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  • Review Article
  • Published:

Heart rate reduction in coronary artery disease and heart failure

Key Points

  • The role of heart rate in coronary artery disease and heart failure has been explored using ivabradine, a drug that selectively targets heart rate

  • Increased heart rate can provoke myocardial ischaemia

  • Heart rate reduction can reduce the symptoms of angina

  • Increased heart rate is a risk marker in patients with coronary artery disease, but heart rate reduction does not improve prognosis in this clinical setting

  • In the setting of heart failure, elevated heart rate is a modifiable risk factor — reducing heart rate improves prognosis in these patients

  • Excessive bradycardia can cause dispersion of atrial fibrillation

Abstract

Elevated heart rate is known to induce myocardial ischaemia in patients with coronary artery disease (CAD), and heart rate reduction is a recognized strategy to prevent ischaemic episodes. In addition, clinical evidence shows that slowing the heart rate reduces the symptoms of angina by improving microcirculation and coronary flow. Elevated heart rate is an established risk factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF). Accordingly, reducing heart rate improves prognosis in patients with HF, as demonstrated in SHIFT. By contrast, data from SIGNIFY indicate that heart rate is not a modifiable risk factor in patients with CAD who do not also have HF. Heart rate is also an important determinant of cardiac arrhythmias; low heart rate can be associated with atrial fibrillation, and high heart rate after exercise can be associated with sudden cardiac death. In this Review, we critically assess these clinical findings, and propose hypotheses for the variable effect of heart rate reduction in cardiovascular disease.

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Figure 1: Beneficial effects of heart rate reduction in angina.
Figure 2: Beneficial effects of heart rate reduction in heart failure.
Figure 3: Molecular explanation for the effects of ivabradine independent of heart rate reduction.
Figure 4: Effects of heart rate increase in various cardiovascular disease states.

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References

  1. Fox, K. M. & Ferrari, R. Heart rate: a forgotten link in coronary artery disease? Nat. Rev. Cardiol. 8, 369–379 (2011).

    Article  PubMed  Google Scholar 

  2. Vilaine, J. P. The discovery of the selective If current inhibitor ivabradine: a new therapeutic approach to ischemic heart disease. Pharmacol. Res. 53, 424–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Beere, P. A., Glagov, S. & Zarins, C. K. Retarding effect of lowered heart rate on coronary atherosclerosis. Science 226, 180–182 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. Rogowski, O. et al. Heart rate and microinflammation in men: a relevant atherothrombotic link. Heart 93, 940–944 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Custodis, F. et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 117, 2377–2387 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Yu, W. C. et al. Tachycardia-induced change of atrial refractory period in humans: rate dependency and effects of antiarrhythmic drugs. Circulation 97, 2331–2337 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Okin, P. M. et al. Incidence of atrial fibrillation in relation to changing heart rate over time in hypertensive patients: the LIFE study. Circ. Arrhythm. Electrophysiol. 1, 337–343 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Soliman, E. Z., Elsalam, M. A. & Li, Y. The relationship between high resting heart rate and ventricular arrhythmogenesis in patients referred to ambulatory 24 h electrocardiographic recording. Europace 12, 261–265 (2010).

    Article  PubMed  Google Scholar 

  9. Adabag, A. S. et al. Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men. Am. J. Cardiol. 101, 1437–1443 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fox, K., Ford, I., Steg, P. G., 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 372, 807–816 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Fox, K. et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 372, 817–821 (2008).

    Article  PubMed  Google Scholar 

  12. Fox, K. et al. Resting heart rate in cardiovascular disease. J. Am. Coll. Cardiol. 50, 823–830 (2007).

    Article  PubMed  Google Scholar 

  13. Diaz, A., Bourassa, M. G., Guertin, M. C. & Tardif, J. C. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur. Heart J. 26, 967–974 (2005).

    Article  PubMed  Google Scholar 

  14. Schirmer, S. H. et al. Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur. Heart J. 33, 1223–1231 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Gloekler, S. et al. The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease. Heart 100, 160–166 (2014).

