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504, 604, 659, 682, 764, 785, 940, 1171, 1256, 1324, 1523, 1539, 1680, 2051, 2220, 2265, 2692, 2763, 2898, 2920, 3062, 3098, 3184, 3300], 'great': [80], 'forerunner': [81], 'noncatechol': [83], 'and': [84, 89, 124, 179, 184, 193, 200, 217, 255, 265, 438, 517, 527, 575, 589, 610, 642, 701, 725, 802, 820, 836, 840, 884, 893, 1036, 1050, 1053, 1116, 1155, 1189, 1200, 1217, 1275, 1285, 1301, 1304, 1401, 1412, 1442, 1447, 1457, 1500, 1544, 1549, 1564, 1572, 1578, 1599, 1617, 1645, 1652, 1661, 1697, 1724, 1747, 1753, 1767, 1773, 1777, 1903, 1939, 1960, 1966, 1970, 2032, 2089, 2095, 2110, 2123, 2149, 2180, 2187, 2255, 2409, 2418, 2442, 2460, 2474, 2480, 2565, 2622, 2753, 2820, 2845, 2870, 2885, 3067, 3119, 3154, 3287, 3326, 3335, 3378, 3424, 3443, 3471, 3477, 3487, 3504], 'nonglycoside': [85], 'novel': [86, 99, 600, 624, 633, 672, 717, 741, 879, 1012, 1357, 1381, 1511, 1770, 1780, 2221, 2320], 'cardiotonic': [87, 100, 546, 601, 673, 684, 718, 742, 880, 1013, 1358, 1382, 1512, 1860, 1920, 2079, 2200, 2222, 2358, 2423, 2451, 2696, 2764], 'agents': [88, 489, 547, 602, 743, 1014, 1359, 1383, 1513, 1620, 1921, 1978, 2069, 2165, 2201, 2243, 2359, 2424, 2815], 'given': [90, 159, 227], 'an': [91, 256, 584, 615, 1948, 1990, 3085], 'extraordinary': [92], 'strong': [93], 'impact': [94, 1246], 'in': [95, 128, 208, 218, 228, 252, 258, 274, 368, 397, 403, 451, 460, 507, 586, 644, 686, 753, 838, 904, 913, 943, 945, 948, 955, 969, 980, 1005, 1015, 1127, 1163, 1174, 1179, 1183, 1224, 1260, 1262, 1288, 1323, 1439, 1478, 1527, 1586, 1726, 1740, 1748, 1803, 1807, 1881, 1929, 1950, 1974, 1992, 2114, 2159, 2267, 2316, 2369, 2505, 2508, 2520, 2550, 2639, 2699, 2706, 2767, 2786, 2792, 2823, 2849, 2877, 2961, 2996, 3035, 3117, 3122, 3180, 3278, 3338, 3343, 3387, 3481], 'development': [97, 205, 596, 670, 715, 1220, 1857, 2197, 2896], 'agents.': [101, 674, 1654, 2117, 2449], 'Unexpectedly,': [102], 'amrinone': [103, 150, 241, 271, 298, 412, 444, 653, 680, 783, 811, 830, 857, 883, 1035, 1078, 1161, 1593, 1738, 2217, 2785], 'failed': [104, 3386], 'rescue': [106, 1515], 'patients': [108, 452, 541, 687, 1365, 1395, 1503, 1517, 1677, 1839, 2175, 2300], 'with': [109, 173, 244, 262, 290, 357, 425, 453, 542, 583, 705, 865, 1242, 1366, 1396, 1491, 1504, 1518, 1542, 1769, 1792, 1818, 1836, 1842, 1989, 2070, 2098, 2107, 2176, 2264, 2293, 3058, 3483], 'chronic': [110, 133, 1367, 1506, 1519, 1531, 1590, 1608, 1700, 2177, 3037, 3055, 3388], 'heart': [111, 134, 259, 314, 454, 497, 510, 543, 587, 648, 694, 847, 1228, 1368, 1397, 1455, 1507, 1520, 1532, 1591, 1609, 1687, 1701, 1789, 1837, 2178, 2209, 2370, 3038, 3056, 3182, 3340, 3389, 3489], 'failure,': [112, 1398, 2179, 3490], 'thereby': [113], 'produced': [114], 'prominent': [116, 1524], 'paradigm': [117, 1525, 1597, 1657], 'shift': [118, 1526, 1598], 'from': [119, 926, 1962, 3392], 'inotropic': [120, 156, 192, 340, 383, 424, 488, 577, 780, 808, 861, 919, 1009, 1032, 1042, 1075, 1535, 1580, 1653, 1735, 2004, 2448, 2782, 2814, 2838, 3086], 'cardioprotective': [122, 1616], 'therapy,': [123], 'contributed': [125, 1600], 'advances': [127], 'current': [130], 'pharmacotherapy': [131, 495], 'failure.Mysterious': [135], 'Agent': [138], 'Acting': [139, 