Regadenoson, a Novel Pharmacologic Stress Agent for Use in Myocardial Perfusion Imaging, Does Not Have a Direct Effect on the QT Interval in Conscious Dogs

Abstract

Our goal was to determine the effect of regadenoson (a novel A2A adenosine receptor agonist) on the QT interval in conscious dogs. Eleven mongrel dogs were chronically instrumented for measurements of blood pressure and ECG. Regadenoson (2.5, 5 and 10 μg/kg, IV) caused a dose-dependent QT interval shortening (ΔQT: 14±3, 24±5 and 27±5 ms, mean±SEM, n=7-11, all p<0.05) associated with significant increases in HR (Peak HR: 114±9, 125±6 and 144±7 bpm). Atrial pacing (135, 150 and 165 bpm) also caused a frequency-dependent shortening of the QT interval (ΔQT: 15±3, 22±3, and 39±5 ms, n=6-7, all p<0.05). Regadenoson- and pacing-induced shortenings in the QT interval were significantly correlated with the R-R interval (r= 0.67 and 0.8, both p<0.05). Regadenoson at 5 and 10 μg/kg did not cause a significant change in HR or QT interval either during atrial pacing at 165 bpm or after administration of propranolol and atropine to prevent HR from changing, or after treatment of dogs with hexamethonium to block autonomic ganglia. Regadenoson (5-10 μg/kg) caused no significant changes of QT interval in the heart in which HR was kept constant via physiological or pharmacological procedures, indicating that regadenoson has no a direct effect on the QT interval.

Regadenoson for myocardial perfusion imaging: Is it safe?

“…In dogs and rats treated with hexamethonium, a blocker of impulse transmission through autonomic nerve ganglia, regadenoson administration (5 lg/kg) did not increase heart rate, and the drop in blood pressure was much greater than in untreated control animals. 23,28 It is therefore possible that patients with poor autonomic control of cardiovascular function may experience an acute drop in blood pressure leading to hemodynamic collapse upon administration of regadenoson, especially when in the standing posture, such as when administered in association with exercise.…”

Adverse effects associated with regadenoson myocardial perfusion imaging

“…18 An alternate explanation could be the A2A-mediated activation of the sympathetic afferent nerves leading to enhanced sympathetic activity and reflex vagal stimulation. [19][20][21] This may prove particularly risky, especially in the subgroup of patients unable to tolerate hypotension, such as the elderly, those with a history of stroke, significant left ventricular outflow tract obstruction, or severe ischemic left ventricular dysfunction and in those undergoing hybrid regadenoson-exercise stress since hypotension may be exacerbated with upright posture. Finally, regadenoson itself may stimulate production of endogenous adenosine further potentiating the following effects: (a) coronary transmural steal phenomenon, (b) adenosine-related vasodilatation which may in turn result in diminished flow through collaterals and arterioles and a drop in perfusion pressure, and (c) a reduction in distal perfusion pressure due to increased flow across a stenosed vessel.…”

“…37 Prolongation of the QT interval might also occur as a result of regadenoson-induced tachycardia and shortening of the R-R interval without appropriate shortening of the QT interval. 20,38 This type of QT prolongation has not been associated with torsades de pointes or sudden cardiac death. Table 1 lists the cardiovascular side effects that may follow use of regadenoson and their respective treatment.…”

“…4 Based on animal experiments, it is now clear that regadenosonmediated tachycardia results from either direct sympathetic stimulation or withdrawal of vagal tone 17,20,21 and is not a baroreflex-mediated epiphenomenon secondary to peripheral vasodilation as once thought. The heart rate response (HRR) to regadenoson is a prognostically important, non-perfusion-derived MPI index 22 and can be calculated as the percent difference in heart rate from baseline with lower values reflecting worse prognosis.…”

Selective adenosine agonists and myocardial perfusion imaging

“…22 Regadenoson (5 and 10 lg/kg) did not cause a significant change in HR after administration of propranolol in dogs. 23 This dissociation of HR and BP responses suggests that regadenoson baroreflex-mediated tachycardia maybe more due to a direct stimulation of the sympathetic nervous system via activation of A2A adenosine receptors rather than an entirely baroreflex-mediated response. 22 Binodenoson (0.1-3 lg/kg/minute infused for 10 minutes) was compared to an infusion of adenosine at 300 lg/kg/minute for 4 minutes in 5 dogs.…”