measurements to the "≥ 70%" group. For asymptomatic lesion thresholds, 78% of "< 60%" cQA-DS measurements were reclassified to the "60-79%" group, whereas 42% of "60-79%" cQA measurements crossed to the "≥ 80%" class. Overall, employing CTA-AS instead of cQA-DS enlarged the "60-79%" and "≥ 80%" lesion severity classes 1.6- and 5.8-fold, respectively, whereas the "≥ 70%" class increased 4.15-fold. Conclusions: Replacing the pivotal carotid trials reference standard cQA-DS "%stenosis" measurement with CTA-AS-based "%stenosis" results in a large-scale lesion/patient erroneous gain of an "indication" to revascularization or migration to a higher revascularization indication class. In consequence, unnecessary carotid procedures may be performed in the absence of cQA verification. Until guidelines rectify the "%stenosis" measurement methods with different guideline-approved imaging modalities (and, where needed, re-adjust decision thresholds), CTA-AS measurement should not be used as a basis for carotid revascularization.

Novel PARADIGM in carotid revascularisation: Prospective evaluation of All-comer peRcutaneous cArotiD revascularisation in symptomatic and Increased-risk asymptomatic carotid artery stenosis using CGuard™ MicroNet-covered embolic prevention stent system.

AIMS: Our aim was to determine (1) periprocedural and 30-day clinical safety and efficacy of the CGuard MicroNet-covered embolic prevention carotid stent system (MN-EPS) in routine use for unselected carotid stenosis (CS) patients undergoing CAS, as well as (2) feasibility of MN-EPS post-dilatation optimisation to minimise residual stenosis after CAS. METHODS AND RESULTS: This was a non-industry-funded, prospective academic study in all-referrals-tracked symptomatic and asymptomatic CS. In asymptomatic lesions, intervention was mandated only in case of increased stroke risk CS features. There was independent neurologist evaluation before CAS, at 48 hours and 30 days. There was external source data verification, angiographic core lab, and statistical analysis. Over 11 months, 108 referrals were recommended by the NeuroVascular Team for revascularisation: 101 (51-86 years, 55 symptomatic, evolving stroke in nine) underwent 106 (100% MN-EPS use) neuroprotection device-assisted (46% proximal, 54% distal) CAS; CEA was performed in seven. MN-EPS device success was 99.1%. Angiographic diameter stenosis was reduced from 83±9% to 6.7±5% (p<0.001). No MN-EPS foreshortening/elongation occurred (30 mm long was 29.82±0.68 mm; 40 mm long was 39.89±0.59 mm). The periprocedural death/major stroke/MI rate was 0%. One event, with no change in NIHSS or modified Rankin Scale and no clinical sequel, was adjudicated by the clinical events committee as minor stroke (0.9%). By 30 days there were no new events (0%). CONCLUSIONS: These increased risk consecutive patient data (1) indicate safety and efficacy of routine MN-EPS use in achieving endovascular reconstruction across all-comer CS lesion subsets, and (2) are consistent with MN-EPS protection against cerebral events extending throughout the stent healing period.

Myocardial regeneration strategy using Wharton's jelly mesenchymal stem cells as an off-the-shelf 'unlimited' therapeutic agent: results from the Acute Myocardial Infarction First-in-Man Study.

INTRODUCTION: In large-animal acute myocardial infarction (AMI) models, Wharton's jelly (umbilical cord matrix) mesenchymal stem cells (WJMSCs) effectively promote angiogenesis and drive functional myocardial regeneration. Human data are lacking. AIM: To evaluate the feasibility and safety of a novel myocardial regeneration strategy using human WJMSCs as a unique, allogenic but immuno-privileged, off-the-shelf cellular therapeutic agent. MATERIAL AND METHODS: The inclusion criterion was first, large (LVEF ≤ 45%, CK-MB > 100 U/l) AMI with successful infarct-related artery primary percutaneous coronary intervention reperfusion (TIMI ≥ 2). Ten consecutive patients (age 32-65 years, peak hs-troponin T 17.3 ±9.1 ng/ml and peak CK-MB 533 ±89 U/l, sustained echo LVEF reduction to 37.6 ±2.6%, cMRI LVEF 40.3 ±2.7% and infarct size 20.1 ±2.8%) were enrolled. RESULTS: 30 × 10(6) WJMSCs were administered (LAD/Cx/RCA in 6/3/1) per protocol at ≈ 5-7 days using a cell delivery-dedicated, coronary-non-occlusive method. No clinical symptoms or ECG signs of myocardial ischemia occurred. There was no epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45 ±8 vs. 44 ±9, p = 0.51), and no patient showed hs-troponin T elevation (0.92 ±0.29 ≤ 24 h before vs. 0.89 ±0.28 ≤ 24 h after; decrease, p = 0.04). One subject experienced, 2 days after cell transfer, a transient temperature rise (38.9°C); this was reactive to paracetamol with no sequel. No other adverse events and no significant arrhythmias (ECG Holter) occurred. Up to 12 months there was one new, non-index territory lethal AMI but no adverse events that might be attributable to WJMSC treatment. CONCLUSIONS: This study demonstrated the feasibility and procedural safety of WJMSC use as off-the-shelf cellular therapy in human AMI and suggested further clinical safety of WJMSC cardiac transfer, providing a basis for randomized placebo-controlled endpoint-powered evaluation.