    Article  PubMed  CAS  Google Scholar 

  16. van der Hoeven, N. W. & van Royen, N. The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease, another funny aspect of the funny channel? Heart 100, 98–99 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Tagliamonte, E. 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. 32, 757–767 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Custodis, F. et al. Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein E-deficient mice. J. Vasc. Res. 49, 432–440 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Reil, J. C. et al. Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur. Heart J. 34, 2839–2849 (2013).

    Article  PubMed  Google Scholar 

  20. Becher, P. M. et al. Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and β-receptor blockade. Hypertension 59, 949–957 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Rizzo, P., Miele, L. & Ferrari, R. The Notch pathway: a crossroad between the life and death of the endothelium. Eur. Heart J. 34, 2504–2509 (2013).

    Article  PubMed  Google Scholar 

  22. Ferrari, R. & Rizzo, P. The Notch pathway: a novel target for myocardial remodelling therapy? Eur. Heart J. 35, 2140–2145 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Mackiewicz, U. et al. Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat. J. Cell. Physiol. 229, 813–823 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Chen, S. L., Hu, Z. Y., Zuo, G. F., Li, M. H. & Li, B. I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice. BMC Cardiovasc. Disord. 14, 150 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Rienzo, M. et al. Ivabradine improves left ventricular function during chronic hypertension in conscious pigs. Hypertension 65, 122–129 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Dedkov, E. I. et al. Effect of chronic heart rate reduction by If current inhibitor ivabradine on left ventricular remodeling and systolic performance in middle-aged rats with postmyocardial infarction heart failure. J. Cardiovasc. Pharmacol. Ther. 20, 299–312 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Fox, K. et al. Ivabradine in stable coronary artery disease without clinical heart failure. N. Engl. J. Med. 371, 1091–1099 (2014).

    Article  PubMed  CAS  Google Scholar 

  28. Borer, J. S., Fox, K., P. & Lerebours, G. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 107, 817–823 (2003).

    Article  PubMed  Google Scholar 

  29. Tardif, J. C., Ford, I., Tendera, M., Bourassa, M. G. & Fox, K. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur. Heart J. 26, 2529–2536 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Tardif, J. C., Ponikowski, P. & Kahan, T. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur. Heart J. 30, 540–548 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tendera, M. et al. Quality of life with ivabradine in patients with angina pectoris: the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease quality of life substudy. Circ. Cardiovasc. Qual. Outcomes 9, 31–38 (2016).

    Article  PubMed  Google Scholar 

  32. 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. 308, 236–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Heusch, G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br. J. Pharmacol. 153, 1589–1601 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nabel, E. G., Selwyn, A. P. & Ganz, P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation 81, 850–859 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Sambuceti, G., Marzilli, M., Fedele, S., Marini, C. & L'Abbate, A. Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease: reversal by angioplasty. Circulation 103, 2352–2360 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Morrison, T. M., Choi, G., Zarins, C. K. & Taylor, C. A. Circumferential and longitudinal cyclic strain of the human thoracic aorta: age-related changes. J. Vasc. Surg. 49, 1029–1036 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hodis, S. & Zamir, M. Mechanical events within the arterial wall: the dynamic context for elastin fatigue. J. Biomech. 42, 1010–1016 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Skalidis, E. I., Hamilos, M. I., Chlouverakis, G., Zacharis, E. A. & Vardas, P. E. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis 215, 160–165 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Algranati, D., Kassab, G. S. & Lanir, Y. Mechanisms of myocardium–coronary vessel interaction. Am. J. Physiol. Heart Circ. Physiol. 298, H861–H873 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Bohm, M., Reil, J. C., Deedwania, P., Kim, J. B. & Borer, J. S. Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease. Am. J. Med. 128, 219–228 (2015).

    Article  PubMed  Google Scholar 

  41. Fox, K. et al. 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. 30, 2337–2345 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled trial. Lancet 376, 875–885 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Heusch, G. Heart rate and heart failure. Not a simple relationship. Circ. J. 75, 229–236 (2011).

