{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:05:57Z","timestamp":1786982757323,"version":"build-2736575974"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2016,4,4]],"date-time":"2016-04-04T00:00:00Z","timestamp":1459728000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100011725","name":"Servier","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drugs"],"published-print":{"date-parts":[[2016,5]]},"DOI":"10.1007\/s40265-016-0567-2","type":"journal-article","created":{"date-parts":[[2016,4,4]],"date-time":"2016-04-04T06:52:49Z","timestamp":1459752769000},"page":"733-740","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Ivabradine: Cardioprotection By and Beyond Heart Rate Reduction"],"prefix":"10.1007","volume":"76","author":[{"given":"Gerd","family":"Heusch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Kleinbongard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,4]]},"reference":[{"key":"567_CR1","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.2165\/00003495-200464160-00003","volume":"64","author":"D DiFrancesco","year":"2004","unstructured":"DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I f current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757\u201365.","journal-title":"Drugs."},{"key":"567_CR2","first-page":"103","volume":"1","author":"JS Borer","year":"2004","unstructured":"Borer JS. Drug insight: I f inhibitors as specific heart-rate-reducing agents. Nature. 2004;1:103\u20139.","journal-title":"Nature."},{"key":"567_CR3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jjcc.2013.02.018","volume":"62","author":"F Custodis","year":"2013","unstructured":"Custodis F, Reil JC, Laufs U, Bohm M. Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol. 2013;62:183\u20137.","journal-title":"J Cardiol."},{"key":"567_CR4","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1161\/CIRCULATIONAHA.112.000145","volume":"127","author":"F Roubille","year":"2013","unstructured":"Roubille F, Tardif JC. New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels. Circulation. 2013;127:1986\u201396.","journal-title":"Circulation."},{"key":"567_CR5","doi-asserted-by":"crossref","first-page":"503","DOI":"10.2170\/jjphysiol.40.503","volume":"40","author":"N Tanaka","year":"1990","unstructured":"Tanaka N, Nozawa T, Yasumura Y, Futaki S, Hiramori K, Suga H. Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart. Jpn J Physiol. 1990;40:503\u201321.","journal-title":"Jpn J Physiol."},{"key":"567_CR6","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/sj.bjp.0707673","volume":"153","author":"G Heusch","year":"2008","unstructured":"Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153:1589\u2013601.","journal-title":"Br J Pharmacol."},{"key":"567_CR7","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1016\/j.jacc.2010.09.014","volume":"56","author":"F Custodis","year":"2010","unstructured":"Custodis F, Schirmer SH, Baumh\u00e4kel M, Heusch G, B\u00f6hm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:1973\u201383.","journal-title":"J Am Coll Cardiol."},{"key":"567_CR8","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1124\/jpet.103.059717","volume":"308","author":"P Colin","year":"2004","unstructured":"Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236\u201340.","journal-title":"J Pharmacol Exp Ther."},{"key":"567_CR9","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1007\/BF01907947","volume":"77","author":"G Heusch","year":"1982","unstructured":"Heusch G, Yoshimoto N, M\u00fcller-Ruchholtz ER. Effects of heart rate on hemodynamic severity of coronary artery stenosis in the dog. Basic Res Cardiol. 1982;77:562\u201373.","journal-title":"Basic Res Cardiol."},{"key":"567_CR10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0002-8703(75)90009-5","volume":"89","author":"W Flameng","year":"1975","unstructured":"Flameng W, W\u00fcsten B, Winkler B, Pasyk S, Schaper W. Inluence of perfusion pressure and heart rate on local myocardial flow in the collateralized heart with chronic coronary occlusion. Am Heart J. 1975;89:51\u20139.","journal-title":"Am Heart J."},{"key":"567_CR11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/0002-9149(75)90555-X","volume":"35","author":"WA Neill","year":"1975","unstructured":"Neill WA, Oxendine JM, Phelps NC, Anderson RP. Subendocardial ischemia provoked by tachycardia in conscious dogs with coronary stenosis. Am J Cardiol. 1975;35:30\u20136.","journal-title":"Am J Cardiol."},{"key":"567_CR12","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/BF00580262","volume":"397","author":"G Heusch","year":"1983","unstructured":"Heusch G, Yoshimoto N. Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pfl\u00fcgers Arch. 1983;397:284\u20139.","journal-title":"Pfl\u00fcgers Arch."