Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management

Login or register to view PDF.
Creative Commons Licence
 
Abstract

Adenosine was identified in 1929 and immediately recognised as having a potential role in therapy for arrhythmia because of its negative chronotropic and dromotropic effects. Adenosine entered mainstream use in the 1980s as a highly effective agent for the termination of supraventricular tachycardia (SVT) involving the atrioventricular node, as well as for its ability to unmask the underlying rhythm in other SVTs. Adenosine has subsequently been found to have applications in interventional electrophysiology. While considered a safe agent because of its short half-life, adenosine may provoke arrhythmias in the form of AF, bradyarrhythmia and ventricular tachyarrhythmia. Adenosine is also associated with bronchospasm, although this may reflect irritant-induced dyspnoea rather than true obstruction. Adenosine is linked to numerous pathologies relevant to arrhythmia predisposition, including heart failure, obesity, ischaemia and the ageing process itself. This article examines 90 years of experience with adenosine in the light of new European Society of Cardiology guidelines for the management of SVT.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Gareth Matthews, Murray Edwards College, University of Cambridge, Huntingdon Road, Cambridge CB3 0DF, UK. E: gdkm2@cam.ac.uk
Received date
27 July 2019
Accepted date
08 November 2019
DOI
https://doi.org/10.15420/aer.2019.05
Open access
This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The use of adenosine in cardiology is ubiquitous. From arrhythmia to coronary intervention to cardiac imaging, adenosine is an essential part of everyday practice because of its widespread effects on electrophysiology and the coronary vasculature. Electrophysiologists will be most familiar with adenosine for its use in terminating supraventricular tachycardias (SVTs) that are dependent on the atrioventricular node (AVN) and in unmasking underlying rhythms.

Decades of clinical experience in the use of adenosine in SVT have refined its clinical applications as reflected in the 2019 update of European Society of Cardiology guidelines for this condition.1 The role of adenosine in disorders encountered in cardiac electrophysiology is set to expand as patients increasingly survive ischaemic heart disease, populations become older and the burden of metabolic syndrome manifests. Adenosine signalling also has roles in atrial flutter, AF and ventricular arrhythmia. New research strongly implicates adenosine in other conditions associated with cardiac consequences, such as obesity, diabetes and pulmonary disease. This article provides an updated and encompassing review of the role of exogenous and endogenous adenosine on cardiac electrophysiology, and provides insights into its potential future therapeutic uses.2,3

Adenosine Discovery and Early Characterisation

Sir Alan Nigel Drury and Sir Albert Szent-Györgyi (Figure 1), who worked at the University of Cambridge in the departments of pathology and biochemistry respectively, are widely acknowledged as being the first to identify the actions of adenosine on the heart in 1929.4 In the same year this work was published, Karl Lohmann was accredited with the discovery of adenosine triphosphate (ATP); these combined works heralded the beginnings of purinergic science.5 Szent-Györgyi later received the Nobel Prize in 1937 for his work on vitamin C and components of the citric acid cycle. Drury, who had previously worked closely with ECG pioneer Sir Thomas Lewis, had been responsible for seminal observations on the re-entrant mechanism of atrial flutter, vagal stimulation and the mechanism of quinidine in AF.6–9

Drury and Szent-Györgyi found that injecting extracts from bullock heart into small animals resulted in transient bradycardia, which was recorded using ECGs (Figure 2A). This was not antagonised by atropine, suggesting a mechanism independent of vagal stimulation. The extract was purified and shown to be composed of adenine, a pentose sugar and phosphoric acid, and was chemically similar to adenosine monophosphate (AMP). Adenosine and adenosine diphosphate (ADP) had similar cardiac effects, whereas other nucleoside products, such as guanosine, did not. The mechanism of the bradycardia was high-grade atrioventricular (AV) block, although sinus bradycardia was observed at higher doses. The effect typically occurred 10–12 seconds following administration, with the maximal effect at 15–30 seconds. Adenosine was also shown to reduce the refractory period and augment conduction velocity during pacing at high heart rates. They hypothesised a role for adenosine in terminating atrial flutter and AF, attributed to its effect on the atrial refractory period. The translation of adenosine use from animal studies into humans was swift, with broadly similar results found a year later.10

Pharmacology of Adenosine

Adenosine is an endogenous purine formed by adenine and D-ribose produced from the degradation of ATP, ADP and AMP by ectoenzymes (predominantly CD39 and CD73) which is a process universal to most mammalian cells.11 The production of adenosine is widely employed in cellular signalling as an indication of ATP turnover. Extracellular adenosine levels may be elevated by additional release from cardiomyocytes, platelets, endothelium and nerves induced by ischaemia/hypoxia, catecholamines and calcium.12,13

There are four G-protein coupled adenosine receptor subtypes present in cardiac tissue: A1 (Galphai), A2A(Galphas), A2B(Galphas) and A3(Galphai), which critically affect three main aspects of cardiac physiology. First, adenosine induces coronary vasodilatation, increasing blood flow according to tissue demand.14,15 This is mediated by A2 receptor signalling, especially A2A, with high potency due to large receptor reserves.16,17 Second, adenosine has negative inotropic effects via antagonism of sympathetic pathways.18,19 Third, adenosine exerts major electrophysiological effects, predominantly mediated by the A1 receptors with AMP and adenosine being 10-fold more efficacious in direct actions on downstream currents than ATP in pharmacological studies.20,21 Abrogation of electrophysiological effects by inhibiting conversion of AMP to adenosine or accelerating the metabolism of adenosine to inosine suggest that adenosine is the primary mediator of endogenous signalling at the A1 receptor.21

The cardiac expression of A1 receptors and associated G-protein-coupled, inward-rectifying potassium (GIRK) channels is concentrated in the right atrium; this is three times higher than it is in the left atrium, especially in superolateral regions. This regional heterogeneity in expression results in greater reduction in right atrial action potential duration (APD) in response to adenosine.22

Adenosine has a short half-life of less than 10 seconds, typically being cleared from the plasma within 30 seconds either by adenosine deaminase, which is present in erythrocytes and vascular endothelium, or by phosphorylation to AMP. A short half-life, as in many applications, can be advantageous because effects are short lived, which limits the potential for adverse events. However, this means both direct oral administration and long-term therapy are precluded. It can also result in drug delivery issues because a peripherally administered adenosine bolus is subject to significant dispersion and longer transit times. This allows greater metabolism and results in higher and more variable dosages. Therefore, it is advocated that adenosine should be delivered either via a central line or a large-bore cannula placed, for example, in the antecubital fossa.1,23

Methylxanthines, such as caffeine and theophylline, are adenosine antagonists, reducing its effect. Caffeine ingested within 4–6 hours, but not 6–8 hours, may mean a higher dose is required.24 Dipyridamole, an antiplatelet and vasodilatory agent, accentuates the actions of adenosine by inhibiting metabolism by adenosine deaminase; it does this both directly and, more importantly, indirectly by preventing erythrocyte uptake of adenosine where it is subsequently deaminated by inhibition of adenosine transporters.25–27

Sir Alan Drury and Sir Albert Szent-Györgyi

Open in new tab
Open ppt

Effects of Adenosine Administration

Open in new tab
Open ppt

Electrophysiological Effects of Adenosine

Adenosine exerts its electrophysiological effects via the A1 receptor, which couples with GIRK channels, similar to the mechanism of the muscarinic acetylcholine receptor.28 There may also be interactions with the KATP channel.29 GIRK channels are responsible for the IKAdo current, which causes membrane hyperpolarisation. In addition, the Galphai subunit of the A1 receptor inhibits cyclic AMP (cAMP) production, therefore reducing the beta1-adrenoreceptor response to catecholamines and reducing L-type Ca2+ channel currents, again paralleling muscarinic pathways.30 Increased IKAdo results in a reduced APD and therefore a shorter refractory period.21 Because of a greater receptor reserve and therefore downstream amplifying signalling pathways, adenosine is 11 times more efficacious at inhibiting beta1-adrenoreceptor response than activating IKAdo.31,32

