& π 3 billion heart beats/lifetime

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π π π π π π π

& π 3 billion heart beats/lifetime Levine H. J Am Coll Cardiol 1997;30:1104 6

& π Ηλικία (έτη) Εξέλιξη του προσδόκιµου επιβίωσης 120 100 80 60 40 20 Ο άνθρωπος ξεχώρισε:0 Επιστήμη0 Ιατρική0 0 1000 1200 1400 1600 1800 2000 2200 Έτος Birngruber, www.sozmed.uni-luebeck.de/ebm-symposium2004

Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis

Pathophysiological mechanisms promoted by increased heart rate myocardial O 2 requirement Imbalance of O 2 supply/demand Diastolic duration Coronary perfusion time Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis

Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia HR Ventricular function and remodelling Atherosclerosis Endothelial dysfunction Hemodynamic stress Plaque rupture Pulsatile shear stress

Pathophysiological mechanisms promoted by increased heart rate Myocardial ischemia Cardiac Noradrenaline synthesis HR Ventricular function and remodelling Atherosclerosis apoptosis

Pharmacological approaches for reducing heart rate Cardiac site of action Effect in cardiac system HR reduction β-blockers Sinus node A-V node ventricule HR reduction (-) Dromotropic effect (-) Inotropic effect - 15,6 bpm 1 Non dihydropyridine calcium antagonist (verapamil, diltiazem) Sinus node A-V node ventricule HR reduction (-) Dromotropic effect (-) Inotropic effect - 7,0 bpm 2 I f Inhibitors : ivabradine Sinus node HR reduction - 14,3 bpm 1 1. Tardif JC, et al. Eur Heart J. 2005;26:2529-2536. 2. Vliegen HW, et al. J Cardiovasc Pharmacol. 1991;18(suppl.19):S55-S60.

: & & Seccareccia F, et al. Am J Public Health. 2001;91:1258. / 100 45 40 35 30 25 20 15 10 5 The MATISS Project 0 40 60 80 100 120 (bpm)

: & 4 3 2 1 0 < 60 60-64 65-69 70-75 > 75 (bpm) Jouven X, et al. N Enlg J Med. 2005;352:1951.

: π π π 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 1.407 < 60 60-80 > 80 (bpm) Benetos A,et al. Am J Geriatr Soc. 2003;51:284.

& π

π π : π The Framingham Study π 2-1000 60 50 40 30 20 10 0 < 65 65-74 75-84 > 84 (bpm) Gillman, et al. Am Heart J. 1993;125:1148.

Δοµή ελαστίνης σε τµήµατα αορτής Τίγρη, 15 ετών (64 bpm) Ιαγουάρος, 15 ετών (130 bpm) 15 years old tiger 505 million cycles 15 years old jaguar 1025 million cycles Avolio A, et al. Hypertension. 1998;32:170-175

Lantelme P, et al. Hypertension 2002;39:1083-1087

Benetos A, et al. Circulation. 2002;105:1202-1207

π : & π Cook St.,et al. Eur Heart J. 2006;27:2387-2393.

&

: & π Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα Αθροιστική επιβίωση 1.0 0.9 0.8 0.7 0.6 Καρδιακή Συχνότητα <62 bpm >83 bpm Αθροιστική επιβίωση 1.0 0.9 0.8 0.7 0.6 0.5 0.5 0 5 10 15 20 Έτη από την ένταξη (y) 0 5 10 15 20 Έτη από την ένταξη (y) Diaz A et al. Eur Heart J. 2005;26:967-974.

Annual event rates in stable CAD outpatients REACH registry (n=38.602) CHF CABG PCI UA Death/MI/Stroke/Hosp* Death/MI/Stroke Nonfatal Stroke Nonfatal MI CV Death 1,4 1,4 1,4 1,8 3,8 4,5 6,9 6,44 15,2 0 5 10 15 20 Rates adjusted for age and risk factors Steg PG et al. JAMA. 2007;297: 1197-1206.