    Article  PubMed  Google Scholar 

  44. Mann, D. L. & Cooper, G. 4th Neurohumoral activation in congestive heart failure: a double-edged sword? Clin. Cardiol. 12, 485–490 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Ferrari, R. Ivabradine: heart rate and left ventricular function. Cardiology 128, 226–230 (2014).

    Article  PubMed  Google Scholar 

  46. Chidsey, C. A., Sonnenblick, E. H., Morrow, A. G. & Braunwald, E. Norepinephrine stores and contractile force of papillary muscle from the failing human heart. Circulation 33, 43–51 (1966).

    Article  CAS  PubMed  Google Scholar 

  47. Ferrari, R. et al. Mechanisms of remodelling: a question of life (stem cell production) and death (myocyte apoptosis). Circ. J. 73, 1973–1982 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Waagstein, F. et al. Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy. Eur. J. Heart Fail. 5, 679–691 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Hasenfuss, G. et al. Influence of the force–frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur. Heart J. 15, 164–170 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Hall, S. A. et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J. Am. Coll. Cardiol. 25, 1154–1161 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Bohm, M. 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 376, 886–894 (2010).

    Article  PubMed  Google Scholar 

  52. Rao, K., Fisher, M. L., Robinson, S., Shorofsky, S. & Gottlieb, S. S. Effect of chronic changes in heart rate on congestive heart failure. J. Card. Fail. 13, 269–274 (2007).

    Article  PubMed  Google Scholar 

  53. Shinbane, J. S. et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 29, 709–715 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Logeart, D. et al. Heart rate per se impacts cardiac function in patients with systolic heart failure and pacing: a pilot study. Eur. J. Heart Fail. 11, 53–57 (2009).

    Article  PubMed  Google Scholar 

  55. Thackray, S. D. et al. The effect of altering heart rate on ventricular function in patients with heart failure treated with β-blockers. Am. Heart J. 152, 713 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Mulieri, L. A., Hasenfuss, G., Leavitt, B., Allen, P. D. & Alpert, N. R. Altered myocardial force-frequency relation in human heart failure. Circulation 85, 1743–1750 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. De Ferrari, G. M. et al. Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur. J. Heart Fail. 10, 550–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Mulder, P. et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 109, 1674–1679 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Reil, J. C. et al. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J. Am. Coll. Cardiol. 62, 1977–1985 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Ma, Y., Chilton, R. J. & Lindsey, M. L. Heart rate reduction: an old and novel candidate heart failure therapy. Hypertension 59, 908–910 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Ceconi, C., Cargnoni, A., Francolini, G., Parinello, G. & Ferrari, R. Heart rate reduction with ivabradine improves energy metabolism and mechanical function of isolated ischaemic rabbit heart. Cardiovasc. Res. 84, 72–82 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Ceconi, C. et al. Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling. Am. J. Physiol. Heart Circ. Physiol. 300, H366–H373 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Ceconi, C. et al. Effect of heart rate redution by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL. Int. J. Cardiol. 146, 408–414 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Tardif, J. C. 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. 32, 2507–2515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cerbai, E. et al. Characterization of the hyperpolarization-activated current, If, in ventricular myocytes from human failing heart. Circulation 95, 568–571 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Stillitano, F. et al. Molecular basis of funny current (If) in normal and failing human heart. J. Mol. Cell. Cardiol. 45, 289–299 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Fernandez-Velasco, M. et al. Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J. Physiol. 553, 395–405 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cerbai, E., Pino, R., Sartiani, L. & Mugelli, A. Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes. Cardiovasc. Res. 42, 416–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Suffredini, S. et al. Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression. Br. J. Pharmacol. 165, 1457–1466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Herrmann, S., Hofmann, F., Stieber, J. & Ludwig, A. HCN channels in the heart: lessons from mouse mutants. Br. J. Pharmacol. 166, 501–509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Postea, O. & Biel, M. Exploring HCN channels as novel drug targets. Nat. Rev. Drug Discov. 10, 903–914 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Vaillant, F. et al. Ivabradine but not propranolol delays the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial metabolic energy status. Resuscitation 84, 384–390 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Vaillant, F. et al. Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion. Resuscitation 82, 1092–1099 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Ng, F. S., Shadi, I. T., Peters, N. S. & Lyon, A. R. Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias. J. Mol. Cell. Cardiol. 59, 67–75 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fang, Y. et al. Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia. J. Cardiovasc. Pharmacol. 59, 260–267 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Heusch, G., Skyschally, A. & Schulz, R. Cardioprotection by ivabradine through heart rate reduction and beyond. J. Cardiovasc. Pharmacol. Ther. 16, 281–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Custodis, F. et al. Vascular pathophysiology in response to increased heart rate. J. Am. Coll. Cardiol. 56, 1973–1983 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Custodis, F. et al. Heart rate contributes to the vascular effects of chronic mental stress: effects on endothelial function and ischemic brain injury in mice. Stroke 42, 1742–1749 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Suenari, K. et al. Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis. J. Cardiovasc. Electrophysiol. 23, 200–206 (2012).