Regional variations in cardiac adenosine response are dependent on the density of adenosine receptors as well as site-specific variations in function, other receptor expression and ion channel distributions. Membrane hyperpolarisation and reduction in cAMP levels in the sinoatrial node result in negative chronotropy via reduced pacemaker currents (If), with effects being more pronounced in conditions of higher sympathetic drive.33,34 Additional negative chronotropic effects might be mediated by reductions in cytosolic Ca2+ release and subsequent decreases in repolarising K+ channels that regulate automaticity.35

In the AVN, which shows high A1 receptor density in the nodal region, the inhibitory effects of adenosine result in negative dromotropy and reduced gradient of the cardiac upstroke.20 In atrial myocardium, shortening of the APD and reduced cAMP result in reduced inotropy and refractory period.36 His-Purkinje automaticity is reduced by adenosine in the basal state but more markedly in the presence of catecholamines.37,38 The ventricular myocardium is relatively unaffected by adenosine at rest; however, ventricular APD and inotropy are reduced by adenosine in the presence of increased sympathetic tone.39

The effects of ATP are broadly similar to those of adenosine, reflecting the rapid metabolism of ATP to adenosine that likely exerts direct cardiac actions with high potency at a molecular level.21 However, ATP has the additional effects of increasing vagal tone via P2X receptor stimulation, which potentially explains the more potent in vivo bradycardic effects of ATP on a mole-for-mole basis.40,41

Role of Adenosine in Supraventricular Tachycardia

Presentation with SVT in the emergency department is common and accounts for significant repeat attendance. SVT usually results in unpleasant symptoms of palpitations and pre-syncope, but is rarely life-threatening in isolation and often spontaneously self-terminates. Guideline-based management of SVT suggests a trial of vagal manoeuvres in the first instance, because these may be effective in up to 43% of patients, particularly modified Valsalva techniques.1,42 Valsalva techniques may be contraindicated in recent MI or stroke, glaucoma, retinopathy, carotid artery stenosis, aortic stenosis or the third trimester of pregnancy.43 Adenosine is then recommended if vagal manoeuvres fail or are inappropriate, and is successful in approximately 90% of cases. Direct current cardioversion is indicated if the patient is haemodynamically compromised.

Atrioventricular Node-dependent Supraventricular Tachycardia

The first published reports of purinergic compounds employed to terminate tachycardias were in 1955 and used ATP.44 However, purinergic compounds did not enter widespread clinical use until the 1980s, when DiMarco et al. first demonstrated the clinical efficacy of adenosine and Greco et al. showed the efficacy of ATP in the termination of SVT.45–47 These case series showed adenosine to be efficacious in SVTs where the re-entrant circuit involved the AVN, particularly atrioventricular re-entrant tachycardia and atrioventricular node re-entrant tachycardia.

Adenosine and ATP are thought to have similar efficacy at terminating SVT.48 Side-effects were noted to be minor and transient, but doses required were variable. This was accounted for by rapid clearance, variable rates of injection through different cannula sizes and the patient’s degree of intrinsic sympathetic tone. In SVTs that were not AVN-dependent, adenosine was established to be useful in unmasking underlying rhythms when these were obscured by rapid ventricular capture. Adenosine can also be used off label to elucidate dual AVN physiology or concealed accessory pathways to facilitate ablation procedures.49,50

While adenosine is effective at terminating AVN-dependent SVT, other pharmacological agents are also useful.1 Calcium channel antagonists (CCAs), of which verapamil is the best studied, are often reluctantly prescribed by general physicians in the emergency department. The potentially mortal risks of verapamil in patients with ventricular arrhythmia misdiagnosed as SVT have earned it the unfortunate epithet of ‘verapakill’. However, when used appropriately in SVT, CCAs are as clinically effective as adenosine.51

The time to cardioversion with CCAs is slightly longer and the risk of hypotension is slightly greater, although the latter is rare and is mitigated by slower infusions.42 The rates of minor side-effects were higher with adenosine. CCAs may therefore be a good alternative to adenosine where patients are haemodynamically stable and in whom adenosine is contraindicated. The longer half-life of verapamil may also make it more cost effective as a single administration than repeated doses of adenosine, and it may be more suitable for longer-term administration. However, CCAs should be avoided in heart failure, concomitant beta-blocker use and in broad complex tachycardias that might represent ventricular tachycardia (VT).

Both adenosine and CCAs are superior to beta-blockers in SVT termination, and beta-blockers are associated with an increased risk of hypotension, which makes them a third-line therapy.1 The exception to this is in pregnancy, where adenosine (which does not cross the placenta) is used as first-line therapy and beta-blockers might be considered before CCAs because the latter pose an increased risk to the fetus.42

Attempts to reduce the burden of SVTs on emergency departments have included examining paramedic-led adenosine administration in the community when the patient has a narrow complex tachycardia without a history of structural or ischaemic heart disease.52 Successful adenosine cardioversion at the scene of presentation allows immediate discharge of certain patients with follow-up arranged by the primary care physician. In this study, 81% of adenosine-treated patients cardioverted to sinus rhythm and 77% of these could be directly discharged, accounting for more than half of the patients treated.

Paramedic-led care was associated with faster treatment times, higher patient satisfaction and a significant cost reduction of about one third. Follow-up rates were similar for paramedic and hospital treated patients. This is important because, while adenosine is effective in the termination of AVN-dependent SVT in the short term, ablation should be considered as the gold-standard, long-term treatment.1 Healthcare use analysis shows that patients seen by an electrophysiologist have a reduced need for emergency services for future episodes and that 78% of the patients referred to an electrophysiologist were subsequently ablated, with a 91% success rate.53 Adenosine sensitivity identified patients who were more likely to respond to ablation therapy.

SVTs are the most commonly encountered arrhythmias in children and may precipitate heart failure in infants.54 Vagal manoeuvres terminate 25% of paediatric cases, with adenosine success in 79% of cases.55 SVT refractory to adenosine is encountered in 15% and is more likely in younger infants; higher doses may be required in these circumstances.54 The reasons for this are not clear but contributors might include the smaller calibre of paediatric cannulae, relative AVN insensitivity or late presentation after which decompensation has already occurred. Verapamil is contraindicated in infants, making adenosine the preferred agent, although digoxin, propranolol, amiodarone and procainamide have been used.

Atrioventricular Node-independent Supraventricular Tachycardia

The circuit in atrial flutter is not AVN dependent so adenosine will not reliably terminate this rhythm. However, the dromotropic effect of adenosine results in ventricular slowing so it is frequently used in the emergency department to evaluate the underlying rhythm in narrow complex tachycardia (Figure 2B). While this is perceived as a low-risk manoeuvre, some case reports suggest haemodynamic instability can occasionally be induced by conversion to 1:1 AVN conduction, induction of AF or increased catecholaminergic drive with paradoxical worsening of tachycardia.56,57 It is therefore advisable that adenosine be avoided if the underlying rhythm is clear from the 12-lead ECG without need for unmasking manoeuvres.58 In the context of a broad complex tachycardia, where atrial flutter with aberrant conduction is suspected, adenosine is safer to use than a CCA.59

Several mechanistic studies suggest that atrial flutter is critically dependent on antecedent AF to produce a line of block between the superior and inferior vena cava, allowing re-entry around the cavotricuspid isthmus (CTI).60,61 This is supported by the results of the Impact of Different Ablation Approaches on Outcome In Coexistent Atrial Fibrillation and Flutter (APPROVAL) study, where ablation outcomes were improved by concomitant flutter and AF ablations, compared to flutter ablation alone. Animal models investigating this mechanism have shown that purine administration may reduce the refractory period of this line of block, preventing it from being sustained and thus converting flutter to AF.62 The implications of this are important for unmasking the underlying rhythm in a narrow, complex tachycardia because adenosine might convert an underlying flutter into AF, therefore misleading the interpretation of the culprit rhythm.

