Head-up tilt induced syncope and adenosine A2A receptor gene polymorphism.

AIMS: High adenosine plasma levels and high expression of adenosine A(2A) receptors are observed in patients with unexplained syncope and a positive head-up tilt test (HUT). This study aimed to evaluate the single nucleotide polymorphism (SNP) (c.1364 T>C) which is the most commonly found polymorphism in the A(2A) receptor gene, in patients with unexplained syncope undergoing HUT. METHODS AND RESULTS: One hundred and five patients with unexplained syncope who underwent HUT were included. Fifty-two had a positive test. Receptor genotype determinations were performed in patients and in 121 healthy subjects. Genotype (TT, CC, TC) was determined from DNA leucocytes. The distribution of the polymorphism showed significant (P < 0.0001) difference when the results of HUT were analysed. Fifty-two per cent of patients with a positive HUT had a CC genotype and 34.6% a TC genotype, whereas 13.2% of the patients with a negative HUT had a CC genotype and 71.7% a TC genotype. Patients with a CC genotype had a higher incidence of spontaneous syncopal episodes. CONCLUSION: In patients with unexplained syncope, a significant association between high incidence of syncopal episodes, positive HUT, and the presence of the CC variant in the adenosine A(2A) receptor gene was elicited.

Increased expression of adenosine A2A receptors in patients with spontaneous and head-up-tilt-induced syncope.

BACKGROUND: Adenosine may play a role in the triggering of neurocardiogenic syncope, but no information on adenosine receptors is available at the present time. OBJECTIVE: The purpose of this study was to investigate whether adenosine A2A receptors expression is altered in patients with neurocardiogenic syncope. METHODS: Adenosine plasma levels (APLs), the expression of A2A receptors, were measured (mean +/- standard error of the mean) during tilt testing. Expression of receptors was assessed on mononuclear cells using a selective receptor ligand. RESULTS: At baseline, the APLs of 16 patients with a positive test were higher than those of 17 patients with a negative test and of those of a control group (2.10 +/- 0.30 vs. 0.40 +/- 0.05 and 0.41 +/- 0.06 muM, respectively; P <.0001). The number of receptors was higher in patients tested positive than in patients tested negative or in the control group (122 +/- 10 vs. 38 +/- 4 and 44 +/- 4 fmol/g of proteins, respectively; P <.0001). No difference was found in the affinity or synthesis among the three groups. CONCLUSION: This study showed an increased number and an up-regulation of adenosine A2A receptors in patients with spontaneous syncope and a positive head-up tilt, which in the context of high APLs may play a role in the recurrence of syncopal episodes.

Release of markers of myocardial damage evaluated in the coronary sinus during cardiac surgery.

Myocardial damage is a frequent complication of cardiac surgery by direct mechanical trauma during the surgical procedure and by myocardial ischemia, which occurs during the cardiopulmonary bypass (CBP). Because the concentrations of biomarkers in the blood collected from the coronary sinus are the best witness of the myocardial damages, we measured the levels of specific cardiac troponin I (c-TnI) and nonspecific (adenosine, myoglobin) markers of left ventricular damages in the coronary sinus of patients during cardiac surgery. Thirty patients who underwent aortic valve replacement for aortic stenosis were included. Blood samples were collected in the coronary sinus and in the radial artery at the beginning (T0), at the end of the CBP (T1), and then 24 hours later (T2). At T0 and T1, adenosine, c-TnI, and myoglobin levels were significantly higher in the coronary sinus than in the radial artery (T0: adenosine: mean +27%; c-TnI: +41%; myoglobin: +28%; T1: adenosine: mean +58%; c-TnI: +58%; myoglobin: +25%; p < .001). These parameters were significantly higher in the coronary sinus at T1 compared with T0 (adenosine: +50%; c-TnI: +229%; myoglobin: +94%; p < .01) and in the radial artery (adenosine: +21%; c-TnI: +194%; myoglobin: +98%; p < .01). At T2, c-TnI further increased. Damages to the myocardium during cardiac surgery are minimal in our surgical conditions but are probably underestimated when using markers measured at the peripheral level. However, most of the damages appear several hours after the surgery.