    Article  PubMed  Google Scholar 

  80. Ohman, E. M. & Alexander, K. P. The challenges with chronic angina. N. Engl. J. Med. 371, 1152–1153 (2014).

    Article  PubMed  CAS  Google Scholar 

  81. McMurray, J. J. It is BEAUTIFUL we should be concerned about, not SIGNIFY: is ivabradine less effective in ischaemic compared with non-ischaemic LVSD? Eur. Heart J. 36, 2047–2049 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Ferrari, R. & Fox, K. M. The role of heart rate may differ according to pathophysiological setting: from SHIFT to SIGNIFY. Eur. Heart J. 36, 2042–2046 (2015).

    Article  PubMed  Google Scholar 

  83. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N. Engl. J. Med. 336, 525–533 (1997).

  84. Castagno, D., Petrie, M. C., Claggett, B. & McMurray, J. Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction in heart failure. Eur. Heart J. 33, 1137–1141 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Follath, F., Cleland, J. G., Klein, W. & Murphy, R. Etiology and response to drug treatment in heart failure. J. Am. Coll. Cardiol. 32, 1167–1172 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Borer, J. S. et al. Efficacy profile of ivabradine in patients with heart failure plus angina pectoris [abstract 902-06]. J. Am. Coll. Cardiol. 65, A791 (2015).

    Article  Google Scholar 

  87. European Medicines Agency. Assessment report: ivabradine. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000597/WC500182140.pdf (2014).

  88. Ferrari, R. Coronary artery disease in 2012: revising common beliefs in the management of stable CAD. Nat. Rev. Cardiol. 10, 65–66 (2013).

    Article  PubMed  Google Scholar 

  89. Dargie, H. J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 357, 1385–1390 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. McAlister, F. A., Wiebe, N., Ezekowitz, J. A., Leung, A. A. & Armstrong, P. W. Meta-analysis: β-blocker dose, heart rate reduction, and death in patients with heart failure. Ann. Intern. Med. 150, 784–794 (2009).

    Article  PubMed  Google Scholar 

  91. Launbjerg, J., Fruergaard, P., Madsen, J. K., Mortensen, L. S. & Hansen, J. F. Ten-year mortality of patients admitted to coronary care units with and without myocardial infarction. Risk factors from medical history and diagnosis at discharge. DAVIT-Study Group. Danish Verapamil Infarction Trial. Cardiology 85, 259–266 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. Cucherat, M. & Borer, J. S. Reduction of resting heart rate with antianginal drugs: review and meta-analysis. Am. J. Ther. 19, 269–280 (2012).

    Article  PubMed  Google Scholar 

  93. Bangalore, S. et al. β-blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 308, 1340–1349 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Andersson, C. et al. β-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J. Am. Coll. Cardiol. 64, 247–252 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Montalescot, G. et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 34, 2949–3003 (2013).

    Article  PubMed  Google Scholar 

  96. Fihn, S. D. et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 126, e354–e471 (2012).

    PubMed  Google Scholar 

  97. Luscher, T. F., Gersh, B., Landmesser, U. & Ruschitzka, F. Is the panic about beta-blockers in perioperative care justified? Eur. Heart J. 35, 2442–2444 (2014).