Κανονικ ή αρτηρία- Αρτηρία με στένωσ η- Nabel et al., Circulation 81:1990:850

Φυσιολογική Παθολογική Ροή 1 Παράπλευρα Πίεση 1 Πίεση 2 Ροή 2 LAD LCX -

2 Boudoulas H. Circulation 1979;60:164-169

π O 2 π Καρδιακή Συχνότητα Μεταφορτίο Προφορτίο Τοιχ. Stress Συσταλτικότητα Opie LH: The Heart, Physiology, from Cell to Circulation. Philadelphia, Lippincott Raven, 1998

π O 2 π Αύξηση MVO2 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Τοιχω ματικ ή Τάσ η MVO 2 π 50% : Συσ ταλτικότητα Έργο Πίεσ ης Καρδιακή Συχνότητα Gould KL: Coronary Artery Stenosis. New York, Elsevier, 1991

2 20 DOG 4 20 DOG 5 20 DOG 6 Κατανάλωση Ο 2 (ml/min/100g) 10 10 10 0 100 200 0 100 200 0 100 200 0.1 DOG 4 0.1 DOG 5 0.1 DOG 6 Κατανάλωση Ο 2 (ml/beat/100g) 0.05 0.05 0.05 0 100 200 0 100 200 0 100 200 Heart rate (min -1 ) Tanaka et al., Jap J Physiol 40: 503-521, 1990

2 MVO 2 (ml O 2 /min) 8 7 6 5 4 3 2 1 0 Saline Ivabradine 0,5 mg/kg Ivabradine 1 mg/kg -10% * -19% * Rest Exercise *P<0.05 vs Saline Colin P. JPET 2004; 308:236 240

Καρδιακή Συχνότητα 100 (bmp) 95 90 ** ** 85 80 ** ** * * 75 70 * Στηθάγχη Κατάσπαση του ST 65 60 20 10 4 2 Σύµβαµα 2 10 20 60 Χρόνος (min) Kop W, et al. J Am Coll Cardiol. 2001;38:742.

π Ρήξη της Πλάκας Αθηροσκλήρυνση Ενδοθηλιακή Δυσλειτουργία Υπέρταση, Δυσλιπιδαιµία, Κάπνισµα, Διαβήτης Στεφανιαία Νόσος ΟΕΜ Δυσλειτουργία της ΑΚ Remodeling Καρδιακή Ανεπάρκεια Θάνατος

π π Καρδιακής Συχνότητας Χρόνου Διαστολικής πλήρωσης Μεταβολικών αναγκών Καρδιακής Συχνότητας Στεφανιαίας αιµατικής ροής Ανάγκες O 2 Προσφορά O 2 Kop W, et al. J Am Coll Cardiol. 2001;38:742

π Adverse outcome incidence (%) 60 50 40 30 20 10 0 4.5 Outcome (all-cause death, non-fatal MI, or nonfatal stroke) 4.0 Hazard ratio 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Estimated hazard ratio Mean follow-up heart rate (bpm) INVEST study, 22.192 CAD patients; 2,7-year follow-up Kolloch et al., Eur Heart J. 2008;29:1327-34.

- π π π π

π > 70 bpm, Ivabradine -. > 70 bpm, Ivabradine Fox K et al. Lancet, 2008; 372: 807-816.

π H Ivabradine π - π,.

& π

π : π CIBIS II, Circulation. 2001:103:1428. 14 12 (%) 10 8 6 4 2 placebo bisoprolol 0 72 bpm 72< 84 bpm > 84 bpm

Thus, there is evidence both in animals and in human beings that an elevated heart rate is conducive to atherosclerosis and its clinical manifestations. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G,. Pessina AC, Ruilope LM and Zanchetti A: Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting Journal of Hypertension 2006, 24:603 610

( ) π π π π π & π π π European Heart Journal 2006; 27: 2387 2393

π π π π π π π π π European Heart Journal 2006; 27: 2387 2393

: & π CASS Registry Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα 62 63-70 71-76 77-82 83 bpm 1.0 1.0 0.9 0.9 Cumulative survival 0.8 0.7 0.6 P<0.0001 0.8 0.7 0.6 P<0.0001 0.5 0.5 0 5 10 15 20 0 5 10 15 20 Έτη παρακολούθησης 24.913 CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:967-974.

