Adenosine Articles 1 - Cardiac

© 2011

Electrophysiological basis for the use of adenosine in the diagnosis and treatment of cardiac arrhythmias

            (Belardinelli and Lerman 1990) Download

Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes

            (Belardinelli, Shryock et al. 1995) Download

The purpose of this review is to examine the role of the extracellular A1-adenosine (Ado) receptor in modulating membrane potential and currents in cardiac cells. The cellular electrophysiological effects of adenosine are both cell type- and species-dependent. In supraventricular tissues (SA, AV node, and atrium) of all species studied, the "direct" cAMP-independent activation of the inwardly rectifying K+ current IKAdo seems to be the most important action of adenosine. This current is activated by both adenosine and acetylcholine and flows through K+ channels with unitary slope conductance of about 45 pS and an open time constant of 1.4 ms. The density of K(+)-ACh,Ado channels is much less in ventricular than in atrial myocytes, and thus adenosine has little or no effect on the ventricular action potential. In atrial myocytes adenosine has a small inhibitory effect on basal L-type calcium current (ICa,L), but no effect on T-type calcium current (ICa,T). In ventricular myocytes, adenosine does not inhibit ICa,L (except ferret), ICa,T, or the sodium inward current INa. Adenosine has recently been shown to activate IKATP in ventricular membrane patches, but the relevance of this finding remains to be defined. Irrespective of cell type and species, adenosine inhibits membrane currents that are stimulated by beta-adrenergic agonists and other agents known to stimulate the activity of the enzyme adenylyl cyclase. This indirect cAMP-dependent mechanism of action has been shown to be responsible for the inhibition by adenosine of isoproterenol-stimulated ICa,L, delayed rectifier K+ current (IK), chloride current (ICl), the transient inward current ITi, and the pacemaker current IF. The importance of the actions of adenosine on membrane currents in modulation of atrial, ventricular, sinoatrial, and atrioventricular nodal function are discussed. Likewise, the antiarrhythmic and proarrhythmic actions of adenosine are discussed and the clinical implications of these actions are noted.


Hypersensitivity of platelets to adenosine diphosphate in patients with stable cardiovascular disease predicts major adverse events despite antiplatelet therapy

            (Christie, Kottke-Marchant et al. 2008) Download

Enhanced platelet activity correlates with early markers of myocardial damage in patients with cardiovascular disease. However, the extent to which enhanced platelet function signals subsequent adverse clinical outcomes in patients with cardiovascular disease is unknown. Blood from patients with stable cardiovascular disease receiving aspirin (325 mg/day) as the only antiplatelet therapy was tested for closure time (CT) with the Dade PFA-100 Platelet Function Analyzer system collagen/adenosine diphosphate (ADP) [CADP] cartridge and platelet aggregometry using 10 microM ADP. This study intentionally focused on those patients defined as aspirin sensitive by previously established criteria of arachidonic acid- and ADP-induced platelet aggregometry, and separately by collagen/epinephrine (CEPI) CT using the PFA-100. Follow up averaged 22 months for the adverse clinical events of death, myocardial infarction or cerebrovascular accident. For aspirin sensitivity determined by aggregometry, patients with CADP CT < 90 seconds (125/296 = 42.2%) had a composite endpoint rate of 19.2% (24/125), while those with CADP CT 90 seconds (171/296 = 57.8%) had an endpoint rate of 5.3% (9/171). Patients with CADP CT <90 seconds had a relative risk (RR) of 3.65 (95% CI.: 1.76-7.57) for recurrent events and 6.56 (95% CI.: 1.93-22.35) for death compared to patients with CADP CT 90s. Nearly identical results were obtained when patients were categorized as aspirin sensitive by CEPI CT. Platelet aggregometry with 10 microM ADP yielded no significant RR for the selected outcomes. Platelet function testing using the PFA-100 system appears to identify a subgroup of stable cardiovascular disease patients with increased risk of major adverse events that is associated with hypersensitivity to ADP, regardless of apparently effective aspirin therapy.

