Heart Rate in Coronary Artery Disease: Should We Lower It?

  • Kelly Axsom
  • Sripal Bangalore
Coronary Artery Disease (PG Steg, Section Editor)

Opinion statement

Elevated resting heart rate is an independent risk factor for cardiovascular morbidity and mortality in patients with and without coronary artery disease. In patients with known coronary artery disease, elevated heart rate reduces diastolic filling time and increases cardiac workload, resulting in supply demand mismatch with consequent ischemia and angina. While lower heart rate is associated with better prognosis, it is not known if pharmacological reduction in heart rate is beneficial and if heart rate is merely a marker for increased risk and worse outcomes. Certainly, physiologically lower resting heart rate as attained by exercise improves morbidity and mortality. While physiological reduction in heart rate is mainly a manifestation of increased parasympathetic drive, pharmacological reduction of heart rate with beta-blockers is mediated via the sympathetic pathway and associated with mixed outcomes. In addition, beta-blockers have other cardiovascular effects (lowering blood pressure), are metabolically active, and it is unknown if the beneficial effects (if any) are mediated via reduction in heart rate versus other cardiovascular effects. Ivabradine is a new medication that lowers heart rate selectively by inhibiting the If current without other cardiovascular effects, offering for the first time a therapeutic agent that selectively targets heart rate. The medication has shown promise in early trials in patients with heart failure, but it is unclear if this agent will be beneficial in patients with stable coronary artery disease without heart failure.