The role of heart rate in the continuum of cardiovascular disease

Heart Rate & Survival Heart Rate (Beats /min) 1000 500 300 100 50 20 Mouse Hamster Rat Monkey Marmot Cat Dog Giraffe Tiger Ass Horse Elephant Lion Whale Whale Man 5 10 15 20 25 30 35 40 80 100 Life Expectancy (Years) Levine et al. J Am Coll Cardiol. 1997;30:1104-1106.

Heart rate & Life Expectancy The progression of life expectancy Age (years) 120 100 80 60 40 20 Human is different: Science Medicine 0 1000 1200 1400 1600 1800 2000 2200 Year Birngruber, www.sozmed.uni-luebeck.de/ebm-symposium2004

General Population: HR & Sudden Death 4 3 Total deaths ACI Sudden Death Relative Risk 2 1 0 < 60 60-64 65-69 70-75 > 75 HR (bpm) Jouven X, et al. N Engl J Med. 2005;352:1951.

Elderly: HR as a risk factor Adjusted relative risk survival 1.407 elderly men 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 < 60 60-80 > 80 HR (bpm) Benetos A,et al. Am J Geriatr Soc. 2003;51:284.

Cardiovascular disease: Role of Heart Rate in the CV Continuum Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:1244-1263.

Cardiovascular disease: Role of Heart Rate in the CV Continuum Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:1244-1263.

Hypertensive Population: HR as a risk factor Age-Adjusted 2-Year Mortality Rate per 1000 60 50 40 30 20 10 0 Coronary Heart Disease Cardiovascular Disease All cause The Framingham Study < 65 65-74 75-84 > 84 ΚΣ (bpm) Gillman, et al. Am Heart J. 1993;125:1148.

Increase of aortic stiffness & Heart rate Tiger, 15 years-old (64 bpm) The structure of elastin in aortic parts Jaguar, 15 years-old (130 bpm) Avolio A, et al. Hypertension. 1998;32:170-175.

Increase of aortic stiffness & Heart rate Clinical data Lantelme P, et al. Hypertension 2002;39:1083-1087.

Increase of aortic stiffness & Heart rate Clinical data Benetos A, et al. Circulation. 2002;105:1202-1207.

Thus, there is evidence both in animals and in human beings that an elevated heart rate is conducive to atherosclerosis and its clinical manifestations. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G,. Pessina AC, Ruilope LM and Zanchetti A: Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting Journal of Hypertension 2006, 24:603 610.

Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:1244-1263.

Preclinical Data

HR reduction and atherosclerosis progression Monkeys; high-cholesterol diet for 6 months Maximum stenosis (%) 60 50 40 30 20 10 P<0.02 Sinus node ablation 0 High Low Heart rate Beere PA, et al. Science. 1984;226:180-182.

Heart Rate in WT, ApoE KO and Treatment Groups 700 ** Heart rate (bpm) 600 500 ** ** 400 Vehicle Iva 10 Iva 2 Iva 10 + L-NAME Hydra Custodis et al. Circulation. 2008;117(18):2377-2387.

Aortic Atherosclerosis in WT, ApoE KO and Treatment Groups 40 Plaque Area (% total) 30 20 10 * 0 Aortic Sinus 30 Plaque Area (% total) 20 10 * Vehicle Ivabradine Vehicle Ivabradine 0 Ascending Aorta Custodis et al. Circulation. 2008;117(18):2377-2387.

Clinical Data

HR reduction and reduction of Ischemia 63 stable angina patients and frequency if asymptomatic ischeamia Larger heart rate reduction is associated with bigger reduction in ischaemic episodes Stone PH. Circulation. 1990;82:1962-1972.

Coronary Artery Disease: HR & Survival CASS Registry Adjusted survival curves for Overall mortality Adjusted survival curves for CV mortality 62 63-70 71-76 77-82 83 bpm 1.0 1.0 0.9 0.9 Cumulative survival 0.8 0.7 0.6 P<0.0001 0.8 0.7 0.6 P<0.0001 0.5 0.5 0 5 10 15 20 0 5 10 15 20 Years of follow-up 24.913 CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:967-974.