Adenosine has been advocated in ablation procedures for the assessment of dormant connection. Injury currents set up as a result of ablation result in membrane depolarisation, which in turn inactivates voltage-gated Na+ channels preventing initiation of excitation. Over time, these injury currents dissipate and the membrane potential may recover, allowing previously isolated regions to propagate. Adenosine transiently hyperpolarises injured regions, which may become electrically excitable following a recovery period, thus unmasking dormant connections.63

Some clinical studies demonstrate an increased detection of dormant connections of the pulmonary veins during AF ablation following adenosine testing, while others have not shown long-term improvements in outcome.64–66 This discrepancy might be due to differences in study protocol.63 Adenosine has also been advocated in CTI-dependent atrial flutter ablations to assess for dormant connections.67,68 A negative adenosine provocation test with bi-directional block after CTI ablation is strongly predictive that reconnection will not occur and may be used to reduce procedure duration by decreasing assessment time for reconnection.69

Role of Adenosine in Other Electrical Cardiac Pathology

Ventricular Arrhythmia

In contrast to the sinoatrial node, AVN and atrial structures, previous animal studies have suggested that the ventricular myocardium has negligible GIRK channels, and therefore the direct electrophysiological effects of adenosine in reducing refractory period are absent.39,70 More recent human studies, however, have demonstrated GIRK expression in the ventricle at approximately half the level of the atrium and this is involved in ventricular repolarisation, including in response to adenosine.71,72 Adenosine exerts indirect effects on ventricular myocytes via inhibition of cAMP and therefore attenuation of sympathetic actions.73 Paradoxically, adenosine may also increase sympathetic drive at the neuronal level via A2-mediated chemoreceptor pathways, though cellular mediated mechanisms are usually dominant.74

Junctional ectopic tachycardias arising from the His-Purkinje system or ventricular myocardium result from either abnormal automaticity or triggered activity, which are often catecholamine driven. Adenosine has been used to differentiate between abnormal automaticity, which is adenosine insensitive, and triggered activity, which is adenosine sensitive.75

There may be a role for adenosine in distinguishing VT whose origin is triggered activity from delayed afterdepolarisations (DADs). DADs are reported to arise when there is Ca2+ overload in the cardiomyocyte that activates the electrogenic Na+/Ca2+ exchanger. Adenosine has been shown to abolish DADs by decreasing Ca2+ influx, thereby reducing triggered activity that might be stimulated by catecholaminergic activity.76

Sick Sinus Syndrome

Some have suggested that sick sinus syndrome might be an adenosine-mediated disease, given its cardioinhibitory effects.77 However, the adenosine antagonist theophylline does not improve sinus node function, which suggests it is not a central mediator in this condition.78 Patients with sick sinus syndrome may have an exaggerated response to adenosine, particularly when challenged in the context of syncope or presyncope, possibly suggesting a role for adenosine as a non-invasive test.79 This may result from an increased expression of adenosine receptors, particularly in the elderly. Similar results have been found for ATP administration.80,81 The antiplatelet agent ticagrelor has been implicated in sinus node dysfunction and ventricular pauses, potentially via increased production of adenosine.82

Syncope

Neurally mediated syncope is thought to arise from paradoxical cardioinhibitory reflexes secondary to reductions in preload. Adenosine may be useful in the diagnosis of neurally mediated and unexplained syncope in combination with tilt table testing, particularly in the under 40s, by identifying patients susceptible to transient AV block.83–85

Pulmonary embolism results in syncope in approximately 10% of cases and may represent a significant proportion of syncope presentations to the emergency department.86,87 Purinergic signalling resulting from the release of ATP by activated platelets following pulmonary embolism has been suggested to result in transient bradycardia and syncope in these cases.88

Role of Adenosine in Other Pathology Related to Arrhythmia

Obesity and Diabetes

The prevalence of obesity has doubled since 1980, with current estimates suggesting that one in three adults is now obese, which has significant costs to healthcare services and the wider economy.89,90 Obesity is an independent risk factor for the development of AF with a 3–7% increased risk of AF per unit increase in BMI.91 Obesity also confers an increased risk of sudden cardiac death (SCD) from ventricular arrhythmia, particularly in middle-aged people and in patients with ischaemic cardiomyopathy.92–94

Suggested mechanisms proposed for increased arrhythmogenicity in obesity include increased pro-inflammatory cytokines, oxidative stress and fibrosis. Changes in electrical properties of the myocardium are also observed with shorter atrial and pulmonary vein refractory periods, impaired repolarisation in the ventricles and conduction abnormalities.95–97

Adenosine shows generally protective actions in the pathophysiology of obesity, the complex metabolic pathways of which have been extensively reviewed.98 Plasma adenosine concentrations are increased in obesity and are typically 1.5 times higher than in lean individuals; tissue levels can be higher still.99 Activation of A1 receptors facilitate insulin-dependent glucose uptake and reduces obesity-related systemic insulin resistance.100,101 Activation of A1 receptors increases plasma leptin and reduces adiponectin levels, both of which would have anti-obesogenic effects.102,103 Activation of the A2B receptors results in the secretion of anti-inflammatory cytokines such as IL–10 and IL–4.104 No studies directly link obesity, adenosine and arrhythmia; however, common pathophysiological pathways are involved. Adenosine may therefore be a significant area for future research and therapy in obesity-related arrhythmia.

Heart Failure

Worldwide, 26 million people have heart failure and estimates predict the prevalence of heart failure will have risen by 46% by 2030 in the US.105,106 The prognosis of heart failure remains worse than that for most cancers and a major contributor is a markedly increased risk of SCD, presumed secondary to ventricular arrhythmia.107 The proportion of deaths related to SCD ranges between 33% and 64%.108 Patients with heart failure also have increased risks of both SVTs and AF, which increase morbidity and mortality.13 Catheter ablation of AF in patients with heart failure may reduce mortality.109

Disruption of cardiac energetics is well established in the pathophysiology of heart failure, particularly a reduced utilisation of free fatty acids in preference to glucose as a metabolic substrate, mitochondrial dysfunction and reduced intracellular ATP levels.110–112 In later stages, insulin resistance might be responsible for reducing glucose supply to the failing heart, further switching metabolism to ketones.113

Purinergic receptors are upregulated in heart failure and plasma levels of adenosine also increase.114,115 Therapy with adenosine may have a cardioprotective role in heart failure via A1 and A3 receptors by reducing cardiac hypertrophy, improving glucose homeostasis, reducing acidosis, improving calcium handling, improving mitochondrial function, reducing sympathetic stimulation and increasing natriuretic peptide release.116–119 However, increased circulating adenosine levels may have deleterious effects on the kidneys via A1 receptor-mediated vasoconstriction of the afferent arterioles, resulting in a decrease in glomerular filtration rate as well as sodium retention via the renin-angiotensin-aldosterone system.120 Therefore, raised adenosine levels may worsen volume overload and precipitate cardiorenal syndrome, although this may be ameliorated to some extent by A2 receptor-mediated vasodilatation.

Ageing

Population ageing is one of the most significant epidemiological pressures facing healthcare systems. During the century between 1900 and 2000, there was a 3.1-fold increase in the proportion of the population above 65 in the US.121 In Europe, where the population is the oldest worldwide, it is estimated that 25% of people will be over the age of 65 by 2030 – an approximate doubling.122 Ageing brings problems of an increased risk of pathology (especially ischaemic heart disease and heart failure), greater comorbidity, polypharmacy, impaired renal function, frailty and cognitive decline, as well as social complexities.