    Article  PubMed  Google Scholar 

  98. Kristensen, S. D. et al. 2014 ESC/ESA guidelines on non-cardiac surgery: cardiovascular assessment and management: the Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur. Heart J. 35, 2383–2431 (2014).

    Article  PubMed  Google Scholar 

  99. Sjoland, H., Caidahl, K., Lurje, L., Hjalmarson, A. & Herlitz, J. Metoprolol treatment for two years after coronary bypass grafting: effects on exercise capacity and signs of myocardial ischaemia. Br. Heart J. 74, 235–241 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Booij, H. G. et al. β-blocker therapy is not associated with reductions in angina or cardiovascular events after coronary artery bypass graft surgery: insights from the IMAGINE trial. Cardiovasc. Drugs Ther. 29, 277–285 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bolli, R., Fisher, D. J. & Entman, M. L. Factors that determine the occurrence of arrhythmias during acute myocardial ischemia. Am. Heart J. 111, 261–270 (1986).

    Article  CAS  PubMed  Google Scholar 

  102. Aupetit, J. F. et al. Efficacy of a β-adrenergic receptor antagonist, propranolol, in preventing ischaemic ventricular fibrillation: dependence on heart rate and ischaemia duration. Cardiovasc. Res. 37, 646–655 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Nemirovsky, D., Hutter, R. & Gomes, J. A. The electrical substrate of vagal atrial fibrillation as assessed by the signal-averaged electrocardiogram of the P wave. Pacing Clin. Electrophysiol. 31, 308–313 (2008).

    Article  PubMed  Google Scholar 

  104. Myrstad, M. et al. Increased risk of atrial fibrillation among elderly Norwegian men with a history of long-term endurance sport practice. Scand. J. Med. Sci. Sports 24, e238–e244 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. DiFrancesco, D. HCN4, sinus bradycardia and atrial fibrillation. Arrhythm. Electrophysiol. Rev. 4, 9–13 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Fox, K. et al. Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study. Eur. Heart J. 36, 3291–3296 (2015).

    CAS  PubMed  Google Scholar 

  107. Beltrame, J. F. Ivabradine and the SIGNIFY conundrum. Eur. Heart J. 36, 3297–3299 (2015).

    CAS  PubMed  Google Scholar 

  108. Cocco, G. & Jerie, P. Torsades de pointes induced by the concomitant use of ivabradine and azithromycin: an unexpected dangerous interaction. Cardiovasc. Toxicol. 15, 104–106 (2015).

    Article  PubMed  Google Scholar 

  109. Mittal, S. R. Slow junctional rhythm, QTc prolongation and transient torsades de-pointes following combined use of ivabradine, diltiazem and ranolazine. J. Assoc. Physicians India 62, 426–427 (2014).

    CAS  PubMed  Google Scholar 

  110. Melgari, D. et al. hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine. J. Am. Heart Assoc. 4, e001813 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Savelieva, I. & Camm, A. J. If inhibition with ivabradine: electrophysiological effects and safety. Drug Saf. 31, 95–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. McMurray, J. J. et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 14, 803–869 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from Fondazione Anna Maria Sechi per il Cuore (FASC), Italy. FASC had no role in the decision to publish or the preparation of the manuscript.

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Both authors contributed equally to researching data, discussion of content, writing the article, and reviewing and editing the manuscript before submission.

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Correspondence to Roberto Ferrari.

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R.F. declares having received honoraria from Servier for steering committee membership, consulting, and speaking, and support for travel to study meetings from Servier. In addition, he received personal fees from Amgen, Boehringer Ingelheim, Irbtech, Merck Serono, and Novartis. K.F. declares having received fees, honoraria, and research grants from Servier.

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Ferrari, R., Fox, K. Heart rate reduction in coronary artery disease and heart failure. Nat Rev Cardiol 13, 493–501 (2016). https://doi.org/10.1038/nrcardio.2016.84

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