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'target': [196, 328, 992], 'long-standing': [198], 'interest.2Article': [199], 'see': [200], 'p': [201], '1763Several': [202], 'lines': [203], 'evidence': [205, 334, 460], 'support': [206], 'that': [207, 314, 441, 530, 604, 667, 978, 1091, 1115, 1195, 1234, 1387, 1451, 1466, 1468, 1581, 1666], 'pathway': [209], 'may': [210, 316, 1248, 1527, 1544], 'be': [211, 627, 981, 1041, 1112, 1249, 1332, 1420, 1604], 'pathophysiological': [213, 1089], 'relevance.': [214], 'First,': [215, 1374], 'serum': [216, 872, 1206, 1917, 1950], 'uric': [217, 256, 649, 816, 873, 1207, 1781, 1918, 1951, 2116, 2132, 2850, 2991], 'acid': [218, 257, 817, 1208, 1782, 1834, 1881, 1919, 1952, 2133, 2726, 2851, 2992, 3207], '(SUA)': [219], 'biomarker': [222, 322], 'stress': [225, 741, 843, 2111], 'several': [227], 'cardiovascular': [228, 357, 1733, 1862, 2999, 3164], 'diseases,': [229], 'including': [230, 607, 1228, 1384], 'HF.3–5': [231], 'This': [232, 934, 1064, 1458], 'elevation': [233], 'SUA': [235, 288, 315, 703, 779, 932, 947, 979], 'due': [237], 'primarily': [238], 'increased': [241, 406], 'amounts': [242], 'available': [244, 1056], 'xanthine': [245, 259, 877, 1151, 1355, 2200, 2378, 2412, 2583, 2961], 'hypoxanthine': [247, 2791], 'after': [248, 1516, 2022, 2462], 'cellular': [249], 'damage,': [250], 'which': [251, 899, 944, 1286, 1302, 1402, 1413], 'then': [253], 'catalyzed': [254], 'into': [255, 1325, 2953], 'via': [258], 'oxidase': [260, 1152, 1391, 2016, 2201, 2379, 3159], '(XO).6': [261], 'XO': [262, 343, 367, 416, 451, 496, 552, 585, 643, 687, 901, 1109, 1417, 1489, 1492, 1522, 1542, 1582], 'uses': [263], 'oxygen': [264, 273, 387, 431, 1187], 'as': [265, 289, 948, 1021, 1574, 1882, 2727], 'electron': [268], 'acceptor,': [269], 'thus': [270], 'forming': [271], 'reactive': [272, 1141, 1186], 'species': [274, 1143, 1188], '(ROS),': [275], 'resulting': [276], 'stress.6Several': [279], 'observational': [280], 'studies': [281, 338, 469, 570, 583, 1083], 'meta-analyses': [283], 'have': [284, 488, 571, 1010, 1365, 1504, 1530, 1572, 1626], 'identified': [285], 'elevations': [286], 'an': [290, 310, 350, 949, 1066, 1085, 1506], 'independent': [291, 628], 'marker': [292, 984], 'poor': [294, 298, 1986], 'cardiac': [295, 423, 763, 2054, 2460], 'function,': [296, 377, 424], 'mortality,': [297, 1509], 'functional': [299, 559, 2333], 'capacity,': [300, 560], 'development': [303], 'atrial': [305, 1922, 1954], 'arrhythmias': [306, 1515], 'HF.7–10': [308], 'active': [311, 640], 'hypothesis': [312], 'represent': [317], 'not': [318, 557, 768, 990, 1131, 1236, 1445, 1684, 2113, 2281], 'only': [319, 1120, 1132, 1546], 'prognostic': [321], 'but': [325, 1037, 1137, 1191, 2279], 'intervention.A': [330], 'second': [331], 'line': [332, 458], 'emerges': [335], 'from': [336, 662, 1198, 1652], 'experimental': [337, 1057], 'exploring': [339], 'role': [341, 2419, 2465, 2959, 2989], 'HF,': [345, 370, 634, 1130, 1430], 'showing': [346, 371, 470], 'first': [347], 'foremost': [349], 'upregulation': [351], 'enzyme': [354], 'system.6': [358], 'Furthermore,': [359], 'preclinical': [360], 'animal': [361, 455, 1502], 'data': [362, 1560], 'supported': [363, 462, 1436, 1460, 1635], 'inhibitors': [368, 417, 644, 902, 1483, 2017, 2322, 3160], 'greater': [372], 'survival,': [373], 'improved': [374, 392, 402, 721, 749, 797, 809, 2144], 'enhanced': [378], 'mechanoenergetic': [379, 