The prognostic value of HR in patients with hypertension and Coronary Artery Disease Adverse outcome incidence (%) 60 50 40 30 20 10 0 Outcome (all-cause death, non-fatal MI, or nonfatal stroke) Hazard ratio 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Estimated hazard ratio Mean follow-up heart rate (bpm) INVEST study, 22.192 CAD patients; 2,7-year follow-up Kolloch et al., Eur Heart J. 2008;29:1327-34.

Heart Rate and Coronary Plaque Rupture Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.

Possible mechanisms through which high Heart Rate provokes atherosclerosis Increases mechanical work in arterial wall Provokes structural and functional changes in endothelial cells Weakens the fibrotic π, leading to plaque rupture and the occurrence of acute coronary syndromes

Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Post MI Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:1244-1263.

-blockers in post-myocardial Infraction (MI) patients 1 year post-mi mortality 6 months post-mi mortality Mortality (%) 50 40 30 20 10 0 Göteborg-Metoprolol Trial <50 50 60 70 80 90 100 110 >120 59 69 79 89 99 109 119 HR (bpm) Mortality (%) 21 18 15 12 9 6 3 0 1,9 < 60 [n=4.038] 3,9 60-80 [n=5.600] 9,3 81-100 [n=1.278] 20,2 > 100 [n=114] HR (bpm) Hjalmarson A, et al. Am J Cardiol. 1990;65:547-553. Tavazzi L. Eur Heart J. 2003;5:G15-G18.

HR reduction with -blockade & ACI mortality R=0.79 P<0.005 Kjekshus J. Eur Heart J 1985;6:A29, Am J Cardiol 1986;57:43F

Relative risk (log) HR reduction & Cardiac Death: Post- MI patients Meta-regression of 17 controlled trials in MI survivors patients treated with beta-blockers or calcium antagonists 2.0 1.0 0.5 0.2 0.1 0 β-blockers Calcium channel blockers P<0.001-5 -10-15 -20 HR (bpm) The beneficial effect of beta-blockers and calcium channel blocke post-mi patients is proportionally related to resting HR reduction Cucherat M. Eur Heart J. 2007;28:3012-3019.

Cardiovascular disease: Role of Heart Rate in the CV Atherosclerosis Plaque rupture Continuum Post MI Remodeling and Heart Failure Hypertension Myocardial Infarction & Stroke Remodeling Ventricular Dilation/ Cognitive Dysfunction Congestive Heart Failure/ Secondary Stroke Atherosclerosis and LVH Risk factors Diabetes Hypertension Heart Rate End-Stage Heart Disease/ Brain Damage & Dementia Cardio/ Cerebrovascular Death Adapted from Dzau V and Braunwald E. Am Heart J. 1991;121:1244-1263.

Cleland J et al, Am Heart J 2006;152:713 HR & LV function in Heart Failure patients End-diastolic/ end-systolic Volumes Ejection Fraction 30 3 Changes in volumes (ml) 20 10 0-10 -20-30 -40-50 -60 LVEDV LVESV 60 bpm 80 bpm LVEDV LVESV change (%) 2 1 0-1 -2-3 -4 60 bpm 80 bpm -70 b-blocker + PACING 80bpm b-blocker + PACING 60bpm -5 b-blocker + PACING 80bpm b-blocker + PACING 60bpm

Heart Failure: Heart Rate as a risk factor 14 12 placebo bisoprolol 1 year mortality (%) 10 8 6 4 2 HR 0 At inclusion 72 bpm 72< At inclusion 84 bpm At inclusion > 84 bpm CIBIS II, Circulation. 2001:103:1428.

Heart Rate reduction and mortality reduction in HF patients 60 40 XAMOTEROL PROFILE Change in mortality (%) 20 PROMISE VHeFT (prazosin) 0-20 -40-60 -80 CIBIS NOR TIMOLOL MOCHA BHAT GESICA ANZ US CARVEDILOL SOLVD CONSENSUS VHeFT (HDZ/ISDN) -100-18 -16-14 -12-10 -8-6 -4-2 -0 2 4 6 8 10 Change in HR (bpm) Swedberg K et al. Eur Heart J. 1999;20:136-139

High Heart Rate Prognostic factor in the general population and in patients with CAD The existing evidence comes from observational studies (retrospective data) This hypothesis wasn t proven perspectively

Heart Rate reduction Heart Rate reduction in patients with stable Coronary Artery Disease could improve clinical outcomes This hypothesis hasn t been proven perspectively

Unique opportunity to prospectively study: Heart rate as a predictor of outcome in CAD Effect of pure heart reduction on outcome in CAD patients

Fox K et al. Lancet Online August 31, 2008.

