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Soluble CD40 Ligand, Platelet Surface CD40 Ligand, and Total Platelet CD40 Ligand in Atrial Fibrillation

Relationship to Soluble P-Selectin, Stroke Risk Factors, and Risk Factor Intervention

*From the Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK.

Correspondence to: Gregory Y. H. Lip, MD, Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK; e-mail: g.y.h.lip{at}bham.ac.uk

Abstract

Background:Abnormal levels of soluble CD40 ligand (sCD40L) have been reported in patients with hypertension, coronary artery disease, diabetes mellitus, heart failure, and stroke, all of which are conditions that are associated with nonvalvular atrial fibrillation (AF). We hypothesized the following: (1) CD40 ligand (CD40L)-related indexes (ie, platelet surface expressed CD40L, the soluble fragment of CD40L [sCD40L], and the total amount of CD40L per platelet [pCD40L]) are elevated in patients with AF compared to control subjects; (2) these indexes correlate with soluble P-selectin (sP-selectin), which is an established platelet marker; and (3) these indexes differentiate "high-risk" from "low-risk" subjects.

Methods:We performed a case-control study of 121 AF patients, 71 "disease control subjects," and 56 "healthy control subjects." Peripheral venous levels of platelet surface-expressed CD40L were analyzed by flow cytometry, while levels of sCD40L, pCD40L, and sP-selectin were measured by enzyme-linked immunosorbent assay.

Results:AF patients had significantly higher sCD40L levels compared to healthy control subjects (p = 0.042), with no difference in platelet surface CD40L and pCD40L levels. A positive correlation was noted between levels of sCD40L and pCD40L, and not with sP-selectin. CD40L-related indexes failed to distinguish between high-risk and low-risk AF patients. AF patients receiving optimal antithrombotic therapy had significantly lower pCD40L levels (p < 0.001) compared to control subjects. Optimized AF management also resulted in significant reductions in the levels of sCD40L (p = 0.023) and pCD40L (p < 0.001).

Conclusion:CD40L-related indexes are not useful in the risk stratification of AF patients, and abnormal sCD40L levels can be reduced by intense multifactorial risk management. While there is a significant, albeit modest, excess of platelet activation in AF patients (as measured by sCD40L levels) compared to healthy control subjects, this is not in excess of that seen in patients with underlying cardiovascular diseases.

Key Words: atrial fibrillation • CD40 ligand • platelet activation • platelet lysate • soluble CD40

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor • AF, atrial fibrillation • ARB, angiotensin receptor blocker • CD40L, CD40 ligand • CHADS₂, congestive heart failure, hypertension, age > 75, diabetes mellitus, and prior stroke or transient ischemic attack • CTAD, citrate, theophylline, adenosine, and dipyridamole • ELISA, enzyme-linked immunosorbent assay • MFI, mean fluorescence index • PAF, paroxysmal atrial fibrillation • pCD40L, CD40 ligand per platelet • PRP, platelet-rich plasma • sCD40L, soluble fragment of CD40 ligand • sP-selectin, soluble P-selectin