Electrophysiologic Effects of a Novel Selective Adenosine A1 Agonist (CVT-510) on Atrioventricular Nodal Conduction in Humans

Lerman, Bruce B.; Ellenbogen, Kenneth A.; Kadish, Alan H.; Platia, Edward V.; Steín, Kenneth M.; Markowitz, Steven M.; Mittal, Suneet; Slotwiner, David J.; Scheiner, Marc A.; Iwai, Sei; Belardinelli, Luiz; Jerling, Markus; Shreeniwas, Revati; Wolff, Andrew

doi:10.1177/107424840100600304

Cited by 32 publications

(43 citation statements)

References 20 publications

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“…Overexpression of A 1 AR caused AV nodal conduction delay in the isolated heart and in vivo, an effect that is comparable to the acute effects of A 1 AR agonists on AV nodal conduction in healthy human subjects (20). In contrast to the heart rate changes observed, AV nodal conduction was prolonged in freely moving TG mice irrespective of exercise status, and pertussis toxin did not fully reverse AV nodal conduction slowing.…”

Section: Av Nodal Conduction Delaymentioning

confidence: 62%

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Kirchhof

Fabritz²,

Fortmüller³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor. Am J Physiol Heart Circ Physiol 285: H145-H153, 2003. First published March 13, 2003 10.1152/ ajpheart.01036.2002To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A 1 adenosine receptor (A1AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 Ϯ 18 vs. 522 Ϯ 24 beats/min, P Ͻ 0.05; exercise: 650 Ϯ 13 vs. 765 Ϯ 28 beats/min, P Ͻ 0.05; 1 h after exercise: 588 Ϯ 18 vs. 720 Ϯ 12 beats/min, P Ͻ 0.05; all values are means Ϯ SE). Mean HR was lower during exercise (589 Ϯ 16 vs. 698 Ϯ 34 beats/min, P Ͻ 0.05) and after exercise (495 Ϯ 16 vs. 592 Ϯ 27 beats/min, P Ͻ 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P Ͻ 0.05) in TG compared with WT mice. Pertussis toxin (n ϭ 4 pairs, 150 g/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 Ϯ 2 vs. 37 Ϯ 2 ms, P Ͻ 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorffperfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P Ͻ 0.05). In conclusion, A 1AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A 1AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias. heart rate regulation; autonomous nervous system; heart rate variability; sinus node dysfunction; atrioventricular block; atrial fibrillation

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Section: Av Nodal Conduction Delaymentioning

confidence: 62%

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Kirchhof

Fabritz²,

Fortmüller³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…7,8 Side effects mediated by the A 2A -, A 2B -, and A 3 -adenosine receptors such as flushing, chest pressure, hypotension, and bronchospasm were infrequent, consistent with the A 1 -adenosine receptor selectivity of the drug.…”

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confidence: 89%

“…Plasma levels of tecadenoson were analyzed by highperformance liquid chromatography with danem mass spectrometry (LC/MS/MS) using positive-ion ray ionization as described previously. 7 The dose concentration at each time point was averaged by the number of full doses.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Although activation of the A 1 receptor results in the desired termination of PSVT, 6 activation of the remaining adenosine receptors presumably is the cause of the adverse effects described above. 7 This study evaluated tecadenoson (6-[N-3Ј-(R)-tetrahydrofuranyl]-amino-purine riboside, formerly CVT-510), a selective A 1 -adenosine agonist, for the acute termination of PSVT. In the atrial-paced guinea pig heart model, 6 tecadenoson was 5-fold more potent in prolonging the stimulus-to-His bundle (S-H) interval, an A 1 -adenosine receptormediated effect, than in increasing coronary conductance, an A 2A -adenosine receptor-mediated effect.…”

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confidence: 99%

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Trial to Evaluate the Management of Paroxysmal Supraventricular Tachycardia During an Electrophysiology Study With Tecadenoson

et al. 2005

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Background-Tecadenoson is a potent selective A 1 -adenosine receptor agonist with a dose-dependent negative dromotropic effect on the AV node. Tecadenoson terminates induced paroxysmal supraventricular tachycardia (PSVT) without the clinically significant side effects caused by stimulation of other adenosine receptors. This trial was designed to determine a safe and effective tecadenoson bolus for termination of electrophysiologically induced PSVT. Methods and Results-Patients with a history of symptomatic PSVT and inducible PSVT at the time of a clinically indicated electrophysiology study were randomized into a multicenter, double-blind, placebo-controlled trial. Five 2-dose tecadenoson bolus regimens were evaluated versus placebo (75/150, 150/300, 300/600, 450/900, 900 g/900 g). The second bolus was administered only if PSVT persisted for 1 minute after the first bolus. Each tecadenoson regimen resulted in a significant therapeutic conversion rate compared with placebo (range, 50.0% to 90.3%, analysis of all patients dosed; nϭ181; PϽ0.0005). Conversion by the first bolus was dose related (range: placebo, 3.3% to 86.7% for 900 g/900 g). Time to conversion was dose dependent, with a median time of Ͻ1 minute for the 3 highest dose regimens. Postconversion arrhythmias were transient, requiring no additional treatment in 4 regimens (including placebo). Transient second-and third-degree heart block occurred at higher doses (300/600, 450/900, 900 g/900 g) and was supported with backup pacing when needed. No effect on blood pressure was observed. Ten patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without bronchospasm. Conclusions-We identified an optimal tecadenoson regimen (300 g/600 g) that effectively and rapidly converted 90% (28 of 31) of PSVT patients to normal sinus rhythm with no significant adverse effects. (Circulation. 2005;111:3202-3208.)

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“…12 Tecadenoson and DTI-0009, selective adenosine derivatives, are A 1 adenosine receptor agonists that are being developed to treat AV nodal-dependent reentrant arrhythmias by slowing conduction through the AV node. [11][12][13][14][15][16] They seem to lack the hypotensive and bronchospastic effects mediated by the A 2B and A 3 adenosine receptors, respectively. In patients with AF requiring immediate rate control involving the AV node, without the negative hemodynamic effects associated with calcium-channel blockers and beta blockers, and the bronchospastic effects observed with adenosine, the therapeutic potential of an A 1 adenosine receptor agonist is clear.…”

Section: Control Of Ventricular Rate During Atrial Fibrillation Drug mentioning

confidence: 99%

A perspective on rate control in the treatment of atrial fibrillation

Waldo

2004

Clinical Cardiology

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Summary:Until recently, the standard approach to therapy of atrial fibrillation (AF) in most cases was restoration and maintenance of sinus rhythm (rhythm control). Although difficult to accomplish, and associated with potential serious adverse effects of antiarrhythmic agents, this therapeutic approach was influenced by the belief that rhythm control was associated with better survival, fewer symptoms, better exercise tolerance, lower risk of stroke, better quality of life, and absence of need for long-term anticoagulation. However, four clinical trials comparing rate control with rhythm control have failed to demonstrate these advantages, indicating that rate control should be considered a legitimate primary therapeutic option, particularly in patients at risk for stroke. Pursuit of rate or rhythm control should be decided on a case-by-case basis.

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Electrophysiologic Effects of a Novel Selective Adenosine A1 Agonist (CVT-510) on Atrioventricular Nodal Conduction in Humans

Cited by 32 publications

References 20 publications

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Trial to Evaluate the Management of Paroxysmal Supraventricular Tachycardia During an Electrophysiology Study With Tecadenoson

A perspective on rate control in the treatment of atrial fibrillation

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