Connexin 43 contribution to ticagrelor?s antiarrhythmic effect is sensible to risk factors

SZEIFFOVA BACOVA B; RENNA NF; PRADO NJ; MIATELLO RM; DIEZ ER; TRIBULOVA N

Munich

Congreso; ESC Congress 2018; 2018

European Society of Cardiology

Ticagrelor inhibits platelet P2Y12 receptors and interferes with vascular and cardiomyocyte uptake of adenosine. Increased adenosine levels during ischemiaand reperfusion protect against ischemia-reperfusion injury. This work evaluateswhether chronic administration of ticagrelor prevents cardiovascular remodelingand ventricular arrhythmias in rats with cardiovascular risk factors. We studiedmale rats from three risk factor models: 1) metabolic syndrome induced by 10%(w/v) fructose feeding (FF) during six weeks, 2) spontaneously hypertensive rats(SHR), and 3) fructose-fed hypertensive rats (FFHR) and compared them to normotensive controls (WKY). At six week of age, the four groups received ticagrelor for six weeks (30 mg/kg intraesophageal) or vehicle (n=8 each group). We measured metabolic variables and blood pressure at weeks six and twelve when cardiac remodeling was assessed. Reperfusion arrhythmias (after 10 min of regional ischemia) and action potentials were evaluated in Langendorff-perfused hearts. Total connexin-43 and PKC-epsilon phosphorylated expression were measured by western blot. Ticagrelor did not prevent metabolic syndrome in FF and FFHR or myocardial remodeling in SHR and FFHR. Ticagrelor reduced reperfusion ventricular fibrillation in WKY, SHR and FFHR rats but failed to protect FF. In all groups, ticagrelor increased connexin 43. However, phosphorylated connexin 43 by PKCepsilon remained low in FF treated rats concurrently with local activation delay in the reperfused area. We conclude that ticagrelor?s antiarrhythmic effects persist in hemodynamically remodeled hearts but are abrogated by metabolic syndrome when the lack of connexin 43 phosphorylation by PKC did not preserve homogeneous activation