1850], 'Through': [140, 1851], 'Unknown': [141], 'MechanismIn': [142], 'this': [143, 391, 523, 747, 984, 1321, 1332, 1656, 1871, 2640], 'study,': [144], 'Alousi': [145, 655, 801, 1194, 1316, 1752, 1828, 2687, 2733], 'al': [147, 657, 1196, 1830], 'showed': [148, 185], 'that': [149, 277, 281, 297, 310, 362, 377, 411, 421, 468, 679, 752, 777, 805, 856, 877, 908, 989, 1124, 1147, 1182, 1380, 1621, 1670, 1797, 1876, 1935, 2163, 2195, 2244, 2286, 2298, 3234], 'is': [151, 490, 750, 812, 831, 960, 994, 1024, 1079, 1136, 1238, 1283, 1664, 1874, 2008, 2015, 2157, 2202, 2334, 2345, 2485], 'potent,': [153], 'long-acting': [154], 'positive': [155, 191, 423, 487, 779, 807, 860, 918, 1008, 1031, 1041, 1074, 1734, 2003, 2837, 3384], 'agent': [157, 349, 625, 2321, 2697, 2839], 'when': [158, 224], 'orally': [160, 171, 598], 'or': [161, 166, 214, 221, 351, 374, 1134, 2399, 2649], 'intravenously': [162], 'either': [164], 'anesthetized': [165], 'unanesthetized': [167], 'dogs.': [168], 'Amrinone': [169, 196, 328, 730], 'was': [170, 226, 272, 296, 322, 342, 360, 408, 466, 603, 677, 902, 910, 924, 987, 1472, 1481, 1710], 'active': [172], 'rapid': [175], 'onset': [176], 'action': [178, 219, 318, 735, 920, 1066, 1082, 2446], 'duration': [180, 209, 2261], '>5': [182], 'hours': [183], 'wide': [187, 273, 434, 786], 'separation': [188], 'between': [189], 'chronotropic': [194, 428], 'effect.': [195], 'increased': [197, 309, 1497], 'contractile': [198, 212, 473, 501, 537, 970, 1795, 1815, 1882, 2065, 2232], 'force': [199, 204, 538, 2844], 'rate': [202, 260, 588, 2269], 'without': [206, 696, 1954], 'changes': [207, 367, 2876], 'cycle': [213], 'time-to-peak': [215], 'tension,': [216], 'potential': [220, 1681, 1926, 2074], 'excitability': [222], 'even': [223], 'it': [225, 465, 676, 749, 873, 959, 986, 1378, 1480, 1873], 'relatively': [229, 426], 'high': [230, 1550, 2757], 'concentrations.': [231], 'The': [232, 267, 387, 825, 1019, 1069, 1230, 1306, 1534, 1556, 2002, 3040, 3168, 3428], 'toxicological': [233], 'studies': [234, 400], 'attested': [235], 'low': [238], 'toxicity': [239], '≤10': [242], 'mg/kg,': [243], 'less': [245, 1158], 'serious': [246, 553, 559], 'side': [247, 697], 'effects': [248, 578, 698, 3169], 'such': [249, 555, 720, 1047, 1152, 1632, 2081, 2138, 2249, 2326, 2468, 2554], 'as': [250, 401, 556, 721, 1048, 1153, 1206, 1633, 2082, 2139, 2219, 2250, 2327, 2469, 2555, 3084], 'lowering': [251, 1087, 2585], 'blood': [253, 1551], 'pressure': [254, 1552], 'increase': [257, 301, 534, 585, 942, 1126, 1949, 1980, 1991, 2025, 2185, 2396, 2903], 'compared': [261, 1241], 'cardiac': [263, 279, 302, 355, 372, 472, 481, 525, 536, 560, 564, 640, 690, 793, 842, 871, 1057, 1413, 1453, 1557, 1567, 1570, 1618, 1794, 1814, 1846, 1878, 2415, 2436, 2769, 2904, 2965, 3152, 3172, 3178, 3231, 3305, 3439], 'glycosides': [264, 280, 526, 565, 641, 691], 'catecholamines.': [266], 'therapeutic': [268, 284], 'index': [269, 285], 'contrast': [275, 1180], 'have': [282, 566, 1310, 1348, 1622, 1832, 1943, 2091, 2152], '≈2': [287], '3,': [289], 'life-threatening': [291], 'arrhythmias.': [292, 561], 'Of': [293], 'greater': [294], 'interest': [295, 1259, 1663], 'did': [299, 329, 413], 'not': [300, 330, 343, 414, 849, 911, 2104, 2182, 2213, 