title: Trapped platelets activated in ischemia initiate ventricular fibrillation.
abstract: BACKGROUND
  We tested the hypothesis that ischemia-induced ventricular fibrillation (VF) is facilitated by platelets, trapped regionally in the ischemic zone and activated to release arrhythmogenic secretome.
  
  
  RESULTS
  In a randomized study in blood-free, buffer-perfused isolated rat hearts, ischemic zone territory (34±1% of left ventricle) was selected so that ischemia evoked VF in only 42% of controls. VF incidence was increased to 91% (P<0.05) by coronary ligation-induced trapping of freshly prepared autologous platelets (infused before and during coronary ligation, with trapping confirmed by 111In-labeled platelet autoradiographic imaging). Trapping of platelet secretome prepared ex vivo, or platelet-sized fluorospheres, did not increase ischemia-induced VF incidence. Secretome alone did, however, evoke VF in 2 sham coronary-ligated hearts. Perfusion did not activate infused platelets in sham coronary-ligated hearts, whereas ligation activated trapped platelets (assessed by thromboxane release). In a separate study, trapping whole-heparinized blood mimicked the ability of trapped platelets to increase VF incidence. This effect was not prevented by >5 days oral pretreatment in vivo with clopidogrel (10 mg/kg per day) or indomethacin (2.4 mg/kg per day).
  
  
  CONCLUSIONS
  Platelets facilitate VF during acute ischemia independently of their ability to participate in occlusive thrombosis. Moreover, the effect is unresponsive to antiplatelet drugs commonly used. Labile secretome constituents appear to be responsible. This opens a novel avenue for antiarrhythmic drug research.
authors.affiliation: Cardiovascular Division, and Division of Imaging Sciences and Medical Engineering, King's College London, United Kingdom.
authors.forename: Tarvinder S
authors.initials: TS
authors.lastname: Dhanjal
authors.forename: Rodolfo A
authors.initials: RA
authors.lastname: Medina
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Leem
authors.forename: James E
authors.initials: JE
authors.lastname: Clark
authors.forename: Richard
authors.initials: R
authors.lastname: Southworth
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001345:Autoradiography; D001792:Blood Platelets / Q000502:physiology*; D004562:Electrocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000503:physiopathology
chemical_list: D010975:Platelet Aggregation Inhibitors
keywords: antiarrhythmia agent; antiarrhythmic drug development; arrhythmias, cardiac; blood platelets; death, sudden, cardiac; myocardial ischemia