Infarct size determines myocardial uptake of CD34+ cells in the peri-infarct zone: results from a study of (99m)Tc-extametazime-labeled cell visualization integrated with cardiac magnetic resonance infarct imaging.

BACKGROUND: Effective progenitor cell recruitment to the ischemic injury zone is a prerequisite for any potential therapeutic effect. Cell uptake determinants in humans with recent myocardial infarction are not defined. We tested the hypothesis that myocardial uptake of autologous CD34(+) cells delivered via an intracoronary route after recent myocardial infarction is related to left ventricular (LV) ejection fraction (LVEF) and infarct size. METHODS AND RESULTS: Thirty-one subjects (age, 36-69 years; 28 men) with primary percutaneous coronary intervention-treated anterior ST-segment-elevation myocardial infarction and significant myocardial injury (median peak troponin I, 138 ng/dL [limits, 58-356 ng/dL]) and sustained LVEF depression at ≤45% were recruited. On day 10 (days 7-12), 4.3×10(6) (0.7-9.9×10(6)) (99m)Tc-extametazime-labeled autologous bone marrow CD34(+) cells (activity, 77 MBq [45.9-86.7 MBq]) were administered transcoronarily (left anterior descending coronary artery). (99m)Tc-methoxyisobutyl isonitrile (99(m)Tc-MIBI) single-photon emission computed tomography before cell delivery showed 7 (2-11) (of 17) segments with definitely abnormal/absent perfusion. Late gadolinium-enhanced infarct core mass was 21.7 g (4.4-45.9 g), and infarct border zone mass was 29.8 g (3.9-60.2 g) (full-width at half-maximum, signal intensity thresholding algorithm). One hour after administration, 5.2% (1.7%-9.9%) of labeled cell activity localized in the myocardium (whole-body planar γ scan). Image fusion of labeled cell single-photon emission computed tomography with LV perfusion single-photon emission computed tomography or with cardiac magnetic resonance infarct imaging indicated cell uptake in the peri-infarct zone. Myocardial uptake of labeled cells activity correlated in particular with late gadolinium-enhanced infarct border zone mass (r=0.84, P<0.0001) and with peak troponin I (r=0.76, P<0.001); it also correlated with severely abnormal/absent perfusion segment number (r=0.45, P=0.008) and late gadolinium-enhanced infarct core (r=0.58 and r=0.84, P<0.0001) but not with echocardiography LVEF (r=-0.07, P=0.68) or gated single-photon emission computed tomography LVEF (r=-0.28, P=0.16). The correlation with cardiac magnetic resonance imaging-LVEF was weak (r=-0.38; P=0.04). CONCLUSIONS: This largest human study with labeled bone marrow CD34(+) cell transcoronary transplantation after recent ST-segment-elevation myocardial infarction found that myocardial cell uptake is determined by infarct size rather than LVEF and occurs preferentially in the peri-infarct zone.

Randomized transcoronary delivery of CD34(+) cells with perfusion versus stop-flow method in patients with recent myocardial infarction: Early cardiac retention of 99(m)Tc-labeled cells activity.

BACKGROUND: For transcoronary progenitor cells' administration, injections under flow arrest (over-the-wire balloon technique, OTW) are used universally despite lack of evidence for being required for cell delivery or being effective in stimulating myocardial engraftment. Flow-mediated endothelial rolling is mandatory for subsequent cell adhesion and extravasation. METHODS: To optimize cell directing toward the coronary endothelium under maintained flow, the authors developed a cell-delivery side-holed perfusion catheter (PC). Thirty-four patients (36-69 years, 30 men) with primary stent-assisted angioplasty-treated anterior MI (peak TnI 151 [53-356]ng/dL, mean[range]) were randomly assigned to OTW or PC autologous 99Tc-extametazime-labeled bone marrow CD34(+) cells (4.34 [0.92-7.54] × 106) administration at 6-14 days after pPCI (LVEF 37.1 [24-44]%). Myocardial perfusion (99(m)Tc-MIBI) and labeled cells' activity were evaluated (SPECT) at, respectively, 36-48 h prior to and 60 min after delivery. RESULTS: In contrast to OTW coronary occlusions, no intolerance or ventricular arrhythmia occurred with PC cells' administration (P < .001). One hour after delivery, 4.86 [1.7-7.6]% and 5.05 [2.2-9.9]% activity was detected in the myocardium (OTW and PC, respectively, P = .84). Labeled cell activity was clearly limited to the (viable) peri-infarct zone in 88% patients, indicating that the infarct core zone may be largely inaccessible to transcoronary-administered cells. CONCLUSIONS: Irrespective of the transcoronary delivery method, only ≈ 5% of native (i.e., non-engineered) CD34(+) cells spontaneously home to the injured myocardium, and cell retention occurs preferentially in the viable peri-infarct zone. Although the efficacy of cell delivery is not increased with the perfusion method, by avoiding provoking ischemic episodes PC offers a rational alternative to the OTW delivery.