Effect of high-dose intracoronary adenosine administration during primary percutaneous coronary intervention in acute myocardial infarction: a randomized controlled trial

            (Fokkema, Vlaar et al. 2009) Download

BACKGROUND: Coronary microvascular dysfunction is frequently seen in patients with ST-elevation myocardial infarction after primary percutaneous coronary intervention. Previous studies have suggested that the administration of intravenous adenosine resulted in an improvement of myocardial perfusion and a reduction in infarct size. Intracoronary adenosine (bolus of 30 to 60 microg) is a guideline-recommended therapy to improve myocardial reperfusion. The effect of intracoronary adenosine during primary percutaneous coronary intervention has not been investigated in a large randomized trial. METHODS AND RESULTS: Patients presenting with acute ST-elevation myocardial infarction were randomized to 2 bolus injections of intracoronary adenosine (2 x 120 microg in 20 mL NaCl) or placebo (2 x 20 mL NaCl). The first bolus injection was given after thrombus aspiration and the second after stenting of the infarct-related artery. The primary end point was the incidence of residual ST-segment deviation <0.2 mV, 30 to 60 minutes after percutaneous coronary intervention. Secondary end points were ST-segment elevation resolution, myocardial blush grade, Thrombolysis in Myocardial Infarction flow on the angiogram after percutaneous coronary intervention, enzymatic infarct size, and clinical outcome at 30 days. A total of 448 patients were randomized to intracoronary adenosine (N=226) or placebo (N=222). The incidence of residual ST-segment deviation <0.2 mV did not differ between patients randomized to adenosine or placebo (46.2% versus 52.2%, P=NS). In addition, there were no significant differences in secondary outcome measures. CONCLUSIONS: In this randomized placebo controlled trial enrolling 448 patients with ST-elevation myocardial infarction, administration of intracoronary adenosine after thrombus aspiration and after stenting of the infarct-related artery did not result in improved myocardial perfusion.

Adenosine and cardiac arrhythmias

            (Garratt, Malcolm et al. 1992) Download

Stroke and aspirin non-responder patients: relation with hypertension and platelet response to adenosine diphosphate

            (Godeneche, Sorel et al. 2009) Download

Despite its widespread use, there are many concerns about the efficacy of aspirin in the secondary prevention of cardiovascular events after stroke, leading to the concept of aspirin non-response (ANR). Although the mechanisms of ANR remain uncertain, it is expected to be due to a combination of clinical, biological and genetic characteristics affecting platelet function. In this study, we investigated whether clinical and/or biological factors such as hypertension and platelet response to ADP could contribute to the ANR. As a secondary objective, we determine whether ANR and collagen/ADP closure time (CADP-CT) could be related to platelet glycoprotein single nucleotide polymorphisms (SNPs). One hundred patients on aspirin (160 mg/day) were enrolled. ANR was measured with a platelet function analyzer (PFA-100); genotyping of four SNPs (GP IIIa, GP Ia, P2Y12 and GP VI) was performed using a tetra-primer amplification refractory mutation system. Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of ANR was 15% (n = 15). In the ANR group, (i) CADP-CT was significantly shorter and (ii) hypertension was an independent clinical predictive factor of ANR (OR = 4.25; 95%CI: 1.06-17.11). No clear relation was found between CADT-CT and platelet gene polymorphism as well as ANR status and SNPs. In conclusion our study confirms the independent relationship between hypertension, platelet hypersensitivity to ADP and aspirin (160 mg/day) non-response. The differential sensitivity to aspirin may have potential clinical implications, where adaptation of antiplatelet therapy is necessary according to a patient's clinical and genetic characteristics.

Adenosine versus intravenous calcium channel antagonists for the treatment of supraventricular tachycardia in adults