The prevalence of AF increases markedly from age 65 and 10% of individuals over the age of 80 have clinically overt AF; the number with unrecognised AF is likely greater.123 It has been suggested that AF itself contributes to the ageing process through to increased cerebral infarcts, tissue hypoperfusion and systemic inflammation.124 AF has been associated with dementia even in the absence of overt stroke.125 SCD also increases with age, with the annual risk seven times greater in 80-year-olds than in 40-year-olds.126 The elderly may gain less benefit from ICD therapy than younger patients.127

Aged myocardium is less tolerant to ischaemia and may show a blunted response to preconditioning.128 It has been suggested that adenosine is a key determinant of enhanced ischaemia tolerance. Aged hearts have greater interstitial levels of adenosine, potentially due to decreased cellular uptake, but produce less adenosine in response to adrenergic stimulation than young hearts.129 Age-related decline in cardioprotective adenosine response might be secondary to reduced downstream signalling from the A1 receptor and, in animal models, ageing lowers the anti-adrenergic effects of adenosine.130,131 However, adenosine remains safe and effective for the use of SVT management in the elderly.132

Adverse Effects and Contraindications of Adenosine

The short half-life of adenosine is advantageous when considering potential adverse effects. The side-effects of adenosine are unpleasant, but usually transient and tolerable. Chest pain, dyspnoea, cutaneous flushing and a sense of impending doom are well known. The most significant adverse effects are bronchospasm and arrhythmogenesis.

Bronchospasm and Pulmonary Effects

Caution has traditionally been exercised with adenosine regarding its propensity to cause bronchospasm in people with asthma or chronic obstructive pulmonary disease (COPD); recently, this practice has been questioned. Original reports suggested that inhaled adenosine, but not other nucleosides, could cause bronchoconstriction in patients with asthma but not in those with normal airway physiology. This appeared to have a maximal effect at 5 minutes after administration with partial recovery after 30 minutes.133 The mechanism proposed was a disturbance in the balance of the autonomic nervous system, which might favour bronchoconstriction, although other studies around that time had demonstrated increased sympathetic outflow without bronchoconstriction.74 A large, multicentre study of adenosine administration in patients undergoing nuclear imaging assessment of coronary perfusion reported that the incidence of bronchospasm was rare, occurring in only seven cases in more than 9,000 patients.134

Other later studies have somewhat refuted these claims. IV adenosine was shown to stimulate minute ventilation and the sensation of dyspnoea in patients with normal airways physiology, which is thought to arise from the activation of vagal C-fibres (J-receptors) and accounts for the well-documented sensation of dyspnoea.135 A study of IV adenosine in patients with asthma showed a similar but augmented response. Importantly, dyspnoeic sensations were not associated with objective spirometry measurements of airways obstruction.136 Animal studies in the rat, where small C-fibres of the vagus nerve were inhibited using capsaicin treatment, showed this eliminated adenosine-induced dyspnoea.137 Furthermore, blockade of the adenosine A1 receptor but not the A2 receptor prevented the response.138

The implication of such studies is that adenosine-induced dyspnoea, a C-fibre mediated response, might have been misinterpreted as bronchospasm in earlier reports, and therefore adenosine is likely to be safer in obstructive airways disease than previously supposed.

Nevertheless, case reports suggestive of bronchospasm continue to be published, mostly in patients with asthma or COPD.139,140 In the latter case, bronchoconstriction was sufficiently severe to cause respiratory failure requiring intubation; however, this was in the context of long-term theophylline use, suggesting that bronchoconstriction might have been a response to rapid theophylline antagonism. Another case report suggests an episode of profound bronchospasm in a young patient with apparently normal airways physiology, although the patient had a BMI of 40, which raises the possibility of obesity-related hypoventilation syndrome, obstructive sleep apnoea and obesity-related asthma.141 Additionally, no cross-sectional imaging or pulmonary function tests were presented to exclude underlying airways disease.

Furthermore, adenosine has recently been associated in the pathophysiology of severe COPD and idiopathic pulmonary fibrosis. In these conditions, CD73 (an enzyme involved in extracellular adenosine production) and adenosine A2 receptors are upregulated, with a particular preponderance in pulmonary macrophages. Adenosine is produced in response to cell damage, and upregulation of production and receptors allows for purinergic remodelling, which ultimately causes fibrosis.142 Similar findings have been reported in cystic fibrosis.143

It is rare that adenosine causes bronchoconstriction in patients with normal airways physiology. However, there are accounts of plausible harm caused in people with asthma and chronic lung disease, and those dependent on methylxanthines. Asthma is prevalent in children, where the most common arrhythmia is SVT. Adenosine should therefore be used with caution in these cases.1

Pro-arrhythmic Effects of Adenosine

Studies in emergency departments suggest adenosine induces arrhythmia in approximately 13% of those treated for SVT.42 These are mostly transient and benign, such as pauses, ventricular ectopy and non-sustained VT; however, major arrhythmias are also encountered, albeit rarely.144 Significant bradyarrhythmia in the form of sinus arrest, heart block and asystole have been reported.145–148

Adenosine-induced bradyarrhythmia may be more common when it is given concomitantly with other rate control medications and in patients with orthotopic liver transplantation, sepsis or heart failure.147,149–151 Adenosine administration has been associated with anoxic seizure in the context of bradyarrhythmia.152

Summary of the Contributions of Adenosine to Arrhythmia

Open in new tab
Open ppt

Significant tachyarrhythmias have also been encountered in the form of torsades de pointes, sustained VT and VF.153–159 The risk of VF may be increased when adenosine is used in stable VT, pre-excitation or in patients with a prolonged QT interval.160–162 Several case series highlight the risk of inducing ventricular arrhythmia during fractional flow reserve measurements following intracoronary adenosine administration, suggesting that IV is a safer route or that lower doses are needed.163–166

Adenosine Following Cardiac Transplant

Concerns regarding adenosine in patients receiving a cardiac transplant have been raised because adenosine receptors are upregulated following parasympathetic denervation, potentially making adenosine more likely to cause asystole. This is of potential concern as up to 50% of cardiac transplant patients develop SVT, which reduces cardiac output and may result in invasive investigations for acute rejection. Alternatives such as CCAs may cause drug interactions with immunosuppressants and are contraindicated in infants. However, a recent case series of patients in sinus rhythm following cardiac transplant given adenosine showed no major adverse events, including asystole, or need for pacing, which calls these views into question.167

Transplant patients may require reduced doses, especially when the PR interval is prolonged. However, it should be noted that these studies were in young patients who did not have manifest SVT at the time of administration, so it remains to be shown if findings are translatable to the different neurohumoral circumstances present during SVT or in older populations.

Conclusion

Adenosine celebrates its ninth decade of recognition this year. It continues to be a crucial member of the armamentarium in the management of arrhythmia (Figure 3), particularly SVT.1 Advances in metabolomics and receptor biology are now elucidating the critical role of adenosine in numerous common conditions related to arrhythmogenesis. In most cases, endogenous adenosine appears to play an anti-arrhythmic role, particularly in the context of ischaemia.168 Purinergic signalling pathways are likely to be future targets in the management of arrhythmia, both directly by actions on cardiac electrophysiology and indirectly in the treatment of its associated risk factors.

