Open AccessDigoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study
Author(s) -
Pastori Daniele,
Carnevale Roberto,
Nocella Cristina,
Bartimoccia Simona,
Novo Marta,
Cammisotto Vittoria,
Piconese Silvia,
Santulli Maria,
Vasaturo Fortunata,
Violi Francesco,
Pignatelli Pasquale
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.009509
Subject(s) - medicine , digoxin , interquartile range , atrial fibrillation , platelet activation , endocrinology , thromboxane , platelet , creatinine , cardiology , heart failure
Background Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation ( AF ). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results Post hoc analysis of a prospective study of anticoagulated patients with AF . Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11‐dehydro‐thromboxane B 2 (TxB 2 ), a marker of platelet activation, and serum digoxin concentration ( SDC ) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6–2.4 ng/mL) with or without prestimulation with a sub‐threshold of collagen. Median 11‐dehydro‐TxB 2 was 105.0 ( interquartile range, 60.0–190.0) ng/mg creatinine, and median SDC was 0.65 ( interquartile range, 0.40–1.00) ng/mL. Urinary 11‐dehydro‐TxB 2 and SDC were correlated ( r s =0.350, P <0.001). Patients in the upper tertile of SDC showed higher 11‐dehydro‐TxB 2 compared with non–digoxin users ( P =0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects . Digoxin (2.4 ng/mL) induced calcium mobilization, PAC ‐1 (procaspase‐activating compound 1) and platelet aggregation in AF patients but not in healthy subjects . After pretreatment with a sub‐threshold of collagen, digoxin dose‐dependent induced calcium mobilization, arachidonic acid release, TxB 2 biosynthesis, PAC ‐1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium‐related phospholipase A 2 phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.