},{"key":"567_CR13","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/eurheartj\/ehn337","volume":"29","author":"G Heusch","year":"2008","unstructured":"Heusch G, Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur Heart J. 2008;29:2265\u201375.","journal-title":"Eur Heart J."},{"key":"567_CR14","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1161\/01.CIR.64.4.708","volume":"64","author":"JD Buck","year":"1981","unstructured":"Buck JD, Hardman HF, Warltier DC, Gross GJ. Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart. Circulation. 1981;64:708\u201315.","journal-title":"Circulation."},{"key":"567_CR15","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1161\/01.RES.53.1.8","volume":"53","author":"G Heusch","year":"1983","unstructured":"Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ Res. 1983;53:8\u201315.","journal-title":"Circ Res."},{"key":"567_CR16","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1161\/01.RES.62.3.436","volume":"62","author":"R Seitelberger","year":"1988","unstructured":"Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary a2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res. 1988;62:436\u201342.","journal-title":"Circ Res."},{"key":"567_CR17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.CIR.81.1.1","volume":"81","author":"G Heusch","year":"1990","unstructured":"Heusch G. \u03b1-Adrenergic mechanisms in myocardial ischemia. Circulation. 1990;81:1\u201313.","journal-title":"Circulation."},{"key":"567_CR18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1161\/01.CIR.101.6.689","volume":"101","author":"G Heusch","year":"2000","unstructured":"Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, et al. \u03b1-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689\u201394.","journal-title":"Circulation."},{"key":"567_CR19","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0022-3565(25)12114-9","volume":"275","author":"L Simon","year":"1995","unstructured":"Simon L, Ghaleh B, Puybasset L, Giudicelli J-F, Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275:659\u201366.","journal-title":"J Pharmacol Exp Ther."},{"key":"567_CR20","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1161\/01.RES.60.5.738","volume":"60","author":"BD Guth","year":"1987","unstructured":"Guth BD, Heusch G, Seitelberger R, Ross J Jr. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res. 1987;60:738\u201346.","journal-title":"Circ Res."},{"key":"567_CR21","doi-asserted-by":"crossref","first-page":"H676","DOI":"10.1152\/ajpheart.00564.2002","volume":"284","author":"P Colin","year":"2003","unstructured":"Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli J-F, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676\u201382.","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"567_CR22","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/S0022-3565(25)31273-5","volume":"205","author":"A Berdeaux","year":"1978","unstructured":"Berdeaux A, Peres da Costa C, Garnier M, Boissier JR, Giudicelli JF. Beta adrenergic blockade, regional left ventricular blood flow and ST-segment elevation in canine experimental myocardial ischemia. J Pharmacol Exp Ther. 1978;205:646\u201356.","journal-title":"J Pharmacol Exp Ther."},{"key":"567_CR23","first-page":"H52","volume":"247","author":"M Matsuzaki","year":"1984","unstructured":"Matsuzaki M, Patritti J, Tajimi T, Miller M, Kemper WS, Ross J Jr. Effects of \u03b2-blockade on regional myocardial flow and function during exercise. Am J Physiol. 1984;247:H52\u201360.","journal-title":"Am J Physiol."},{"key":"567_CR24","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1161\/01.RES.50.4.510","volume":"50","author":"UJ Johannsen","year":"1982","unstructured":"Johannsen UJ, Mark AL, Marcus ML. Responsiveness to cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine. Circ Res. 1982;50:510\u20137.","journal-title":"Circ Res."},{"key":"567_CR25","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1161\/01.RES.73.5.869","volume":"73","author":"D Baumgart","year":"1993","unstructured":"Baumgart D, Ehring T, Kowallik P, Guth BD, Krajcar M, Heusch G. The impact of a-adrenergic coronary vasoconstriction on the transmural myocardial blood flow distribution during humoral and neuronal adrenergic activation. Circ Res. 1993;73:869\u201386.","journal-title":"Circ Res."},{"key":"567_CR26","first-page":"H359","volume":"239","author":"JF Giudicelli","year":"1980","unstructured":"Giudicelli JF, Berdeaux A, Tato F, Garnier M. Left stellate stimulation: regional myocardial flows and ischemic injury in dogs. Am J Physiol. 1980;239:H359\u201364.","journal-title":"Am J Physiol."