Clinical Perspective

  • Adenosine is the first-line pharmacological therapy, following vagal manoeuvres where these are appropriate, in the treatment of acute atrioventricular node-dependent tachycardias, particularly atrioventricular re-entrant tachycardia and atrioventricular nodal re-entrant tachycardia, and has a termination rate of approximately 90%.
  • Although administration is frequently associated with transient unpleasant symptoms, in the majority of cases adenosine is safe to use because of its short half-life. However, patients must be monitored for rare major adverse events, including arrhythmia, bronchospasm and severe dyspnoea.
  • Calcium-channel antagonists are a good alternative to adenosine and have similar termination efficacy. They should be considered in patients with contraindications to adenosine or where a longer-acting pharmacological strategy is required.
References
  1. Brugada J, Katritsis D, Arbelo E, et al. 2019 ESC guidelines for the management of patients with supraventricular tachycardia. Eur Heart J 2019;00:1–65.
    Crossref | PubMed
  2. Lerman BB, Markowitz SM, Cheung JW, et al. Supraventricular tachycardia: mechanistic insights deduced from adenosine. Circ Arrhythm Electrophysiol 2018;11:e006953.
    Crossref | PubMed
  3. Mustafa SJ, Morrison RR, Teng B, et al. Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol 2009;161–88.
    Crossref | PubMed
  4. Drury AN, Szent-Györgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 1929;68:213–37.
    Crossref | PubMed
  5. Lohmann K. On the pyrophosphate fraction in muscle. Naturwissenschaften 1929;17:624–5 [in German].
    Crossref
  6. Lewis T, Drury A, Iliescu C. A demonstration of circus movement in clinical flutter of the auricles. Heart 1921;8:341–59.
  7. Lewis T, Drury A, Bulger H. Observations upon flutter and fibrillation. VII. The effect of vagal stimulation. Heart 1921;8:141–69.
  8. Lewis T, Drury AN, Iliescu CC, et al. The manner in which quinidine sulphate acts in auricular fibrillation. Br Med J 1921;2:514–5.
    Crossref | PubMed
  9. Grace AA, Matthews GDK. Quinidine rebooted: contemporary approaches to multichannel blockade. JACC Clin Electrophysiol 2019;5:383–6.
    Crossref | PubMed
  10. Honey RM, Ritchie WT, Thomson WAR. The action of adenosine upon the human heart. QJM 1930;os-23:485–9.
    Crossref
  11. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257–65.
    Crossref | PubMed
  12. Shen W-K, Kurachi Y. Mechanisms of adenosine-mediated actions on cellular and clinical cardiac electrophysiology. Mayo Clin Proc 1995;70:274–91.
    Crossref | PubMed
  13. Olsson LG, Swedberg K, Ducharme A, et al. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006;47:1997–2004.
    Crossref | PubMed
  14. Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 1963;204:317–2.
    Crossref | PubMed
  15. Rubio R, Wiedmeier VT, Berne RM. Relationship between coronary flow and adenosine production and release. J Mol Cell Cardiol 1974;6:561–6.
    Crossref | PubMed
  16. Frøbert O, Haink G, Simonsen U, et al. Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation. J Physiol 2006;570:375–84.
    Crossref | PubMed
  17. Shryock JC, Snowdy S, Baraldi PG, et al. A2A-adenosine receptor reserve for coronary vasodilation. Circulation 1998;98:711–8.
    Crossref | PubMed
  18. Schrader J, Baumann G, Gerlach E. Adenosine as inhibitor of myocardial effects of catecholamines. Pflugers Arch 1977;372:29–35.
    Crossref | PubMed
  19. Rockoff JB, Dobson JG. Inhibition by adenosine of catecholamine-induced increase in rat atrial contractility. Am J Physiol 1980;239:H365–70.
    Crossref | PubMed
  20. Clemo HF, Belardinelli L. Effect of adenosine on atrioventricular conduction. I: site and characterization of adenosine action in the guinea pig atrioventricular node. Circ Res 1986;59:427–36.
    Crossref | PubMed
  21. Ragazzi E, Wu SN, Shryock J, et al. Electrophysiological and receptor binding studies to assess activation of the cardiac adenosine receptor by adenine nucleotides. Circ Res 1991;68:1035–44.
    Crossref | PubMed
  22. Li N, Csepe TA, Hansen BJ, et al. Adenosine-induced atrial fibrillation: localized reentrant drivers in lateral right atria due to heterogeneous expression of adenosine A1 receptors and GIRK4 subunits in the human heart. Circulation 2016;134:486–98.
    Crossref | PubMed
  23. Ng GA, Martin W, Rankin AC. Imaging of adenosine bolus transit following intravenous administration: insights into antiarrhythmic efficacy. Heart 1999;82:163–9.
    Crossref | PubMed
  24. Cabalag MS, Taylor DM, Knott JC, et al. Recent caffeine ingestion reduces adenosine efficacy in the treatment of paroxysmal supraventricular tachycardia. Acad Emerg Med 2010;17:44–9.
    Crossref | PubMed
  25. Bunag RD, Douglas CR, Imai S, et al. Influence of a pyrimidopyrimidine derivative on deamination of adenosine by blood. Circ Res 1964;15:83–8.
    Crossref | PubMed
  26. Harker LA, Kadatz RA. Mechanism of action of dipyridamole. Thromb Res Suppl 1983;4:39–46.
    Crossref | PubMed
  27. Thorn JA, Jarvis SM. Adenosine transporters. Gen Pharmacol 1996;27:613–20.
    Crossref | PubMed
  28. Kurachi Y, Nakajima T, Sugimoto T. On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pflugers Arch 1986;407:264–74.
    Crossref | PubMed
  29. Ito H, Tung RT, Sugimoto T, et al. On the mechanism of G protein beta gamma subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. Comparison with the ATP-sensitive K+ channel. J Gen Physiol 1992;99:961–83.
    Crossref | PubMed
  30. Isenberg G, Belardinelli L. Ionic basis for the antagonism between adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res 1984;55:309–25.
    Crossref | PubMed
  31. Baker SP, Scammells PJ, Belardinelli L. Differential A(1)-adenosine receptor reserve for inhibition of cyclic AMP accumulation and G-protein activation in DDT(1) MF–2 cells. Br J Pharmacol 2000;130:1156–64.
    Crossref | PubMed
  32. Srinivas M, Shryock JC, Dennis DM, et al. Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Mol Pharmacol 1997;52:683–91.
    Crossref | PubMed
  33. Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989;32:73–97.
    Crossref | PubMed
  34. West GA, Belardinelli L. Correlation of sinus slowing and hyperpolarization caused by adenosine in sinus node. Pflugers Arch 1985;403:75–81.
    Crossref | PubMed
  35. Hata T, Noda T, Nishimura M, Watanabe Y. The role of Ca2+ release from sarcoplasmic reticulum in the regulation of sinoatrial node automaticity. Heart Vessels 1996;11:234–41.
    PubMed
  36. Kabell G, Buchanan LV, Gibson JK, et al. Effects of adenosine on atrial refractoriness and arrhythmias. Cardiovasc Res 1994;28:1385–9.
    Crossref | PubMed
  37. Rosen MR, Danilo P, Weiss RM. Actions of adenosine on normal and abnormal impulse initiation in canine ventricle. Am J Physiol 1983;244:H715–21.
    Crossref | PubMed
  38. Lerman BB, Wesley RC, DiMarco JP, et al. Antiadrenergic effects of adenosine on His-Purkinje automaticity. Evidence for accentuated antagonism. J Clin Invest 1988;82:2127–35.
    Crossref | PubMed
  39. Raberger G, Kraupp O, Stühlinger W, et al. The effects of an intracoronary infusion of adenosine on cardiac performance, blood supply and on myocardial metabolism in dogs. Pflugers Arch 1970;317:20–34.
    Crossref | PubMed
  40. Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol 1996;490:265–75.
    Crossref | PubMed
  41. Pelleg A, Katchanov G, Xu J. Autonomic neural control of cardiac function: modulation by adenosine and adenosine 5’-triphosphate. Am J Cardiol 1997;79:11–4.