            (Holdgate and Foo 2006) Download

BACKGROUND: Patients with paroxysmal supraventricular tachycardia frequently present to the Emergency Department. Where vagal manoeuvres fail, the two most commonly used drugs are adenosine and calcium channel antagonists. Both are known to be effective but both have a significant side-effect profile. OBJECTIVES: To examine the relative effects of adenosine and calcium channel antagonists and, if possible, to determine which is most appropriate for the management of supraventricular tachycardia. SEARCH STRATEGY: Studies were identified from The Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3 2006, MEDLINE (1966 to June 2006), Pre-MEDLINE and EMBASE (1980 to June 2006). Bibliographies of identified studies were also examined. No language restrictions were applied. SELECTION CRITERIA: Inclusion criteria: randomised trials comparing adenosine and a calcium channel antagonist in patients of any age with supraventricular tachycardia, where one of the defined outcomes was reported. Outcomes of interest were: reversion rate, mortality, time to reversion, rate of relapse, minor adverse events, major adverse events, length of hospital stay and patient satisfaction. Major adverse events were defined as cardiac arrest, prolonged hypotension, symptomatic bradycardia requiring treatment and acute cardiac failure. Minor adverse events were any other reported event. DATA COLLECTION AND ANALYSIS: Two reviewers independently checked the results of searches to identify relevant studies. Dichotomous outcomes were reported as Peto Odds ratios and continuous outcomes as weighted mean differences. MAIN RESULTS: Eight trials were identified. In the pooled analysis there was no significant difference in reversion rate or relapse rate between the two drugs. Time to reversion was slower for verapamil than adenosine in all studies that reported this outcome, but the data were not suitable for combining. Minor adverse events such as nausea, chest tightness, shortness of breath and headache were reported much more frequently in patients treated with adenosine with 10.8 % of patients reporting at least one of these events, compared with 0.6% of those treated with verapamil (OR 0.15, 95% CI 0.09 to 0.26, P<0.001). There was no significant difference in the rate of major adverse events between the two groups, although hypotension was reported exclusively in the verapamil treatment group (3/166 patients treated with verapamil, 0/171 treated with adenosine). AUTHORS' CONCLUSIONS: Adenosine and verapamil are both effective treatments for supraventricular tachycardia in the majority of patients. However, given the high incidence of minor but unpleasant side effects in patients treated with adenosine and the potential for hypotension with verapamil, patients should be fully informed of these risks prior to treatment.

Vasodilatory responsiveness to adenosine triphosphate in ageing humans

            (Kirby, Crecelius et al. 2010) Download

Endothelium-dependent vasodilatation is reduced with advancing age in humans, as evidenced by blunted vasodilator responsiveness to acetylcholine (ACh). Circulating adenosine triphosphate (ATP) has been implicated in the control of skeletal muscle vascular tone during mismatches in oxygen delivery and demand (e.g. exercise) via binding to purinergic receptors (P2Y) on the endothelium evoking subsequent vasodilatation, and ageing is typically associated with reductions in muscle blood flow under such conditions. Therefore, we tested the hypothesis that ATP-mediated vasodilatation is impaired with age in healthy humans. We measured forearm blood flow (venous occlusion plethysmography) and calculated vascular conductance (FVC) responses to local intra-arterial infusions of ACh, ATP, and sodium nitroprusside (SNP) before and during ascorbic acid (AA) infusion in 13 young and 13 older adults. The peak increase in FVC to ACh was significantly impaired in older compared with young adults (262 +/- 71% vs. 618 +/- 97%; P < 0.05), and this difference was abolished during AA infusion (510 +/- 82% vs. 556 +/- 71%; not significant, NS). In contrast, peak FVC responses were not different between older and young adults to either ATP (675 +/- 105% vs. 734 +/- 126%) or SNP (1116 +/- 111% vs. 1138 +/- 148%) and AA infusion did not alter these responses in either age group (both NS). In another group of six young and six older adults, we determined whether vasodilator responses to adenosine and ATP were influenced by P1-receptor blockade via aminophylline. The peak FVC responses to adenosine were not different in young (350 +/- 65%) versus older adults (360 +/- 80%), and aminophylline blunted these responses by approximately 50% in both groups. The peak FVC responses to ATP were again not different in young and older adults, and aminophylline did not impact the vasodilatation in either group. Thus, in contrast to the observed impairments in ACh responses, the vasodilatory response to exogenous ATP is not reduced with age in healthy humans. Further, our data also indicate that adenosine mediated vasodilatation is not reduced with age, and that ATP-mediated vasodilatation is independent of P1-receptor stimulation in both young and older adults.


Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial

            (Kloner, Forman et al. 2006) Download

AIMS: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II). METHODS AND RESULTS: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine. CONCLUSION: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

Slow infusion of calcium channel blockers compared with intravenous adenosine in the emergency treatment of supraventricular tachycardia