426, 445], 'coupling,': [380], 'attenuation': [381], 'remodeling,': [384, 1512], 'decreased': [385], 'myocardial': [386, 403, 430, 1289, 1517, 1760, 2350, 2463, 2499, 2694], 'consumption,': [388], 'reduced': [389], 'afterload,': [390], 'vascular': [394, 2109, 2331], 'coupling.11,12': [395], 'In': [396, 502, 549, 906, 995, 1129, 1240, 1259], 'humans,': [397], 'intracoronary': [398], 'intravenous': [400], 'allopurinol': [401, 536, 555, 725, 1029, 2050, 2102, 2136], 'efficiency': [404, 1761], 'concentration': [408], 'high-energy': [410], 'phosphates': [411], 'within': [412], 'heart.3,13': [414], 'Therefore,': [415], 'animals': [419], 'humans': [421, 1060], 'improve': [422, 558, 769, 1595, 2018], 'enhancing': [425], 'coupling': [427, 446, 1282], 'while': [428], 'reducing': [429, 2108], 'consumption': [432], 'improving': [434, 3245], 'afterload.': [435], 'An': [436], 'important': [437, 600, 1138, 1357, 1559], 'insight,': [438], 'however,': [439, 603, 1216], 'enhancement': [443], 'depends': [447], 'degree': [450, 930], 'overexpression': [452], 'models.6A': [456], 'third': [457], 'by': [463, 880, 969, 1212, 1238, 1257, 1334, 1370, 1437, 1461, 1636, 1650, 2106, 2114], 'nested': [464], 'case-control': [465], 'retrospective': [467], 'cohort': [468], 'decrease': [472, 648, 855, 1074, 1205, 1496], 'readmissions': [475], 'all-cause': [477, 1886], 'mortality': [478, 1887, 2458, 2504, 3209], 'patients': [480, 499, 635, 813, 920, 958, 1588, 1763, 1989, 2250, 2855, 3276], 'with': [481, 500, 537, 546, 554, 702, 706, 776, 814, 853, 903, 921, 959, 1589, 1621, 1664, 1764, 1785, 1920, 1990, 2049, 2143, 2251, 2586, 2692, 2856, 3014, 3215], 'gout': [482], 'who': [483], 'receive': [484], 'allopurinol.14,15Together,': [485], 'these': [486, 671], 'findings': [487, 967, 1078, 1369], 'prompted': [489], 'series': [491, 1463], 'clinical': [493, 561, 595, 656, 1596, 1627], 'trials': [494, 665, 677], 'examining': [495], 'inhibition': [497, 553, 586, 1110, 1154, 1418, 1493, 1520, 1543, 1583, 1622, 2202, 2380, 2797], 'HF.': [501], 'issue': [504], 'Circulation,': [506], 'Givertz': [507, 881, 970, 1371, 2153, 2240, 3112], 'colleagues16': [509, 883], 'report': [510], 'results': [512, 624, 1058, 1554, 2255], 'Xanthine': [515, 2209, 3158], 'Inhibition': [517, 688, 2211], 'Hyperuricemic': [519, 2213], 'Patients': [522, 2216, 2922, 3013, 3118], '(EXACT-HF)': [523, 2217], 'trial,': [524, 610], 'double-blind,': [526], 'multicenter,': [527], 'randomized': [528, 569, 582, 664, 3172], 'trial': [529, 897, 1579], 'compared': [531, 802, 900], 'guideline': [532, 904], 'adherent': [533], 'therapy': [534, 539], 'plus': [535], 'guideline-adherent': [538], 'alone': [540], 'high-risk': [543, 709], 'population': [545], 'elevated': [547, 922, 946, 960], 'SUA.': [548], 'study,': [551, 912, 943, 2599], 'did': [556, 767, 1444], 'status,': [562], 'or': [563, 795, 1254, 1266, 1537, 1690, 2934, 2996], 'ejection': [566, 621, 864, 2382, 2865], 'fraction.': [567], 'Other': [568], 'reached': [572], 'similar': [573], 'conclusions': [574], 'summarized': [577], 'Table.17–21': [580], 'The': [581, 623, 1160, 1578, 2531, 2638, 2697, 2936, 2987, 2994], 'consistently': [589], 'fail': [590, 1528], 'show': [592, 611], 'improvement': [593, 614], 'composite': [596, 657, 770], 'outcomes.': [597, 658, 1597], 'It': [598], 'note,': [602], '2': [605, 1123], 'studies,': [606], 'EXACT-HF': [609, 1080, 1556], 'trends': [612], 