Adenosine receptors expression in cardiac fibroblasts of patients with left ventricular dysfunction due to valvular disease.

CONTEXT: Adenosine restores tissue homeostasis through the interaction with its membrane receptors (AR) expressed on fibroblasts, endothelial cells, smooth muscle cells and leukocytes, but their modulation is still not fully understood. OBJECTIVE: To evaluate whether changes in the transcriptomic profiling of adenosine receptors (AR) occur in cardiac fibroblasts (CF) of patients (pts) with LV dysfunction due to valvular disease (V). The secondary aim was to compare in the same pts the results obtained at cardiac level with those found in circulating leukocytes. MATERIALS AND METHODS: Auricle fragments were excised from 13 pts during prosthetic implantation while blood samples were collected from pts (n = 9) and from healthy subjects (C, n = 7). In 7 pts cardiac biopsy and blood samples were taken simultaneously. A human CF atrial cell line (cc) was used as control. RESULTS: AR higher levels of mRNA expression were observed with real-time PCR in Vpts compared to C, both at cardiac (overexpression A1R:98%, A2AR:63%, A2BR:87%, A3R:85%, CD39:92%, CD73:93%) and at peripheral level (A1R vs C: p = .0056; A2AR vs C: p = .0173; A2BR vs C: p = .0272; A3R vs C: p = .855; CD39 vs C: p = .0001; CD73 vs C: p = .0091). CONCLUSION: All AR subtypes were overexpressed in CF of Vpts. The same trends in AR expression at cardiac level was assessed on circulating leukocytes, thus opening a new road to minimally invasive studies of the adenosinergic system in cardiac patients.

Cardiogenic shock complicating myocardial infarction in a doped athlete.

Abuse of doping agents may pose a higher risk for heart disease including acute myocardial infarction. We report the case of a 50-year-old body-builder Caucasian man with a long-standing abuse of nandrolone and erythropoietin that developed a ventricular septal defect following acute myocardial infarction. This mechanical complication led to cardiogenic shock ultimately treated with the implantation of a circulatory support by means of extracorporeal membrane oxygenation. The patient subsequently underwent orthotopic heart transplantation. The association of intense isometric exercise, abuse of erythropoietin and nandrolone is likely to have predisposed to coronary thrombus formation and acute myocardial infarction, as the patient presented no traditional cardiovascular risk factors.

Upregulation of A2A adenosine receptor expression by TNF-alpha in PBMC of patients with CHF: a regulatory mechanism of inflammation.

BACKGROUND: Tumor necrosis factor (TNF)-alpha plays a role in congestive heart failure (CHF). A2A adenosine receptor (A(2A)R) activation on immune cells putatively reduces the release of cytokines contributing to CHF progression. The study is aimed at determining the role of the A(2A)R in the modulation of TNF-alpha production, and the ex vivo effect of TNF-alpha on A(2A)R in peripheral blood mononuclear cells (PBMC) from CHF patients. METHODS AND RESULTS: Plasma levels of TNF-alpha and TNF-alpha production from lipopolysaccharide (LPS)-stimulated PBMC were evaluated in 26 CHF patients in comparison to controls. The effects of the A(2A)R agonist CGS-21680 and antagonist ZM-241385 on TNF-alpha production from PBMC were also evaluated. Finally, reverse transcriptase-polymerase chain reaction and Western blot analyses of A(2A)R in PBMC were performed in TNF-alpha-treated and untreated cells. TNF-alpha production from LPS-stimulated PBMC was enhanced in CHF patients with respect to controls. CGS-21680 blunted TNF-alpha production in both groups; ZM-241385 reverted this effect. A(2A)R expression in PBMC was higher in CHF patients than in controls. TNF-alpha addition produced an increase in A(2A)R in PBMC from controls but not in PBMC from CHF patients. CONCLUSIONS: PBMC from CHF patients show an upregulation of A(2A)R-mediated inhibition of TNF-alpha, which may represents a mechanism of protection against inappropriate cytokine production.

Serial assessment of peak VO2 and VO2 kinetics early after heart transplantation.

PURPOSE: Serial evaluation of aerobic metabolism and exercise tolerance early after heart transplantation (HT). METHODS: Fifteen heart transplant recipients (HTR), aged 52.0 +/- 9.9 yr (mean +/- SD), not undergoing structured rehabilitation programs, were tested two to four times during the first 2 yr post-HT. As a reference, a group of 11 healthy untrained controls (C) was utilized. Peak heart rate (peak HR), peak O2 uptake (peak VO2), and ventilatory threshold (VT) were determined during incremental bicycle exercise to voluntary exhaustion. VO2 kinetics were evaluated during constant-load exercise below VT, with determination of the duration of the "cardiodynamic" component (TDp) and of the time constant of the "primary" component (taup). RESULTS: Peak VO2 (L.min-1) was positively related to months post-HT (y=1.17 + 0.02x, P=0.003), and it increased by approximately 30% during the investigated period, although values in HTR were lower than in C (2.19 +/- 0.24). Peak HR was lower in HTR (136 +/- 15 beats.min-1) than in C (168 +/- 5), and it was not related to time post-HT. TDp was longer in HTR (31.4 +/- 6.3 s) than in C (23.2 +/- 6.1), and it was not related to time post-HT. A subgroup of HTR with markedly longer taup during the first months post-HT showed a significant decrease of this parameter as a function of time post-HT. CONCLUSIONS: Aerobic metabolism is impaired in HTR. Both central (cardiovascular) and peripheral (skeletal muscle) factors contribute to the reduced exercise tolerance. HTR showed, during the first 2 yr post-HT, a significant increase in peak VO2 and (in the patients with the slowest VO2 kinetics during the first months after HT) a significant improvement of the VO2 kinetics. The main gains seem to occur at the peripheral level.

Changes of peripheral A2A adenosine receptors in chronic heart failure and cardiac transplantation.

Peripheral blood mononuclear cells of chronic heart failure (CHF) patients produce great amounts of pro-inflammatory cytokines, indicating that circulating cells are activated and could mirror changes occurring in inflammatory cells infiltrating the failing heart. Adenosine is a regulatory metabolite acting through four membrane receptors that are linked to adenylyl cyclase: activation of the A2A receptor subtype has been reported to inhibit cytokine release. Changes of the adenosinergic system may play a role in CHF development. Here we report an increase of A2A receptor expression, density, and coupling to adenylyl cyclase in blood circulating cells of CHF patients. A2A receptor up-regulation was also found in the explanted hearts of these patients, suggesting that changes of peripheral adenosine receptors mirror changes occurring in the disease target organ. In a cohort of patients followed longitudinally after heart transplantation, alterations of peripheral A2A adenosine receptor progressively normalized to control values within 6 months, suggesting that improvement of cardiac performance is accompanied by progressive restoration of a normal adenosinergic system. These results validate the importance of the A2A receptor in human diseases characterized by a marked inflammatory/immune component and suggest that the evaluation of this receptor in peripheral blood cells may be useful for monitoring hemodynamic changes and the efficacy of pharmacological and non-pharmacological treatments in CHF patients.