1. Old and New Stress Agent 계명의대 김기식

2. Ischemic cascade Myocardial ischemia Diastolic dysfunction Regional systolic dysfunction ECG changes Chest pain

3. Stress Dipyridamole Adenosine Exercise TM, bicycle Dobutamine Arbutamine Pacing Sx & sign (angina, BP ) ST (ECG) Perfusion defect (Thallium, sestamibi Contrast echo) RWMA (Echo) Metabolic Abnormality (PET) Ischemia

4. Indication pharmacological stress echocardiography Inadequate exercise Left bundle branch block Paced ventricular rhythm pre-excitation or conduction abnormality Medication: beta-blocker, calcium channel blocker Evaluation of patients very early after MI(<3 days) or angioplasty stent(<2weeks) Poor image degradation with exercise Poor patient motivation to exercise

5. Stress Echo Stress Echocardiography Diagnosis PrognosisViability Treatment

6. Pharmacologic Stress Agents Stress agents Coronary vasodilator Dipyridamole Adenosin New agents Inotropic agents Dobutamine Arbutamine New agents

7. Increased vasomotor tone Reduced flow reserve Percent contribution to myocardial ischemia Ergonovine Hyperventilation Exercise Handgrip Dobutamine Dipyridamole Pacing Conceptual Role of Different Stress test

8. Dobutamine Adenosine

9. Vasodilator Dipyridamole Adenosine New agent

10. Dipyridamole / adenosine Baseline dipyridamole

11. Dipyridamole Potent coronary vasodilator Provoked anginal attack in angina patients Vasodilation effect inhibition of reuptake of adenosine by the endothelial cell Coronary blood flow maldistribution Reduction of subendocardial blood flow in stenotic coronary artery

12. Dipyridamole Coronary steal phenomenon Onset and duration of action: prolong Standard protocol: 0.54 mg/kg for 4 min High doseprotocol: 0.84mg/kg Antidote: theophylline

13. Dipyridamole Contraindication active wheezing high degree AV block hypotension(SBP<90 mmHg) recent use of dipyridamole(<24 hours) Relative contraindication Hx of reactive airway disease sick sinus syndrome severe sinus bradycardia

14. Adenosine Naturally occuring agent Two types of receptor A1: slowing HR and conduction A2: c-AMP – decrease calcium uptake by SR -- smooth muscle relaxation vasodilation Half life: 2 seconds need constanr IV infusion Rapidly removed from RBC and endothelial cell

15. Adenosine-protocol 140 mcg/kg/min for 6 min Theophylline/Caffeine: proto type adenosine receptor antagonist

16. Adenosine – side effect Flushng: 37% Dyspnea: 35% GI discomfort: 15% Headache:14% Light-headedness 9% Most side effect – short-lived and mild

17. Inotropic agent Dobutamine Arbutamine Isoproterenol Amrinine milinone

18. Dobutamine Mid, late 1980 Synthetic catecholamine Prominent inotropic action Less chronotropic action Beta 1 Beta2/alpha

19. Dobutamine 2 Myocardial oxygen demand Normal vessel dilatation Stenotic vessel: not directly affect Action: onset – 2 min half life – 2 min: continous IV Metabolizd by cathechol-o-methyl transferase Excretion: hepatobiliary system and kidney

20. Application of Stress Echo  Detection and localization of coronary artery disease  Risk stratification after myocardial infarction  Assessment of myocardial viability  Evaluation of myocardial reserve function in non-coronary heart disease

21. Dobutamine : protocol Initial dose: 5-10 mcg/kg/min 10 mcg/kg/min every 3-5 min Maximum dose: 40-50 mcg/kg/min Suboptimal chronotropic effect add atropine

22. Protocol for Dobutamine Stress Echo.

23. Arbutamine Synthetic catecholamine Hemodynamically similat to dobutamine x10 affinity to beta receptor x 5 lower binding at alpha receptor Action onset: 1-2 min Half-life: 8 min Dose dependant increase heart rate, cardiac output, LV systolic pressure, DP/DT mean arterial pressure: decrease

24. Arbutamine II Increatment of heart rate Increatment of SBP Arbutamine 76% 27% Exercise 72% 36% Cohen et al JACC 1995 26:1168

25. Arbutamine Change of blood pressure heart rate time to peak HR Korean J Med 2000 58:1013 Arb Dob Sensitivity 81% 78% Specificity 90% 72%

26. Arbutamine: side effect Tremor: 22% Dizziness: 11% Headache: 11% Paresthesia: 7% Arrhythmia: 6% Hypotension: 4% 1997 FDA approval 1999 withdraw from the marget

27. Sensitivity and specificity of exercise and pharmacologic stress test Sensitivity(%) Specificity(%) Dobutamine 71 – 96 66 - 83 Dipyridamole 43 – 74 92 - 100 Exercise 74 – 97 64 - 88

28. Combined or Acceleraed stress test Dobtamine + atropine Dipyridamole + Exercise Dipyridamole + Dobutamine High dose dipyridamole High dose dobutamine Combined contrast echo

29. Accelelated Dobutamine Stress High dose dobutamine infusion 50 mcg/kg/min for 10 min P-HR SBP duration dose Acc 140 169 6.4 320 Stan 140 162 12.9 353 Similar side effect AJC 86:825

30. Combined dipyridamole and dobutamine echocardiography Borges et al. JASE 2000:14 1057 Predicting functional recovery after PTCA Low dose Dob(10 mcg/kg/min) + dip(0.28mg/kg) * **

31. New Vasodilator: WRC-0470/CGS-21680 Adenosine A 2A receptor agonist

32. Ultrasonically measured flow in the critically stenotic LAD and normal LCx of protocol 2 dogs. Left, LAD and LCx flows at rest (solid bars) and during pharmacological stress (hatched bars) with adenosine (250 micro gram *symbol* kg sup -1 *symbol* min sup -1); right, coronary flow responses to WRC-0470 (0.6 micro gram *symbol* kg sup -1 *symbol* min sup -1). LCx flow increased threefold with adenosine and fivefold with WRC-0470. Flow in the critically stenotic LAD did not change with either stress. From: Glover: Circulation, Volume 94(7).October 1, 1996.1726-1732

33. Figure. Comparison between the decrease in mean arterial pressure produced by adenosine or WRC-0470 in protocol 2 dogs. Solid bars represent mean arterial pressure at rest; hatched bars show pressure during pharmacological stress. Adenosine infusion resulted in a significant hypotensive response (100 to 76 mm Hg), whereas WRC-0470 produced no hypotension. *P <.0001 vs rest; +P =.02 adenosine vs WRC-0470. From: Glover: Circulation, Volume 94(7).October 1, 1996.1726-1732

34. Inotropic agent for myocardial viabilty Amrinone Milinone Enoximone Phosphodiesterase inhibitor Potent Inotropic and vasodilating effect

35. Amrinone stimulation test Amrinone: Not augment myocardial oxygen demand Amrinone 1mg/kg IV over 4 min after CABG Observe change of LVEF: greater than 10% or not 89% 6% LVEF >10% < 10%JACC 1996 28:1488 Improve LVEF>10%

36. Milinone Stress Echo Milinone: bipyridine inotropic/vasodialor 50 mcg/kg over 10 min IV infusion LV dysfunction + CABG Results: Akinetic/dyskinetic segments Sensitivity: 97.8%97.5% Spcificity: 94.0%78.8% PP: 92.9%84.8% NP: 98.2%96.3% JASE 2001, 14:668

37. Conclusion Pharmacologic stress imaging technique more and more acceptance in clinical cardiology for evaluation of CAD Future development safe and reliable pharmacologic stressor agent