Old and New Stress Agent

계명의대김기식

Ischemic cascade

Myocardial ischemia

Diastolic dysfunction

Regional systolic dysfunction

ECG changesChest pain

StressDipyridamole

Adenosine

ExerciseTM, bicycle

Dobutamine

Arbutamine

Pacing

Sx & sign(angina, BP )

ST (ECG)Perfusion defect

(Thallium, sestamibiContrast echo)

RWMA(Echo)

Metabolic Abnormality

(PET)

Ischemia

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

Stress Echo

Stress Echocardiography

Diagnosis Prognosis Viability

Treatment

Pharmacologic Stress Agents

Stress agents

Coronary vasodilator

DipyridamoleAdenosinNew agents

Inotropic agents

Dobutamine Arbutamine New agents

Increased vasomotor tone

Reducedflowreserve

Percent contribution to myocardialischemia

ErgonovineHyperventilation

ExerciseHandgripDobutamine

DipyridamolePacing

Conceptual Role of Different Stress test

Dobutamine

Adenosine

Vasodilator

DipyridamoleAdenosineNew agent

Dipyridamole / adenosine

Baseline dipyridamole

Dipyridamole

Potent coronary vasodilatorProvoked anginal attack in angina patients

Vasodilation effectinhibition of reuptake of adenosine by the endothelial cell

Coronary blood flow maldistributionReduction of subendocardial blood flow

in stenotic coronary artery

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

Dipyridamole

Contraindicationactive wheezinghigh degree AV blockhypotension(SBP<90 mmHg)recent use of dipyridamole(<24 hours)

Relative contraindicationHx of reactive airway diseasesick sinus syndromesevere sinus bradycardia

Adenosine

Naturally occuring agentTwo types of receptor

A1: slowing HR and conductionA2: c-AMP

– decrease calcium uptake by SR-- smooth muscle relaxation vasodilation

Half life: 2 seconds need constanr IV infusionRapidly removed from RBC and endothelial cell

Adenosine-protocol

140 mcg/kg/min for 6 min

Theophylline/Caffeine: proto type adenosine receptor antagonist

Adenosine – side effect

Flushng: 37%Dyspnea: 35%GI discomfort: 15%Headache:14%Light-headedness 9%

Most side effect – short-lived and mild

Inotropic agent

DobutamineArbutamine IsoproterenolAmrininemilinone

Dobutamine

Mid, late 1980Synthetic catecholamineProminent inotropic actionLess chronotropic action

Beta 1

Beta2/alpha

Dobutamine 2

Myocardial oxygen demand Normal vessel dilatationStenotic vessel: not directly affect

Action: onset – 2 min half life – 2 min: continous IV

Metabolizd by cathechol-o-methyl transferaseExcretion: hepatobiliary system and kidney

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

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 effectadd atropine

Protocol for Dobutamine Stress Echo.

Arbutamine

Synthetic catecholamineHemodynamically similat to dobutamine

x10 affinity to beta receptorx 5 lower binding at alpha receptor

Action onset: 1-2 minHalf-life: 8 min

Dose dependant increaseheart rate, cardiac output, LV systolic pressure, DP/DTmean arterial pressure: decrease

Arbutamine II

Increatment of heart rate

Increatment of SBP

Arbutamine

76%

27%

Exercise

72%

36%

Cohen et al

JACC 1995 26:1168

Arbutamine

0

20

40

60

80

100

120

140

SBP-b SBP-p DBP-b DBP-p

Arb Dob

0

20

40

60

80

100

120

140

HR-b HR-p 0

2

4

6

8

10

12

Change of blood pressure heart rate time to peak HR

Korean J Med 2000 58:1013

Arb DobSensitivity 81% 78%Specificity 90% 72%

Arbutamine: side effect

Tremor: 22%Dizziness: 11%Headache: 11%Paresthesia: 7%Arrhythmia: 6%Hypotension: 4%

1997 FDA approval1999 withdraw from the marget

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

Combined or Acceleraed stress test

Dobtamine + atropineDipyridamole + ExerciseDipyridamole + DobutamineHigh dose dipyridamoleHigh dose dobutamineCombined contrast echo

Accelelated Dobutamine Stress

High dose dobutamine infusion50 mcg/kg/min for 10 min

P-HRSBPdurationdose

Acc

1401696.4320

Stan

14016212.9353

Similar side effect

AJC 86:825

Combined dipyridamole and dobutamine echocardiography

Borges et al. JASE 2000:14 1057

Predicting functional recovery after PTCALow dose Dob(10 mcg/kg/min) + dip(0.28mg/kg)

0102030405060708090

100

Sensitivity Specificity

DipDobDIDOTL

*

**

New Vasodilator:WRC-0470/CGS-21680

Adenosine A2A receptor agonist

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

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

Inotropic agent for myocardial viabilty

AmrinoneMilinoneEnoximone

Phosphodiesterase inhibitorPotent Inotropic and vasodilating effect

Amrinone stimulation testAmrinone: Not augment myocardial oxygen demandAmrinone 1mg/kg IV over 4 min after CABGObserve change of LVEF: greater than 10% or not

89%

6%

LVEF >10% < 10% JACC 1996 28:1488

ImproveLVEF>10%

Milinone Stress Echo

Milinone: bipyridine inotropic/vasodialor

50 mcg/kg over 10 min IV infusionLV dysfunction + CABGResults:

Akinetic/dyskinetic segmentsSensitivity: 97.8% 97.5%Spcificity: 94.0% 78.8%PP: 92.9% 84.8%NP: 98.2% 96.3%

JASE 2001, 14:668

Conclusion

Pharmacologic stress imaging techniquemore and more acceptance in clinical cardiologyfor evaluation of CAD

Future developmentsafe and reliable pharmacologic stressor agent