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The pivotal role of heart rate in cardiovascular disease

The pivotal role of heart rate in cardiovascular disease. The role of heart rate in cardiovascular disease. Elevated heart rate. +. +. Atherosclerosis Endothelial dysfunction↑ Oxidative stress↑ Plaque stability↓ Arterial stiffness↑. Chronic heart failure Oxygen demand↑

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The pivotal role of heart rate in cardiovascular disease

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  1. The pivotal role of heart rate in cardiovascular disease

  2. The role of heart rate in cardiovascular disease Elevated heart rate + + Atherosclerosis Endothelial dysfunction↑ Oxidative stress↑ Plaque stability↓ Arterial stiffness↑ Chronic heart failure Oxygen demand↑ Ventricular efficiency ↓ Ventricular relaxation↑ + + Ischemia Oxygen consumption↑ Duration of diastole↓ Coronary perfusion↓ Remodeling Cardiac hypertrophy↑

  3. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  4. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  5. 70 60 50 40 30 20 10 0 60 25 30 35 40 45 50 55 The first evidence of the prognostic importanceof heart rate: 1945 Transienttachycardia Transienthypertension – – – + + – + + Rate per 1000 person-years Age (years) Levy RL et al. JAMA. 129 (1945): 585-588.

  6. Prognostic importance of resting heart rate:epidemiological evidence (in general population and hypertensives) Study Population Follow-up Cardiovascular mortality RR Chicago Gas Company ’801 233 M 15 y >94 vs. ≤60 bpm 2.3 Chicago Heart Ass.Project ’8033 781 M&W 22 y ≥90 vs. <70 bpm M: 1.6 W: 1.1 (ns) Framingham ’934 530 M&W HTN 36 y >100 vs. <60 bpm M: 1.5 W: 1.4 (ns) British Regional Heart ’93735 M 8 y >90 vs. ≤ 90 bpm IHD death 3.3 Spandau ’974 756 M&W 12 y Sudden death 5.2 per 20 bpm Benetos ’9919 386 M&W 18.2 y >100 vs. <60 bpm M: 2.2 W: 1.1 (ns) Castel ’991 938 M&W 12 y 5th vs. 3rd quintile M: 1.6 W: 1.1 Cordis ’003 257 M 8 y ≥90 vs. <70 bpm 2.0 Reunanen ’0010 717 M&W 23 y M: 1.4 (>84 vs. <60) W: 1.5 (>94 vs.<66) Thomas ’0160 343 M HTN 14 y >80 vs. ≤ 80 bpm <55y:1.5 >55y:1.3 Matiss ’012 533 M 9 y per 20 bpm: 1.5 ≥90 vs. <60 bpm: 2.7 Ohasama ’041 780 M&W 10 y M: 1.2 W: 1.1 (ns) per 5 bpm Okamura ’048 800 M&W 16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2 Jouven ’055 713 M 23 y Sudden death from AMI 3.92 (>75 bpm) During 25 years - more than 155 000 patients, follow-up 8-36 years Adapted from V. Aboyans et al., J Clin Epidemiol. 2006;59:547-558.

  7. 4.0 3.5 P<0.001 3.0 2.5 2.0 1.5 Relative risk 1.0 0.5 0.0 <60 60-64 65-69 70-75 >75 Resting heart rate (bpm) Sudden death risk increases progressively withresting HR in the general population The Paris Prospective Study I , general population, 5713 men; 23-year follow-up Jouven X, et al., N Engl J Med. 2005;352:1951-1958.

  8. Prognostic dimension of resting heart rate and its changes The Paris Prospective Study I , general population, n=5139; > 20-year follow-up Relative risk of total mortality according to baseline HR and HR change after 5 years (after adjustment) Tertiles of baseline HR: - low (64 bpm) - medium (64 to 70 bpm) - high (70 bpm) Tertiles of HR change: - tertile 1 - decrease 4 bpm - tertile 2 - 4- 3 bpm - tertile 3 - increase 3 bpm Jouven X, et al. Am J Cardiol. 2009;103:279-283

  9. All-cause mortality increases progressivelywith resting heart rate in men with hypertension The Framingham Study, 2037 men with untreated hypertension, 36-year follow-up 60 CHD: 95% CI 1.20, 2.71 CVD: 95% CI 1.19, 2.37 50 All-cause: 95% CI 1.68, 2.83 40 Age-adjusted 2-year death rate per 1000 30 20 10 0 <65 65-74 75-84 >84 Resting heart rate (bpm) Gillman MW, et al., Am Heart J. 1993;125:1148-1154.