    Crossref | PubMed
  42. Brubaker S, Long B, Koyfman A. Alternative treatment options for atrioventricular-nodal-reentry tachycardia: an emergency medicine review. J Emerg Med 2018;54:198–206.
    Crossref | PubMed
  43. Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial. Lancet 2015;386:1747–53.
    Crossref | PubMed
  44. Somló E. Adenosine triphosphate in paroxysmal tachycardia. Lancet 1955;265:1125.
    Crossref
  45. DiMarco JP, Sellers TD, Berne RM, et al. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983;68:1254–63.
    Crossref | PubMed
  46. DiMarco JP, Sellers TD, Lerman BB, et al. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985;6:417–25.
    Crossref | PubMed
  47. Greco R, Musto B, Arienzo V, et al. Treatment of paroxysmal supraventricular tachycardia in infancy with digitalis, adenosine-5’-triphosphate, and verapamil: a comparative study. Circulation 1982;66:504–8.
    Crossref | PubMed
  48. Belhassen B, Viskin S. What is the drug of choice for the acute termination of paroxysmal supraventricular tachycardia: verapamil, adenosine triphosphate, or adenosine? Pacing Clin Electrophysiol 1993;16:1735–41.
    Crossref | PubMed
  49. Belhassen B. Close look at ECG tracing after termination of supraventricular tachycardia with adenosine. Isr Med Assoc J 2006;8:361–2.
    PubMed
  50. Viskin S, Fish R, Glick A, et al. The adenosine triphosphate test: a bedside diagnostic tool for identifying the mechanism of supraventricular tachycardia in patients with palpitations. J Am Coll Cardiol 2001;38:173–7.
    Crossref | PubMed
  51. Alabed S, Providência R, Chico TJA. Cochrane corner: adenosine versus intravenous calcium channel antagonists for supraventricular tachycardia. Heart 2018;104:1993–4.
    Crossref | PubMed
  52. Honarbakhsh S, Baker V, Kirkby C, et al. Safety and efficacy of paramedic treatment of regular supraventricular tachycardia: a randomised controlled trial. Heart 2017;103:1413–8.
    Crossref | PubMed
  53. Dewland TA, Oesterle A, Stein J, et al. Health care utilization among adenosine-sensitive supraventricular tachycardia patients presenting to the emergency department. J Interv Card Electrophysiol 2017;49:103–9.
    Crossref | PubMed
  54. Dadi G, Fink D, Weiser G. High-dose adenosine for refractory supraventricular tachycardia: a case report and literature review. Cardiol Young 2017;27:981–4.
    Crossref | PubMed
  55. Lewis J, Arora G, Tudorascu DL, et al. Acute management of refractory and unstable pediatric supraventricular tachycardia. J Pediatr 2017;181:177–82.e2.
    Crossref | PubMed
  56. Robles Velasco P, Monedero Sánchez I, Rubio Caballero A, et al. Adenosine administration in supraventricular tachycardia. Neth Heart J 2018;26:221–2.
    Crossref | PubMed
  57. Kunnumpuram GK, Patel A. Adenosine-induced worsening of supraventricular tachycardia. BMJ Case Rep 2012;2012.
    Crossref | PubMed
  58. Gottlieb M, Gore K, Gore SR. Is adenosine or an intravenous calcium channel blocker more effective for treating supraventricular tachycardia? Ann Emerg Med 2018;72:553–5.
    Crossref | PubMed
  59. Garratt CJ, Griffith MJ, O’Nunain S, et al. Effects of intravenous adenosine on antegrade refractoriness of accessory atrioventricular connections. Circulation 1991;84:1962–8.
    Crossref | PubMed
  60. Waldo AL. Atrial fibrillation and atrial flutter: two sides of the same coin! Int J Cardiol 2017;240:251–2.
    Crossref | PubMed
  61. Waldo AL. More musing about the inter-relationships of atrial fibrillation and atrial flutter and their clinical implications. Circ Arrhythm Electrophysiol 2013;6:453–4.
    Crossref
  62. Ortiz J, Niwano S, Abe H, et al. Mapping the conversion of atrial flutter to atrial fibrillation and atrial fibrillation to atrial flutter. Insights into mechanisms. Circ Res 1994;74:882–94.
    Crossref | PubMed
  63. Gourraud J-B, Andrade JG, Macle L, et al. Pharmacological tests in atrial fibrillation ablation. Arrhythmia Electrophysiol Rev 2016;5:170–6.
    Crossref | PubMed
  64. Macle L, Khairy P, Weerasooriya R, et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015;386:672–9.
    Crossref | PubMed
  65. Kobori A, Shizuta S, Inoue K, et al. Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial. Eur Heart J 2015;36:3276–87.
    Crossref | PubMed
  66. Ghanbari H, Jani R, Hussain-Amin A, et al. Role of adenosine after antral pulmonary vein isolation of paroxysmal atrial fibrillation: a randomized controlled trial. Heart Rhythm 2016;13:407–15.
    Crossref | PubMed
  67. Morales GX, Macle L, Khairy P, et al. Adenosine testing in atrial flutter ablation: unmasking of dormant conduction across the cavotricuspid isthmus and risk of recurrence. J Cardiovasc Electrophysiol 2013;24:995–1001.
    Crossref | PubMed
  68. Lehrmann H, Weber R, Park C, et al. ‘Dormant transisthmus conduction’ revealed by adenosine after cavotricuspid isthmus ablation. Heart Rhythm 2012;9:1942–6.
    Crossref | PubMed
  69. Morales G, Darrat YH, Lellouche N, et al. Use of adenosine to shorten the post ablation waiting period for cavotricuspid isthmus-dependent atrial flutter. J Cardiovasc Electrophysiol 2017;28:876–81.
    Crossref | PubMed
  70. Dobrzynski H, Marples DD, Musa H, et al. Distribution of the muscarinic K+ channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart. J Histochem Cytochem 2001;49:1221–34.
    Crossref | PubMed
  71. Yang Y, Yang Y, Liang B, et al. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet 2010;86:872–80.
    Crossref | PubMed
  72. Liang B, Nissen JD, Laursen M, et al. G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization. Cardiovasc Res 2014;101:175–84.
    Crossref | PubMed
  73. Dobson JG. Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3’,5’-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Circ Res 1978;43:785–92.
    Crossref | PubMed
  74. Biaggioni I, Olafsson B, Robertson RM, et al. Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation. Circ Res 1987;61:779–86.
    Crossref | PubMed
  75. Liu CF, Ip JE, Lin AC, et al. Mechanistic heterogeneity of junctional ectopic tachycardia in adults. Pacing Clin Electrophysiol PACE 2013;36:e7–10.
    Crossref | PubMed
  76. Song Y, Thedford S, Lerman BB, et al. Adenosine-sensitive afterdepolarizations and triggered activity in guinea pig ventricular myocytes. Circ Res 1992;70:743–53.
    Crossref | PubMed
  77. Watt AH. Sick sinus syndrome: an adenosine-mediated disease. Lancet 1985;1:786–88.
    Crossref | PubMed
  78. Lai WT, Lai HM, Lin CT, et al. Is sick sinus syndrome an adenosine-mediated disease? Effects of intravenous aminophylline on sick sinus node function after pharmacologic autonomic blockade. Chest 1991;99:887–91.
    Crossref | PubMed
  79. Fragakis N, Antoniadis AP, Korantzopoulos P, et al. Sinus nodal response to adenosine relates to the severity of sinus node dysfunction. Europace 2012;14:859–64.
    Crossref | PubMed
  80. Benedini G, Cuccia C, Bolognesi R, et al. Value of purinic compounds in assessing sinus node dysfunction in man: a new diagnostic method. Eur Heart J 1984;5:394–403.
    Crossref | PubMed
  81. Saito D, Yamanari H, Matsubara K, et al. Intravenous injection of adenosine triphosphate for assessing sinus node dysfunction in patients with sick sinus syndrome. Arzneimittelforschung 1993;43:1313–6.
    PubMed
  82. Nicol M, Deblaise J, Choussat R, et al. Side effects of ticagrelor: sinus node dysfunction with ventricular pause. Int J Cardiol 2015;191:56–7.
