Comparison of the Novel Vasodilator Uridine Triphosphate and Adenosine for the Measurement of Fractional Flow Reserve

Abstract: Aim. Examination of the fractional flow reserve (FFR) responses of intravenous (IV) adenosine with increasing doses of intracoronary (IC) adenosine versus IC uridine triphosphate (UTP) in patients with coronary artery disease. Methods and Results. We measured FFR in 25 patients during continuous IV and IC infusion (using a microcatheter in the coronary ostium). Standard IV adenosine infusion (140 µg/kg/min) was compared to 8 equimolar incremental doses of IC UTP and IC adenosine (20, 40, 60, 80, 160, 240, 320 and 640 µg/min) in a randomized order. Across all doses, ∆FFR_{IC UTP - IC adenosine} was -0.038 ± 0.008, P<.001. At the highest dose of IC UTP, FFR was significantly lower (FFR_{IC UTP}= 0.62 ± 0.04) than during IV adenosine (FFR_{IV adenosine} = 0.72 ± 0.05; P=.02) and IC adenosine (FFR_{IC adenosine} = 0.68 ± 0.05; P=.03). Furthermore, UTP had significantly fewer side effects compared to IV (P<.001) and IC adenosine (P<.05). Conclusion. IC UTP lowered FFR significantly more than both IV and IC adenosine and with fewer side effects, and could be a more precise alternative to adenosine.  

J INVASIVE CARDIOL 2014;26(10):512-518

Key words: UTP, fractional flow reserve, adenosine, P2Y2 receptors, coronary blood flow

___________________________________

Fractional flow reserve (FFR) is a stenosis-specific method for measuring ischemia. It is considered the gold standard method for investigating whether any particular stenosis is responsible for inducing ischemia. However, a prerequisite for a correct FFR measurement is the achievement of pharmacologically induced maximal coronary hyperemia, ie, elimination of all active vasomotor tone to ensure that coronary blood flow and pressure are linearly correlated (Ohm’s Law).^1-3 Recent studies have pointed out the crux in achieving maximal hyperemia, as the current recommendation of central intravenous (IV) adenosine (140 µg/kg/min) may not be enough to achieve the correct FFR, thereby leading to an underestimation of lesion severity.⁴ 

An ideal coronary vasodilator for studying FFR in humans should rapidly produce maximal coronary vasodilation, be very short acting, and have minimal side effects, and so far no other agents have been superior to adenosine in producing maximal hyperemia.^5-9 Use of IV adenosine, however, has a few contraindications and side effects even with low-dose intracoronary (IC) infusions.⁸ This is due to its widespread P1 receptor activation (A1, A2a, A2b, and A3), which can causes dyspnea, anxiety, angina, and rarely atrioventricular block. Furthermore, patients have to refrain from using caffeine prior to the examination in order to get an accurate hyperemic assessment, since caffeine blocks P1 receptors.⁸ Also, some patients are non-responsive to adenosine.¹⁰

Uridine triphosphate (UTP) is a nucleotide and a potent peripheral vasodilator in humans.^11,12 It selectively stimulates the P2Y2 receptors and is concomitantly capable of inhibiting the counter-regulatory sympathetic vasoconstriction in humans.¹² This is clinically relevant, as most cardiac patients are elderly and have concomitant diseases that can raise the sympathetic nervous drive¹³ and produce coronary vasoconstriction, which cannot be opposed by adenosine.^12,14 

The aim of this randomized feasibility study was to compare the efficacy of IC UTP, IC adenosine, and continuous IV adenosine in a central vein for assessing FFR in patients with intermediate coronary artery stenoses. 

Methods

Patient Population. The patient population consisted of 25 patients presenting for elective coronary angiography who underwent a clinically indicated FFR assessment of a coronary artery stenosis. FFR was measured when uncertainty with regard to the hemodynamic significance of the lesion existed and when the results would influence the management strategy. In accordance with the FAME study (Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention) criteria, a FFR cutoff of 0.80 or less after IV adenosine administration was used to decide whether to perform revascularization.¹⁵ 

The inclusion criteria were patient age between 18 and 75 years and signed informed consent. Patients with ST-segment elevation myocardial infarction were excluded, as were patients with contraindications to adenosine infusion such as severe asthma, atrioventricular block, and hypotension. Patients with technically inaccessible stenoses or no stenosis suitable for FFR measurement were also excluded. 

