During exercise, cardiac oxygen consumption increases and the resulting low oxygen level in the myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A 2A receptor (A 2A R). According to the "spare receptor" pharmacological model, a strong A 2A R-mediated response can occur in the context of a large number of receptors remaining unoccupied, the activation of only a weak fraction of A 2A R (evaluated using K D ), which results in maximal cAMP production (evaluated using EC 50 ), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A 2A R is present in CAD patients to correct ischemia. Seventeen patients with angiographically documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A 2A R-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A 2A R was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients and in none of the controls. Adenosine plasma concentration increased by 60% at peak exercise in patients and in none of the controls (p < 0.01). Most patients (65%), and none of the controls, had spare A 2A R (identified when EC 50 /K D ≤ 0.1) and a low A 2A R-expression (mean: -37% versus controls; p < 0.01). All patients with spare A 2A R had a positive EST whereas the subjects without spare A 2A R had a negative EST (p < 0.05). Spare A 2A R is therefore associated with positive EST in CAD patients and its detection may be used as a diagnostic marker.
We questioned whether electromyographic (EMG) signs of neuromuscular fatigue accompany the changes in respiratory variables measured at the ventilatory threshold (VTh) during exercise on a cycloergometer. This was based on the assumption that the activation of muscle afferents sensitive to accumulation of lactate and potassium is suspected to elicit both the EMG signs of fatigue and hyperventilation. In 39 subjects performing an incremental cycling, the EMG estimates of neuromuscular fatigue in vastus lateralis were a non-linear increase in root mean square (RMS), a decrease in median frequency (MF), a non-linear increase in low-frequency EMG energies (EL), and/or a decrease in high-frequency energies (EH). VTh was determined from a non-linear increase in VCO2 [VTh(VCO2 slope)] and an increased value of the respiratory equivalent for oxygen [VTh(VE/VO2)]. We measured a significant increase in venous blood concentration of lactate and potassium, and a significant pHv fall at VTh. One EMG estimate of fatigue was detected in 33/39 individuals and two EMG estimates in 17 subjects. Highly significant positive correlations were found between the oxygen uptakes corresponding to each EMG estimate and to each detection criterion of VTh. These observations suggest that the activation of muscle sensory pathways contribute to the mechanism of VTh.
Common clinical features and a low adenosine plasmatic level define a distinct form of syncope, distinguish it from VVS, and suggest a causal role of the adenosine pathway.
nus bradycardia and/or atrioventricular block.For patients with typical VVS, a combination of neural outflow and purinergic activation is likely. Letters J A C C V O L . 6 6 , N O . 2 , 2 0 1 5 J U L Y 1 4 , 2 0 1 5 : 2 0 2 -7 R E F E R E N C E S 1. Deharo JC, Mechulan A, Giorgi R, et al. Adenosine plasma level and A2A adenosine receptor expression: correlation with laboratory tests in patients with neurally mediated syncope. Heart 2012;98:855-9. 2. Deharo JC, Guieu R, Mechulan A, et al. Syncope without prodromes in patients with normal heart and normal electrocardiogram: a distinct entity. J Am Coll Cardiol 2013;62:1075-80. 3. Brignole M, Deharo JC, De Roy L, et al. Syncope due to idiopathic paroxysmal atrioventricular block: long-term follow-up of a distinct form of atrioventricular block. J Am Coll Cardiol 2011;58:167-73. 4. Saadjian AY, Gerolami V, Giorgi R, et al. Head-up tilt induced syncope and adenosine A2A receptor gene polymorphism. Eur Heart J 2009;30:1510-5. 5. Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J 2014;35:2211-2.
Early Repolarization A Risk Factor in Brugada SyndromeConte et al. (1) reported their long-term results of implantable cardioverter-defibrillator therapy in Brugada syndrome (BS). The investigators noted that 4 patients experienced an electrical storm and 1 (Patient #3) had a "fragmentation of the QRS complex (f-QRS)." In fact, this patient's electrocardiogram (ECG) showed a spike mainly at the terminal portion of all QRS complexes. After ajmaline challenge, a coved-type ECG was induced, and the spike disappeared, unmasking an S wave in leads V 4 to V 6 .We believe that the terminal QRS spike may signify early repolarization (ER) rather than f-QRS in this BS patient. Unlike in myocardial infarction, f-QRS has
Expression of AR on PBMC correlated with those measured in coronary artery and aortic tissues in CAD patients, AR activity of PBMC matched that observed in aorta, and AR expression and activity in PBMC were found reduced as compared to controls. Measuring the expression level of AR on PBMC represents a good tool to address in situ expression in coronary tissues of CAD patients.
BackgroundThe rapid and reliable exclusion of myocardial revascularization is a major unmet clinical need in patients with suspected coronary artery disease (CAD) and non‐contributive electrocardiography and troponin. Non‐invasive tests have high rates of false positives and negatives, and there is no biomarker to assess myocardial ischemia. The presence of spare adenosine A2A receptors (A2
AR)—characterized by a high dissociation constant/half maximal effective concentration (KD/EC
50) ratio—expressed on peripheral blood mononuclear cells (PBMC) has been associated with ischemia during exercise stress testing in patients with CAD. In this work, we investigated the diagnostic accuracy of spare A2
AR versus fractional flow reserve (FFR) in patients with suspected CAD.Methods and ResultsSixty patients with suspected CAD, but non‐contributive electrocardiography and troponin, were consecutively enrolled in this prospective study. The binding (KD), functional response (cyclic adenosine monophosphate [cAMP] production; EC
50) on PBMC A2
AR were compared with FFR results. Patients were divided into 3 groups: 17 (group 1) with normal coronary angiography (n=13) or stenosis <20% (n=4); 21 with CAD and non‐significant FFR (group 2); and 22 with CAD and significant FFR (group 3). Median KD/EC
50 was 6‐fold higher in group 3 (4.20; interquartile range: 2.81–5.00) than group 2 (0.66; interquartile range: 0.47–1.25) and 7‐fold higher than group 1 (0.60; interquartile range: 0.30–0.66).ConclusionsIn patients with suspected CAD and non‐contributive electrocardiography and troponin, the absence of spare A2
AR on PBMC may help to rule out myocardial ischemia.Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT03218007.
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