# Factors Determining Ticagrelor-Induced Dyspnea in Patients with Acute Coronary Syndrome
###### Abstract
The most recent data indicate that enzymes encoded by _CYP2C19_ and _SLCO1 BI_ can have an impact on the rate of elimination of M8, a tiagrelor metabolite, and the clinical effect of dicagrelor itself [16]. However, in the PLATO trial, _CYP2C19_ and _ABCB1_ variants were not significantly related to the antiplatelet effect of ticagrelor [17]. An analysis of the literature related to ticagrelor has revealed that different enzymes may be involved in determining the therapeutic effect of ticagrelor. [PERSON] et al. showed that _CYP4F2_ rs2074900 had an effect on the pharmacokinetics of ticagrelor [18]. Our previous studies showed [16; 19] that _CYP4F2_ variants may determine bleeding during ticagrelor therapy. CYP4F2 may participate in the resolution of inflammation after myocardial infarction [20]. The pleiotropic effects of ticagrelor could also be related to beneficial cyclooxygenase-2 (COX2) activation. In contrast, aspirin may reduce the activity of COX2 [21]. Plasminogen activator inhibitor-1 (PAI-1) slows down the activity of the fibrinolysis system and contributes to thrombus formation. The study by [PERSON] et al. showed that ticagrelor may reduce the activity of PAI-1 [22]. Ticagrelor blocks platelet P2Y\({}_{12}\) receptors, inhibits platelet activation, and, finally, aggregation through binding \(\alpha\)2\(\beta\)3 receptors, which bind fibrinogen [23]. In addition, the study by [PERSON] et al. showed that ticagrelor may reduce the release of extracellular vesicles (EVs) [24]. During acute myocardial infarction, platelets, endothelial cells, and leukocytes release EVs that contain pro-thrombotic enzymes such as fibrinogen. Studies showed that about twice higher EV concentrations were present in patients with acute myocardial infarction as compared to healthy ones [25]. Different studies suggest that 1 in every 20 patients treated with ticagrelor experiences dyspnea of varying intensity [7; 26; 27]. The causes of ticagrelor-related dyspnea remain unknown. Dyspnea can be mild, moderate, and severe, manifesting in 56.5, 28.3, and 15.2% of patients, respectively [28]. Ticagrelor-related dyspnea can last less than 24 h or can persist over the course of the treatment. Up to 6% of patients with moderate or severe dyspnea discontinue ticagrelor prematurely more frequently or ticagrelor is changed to a less effective combination of clopidogrel and aspirin [6; 7]. In clinical practice, dyspnea caused by pulmonary, cardiac, and metabolic diseases is most common [29]. There are several clinical trials during which cardiac and pulmonary function was investigated in patients with ACS or stable angina pectoris, receiving ticagrelor or clopidogrel. The findings of these clinical trials have shown that dyspnea is not related to drug-induced impairment of pulmonary and cardiac function or acidosis [10; 30]. The incidence of ticagrelor-related dyspnea was the same in both patients with chronic heart failure or chronic obstructive pulmonary disease and those without these diseases [31]. Up to date, the two most plausible hypotheses explaining the potential mechanisms of ticagrelor-induced dyspnea have been debated [10; 32]. In the literature, the greatest attention is paid to a structural similarity between ticagrelor and adenosine, activation of adenosine receptors (A1R), and stimulation of vagal C fibers via receptors. Other authors state that ticagrelor can induce dyspnea via P2Y\({}_{12}\) receptors present on vagal C fibers themselves. Some literature sources mention the third cause of dyspnea, i.e., ticagrelor-induced release of adenosine triphosphate (ATP) from erythrocytes; however, this hypothesis is less plausible (Figure 1) [10; 32]. The most plausible hypotheses explaining the causes for the occurrence of ticagrelor-related dyspnea are as follows [10; 32]:  
1. An increase in extracellular adenosine levels. One of the possible causes of dyspnea is related to the effect of adenosine on specific receptors in the respiratory system, resulting in the stimulation of specific sensory receptors.