2290, 2302, 2643], 'output': [303], 'normal': [306, 3118], '(nonfailing),': [307], 'but': [308, 1399, 1985, 2275, 2538], 'failing': [313], 'model.The': [315], 'mechanism': [316, 337, 634, 736, 915, 1425], 'amrinone,': [320, 922, 1132, 1864, 2121, 2454], 'however,': [321, 393, 1309, 2308], 'shown': [323, 410, 1482, 1624, 2158], 'only': [324], 'by': [325, 345, 352, 484, 513, 519, 630, 654, 815, 863, 887, 1095, 1108, 1131, 1138, 1266, 1437, 1650, 1751, 1863, 1947, 1996, 2018, 2038, 2048, 2057, 2067, 2355, 2407, 2571, 2578, 3097, 3115, 3281], 'exclusion': [326], 'criteria.': [327], 'seem': [331, 2183], 'act': [333, 886, 1922, 1936, 2226, 2245, 2462, 2477], 'via': [334, 731, 1090, 1923, 2463, 2478, 2595], 'catecholamine': [336, 2900], 'because': [338, 499, 571, 592, 1080, 1162, 1449, 1678, 1998, 2028], 'its': [339, 859, 1203, 1485], 'effect': [341, 384, 685, 781, 809, 862, 1010, 1033, 1043, 1055, 1076, 1736, 2005, 2012, 2783], 'blocked': [344], 'β-receptor': [347], 'blocking': [348], 'propranolol': [350], 'depletion': [353], 'norepinephrine': [356], 'reserpine.': [358], 'It': [359, 407, 1120, 1143], 'reported': [361, 678, 903], 'there': [363], 'were': [364, 394, 1416, 1968], 'no': [365, 2132, 2153], 'significant': [366], 'level': [370, 932, 1761, 2042, 2518, 2534], 'cAMP': [373, 909, 931, 944, 968, 978, 1004, 1089, 1178, 1280, 1282, 1438, 1766, 1822, 1997, 2039, 2055, 2500, 2517, 2587, 2959], 'phosphodiesterase': [375, 2511, 2765], '(PDE)': [376], 'could': [378, 638, 1326, 1428, 2237], 'be': [379, 997, 1122, 1429, 1885, 2061, 2112], 'responsible': [380], 'for': [381, 448, 692, 1209, 1683, 1855, 2063, 2205, 2618, 2633, 2761, 3304], 'amrinone.': [386, 770, 852], 'original': [388, 906, 1825], 'observations': [389, 854, 2284], 'on': [390, 668, 974, 1212, 1714, 2722, 2816, 2842, 2866, 3033, 3150, 3177, 3333], 'respect,': [392], 'disproved': [395], 'soon': [396, 876], 'subsequent': [399, 714, 755, 894, 1906, 2373], 'detailed': [402], 'following': [405], 'section.': [406], 'further': [409, 1210, 1868], 'inhibit': [415, 1027], 'Na+/K+': [416], 'ATPase': [417], 'activity.The': [418], 'authors': [419], 'suggested': [420], 'weak': [427], 'effect,': [429], 'vasodilatory': [431], 'properties,': [432], 'margin': [435, 570], 'safety,': [437], 'oral': [440, 1492, 3031], 'activity': [441, 892, 2724], 'would': [442], 'make': [443], 'prime': [446], 'candidate': [447], 'clinical': [449, 611, 1346, 1354, 1376, 1460, 1708, 2161, 2314, 2341, 2353, 3068], 'testing': [450], 'failure.State-of-the-Art': [455], 'Therapy': [459], '1970sIn': [461], 'late': [463, 2279], '1970s': [464], 'believed': [467], 'reverse': [470, 2401], 'dysfunction': [474, 502, 1796, 2288], 'leading': [475], 'improvement': [477, 1812], 'impaired': [480, 2403], 'pump': [482, 1562, 2416], 'function': [483, 1563, 2417, 3179], 'means': [485, 2356], 'mainstay': [492], 'failure': [498, 511, 695, 1509, 1521, 1688, 1702, 1790, 1806, 1838, 2210, 2371, 2705, 3057, 3341], 'plays': [503, 1170], 'key': [505], 'role': [506, 966, 1002, 1173, 1214, 1541, 3000], 'symptoms': [508], 'directly': [512], 'causing': [514, 557], 'hemodynamic': [515, 1487, 1805], 'disorders': [516], 'indirectly': [518], 'driving': [520, 662], 'compensatory': [521], 'mechanisms.For': [522], 