The study was approved by The National Committee on Health Research Ethics, the local research committee in Copenhagen University Hospital Gentofte, and conducted in accordance with the guidelines of the Declaration of Helsinki. All participants gave written informed consent.

Study design. This randomized, prospective, crossover study was performed in order to compare FFR measurements in the same patients with consecutive randomized patient-blinded infusions of: (1) a 2-minute continuous IV infusion of adenosine; (2) a continuous IC infusion of incremental dosages of adenosine; and (3) a continuous IC infusion of incremental dosages of UTP. This was done to see whether UTP could induce a closer to maximum hyperemia than adenosine, as measured by a lower FFR. Also, side effects and changes in hemodynamic parameters (heart rate [HR] and mean arterial pressure [MAP]), during IC UTP, IC adenosine, and IV adenosine infusion were compared. Each IC infusion step lasted for 2 minutes with equimolar increasing dosages of UTP and adenosine (Figure 1). Initially, a total of 25 patients received 20-320 µg/min, while an additional 15 patients also received a 640 µg/min dose. All IV infusions were administered in a central vein (femoral vein). There was a 5-minute wash-out period between UTP and adenosine infusions to ensure that changes in hemodynamic parameters (coronary pressure and flow, heart rate, and MAP) returned to baseline. All infusions were given in a randomized order. Furthermore, all IC infusions were double-blinded, and the IV infusions were patient and operator blinded, but not blinded to the researcher. 

Procedural details. Prior to the experiment, the patients were caffeine abstinent for at least 24 hours. The patients maintained their usual treatment for heart disease, including beta-blockers, renin angiotensin inhibitors, nitrates, and calcium antagonists. 

Using a 7 Fr coronary catheter, we first performed a coronary angiography in standard multiple views by one of two experienced operators. The heart rate and MAP were continuously monitored throughout the procedure. To ensure continuous IC infusion and thereby a more precise comparison of IC infusions than if IC bolus was used, a microcatheter (2.8 Fr Progreat [Terumo Corp.] or 0.014˝ Trailblazer Support Catheter [ev3 Inc]) was advanced through the guiding catheter and a few millimeters into the coronary artery. This technique has previously been described, has no impact on aortic pressure and also allows the pull-back maneuver to be performed.¹⁶ Then, a 0.014˝ diameter pressure-recording wire (Volcano Corp.) was externally calibrated and advanced through the guiding catheter into the first segment of the investigated coronary artery. From this position, equalization of pressures from the aorta and pressure wire was confirmed. The wire was then placed distal to the stenosis to measure distal coronary pressure (P_d), while careful attention was paid to avoid arterial pressure dampening by slightly disengaging the guiding catheter from the coronary ostium. The microcatheter was left in place during all infusions, ensuring that all patients had the same technical conditions regardless of whether the patient first received an IV or an IC infusion. IV adenosine was infused through a large central IV access in the femoral vein. All FFR measurement recordings were performed by the researcher and blinded to the patient and operator.

Mean distal coronary (P_d) and aortic pressure (P_a) were then measured at baseline and during hyperemia induced by the vasodilators. The transstenotic FFR, defined as P_d/ P_a, was measured as an average over a 5-heartbeat series. The reported FFR values are the lowest FFR ratios obtained during each 2-minute steady-state infusion, whether that was IV or IC infusions.

Additionally, heart rate, blood pressure, and side effects were continuously monitored and recorded at baseline and during maximal hyperemia for each dosage. 

After completion of the study protocol, the patient received percutaneous coronary intervention (PCI), a referral for coronary arterial bypass graft (CABG) surgery, or optimal medical therapy (OMT) on the basis of the overall findings of the IV adenosine response according to the currently recommended guidelines. 

Pharmacological protocol. All infusions were randomized so that all patients received a different infusion order of IV adenosine, IC adenosine in increasing dosages, and IC UTP in increasing dosages (Figure 1). The IV adenosine (Life Medical Sweden AB) infusion was a standard 2-minute 140 µg/kg/min continuous infusion. IC UTP (Sigma-Aldrich) and IC adenosine were infused through    the microcatheter into the proximal coronary artery in equimolar dosages in steps with increasing adenosine doses of 20, 40, 80, 160, 240, 320 and 640 µg/min. UTP has nearly twice the molar mass of adenosine (550.09 g/mol and 267.24 g/mol) and was therefore infused in a higher concentration (2.06 times that of adenosine) in order to secure a true equimolar comparison. Since adenosine is the current standard, doses for both UTP and adenosine are presented as µg/min of adenosine. 