},{"key":"567_CR27","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0002-9149(86)90889-1","volume":"57","author":"GM Berkenboom","year":"1986","unstructured":"Berkenboom GM, Abramowicz M, Vandermoten P, Degre SG. Role of alpha-adrenergic coronary tone in exercise-induced angina pectoris. Am J Cardiol. 1986;57:195\u20138.","journal-title":"Am J Cardiol."},{"key":"567_CR28","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1161\/01.CIR.99.4.482","volume":"99","author":"L Gregorini","year":"1999","unstructured":"Gregorini L, Marco J, Koz\u00e0kov\u00e0 M, Palombo C, Anguissola GB, Marco I, et al. \u03b1-Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999;99:482\u201390.","journal-title":"Circulation."},{"key":"567_CR29","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1161\/01.CIR.99.16.2090","volume":"99","author":"D Baumgart","year":"1999","unstructured":"Baumgart D, Haude M, Goerge G, Liu F, Ge J, Gro\u00dfe-Eggebrecht C, et al. Augmented \u03b1-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090\u20137.","journal-title":"Circulation."},{"key":"567_CR30","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1161\/01.CIR.0000040998.88272.A7","volume":"106","author":"L Gregorini","year":"2002","unstructured":"Gregorini L, Marco J, Farah B, Bernies M, Palombo C, Kozakova M, et al. Effects of selective \u03b11- and \u03b12-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation. 2002;106:2901\u20137.","journal-title":"Circulation."},{"key":"567_CR31","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yjmcc.2011.03.007","volume":"51","author":"G Heusch","year":"2011","unstructured":"Heusch G. The paradox of alpha-adrenergic coronary vasoconstriction revisited. J Mol Cell Cardiol. 2011;51:16\u201323.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR32","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1161\/01.CIR.0000048143.25023.87","volume":"107","author":"JS Borer","year":"2003","unstructured":"Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an I f inhibitor, in stable angina. Circulation. 2003;107:817\u201323.","journal-title":"Circulation."},{"key":"567_CR33","first-page":"A878","volume":"25","author":"W Ruzyllo","year":"2004","unstructured":"Ruzyllo W, Ford IF, Tendera MT, Fox KF. Antianginal and antiischaemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapies in patients with chronic stable angina. Randomised, controlled, double-blind trial. Eur Heart J. 2004;25:A878.","journal-title":"Eur Heart J."},{"key":"567_CR34","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1093\/eurheartj\/ehi586","volume":"26","author":"J-C Tardif","year":"2005","unstructured":"Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529\u201336.","journal-title":"Eur Heart J."},{"key":"567_CR35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2165\/00003495-200767030-00005","volume":"67","author":"W Ruzyllo","year":"2007","unstructured":"Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67:393\u2013405.","journal-title":"Drugs."},{"key":"567_CR36","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1159\/000108387","volume":"108","author":"L Lopez-Bescos","year":"2007","unstructured":"Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108:387\u201396.","journal-title":"Cardiology."},{"key":"567_CR37","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S0140-6736(08)61170-8","volume":"372","author":"K Fox","year":"2008","unstructured":"Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807\u201316.","journal-title":"Lancet."},{"key":"567_CR38","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1093\/eurheartj\/ehp358","volume":"30","author":"K Fox","year":"2009","unstructured":"Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J. 2009;30:2337\u201345.","journal-title":"Eur Heart J."},{"key":"567_CR39","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1093\/eurheartj\/ehp360","volume":"30","author":"G Heusch","year":"2009","unstructured":"Heusch G. A BEAUTIFUL lesson: ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more? Eur Heart J. 2009;30:2300\u20131.","journal-title":"Eur Heart J."},{"key":"567_CR40","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1056\/NEJMoa1406430","volume":"371","author":"K Fox","year":"2014","unstructured":"Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091\u20139.","journal-title":"N Engl J Med."},{"key":"567_CR41","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/S0008-6363(97)00246-0","volume":"37","author":"T Neumann","year":"1998","unstructured":"Neumann T, Ravens U, Heusch G. Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure. Cardiovasc Res. 1998;37:456\u201366.","journal-title":"Cardiovasc Res."