Régis Guieu

High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock

ObjectiveSepsis and septic shock are a common cause of mortality in critically ill patients. Many substances have been implicated in the pathophysiology of these syndromes. We postulated that adenosine may be implicated in the sepsis- or septic shock-induced blood pressure failure. Indeed, this nucleoside is a strong endogenous vasodilating agent released by endothelial cells and myocytes under circumstances of metabolic stress, such as during critical illness. DesignA prospective, comparative observational study. SettingThe adult intensive care unit of a tertiary care university hospital. PatientsWe measured adenosine plasma concentration (APC) in patients with severe sepsis (n = 11), in patients with septic shock (n = 14), in patients with hemorrhagic traumatic shock (n = 14), and in 12 healthy volunteers. APC was evaluated every 12 hrs over 3 days. InterventionsNone. Measurements and Main ResultsAt study entry, we found that APC was higher in patients with septic shock (mean ± sd = 8.4 ± 3.5 &mgr;mol/L) than in patients with hemorrhagic traumatic shock (1.1 ± 0.6 &mgr;mol/L) and controls (0.8 ± 0.3 &mgr;mol/L). Intermediate values (3.9 ± 1.9 &mgr;mol/L) were found in patients with severe sepsis. APC in patients with traumatic shock did not differ from controls. In the course of the hospitalization, for both sepsis and septic shock patients, APC decreased significantly but remained higher than controls 72 hrs after entry into the study. In the septic shock group, APC was significantly higher in the nonsurvivor group (n = 6) than in the survivor group (n = 8), whatever the time of sample collection and assay. ConclusionsHigh adenosine plasma concentrations are found in patients with septic shock but not during traumatic shock, or in healthy volunteers. Intermediate values of circulating adenosine are found in patients with severe sepsis. APC may be a prognostic index for outcome in septic patients, with much higher values being found in nonsurvivors.

Syncope due to idiopathic paroxysmal atrioventricular block : long-term follow-up of a distinct form of atrioventricular block.

OBJECTIVES We present data on patients with syncope due to paroxysmal atrioventricular (AV) block unexplainable in terms of currently known mechanisms. BACKGROUND Paroxysmal AV block is known to be due to intrinsic AV conduction disease or to heightened vagal tone. METHODS We evaluated 18 patients presenting with unexplained syncope who had: 1) normal baseline standard electrocardiogram (ECG); 2) absence of structural heart disease; and 3) documentation, by means of prolonged ECG monitoring at the time of syncopal relapse, of paroxysmal third-degree AV block with abrupt onset and absence of other rhythm disturbances before or during the block. RESULTS The study group consisted of 9 men and 9 women, mean age 55 ± 19 years, who had recurrent unexplained syncope for 8 ± 7 years and were subsequently followed up for as long as 14 years (4 ± 4 years on average). The patients had no structural heart disease, standard ECG was normal, and electrophysiological study was negative. In all patients, prolonged ECG monitoring documented paroxysmal complete AV block with 1 or multiple consecutive pauses (mean longest pause: 9 ± 7 s at the time of syncope); AV block occurred without P-P cycle lengthening or PR interval prolongation. During the observation time, no patient had permanent AV block; on permanent cardiac pacing, no patient had further syncopal recurrences. CONCLUSIONS Common clinical and electrophysiological features define a distinct form of syncope due to idiopathic paroxysmal AV block characterized by a long history of recurrent syncope, absence of progression to persistent forms of AV block, and efficacy of cardiac pacing therapy.

Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure.

Objective:Repeated episodes of pulmonary embolism can persistently increase pulmonary arterial pressure and depress right ventricular contractility. We investigated the effects of levosimendan on right ventricular-pulmonary arterial coupling in this model of right ventricular failure. Design:Prospective, controlled, randomized animal study. Setting:University research laboratory. Subjects:Fourteen anesthetized piglets. Interventions:Repeated acute pulmonary embolisms were induced with autologous blood clots to induce persistent right ventricular failure. Animals were randomly assigned to a control or levosimendan group. Levosimendan 20 &mgr;g/kg was administered in 10 mins followed by 0.2 &mgr;g/kg/min or same volumes of isotonic saline. Measurements and Main Results:Pulmonary artery distal resistance and proximal elastance by pressure-flow relationships and vascular impedance were measured. We noted right ventricle contractility by the end-systolic pressure-volume relationship (Ees), pulmonary artery effective elastance by the end-diastolic to end-systolic relationship (Ea), and right ventricular-pulmonary arterial coupling efficiency by the Ees/Ea ratio. The gradual pulmonary artery embolism increased pulmonary artery resistance and elastance, increased Ea from 1.01 ± 0.17 to 5.58 ± 0.37 mm Hg/mL, decreased Ees from 1.75 ± 0.12 to 1.29 ± 0.20 mm Hg/mL, and decreased Ees/Ea from 1.74 ± 0.20 to 0.24 ± 0.09. Compared with placebo, levosimendan decreased pulmonary arterial elastance and characteristic impedance. Right ventricular-pulmonary arterial coupling was restored by both an increase in right ventricular contractility and a decrease in right ventricular afterload. Conclusions:A gradual increase in pulmonary artery pressure induced by pulmonary embolism persistently worsens pulmonary artery hemodynamics, right ventricular contractility, right ventricular-pulmonary arterial coupling, and cardiac output. Levosimendan restores right ventricular-pulmonary arterial coupling better than placebo, because of combined pulmonary vasodilation and increased right ventricular contractility.