            (Lim, Anantharaman et al. 2009) Download

INTRODUCTION: The emergency treatment of supraventricular tachycardia (SVT) has, over the last two decades, changed from verapamil to adenosine primarily owing to documented hypotensive episodes occurring with rapid bolus infusions of the calcium channel blocker. Slow infusions of calcium channel blockers have not previously demonstrated hypotension to any significant degree. The aim of this study was to compare the efficacy and safety of bolus intravenous adenosine and slow infusion of the calcium channel blockers verapamil and diltiazem in the emergency treatment of spontaneous SVT. METHODS: A prospective randomized controlled trial with one group receiving bolus intravenous adenosine 6 mg followed, if conversion was not achieved, by adenosine 12 mg; and the other group receiving a slow infusion of either verapamil at a rate of 1mg per minute up to a maximum dose of 20mg, or diltiazem at a rate of 2.5mg per minute up to a maximum dose of 50mg. These infusions would be stopped at time of conversion of the SVT or when the whole dose was administered. Heart rate and blood pressure was continuously monitored during drug infusion and for up to 2h post-conversion. RESULTS: A total of 206 patients with spontaneous SVT were analysed. Of these, 102 were administered calcium channel blockers (verapamil=48, diltiazem=54) and 104 were given adenosine. The conversion rates for the calcium channel blockers (98%) were statistically higher than the adenosine group (86.5%), p=0.002, RR 1.13, 95% CI 1.04-1.23. The initial mean change in blood pressure post-conversion in the calcium channel blocker group was -13.0/-8.1 mmHg (verapamil) and -7.0/-9.4 mmHg (diltiazem) and 2.6/-1.7 mmHg for adenosine. Only one patient in the calcium channel group (0.98%) (95% CI 0.025-5.3) developed hypotension, and none in the adenosine group. CONCLUSION: Slow infusion of calcium channel blockers is an alternative to adenosine in the emergency treatment of stable patients with SVT. Calcium channel blockers are safe and affordable for healthcare systems where the availability of adenosine is limited.

Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway

            (Manintveld, te Lintel Hekkert et al. 2005) Download

Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. In pentobarbital-anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60-min coronary artery occlusion (CAO), using trypan blue and nitro-blue-tetrazolium staining, respectively. IPC with a single 15-min CAO and a 15-min adenosine infusion (ADO, 200 microg min(-1) i.v.) limited IS to the same extent (IS = 41 +/- 6% and IS = 40 +/- 4%, respectively) compared to control rats (IS = 63 +/- 3%, both P < 0.05). However, IPC increased myocardial interstitial adenosine levels seven-fold from 4.3 +/- 0.7 to 27.1 +/- 10.0 microM (P < 0.05), while ADO had no effect on interstitial adenosine (4.1 +/- 1.2 microM), or any of the other purines. The NO synthase inhibitor N(omega)-nitro-L-arginine (LNNA), which did not affect IS (IS = 62 +/- 3%), attenuated the protection by ADO (IS = 56 +/- 3%; P < 0.05 vs ADO, P = NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS = 66 +/- 3%), blunted the protection by ADO (IS = 55 +/- 4%; P < 0.05 vs ADO and vs hexamethonium). These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.


The intravenous adenosine test: a new test for the identification of bradycardia pacing indications? A pilot study in subjects with bradycardia pacing indications, vasovagal syncope and controls

            (Parry, Chadwick et al. 2009) Download

BACKGROUND: Intravenous adenosine has recently been used in the diagnosis of unexplained syncope, but there is no consensus as to the meaning of a 'positive' test. The objective is to determine the sensitivity and specificity of intravenous adenosine testing in the diagnosis of bradycardia-pacing indications [sinus node dysfunction(SND), atrio-ventricular block (AVB) and cardio-inhibitory carotid sinus syndrome (CSS)]. DESIGN: Pilot cohort study. METHODS: Patients-(i) Bradycardia-pacing group: Consecutive patients referred for pacing for SND, AVB and CSS; (ii) Consecutive head-up tilt (HUT)-positive VVS patients. Controls-(i) Simple controls (S-Con: normal examination/ECG) and (ii) Electrophysiology controls (EP-Con: consecutive subjects referred for accessory pathway ablation). Pacing referrals and EP-Con had electrophysiology studies to confirm referral diagnosis and exclude others. All subjects had bolus injection of 20 mg intravenous adenosine during continuous ECG and blood pressure monitoring (positive test: >or=6 s asystole, >or=10 s high-degree AVB post-injection). Sensitivity, specificity, safety and tolerability of the test were measured. RESULTS: Of 264 potential participants (4 SND, 8 AVB, 7 CSS, 10 VVS, 10 EP-Con and 11 S-Con) 50 were studied. All (100%) of the bradycardia-pacing group were adenosine test-positive, as were 6 (60%) VVS. None (0%) and 3 (27%) of the EP- and S-Con groups were positive. Adenosine testing was 100% sensitive and 86% specific for bradycardia-pacing indications, and 100% specific using the diagnostically 'clean' EP-Con results. There were no significant adverse or side effects. CONCLUSION: Adenosine testing reliably identified patients with definitive bradycardia-pacing indications in whom alternative diagnoses were excluded. Further work is needed to evaluate the role of this test in the diagnosis of unexplained syncope.