Side effects. Side effects were registered after each IV or IC infusion steps on a general scale from 1-4, with 1 representing “feeling comfortable,” 2 representing “slight discomfort,” 3 representing “severe discomfort,” and 4 representing “extreme discomfort.”

Statistical analysis. Baseline demographic data are presented as median (25th to 75th percentile) for continuous variables (age, weight, height, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, left ventricular ejection fraction) and tallied for categorical variables (sex, hypertension, diabetes, dyslipidemia, smoking, previous acute myocardial infarction, previous PCI, Canadian Cardiovascular Society [CCS] angina grading scale, New York Heart Association [NYHA] functional classification). Repetitive continuous data with a normal distribution were analyzed with a random effect model. Other continuous data with a normal distribution were compared with the paired t-test and categorical data were compared with Wilcoxon rank-sum test. Statistical analyses were performed with SAS 9.2 statistical software (SAS Institute, Inc) and  IBM SPSS statistics 20 (IBM Corp.). 

Results

Baseline and angiographic characteristics. Baseline characteristics at admission of the 25 patients enrolled in the study are shown in Table 1 and angiographic characteristics of the stenoses are shown in Table 2. We studied intermediate stenoses and the procedural success rate was 100% for advancing the pressure wire distally to the stenosis. There were no procedure-related complications. Most stenoses were located on the left descending artery.

Fractional flow reserve. FFR decreased with increasing doses of IV adenosine, IC adenosine, and IC UTP (Figure 2A). However, IC UTP produced significantly lower FFR across all doses compared to IC adenosine as an expression of increased ability to produce maximal hyperemia (ΔFFR_{IC UTP - IC adenosine} = -0.038 ± 0.008; P<.001).

Although only 15 of the 25 patients received the highest dose of 640 µg/min, IC UTP still lowered FFR (0.62 ± 0.04) significantly more than both IV adenosine in a central vein (0.72 ± 0.05; P=.02) and IC adenosine (0.68 ± 0.05; P=.03). IC adenosine lowered FFR slightly more than IV adenosine, but this difference was not significant (0.72 ± 0.05 vs 0.68 ± 0.05; P=.39. When FFR was stratified by examined vessel, UTP lowered FFR more than both IV and IC adenosine; however, due to low numbers (left anterior descending [LAD] coronary artery n=7; left circumflex n=4; right coronary artery n=4), this was only significant in the LAD (Figure 2B). 

As seen from the individual data in Figure 2C, there was a larger variation in FFRs with IV adenosine compared to the IC adenosine and IC UTP infusions.

During UTP infusion, there was an increase in number of stenoses identified according to the FAME study criteria with an FFR ≤0.8. Using those criteria, 73% of lesions were rendered significantly ischemic during the highest dose of UTP infusion, vs 53% with IC adenosine and 60% with IV adenosine (Figure 3). 

Blood pressure and heart rate. The IC infusions produced a slight and transient decrease in MAP, whereas IV adenosine lowered MAP 9 mm Hg (from 101 ± 4.4 mm Hg to 92 ± 4.3 mm Hg), as shown in Figure 4. The IC infusions had only minimal effect on heart rate. 

Corresponding to the reduction in MAP with IV adenosine, HR increased 17 beats/min (from 65 ± 2 beats/min to 82 ± 3 beats/min), as shown in Figure 5.

Side effects. No serious events occurred with administration of either adenosine or UTP. During IV adenosine, patients experienced higher levels of discomfort with chest pain, dizziness and dyspnea, and the average response to IV adenosine on the discomfort scale from 1 to 4 was 3.0 ± 0.3 (equal to severe discomfort; Figure 6). As expected, side effects increased with increasing IC adenosine doses, and were in the highest doses 1.9 ± 0.3 (equal to slight discomfort). However, the patients reported no side effects in response to IC UTP until reaching the highest UTP doses, and then only 3 patients had mild side effects in the form of chest discomfort with an average of 1.3 ± 0.2, which was significantly lower than both IV adenosine (ΔSide effectsIV adenosine - IC UTP = 1.71 ± 1.1; P<.001) and IC adenosine (ΔSide effects_{IC adenosine - IC UTP} = 0.67 ± 0.25; P=.02) in the highest dose. Across all eight doses, IC UTP had fewer side effects than IC adenosine (P=.02). No atrioventricular block was registered with either drug.