    Crossref | PubMed
  83. Mittal S, Stein KM, Markowitz SM, et al. Induction of neurally mediated syncope with adenosine. Circulation 1999;99:1318–24.
    Crossref | PubMed
  84. Mittal S, Stein KM, Markowitz SM, et al. Single-stage adenosine tilt testing in patients with unexplained syncope. J Cardiovasc Electrophysiol 2004;15:637–40.
    Crossref | PubMed
  85. Flammang D, Benditt DG, Church TR, et al. Adenosine 5’-triphosphate test in the management of patients with syncope. Am J Ther 2016;23:e1347–52.
    Crossref | PubMed
  86. Calvo-Romero JM, Pérez-Miranda M, Bureo-Dacal P. Syncope in acute pulmonary embolism. Eur J Emerg Med 2004;11:208–9.
    Crossref | PubMed
  87. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016;375:1524–31.
    Crossref | PubMed
  88. Pelleg A, Schulman ES, Barnes PJ. Adenosine 5’-triphosphate’s role in bradycardia and syncope associated with pulmonary embolism. Respir Res 2018;19:142.
    Crossref | PubMed
  89. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13–27.
    Crossref | PubMed
  90. von Lengerke T, Krauth C. Economic costs of adult obesity: a review of recent European studies with a focus on subgroup-specific costs. Maturitas 2011;69:220–9.
    Crossref | PubMed
  91. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004;292:2471–7.
    Crossref | PubMed
  92. Jouven X, Desnos M, Guerot C, Ducimetière P. Predicting sudden death in the population: the Paris Prospective Study I. Circulation 1999;99:1978–83.
    Crossref | PubMed
  93. Noheria A, Teodorescu C, Uy-Evanado A, et al. Distinctive profile of sudden cardiac arrest in middle-aged vs older adults: a community-based study. Int J Cardiol 2013;168:3495–9.
    Crossref | PubMed
  94. Pietrasik G, Goldenberg I, McNitt S, et al. Obesity as a risk factor for sustained ventricular tachyarrhythmias in MADIT II patients. J Cardiovasc Electrophysiol 2007;18:181–4.
    Crossref | PubMed
  95. Munger TM, Dong Y-X, Masaki M, et al. Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation. J Am Coll Cardiol 2012;60:851–60.
    Crossref | PubMed
  96. El-Gamal A, Gallagher D, Nawras A, et al. Effects of obesity on QT, RR, and QTc intervals. Am J Cardiol 1995;75:956–9.
    Crossref | PubMed
  97. Lalani AP, Kanna B, John J, et al. Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res 2000;8:20–8.
    Crossref | PubMed
  98. Pardo F, Villalobos-Labra R, Chiarello DI, et al. Molecular implications of adenosine in obesity. Mol Aspects Med 2017;55:90–101.
    Crossref | PubMed
  99. Kaartinen JM, Hreniuk SP, Martin LF, et al. Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity. Biochem J 1991;279:17–22.
    Crossref | PubMed
  100. Thong FSL, Lally JSV, Dyck DJ, et al. Activation of the A1 adenosine receptor increases insulin-stimulated glucose transport in isolated rat soleus muscle. Appl Physiol Nutr Metab 2007;32:701–10.
    Crossref | PubMed
  101. Dhalla AK, Wong MY, Voshol PJ, et al. A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am J Physiol Endocrinol Metab 2007;292:E1358–63.
    Crossref | PubMed
  102. Rice AM, Fain JN, Rivkees SA. A1 adenosine receptor activation increases adipocyte leptin secretion. Endocrinology 2000;141:1442–5.
    Crossref | PubMed
  103. Szkudelski T, Nogowski L, Szkudelska K. Short-term regulation of adiponectin secretion in rat adipocytes. Physiol Res 2011;60:521–30.
    PubMed
  104. Csóka B, Selmeczy Z, Koscsó B, et al. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J 2012;26:376–86.
    Crossref | PubMed
  105. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Fail 2014;1:4–25.
    Crossref | PubMed
  106. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics – 2016 update: a report from the American Heart Association. Circulation 2016;133:e38–360.
    Crossref | PubMed
  107. Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail 2017;19:1095–104.
    Crossref | PubMed
  108. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.
    Crossref | PubMed
  109. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–7.
    Crossref | PubMed
  110. Allard MF, Schonekess BO, Henning SL, et al. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol 1994;267:H742–50.
    Crossref | PubMed
  111. Bugger H, Schwarzer M, Chen D, et al. Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res 2010;85:376–84.
    Crossref | PubMed
  112. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med 2007;356:1140–51.
    Crossref | PubMed
  113. Bedi KC, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 2016;133:706–16.
    Crossref | PubMed
  114. Funakoshi H, Chan TO, Good JC, et al. Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Circulation 2006;114:2240–50.
    Crossref | PubMed
  115. Funaya H, Kitakaze M, Node K, et al. Plasma adenosine levels increase in patients with chronic heart failure. Circulation 1997;95:1363–5.
    Crossref | PubMed
  116. Chuo CH, Devine SM, Scammells PJ, et al. VCP746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model. Clin Exp Pharmacol Physiol 2016;43:976–82.
    Crossref | PubMed
  117. Finegan B A, Lopaschuk G D, Coulson C S, et al. Adenosine alters glucose use during ischemia and reperfusion in isolated rat hearts. Circulation 1993;87:900–8.
    Crossref | PubMed
  118. Schütte F, Burgdorf C, Richardt G, et al. Adenosine A1 receptor-mediated inhibition of myocardial norepinephrine release involves neither phospholipase C nor protein kinase C but does involve adenylyl cyclase. Can J Physiol Pharmacol 2006;84:573–7.
    Crossref | PubMed
  119. Yuan K, Cao C, Han JH, et al. Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype. Hypertension 2005;46:1381–7.
    Crossref | PubMed
  120. Vallon V, Miracle C, Thomson S. Adenosine and kidney function: potential implications in patients with heart failure. Eur J Heart Fail 2008;10:176–87.
    Crossref | PubMed
  121. Ferrucci L, Giallauria F, Guralnik JM. Epidemiology of aging. Radiol Clin North Am 2008;46:643–52.
    Crossref | PubMed
  122. The Census Bureau on prospects for US population growth in the twenty-first century. Population and Development Review 2000;26:197–200.
    Crossref
  123. Boriani G, Diemberger I, Martignani C, et al. The epidemiological burden of atrial fibrillation: a challenge for clinicians and health care systems. Eur Heart J 2006;27:893–4.
    Crossref | PubMed
  124. Boriani G. Atrial fibrillation and aging: risky mutual relationships. Chest 2016;149:301–2.
    Crossref | PubMed
  125. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology 2013;81:119–25.
    Crossref | PubMed
  126. Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large US community. J Am Coll Cardiol 2004;44:1268–75.
    Crossref | PubMed
  127. Santangeli P, Di Biase L, Dello Russo A, et al. Meta-analysis: age and effectiveness of prophylactic implantable cardioverter-defibrillators. Ann Intern Med 2010;153:592–9.
    Crossref | PubMed
  128. Mariani J, Ou R, Bailey M, et al. Tolerance to ischemia and hypoxia is reduced in aged human myocardium. J Thorac Cardiovasc Surg 2000;120:660–7.
    Crossref | PubMed
  129. Lorbar M, Fenton RA, Duffy AJ, et al. Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats. J Mol Cell Cardiol 1999;31:401–12.
    Crossref | PubMed
  130. Gao E, Snyder DL, Johnson MD, et al. The effect of age on adenosine A1 receptor function in the rat heart. J Mol Cell Cardiol 1997;29:593–602.
    Crossref | PubMed