Relationship between A2A adenosine receptor expression and intradialytic hypotension during hemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is a common complication of hemodialysis sessions (HDSs). Adenosine may contribute to the drop in blood pressure during IDH events because it has hypotensive effects. As A(2A) adenosine receptor expression is essential for blood pressure control, we compared the expression of A(2A) receptors (Bmax, K(D), and messenger ribonucleic acid [mRNA] levels) in peripheral blood mononuclear cells from IDH and non-IDH patients and from controls. We also evaluated adenosine plasma levels (APLs). METHODS: We included 10 hemodialyzed patients with at least three IDH events per month. We also included 11 hemodialyzed patients with no history of IDH events and 10 healthy subjects as controls. RESULTS: IDH patients had higher Bmax values than non-IDH patients (mean before HDS, +86%; after HDS, +112%), whereas non-IDH patients had lower Bmax values than controls (mean -72%). K(D) values were not significantly different between patients and controls. The levels of mRNA increased significantly during HDS but without an increase in receptor expression on the cell membranes. APLs were higher in hemodialyzed patients than in controls. CONCLUSION: We found that A(2A) receptors are more expressed in IDH patients than in non-IDH patients, whereas APL was high in all patients. Both high APL and a relative increase in A(2A) receptor expression may favor IDH events.

Role of endogenous adenosine as a modulator of syncope induced during tilt testing.

BACKGROUND: Previous reports that used head-up tilt testing and adenosine administration have suggested that adenosine may be an important endogenous mediator that may trigger a vasovagal response in susceptible patients. However, little is known regarding endogenous adenosine plasma levels (APLs) during vasovagal syncope provoked by tilt testing. The aim of this study was to determine whether APLs differ in patients with a positive head-up tilt test compared with those with a negative test and whether APLs are modified during tilt-induced vasovagal syncope. METHODS AND RESULTS: APLs (mean+/-SEM) were measured during head-up tilt test in 26 patients who presented with unexplained syncope. In the 15 patients with a negative test, APLs were 0.39+/-0.03 micromol/L at baseline, 0.22+/-0.03 micromol/L immediately after tilting, and 0.44+/-0.03 micromol/L after 45 minutes. APLs were significantly higher in the 11 patients with a positive test (2.66+/-0.67 micromol/L at baseline and 3.22+/-0.85 micromol/L immediately after tilting) than in those with a negative test. During tilt testing-induced syncope, APLs increased to reach 4.03+/-0.66 micromol/L (ie, a 52% increase compared with baseline levels; P<0.02). Furthermore, we observed that the higher the APL during syncope, the shorter the time to appearance of symptoms. CONCLUSIONS: This study showed that APLs were higher in patients with a positive tilt test than in patients with a negative test and that they increased during tilt testing-induced syncope. These observations suggest that adenosine release may be involved in the triggering mechanism of syncope induced during tilt testing.

Intra-atrial thrombosis and pulmonary embolism complicating pacemaker leads for cardiac resynchronization therapy.

This is the first report of intracardiac thrombi and pulmonary embolism complicating pacemaker leads implanted for cardiac resynchronization therapy. Prompt diagnosis and successful therapy with a thrombolytic agent lead to a favourable outcome. This report suggests that long-term oral anticoagulation should be considered in patients with depressed left ventricular function undergoing cardiac resynchronization therapy in order to prevent this potentially serious complication.

Influence of haemodialysis and left ventricular failure on peripheral A(2A) adenosine receptor expression.