'purpose,': [524], 'catecholamines': [528, 580, 643], 'had': [529, 618, 1537, 1671], 'long': [530], 'administered': [532], 'failure.': [544, 1229, 1369, 1533, 1610, 3039], 'However,': [545, 2192, 2367], 'belonging': [548], 'these': [550, 628, 740, 878, 1164, 1342, 2068, 2101, 2164, 2294], 'classes': [551], 'possess': [552, 2131], 'drawbacks,': [554], 'readily': [558, 2291], 'In': [562, 746, 771, 795, 1038, 1655, 1870], 'addition,': [563], 'very': [567], 'narrow': [568], 'safety': [569], 'Ca2+': [573, 1045, 1128, 1434, 1879, 1890, 1899, 1908, 1933, 1952, 1963, 1983, 1993, 2026, 2035, 2136, 2224, 2235, 2295, 2404, 2466, 2552, 2557, 2868, 2881, 3113], 'overload,': [574], 'are': [581, 1061, 1157, 1614, 1755, 1783, 1932, 1971, 1986, 2103, 2166, 2301, 2425, 2502, 2642], 'associated': [582, 1791, 1988, 2106], 'energetic': [590, 1944], 'disadvantages': [591, 629], 'metabolic': [594], 'stimulation.The': [595], 'available': [599, 1919, 1973], 'dream': [605, 1826], 'both': [607, 1198, 2092], 'basic': [608], 'researchers': [609], 'cardiologists,': [612], 'and,': [613], 'therefore,': [614], 'extensive': [616, 1345, 2304, 2428], 'effort': [617, 1854, 2344], 'accumulated': [620], 'discover': [622], 'overcome': [627, 983], 'acting': [631, 1205, 1384, 1946, 2322], 'through': [632, 1385, 1937, 2228, 2246, 2323, 2589, 2883], 'action,': [636, 2134], 'which': [637, 923, 1237, 1427, 1479], 'replace': [639], 'treatment': [646, 1226, 1529, 1588, 2701], 'failure.Consequently,': [649], 'study': [651, 1471], 'caused': [658, 1522], 'big': [660, 1245], 'sensation,': [661], 'several': [663, 1917, 2078], 'pharmaceutical': [664], 'companies': [665], 'target': [667], 'Furthermore,': [675], 'induced': [681, 1130, 2056], 'marked': [683], 'already': [688], 'taking': [689], 'severe': [693, 1505, 3036], 'arrhythmias': [700, 1411], 'altered': [702, 2215], 'arterial': [703], 'pressure.1Amrinone': [704], 'bipyridine': [707], 'skeleton': [708], 'became': [709, 744, 874, 1144, 1574, 1582], 'lead': [711], 'compound': [712], 'agents,': [719, 881, 1861, 2080, 2452], 'milrinone,': [722, 885, 1133, 1776, 2122, 2455], 'enoximone,': [723], 'piroximone,': [724], 'orprinone.Mechanism': [726], 'Action': [728], 'PDE3': [732, 891, 937, 1386, 1781, 2000, 2030, 2058, 2118], 'InhibitionMeanwhile,': [733], 'all': [738, 2540], 'evident.': [745], 'context,': [748, 1872], 'noteworthy': [751, 1875], 'issue': [756], 'Circulation': [758, 1247], 'Research,': [759], 'Katz': [760, 1744, 2711], 'al2': [762, 1746], 'sent': [763], 'letter': [765, 1742], 'editor': [768], 'concerning': [769], 'letter,': [773, 800], 'they': [774], 'pointed': [775], 'out': [776], 'shows': [784], 'range': [787], 'species-dependent': [789, 1730], 'variation': [790], 'among': [791], 'mammalian': [792, 1016, 1150, 1185], 'muscle.': [794], 'reply': [797, 1750], 'Farah3': [803], 'recognized': [804], 'markedly': [813], 'influenced': [814], 'species': [817, 1165], 'animals': [819], 'stage': [822], 'development.': [824], 'order': [826], 'sensitivity': [828, 1953, 1984, 3114], 'dog,': [832], 'cat,': [833], 'monkey,': [834], 'rabbit,': [835], 'least': [837], 'rat,': [839], 'fetal': [841], 'tissue': [843], 'sheep': [846], 'does': [848], 'respond': [850], 'These': [853, 1977, 2283], 'imply': [855], 