Effects of oral theophylline on sick sinus syndrome

Saito, Daiji; Matsubara, K; Yamanari, Hiroshi; Obayashi, Naotsugu; Uchida, Sinji; Maekawa, Kiyoaki; Sato, Tetsuya; Mizuo, Kouzou; Kobayashi, Hiroyuki; Haraoka, Shoichi

doi:10.1016/0735-1097(93)90246-w

Cited by 47 publications

(16 citation statements)

References 22 publications

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“…5 Our results further indicate that A1R blockade may prevent and restore adenosine-induced atrial pauses in HF subjects. However, since A1Rs are expressed in a variety of tissues in addition to cardiac muscle, long-term use of theophylline can produce off-target side effects such as seizures 49 and therefore should be evaluated with caution.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping

Lou¹,

Hansen²,

Fedorenko³

et al. 2014

Circulation

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Background While sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF. Methods and Results We applied multiple approaches to characterize SAN structure, function and adenosine A1 receptor (A1R) expression in control (n=17) and four month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10μM) markedly prolonged post-pacing SAN conduction time in HF by 206±99ms (vs. 66±21ms in control, p=0.02). Adenosine induced SAN intra-nodal conduction block and/or micro-reentry in 6/8 HF vs. 0/7 controls (p=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused post-pacing atrial pauses in HF vs. control (17.1±28.9s vs. 1.5±1.3s, p<0.001). Furthermore, 10μM adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation (AF) in 6/7 HF vs. 0/7 control (p=0.002). Adenosine-induced SAN dysfunction and AF were abolished/prevented by A1R antagonists (50μM Theophylline/1μM DPCPX). A1R protein expression was significantly upregulated during HF in the SAN (by 47±19%) and surrounding atrial myocardium (by 90±40%). Interstitial fibrosis was significantly increased within the SAN in HF vs. control (38±4% vs. 23±4%, p<0.001). Conclusions In chronic HF, A1R upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN leading to SAN dysfunction, and potentiate atrial repolarization shortening thereby facilitating AF. AF may further depress SAN function and lead to tachy-brady arrhythmias in HF.

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Section: Discussionmentioning

confidence: 99%

Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping

Lou¹,

Hansen²,

Fedorenko³

et al. 2014

Circulation

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“…Previous studies have reported that oral administration of theophylline, a phosphodiesterase inhibitor, may be effective in patients with symptomatic sinus bradycardia. 5,6 Since cilostazol also has an inhibitory action on phosphodiesterase, it may be useful for treating SSS. The effects of cilostazol on intracellular cyclic adenosine monophosphate levels and cellular function have been demonstrated in cardiac ventricular myocytes.…”

Section: Discussionmentioning

confidence: 99%

Chronotropic Effect of the Antithrombotic Agent Cilostazol in a Patient with Sick Sinus Syndrome and Syncope

et al. 2004

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In this case report we describe an 80-yearold man with sick sinus syndrome (SSS) who developed syncope attacks. The diagnosis of SSS was based on electrocardiographic evidence of markedly prolonged sinus arrests associated with syncope attacks while in hospital. The patient was given cilostazol, an antithrombotic agent that selectively inhibits cyclic nucleotide phosphodiesterase type 3, at a dose of 100 mg twice daily. The syncope attacks ceased, and an electrocardiogram obtained 1 week after the start of cilostazol administration showed no evidence of sinus arrest. The outcome of this case suggests that cilostazol may be useful in patients with syncope attacks due to SSS, although the long-term chronotropic effects of cilostazol need to be evaluated.

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“…This is supported by the clinical findings that (1) bolus injection of adenosine suppresses SAN function and produces pauses especially in patients with SAN dysfunction 12, 13 and (2) orally administrated theophylline, a potent nonselective antagonist of adenosine receptors, reduces both the frequency and duration of the pauses in patients with sick sinus syndrome. 14 …”

Section: Introductionmentioning

confidence: 99%

Tachy-brady arrhythmias: The critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses

Lou¹,

Glukhov²,

Hansen³

et al. 2013

Heart Rhythm

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Background In patients with sinoatrial nodal (SAN) dysfunction, atrial pauses lasting several seconds may follow rapid atrial pacing or paroxysmal tachycardia (tachy-brady arrhythmias). Clinical studies suggest that adenosine may play an important role in SAN dysfunction, but the mechanism remains unclear. Objective To define the mechanism of SAN dysfunction induced by the combination of adenosine and tachycardia. Methods We studied the mechanism of SAN dysfunction produced by a combination of adenosine and rapid atrial pacing in isolated coronary-perfused canine atrial preparations using high-resolution optical mapping (n=9). Sinus cycle length (SCL) and sinoatrial conduction time (SACT) were measured during adenosine (1–100μM) and 1μM DPCPX (A1 receptor antagonist, n=7) perfusion. Sinoatrial node recovery time was measured after one minute of “slow” pacing (3.3Hz) or tachypacing (7–9Hz). Results Adenosine significantly increased SCL (477±62 vs. 778±114 ms, p<0.01), and SACT during sinus rhythm (41±11 vs. 86±16 ms, p<0.01) dose-dependently. Adenosine dramatically affected SACT of the first SAN beat after tachypacing (41±5 vs. 221±98ms, p<0.01). Moreover, at high concentrations of adenosine (10–100μM), termination of tachypacing or atrial flutter/fibrillation produced atrial pauses of 4.2±3.4 seconds (n=5) due to conduction block between the SAN and atria, despite a stable SAN intrinsic rate. Conduction block was preferentially related to depressed excitability in SAN conduction pathways. Adenosine-induced changes were reversible upon washout or DPCPX treatment. Conclusions These data directly demonstrate that adenosine contributes to post-tachycardia atrial pauses through SAN exit block rather than slowed pacemaker automaticity. Thus, these data suggest an important modulatory role of adenosine in tachy-brady syndrome.

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Effects of oral theophylline on sick sinus syndrome

Abstract: The results suggest that oral theophylline may be beneficial for the treatment of patients with sick sinus syndrome.

Cited by 47 publications

References 22 publications

Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping

Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping

Chronotropic Effect of the Antithrombotic Agent Cilostazol in a Patient with Sick Sinus Syndrome and Syncope

Tachy-brady arrhythmias: The critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses

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