  131. Xu J, Gao F, Ma XL, et al. Effect of aging on the negative chronotropic and anti-beta-adrenergic actions of adenosine in the rat heart. J Cardiovasc Pharmacol 1999;34:904–12.
    Crossref | PubMed
  132. Camaiti A, Del Rosso A, Morettini A, et al. Efficacy and safety of adenosine in diagnosis and treatment of regular tachycardia in the elderly. Coron Artery Dis 1998;9:591–6;
    Crossref | PubMed
  133. Cushley MJ, Tattersfield AE, Holgate ST. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983;15:161–5.
    Crossref | PubMed
  134. Cerqueira MD, Verani MS, Schwaiger M, et al. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry. J Am Coll Cardiol 1994;23:384–9.
    Crossref | PubMed
  135. Burki NK, Dale WJ, Lee L-Y. Intravenous adenosine and dyspnea in humans. J Appl Physiol (1985) 2005;98:180–5.
    Crossref | PubMed
  136. Burki NK, Alam M, Lee L-Y. The pulmonary effects of intravenous adenosine in asthmatic subjects. Respir Res 2006;7:139.
    Crossref | PubMed
  137. Kwong K, Hong JL, Morton RF, et al. Role of pulmonary C fibers in adenosine-induced respiratory inhibition in anesthetized rats. J Appl Physiol (1985) 1998;84:417–24.
    Crossref | PubMed
  138. Hong JL, Ho CY, Kwong K, et al. Activation of pulmonary C fibres by adenosine in anaesthetized rats: role of adenosine A1 receptors. J Physiol 1998;508:109–18.
    Crossref | PubMed
  139. DeGroff CG, Silka MJ. Bronchospasm after intravenous administration of adenosine in a patient with asthma. J Pediatr 1994;125:822–23.
    Crossref | PubMed
  140. Burkhart KK. Respiratory failure following adenosine administration. Am J Emerg Med 1993;11:249–50.
    Crossref | PubMed
  141. Coli S, Mantovani F, Ferro J, et al. Adenosine-induced severe bronchospasm in a patient without pulmonary disease. Am J Emerg Med 2012;30:2082.e3–5.
    Crossref | PubMed
  142. Zhou Y, Murthy JN, Zeng D, et al. Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PloS One 2010;5:e9224.
    Crossref | PubMed
  143. Picher M, Burch LH, Boucher RC. Metabolism of P2 receptor agonists in human airways: implications for mucociliary clearance and cystic fibrosis. J Biol Chem 2004;279:20234–41.
    Crossref | PubMed
  144. Pelleg A, Pennock RS, Kutalek SP. Proarrhythmic effects of adenosine: one decade of clinical data. Am J Ther 2002;9:141–7.
    Crossref | PubMed
  145. Reed R, Falk JL, O’Brien J. Untoward reaction to adenosine therapy for supraventricular tachycardia. Am J Emerg Med 1991;9:566–70.
    Crossref | PubMed
  146. Tomcsányi J, Tenczer J, Horváth L. Unusual effect of adenosine. Int J Cardiol 1995;49:89–91.
    Crossref | PubMed
  147. Brodsky MA, Hwang C, Hunter D, et al. Life-threatening alterations in heart rate after the use of adenosine in atrial flutter. Am Heart J 1995;130:564–71.
    Crossref | PubMed
  148. McCollam PL, Uber WE, Van Bakel AB. Adenosine-related ventricular asystole. Ann Intern Med 1993;118:315–6.
    Crossref | PubMed
  149. Giedd KN, Bokhari S, Daniele TP, et al. Sinus arrest during adenosine stress testing in liver transplant recipients with graft failure: three case reports and a review of the literature. J Nucl Cardiol 2005;12:696–702.
    Crossref | PubMed
  150. Dierkes S, Hennersdorf MG, Perings C, et al. Enlarged effects of adenosine in a septic patient with multiple myeloma and atrial flutter. Acta Cardiol 2003;58:363-6.
    Crossref | PubMed
  151. Belloni FL, Wang J, Hintze TH. Adenosine causes bradycardia in pacing-induced cardiac failure. Circulation 1992;85:1118–24.
    Crossref | PubMed
  152. Webster DP, Daar AA. Prolonged bradyasystole and seizures following intravenous adenosine for supraventricular tachycardia. Am J Emerg Med 1993;11:192–4.
    Crossref | PubMed
  153. Harrington GR, Froelich EG. Adenosine-induced torsades de pointes. Chest 1993;103:1299–301.
    Crossref | PubMed
  154. Wesley RC, Turnquest P. Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J 1992;123:794–6.
    Crossref | PubMed
  155. Teodorovich N, Margolin E, Kogan Y, et al. Torsades de pointes after adenosine administration. J Electrocardiol 2016;49:171–3.
    Crossref | PubMed
  156. Frank R, Marty H. Polymorphic ventricular tachycardia after intravenous adenosine. Schweiz Med Wochenschr 2000;130:1576 [in German].
    PubMed
  157. Kaplan IV, Kaplan AV, Fisher JD. Adenosine induced atrial fibrillation precipitating polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 2000;23:140–1.
    Crossref | PubMed
  158. Huemer M, Boldt L-H, Rolf S, et al. Sustained monomorphic ventricular tachycardia after adenosine infusion. Int J Cardiol 2009;131:e97–100.
    Crossref | PubMed
  159. Pella J, Stancák B, Komanová E, et al. Ventricular fibrillation after administration of adenosine. Vnitr Lek 1995;41:832–5 [in Slovak].
    PubMed
  160. Parham WA, Mehdirad AA, Biermann KM, et al. Case report: adenosine induced ventricular fibrillation in a patient with stable ventricular tachycardia. J Interv Card Electrophysiol 2001;5:71–4.
    Crossref | PubMed
  161. Gupta AK, Shah CP, Maheshwari A, et al. Adenosine induced ventricular fibrillation in Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 2002;25:477–80.
    Crossref | PubMed
  162. Celiker A, Tokel K, Cil E, et al. Adenosine induced torsades de pointes in a child with congenital long QT syndrome. Pacing Clin Electrophysiol 1994;17:1814–7.
    Crossref | PubMed
  163. Piccolo R, Niglio T, Di Gioia G, et al. Adenosine-induced torsade de pointes complicating a fractional flow reserve measurement in a right coronary artery intermediate stenosis. Cardiovasc Revasc Med 2013;14:118–20.
    Crossref | PubMed
  164. Shah AH, Chan W, Seidelin PH. Ventricular fibrillation precipitated by intracoronary adenosine during fractional flow reserve assessment – a cautionary tale. Heart Lung Circ 2015;24:e173–5.
    Crossref | PubMed
  165. Khan ZA, Akbar G, Saeed W, et al. Ventricular fibrillation with intracoronary adenosine during fractional flow reserve assessment. Cardiovasc Revasc Med 2016;17:487–9.
    Crossref | PubMed
  166. Patel HR, Shah P, Bajaj S, et al. Intracoronary adenosine-induced ventricular arrhythmias during fractional flow reserve (FFR) measurement: case series and literature review. Cardiovasc Interv Ther 2017;32:374–80.
    Crossref | PubMed
  167. Flyer JN, Zuckerman WA, Richmond ME, et al. Prospective study of adenosine on atrioventricular nodal conduction in pediatric and young adult patients after heart transplantation. Circulation 2017;135:2485–93.
    Crossref | PubMed
  168. Conti JB, Belardinelli L, Utterback DB, et al. Endogenous adenosine is an antiarrhythmic agent. Circulation 1995;91:1761–7.
    Crossref | PubMed
  169. Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med 1991;325:1621–9.
    Crossref | PubMed
  170. Watt AH, Bernard MS, Webster J, et al. Intravenous adenosine in the treatment of supraventricular tachycardia: a dose-ranging study and interaction with dipyridamole. Br J Clin Pharmacol 1986;21:227–30.
    Crossref | PubMed
  171. Znojkiewicz P, Spector PS. Dysrhythmias and tachyarrhythmias. In: Parsons PE, Wiener-Kronish JP, eds. Critical Care Secrets. 5th ed. Philadelphia, PA: Mosby, 2013:197–203.
    Crossref
  172. Kanei Y, Hanon S, Van-Tosh A, et al. Adenosine-induced atrial fibrillation during pharmacologic stress testing: Report of eight cases and review of the literature. Int J Cardiol 2008;129:e15–7.
    Crossref | PubMed
  173. Knight BP, Zivin A, Souza J, et al. Use of adenosine in patients hospitalized in a university medical center. Am J Med 1998;105:275–80.
    Crossref | PubMed