'elicits': [858], 'interacting': [864], 'intrinsic': [867], 'regulatory': [868, 2405], 'process': [869, 1905, 2439], 'contraction.Actually,': [872], 'evident': [875, 1145], 'including': [882, 1086, 1187, 1295, 2120, 2453], 'inhibition': [888, 938, 1070, 1091, 1111, 1387, 2031, 2059], 'activation': [895, 1096, 1117, 1958, 2330, 2488, 2596], 'cAMP/protein': [897, 2495], 'kinase': [898, 1114, 2496], 'A/Ca2+': [899], 'pathway': [900], '(Figure).It': [901], 'article': [907, 1192, 1231, 1314, 1322, 2641], 'involved': [912, 2549], 'concluded': [925], 'measurements': [927], 'global': [930], 'myocardial': [934, 956, 981, 1440, 2365, 2397, 2704, 3095], 'tissue.': [935], 'Because': [936], 'induces': [939], 'regional': [941], 'microdomain,': [946], 'mainly': [947, 2519], 'vicinity': [950, 2522], 'sarcoplasmic': [952, 2525], 'reticulum': [953, 2526, 2603], 'membrane': [954], 'cells': [957, 1441, 2398, 3233, 3277], '(Figure),4': [958], 'extremely': [961], 'difficult': [962], 'evaluate': [964], 'regulation': [971, 1883, 1897, 2066, 3110], 'just': [972], 'based': [973], 'measurement': [976], 'levels': [979, 2501], 'tissue.To': [982], 'difficulty,': [985], 'proposed': [988], 'stimulation': [990, 1104], 'muscarinic': [992, 1020, 1140, 2020, 2575], 'receptors': [993], 'able': [995, 1025], 'used': [998, 1613, 1785], 'differentiate': [1000], 'mediating': [1006], 'ventricular': [1017, 1410, 2795, 2825, 2852, 3125], 'muscle.5': [1018], 'receptor': [1021, 1059, 1141, 1640, 1643, 2021, 2257, 2484, 2577, 3060, 3065], 'agonist': [1022, 2458, 2531], 'carbachol': [1023], 'selectively': [1028, 2902], 'cAMP-mediated': [1030, 1073], 'milrinone.5,6': [1037], 'contrast,': [1039], 'sensitizers,': [1046, 2137, 2296, 2467], 'sulmazole6': [1049], 'Org': [1051, 2086, 2251, 2472, 2840], '30019,7': [1052, 2252], 'α-adrenergic': [1058, 2150, 2256], 'agonist8': [1060], 'resistant': [1062], 'inhibitory': [1065, 1099, 2094, 2155], 'carbachol.': [1068], 'at': [1083, 1759, 2040, 2231], 'multiple': [1084], 'sites,': [1085], 'adenylyl': [1093, 1296, 2592], 'cyclase': [1094, 2593], 'GTP-binding': [1100], 'protein': [1101, 1113, 2491, 2568], 'Gi': [1102, 2490, 2598], '(Figure),': [1103], 'PDE': [1106, 2093, 2154], '2': [1107, 3190], 'cyclic': [1109, 2789, 2817, 2993, 3002], 'GMP,': [1110], 'A,': [1115, 2718, 2936, 2940, 2944, 2982, 3210, 3218, 3296], 'phosphatase.': [1119], 'should': [1121], 'noted': [1123, 1739], 'transients': [1129, 1900, 1994, 2027, 2822, 2848, 2869], 'forskolin': [1135], 'abolished': [1137], 'agonist.6': [1142], 'later': [1146], 'small': [1149, 2052], 'species,': [1151, 1186], 'rat': [1154, 2964], 'mouse,': [1156], 'sensitive': [1159], 'PDE4,': [1166], 'rather': [1167, 1239, 2276], 'than': [1168], 'PDE3,': [1169], 'main': [1172, 1418], 'hydrolysis': [1176], 'larger': [1184], 'human': [1188, 3230], 'dog.Hence,': [1190], 'created': [1197], 'excitement': [1199], 'controversy': [1201], 'after': [1202, 2918], 'publication,': [1204], 'catalyst': [1208], 'research': [1211], 'PDEs': [1216, 1223, 1261, 1768], 'drug': [1219, 3431], 'related': [1221], 'cited': [1234], '≈340': [1235], 'times,': [1236], 'modest': [1240], 'many': [1243], 'other': [1244, 1302, 1779, 2109, 2115], 'Research': [1248, 3043], 'articles': [1249], '(eg,': [1250], 