Coronary artery disease Heart rate Prognosis Reduction 



K. Axsom: none. S. Bangalore: Consultancy for Daiichi Sankyo and Boehringer Ingelheim, travel/accommodations expenses covered or reimbursed by Pfizer.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104–6.PubMedCrossRefGoogle Scholar
  2. 2.
    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(4):169–93.PubMedGoogle Scholar
  3. 3.
    Anderson GF, Chu E. Expanding priorities—confronting chronic disease in countries with low income. N Engl J Med. 2007;356(3):209–11.PubMedCrossRefGoogle Scholar
  4. 4.
    Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;349(9061):1269–76.PubMedCrossRefGoogle Scholar
  5. 5.
    Reunanen A, et al. Heart rate and mortality. J Intern Med. 2000;247(2):231–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J. 1997;18(9):1404–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Benetos A, et al. Influence of heart rate on mortality in a French population: role of age, gender, and blood pressure. Hypertension. 1999;33(1):44–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study. Am Heart J. 1991;121:172–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Kannel WB, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113(6):1489–94.PubMedCrossRefGoogle Scholar
  10. 10.
    Jouven X, et al. Predicting sudden death in the population: the Paris Prospective Study I. Circulation. 1999;99(15):1978–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Gillman MW, et al. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993;125(4):1148–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Palatini P, et al. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002;162(20):2313–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Paul L, et al. Resting heart rate pattern during follow-up and mortality in hypertensive patients. Hypertension. 2010;55(2):567–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Disegni E, et al. The predictive value of admission heart rate on mortality in patients with acute myocardial infarction. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. J Clin Epidemiol. 1995;48(10):1197–205.PubMedCrossRefGoogle Scholar
  15. 15.
    Zuanetti G, et al. Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study. Eur Heart J. 1998;19 Suppl F:F19–26.PubMedGoogle Scholar
  16. 16.••
    Bangalore S, et al. The association of admission heart rate and in-hospital cardiovascular events in patients with non-ST-segment elevation acute coronary syndromes: results from 135 164 patients in the CRUSADE quality improvement initiative. Eur Heart J. 2010;31(5):552–60. Evaluation of nearly 140,000 patients with non-ST-segment elevation myocardial infarction found a J-shaped curve relationship between resting heart rate and all-cause mortality. Lowest mortality rates were seen with heart rates between 60–69 bpm, heart rates < 50 bpm and ≥ 100 bpm were associated with increased mortality rates.PubMedCrossRefGoogle Scholar
  17. 17.
    Eagle KA, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291(22):2727–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Morrow DA, et al. TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation. 2000;102(17):2031–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kushner FG, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23):2205–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Anderson JL, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–e157.PubMedCrossRefGoogle Scholar
  21. 21.
    Diaz A, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26(10):967–74.PubMedCrossRefGoogle Scholar
  22. 22.
    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. 2008;372(9641):817–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Steg PG, et al. Heart rate and use of beta-blockers in stable outpatients with coronary artery disease. PLoS One. 2012;7(5):e36284.PubMedCrossRefGoogle Scholar
  24. 24.
    Kolloch R, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008;29(10):1327–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Bangalore S, et al. Heart rate in patients with coronary artery disease - the lower the better? An analysis from the Treating to New Targets (TNT) trial (Abstr). Eur Heart J. 2011;32:339.Google Scholar
  26. 26.
    Bangalore S, et al. Relationship of Heart Rate and Cardiovascular Events in Patients after Acute Coronary Syndromes: An Analysis from the PROVE-IT TIMI 22 Trial. J Am Coll Cardiol. 2010;55:A98, E924.Google Scholar
  27. 27.
    Cucherat M, Borer JS. Reduction of resting heart rate with antianginal drugs: review and meta-analysis. Am J Ther. 2012;19(4):269–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Palatini P, et al. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24(4):603–10.PubMedCrossRefGoogle Scholar
  29. 29.
    Dahlof B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895–906.PubMedCrossRefGoogle Scholar
  30. 30.
    Poulter NR, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366(9489):907–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Poulter NR, et al. Baseline heart rate, antihypertensive treatment, and prevention of cardiovascular outcomes in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). J Am Coll Cardiol. 2009;54(13):1154–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker-induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol. 2008;52(18):1482–9.PubMedCrossRefGoogle Scholar
  33. 33.•
    Williams B, Lacy PS. Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-Heart Rate. J Am Coll Cardiol. 2009;54(8):705–13. For the same effect on reduction of brachial systolic pressure, atenolol was shown to have a higher central systolic pressure compared to amlodipine due to the reduction in heart rate.PubMedCrossRefGoogle Scholar
  34. 34.
    Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986;57(12):43F–9F.PubMedCrossRefGoogle Scholar
  35. 35.
    Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol. 1998;21(12 Suppl 2):II3–7.PubMedGoogle Scholar
  36. 36.
    Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986;2(8498):57–66.Google Scholar
  37. 37.
    Roberts R, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation. 1991;83(2):422–37.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen ZM, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1622–32.PubMedCrossRefGoogle Scholar
