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Anti-thrombin nanoparticles limit ischemia-reperfusion injury and no-reflow in myocardial infarction

Session Innovations in CMR for coronary artery disease

Speaker Assistant Professor Hua Pan

Congress : ESC Congress 2019

  • Topic : imaging
  • Sub-topic : Imaging: Acute Coronary Syndromes
  • Session type : Moderated Posters
  • FP Number : P3100

Authors : H Pan (Tampa,US), A Lindon (Tampa,US), R Grabau (Tampa,US), W Dominguez (Tampa,US), S Wickline (Tampa,US)

Authors:
H Pan1 , A Lindon1 , R Grabau1 , W Dominguez1 , S Wickline1 , 1University of South Florida, The Heart Institute - Tampa - United States of America ,

Citation:

Introduction: Persistent microvascular thrombosis and thrombin signaling in cardiac ischemia reperfusion injury (IRI) combine to promote infarct expansion and heart failure. We have reported previously that treatment of acute ischemic kidney injury (AKI) in rodents with anti-thrombin perfluorocarbon nanoparticles (PFC NP) limits damage to endothelium, reduces "no reflow," and hastens recovery of kidney function.  In cardiac IRI, we hypothesized that thrombin continues to exert deleterious effects well after reperfusion, but whether this strategy is effective in preserving vascular barrier function and preventing no reflow in cardiac IRI is not known. Accordingly, we postulated that sustained local thrombin inhibition with long acting anti-thrombin nanoparticles might limit vascular damage and barrier disruption that otherwise leads to hemorrhage and no reflow.

Methods: 14 Sprague Dawley rats undergoing LAD occlusion for 45 min were pretreated with i.v. injection of anti-thrombin PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone)-conjugated PFC NP (~ 13,000 PPACK per PFC NP), or saline (control) followed by 2 hours of reperfusion. Sham controls (no LAD ligation) were compared. Simultaneous to treatments, a different and unique nontargeted CE PFC NP (CE: Crown Ether core) was injected for subsequent tracking and spectroscopic quantification of the relative distributions and amounts of PFC NP trapped in non-reperfused myocardium. Hearts were perfused with saline in situ, then extracted for ex vivo 19F (fluorine) MRI and spectroscopy at 7T (Bruker).  T2* images were acquired for hemorrhage/edema in the area at risk. 19F MRI was acquired for PFC NP trapping (spin echo: TR 2000ms, TE 4.51 ms, FOV 20x20, 64x64 slice 1mm), along with whole heart 19PFC CE spectroscopy.

Results: Fluorine MRI of an intact heart illustrates the trapping of PFC NP in areas of nonreperfusion (Figure) amidst infarct scar region. Quantification of total heart CE PFC NP signal emanating from trapped NP revealed reduced accumulation (¯49%) in the hearts of treated rats (0.47±0.09 vs 0.92±0.19, treated vs control; p < 0.05). For sham occlusions, minimal deposition of CE PFC NP was observed irrespective of PPACK PFC NP treatment (n=10 per group). Areas of T2* signal indicative of vascular leakage extended beyond that of the 19F signals (Figure T2*), indicating more severe damage and trapping in central infarct zones than in more peripheral border zones after 2 hours.

Discussion: Continued inhibition of thrombin in cardiac IRI with locally-acting PPACK PFC NP preserved vascular integrity, and limited hemorrhage and No Reflow (less trapping). Because these PPACK PFC NP do not prolong bleeding times or coagulation parameters beyond ~30-60 min after injection, yet maintain prolonged local surveillance against activated thrombin, they represent a potentially useful therapeutic strategy for cardiac IRI.

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