'dobutamine).9': [1252], 'There': [1253], 'resurgence': [1257], 'recent': [1263, 1307], 'years,': [1264], 'driven': [1265], 'ability': [1268], 'better': [1270], 'characterize': [1271], 'molecular': [1273], 'localization': [1274], 'effector': [1277], 'targets': [1278], 'signaling.': [1281, 2499], 'complexly': [1284], 'locally': [1286], 'regulated': [1287], 'subcellular': [1289], 'functional': [1290, 2547], 'compartments': [1291], 'containing': [1292], 'marcomolecular': [1293], 'complexes,': [1294], 'cyclase,': [1297], 'β-adrenergic': [1298, 1642, 1668, 1718, 3059], 'receptors,': [1299, 2560], 'PDEs,': [1300], 'enzymes': [1303], 'proteins.10–12': [1305], 'publications,': [1308], 'largely': [1311], 'ignored': [1312], 'al.': [1318, 3167], 'Therefore,': [1319, 2390], 'highlighting': [1320], 'commentary': [1325], 'conceivably': [1327], 'draw': [1328], 'attention': [1329], 'back': [1330], 'early': [1333, 1728, 2271, 2340], 'pioneering': [1334], 'work.Paradigm': [1335], 'FailureDuring': [1341], '3': [1343, 1888, 2512], 'decades,': [1344], 'trials': [1347, 1709, 2162], 'performed': [1350], 'elucidate': [1352], 'effectiveness': [1355, 1666, 2387, 2421], 'prolong': [1361, 1626, 2259], 'life': [1363, 1393, 1628, 2173], 'After': [1370], 'accumulation': [1371, 2049], 'tremendous': [1373], 'amount': [1374, 2053], 'trials,': [1377, 1461, 3395], 'proved': [1379, 1691], 'effectively': [1388, 1693], 'improved': [1389], 'quality': [1391, 2171], 'surprisingly': [1400], 'disappointedly': [1402], 'abbreviated': [1403], 'lifespan': [1405], 'patients.': [1408, 2191], 'Severe': [1409], 'sudden': [1414], 'death': [1415], 'cause': [1419], 'patient': [1422], 'death,': [1423], 'ascribed': [1430], 'intracellular': [1433, 1763], 'overload': [1435], 'mediated': [1436, 1995, 2882], 'excessive': [1443], 'expenditure': [1444, 1955], 'energy': [1446, 1959, 2955], 'oxygen': [1448], 'facilitation': [1451], 'contractility,': [1454], 'rate,': [1456], 'metabolism.': [1458], 'Among': [1459], 'outcome': [1463, 1706], 'Prospective': [1466], 'Randomized': [1467], 'Milrinone': [1468], 'Survival': [1469], 'Evaluation': [1470], 'one': [1473], 'most': [1476], 'influential,': [1477], 'that,': [1483], 'despite': [1484], 'beneficial': [1486], 'actions,': [1488], 'long-term': [1489], 'therapy': [1490, 1536, 1581, 1606, 2207, 3303], 'milrinone': [1493, 3032], '(40': [1494], 'mg': [1495], 'daily)': [1496], 'morbidity': [1499, 1698, 2186], 'mortality': [1501, 1696, 2188, 3034], 'failure.13The': [1508], 'played': [1538], 'central': [1540, 1938, 2479], 'diuretics,': [1543], 'control': [1545], 'neurohumoral': [1547], 'factors': [1548], 'being': [1553, 1648, 1757, 1840], 'ancillary': [1554], 'therapy.': [1555], 'protection,': [1558], 'unloading': [1559, 1619], 'suppression': [1565, 2590], 'remodeling,': [1568], 'namely': [1569], 'hypertrophy': [1571], 'fibrosis,': [1573], 'first': [1576], 'choice,': [1577], 'secondary': [1584], 'choice': [1585], 'failure.Ironically,': [1592], 'thus': [1594], 'triggered': [1595], 'establish': [1602], 'modern': [1604], 'pharmacological': [1605, 2754], 'Nowadays,': [1611], 'primarily': [1612, 2535], 'span': [1629], 'patients,': [1631, 1703], 'angiotensin-converting': [1634], 'enzyme': [1635], 'inhibitors,': [1636, 