Objective To examine the effects of high heart rate on the prevention of cardiovascular events in patients with coronary artery disease and left ventricular systolic dysfunction

End-points Primary (combined) : Cardiovascular death. Admission for AMI. Admission for acute heart failure. Secondary end-points: The composite of hospitalization for ACS, for newonset or worsening heart failure, or coronary revascularization All-cause mortality. Mortality due to coronary artery disease. Fatal or non-fatal AMI. The individual components of the composite primary and secondary end points. Fox K et al. Lancet Online August 31, 2008.

Study population Male or female Nondiabetic 55 years, diabetic 18 years Documented coronary artery disease Sinus rhythm and resting heart rate 60 bpm Documented left ventricular systolic dysfunction (<40%) Clinically stable for 3 months with regards to angina or heart failure symptoms or both Therapeutically stable for 1 month (appropriate or stable doses of conventional medications) Fox K et al. Lancet Online August 31, 2008.

Baseline characteristics at inclusion (placebo group ) HR<70 HR 70 Number of patients 2.745 2.693 Age, years 65.6 65.3 Men, % 84 82 Systolic BP, mm Hg 127.2 128.5 Diastolic BP, mm Hg 76.7 78.3 Heart Rate (at rest), bpm 64.1 79.2 Ejection Fraction, % 32.7 31.9 Values in parentheses are standard deviations Fox K et al. Lancet Online August 31, 2008.

Baseline characteristics HR<70 HR 70 at inclusion NYHA class I, % II, % III, % 17 64 19 14 60 26 Ejection Fraction, % 32,7 31,9 Fox K et al. Lancet Online August 31, 2008.

Medical history HR<70 HR 70 Previous MI, % 90 87 Previous PCI /CABG, % 53 51 History of diabetes, % 31 43 History of Hypertension, % 70 72 Values in parentheses are standard deviations Fox K et al. Lancet Online August 31, 2008.

Concomitant treatment HR<70 HR 70 Antithrombotic agents, % Statines, % β-blockers, % Renin-angiotensin system agents, % 95 76 90 89 93 72 84 90 Fox K et al. Lancet Online August 31, 2008.

Results Fox K et al. Lancet Online August 31, 2008.

Heart Rate as prognostic factor in the placebo group Primary compined end-point % of patients with primary end-point 25 P < 0.0001 Heart rate 70 bpm 20 15 10 5 Heart rate < 70 bpm 0 0 0.5 1 1.5 2 Years Fox K et al. Lancet Online August 31, 2008.

Heart Rate as prognostic factor in the placebo group Cardiovascular Death % with cardiovascular death 15 Hazard ratio = 1.34 (1.10 1.63) P = 0.0041 Heart rate 70 bpm 10 +34% 5 Heart rate < 70 bpm 0 0 0.5 1 1.5 2 Έτη Fox K et al. Lancet Online August 31, 2008.

Heart Rate as prognostic factor in the placebo group % Admission to hospital for Heart Failure 15 Admission to hospital for Heart Failure Hazard ratio = 1.53 (1.25 1.88) P < 0.0001 Heart rate 70 bpm 10 +53% 5 Heart rate < 70 bpm 0 0 0.5 1 1.5 2 Years Fox K et al. Lancet Online August 31, 2008.

Heart Rate as prognostic factor in the placebo group % admission to hospital for fatal or non fatal myocardial infarction 10 Myocardial Infarction 5 +46% Heart Rate 70 bpm Heart Rate < 70 bpm 0 0 0.5 1 1.5 2 Years P=0.006 Fox K et al. Lancet Online August 31, 2008.

Heart Rate as prognostic factor in the placebo group % with event of coronary revascularisation 6 Hazard ratio = 1.38 (1.02 1.86) P = 0.037 Coronary revascularisation Heart rate 70 bpm 4 +38% 2 Heart rate < 70 bpm 0 0 0.5 1 1.5 2 Years Fox K et al. Lancet Online August 31, 2008.