  10. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  11. Survival probability Survival probability 1.00 1.00 0.95 0.95 0.90 0.90 0.85 0.85 0.80 0.80 0.75 0.75 0.70 0.70 P (Cox)=0.0001 P (Cox)=0.0001 1 3 5 7 9 11 13 15 17 19 21 1 3 5 7 9 11 13 15 17 19 21 Follow-up (years) Follow-up (years) HR<60 80<HR≤100 HR>100 bpm 60≤HR≤80 Resting heart rate independently predicts totaland CV mortality in men and women French cohort study, n=19 386 (12 123 men, 7263 women), 18-year follow-up Men: all-cause mortality Women: all-cause mortality Benetos A, et al., Hypertension.1999;33:44-52.

  12. Resting heart rate as an independent predictor of coronary events in women 129 135 postmenopausal women, a mean of 7.8 years of follow-up Hsia J et al. BMJ. 2009;338:b219

  13. Resting heart rate:predicts survival in people aged >65 years Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 60-80 >80 <60 Resting heart rate (bpm) Benetos A et al., J Am Geriatr Soc. 2003;51:284-285.

  14. 1.00 1.00 Survival probability 1.00 0.95 0.99 0.99 0.90 0.98 0.98 0.85 0.97 0.97 P (Cox)=0.0001 0.80 1 3 5 7 13 13 10 13 15 17 19 21 Follow-up (years) HR<60 80<HR≤100 HR>100 bpm 60≤HR≤80 Resting heart rate independently predicts mortality in Western and Asian populations Survival probability curves for CVmortality in French men (n=12 123) Cumulative survival rates due to cardiacevents in Japanese men (n=3856) Q1 <60 bpm Q2 60-65 bpm Q3 66-73 bpm Cumulative survival rate Q4 78 bpm 0 0 5 10 15 20 Person-years Okamura T et al., Am Heart J. 2004;147:1024-1032. Benetos A et al., Hypertension.1999;33:44-52.

  15. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  16. Mortality versus admission heart rate with acute myocardial infarction 1807 patients within 24 h of onset of symptoms of acute myocardial infarction 50 Total In-hospital 40 Post-discharge 30 Mortality (%) 20 10 0 <50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120 Resting heart rate (bpm) Hjalmarson A, et al., Am J Cardiol.1990;65:547-553.

  17. Heart rate at admission and in-hospital mortality in MI survivors 12 10 8 6 In-hospital mortality (%) 4 2 0 GISSI-3 study, 6-month follow-up; ECG 10.1 6.3 3.5 3.3 <60 60-80 81-100 >100 n=713 n=2364 n=5305 n=2785 Heart rate (bpm) Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.

  18. Heart rate at discharge and 6-month mortalityin MI survivors GISSI-3 study, 6-month follow-up; ECG 25 20.2 20 15 6-month mortality (%) 9.3 10 3.9 5 1.9 0 <60 60-80 81-100 >100 n=114 n=4038 n=5600 n=1278 Heart rate (bpm) Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.

  19. 1.0 1.0 0.9 0.9 0.8 0.8 P<0.0001 0.7 0.7 0.6 0.6 0.5 0.5 ≤62 63-70 5 5 10 10 15 15 20 20 0 0 71-76 77-82 ≥83 bpm A high resting heart rate as an independentpredictor of mortality in CAD patients The Coronary Artery Surgery Study (CASS) registry; 24 913 CAD patients; 14.1-year follow-up Adjusted survival curves foroverall mortality Adjusted survival curvesfor cardiovascular mortality P<0.0001 Cumulative survival Years after enrolment Diaz A, et al. Eur Heart J. 2005;26:867-874.

  20. Impact of heart rate in patients with hypertension and coronary artery disease INVEST study, 22 192 CAD patients; 2.7-year follow-up 60 4.5 Outcome (all-cause death, nonfatal MI, or nonfatal stroke) 4.0 50 Hazard ratio 3.5 40 3.0 2.5 30 Adverse outcome incidence (%) Estimated hazard ratio 2.0 20 1.5 1.0 10 0.5 0 0 ≤ 50 > 100 > 85 to ≤ 90 > 50 to ≤ 55 > 65 to ≤ 70 > 80 to ≤ 85 > 70 to ≤ 75 > 75 to ≤ 80 > 60 to ≤ 65 > 55 to < 60 > 90 to ≤ 95 > 95 to ≤ 100 Mean follow-up heart rate (bpm) Kolloch et al., Eur Heart J. 2008;29:1327-34.