2119], 'angiotensin': [1637], 'II': [1638], 'AT1': [1639], 'blockers,': [1641, 1644], 'aldosterone': [1646], 'antagonists,': [1647], 'followed': [1649], 'diuretic': [1651], 'shift,': [1658], 'especially': [1659, 2368], 'impressive': [1660], 'blockers': [1669, 1719], 'previously': [1673], 'contraindicated': [1674], 'risk': [1682], 'exacerbation': [1684], 'concealed': [1686], 'syndrome.': [1689], 'β-Blockers': [1690], 'improve': [1694], 'although': [1704], 'quite': [1711], 'controversial': [1712], 'depending': [1713], 'type': [1716], 'used,': [1720], 'dosage': [1722], 'regiment,': [1723], 'races': [1725], 'days.14The': [1729], 'differences': [1731], 'Falah3': [1754], 'currently': [1756, 1784, 1866, 2212, 2426], 'elucidated': [1758], 'compartmentalization': [1764], 'molecular,': [1771], 'biochemical,': [1772], 'imaging': [1774], 'tools.10–12Amrinone,': [1775], 'some': [1778, 1975], 'inhibitors': [1782, 2514], 'treat': [1787], 'acute': [1788, 1793, 1804, 2375], 'constitutes': [1798], 'cardiovascular': [1799], 'emergency': [1800], 'result': [1802], 'absence': [1809], 'immediate': [1811, 1843], 'function.': [1816], 'Thus,': [1817], 'selective': [1819, 2329], 'targeting': [1820], 'pools,': [1823], 'may': [1831, 2024, 2060, 2289], 'finally': [1833], 'reached': [1834], 'fruition': [1835], 'treated': [1841], 'elevation': [1844], 'contractility.Potential': [1847], 'Agents': [1849], 'MechanismThe': [1853], 'ideal': [1859, 2199], 'initiated': [1862], 'continuing.': [1869], 'signaling': [1880, 2995], 'can': [1884, 2111], 'classified': [1886], 'into': [1887], 'processes:': [1889], 'binding': [1891, 1909, 2567, 2759], 'troponin': [1893, 1911, 2563, 3440], 'C': [1894, 1912], '(central': [1895], 'mechanism),': [1896, 1902], '(upstream': [1901], '(downstream': [1913], 'mechanism)15,16': [1914], '(Figure).': [1915], 'Although': [1916, 2077, 2450], 'clinically': [1918, 1972], 'upstream': [1924, 2464], 'mechanism,': [1925, 2248, 2325, 2465], 'promising': [1927], 'candidates': [1928], 'future': [1931, 2392], 'sensitizers15,16': [1934], 'downstream': [1940, 2481, 3099], 'mechanism.': [1941, 2482], 'They': [1942], 'advantages': [1945], 'myofilament': [1951, 1982, 2332, 3112], 'free': [1961], 'overload.': [1964], 'Pimobendan': [1965], 'levosimendan': [1967, 2007, 3116], 'developed': [1969, 2843], 'countries.': [1976], 'actually': [1979], 'also': [1987], 'inhibition.': [2001], 'abolished,': [2009], 'whereas': [2010, 2135, 2528], 'pimobendan': [2014, 3480], 'partially': [2016], 'inhibited': [2017], 'agonist.': [2022], 'Levosimendan': [2023], 'enhance': [2033], 'signal': [2036], 'facilitated': [2037], 'myofilaments.17': [2044], 'Acceleration': [2045], 'relaxation': [2047], 'favorable': [2062], 'respect': [2071], 'avoiding': [2073], 'diastolic': [2075, 2240, 2287], 'disturbance.': [2076], 'theophylline,': [2083], 'caffeine,': [2084], 'sulmazole,15': [2085], '30029,7': [2087], 'levosimendan,17': [2088], 'pimobendan,': [2090], 'Ca2+-sensitizing': [2096, 2133, 2247], 'actions': [2097, 2102, 3147], 'different': [2099], 'extents,': [2100], 'always': [2105], 'each': [2108], 'separated': [2113], 'pure': [2116], 'EMD': [2124, 2140, 2253, 2470], '57439': [2125], '[(−)-enantiomer': [2126], 'thiadiazine': [2129, 2145], 