DOI: 10.1161/CIRCULATIONAHA.115.016379

Xanthine Oxidase Inhibitors in Heart Failure: Where Do We Go From Here?

Running title: Tamariz et al.; Xo inhibitors in heart failure Leonardo Tamariz, MD, MPH1,2; Joshua M. Hare, MD1,3

1

Dept of Medicine, Miller School of Medicine at the University of Miami, Miami, FL; 2The

Vete Veterans tera te rans ra ns A Affairs ffai ff a rss Medical Medical Center, Miami, FL; 3In Interdisciplinary nte terrdisciplinary Stem C Cell ell Institute, University oof el Miam Mi Miami ami Miller am Mill Mi l er School Sch hoo ool off Medicine, Med dic iciinee, Miami, Miaami mi, FL

Add Ad dress for for Correspondence: Correspondence: d Address Joshua M. Hare, MD University of Miami 1501 NW 10th St Miami, Fl 33136 Tel: 305-243-5579 Fax: 305- 243-5584 E-mail: [email protected] Journal Subject Code: Heart failure:[10] Cardio-renal physiology/pathophysiology

Key words: Editorial, heart failure, uric acid, xanthine oxidase inhibitors heart failure, nitric oxide,nitroso-redox balance

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DOI: 10.1161/CIRCULATIONAHA.115.016379

Despite its public health impact, there are relatively few classes of drugs in use for the treatment of heart failure (HF) and left ventricular dysfunction. 1 HF pharmacology is based upon relatively few signal transduction pathways – most prominently the sympathetic nervous system and the renin angiotensin aldosterone system. 1 As such the quest for additional therapeutic targets remains critically important, and in this regard oxidative stress/nitroso-redox imbalance is a potential target of long standing interest. 2 Several lines of evidence support that this pathway may be of pathophysiologic relevance. First, serum uric acid (SUA) is a biomarker of oxidative stress in several cardiovascular diseases including heart failure. 3-5 This elevation of SUA is primarily due to the increased ncreased amounts of available xanthine and hypoxanthine after cellular damage, wh whic which ichh is then ic the henn catalyzed into uric acid via xanthine oxidase (XO). 6 XO uses oxygen as a potential electron acce ept ptor or,, thus or thus forming for ormi or m ng reactive oxygen species (ROS) (RO ROS) resulting in oxidative oxid dat ativ i e stress.6 acceptor, Severall observational obsserv rvattio iona nall st na stud studies udie ud iees aand ndd me meta-analysis etaa-anallysiss ha have ve identified ide d nt de ntif ifie if iedd elevations ie ellevaati tioons ons of SUA SUA aass an independent nde depe penden pe nt marker marker off poor poor cardiac car ardi d ac function, fun uncctionn, mortality, un morrtaalityy, poor poo or functional funncttion fu onall capacity on cap pac acit i y ass well well aass th the he 7 10 7development deve de velo elo lopm pmen pm entt of aatrial en tria tr iall ar ia arrh arrhythmias rhyt rh ythm thm hmia iass in hheart ia eart ea rt ffailure. ailu ai lure re. 7-10 re Thus Thu huss an active act ctiv ivee hypothesis hypo hy poth po thes th esis es is is is that that SUA SUA may may y

not only represent a prognostic biomarker of heart failure but may also represent a potential target for intervention. A second line of evidence emerges from experimental studies exploring the role of XO in heart failure, showing first and foremost an upregulation of this enzyme in the cardiovascular system. 6 Furthermore, preclinical animal data supported the use of XO inhibitors in heart failure showing greater survival, improved left ventricular function, enhanced mechanoenergetic coupling, attenuation of ventricular remodeling, decrease in myocardial oxygen consumption, reduced afterload and improved ventricular vascular coupling. 11,12 In humans, intracoronary and

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DOI: 10.1161/CIRCULATIONAHA.115.016379

intravenous allopurinol improved myocardial efficiency and increased the concentration of highenergy phosphates within the heart.