  21. Resting heart rate as a predictor of prognosis in patients with stable CAD Post hoc analysis in 9580 patients from the TNT study, median follow-up was 4.9 years JE. Ho et al. Presented at ACC 2009 JE. Ho et al. Presented at ACC 2009

  22. 15 Hazard ratio = 1.34 (1.10 – 1.63) Heart rate ≥ 70 bpm P = 0.0041 10 5 Heart rate < 70 bpm 0 Years 0 0.5 1 1.5 2 Heart rate as a predictor ofcardiovascular death Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD % with cardiovascular death Fox K, et al. Lancet. 2008;372:817-821

  23. 15 Hazard ratio = 1.53 (1.25 – 1.88) Heart rate ≥ 70 bpm P< 0.0001 10 5 Heart rate < 70 bpm 0 Years 0 0.5 1 1.5 2 Heart rate as a predictor ofhospitalization for heart failure Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD % with hospitalization for heart failure Fox K, et al. Lancet. 2008;372:817-821

  24. 0 0.5 1 1.5 2 Heart rate as a predictor of hospitalization for myocardial infarction Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD % with hospitalization for fatal and nonfatal MI 8 Hazard ratio = 1.46 (1.11 – 1.91) P= 0.0066 Heart rate ≥ 70 bpm 6 4 Heart rate < 70 bpm 2 0 0 Years Fox K, et al. Lancet. 2008;372:817-821

  25. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  26. Role of elevated HR in the pathophysiology of CAD Elevated Heart Rate Vascular damage Atherosclerosis Increased O2 demand Decreased supply Plaque rupture Progression of atherosclerosis Ischemia Major CV events Short term Long term

  27. HR as a trigger of ischemia in stable angina patients n=19 men with stable CAD; 48-AECG 100 100 100 * P <0.05 ** P <0.01 ** ** ** ** ** ** 95 95 95 90 90 90 * * * ** ** ** 85 85 85 Heart rate, bpm * * * ** ** ** 80 80 80 * * * 75 75 75 Angina STdepression 70 70 70 65 Event Event Event 60 20 10 4 2 60 20 10 4 2 60 20 10 4 2 2 10 20 60 2 10 20 60 2 10 20 60 Time (min) Kop W et al. J Am Coll Cardiol. 2001;38:742.

  28. Heart rate as a major determinant of ischemia n=50 stable CAD patients; 48-AECG Likelihood of ischemia, % 20 x2 16 12 8 4 0 60-69 70-79 80-89 >89 Heart rate at rest, bpm <60 Andrews TC et al. Circulation.1993;88:90-100.

  29. Heart rate as predictor of ischemic episodes: multivariate analysis n=50 stable CAD patients; 48-AECG n=50 stable CAD patients; 48-AECG Multivariate analysis of variables predictive of an ischemic episode after a period of HR increase Standardized estimate P Magnitude of heart rate increase -0.56 0.0001 Baseline heart rate -0.45 0.0001 Duration of heart rate increase -0.04 0.05 Andrews TC et al. Circulation.1993;88:90-100.

  30. HR as a predictor of coronary events n=1311 older CHD patients; 48-month follow-up; 24-h AECG 5 bpm of HR = 1.14 incidence of coronary events 70 60 P<0.0001 50 40 New coronary events, % 30 20 10 0 61-70 71-80 81-90 91-100 >100 <60 Mean heart rate Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176.

  31. Heart rate and coronary atherosclerosis 4 3 2 1 0 16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG Coronary atherosclerosis score (%) r= 0.70 P<0.002 50 60 70 80 90 40 Minimum heart rate (bpm) Perski A, et al. Am Heart J. 1988;116:1369-1373.

  32. OR (95% CI) P Left ventricular mass >270 g 4.92 (1.83-13.25) 0.02 Mean heart rate >80 bpm 3.19 (1.15-8.85) 0.02 -Blocker use 0.32 (0.13-0.88) 0.02 Wall thickness IVS 1.68 (0.57-9.91) 0.06 Fractional pulse pressure 1.81 (0.67-4.90) 0.07 Statins 0.42 (0.16-1.22) 0.06 Heart rate and coronary plaque rupture 106 patients with 2 coronary angiographies; 6-month follow-up; 24-h EGG Multivariate analysis of association with coronary plaque disruption ACE inhibitors 0.51 (0.19-1.34) 0.06 Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.