European Stroke Prevention Study-2 results: serendipitous demonstration of neuroprotection induced by endogenous adenosine accumulation?

            (Picano and Abbracchio 1998) Download

In patients with prior stroke or transient ischaemic attack, anti-platelet treatment with dipyridamole substantially reduced stroke recurrence, with a beneficial effect comparable to and additive with that induced by aspirin (the European Stroke Prevention Study-2). Eugenio Picano and Maria Abbracchio present here a platelet-independent hypothesis, according to which cardiovascular and neuroprotective actions achieved by dipyridamole through chronic elevation of endogenous adenosine levels may have contributed to the therapeutic success of this study.


Cardioprotection with adenosine: 'a riddle wrapped in a mystery'

            (Przyklenk and Whittaker 2005) Download

Review of the published literature on adenosine and cardioprotection could lead one to paraphrase the famous words of Sir Winston Churchill (Radio broadcast, 1 October 1939 (in reference to Russia)) and conclude: 'I cannot forecast to you the action of adenosine. It is a riddle wrapped in a mystery inside an enigma'. That is, although it is well-established that adenosine can render cardiomyocytes resistant to lethal ischemia/reperfusion-induced injury, new and intriguing insights continue to emerge as to the mechanisms by which adenosine might limit myocardial infarct size.

Efficacy and safety of adenosine in the treatment of supraventricular tachycardia in infants and children

            (Till, Shinebourne et al. 1989) Download

One hundred and seventeen episodes of supraventricular tachycardia in 50 children, including 28 infants, were treated with intravenous adenosine. Adenosine was prepared in a sterile solution of 0.9% saline (1 mg/ml) and given in incremental doses of 0.05 mg/kg every two minutes to a maximum of 0.25 mg/kg. Ninety of the 117 episodes were terminated. This included 88 of the 102 episodes of junctional tachycardia (79 of the 92 episodes of atrioventricular reentry tachycardia, seven of the eight episodes of atrioventricular nodal reentry tachycardia, and both of the episodes of long R-P' tachycardia). Only one of four episodes of His bundle tachycardia and one of the eight episodes of ectopic atrial tachycardia were terminated. None of the three episodes of atrial flutter were terminated. Side effects were frequent but mild and included transient complete atrioventricular block (less than 6 s), sinus bradycardia (less than 40 s), ventricular extrasystoles, flushing, nausea, headache, and respiratory disturbance. Reinitiation (within 5 s) of supraventricular tachycardia occurred in 13 of the terminated episodes. Although reinitiation limited its clinical efficacy in some patients, intravenous adenosine offered a safe and efficient method of rapid termination of most episodes of supraventricular tachycardia and in some cases facilitated diagnosis of the mechanism.


Intravenous administration of adenosine triphosphate disodium during primary percutaneous coronary intervention attenuates the transient rapid improvement of myocardial wall motion, not myocardial stunning, shortly after recanalization in acute anterior myocardial infarction