'derivative],18': [2130, 2146], '57033': [2141], '[(+)-enantiomer': [2142], 'CGP': [2147], '48506,16': [2148], 'agonist,8': [2151, 2258], 'action.It': [2156], 'middle-scale': [2160], 'capable': [2167], 'improving': [2169, 2414], 'do': [2181], 'situation': [2194], 'earnestly': [2203], 'desired': [2204], 'since': [2216], 'appeared': [2218], 'agent.': [2223], 'sensitizers': [2225, 2236], 'likewise': [2227], 'various': [2229, 2313], 'mechanisms': [2230], 'proteins.15,16,18': [2233], 'Whereas': [2234], 'theoretically': [2238], 'induce': [2239], 'dysfunction,': [2241], '57033,18': [2254], 'contraction': [2263], 'decrease': [2266], 'phase': [2272, 2280, 2338, 3189], 'relaxation,': [2274], 'accelerate': [2277], 'relaxation.7,8,18': [2282], 'indicate': [2285], 'occur': [2292], 'provided': [2297], 'experiencing': [2303], 'tachycardia.': [2305], 'This': [2306], 'issue,': [2307], 'requires': [2309, 2360], 'careful': [2310], 'investigations': [2311], 'under': [2312, 2336, 2427], 'situations': [2315], 'future.': [2318], 'A': [2319, 2497], 'unique': [2324], 'ATPase,': [2333], 'still': [2335], 'trial.19': [2342], 'Further': [2343], 'necessary': [2346], 'achieve': [2348], 'goal': [2350], 'establishing': [2352], 'effectiveness.Pharmacotherapy': [2354], 'presence': [2362], 'intact': [2364, 2850], 'cells.': [2366], 'developing': [2372], 'coronary': [2376], 'syndrome,': [2377], 'lack': [2379], 'sufficient': [2381], 'number': [2382], 'myocytes': [2384, 2966, 3153], 'limits': [2385], 'pharmacotherapy.': [2389], 'nonpharmacological': [2393], 'options': [2394], 'apparatus': [2406], 'gene': [2408, 3282], 'stem': [2410, 3232], 'cell–based': [2411], 'approaches': [2412], 'increasing': [2419, 2515], 'development.20–22Download': [2429], 'figureDownload': [2430], 'PowerPointFigure.': [2431], 'Tales': [2432], 'Ocean:': [2435], 'excitation–contraction': [2437], 'coupling': [2438], 'focusing': [2440], 'Ca2+signaling': [2441], 'site': [2444], 'β1-receptor': [2457, 2530], 'dobutamine,9': [2459], 'forskolin,': [2461], '57033,': [2471], '30029,': [2473], 'Omecamtiv': [2475], 'mecarbil,': [2476, 3176], 'M2': [2483, 2576], 'coupled': [2486], 'suppress': [2493], '(PKA)': [2498], 'finely': [2503], 'tuned': [2504], 'microdomain': [2507], 'cardiomyocyte,': [2510], '(PDE3)': [2513], 'membrane,': [2527], 'elevating': [2532], 'near': [2536], 'sarcolemma,': [2537], 'then': [2539], 'over': [2541], 'cardiomyocyte.': [2543], 'Phosphorylation': [2544], '(P)': [2545], 'proteins': [2548], 'regulating': [2551], 'signaling,': [2553], 'L-type': [2556], 'channels,': [2558], 'ryanodine': [2559], 'phospholamban': [2561], '(PLB),': [2562], 'I,': [2564], 'myosin': [2566, 3173], 'C,': [2569, 3204, 3265, 3319, 3441], 'catalyzed': [2570], 'PKA.': [2572], 'Activation': [2573], 'acetylcholine': [2579], '(ACh)': [2580], '(or': [2581], 'carbachol)': [2582], 'leads': [2583], 'partly': [2588], '(AC)': [2594], 'protein.': [2599], 'SERCA2': [2600], 'indicates': [2601], 'sarcoendoplasmic': [2602], 'Ca2+-ATPase.AcknowledgmentsI': [2604], 'thank': [2605], 'Dr': [2606], 'Kuniaki': [2607], 'Ishii,': [2608], 'Professor,': [2609], 'Medicine': [2617, 2632], 'reading': [2619], 'article,': [2621], 'Ikuo': [2623], 'Norota,': [2624], 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