},{"key":"567_CR42","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1152\/ajplegacy.1974.227.3.569","volume":"227","author":"F Mahler","year":"1974","unstructured":"Mahler F, Yoran C, Ross J Jr. Inotropic effects of tachycardia and poststimulation potentiation in the conscious dog. Am J Physiol. 1974;227:569\u201375.","journal-title":"Am J Physiol."},{"key":"567_CR43","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1253\/circj.CJ-10-0925","volume":"75","author":"G Heusch","year":"2011","unstructured":"Heusch G. Heart rate and heart failure. Circ J. 2011;75:229\u201336.","journal-title":"Circ J."},{"key":"567_CR44","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1161\/01.CIR.86.2.563","volume":"86","author":"T Miura","year":"1992","unstructured":"Miura T, Miyazaki S, Guth BD, Kambayashi M, Ross J Jr. Influence of the force\u2013frequency relation on left ventricular function during exercise in conscious dogs. Circulation. 1992;86:563\u201371.","journal-title":"Circulation."},{"key":"567_CR45","first-page":"H2516","volume":"267","author":"GP Eising","year":"1994","unstructured":"Eising GP, Hammond HK, Helmer GA, Gilpin E, Ross J Jr. Force\u2013frequency relations during heart failure in pigs. Am J Physiol. 1994;267:H2516\u201322.","journal-title":"Am J Physiol."},{"key":"567_CR46","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.cardiores.2006.05.014","volume":"71","author":"FR Heinzel","year":"2006","unstructured":"Heinzel FR, Luo Y, Dodoni G, Boengler K, Petrat F, Di Lisa F, et al. Formation of reactive oxygen species at increased contraction frequency in rat cardiomyocytes. Cardiovasc Res. 2006;71:374\u201382.","journal-title":"Cardiovasc Res."},{"key":"567_CR47","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1093\/eurheartj\/15.suppl_2.164","volume":"15","author":"G Hasenfuss","year":"1994","unstructured":"Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force\u2013frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J. 1994;15:164\u201370.","journal-title":"Eur Heart J."},{"key":"567_CR48","doi-asserted-by":"crossref","first-page":"H2452","DOI":"10.1152\/ajpheart.1997.273.5.H2452","volume":"273","author":"T Neumann","year":"1997","unstructured":"Neumann T, Heusch G. Myocardial, skeletal muscle, and renal blood flow during exercise in conscious dogs with heart failure. Am J Physiol Heart Circ Physiol. 1997;273:H2452\u20137.","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"567_CR49","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1006\/jmcc.1998.0726","volume":"30","author":"G Heusch","year":"1998","unstructured":"Heusch G, Neumann T. Calcium responsiveness in canine pacing-induced heart failure. J Mol Cell Cardiol. 1998;30:1605\u201313.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR50","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1006\/jmcc.1998.0853","volume":"31","author":"T Neumann","year":"1999","unstructured":"Neumann T, Vollmer A, Schaffner T, Hess OM, Heusch G. Diastolic dysfunction and collagen structure in canine pacing-induced heart failure. J Mol Cell Cardiol. 1999;31:179\u201392.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR51","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S0008-6363(99)00032-2","volume":"42","author":"GW Moe","year":"1999","unstructured":"Moe GW, Armstrong P. Pacing-induced heart failure: a model to study the mechanism of disease progression and novel therapy in heart failure. Cardiovasc Res. 1999;42:591\u20139.","journal-title":"Cardiovasc Res."},{"key":"567_CR52","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1136\/hrt.53.3.323","volume":"53","author":"CJ McLaran","year":"1985","unstructured":"McLaran CJ, Gersh BJ, Sugrue DD, Hammill SC, Seward JB, Holmes DR Jr. Tachycardia induced myocardial dysfunction. A reversible phenomenon? Br Heart J. 1985;53:323\u20137.","journal-title":"Br Heart J."},{"key":"567_CR53","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/0002-9149(86)90836-2","volume":"57","author":"DL Packer","year":"1986","unstructured":"Packer DL, Bardy GH, Worley SJ, Smith MS, Cobb FR, Coleman RE, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol. 1986;57:563\u201370.","journal-title":"Am J Cardiol."},{"key":"567_CR54","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1161\/01.CIR.0000135472.28234.CC","volume":"110","author":"P Nerheim","year":"2004","unstructured":"Nerheim P, Birger-Botkin S, Piracha L, Olhansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation. 2004;110:247\u201352.","journal-title":"Circulation."},{"key":"567_CR55","doi-asserted-by":"crossref","unstructured":"Custodis F, Roggenbuck U, Lehmann N, Moebus S, Laufs U, Mahabadi AA, et al. Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population. Clin Res Cardiol. Epub 23 Jan 2016.","DOI":"10.1007\/s00392-015-0956-7"},{"key":"567_CR56","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/S0140-6736(10)61259-7","volume":"376","author":"M B\u00f6hm","year":"2010","unstructured":"B\u00f6hm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886\u201394.","journal-title":"Lancet."},{"key":"567_CR57","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jacc.2007.04.079","volume":"50","author":"K Fox","year":"2007","unstructured":"Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823\u201330.","journal-title":"J Am Coll Cardiol."},{"key":"567_CR58","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.amjcard.2007.11.023","volume":"101","author":"G Flannery","year":"2008","unstructured":"Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865\u20139.","journal-title":"Am J Cardiol."},{"key":"567_CR59","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(10)61198-1","volume":"376","author":"K Swedberg","year":"2010","unstructured":"Swedberg K, Komajda M, B\u00f6hm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875\u201385.","journal-title":"Lancet."},{"key":"567_CR60","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/eurheartj\/ehr311","volume":"32","author":"JC Tardif","year":"2011","unstructured":"Tardif JC, O\u2019Meara E, Komajda M, Bohm M, Borer JS, Ford I, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011;32:2507\u201315.","journal-title":"Eur Heart J."},{"key":"567_CR61","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/bjp.2008.347","volume":"155","author":"G Heusch","year":"2008","unstructured":"Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J Pharmacol. 2008;155:970\u20131.","journal-title":"Br J Pharmacol."},{"key":"567_CR62","doi-asserted-by":"crossref","first-page":"4380","DOI":"10.1111\/bph.13220","volume":"172","author":"P Kleinbongard","year":"2015","unstructured":"Kleinbongard P, Gedik N, Witting P, Freedman B, Klocker N, Heusch G. Pleiotropic, heart rate-independent cardioprotection by ivabradine. Br J Pharmacol. 2015;172:4380\u201390.","journal-title":"Br J Pharmacol."},{"key":"567_CR63","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.yjmcc.2011.09.005","volume":"51","author":"S Herrmann","year":"2011","unstructured":"Herrmann S, Layh B, Ludwig A. Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol. 2011;51:997\u20131006.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR64","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/cvr\/cvs184","volume":"95","author":"F Hofmann","year":"2012","unstructured":"Hofmann F, Fabritz L, Stieber J, Schmitt J, Kirchhof P, Ludwig A, et al. Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. Cardiovasc Res. 2012;95:317\u201326.","journal-title":"Cardiovasc Res."},{"key":"567_CR65","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1006\/jmcc.2000.1316","volume":"33","author":"E Cerbai","year":"2001","unstructured":"Cerbai E, Sartiani L, DePaoli P, Pino R, Maccherini M, Bizzarri F, et al. The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol. 2001;33:441\u20138.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR66","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.yjmcc.2008.04.013","volume":"45","author":"F Stillitano","year":"2008","unstructured":"Stillitano F, Lonardo G, Zicha S, Varro A, Cerbai E, Mugelli A, et al. Molecular basis of funny current If in normal and failing human heart. J Mol Cell Cardiol. 2008;45:289\u201399.","journal-title":"J Mol Cell Cardiol."},{"key":"567_CR67","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1177\/2048872613489305","volume":"2","author":"P Steg","year":"2013","unstructured":"Steg P, Lopez-de-Sa E, Schiele F, Hamon M, Meinertz T, Goicolea J, et al. Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a randomized, placebo-controlled, double-blind, pilot study. Eur Heart J Acute Cardiovasc Care. 2013;2:270\u20139.","journal-title":"Eur Heart J Acute Cardiovasc Care."},{"key":"567_CR68","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1161\/CIRCRESAHA.116.305348","volume":"116","author":"G Heusch","year":"2015","unstructured":"Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post- and remote conditioning. Circ Res. 2015;116:674\u201399.","journal-title":"Circ Res."},{"key":"567_CR69","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.jacc.2015.02.032","volume":"65","author":"B Ibanez","year":"2015","unstructured":"Ibanez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia\/reperfusion injury. J Am Coll Cardiol. 2015;65:1454\u201371.","journal-title":"J Am Coll Cardiol."},{"key":"567_CR70","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1161\/HYPERTENSIONAHA.114.04323","volume":"65","author":"M Rienzo","year":"2015","unstructured":"Rienzo M, Melka J, Bize A, Sambin L, Jozwiak M, Su JB, et al. Ivabradine improves left ventricular function during chronic hypertension in conscious pigs. Hypertension. 