Influence of leukotriene biosynthesis inhibition on heart rate in patients with atrial fibrillation

Abstract

Atrialfibrillation (AF) is themost common cardiac arrhythmia. There is an increasing evidence linking systemic and/or local inflammation to AF pathogenesis [1–3]. Leukotrienes (LT) are potent proinflammatory mediators produced via 5-lipoxygenase (5-LO) pathway of arachidonic acid. Both experimental [4,5] and clinical [6,7] data point to their role in cardiac pathology. Our recent results [8] indicate that pharmacological inhibition of LT biosynthesis is associatedwith decrease in the heart rate and enhanced heart rate variability in patients with stable angina pectoris undergoing elective coronary catheterization or angioplasty. This suggested to us that LT biosynthesis inhibition could be of potential interest in patients with AF. We studied49 subjects, recruited from103 consecutive patientswith permanent AF, hospitalized in the Department of Medicine. Exclusion criteria encompassed: age over 80 years, heart failure, asthma, acute or chronic inflammatory diseases, renal or liver insufficiency, hyperthyroidism and pacemaker implantation. The clinical characteristics of the patients are presented in Table 1. Informed written consent was obtained from all patients. The study protocol, that complied with the Helsinki Declaration, was approved by the local Ethics Committee. The participants underwent a single-blind, placebo-controlled study with the inhibitor of 5-lipoxygenase (zileuton; Zyflo, Cornerstone Therapeutics Inc., Cary, NC USA). The study lasted 2 days; placebo was administered on the first day (4×1 tablets/day) and zileuton – in its standard daily dosage (4×600 mg/day) – on the second day. Measurements of the urinary leukotriene E4 , considered to reflect global leukotriene production (uLTE4) (ELISA; Cayman Chemicals, Ann Arbor, MI, USA) were carried out twice; at base and after zileuton treatment. They were expressed as LTE4 pg/mg of creatinine [9]. 24-h, threechannel digital ECG Holter recordings (Aspel, HolCARD 24W, Poland) were performed in all patients on thefirst and the second study day. The mean values of 24-h heart rate (HR), the number of ventricular extrasystoles (VEs), ST-segment depression, as well as episodes of tachycardia, bradycardia and pauses were evaluated. Echocardiography was performed to assess left ventricular ejection fraction and left atrial area. Datawere analyzedusing StatSoft, Inc. STATISTICA software. Theyare presented as mean±SD or median with interquartile range and log transformed when applicable. For comparisons between groups,