The CD40-CD40L system in cardiovascular disease

Figures & data

Figure 1. Proinflammatory stimuli increasing expression of both CD40 and CD40L. Once CD40 is expressed on cell surface it interacts with its ligand sCD40L, and intracellular pathways conduct the signal. MKK, NF-κB, and PI3K/PKB (Akt) pathways induce transcription of many inflammatory and prothrombotic mediators. (Act1 = nuclear factor κB activator 1; GP = glycoprotein; IkK = inhibitory κB kinase; IL = interleukin; MKKs = mitogen-activated protein kinase complex; NF-κB = nuclear factor κB; PI3K/PKB (Akt) = phosphoinositide 3 kinases/protein kinase B; TNF-α = tumour necrosis factor α; TRAF = TNF receptor-associated factor.)

Table I. Impact of sCD40L on cardiovascular outcomes in acute coronary syndromes and stroke.

Authors	Study population	Samples	Main findings/impact on cardiovascular outcomes
Wykrzykowska JJ et al. (80)	98 non-diabetic CAD patients treated with drug-eluting stents	Plasma	sCD40L increased after clopidogrel cessation
Morrow DA et al. (62)	1524 patients with non-ST-elevation ACS	Plasma	No increase in risk of non-fatal recurrent ischaemic events with higher sCD40L in patients treated with glycoprotein inhibitors
Olenchock BA et al. (81)	2403 patients with ACS	Plasma	Absence of association between sCD40L and cardiovascular outcomes (risk of death, MI)
Davi G et al. (59)	90 diabetic patients with acute stroke	Plasma	Up-regulation of CD40L and monocyte chemoattractant protein-1 is associated with increased risk of recurrence of cardiovascular events
Ferro D et al. (64)	231 patients with atrial fibrillation	Plasma	Enhanced sCD40L level predicted vascular events in patients with non-valvular atrial fibrillation
Novo S et al. (82)	42 patients with asymptomatic low-grade carotid stenosis	Plasma	High levels of sCD40L predict the risk of cardiovascular events in this patient group
Malarstig A et al. (83)	2359 patients with non-ST-elevation ACS	Plasma	In a 24-month follow-up, patients with sCD40L levels > 290 pg/mL had increased risk of acute MI; dalteparin reduced MI risk in these patients. A single nucleotide polymorphism, 3459A > G, was associated with increased sCD40L levels
Heeschen C et al. (58)	1088 ACS patients, 626 non-cardiac chest pain patients	Plasma	Higher sCD40L levels were associated with increased risk of death or MI in ACS group and controls. Abciximab reduced cardiac risk in patients with higher sCD40L levels
Manenti ER et al. (84)	172 patients with non-ST-elevation ACS	Serum	No additional prognostic value of CD40L to TIMI risk score
Apple FS et al. (85)	457 patients with ACS	Plasma	No differences in mortality rates were observed between those with increased versus normal concentrations of CD40L

CAD = coronary artery disease; ACS = acute coronary syndrome; MI = myocardial infarction; TIMI = thrombolysis in myocardial infarction.

Table II. Relationship between sCD40L levels and cardiovascular outcomes in patients with stable coronary artery disease.

Authors	Study population	Samples	Main findings/impact on cardiovascular outcomes
Obradovic SD et al. (86)	52 CAD patients receiving acetyl salicylic acid and thienopyridine	Plasma	sCD40L increased after percutaneous coronary intervention in patients with high adenosine diphosphate-induced platelet aggregation
Rondina MT et al. (87)	606 patients with stable CAD and 303 controls	Serum	sCD40L levels were lower in patients with CAD. Higher sCD40L was associated with decreased risk of CAD
Tousoulis D et al. (88)	201 stable CAD patients, 109 ACS patients, and 286 controls	Plasma	sCD40L levels were increased in both stable CAD and ACS patients
Tanne D et al. (89)	203 patients with CAD and 203 control subjects	Serum	Higher serum CD40L was not associated with increased risk of ischaemic stroke or coronary events in patients with chronic CAD

ACS = acute coronary syndrome; CAD = coronary artery disease.

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Malarstig A, Lindahl B, Wallentin L, Siegbahn A. Soluble CD40L levels are regulated by the -3459 A > G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome. Arterioscler Thromb Vasc Biol. 2006;26:1667–73.

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Tousoulis D, Antoniades C, Nikolopoulou A, Koniari K, Vasiliadou C, Marinou K, . Interaction between cytokines and sCD40L in patients with stable and unstable coronary syndromes. Eur J Clin Invest. 2007;37:623–8.

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Tanne D, Haim M, Goldbourt U, Boyko V, Reshef T, Adler Y, . CD40 ligand and risk of ischemic stroke or coronary events in patients with chronic coronary heart disease. Int J Cardiol. 2006;107:322–6.

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