Discussion

This study is the first to use the novel vasodilator UTP for FFR measurements in patients with coronary artery disease. In this randomized study, we found that the novel vasodilator UTP, when infused IC, consistently lowered FFR more than both IC adenosine across a wide range of doses, and more than IV adenosine infused in the femoral vein in the highest dose of 640 µg/min.  Furthermore, IC UTP had only minimal effects on arterial pressure and heart rate, and produced only few and mild side effects, when compared to either IV or IC adenosine infusions. 

Fractional flow reserve. FFR expresses the maximal flow through a vessel in the presence of a stenosis compared to the maximal flow in the hypothetical absence of the same stenosis, and is defined as the pressure distal to a stenosis relative to the pressure before the stenosis during maximal hyperemia.

Coronary blood flow increases almost linearly under physiological circumstances when pressure is less than 40-50 mm Hg. With increasing pressure, autoregulation dampens any further increase in coronary blood flow such that in a range of pressures from 70-130 mm Hg, coronary blood flow is largely pressure-independent. The level of this autoregulatory function is set by myocardial performance and metabolism. With a hypothetical maximal vasodilation, ie, elimination of any active vasomotor tone, autoregulation is abolished and coronary blood flow is, at any pressure, linearly related to perfusion pressure. Therefore, if maximum hyperemia is not achieved during the vasodilator infusion, stenosis severity is measured less precisely and isunderestimated.^3,17 

We found that UTP consistently lowered FFR more than both IC and IV adenosine in all coronary vessels, and therefore might induce a more complete hyperemia than adenosine. Therefore, this study questions if adenosine is potent enough to induce maximal hyperemia in all patients. 

Although it seems that FFR continues to fall with increasing dilator dose and that we did not reach a plateau response in our maximum dose of 640 µg/min, we believe that we are close to the maximum coronary dilation. In a previous study by Yoon et al, FFR responses after IV and continuous IC adenosine infusion were compared. In their study, there was a plateau with IC adenosine at 300 µg/min and beyond that there was no further effect of higher doses.¹⁶ In our patients, both adenosine and UTP do not seem to have reached a plateau response, even though we infused double the dose used in Yoon’s study. However, further studies are needed to evaluate the optimal target dose of UTP.

Our results show a larger variability of IV adenosine compared to the IC infusions. This variability might be due to systemic vasodilation affecting aortic blood pressure,^18,19 incomplete microcirculation response to adenosine,²⁰ and the direct effect of adenosine on myocardial function.²¹ Some of these characteristics are minimized by intracoronary administration of adenosine, but as our results show, even then there is a significantly more complete vasodilation with UTP than with adenosine across a wide dose range from 20 µg/min to 640 µg/min (P<.001).

UTP, like adenosine, is a naturally occurring peptide and possesses many of the same cardiovascular qualities as adenosine. It has the same fast clearance, but selectively stimulates a completely different purinergic receptor, the P2Y2 receptor.²² 

It has been shown that in type 2 diabetes patients, the impairment of coronary blood flow includes abnormalities in sympathetic drive regardless of coronary artery stenoses.²³ In this study of patients with coronary artery disease, UTP consistently produced a lower FFR over a wide equimolar concentration range in comparison to adenosine. A number of factors may contribute to this. In contrast to adenosine, UTP opposes sympathetic vasoconstriction. As the sympathetic drive is up-regulated in many pathological conditions including coronary artery disease, UTP therefore increases blood flow both by direct vasodilation and by opposing sympathetic vasoconstriction.^11,12 The P2Y2 receptors could also be less affected by endothelial dysfunction, and UTP may also have higher receptor sensitivity in comparison to the adenosine receptors (P1 receptors). Importantly, UTP is also less dependent on endothelial nitric oxide release than adenosine in order to induce vasodilation, and since the bioavailability of nitric oxide is lower in patients with coronary artery disease, this may indirectly influence the vasodilator potential for adenosine.²⁴ 

Side effects. In this study, the infusion order was randomized between IV adenosine, IC adenosine, and IC UTP, and was blinded to the patient. We found that both IC adenosine and IC UTP infusions were associated with significantly fewer side effects than with IV adenosine infusion. It has previously been demonstrated that adenosine causes many side effects, particularly during IV infusion, which was confirmed in this study as patients on average had severe discomfort (3.0; Figure 6). Even when using IC administration, adenosine caused significantly more side effects than UTP across all doses (P=.01) and in the highest dose (P=.02). Only 3 patients experienced slight chest discomfort at the highest UTP infusion dose, while patients experienced side effects already in the lowest doses when infused with IC adenosine.

