Brief communication

Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome

Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.

Risk factors are important for the development of torsades de pointes (TdP), and drug-induced TdP is extremely rare in the absence of risk factors. Traditional risk factors for QTc interval prolongation and TdP include acute myocardial infarction/ischemia, older age, anorexia/malnutrition, bradyarrhythmias, conversion from atrial fibrillation to sinus rhythm, elevated plasma concentrations of QT interval-prolonging drugs, female sex, heart failure with reduced ejection fraction, hepatic cirrhosis, electrolyte abnormalities (hypocalcemia, hypokalemia, and hypomagnesemia), hypothyroidism, history of TdP, possibly premature ventricular complexes, and prolongation of the QTc interval to ≥ 500 ms and/or > 60 ms from baseline (as a risk factor for TdP). Concomitant administration of multiple QT interval-prolonging drugs may be a risk factor for QTc prolongation and TdP, but not all studies support this concept, and whether a combination of QT interval-prolonging drugs increases the risk of QTc prolongation compared to that associated with individual QT-prolonging drugs alone likely depends on the specific drugs being combined. To minimize the risk of TdP, correctable risk factors should be ameliorated. In patients with non-modifiable risk factors who require therapy with a QT interval-prolonging medication, QTc interval-prolonging drugs should be used cautiously, and frequent QT interval monitoring should be implemented where feasible.

Adenosine can produce arrhythmias, which are generally short living. It may induce PACs and PVCs, sinus bradycardia, and atrial fibrillation. There have been reports of transient polymorphic VT (torsades de pointes) in patients with LQTS and others in people with normal QT interval. We report a case of a long episode of polymorphic VT induced by adenosine. A 27 year old woman received 6 mg adenosine for PSVT, which terminated and torsades de pointes developed, persisting for 17 seconds and terminated spontaneously. This is the longest described duration of the torsades after adenosine administration in patients with normal QT interval.

Syncope is a significant source of cardiovascular-related morbidity yet the etiology is frequently obscure and the identification of patients at highest risk is challenging. Adenosine (AD) and adenosine triphosphate (ATP) administrations have been suggested as potentially useful non-invasive tools in the diagnostic workup of patients with neurally-mediated or bradycardia-related syncope. It has been postulated that both compounds by modulating the autonomic innervation in the heart and exerting negative chronotropic and dromotropic effects in the conduction system, may unmask the mechanism of syncope. However, the clinical implications derived from the efficacy of both tests in the investigation of syncope remain unclear mainly due to inconclusive and occasionally contradictory results of published studies. This review article summarizes recent and past information in the use of ATP and AD in the investigation of syncope with emphasis on clinical trials. We present the current level of evidence for the use of these agents in clinical practice, identify areas where further research is warranted and highlight the future perspectives of these agents as complements to an accurate risk-stratification of patients with syncope.