  39. 39.••
    Jneid, H., et al. 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 Guideline and Replacing the 2011 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 2012. 2012 ACC/AHA Update of the unstable angina and non-ST segement elevation myocardial infarction guidelines.Google Scholar
  40. 40.••
    Kushner FG, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120(22):2271–306. 2009 ACC/AHA Update ST-segement elevation myocardial infarction guidelines.PubMedCrossRefGoogle Scholar
  41. 41.
    Bangalore S, et al. Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: an INternational VErapamil SR-Trandolapril (INVEST) substudy. Am Heart J. 2008;156(2):241–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Gullestad L, et al. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll Cardiol. 2005;45(2):252–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Lechat P, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation. 2001;103(10):1428–33.PubMedCrossRefGoogle Scholar
  44. 44.
    Poldermans D, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341(24):1789–94.PubMedCrossRefGoogle Scholar
  45. 45.
    Bangalore S, et al. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008;372(9654):1962–76.PubMedCrossRefGoogle Scholar
  46. 46.
    Kramer JM, et al. National evaluation of adherence to beta-blocker therapy for 1 year after acute myocardial infarction in patients with commercial health insurance. Am Heart J. 2006;152(3):454 e1–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith Jr SC, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113(19):2363–72.PubMedCrossRefGoogle Scholar
  48. 48.
    Gibbons RJ, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41(1):159–68.PubMedCrossRefGoogle Scholar
  49. 49.
    Fox K, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Borer JS, et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107(6):817–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Tardif JC, et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529–36.PubMedCrossRefGoogle Scholar
  52. 52.••
    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. 2010;376(9744):886–94. SHIFT trial results, confirming that elevated heart rate in patients with chronic systolic heart failure is associated with worse outcomes. Ivabradine reduced heart rate and decreased primary end-point of cardiovascular death or hospitalization for heart failure.PubMedCrossRefGoogle Scholar
  53. 53.
    Sa Cunha R, et al. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertens. 1997;15(12 Pt 1):1423–30.PubMedCrossRefGoogle Scholar
  54. 54.
    Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998;18(5):677–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Huikuri HV, et al. Heart rate variability and progression of coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 1999;19(8):1979–85.PubMedCrossRefGoogle Scholar
  56. 56.
    Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104(13):1477–82.PubMedCrossRefGoogle Scholar
  57. 57.
    Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153(8):1589–601.PubMedCrossRefGoogle Scholar
  58. 58.
    Sambuceti G, et al. Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease. Circulation. 1997;95(12):2652–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Tanaka N, et al. Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart. Jpn J Physiol. 1990;40(4):503–21.PubMedCrossRefGoogle Scholar
  60. 60.
    Sugimachi M, et al. Reduction of myocardial oxygen demand by controlling heart rate and hemodynamics simultaneously by novel circulatory model. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:4297–300.PubMedGoogle Scholar
  61. 61.
    Guth BD, et al. Mechanisms of benefit in the ischemic myocardium due to heart rate reduction. Basic Res Cardiol. 1990;85 Suppl 1:157–66.PubMedGoogle Scholar
  62. 62.
    Guth BD, et al. Role of heart rate reduction in the treatment of exercise-induced myocardial ischaemia. Eur Heart J. 1987;8(Suppl L):61–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Pratt CM, et al. Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study). Am J Cardiol. 1996;77(15):1302–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Nagatsu M, et al. Bradycardia and the role of beta-blockade in the amelioration of left ventricular dysfunction. Circulation. 2000;101(6):653–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Thackray SD, et al. The effect of altering heart rate on ventricular function in patients with heart failure treated with beta-blockers. Am Heart J. 2006;152(4):713 e9–13.PubMedCrossRefGoogle Scholar
  66. 66.
    Bolli R, Fisher DJ, Entman ML. Factors that determine the occurrence of arrhythmias during acute myocardial ischemia. Am Heart J. 1986;111(2):261–70.PubMedCrossRefGoogle Scholar
  67. 67.
    Reynolds RD, Calzadilla SV, Lee RJ. Spontaneous heart rate, propranolol, and ischaemia-induced ventricular fibrillation in the dog. Cardiovasc Res. 1978;12(11):653–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Bauer A, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 2006;367(9523):1674–81.PubMedCrossRefGoogle Scholar
  69. 69.
    Ghuran A, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol. 2002;89(2):184–90.PubMedCrossRefGoogle Scholar
  70. 70.
    Camm AJ, et al. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation. 2004;109(8):990–6.PubMedCrossRefGoogle Scholar
  71. 71.
    La Rovere MT, et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001;103(16):2072–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984;226(4671):180–2.PubMedCrossRefGoogle Scholar
  73. 73.
    Beere PA, Glagov S, Zarins CK. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey. Localization, compensatory enlargement, and the sparing effect of lowered heart rate. Arterioscler Thromb. 1992;12(11):1245–53.PubMedCrossRefGoogle Scholar
  74. 74.
    Kaplan JR, et al. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987;76(6):1364–72.PubMedCrossRefGoogle Scholar
  75. 75.
    Effects of ivabradine in patients with stable coronary artery disease without heart failure. 2012 website]. Available from: Accessed October 1, 2012.

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.The Leon H. Charney Division of CardiologyNew York University School of MedicineNew YorkUSA

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