Conclusion High Heart Rate is a risk factor of cardiovascular morbidity & mortality, independent of other major risks factors HR measurement should: be used for the evaluation of cardiovascular risk guide optimal medical treatment in coronary patients Fox K et al. Lancet Online August 31, 2008.

π... 9

& π 1000 500 Mouse Hamster Heart Rate (Beats /min) 300 100 50 20 Rat Marmot Dog Tiger Monkey Cat Ass Giraffe Elephant Whale Horse Lion Whale Man 5 10 15 20 25 30 Life Expectancy (Years) 35 40 80 100 Levine et al. J Am Coll Cardiol. 1997;30:1104-1106.

: & Σχετικός κίνδυνος 4 3 2 1 Σύνολο Θανάτων ΟΕΜ Αιφνίδιος Θάνατος 0 < 60 60-64 65-69 70-75 > 75 ΚΣ (bpm) Jouven X, et al. N Engl J Med. 2005;352:1951.

: & π CASS Registry Προσαρµοσµένες καµπύλες επιβίωσης για Συνολική θνητότητα Προσαρµοσµένες καµπύλες επιβίωσης για Καρδιαγγειακή θνητότητα 62 63-70 71-76 77-82 83 bpm 1.0 1.0 0.9 0.9 Cumulative survival 0.8 0.7 0.6 P<0.0001 0.8 0.7 0.6 P<0.0001 0.5 0.5 0 5 10 15 20 0 5 10 15 20 Έτη παρακολούθησης 24.913 CAD patients; 14,1-year follow-up Diaz A et al. Eur Heart J. 2005;26:967-974.

MorBidity-mortality EvAlUation of The I f inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction Fox K et al. Lancet Online August 31, 2008.

π π π π.

Annual event rates in stable CAD outpatients REACH registry (n=38.602) CHF CABG PCI UA Death/MI/Stroke/Hosp* Death/MI/Stroke Nonfatal Stroke Nonfatal MI CV Death 1,4 1,4 1,4 1,8 3,8 4,5 6,9 6,44 15,2 0 5 10 15 20 Rates adjusted for age and risk factors Steg PG et al. JAMA. 2007;297: 1197-1206.

π.

π π π. π π, - π

Gi π Ca π T - AC + camp Gs π β- π f P P Ca π L K

π Ca 2+ mv 0-50 Na + K + 500 ms pa -50 50-50 -50-50 I f I K I Ca,L I Ca,T I Na,Ca Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:1757-1765.

I f -f 0 mv -40 mv -70 mv I f Το ρεύµα I f καθορίζει την κλίση της διαστολικής εκπόλωσης, τη συχνότητα των δυναµικών ενέργειας και, συνεπώς, την καρδιακή συχνότητα Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:1757-1765.

f Ivabradine Προσαρµογή από DiFrancesco D, Camm AJ. Drugs. 2004;64:1757-1765.

I f 0 mv -40 mv -70 mv RR PROCORALAN Ivabradine π Η αναστολή του ρεύµατος Ι f οδηγεί σε µείωση της κλίσης διαστολικής εκπόλωσης στα κύτταρα του φλεβόκοµβου Προσαρµογή από Thollon C et al. Br J Pharmacol 1994; 112:37-42.

I f 0 mv -40 mv -70 mv RR Ivabradine π Η αναστολή του ρεύµατος Ι f οδηγεί σε µείωση της κλίσης διαστολικής εκπόλωσης στα κύτταρα του φλεβόκοµβου Thollon C et al. Br J Pharmacol 1994; 112:37-42.

π π π π.

The CASS registry: n=24.913 100 (%) 80 50 100 π (%) 60 40 20 P<0.0001 35 49 0 34 0 0 2 4 6 8 10 12 14

The CASS registry: n=24.913 100 80 Κλάσµα Εξώθησης (%) 50 100 Επιβίωση (%) 60 40 35 49 20 P<0.0001 0 34 0 0 2 4 6 8 10 12 14 Έτη Emond M. Circulation. 1994;90:2645-57

π ( 70 / π ) π

781 π Northern Europe Austria Belgium Denmark Finland France Germany Ireland Netherlands Norway Sweden Switzerland UK North America Canada Latin America Argentina Brazil Southern Europe Greece Italy Portugal Spain Eastern Europe Czech Republic Hungary Poland Romania Russia Slovakia Australia Oriental Europe Bulgaria Estonia Latvia China Lithuania Slovenia Ukraine Near & Middle East Turkey Kim Fox, Roberto Ferrari, Michael Tendera et al. Am Heart J 2006;152:860-6.

