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.

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.

Determinants of immediate and long-term results of subclavian and innominate artery angioplasty.

BACKGROUND: Percutaneous angioplasty (PTA) is widely used in the treatment of subclavian/innominate artery obstruction, but factors of long-term PTA outcome are poorly understood. Our aim was to evaluate the efficiency of PTA on symptom resolution and identify determinants of long-term outcome. METHODS AND RESULTS: Seventy-six lesions were treated in 75 patients (58.7% men) aged 60 +/- 8.5 years. PTA was successful in 70 (93.3%) patients, including 58/58 (100%) stenotic lesions and 13/18 (72.2%) occlusions. The mean stenosis grade (QCA) was reduced from 78.9% +/- 16.6% to 13.5% +/- 10.7% (P < 0.01). A great majority of lesions (87.1%) were stented. In 5 (7.1%) high-risk lesions a proximal or distal neuroprotection system was used. There were no strokes or embolic events. Minor complications occurred in 7 (9.3%) cases. Fifty-seven (89%) of 64 symptomatic patients had complete symptom resolution. The mean follow-up was 24.4 +/- 15.5 months (up to 66 months). Ten restenoses (15.6%), including 9 (13.8%) in-stent restenoses and 1 (16.7%) restenosis after balloon angioplasty, were diagnosed in 64 patients and followed up for at least 6 months. Nine symptomatic restenoses were successfully treated with repeated angioplasty. Cox multivariable analysis revealed the following independent predictors of restenosis: implantation of more than one stent (P = 0.005), low stent diameter (P = 0.088), and postprocedural systolic blood pressure difference between upper extremities (P = 0.044). CONCLUSIONS: PTA is a safe and effective method for the treatment of the subclavian/innominate artery obstruction and leads to symptom resolution in majority of patients. Restenosis is not frequent and it can be effectively treated with repeat angioplasty. Low stent diameter, implantation of two stents, and upper limb systolic blood pressure difference are independent predictors of restenosis.

Use of the Parodi Anti-Emboli System and transient subclavian steal for cerebral protection during emergent vertebral artery recanalization.

PURPOSE: To report the use of the Parodi Anti-Emboli System (PAES) for cerebral protection during emergent vertebral artery recanalization. CASE REPORT: A 56-year-old chimney sweep was referred with recurrent episodes of vertigo and gait ataxia. Left vertebral artery (LVA) flow was barely detectable on duplex Doppler, and brain computed tomography revealed a small infarct in the posterior inferior cerebellar artery territory. Angiography showed subtotal ostial stenosis of the LVA with poor distal flow and possible thrombus. Due to a high risk of distal embolization with percutaneous treatment, anticoagulation was initiated, and the lesion was to be re-evaluated in 2 to 3 weeks. However, 2 days later, the patient developed severe, aggravating headache, gait and left-limb ataxia, horizontal nystagmus, and vomiting. Emergent angiography showed a total ostial LVA occlusion. The PAES was employed to elicit a temporary subclavian steal during percutaneous LVA recanalization, thus protecting the brain from embolization. The ostial LVA was successfully recanalized and stented, with immediate symptom cessation. CONCLUSIONS: The PAES can be successfully applied in the subclavian artery to prevent distal embolization during emergent vertebral artery recanalization. Since a significant proportion of vertebral strokes are embolic, PAES may play a novel role in the treatment of acute cerebellar stroke.

Detection of microvascular injury by evaluating epicardial blood flow in early reperfusion following primary angioplasty.

BACKGROUND: In a significant proportion of patients with acute myocardial infarction (AMI), successful opening of the infarct related artery (IRA) does not translate into adequate perfusion at the tissue level. We hypothesised that deterioration of epicardial blood flow in early reperfusion may identify early signs of coronary microvascular injury. METHODS: In 272 consecutive patients (age 56.9+/-10.4 years) with AMI treated by primary angioplasty (PCI), coronary blood flow (Trombolysis in Myocardial Infarction (TIMI) scale and corrected TIMI frame count (cTFC)) was evaluated before [B], immediately after [O] and 15 min after [O15] opening of the IRA. The sum of ST-segment elevation in standard ECG leads (sigmaST) was measured at [B], at [O15] and 24 h after [C24]. Microvascular injury was assessed by indexes STi(O15)=sigmaST(O15)/sigmaST(B), STi(C24)=sigmaST(C24)/sigmaST(B), and by peak CK-MB release. Coronary flow deterioration (cTFC(DET)) was defined as the difference between cTFC(O15) and cTFC(O). RESULTS: TIMI-3 flow was achieved in 236 (90.8%) patients at [O]. In the early phase of reperfusion (between [O] and [O15]), TIMI flow deteriorated by >/=1 point in 19 (7.3%) patients despite angiographic optimisation of the PCI result. At [O15] 224 (86.2%) patients had TIMI-3 flow (reflow), 36 (13.8%) patients had TIMI

Impact of Chlamydia pneumoniae infection on survival rate after heart transplantation.

BACKGROUND: As Chlamydia pneumoniae (Cp), a common cause of respiratory infection, is of vasotropic character, chronic infection may be associated with the development of coronary disease, although there have been few reports on the impact of Cp infection on the post-orthotopic heart transplantation (OHT) survival rate. MATERIAL/METHODS: A total of 41 patients (4 females) were followed up for one year after OHT. Serology investigations for IgM, IgG and IgA antibodies against Cp were performed using the enzyme immunoassay (EIA) method. Univariate and multivariate analyses were carried out with respect to IgA, IgG, gender and type of cardiomyopathy. The IgA-IgG joint effect was also studied. RESULTS: The one-year survival rate was reported for patients with IgA < 8 EIU to be 72.2%, whereas those with IgA >or= 8 EIU accounted for only 43.5% (Kaplan-Meier analysis, p = 0.0548). In multivariate analysis IgA /IgG status proved to be a highly significant factor in survival. IgA positive outcome combined with IgG negative outcome showed that the relative risk of death equaled 12.08 versus other combinations of IgA/IgG status. In the Cox multivariate model ischemic cardiomyopathy showed a relative risk of 2.79 (p=0.0594), although it was not significant in univariate CONCLUSIONS: Chronic Cp infection, as expressed through a high IgA level, seems to have adverse impact on the survival rate in one-year follow-up after OHT. IgA titers against Cp in heart transplant recipients should therefore be assessed, as the high values might be a predictive risk factor within the first post-operative year.