3,13

Therefore, XO inhibitors in animals and humans

improve cardiac function enhancing mechanoenergetic coupling while reducing myocardial oxygen consumption and improving afterload. An important insight however is that the enhancement of mechanoenergetic coupling depends on the degree XO overexpression in heart failure animal models.6 A third line of evidence is supported by nested case-control and retrospective cohort studies showing a decrease in heart failure readmissions as well as all-cause mortality in patients with gout who receive allopurinol. 14,15 Together these findings have prompted a series of clinical trials examinin examining ng XO iinhibition nhib nh ibit ib itiion it in n patients with HF. In this issue of Circulation, Givertz and colleagues16 report the results of he Xa Xant nthi nt hine hi ne Oxi xida xi d se Inhibition for Hyperuricemi da micc Heart Failure Patie mi ent ntss (EXACT-HF) trial, a the Xanthine Oxidase Hyperuricemic Patients ddouble dou ouble blind, multicenter multticcen mu enteer randomized rand ra ndom nd omiz om ized iz ed trial triial that tha hatt compared com mparred guideline gui uide deli linee adherent li adh dherrentt therapy ther th erap apyy pl ap plus u allopurinol al llo lopu purinol to gu pu guideline uidelinne adhe adherent ereent n the therapy heraapy alo he alone one in a high gh ris risk sk H HF F po popu population p laatiionn w pu with i h el it ele elevated ev ed evated d SUA SUA. UA. In n tthis hiss st hi stud study udy d XO iinhibition nhib nh ibit ib itio it ionn with io wiith al allo allopurinol lopu lo puri rino ri noll di no didd no nott im impr improve prov pr ovee functional func fu ncti nc tion ti onal on al ccapacity, apac ap acit ac ity, cclinical it lini li nica ni call st ca stat status atus at uss or left ventricular ejection fraction. Other randomized studies have reached similar conclusions and are summarized in Table 1. 17-21 The randomized studies of XO inhibition in HF consistently fail to show improvement in clinical composite outcomes. It is important to note however that two studies, including the EXACT-HF trial, do show trends toward improvement of secondary outcomes like hospitalizations and ejection fraction. 16,21 The results seem to be independent of the severity of the HF, patients enrolled, the use of active metabolites of XO inhibitors and dosages to decrease uric acid, as well as the use of different clinical composite outcomes. Another potential caveat from the randomized trials is that long-term effects of these medications

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DOI: 10.1161/CIRCULATIONAHA.115.016379

remain unknown since the trials had relatively short-term follow-up. The study by Givertz is based in part on the Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial results which compared xanthine oxidase inhibitors to guideline therapy. In post-hoc analysis of this study oxypurinol showed a potential benefit in HF patients with elevated SUA and this benefit correlated to the degree of SUA reduction. This study contributed to the rationale for the present study, which employed elevated SUA as an enrollment criteria in order to select for a group of patients with elevated XO. Potential epidemiological explanations for the negative findings reported by Givertz 16 and others include the possibility that SUA might be just a marker of disease severity and prognosis and not a target for therapy. Also, a combination of sample size, low ev event ven entt ra rate rates tess an te andd short hort follow-up time could have limited the ability to detect a real long-term effect shown as a trend ren nd towards towa to ward wa rdss lower rd lowe wer hospitalizations in the allop we allopurinol pur urin inol group reported iin in n th tthis is study. Another potential explanation could use medications subject poteential but unlikely unnli likkely ly y exp xpla xp lana la nati na tion ti onn co coul uld lie in ul i the us se ooff or oral al m edi d ca cati tion ti onss subj on bjeect bj ect to ffirst irrst ppass asss as effect metabolism used efffe f ct metab bol o ism m of the the liver liveer since sincee the thee available avaiila labble experimental ex xpe perrim menntaal al results reesuultts inn hhumans um man ans us sed pparental arrentaal 3,,13 allopurinol. allo al lopu lo puri rino ri noll. 3,13 no This Thi hiss is an an unlikely un unli nli like kely ke ly theory the heor ory because or beca be caus ca use se there ther th eree was er waas a significant sign si gnif gn ific if ican ic antt decrease an decr de crea cr ease ea se in in SUA. SUA SU A.

The non-significant findings of EXACT-HF and other studies prompt an examination of the pathophysiological mechanisms that are the basis for this novel therapeutic strategy. A leading possibility explaining the lack of response to XO inhibition could be the fact that this pharmacologic strategy only addressed one of two limbs underlying nitroso-redox imbalance (Figure 1). In HF, not only are ROS generating pathways upregulated but important aspects of reactive nitrogen species (RNS) production are downregulated. 2 Three important factors related to the nitroso-redox balance might have bearing on the findings by Givertz and colleagues. 16 First, other enzymes and metabolic pathways contribute to

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DOI: 10.1161/CIRCULATIONAHA.115.016379

nitroso-redox imbalance, including other enzymes that produce ROS (NADPH oxidase enzymes and the respiratory chain in the mitochondria), superoxide dismutase that neutralizes superoxide, and the family of nitric oxide synthases (NOSs) which produces nitric oxide (NO). Selective XO inhibition might be inadequate to curtail the cascade of ROS accumulated in HF and, very importantly, this is supported by the present study because myeloperoxidase levels did not change. Second, we now know that the nitroso-redox balance is intimately interconnected. This is supported by a series of experiments that found that NO binds superoxide to produce peroxynitrite, NO modulates the expression of XO, NOS inhibitors abolish the contractile effect of XO inhibitors and XO inhibition can actually decrease NO production.

