The effects of P2Y12 adenosine receptors' inhibitors on central and peripheral chemoreflexes

Abstract

Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min^-1 %^-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04 L min^-1 mmHg^-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min^-1%^-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64 L min^-1 mmHg^-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

Keywords: P2Y12 adenosine receptor inhibitors; carotid body; central chemoreflex; clopidogrel; dyspnea; peripheral chemoreflex; ticagrelor.

FIGURE 1

Study protocol (HVR–hypoxic ventilatory response; HCVR–hypercapnic hyperoxic ventilatory response; * the switch took place 1–2 days following PCI).

FIGURE 2

Comparison of post-drug changes between the study groups. Data are presented as mean absolute change from the baseline (delta) in hypoxic ventilatory response (HVR), systolic blood pressure response to hypoxia (SBPR), heart rate response to hypoxia (HRR), and hypercapnic hyperoxic ventilatory response (HCVR).

FIGURE 3

Influence of ticagrelor and clopidogrel on hypoxic ventilatory response (HVR) (A), systolic blood pressure response to hypoxia (SBPR) (B), heart rate response to hypoxia (HRR) (C), and hypercapnic hyperoxic ventilatory response (HCVR) (D) in particular individuals.

FIGURE 4

Raw data from central and peripheral chemosensitivity testing in one of the subjects experiencing ticagrelor-related dyspnea (SpO₂—oxygen saturation; VI–minute ventilation; SBP–systolic blood pressure; HR–heart rate; ETCO₂—end-tidal carbon dioxide).

FIGURE 5

Relationship between chemoreflex changes in patients receiving ticagrelor (HVR–hypoxic ventilatory response; HCVR–hypercapnic hyperoxic ventilatory response).