'toward': [613, 1024], 'secondary': [616], 'outcomes': [617, 2853, 3247], 'like': [618], 'hospitalizations': [619, 1026], 'fraction.16,21': [622], 'seem': [625], 'severity': [631, 987, 2683], 'enrolled,': [636], 'metabolites': [641], 'dosages': [646], 'acid,': [650], 'different': [655], 'Another': [659, 1035], 'caveat': [661], 'long-term': [668, 1018], 'effects': [669, 1532, 2329, 2789], 'medications': [672, 1046], 'remain': [673], 'unknown': [674], 'because': [675, 1054, 1069, 1441], 'had': [678], 'short-term': [680], 'follow-up.Table.': [681], 'Comparison': [682, 2916], 'Randomized': [684, 2635], 'Studies': [685], 'Using': [686], 'HFAuthorHF': [690], 'Population,': [691], 'nXO': [692], 'InhibitorFollow-Up,': [693], 'wkPrimary': [694], 'Outcome': [695, 697], 'DefinitionPrimary': [696], 'ResultGivertz': [698], 'et': [699, 729, 773, 819, 971], 'al,16': [700], '2015253': [701], '>9.5': [704], 'mg/dL': [705, 782], 'more': [708], 'markerAllopurinol': [710], '300–600': [711], 'mg/d24Clinical': [712, 788], 'status:': [713], 'outcomes,': [714], 'medication': [715, 790], 'change,': [716, 791], 'patient': [718, 792], 'global': [719, 762, 793, 2348], 'assessment13%': [720], 'both': [723], 'placebo': [727, 807, 833], 'armsGreig': [728], 'al,19': [730], '201132': [731], 'NYHA': [732, 755, 784, 822, 838], 'class': [733, 756, 785, 823, 839], 'II–IIIAllopurinol': [734, 840], '300': [735, 758, 841], 'mg/d46-min': [736], 'walk': [737, 746, 847], 'test': [738, 747, 844], 'markersNo': [742], 'difference': [743, 849], '6-min': [745, 846], 'markersNasr': [751], 'Maurice,20': [753], '201059': [754], 'III–IVAllopurinol': [757], 'mg/d36Composite': [759], 'end': [760, 771], 'point:': [761], 'function': [764, 2021, 2105, 2351], 'mortality/morbidityAllopurinol': [766], 'pointHare': [772], 'al,17': [774], '2008405': [775], 'median': [778], '7.8': [781], 'III–IVOxypurinol': [786], '600': [787, 825], 'status:outcomes,': [789], 'assessment,': [794], 'NYHA43%': [796], 'oxypurinol': [800, 831, 913, 2248], 'arm': [801], 'vs': [803], '45%': [804], 'arm;': [808], 'primary': [810], 'outcome': [811, 1987], 'higher': [815, 827], 'levelsCingolani': [818], 'al,21': [820], '200660': [821], 'II–IIIOxypurinol': [824], 'mg/d4EF4.7±2.6%': [826], 'EF': [828], 'between': [829, 1949], 'armsGavin': [834], 'Struthers,18': [836], '200550': [837], 'mg/d12Exercise': [842], 'testNo': [848], 'exercise': [851, 2283], 'performance': [852], 'plasma': [857, 1786], 'BNPBNP': [858], 'indicates': [859, 1345], 'brain': [860], 'natriuretic': [861, 2274], 'peptide;': [862], 'EF,': [863], 'fraction;': [865], 'NYHA,': [866], 'New': [867, 2951, 3021], 'York': [868], 'Association;': [870], 'SUA,': [871, 923, 1591], 'acid;': [874], 'XO,': [876, 1480], 'oxidase.The': [878], 'study': [879, 935, 1440], 'part': [887], 'Oxypurinol': [890], 'Therapy': [891], 'Congestive': [893], '(OPT-CHF)': [896], 'results,': [898], 'therapy.': [905, 994], 'post': [907], 'hoc': [908], 'analysis': [909], 'showed': [914], 'benefit': [917, 926], 'correlated': [927], 'reduction.': [933], 'contributed': [936], 'rationale': [939], 'present': [942, 1439], 'used': [945, 1061], 'enrollment': [950], 'criterion': [951], 'select': [953], 'group': [956, 1030], 'XO.Potential': [961], 'epidemiological': [962], 'explanations': [963], 'negative': [966], 'reported': [968, 1031], 'al16': [972], 'others': [974], 'include': [975], 'possibility': [977, 1102], 