# Factors Determining Ticagrelor-Induced Dyspnea in Patients with Acute Coronary Syndrome
###### Abstract
Adenosine receptors are abundantly expressed in all tissues, including the myocardium, nervous system, kidneys, and respiratory system. Purine receptors P1 and P2, so-called adenosine receptors, are specific to adenosine. There are four known types of P1 adenosine receptors: A1, A2A, A2B, and A3. Activated P1 receptors interact with vagal receptors in the lungs and airways, which leads to airway smooth muscle contraction and the sensation of dyspnea. Sensory receptors in the airways are innervated by the vagal nerve and consist of myelinated and unmyelinated C fibers and stretch receptors. Unmyelinated C fibers (type J receptors) provide sensory input from the airways to lung structures. Vagal C fibers in the lungs are involved in the development of tachypnea and dyspnea. Figure 1: Possible mechanisms of ticagrelor-related dyspnea. The effect of an activated adenosine receptor depends on receptor and tissue systemic innervation. An increase in adenosine levels activates A1R receptors, which mediate airway smooth muscle contraction. Activation of A1R receptors stimulates sensory receptors in lung tissue, causing the sensation of dyspnea and cough. A2B receptors are linked to inflammation and bronchoconstriction due to mast cell degranulation (release of specific mediators), leading to the development of bronchospasm and dyspnea [10; 32]. 2. Dyspnea is caused via P2Y\({}_{12}\) receptors. P2Y\({}_{12}\) receptors are present not only on the outer membrane of platelets but are also abundant on the cells of other tissues (endothelium, smooth muscles, and neurons) and microglia in the central nervous system. Inhibition of P2Y\({}_{12}\) receptors on neurons and glial cells leads to increased signaling of vagal C fibers and glial cells to the central nervous system. Glial cells can stimulate the central chemoreflex system, eliciting the sensation of acute dyspnea [10; 32]. 3. Dyspnea is associated with ATP release from erythrocytes. It is thought that ticagrelor induces a directly dose-dependent ATP release from erythrocytes due to changes in pH, which is greater than physiological ATP levels. However, this hypothesis seems to be unlikely as ticagrelor-mediated, erythrocyte-derived ATP is rapidly degraded and has no influence on the occurrence of dyspnea [10; 32]. Up to date, no clinically relevant biomarkers that would allow prediction of the risk of developing dyspnea or bleeding during treatment with ticagrelor are available [10]. Moreover, information on pharmacokinetic characteristics in patients with or without dyspnea is scarce [10]. It is known that aspirin, depending on the consumed amount, exhibits different activities: at low doses, it inhibits platelets; at higher doses, it provides anti-inflammatory effects; and at even higher doses, it causes vasodilation and a toxic effect on the body (respiratory alkalosis, fever, dehydration, acidosis, and shock) [33]. Most of the sustained episodes of dyspnea resolve with the discontinuation of ticagrelor use and a decrease in ticagrelor plasma levels in all patients [31]. Based on the accumulated clinical data and experience of our center, ticagrelor-induced dyspnea is a subjective sensation and does not have any negative impact on the patient's pulmonary function (respiratory rate, spirometry, total lung capacity, oxygen saturation, and other) [26; 31]. The aim of this study was to determine clinical and genetic factors that would allow prediction of the development of dyspnea in patients receiving ticagrelor. This is important to ensure a safe and continuing use of this drug during the entire treatment period and to prevent the occurrence of complications such as stent thrombosis and recurrent ACS.