  33. Variation of coronary flow and shear stressduring the cardiac cycle SYSTOLE DIASTOLE 10 mm Hg 120 mm Hg Coronary arterial flow (myocardial perfusion) No flow (even retrograde subendocardialflow) Low and oscillatory shear stress Increased shear stress Coronary arteries are prone to atherosclerosis Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312

  34. Heart rate and atherosclerosis: potential mechanisms Elevated heart rate Mechanical arterial wall stress Shortening of diastolic period Shortening of coronary perfusion time Endothelial damage Wall damage Shift of endothelial cells to an atherosclerotic phenotype Atherosclerosis Plaque rupture Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312

  35. Long-term consequences of a low shear stress for the coronary arterial wall Low shear stress Impaired NO-dependent atheroprotection ROS Apoptosis and proliferation NO Thrombogenicity eNOS NAPDHoxidase VCAM-1, ICAM-1 E-selectin ROS TNF–  IL-1, IFN- Growth promoters LDL uptake and synthesis Growth inhibitors, eg, TGF-, NO Inflammation oxLDL Matrix degradation Angiogenesis Matrix synthesis Atherosclerotic plaque formation/progression and vascular remodeling Adapted from Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379–2393

  36. Natural history of coronary atherosclerosis Inner curvature: low ESS region (artherosclerosis-prone) • Local factors, eg, low ESS • Systemic factors, eg, hyperlipidemia • Genetic factors Low ESS Early fibroatheroma Fibroproliferation Microruptures Lower ESS Vulnerability Intense inflammmation Physiologic ESS Limited inflammation High ESS Erosion Excessive expansive remodeling Thin cap fibroatheroma Compensatory expansive remodeling Quiescent plaque Constricitve remodeling Stenotic plaque Rupture Acute coronary syndrome Asymptomatic Stable angina Adapted from Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93)

  37. Increases the mechanicalload on the arterialwall Induces structural and functional changes of the endothelialcells making intima more permeable to circulating LDL andinflammatory cells Promotes the weakening of the fibrous cap, leading to plaquedisruption and the onset of acute coronary syndrome Putative mechanisms underlyingpro-atherosclerotic effect of increasing heart rate

  38. The prognostic validity of resting heart rate • Positive association with total and/or cardiovascular mortality • Association independent of other cardiovascular risk factors • Association valid in both genders, in the elderly, in differentethnicities • A strong predictor of mortality in patients with coronary artery disease • Relation to known pathophysiologic mechanisms ofcoronary artery disease • Clinical outcome benefit associated with heart rate reduction

  39. Heart rate reduction with Ivabradine prevents endothelial dysfunction associated with dyslipidemia in mice Metoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemia Drouin et al. Br J Pharmacol. 2008;154:749-757

  40. Vehicle Ivabradine  Reduction in atherogenesis with ivabradine Apolipoprotein E–deficient mouse model Aortic sinus 40 A B  40% 30  Plaque area[% total] 20 * 10 0 Ascending aorta *P<0.05 30 C D  70% 20 Plaque area[%total] 10 0 Ivabradine Vehicle Böhm M et al. Circulation. 2008;117:2377-2387

  41. Hazard ratio = 0.64 (0.49 – 0.84) P = 0.001 Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) 8 Placebo (HR >70 bpm) RRR 36% Hospitalization for fatal or nonfatal MI % 4 Ivabradine 0 0 0.5 1 1.5 2 years RRR: relative risk reduction Fox K, et al. Lancet. 2008;372:807-816

  42. 0 0.5 1 1.5 2 Ivabradine reduces the need for revascularization (HR ≥70 bpm) 8 Hazard ratio = 0.70 (0.52 – 0.93) P = 0.016 Placebo RRR 30% Coronary revascularization % 4 Ivabradine 0 years RRR: relative risk reduction Fox K, et al. Lancet. 2008;372:807-816

  43. Fatal MI 0.69 31% 0.114 Fatal and nonfatal MI 0.64 36% 0.001 Fatal and nonfatal MI or unstable angina 0.78 22% 0.023 Fatal and nonfatal MI, unstable anginaor revascularization 0.77 23% 0.009 Coronary revascularization 0.70 30% 0.016 Ivabradine reduces coronary risk instable coronary patients with HR ≥ 70 bpm Predefined end point Hazardratio Riskreduction P value Fox K, et al. Lancet. 2008;372:807-816

  44. Hazard ratio = 0.64 (0.49 – 0.84) P = 0.001 Placebo (HR <70 bpm) Ivabradine shifts the patients from high risk to low risk 8 Placebo (HR >70 bpm) RRR 36% Hospitalization for fatal or nonfatal MI % 4 Ivabradine(HR baseline > 70 bpm) 0 0 0.5 1 1.5 2 years RRR: relative risk reduction Fox K, et al. Lancet. 2008;372:807-816

  45. Conclusions • Heart rate is a risk factor for cardiovascular mortality, independent of major conventional risk factors • Heart rate should be used to assess cardiovascular risk and to guide medical therapy of patients with coronary disease • BEAUTIFUL data suggest benefit from heart rate reduction with Ivabradine in patients with coronary artery disease and heart rate above 70 bpm

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