'might': [980, 1196, 1364, 1419], 'just': [982], 'disease': [986], 'prognosis,': [989], 'addition,': [996, 1241], 'combination': [998], 'sample': [1000], 'size,': [1001], 'low': [1002], 'event': [1003], 'rates,': [1004], 'short': [1006], 'follow-up': [1007], 'time': [1008], 'could': [1009, 1040, 1111], 'limited': [1011], 'ability': [1013], 'detect': [1015], 'real': [1017], 'effect': [1019, 1487, 2376], 'shown': [1020], 'trend': [1023], 'lower': [1025], 'study.': [1034], 'unlikely': [1038, 1067], 'explanation': [1039], 'oral': [1045], 'subject': [1047], 'first-pass-effect': [1049], 'metabolism': [1050, 2955], 'liver': [1053], 'parenteral': [1062], 'allopurinol.3,13': [1063], 'theory': [1068], 'was': [1071], 'significant': [1073], 'SUA.The': [1076], 'nonsignificant': [1077], 'other': [1082, 1193, 1219, 1276, 1375, 1385, 1608], 'prompt': [1084], 'examination': [1086], 'mechanisms': [1090], 'basis': [1094, 1163], 'novel': [1097], 'strategy.': [1099], 'A': [1100, 2844, 2847, 3080, 3380, 3401], 'leading': [1101], 'explaining': [1103], 'lack': [1105], 'response': [1107], 'fact': [1114], 'pharmacological': [1117], 'strategy': [1118], 'addressed': [1119], 'limbs': [1124, 1609], 'underlying': [1125, 1161], 'nitroso-redox': [1126, 1158, 1202, 1337, 1362, 1382, 1453, 1551, 1570, 2467], '(Figure).': [1128], 'ROS-generating': [1134], 'pathways': [1135, 1379], 'upregulated,': [1136], 'aspects': [1139, 1568], 'nitrogen': [1142], 'production': [1144, 1190, 1211, 1223, 1293, 1619, 1624], 'downregulated.2Download': [1146], 'figureDownload': [1147], 'PowerPointFigure.': [1148], 'Effect': [1149], '(XO)': [1153], '(XOI)': [1155], 'balance.': [1159, 1203], 'mechanistic': [1162, 2733], 'XOIs': [1168, 1175, 1204], 'failing': [1171, 1226, 1525, 2025, 2081], 'heart.': [1172], 'As': [1173, 1598], 'shown,': [1174], 'act': [1176], 'key': [1179, 1277], 'enzyme,': [1180], 'XO/xanthine': [1181], 'dehydrogenase': [1182], '(XDH),': [1183], 'inhibit': [1185], '(ROS)': [1189], 'has': [1192], 'actions': [1194], 'detract': [1197], 'full': [1199], 'restoration': [1200], 'superoxide': [1210, 1351, 1400, 1471], 'inhibiting': [1213], 'XO.': [1214], 'Importantly,': [1215], 'sources': [1220], 'ROS': [1222, 1292, 1389, 1427, 1623], 'heart,': [1227], 'mitochondrial': [1229], 'respiration': [1230], 'NADPH': [1232, 1346], 'oxidases,': [1233], 'affected': [1237], 'XOIs.': [1239, 1258], 'nitric': [1242, 1409, 2423, 2454, 2494], 'oxide': [1243, 1410, 2424, 2455, 2495], '(NO)': [1244, 1411], 'synthase': [1245, 1482, 1500, 1535, 2456, 2496], '(NOS)': [1246], 'activity': [1247, 1536, 2585], 'impaired': [1250], 'further': [1255], 'disrupted': [1256], 'states': [1260], 'inadequate': [1262, 1421, 1593], 'NO': [1263, 1296, 1329, 1469, 1475, 1481, 1497, 1499, 1534, 1618], 'production,': [1264], 'oxidation': [1265], 'diminished': [1267], 'S-nitrosylation': [1268], 'ryanodine': [1271], 'receptor': [1272, 1274], '(RYR)': [1273], 'proteins': [1278], 'involved': [1279], 'excitation-contraction': [1281, 1342], 'impairs': [1283], 'calcium': [1284, 1313, 1319, 1323], 'cycling,': [1285], 'drives': [1287], 'optimal': [1288], 'performance.': [1290], 'Persistent': [1291], 'also': [1294, 1540], 'consumes': [1295], 'leads': [1298], 'peroxynitrite': [1300], 'formation,': [1301], 'can': [1303, 1494], 'cause': [1304, 2997], 'DNA,': [1305], 'protein,': [1306], 'lipid': [1308], 'damage.': [1309], 'Peroxynitrite': [1310], 'oxidizes': [1311], 