6,22

NOS1 deficient

animal models have proven an increase in mortality, left ventricular remodeling, an andd ve vent ventricular ntri nt ricu ri cula cu lar la arrhythmias after myocardial infarction. 23,24 Thus, inhibition of XO in the failing circulation y fail fail to to have ha beneficial beneficial effects if NOS activity activit itty and/or and/or signaling is also als lsoo depressed; XO may inhibition nhiibition may aaffect ffeect on ff only ly oone ne llimb imbb off th im the he nnitroso-redox i rosoit ro -reedox ox iimbalance. mbal mb a an ancee. Thus, Thus uss, thee results re ltss of EXACT-HF resul EXA XACT T-H - F add a d another ad an nothherr important im mport po tan nt da data ataa ppoint oint nt inn th thee ques quest estt to es o uunravel nrav ve l whether whhet whet ethe herr as he aspe aspects pect pe ctss of nnitroso-redox ct itro it roso ro so-red red edox ox iimbalance mbal mb alan al ance an ce hhave avee po av pote potential tent te ntia nt iall as a ttherapeutic ia hera he rape ra peuti pe ticc ta ti targ target. rget rg et. Th et Thee tr tria trial iall ia suggests that XO inhibition even in high SUA heart failure patients alone is inadequate to improve clinical outcomes. As this field progresses it will be crucial to examine other limbs of this balance and to ask whether augmenting NO production concomitantly with inhibition ROS production will have clinical benefits in HF.

Funding Sources: JMH is supported by NIH grants R01 HL110737, R01 HL107110, R01HL084275, 5UMHL113460 and grants from the Starr Foundation and Soffer Family Foundation.

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DOI: 10.1161/CIRCULATIONAHA.115.016379

Conflict of Interest Disclosures: JMH discloses a relationship with Vestion that includes equity, board membership, and consulting. LT has no disclosures.

References: 1. Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385:812-824. 2. Hare JM. Nitroso-redox balance in the cardiovascular system. N Engl J Med. 2004;351:21122114. 3. Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E, Hare JM. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation. 2001;104:2407-2411. 4. Tsukimori K, Yoshitomi T, Morokuma S, Fukushima K, Wake N. Serum uric acid levels correlate with plasma hydrogen peroxide and protein carbonyl levels in preeclampsia. a Am J Hypertens. 2008;21:1343-1346. 5. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJ. survival application Uricc acid aci cidd an andd su urv rviv i al in chronic heart failure: validation val alid idation and applicatio id on in metabolic, functional, hemodynamic staging. Circulation. 2003;107:1991-1997. fu unc ncttional, ti and hemody an ynamic stag ging. Circulation n. 2003;107:199 91-1997. interactions Circulation. 66. Zimmet Zimmet JM, Hare Hare JM. Ha JM. M Nitroso-redox Nittro oso-redoxx intera ract ra c ions nss in th thee ca ccardiovascular rdio ovaascullarr system. syysttem. te C irrcuulaationn. 2006;114:1531-1544. 20 006 06;1 ; 14:153 531-15 53 1544. 15 Tamariz L,, Ha Harzand A,, P Palacio A,, V Verma S,, Jo Jones Hare Uric predictor 77.. T amar am ariz ar iz L Harz rzan andd A an alac al acio ac io A erma er ma S Jone ness JJ,, H ne aree JJ.. U ar ricc ac ri acid id aass a pr pred edic ed icto ic torr of aallto llll cause mortality in heart failure: a meta-analysis. Congest Heart Fail. 2011;17:25-30. 8. Tamariz L, Agarwal S, Soliman EZ, Chamberlain AM, Prineas R, Folsom AR, Ambrose M, Alonso A. Association of serum uric acid with incident atrial fibrillation (from the Atherosclerosis Risk in Communities [ARIC] study). Am J Cardiol. 2011;108:1272-1276. 9. Tamariz L, Hernandez F, Bush A, Palacio A, Hare JM. Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm. 2014;11:1102-1108. 10. Jankowska EA, Ponikowska B, Majda J, Zymlinski R, Trzaska M, Reczuch K, BorodulinNadzieja L, Banasiak W, Ponikowski P. Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol. 2007;115:151-155. 11. Naumova AV, Chacko VP, Ouwerkerk R, Stull L, Marban E, Weiss RG. Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts. Am J Physiol Heart Circ Physiol. 2006;290:H837-43.