Clinical implications. It is well recognized that an FFR >0.80 excludes ischemia in 90% of the cases if diagnosed with adenosine.²⁵ However, concerns with the adequacy of adenosine to promote maximal microvascular dilation are increasing with the expanded use of FFR, and higher dosages of adenosine have been recommended if a visual stenosis is present without reaching a FFR ≤0.8.^26,27 In the current study, 53% and 60% of the patients had FFR ≤0.8 with IC or IV adenosine, respectively. However, UTP lowered FFR ≤0.80 in 73% of patients, reclassifying significantly more stenoses under the current FFR cut-off point, and leading to a situation where more patients would be treated with stents, if diagnosed with UTP. 

The FAME trials have shown a clear benefit of only revascularizing patients with physiologically relevant stenoses using IV adenosine. Mortality is lower if FFR is performed prior to placing the stent; however, it has still not been shown that PCI + OMT is better than OMT alone with regard to lowering mortality, but primarily that the degree of urgent revascularization is reduced as confirmed by the recent FAME 2 trial.²⁸ One reason for a greater need for urgent revascularization in the OMT group could be that maximal hyperemia was not always obtained during IV adenosine infusion, resulting in an underestimation of lesion severity in some patients. If a more accurate hyperemic test such as with UTP could be implemented, a greater number of patients would be more correctly diagnosed; this could potentially impact the outcome, since some patients who are low-responders or non-responders to adenosine would fall into another treatment category. 

Even though UTP creates a different hyperemic response than adenosine, it is not a priori clear that using UTP with the known threshold of 0.80 would have better clinical value. Most likely, the threshold would be lowered, but larger studies are required to evaluate whether that would produce a clinical benefit. This study was a feasibility study, and not powered or designed to make such a conclusion. 

Study limitations. Continuous infusion of adenosine in a central IV line is the recommended method for FFR measurements. In this study, we also used a microcatheter to ensure continuous steady-state IC infusions. This was done to minimize the measurement error related to missing the peak flow of bolus injections and to reduce systemic side effects.

In this study, only mild and transient side effects of UTP were reported by the 25 patients and there were no non-responders. In studies on a larger scale, there could be non-responders as well as patients who have more pronounced side effects to UTP whether it is for measurement purposes as well as for tolerance. Nevertheless, UTP is a selective P2Y2 receptor agonist, and all side effects should therefore be related to P2Y2 receptor activation, which primarily should produce decreases in blood pressure due to sympathetic blockade.²²

Conclusion

In this randomized study, IC-administered UTP lowered FFR more than both IC and IV adenosine, with negligible effects on hemodynamic parameters and fewer side effects, making it a safe and possible future vasodilator option for measuring FFR. However, further studies are warranted to confirm our results.

