DECLARATION OF CONFLICT OF INTEREST

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1 DECLARATION OF CONFLICT OF INTEREST

2 Heart rate and coronary artery disease Uta C. Hoppe Dep. of Internal Medicine II Paracelsus Medical University Salzburg

3 Percent [%] Relevance of CAD in general practice DETECT-Study All years years years years years 75+ years total n = CAD all stabile A.p. unstabile A.p. post MI post PCI post CABG Bischoff, B. et al., Clin Res Cardiol 26;95:45

4 Heart rate and coronary artery disease - Vascular remodeling, occurrence of atherosclerosis

5 Heart rate and arterial distensibility Common carotid artery Atrial pacing model Mangoni et al. J Hypertens 1996;14:897

6 ΔPWV pro year (mm/s) n=483, follow-up 6 years Progression of arterial stiffness 4 Normotensives Treated Hypertensives > >75 Heart rate (bpm) PWV = Carotid-femoral pulse wave velocity Benetos et al. Circulation 22;15:122

7 Heart rate and endothelial dysfunction Dyslipidemic mouse, treatment mo 3-6 Drouin et al., Br J Pharmacol 28;154:749

8 Coronary artery stenoses (%) Heart rate and Atherosclerosis Sinus node modulation yes no p<,2 HR ca. 11 bpm HR ca. 15 bpm months high-cholesterol diet High HR Low HR Beere et al., Science 1984;226:18

9 Coronary Atherosclerosis Score Heart rate and Atherosclerosis Score post MI Coronary Atherosclerosis Score 4 R=.7; p< Minimum heart rate (bpm) young men post MI Perski et al., Am Heart J 1988;116:1369

10 Plaque Area [% total] Plaque Area [% total] Ivabradine inhibits arteriosclerotic plaque formation Ivabradine 1 mg/kg/d, 6 weeks, ApoE-/-, oil red O staining, n=1 each group, *p<.5 vs vehicle Aortic Sinus Aortic Sinus * Vehicle Ivabradine 3 Ascending Aorta 2 1 * Vehicle Ivabradine Ascending Aorta Custodis et al., Circulation 28;117:

11 Lipid Hydroperoxides [µmol/µg] DHE-staining [arbitrary units] NADPH Oxidase Activity [% Vehicle] Superoxide Production [L12-Assay RLU/mg/min] Ivabradine reduces vascular oxidative stress Ivabradine 1 mg/kg/d, 6 weeks, ApoE-/-, oil red O staining, n=1 each group, *p<.5 vs vehicle 15 Vehicle Ivabradine 3 DHE-flourescence * 1 * Vehicle * * * Ivabradine. Custodis et al., Circulation 28;117:

12 Heart rate and coronary artery disease - Vascular remodeling, occurrence of atherosclerosis - Plaque rupture

13 Heart rate and arteriosclerosis: Coronary Plaque Disruption 16 pts. with soft plaques, 53 pts. had plaque disruption vs. controls Heidland et al. Circulation. 21;14:1477

14 Heart rate and arteriosclerosis: Coronary Plaque Disruption Pathophysiology: - Mechanical cause Shear stress - Increased expression of inflammatory/pro-apoptotic mediators HR marker of elevated sympathetic tone

15 Heart rate and coronary artery disease - Vascular remodeling, occurrence of atherosclerosis - Plaque rupture - Myocardial oxygen supply, symptoms, angina pectoris

16 Heart rate and diastolic duration Diastolic duration (ms) Heart rate (bpm) Colin P, et al. J Pharmacol Exp Ther. 24;38:

17 Heart rate and coronary blood flow Heusch et al. Br J Pharmacol 28;153:1589

18 Heart rate and coronary blood flow Heusch et al. Br J Pharmacol 28;153:1589

19 Heart rate and coronary blood flow Heusch et al. Br J Pharmacol 28;153:1589

20 Guidelines in stable coronary artery disease/angina AHA-Guidelines Gibbons et al. Circulation. 22;18:1883

21 Heart rate and coronary artery disease - Vascular remodeling, occurrence of atherosclerosis - Plaque rupture - Myocardial oxygen supply, symptoms, angina pectoris - Morbidity & mortality

22 Incidens (%) Heart rate & prognosis Study population Total mortality Cardiovascular death Cancer Other deaths Stroke < >1 Heart rate (bpm) Wilhelmsen L, et al. Eur Heart J. 1986;7:279

23 Mortality (%) 6-month Mortality in Patients with MI 25 GISSI Experience 2 n = < >1 Heart rate (bpm) Zuanetti et al. Eur Heart J 1999;1(suppl. H):H52

24 Mortality reduction [%] Heart rate reduction and prognosis after myocardial infarction Practolol Oxprenolol Pindolol Metoprolol Propranolol Propranolol Sotalol Timolol Heart rate reduction (bpm) Kjekshus J. Eur Heart J

25 Inclusion criteria - Documented coronary artery disease - Documented systolic left ventricular dysfunction (EF < 4%) - Sinus rhythm and resting heart rate 6 bpm K. Fox et al. Am Heart J. 26;152:86-866

26 BEAUTI f UL-Study (Placebo) Heart rate as a risk factor for CAD??

27 Primary Endpoint % Risk factor Heart rate Primary Endpoint (cardiovasc. death, MI, CHF hospitalization) P <.1 HF 7/min HF < 7/min Jahre Placebo Group Fox et al. Lancet 28; 372:817

28 Cardiovascular death % Risk factor Heart rate Cardiovascular death 15 Hazard ratio = 1.34 ( ) 1 P =.41 HF 7 bpm +34 % 5 HF < 7 bpm Placebo Group Years Fox et al. Lancet 28; 372:817

29 Hospitalization for MI % Revascularisation % Risk factor Heart rate Hospitalization for myocardial infarction Revascularization 8 4 HR = 1.46 ( ) P =.66 HF 7 bpm +46 % 6 4 HR = 1.38 ( ) P =.37 HF 7 bpm +38 % HF < 7 bpm 2 HF < 7 bpm Placebo Group Years Years Fox et al. Lancet 28; 372:817

30 CAD-patients with a heart rate at rest 7 bpm have a higher risk for cardiovascular events, e.g. myocardial infarction

31 Heart rate > 7 bpm despite beta-blocker The Euro Heart Survey CAD population (all, n= 3674) 6 CAD subpop. with beta-blocker (n=25) > 7 Resting HR (bpm)

32 Heart rate and coronary artery disease Increased heart rate associated with: - Endothelial dysfunction - Increased occurrence of atherosclerosis - Plaque instability / rupture - Reduced myocardial oxygen supply - Symptoms, angina pectoris - Increased morbidity & mortality

33 Heart rate and coronary artery disease Uta C. Hoppe Dep. of Internal Medicine II Paracelsus Medical University Salzburg

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