'ATPase': [1314], 'SERCA': [1315], '(sarcoplasmic': [1316], 'reticulum': [1317], '[SR]': [1318], 'ATPase;': [1320], 'responsible': [1321], 'reuptake': [1324], 'SR).': [1327], 'continues': [1330], 'depleted': [1333], 'XOI,': [1335], 'perpetuating': [1336], 'causing': [1340], 'ineffective': [1341], 'coupling.': [1343], 'NOX': [1344], 'oxidases;': [1347], 'O−,': [1348], 'superoxide;': [1349, 1404], 'SOD,': [1350], 'dismutase;': [1352], 'XOR,': [1354], 'oxidoreductase.Three': [1356], 'factors': [1358], 'related': [1359], 'balance': [1363, 1454, 1612, 1730], 'bearing': [1366], 'colleagues.16': [1373], 'enzymes': [1376, 1386, 1392], 'metabolic': [1378, 2957, 3278], 'contribute': [1380], 'imbalance,': [1383], 'produce': [1388, 1414, 1473], '(NADPH': [1390], 'respiratory': [1395], 'chain': [1396], 'mitochondria);': [1399], 'dismutase,': [1401], 'neutralizes': [1403], 'family': [1407], 'synthases,': [1412], 'NO.': [1415], 'Selective': [1416], 'curtail': [1423], 'cascade': [1425], 'accumulated': [1428], 'and,': [1431], 'very': [1432], 'importantly,': [1433], 'myeloperoxidase': [1442], 'levels': [1443, 1783, 1792, 2134], 'change.': [1446], 'Second,': [1447], 'we': [1448], 'now': [1449], 'know': [1450], 'intimately': [1456], 'interconnected.': [1457], 'experiments': [1465], 'found': [1467], 'binds': [1470], 'peroxynitrite,': [1474], 'modulates': [1476], 'expression': [1478], 'abolish': [1484], 'contractile': [1486], 'inhibitors,': [1490], 'actually': [1495], 'production.6,22': [1498], '1–deficient': [1501], 'models': [1503], 'proven': [1505], 'increase': [1507], 'infarction.23,24': [1518], 'circulation': [1526], 'beneficial': [1531], 'if': [1533], 'signaling': [1538], 'depressed;': [1541], 'affect': [1545], 'limb': [1548], 'imbalance.Thus,': [1552], 'add': [1557], 'another': [1558], 'point': [1561], 'unravel': [1566], 'whether': [1567, 1616], 'target.': [1577], 'suggests': [1580], 'alone,': [1584], 'even': [1585], 'high': [1590], 'field': [1600], 'progresses,': [1601], 'it': [1602], 'will': [1603, 1625], 'crucial': [1605], 'examine': [1607], 'ask': [1615], 'augmenting': [1617], 'concomitantly': [1620], 'benefits': [1628], 'HF.Sources': [1630], 'FundingDr': [1632], 'National': [1637], 'Institutes': [1638], 'Health': [1640], 'grants': [1641, 1651], 'R01': [1642, 1644], 'HL110737,': [1643], 'HL107110,': [1645], 'R01HL084275,': [1646], '5UMHL113460': [1648], 'Starr': [1654], 'Foundation': [1655], 'Soffer': [1657], 'Family': [1658], 'Foundation.DisclosuresDr': [1659], 'discloses': [1661], 'relationship': [1663], 'Vestion': [1665], 'includes': [1667], 'equity,': [1668], 'board': [1669], 'membership,': [1670], 'consulting.': [1672], 'Dr': [1673], 'reports': [1675], 'no': [1676], 'conflicts.FootnotesThe': [1677], 'opinions': [1678], 'expressed': [1679], 'article': [1682], 'necessarily': [1685], 'those': [1686], 'editors': [1689], 'American': [1693, 2937, 2964, 3125, 3432], 'Association.Correspondence': [1695], '1501': [1704], 'NW': [1705], '10th': [1706], 'St,': [1707], '33136.': [1710], 'E-mail': [1711], '[email': [1712], 'protected]References1.': [1713], 'Braunwald': [1714], 'E.The': [1715], 'war': [1716], 'against': [1717, 2498, 2760], 'failure:': [1719, 1840, 1890, 2141, 2254, 2328], 'Lancet': [1721], 'lecture.Lancet.': [1722], '2015;': [1723, 2219], '385:812–824.': [1724], 'doi:': [1725, 1740, 1799, 1852, 1866, 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