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12. Stull LB, Leppo MK, Szweda L, Gao WD, Marban E. Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy. Circ Res. 2004;95:1005-1011. 13. Hirsch GA, Bottomley PA, Gerstenblith G, Weiss RG. Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts. J Am Coll Cardiol. 2012;59:802808. 14. George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114:2508-2516. 15. Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. J Card Fail. 2012; 18: 694-701. 16. Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tamg W, Dunlap ME, LeWinter MM, Mann D, Felker M, O'Connor C, Goldsmith SR, Ofili EO, Saltzberg MT, Shah Marguiles KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Sha ah MR, failure Hernandez AF. Effects of xanthine oxidase inhibition in hyperuricemic heart failu ure ppatients: atie at ient ie nts: nt s: tthe he EXACT-HF study. Circulation. 2015;131:XX-XXX. 17. Hare JM, Mangal B, Brown J, Fisher C,Jr, Freudenberger R, Colucci WS, Mann DL, Liu P, Givertz Schwarz Investigators. oxypurinol Give veert rtzz MM MM,, Schw hwarz RP, OPT-CHF Investigat hw tor ors.. Impact of oxypurino nol in patients with no symptomatic OPT-CHF Coll ymp mptomatiic heart failure. Results of the OPT-CH HF study. y J Am C oll Cardiol. 2008;51:230122309. 3009. 18. Gavin Struthers AD. Allopurinol B-type natriuretic peptide concentrations 18 8. G avin AD AD, S tru utheerss AD D. A llopu purin pu in nol reduces reeduucess B -typ ypee na yp natr riu urettic tic pe pept pttidee co oncen enttrati en tr ionns and nd haemoglobin chronic failure. 2005;91:749haem mog oglo lobi lo bin but bi buut does does not not alter err exercise exercise xe e capacity capa ca paaci city ty y in in cch hro roni nic heart ni he t fa fai ilur uree. Heart. H arrt. 20 He 2005;9 ;9 91: 1:74 74974 9 753. 753 75 3. 19. Greig D, Alcaino H, Castro PF, Garcia L, Verdejo HE, Navarro M, Lopez R, Mellado R, Tapia F, Gabrielli LA, Nogerol C, Chiong M, Godoy I, Lavandero S. Xanthine-oxidase inhibitors and statins in chronic heart failure: effects on vascular and functional parameters. J Heart Lung Transplant. 2011;30:408-413. 20. Nasr G, Maurice C. Allopurinol and global left myocardial function in heart failure patients. J Cardiovasc Dis Res. 2010;1:191-195. 21. Cingolani HE, Plastino JA, Escudero EM, Mangal B, Brown J, Perez NG. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. J Card Fail. 2006;12:491-498. 22. Li H, Samouilov A, Liu X, Zweier JL. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. Biochemistry. 2003;42:1150-1159.

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23. Saraiva RM, Minhas KM, Raju SV, Barouch LA, Pitz E, Schuleri KH, Vandegaer K, Li D, Hare JM. Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: role of nitroso-redox equilibrium. Circulation. 2005;112:3415-3422. 24. Burger DE, Lu X, Lei M, Xiang FL, Hammoud L, Jiang M, Wang H, Jones DL, Sims SM, Feng Q. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. Circulation. 2009;120:1345-1354.

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Table 1. Comparison of randomized studies using xanthine oxidase inhibition in heart failure. Author

Heart failure Population

Xanthine oxidase inhibitor

Follow-up in weeks

Primary Outcome definition

Primary outcome result

253 with SUA >9.5 mg/dl with one more high risk marker

Allopurinol 300-600 mg/day

24

Clinical status: Outcomes, medication change and patient global assessment.

13% improved in both allopurinol and placebo arms.

Greigg et al. 2011

32 NYHA II-III

Allopurinol 300 mg/day

4

6-minute walk test and oxidative stress markers

No ddifference iffe if f rence in 6-min 6-minute walk wa lk ttest estt and es and im impr p ov improved ooxidative ox idat id ativ at ivee ma iv mark rker rk erss er markers

Nasr et al. 2010

59 NYHA III-IV

Allopurinol 300 mg/day

36

Composite endpoint: Global cardiac function and mortality/ mor o bi b dity morbidity

Allopurinol did not improve imp composite endpoin endpoint

Hare et et al. all. 2008

405 with a median SUA SU UA of o 77.8 .8 m mg/dl g/dl g/ dl aand nd NY YHA A III-IV III I -IV II NYHA