BACKGROUND: Haemodialysis (HD) sometimes accelerates left ventricular failure (LVF). As adenosine (ADO) is strongly implicated in cardiovascular functions, particularly via A(2A) receptor activation and as changes of peripheral A(2A) receptors mirror changes occurring in the cardiovascular system, we examined the influence of HD and LVF on both ADO plasma concentration and the expression of A(2A) receptors (i.e. Bmax, K(D) and mRNA amount) of peripheral blood mononuclear cells. METHODS: This cross-sectional study included 61 chronic renal failure (CRF) patients: 41 without LVF (24 haemodialysed and 17 undialysed) and 20 with LVF (9 haemodialysed and 11 undialysed). Ten LVF patients without CRF and 10 healthy subjects were also examined. RESULTS: (i) Bmax values of CRF patients without LVF were significantly decreased in undialysed patients compared with haemodialysed patients, and compared with controls (69 +/- 25 vs 98 +/- 33 vs 180 +/- 60 fmol/mg of protein, P < 0.05). Bmax values of CRF patients with LVF were lower in undialysed patients than in haemodialysed patients (60 +/- 27 vs 101 +/- 27 fmol/mg of protein, P < 0.05). Bmax values of LVF patients without CRF were lower than in controls (51 +/- 19 vs 180 +/- 60 fmol/mg of protein). (ii) A(2A) mRNA expression was increased in haemodialysed patients compared with controls (20.2 +/- 0.75 vs 17.6 +/- 1.3, P < 0.05). (iii) ADO plasma levels were high in haemodialysed patients and further increased during the HD sessions. CONCLUSION: The number of A(2A) receptors was decreased by CRF with or without LVF. However, this decrease was less important in haemodialysed patients. The changes in peripheral A(2A) receptor expression suggest a significant inflammatory response to HD and heart or kidney failure. Whether these changes do reflect alterations in cardiomyocytes needs further investigation.

Role of endogenous adenosine as a predictive marker of vasoplegia during cardiopulmonary bypass and postoperative severe systemic inflammatory response.

OBJECTIVE: Systemic inflammatory response (SIRS) and severe SIRS (SIRS with organ dysfunction) occurring after cardiopulmonary bypass (CPB) are common causes of morbidity and mortality among cardiac surgical patients. These syndromes are often preceded by a profound vasodilation, characterized by vasoplegia occurring during surgery. Many substances have been implicated in their pathophysiology. Adenosine is a strong endogenous vasodilating agent released by endothelial cells and myocytes under metabolic stress and may be involved in blood pressure failure during CPB induced by severe SIRS. DESIGN: A prospective comparative observational study. SETTING: The operating room and intensive care unit of a tertiary care university hospital. PATIENTS: Adenosine plasma levels (mean+/-sd; APLs) were measured before (baseline), during, and immediately after surgery in 35 patients who underwent aortic valve replacement involving CPB. APLs were correlated to operative and postoperative clinical courses. MEASUREMENTS AND MAIN RESULTS: APLs were significantly higher in seven patients with vasoplegia and postoperative severe SIRS (1.6 micromol.L [0.2-2.6] vs. 0.4 micromol.L [0.1-1.0]) at baseline and during surgery. The duration of mechanical ventilation and stay in the intensive care unit were significantly longer for patients with higher APLs. Mean arterial pressure was inversely correlated with mean arterial APLs (Pearson's correlation coefficient: R=-0.66; p<.001). CONCLUSIONS: High APLs were found in patients with operative vasoplegia and postoperative severe SIRS occurring after cardiopulmonary bypass. This suggests that adenosine release is involved in vasoplegia that occurs during the systemic inflammatory response to cardiac surgery. Further studies are needed to clarify the association between cytokine production and adenosine release in severe SIRS following cardiac surgery.

Supraspinal antinociceptive effects of mu and delta agonists involve modulation of adenosine uptake.

BACKGROUND: The modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine uptake by opioid agonists and the analgesic effects of these compounds. METHODS: The authors used the hot plate and tail-pinch tests to evaluate in mice (C57BL/6 females; weight, 25-30 g) the effects of caffeine, a nonspecific adenosine receptor antagonist, on the antinociceptive effect induced by the intracerebroventricular administration of oxymorphone as a mu agonist, SNC80 as a delta agonist, or U69593 as a kappa agonist. They also investigated the effect of these opioid receptor agonists on the uptake of adenosine by whole brain synaptosomes. RESULTS: Caffeine decreased the analgesic effects induced by oxymorphone or SNC80 but not those induced by U69593. Oxymorphone and SNC80 inhibited adenosine uptake by brain cells, but U69593 did not. CONCLUSION: The antinociceptive effects obtained with mu or delta (but not kappa) agonists administered supraspinally were indicative of the involvement of modulation of adenosine uptake.