2015;65:122\u20139.","journal-title":"Hypertension."},{"key":"567_CR71","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.ehj.2003.10.010","volume":"25","author":"X Monnet","year":"2004","unstructured":"Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli J-F, Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J. 2004;25:579\u201386.","journal-title":"Eur Heart J."},{"key":"567_CR72","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00395-015-0511-8","volume":"110","author":"F Maranta","year":"2015","unstructured":"Maranta F, Tondi L, Agricola E, Margonato A, Rimoldi O, Camici PG. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. Basic Res Cardiol. 2015;110:55.","journal-title":"Basic Res Cardiol."},{"key":"567_CR73","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s003950050079","volume":"93","author":"R Bolli","year":"1998","unstructured":"Bolli R. Causative role of oxyradicals in myocardial stunning: a proven hypothesis. A brief review of the evidence demonstrating a major role of reactive oxygen species in several forms of postischemic dysfunction. Basic Res Cardiol. 1998;93:156\u201362.","journal-title":"Basic Res Cardiol."},{"key":"567_CR74","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1161\/CIRCULATIONAHA.107.746537","volume":"117","author":"F Custodis","year":"2008","unstructured":"Custodis F, Baumh\u00e4kel M, Schlimmer N, List F, Gensch C, B\u00f6hm M, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E deficient mice. Circulation. 2008;117:2377\u201387.","journal-title":"Circulation."},{"key":"567_CR75","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/bjp.2008.116","volume":"154","author":"A Drouin","year":"2008","unstructured":"Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F, Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154:749\u201357.","journal-title":"Br J Pharmacol."},{"key":"567_CR76","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.atherosclerosis.2010.11.035","volume":"215","author":"EI Skalidis","year":"2011","unstructured":"Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215:160\u20135.","journal-title":"Atherosclerosis."},{"key":"567_CR77","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s12325-015-0237-x","volume":"32","author":"E Tagliamonte","year":"2015","unstructured":"Tagliamonte E, Cirillo T, Rigo F, Astarita C, Coppola A, Romano C, et al. Ivabradine and bisoprolol on doppler-derived coronary flow velocity reserve in patients with stable coronary artery disease: beyond the heart rate. Adv Ther. 2015;32:757\u201367.","journal-title":"Adv Ther."},{"key":"567_CR78","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/S0735-1097(97)00246-5","volume":"30","author":"HJ Levine","year":"1997","unstructured":"Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104\u20136.","journal-title":"J Am Coll Cardiol."},{"key":"567_CR79","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s00395-014-0460-7","volume":"110","author":"S Gent","year":"2015","unstructured":"Gent S, Kleinbongard P, Dammann P, Neuhauser M, Heusch G. Heart rate reduction and longevity in mice. Basic Res Cardiol. 2015;110:2.","journal-title":"Basic Res Cardiol."},{"key":"567_CR80","first-page":"169","volume":"128","author":"AF Coburn","year":"1971","unstructured":"Coburn AF, Grey RM, Rivera SM. Observations on the relation of heart rate, life span, weight and mineralization in the digoxin-treated A-J mouse. Johns Hopkins Med J. 1971;128:169\u201393.","journal-title":"Johns Hopkins Med J."},{"key":"567_CR81","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.arr.2011.11.005","volume":"11","author":"EM Mercken","year":"2012","unstructured":"Mercken EM, Carboneau BA, Krzysik-Walker SM, de Cabo R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev. 2012;11:390\u20138.","journal-title":"Ageing Res Rev."}],"container-title":["Drugs"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40265-016-0567-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s40265-016-0567-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40265-016-0567-2","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T23:30:05Z","timestamp":1748820605000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s40265-016-0567-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,4]]},"references-count":81,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,5]]}},"alternative-id":["567"],"URL":"https:\/\/doi.org\/10.1007\/s40265-016-0567-2","relation":{},"ISSN":["0012-6667","1179-1950"],"issn-type":[{"value":"0012-6667","type":"print"},{"value":"1179-1950","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,4]]}}}