References

1. Kern MJ, Samady H. Current concepts of integrated coronary physiology in the catheterization laboratory. J Am Coll Cardiol. 2010;55(3):173-185.
2. Pijls NH, Kern MJ, Yock PG, De Bruyne B. Practice and potential pitfalls of coronary pressure measurement. Catheter Cardiovasc Interv. 2000;49(1):1-16.
3. Heusch G. Adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve. Basic Res Cardiol. 2010;105(1):1-5.
4. De Luca G, Venegoni L, Iorio S, Giuliani L, Marino P. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. J Am Coll Cardiol. 2011;4(10):1079-1084.
5. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J. 2000;140(4):651-657.
6. van der Voort PH, van Hagen E, Hendrix G, van Gelder B, Bech JW, Pijls NH. Comparison of intravenous adenosine to intracoronary papaverine for calculation of pressure-derived fractional flow reserve. Catheter Cardiovasc Diagn. 1996;39(2):120-125.
7. Jeremias A, Filardo SD, Whitbourn RJ, et al. Effects of intravenous and intracoronary adenosine 5’-triphosphate as compared with adenosine on coronary flow and pressure dynamics. Circulation. 2000;101(3):318-323.
8. McGeoch RJ, Oldroyd KG. Pharmacological options for inducing maximal hyperaemia during studies of coronary physiology. Catheter Cardiovasc Interv. 2008;71(2):198-204.
9. De Bruyne B, Pijls NH, Barbato E, et al. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation. 2003;107(14):1877-1883.
10. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation. 1990;82(5):1595-1606.
11. Thaning P, Bune LT, Hellsten Y, Pilegaard H, Saltin B, Rosenmeier JB. Attenuated purinergic receptor function in patients with type 2 diabetes. Diabetes. 2010;59(1):182-1829.
12. Rosenmeier JB, Yegutkin GG, Gonzalez-Alonso J. Activation of ATP/UTP-selective receptors increases blood flow and blunts sympathetic vasoconstriction in human skeletal muscle. J Physiol. 2008;586(Pt 20):4993-5002.
13. Rahn KH, Barenbrock M, Hausberg M. The sympathetic nervous system in the pathogenesis of hypertension. J Hypertens Suppl. 1999;17(3):S11-S14.
14. Rosenmeier JB, Fritzlar SJ, Dinenno FA, Joyner MJ. Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs. J Appl Physiol. 2003;95(6):2370-2374.
15. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224.
16. Yoon MH, Tahk SJ, Yang HM, et al. Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement. Am Heart J. 2009;157(6):1050-1056.
17. Pijls NH, Sels JW. Functional measurement of coronary stenosis. J Am Coll Cardiol. 2012;59(12):1045-1057.
18. Cox DA, Vita JA, Treasure CB, Fish RD, Selwyn AP, Ganz P. Reflex increase in blood pressure during the intracoronary administration of adenosine in man. J Clin Invest. 1989;84(2):592-596.
19. Sollevi A. Cardiovascular effects of adenosine in man; possible clinical implications. Progress Neurobiol. 1986;27(4):319-349.
20. Meuwissen M, Chamuleau SA, Siebes M, et al. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation. 2001;103(2):184-187.
21. Vinereanu D, Fraser AG, Robinson M, Lee A, Tweddel A. Adenosine provokes diastolic dysfunction in microvascular angina. Postgrad Med J. 2002;78(915):40-42.
22. Rieg T, Gerasimova M, Boyer JL, Insel PA, Vallon V. P2Y(2) receptor activation decreases blood pressure and increases renal Na(+) excretion. Am J Physiol Regul Integ Comp Physiol. 2011;301(2):R510-R518.
23. Cosson E, Pham I, Valensi P, Paries J, Attali JR, Nitenberg A. Impaired coronary endothelium-dependent vasodilation is associated with microalbuminuria in patients with type 2 diabetes and angiographically normal coronary arteries. Diabetes Care. 2006;29(1):107-112.
24. Erlinge D, Harnek J, van Heusden C, Olivecrona G, Jern S, Lazarowski E. Uridine triphosphate (UTP) is released during cardiac ischemia. Int J Cardiol. 2005;100(3):427-433.
25. Hau WK. Routine pressure-derived fractional flow reserve guidance: from diagnostic to everyday practice. J Invasive Cardiol. 2006;18(5):240-245.
26. Leone AM, Porto I, De Caterina AR, et al. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. J Am Coll Cardiol. 2012;5(4):402-408.
27. Pijls NH, Tonino PA. The crux of maximum hyperemia: the last remaining barrier for routine use of fractional flow reserve. J Am Coll Cardiol. 2011;4(10):1093-1095.
28. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001.

_____________________________________

From the ¹Copenhagen University Hospital Gentofte; and ²Copenhagen University Hospital, Bispebjerg, Denmark.

Funding: This investigator-initiated study was sponsored by Novo A/S, Denmark and Terumo, Europe. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The study was performed under a research contract between Dr Rosenmeier and Novo A/S entailing IP rights for the clinical application of UTP. None of the sponsors had access to the data or has been involved in writing this paper. UTP is currently not commercially available. The remaining authors have no disclosures.

Manuscript submitted December 16, 2013, provisional acceptance given December 30, 2013, final version accepted January 21, 2014.

Address for correspondence: Jaya B. Rosenmeier, MD, PhD, Copenhagen University Hospital, Bispebjerg, Department of Cardiology, Bispebjerg Bakke 23, Copenhagen N, 2400, Denmark. Email: jaya@dadlnet.dk