10.917 Ivabradine: 5mg bid 2, 7,5mg Run-in Ivabradine 7.5 mg bid n=5479 π ( -2) Placebo M 0 M 12 M 18 M 24 M 30 M 36, M 6 n=5438 Event rate: 6-8%/ RRR: 20% Kim Fox, Roberto Ferrari, Michael Tendera et al. Am Heart J 2006;152:860-6.

Placebo Ivabradine n=5.438 n=5.479 n=10.917 NYHA class I, % 15 15 15 II, % 62 61 61 III, % 23 24 23 %, 16 15 16, 32 % 32 32 Fox K et al. Lancet, 2008; 372: 807-816

Placebo Ivabradine, 94 % 94, % 74 74 - π, % 87 87, 90 90 % 94 74 87 90 Fox K et al. Lancet, 2008; 372: 807-816

Placebo Ivabradine, 94 % 94, % 74 74 - π, % 87 87, 90 90 % 94 74 87 90 Fox K et al. Lancet, 2008; 372: 807-816

π 25 20 15 10 5 0 P < 0.0001 π π placebo 70 bpm < 70 bpm 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 817-821

% π 15 10 5 0 P < 0.0001 π π placebo π Hazard ratio = 1.53 (1.25 1.88) +53% 70 bpm < 70 bpm 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 817-821.

% µε θάνατο 15 10 5 P = 0,0041 π π placebo +34% 70 bpm < 70 bpm 0 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 817-821.

10 5 0 P=0.0066 π π placebo +46% 70 bpm < 70 bpm 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 817-821.

% π 6 4 2 0 P = 0,037 π π placebo π +38% 70 bpm < 70 bpm 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 817-821.

25 20 15 10 5 0 π Ivabradine π ( π, n=10.917) = 1,00 (0,91 1,10) P = 0,94 Ivabradine Placebo 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 807-816.

(bp π (n=10.917) Ivabradine: 6,18 mg (2 / ) 80 70 60 50 72 69 61 Placebo 69 64 Ivabradine 0 15 30 90 180 360 540 720 ( ) Fox K et al. Lancet, 2008; 372: 807-816.

(bp ( 70 / π, n=5.392) Ivabradine: 6,64 mg (2 / 80 70 60 79 75 65 Placebo ( ) 50 0 15 30 90 180 360 540 720 Fox K, et al. Lancet. In press. Fox K et al. Lancet, 2008; 372: 807-816 73 66 Ivabradine

π Ivabradine π ( 70 / π, n=5.392) % 8 P = 0,001-36% Placebo 4 Ivabradine 0 0 0.5 1 1.5 2 Fox K et al. Lancet, 2008; 372: 807-816.

π Ivabradine π ( 70 / π, π n=5.392) 8 P = 0,016 Placebo 4-30% Ivabradine 0 0 0.5 1 1.5 2 PCI: 1,29 vs 1,61 100 / CABG: 0,47 vs 0,55 100 / Fox K et al. Lancet, 2008; 372: 807-816.

π Ivabradine ( 70 / π, n=5.392) P 0,68 32% 0,114 0,64 0,78 36% & 22% 0,001 0,023 0,77 23%, π 0,009 π 0,70 30% 0,016 Fox K et al. Lancet, 2008; 372: 807-816.

Ivabradine: H π ( BEAUTIFUL), π π π 70 bpm. -.

- π, 50% > 70 bpm 60 40 % 70 bpm 53% Euro Heart Survey 40% 20 0 π π ( - π ) - π Euro Heart Survey in stable angina ESC 08

- π Inconsistent Users 18% Use to No Use 5% Always Users 37% Never Users 30% 31.750 Ασθενείς µε ΣΝ (1995-2002) Positive Converters 10% Califf R et al Circulation 2006;113:203-212.