Mean Infarct Research Articles

Abstract 20536: ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR): the One Year Phase I Results

Introduction: In CADUCEUS, autologous cardiosphere-derived cells decreased infarct size and increased viable tissue in post-myocardial infarction (MI) subject s. Hypothesis: The first-in-human Phase I ALLSTAR trial was designed to test the safety and feasibility of intracoronary infusion of allogeneic cardiosphere-derived cells (CAP-1002) in patients with an anterior MI, within the prior 12 months with a scar size >15% by Magnetic Resonance Imaging (MRI). Methods: A total of 14 adult subjects (mean age = 55.6 yr; range 40-66 years) with a recent (28 - 90 days; n=9) or chronic (91-365 days; n=5) anterior MI (mean infarct size 25.4%; range 15.3% - 32.7%) and LV dysfunction (mean LVEF 42%; range 26.7% - 55.1%) were prospectively enrolled and infused with CAP-1002 (n=4 at 12.5M dose; n=10 at 25M dose) via stop-flow intracoronary infusion. Primary safety endpoints were: MACE events (recurrent MI, hospitalization or ER treatment for heart failure, Left Ventricular Assist Device placement or heart transplantation), acute myocarditis, death due to arrhythmias or unwitnessed death. Humoral and cellular immunologic responses were assessed via single antigen bead and ELISpot assays. Results: No pre-specified safety endpoint occurred. Only two adverse events were treatment-related, both transient hypotension related to nitroglycerin. There were no clinically significant rises in peri-procedural cardiac enzymes. Donor specific antibodies (DSAs) were present in four subjects prior to infusion; one resolved and three presistent at 6 months of follow up. De novo DSA’s developed in four subjects, three resolved during follow up and one persisted at 6 months of follow up. All DSA levels were low (MFI<5000). ELISpot revealed no de novo cellular immune responses. One year follow-up safety data as well as full 6 month and available 12 month MRI results on scar size and LVEF will be presented. Conclusions: Intracoronary infusion of allogeneic cardiosphere-derived cells (CAP-1002) appears to be safe and feasible. On the basis of the Phase 1 findings, the ALLSTAR trial has proceeded to a Phase II randomized, double-blind trial, powered to assess reduction of scar size by MRI.

Adamts-18 Is a Novel Candidate Gene Of Vascular Development That Is Related To Aggravated Thrombosis: Evidence From a Adamts-18 Knock Out Mice

HIV-ITP patients have a unique antibody (Ab) against platelet GPIIIa49-66 which induces oxidative platelet fragmentation in the absence of complement (Cell 106: 551, 2001; JCI 113: 973, 2004). The search for a physiologic ligand that could induce this reaction was undertaken by panning the GPIIIa49-66 peptide with a phage surface display 7-mer peptide library. From 20 positive clones, 1 had 70% identity with a C-terminal region of ADAMTS-18 (a disintegrin and metalloproteinase with thrombospondin (TSR)-like motif 18), which is secreted by endothelial cell (EC). The recombinant C-terminal fragment of ADAMTS-18 can completely dissolve platelet aggregates formed in vitro. Moreover, this fragment lyses thrombi formed in the cerebral artery of mice and reduces infarction and neurologic impairment in murine ischemic stroke model (Blood 113: 6051, 2009). However, whether ADAMTS-18 represents the dominant physiologic mechanism controlling thrombus dissolution in vivo remains to be clarified.Here, we used ADAMTS-18-deficient (ADAMTS-18-/-) mice to study the contributions of ADAMTS-18 to thrombus formation in vivo. To investigate possible functional differences between WT and ADAMTS-18-/- platelets, we tested WT and ADAMTS-18-/- platelets in a model of pulmonary thromboembolism induced by infusion of a mixture of platelet agonist collagen (25 µg per mouse) and epinephrine (1 µg per mouse). In lung tissue Hematoxylin and eosin-stained (HE) slides, the mean number of thrombi per lung was same in the ADAMTS-18-/- group compared with WT group (163.7 ±14.38 vs 174.9 ±11.73, n=30/group, P=0.5480). In vitro, there is no difference between WT and ADAMTS-18-/- platelet aggregation trace and activation initiated by various platelet agonists ADP (10 µM) or collagen (2 µg/mL). No difference was noted on WT and ADAMTS-18-/- platelet adhesion on immobilized ligand (fibrinogen). These results indicated ADAMTS-18 had no effect on platelet function.We next evaluate the effect of ADAMTS-18 on thrombus formation in a second well-established carotid artery thrombosis model, which is induced by 10% FeCl3 patch. In the process of surgical operation, we unexpectedly observed that all ADAMTS-18-/- mice have premature common carotid artery bifurcation compared with WT mice. A Doppler flow monitor showed ADAMTS-18-/- mice exhibited significantly reduced carotid artery blood flow than WT mice (ADAMTS-18-/- vs WT, 0.5 ± 0.11 vs 0.75 ± 0.21 mL/min, n=7/group, P=0.0298), which results in shortened time of thrombus formation (ADAMTS-18-/- vs WT, 452.17 ± 68.88 vs 611.43 ± 92.02 sec, n=7/group, P=0.0005 ). Immunohistochemistry staining showed that the common carotid artery of ADAMTS-18-/- mice had increased adventitial collagen deposition compared with WT mice. In vivo matrigel plug assay demonstrated that ADAMTS-18-/- mice had significantly lower density of blood vessels compared to the WT mice. Since the middle cerebral artery arises from the internal carotid artery, we conjecture that ADAMTS-18-/- mice would have aggravated brain infarction for the less cerebral blood flow supplying. This proved to be true. In transient middle cerebral artery occlusion (tMCAO) model, the infarction size in ADAMTS-18-/- mice was significantly larger than in WT mice (mean infarction %, 25.68 ± 4.13 vs 17.41 ± 3.24, n=8, P=0.0012). Taken together, these observations suggest vasculature is the potential site of action of ADAMTS-18. To our knowledge, this is the first validation study of linkage and association of ADAMTS-18 as a pro-vasculature gene that is related to aggravated thrombosis. Disclosures:No relevant conflicts of interest to declare.