Increased Gut Redox and Depletion of Anaerobic and Methanogenic Prokaryotes in Severe Acute Malnutrition

Severe acute malnutrition (SAM) is associated with inadequate diet, low levels of plasma antioxidants and gut microbiota alterations. The link between gut redox and microbial alterations, however, remains unexplored. By sequencing the gut microbiomes of 79 children of varying nutritional status from three centers in Senegal and Niger, we found a dramatic depletion of obligate anaerobes in malnutrition. This was confirmed in an individual patient data meta-analysis including 107 cases and 77 controls from 5 different African and Asian countries. Specifically, several species of the Bacteroidaceae, Eubacteriaceae, Lachnospiraceae and Ruminococceae families were consistently depleted while Enterococcus faecalis, Escherichia coli and Staphylococcus aureus were consistently enriched. Further analyses on our samples revealed increased fecal redox potential, decreased total bacterial number and dramatic Methanobrevibacter smithii depletion. Indeed, M. smithii was detected in more than half of the controls but in none of the cases. No causality was demonstrated but, based on our results, we propose a unifying theory linking microbiota specificity, lacking anaerobes and archaea, to low antioxidant nutrients, and lower food conversion.

Adenosine and the Nervous System: Clinical Implications

After a review of the metabolism and pharmacology of adenosine, this work will examine the various therapeutic possibilities involving the use of agonists or antagonists of adenosine A1 or A2 receptors in neurological disorders. Promising preclinical results have been obtained with epilepsy, cerebral ischemia, alcoholism, and pain.

Adenosine in painful legs and moving toes syndrome

Painful legs and moving toes is a rare syndrome with controversial physiopathology. We report two cases that were relieved by applying transcutaneous vibratory simulation. The pain relief was objectively evaluated using the nociceptive flexion reflex of the lower limb (RIII reflex). In these patients, we found a deficiency in circulating adenosine levels, which was not found in other chronic painful syndromes (sciatic pain). Based on these observations, we successfully treated patients with painful legs and moving toes by the administration of ATP. The deficit in blood adenosine may be an explanation of the physiopathology of this syndrome.

Adenosine plasma level and A2A adenosine receptor expression: correlation with laboratory tests in patients with neurally mediated syncope

Objectives The purpose of this study was to investigate the hypothesis that responses to the ATP test and head-up tilt test (HUT) may be correlated with different purinergic profiles. Design and setting The ATP and HUT identify distinct subsets of patients with neurally mediated syncope (NMS). Adenosine and its A2A receptors (A2AR) may be implicated in the pathophysiology of NMS in patients with positive HUT. Nothing is known about the purinergic profile of patients with positive ATP. Patients and measures This prospective study includes a consecutive series of patients with suspected NMS. All patients underwent both HUT and ATP. Before testing, samples were collected for measurement of baseline adenosine plasma level (APL) and expression. Results A total of 46 patients (25 men and 21 women) with a mean age of 57±18 years were enrolled. The HUT test was positive in 27 patients and the ATP test in 20. Both tests were positive in 9 and negative in 8. High APL was associated with high probability of positive HUT while low APL was associated with high probability of positive ATP. Expression of A2AR was lower in patients with positive ATP than in those with positive HUT. Conclusion These findings indicate that patients with NMS present different purinergic profiles and that responses to HUT and ATP are correlated with these profiles.

Monoclonal antibody–assisted stimulation of adenosine A2A receptors induces simultaneous downregulation of CXCR4 and CCR5 on CD4+ T-cells

Immunocompetent cells express various G-protein-coupled receptors that transduce extracellular signals across the plasma membrane. Among them, CXCR4 and CCR5 chemokines receptors and adenosine A(2A) receptors (A(2A)R) are involved in inflammatory processes. Considering that A(2A)R activation may have incidence on CXCR4 and CCR5 protein expression through heterologous desensitization process, we tested Adonis, an agonist-like monoclonal antibody to A(2A)R on CD4+ CEM T-cells. We found that Adonis inhibited the CEM cell growth, upregulated A(2A)R and downregulated CXCR4 and CCR5 without modifying the CD4 expression. By reducing the expression of CXCR4 and CCR5 chemokines receptors utilized as entry co-receptors by HIV-1 during viral infection of CD4 expressing cells, Adonis stimulation of A(2A)R appears as a valuable means to treat infected cells.

Plasma Xanthine Oxidase Activity Is Predictive of Cardiovascular Disease in Patients with Chronic Kidney Disease, Independently of Uric Acid Levels

Background: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. Methods: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. Results: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. Conclusion: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress.

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.