Oxypurinol 600 600 mg m mg/day /d day y

24

olani l i ett al l. Cingolani al. 2006

YHA YH A II -III III 60 N NYHA II-III

O xypurinol i l Oxypurinol /d 600 mg/day

4

Gavin et al. 2005

50 NYHA II-III

Allopurinol 300 mg/day

12

Givertz et al. 2015

Clinical Cli lini n cal status: 43% improved impr p oved in th the Outcomes, O tc Ou tcom omes om es, me es medica medication c tionn oxypurinol oxyp ox ypur yp urin ur nol arm m compared com ompa p r to change g , pati ent n gl gglobal obbal a 45% 5% in i the h pplacebo laceebo o ar change, patient arm. assessment a sess as ssme m nt or NYHA N HA NY H Im prrovved pprimary rima m ry y out uc Improved outcome atie at i nts with ie i higher hig i he h r uric in ppatients aacid ac id llevels ev vel els l Ejec Ej tion ti i ffraction racti tion Ejection

44.7+/.77+/ 7+/- 22.6 .66 % hhigher ighher E EF b i l and between oxypurinol placebo arms

Exercise stress test No difference in exercise and 6 minute walk test performance with a decrease in plasma BNP.

SUA: Serum uric acid, NYHA: New York Heart Association, EF: ejection fraction, BNP: Brain natriuretic peptide

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DOI: 10.1161/CIRCULATIONAHA.115.016379

Figure Legend:

Figure 1. Effect of XO inhibition on the nitroso-redox balance. The underlying mechanistic basis for the use of xanthine oxidase inhibitors in the failing heart. As depicted xanthine oxidase inhibitors (XOI) act on one key enzyme – XO/XDH – to inhibit ROS production but has other actions that might detract from full restoration of nitroso-redox balance. XOI decrease serum uric acid and superoxide production by inhibiting xanthine oxidase. Importantly, however, there are other sources of ROS production in the failing heart, including mitochonrdrial respiration and NADPH oxidases, that are not affected by XOI. In addition, NOS activity may be impaired in by XOI. In states of inad inadequate oxidation heart failure, or further disrupted r equate NO production,, ox oxid idat id atio at ionn or io diminished S-nitrosylation of the RYR receptor and other key proteins involved in excitationcontraction which myocardial cont tra ract ctio ct ionn co io ccoupling uppli linng impairs calcium cycling wh hic ichh drives optimal myo yo ocardial performance. Persistent formation which P ers rsistent ROS rs S pproduction ro odu duct c io ct ionn al also so cconsumes onsu on s me su mes NO andd leads lead ds to to peroxynitrite perox oxyn ox ynit yn itri it ritte forma ri mati ma tion ti on w hich hi ch ccan an cause the ATPase SERCA ca aus usee DNA, A, pprotein rottein and nd lipid id d damage. dam a ag age.. Peroxynitrite Per e ox xynitr yn ritee oxidizes oxi xiddize xi zees th he calc ccalcium alcciu um AT ATP Pase S ERCA CA A (responsible res espo pons po nsib ns ible ib le for for calcium cal alci cium ci um m reuptake reu eupt ptak pt akee into ak into the the SR). SR). Thus, Thu huss, NO NO continues cont co ntin nt inue in ues es to be be depleted depl de plet pl eted et ed by by XO inhibition perpetuating nitroso-redox imbalance and causing ineffective excitation-contraction coupling. Abbreviations: XOR: xanthine oxidoreductase, XO: xanthine oxidase, XDH: xanthine dehydrogenase, O-: Superoxide, NO: nitric oxide, NADPH: nicotine adenine dinucleotide phosphate, NOX: NADPH oxidases, 2NOS: nitric oxide synthase, SOD: superoxide dismutase, SR: sarcoplasmic reticulum, SERCA: sarcoplasmic reticulum calcium ATPase, RyR: ryanodine receptor.

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NOS1

M

te y c yo

lm l e c

e

NOS3

ne a r mb

Oxidationof RYR

SR

Oxidationof ation SERCA

XO inhibitors XOinhibitors SͲnitrosylation

XDH XO OR XO XOR

Ine Ineffective EExcitation x C o Contraction C o Coupling

NOX

NA ADP NADP OͲ

NO

NO

NADPH SOD Mitochondria

H2O2

ONOO_

Peroxynitrite

DNA Damage

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Nucleus

Xanthine Oxidase Inhibitors in Heart Failure: Where Do We Go From Here? Leonardo Tamariz and Joshua M. Hare Circulation. published online April 14, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2015/04/14/CIRCULATIONAHA.115.016379

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Xanthine oxidase inhibitors in heart failure: where do we go from here?

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