Non spherical polyvinyl alcohol versus gelatin sponge particles for uterine artery embolization for symptomatic fibroids

Purpose:To compare clinical and magnetic resonance imaging (MRI) outcomes after uterine artery embolization (UAE) with non spherical polyvinyl alcohol (nPVA) versus gelatin sponge particles. Material and methods: During ten months, from Jan 2011 to Oct 2011, 60 patients underwent UAE in a standardized manner. nPVA (n = 30) or gelatin sponge particles (n = 30) were used in all patients. Pelvic MRI and clinical symptoms were reviewed before and after the procedure. Changes in tumor, uterine volume and infarction rate of dominant tumor were assessed using MRI. Result:At three months after embolization, the outcome data were collected. The improvement of the mean bleeding score was more pronounced with gelatin sponge particles than with nPVA particles (p = 0.035). The mean volume reduction rate and infarction rate of dominant fibroid were 47.9 ± 20.8%, 97.7 ± 5.2% and 60.2 ± 18.1, 96 ± 7.0% after UAE with nPVA compared to gelatin sponge particles, respectively. Conclusion: This study showed the superiority of gelatin sponge particles over nPVA in terms of improvement of mean bleeding score and volume reduction rate of dominant fibroid at three months follow-up after UAE, although the infarction rate of dominant fibroid was similar across groups at three months.

A photothrombotic model of small early ischemic infarcts in the rat brain with histologic and MRI correlation

Over the last two decades several studies have suggested the role of photothrombotic occlusion of cerebral microvessels using rose bengal, resulting in small strokes in rodents that resemble those in humans. This paper describes such a photothrombotic method of acute small stroke induction in rats with histopathologic and in vivo magnetic resonance imaging (MRI) observations from 3 to 6 h after irradiation, which is homologous to a human autopsy specimen. Utilizing 30 min of irradiation with minimal beam intensity (0.1 W/cm 2) cold white light in conjunction with 20 mg of intravenous (iv) rose bengal as a rapid infusion, small infarcts were induced photochemically in the frontal lobes of six rats. The infarcts showed a consistent pattern on histologic and in vivo MR sections when examined within 7 h or less of irradiation. Both MRI and histologic sections were comprised of (a) a superior zone of infarcted neurons, (b) a middle curvilinear transition zone of edema on MRI and histologically vacuolated neuropil, and (c) an inferior zone of normal neurons. Shorter duration water-sensitive (T2)- and postgadolinium longer duration (T1)-weighted signal decay images both showed a curvilinear hyperintense transition zone of edema. The mean infarct and transition zone areas measured from the histologic sections were comparable to those measured on the MRI. The infarct model described above allows in vivo observations using MRI with the potential for use in testing putative neuroprotective agents. As demonstrated by a comparison with the histologic features of such infarcts in surgical and autopsy brain specimens, the model is relevant to acute human ischemic infarcts.

Effect of hyperosmotic mannitol on magnetic resonance relaxation parameters in reperfused canine myocardial infarction

To determine how administration of a hyperosmotic agent alters regional nuclear magnetic resonance (NMR) relaxation parameters and imaging characteristics in ischemic-reperfused myocardium, 7 dogs were infused with mannitol for 15 minutes before and after the release of a 3 hour left anterior descending coronary artery (LAD) occlusion. Nine control animals received normal saline during the 3 hour occlusion and 1 hour reperfusion periods. Normal posterior left ventricular (LV) wall and the ischemic anterior LV wall (risk area) myocardium was sampled for calculation of segmental microsphere myocardial blood flow, % tissue water content, NMR relaxation times ( T 1, T 2) and myocyte ultrastructure using electron microscopy. Mean infarct T 1 values were 14% greater than normal segments in saline-treated controls, but only 5% greater after mannitol. The difference in tissue water content between infarcted and normal segments was 4% in saline-treated (83 vs. 79%) compared to 2% in mannitol-treated dogs (79 vs. 77%). T 1, T 2 and % water content of control infarct segments were greater than treated infarcts (p < 0.01). T 1 and T 2 rose as occlusion flow fell below 0.5 ml/min/g in control hearts but did not rise until flows were reduced to 0.1 ml/min/g in mannitol-treated hearts. Areas of increased signal in T 1 and T 2 NMR images correlated well with histochemical infarct volume ( r = 0.98, SEE = 1.1 cc) in mannitol-treated dogs, but infarct borders were qualitatively less well-defined than in controls. We concluded that mannitol (1) diminishes tissue edema and reduces NMR relaxation parameters ( T 1, T 2) in infarcted myocardium; and (2) attenuates the rise in T 1 and T 2 and ultrastructural myocyte injury in ischemic-reperfused myocardium.