Ticagrelor And PrEconditioning in Patients With coronaRy Artery diSease

Ticagrelor is a reversibly binding, direct-acting, oral P2Y12 antagonist used for prevention of atherothrombotic events in patients with acute coronary syndrome. It does not belong to thienopyridines; it is a carbocyclic nucleoside, representing a "first-in-class" cyclopentyl-triazolo-pyrimidine.

In 2 phase II studies, dyspnea was noted to occur as a side effect to ticagrelor in a dose-dependent fashion; and in the PLATO study, there was a 6% absolute excess of dyspnea in ticagrelor-treated patients compared with patients treated with clopidogrel. In the ONSET/OFFSET study dyspnea was more commonly associated with ticagrelor therapy in comparison with clopidogrel and placebo in patients with stable coronary artery disease (38.6%, 9.3%, and 8.3%, respectively), but was not associated in this study with any adverse change in cardiac or pulmonary function. This result was confirmed in patients with acute coronary syndrome.

The mechanisms for this side effect are largely unknown, although early data indicate that ticagrelor blocks adenosine reuptake through inhibition of ENT-1 by red blood cells, and it is known that intravenous adenosine infusion can cause transient dyspnea in the absence of bronchoconstriction. Another mechanism potentially increasing adenosine levels by ticagrelor consists in adenosine triphosphate (ATP) release from red blood cells. Moreover, comparison between ticagrelor and adenosine molecules suggests their similarity; Adenosine is a well-known key endogenous molecule that regulates tissue functions by activating 4 G-protein-coupled adenosine receptors: A1, A2A, A2B, and A3. Adenosine accumulates in the extracellular space in response to metabolic stress and cell damage; and elevations of adenosine are found in ischemia, hypoxia, inflammation, and trauma. Adenosine acts as cytoprotector by its anti-inflammatory, cardioprotective, cerebroprotective, antisclerotic, and antifibrotic properties, as well as by platelet inhibition and vasodilation.

It was hypothesized that chronic adenosine overload induced by ticagrelor may contribute to the vascular outcome benefit observed in PLATO, in addition to its inhibitory effect on platelet activity via P2Y12 receptor blockade. Very recently, ticagrelor has been shown to increase adenosine-induced physiological responses in human healthy subjects by shifting the dose-response curve for adenosine-induced coronary blood flow velocity (CBFV) to the left and, in non-ST-segment elevation acute coronary syndrome patients treated with percutaneous coronary intervention and receiving a maintenance dose of ticagrelor, coronary blood flow velocity augments to a greater degree compared with patients on a prasugrel maintenance dose in response to increasing adenosine concentrations. These effects are also compatible with adenosine reuptake blockage, another of the purported pleiotropic effects of ticagrelor. The enhanced ticagrelor-related adenosine bioavailabilty may have beneficial effects through three interrelated mechanisms.

Activation of preconditioning: Ischemic preconditioning, consisting in episodes of ischemia as short as 5 minutes, followed by reperfusion, has been showed to protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis. Adenosine plays a key role in triggering ischemic preconditioning. Indeed, stimulation of A1 adenosine receptors triggers a complex pathway including the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, the mitochondrial permeability transition pores as well as others, like a paradoxical protective release of oxygen radicals eventually making cells more resistant to ischemia. In humans, examples of preconditioning are the preinfarction angina and the angina "warm-up phenomenon". Preconditioning can be reproduced experimentally by repetitive balloon inflations in the coronary artery that have as principal consequences less chest pain and ST-segment elevation. Pharmacological preconditioning can be induced by intravenous or intracoronary administration of adenosine or A1 agonists of adenosine. In a recent study in rabbits authors observed an anti-infarct effect of clopidogrel and cangrelor (the intravenous analog of ticagrelor) and that it was not the result from blockade of platelet aggregation, but rather from activation of the signal transduction pathway of pre- and postconditioning, involving the reperfusion injury salvage kinases (RISK) including Akt and ERK as well as adenosine A2B receptors, mitochondrial KATP channels, and redox signalingi. This cardioprotective effect of cangrelor was confirmed in a primate model.