            (Tokuyama, Sakuma et al. 2009) Download

BACKGROUND AND PURPOSE: Administration of adenosine attenuates myocardial stunning after reperfusion in a canine experimental ischemic model. However, it is unknown whether administration of adenosine triphosphate disodium (ATP) during reperfusion can attenuate myocardial stunning after coronary recanalization in patients with acute myocardial infarction (MI). Therefore, we sought to elucidate the effects of ATP administration on serial changes of left ventricular systolic function before and after coronary recanalization. METHODS: In 27 patients with first ST-elevation acute anterior MI, in whom primary percutaneous coronary intervention (PCI) was completed within 10 h after symptom onset, ATP at a mean rate of 103 microg/kg/min (n=16) or normal saline (n=11) was intravenously administered for 1 h during reperfusion. Left ventricular regional wall motion within the initially severely ischemic region was serially analyzed using the standard wall motion score index (WMSI) by transthoracic echocardiography. RESULTS: Means of WMSIs were similar shortly before primary PCI in both groups (2.79 in ATP group and 2.69 in controls). They changed to 2.56 and 2.22 shortly after PCI, 2.49 and 2.39 on day 2, 2.34 and 2.30 on day 3, 2.19 and 2.25 on day 10, and 1.85 and 2.02, 6 months later, respectively. Transient improved regional wall motion within the initially severely ischemic region was observed shortly after PCI in controls (10.3% of observed segments); however, it was significantly suppressed in the ATP group (2.55%). The percent recovery of WMSI on day 10, which was defined as WMSI on day 10 normalized by improvement of WMSI for 6 months, was 63.8% in ATP group and 65.7% in controls, implying ATP administration could not reduce myocardial stunning by day 10 after primary PCI. CONCLUSIONS: The high-dose administration of ATP during primary PCI prevented transient improved wall motion shortly after coronary recanalization rather than preventing left ventricular stunning. These results suggest that ATP can prevent reperfusion injury during primary PCI.


References

Belardinelli, L. and B. B. Lerman (1990). "Electrophysiological basis for the use of adenosine in the diagnosis and treatment of cardiac arrhythmias." Br Heart J 63(1): 3-4.

Belardinelli, L., J. C. Shryock, et al. (1995). "Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes." FASEB J 9(5): 359-65.

Christie, D. J., K. Kottke-Marchant, et al. (2008). "Hypersensitivity of platelets to adenosine diphosphate in patients with stable cardiovascular disease predicts major adverse events despite antiplatelet therapy." Platelets 19(2): 104-10.

Fokkema, M. L., P. J. Vlaar, et al. (2009). "Effect of high-dose intracoronary adenosine administration during primary percutaneous coronary intervention in acute myocardial infarction: a randomized controlled trial." Circ Cardiovasc Interv 2(4): 323-9.

Garratt, C. J., A. D. Malcolm, et al. (1992). "Adenosine and cardiac arrhythmias." BMJ 305(6844): 3-4.

Godeneche, G., N. Sorel, et al. (2009). "Stroke and aspirin non-responder patients: relation with hypertension and platelet response to adenosine diphosphate." Platelets 20(7): 471-7.

Holdgate, A. and A. Foo (2006). "Adenosine versus intravenous calcium channel antagonists for the treatment of supraventricular tachycardia in adults." Cochrane Database Syst Rev(4): CD005154.

Kirby, B. S., A. R. Crecelius, et al. (2010). "Vasodilatory responsiveness to adenosine triphosphate in ageing humans." J Physiol 588(Pt 20): 4017-27.

Kloner, R. A., M. B. Forman, et al. (2006). "Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial." Eur Heart J 27(20): 2400-5.

Lim, S. H., V. Anantharaman, et al. (2009). "Slow infusion of calcium channel blockers compared with intravenous adenosine in the emergency treatment of supraventricular tachycardia." Resuscitation 80(5): 523-8.

Manintveld, O. C., M. te Lintel Hekkert, et al. (2005). "Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway." Br J Pharmacol 145(6): 703-11.

Parry, S. W., T. Chadwick, et al. (2009). "The intravenous adenosine test: a new test for the identification of bradycardia pacing indications? A pilot study in subjects with bradycardia pacing indications, vasovagal syncope and controls." QJM 102(7): 461-8.

Picano, E. and M. P. Abbracchio (1998). "European Stroke Prevention Study-2 results: serendipitous demonstration of neuroprotection induced by endogenous adenosine accumulation?" Trends Pharmacol Sci 19(1): 14-6.

Przyklenk, K. and P. Whittaker (2005). "Cardioprotection with adenosine: 'a riddle wrapped in a mystery'." Br J Pharmacol 145(6): 699-700.

Till, J., E. A. Shinebourne, et al. (1989). "Efficacy and safety of adenosine in the treatment of supraventricular tachycardia in infants and children." Br Heart J 62(3): 204-11.

Tokuyama, T., T. Sakuma, et al. (2009). "Intravenous administration of adenosine triphosphate disodium during primary percutaneous coronary intervention attenuates the transient rapid improvement of myocardial wall motion, not myocardial stunning, shortly after recanalization in acute anterior myocardial infarction." J Cardiol 54(2): 289-96.