Standardisation and Hyperaemia

Home , Hyperaemia

FFR

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Bernard De Bruyne Cardiovascular Center Aalst Belgium

ETP April 24-26, 2014 Hyperemic Stimuli

Why ?

How ? aalst.be

FAQ ! - www.cardio

Bernard De Bruyne, MD, PhD Cardiovascular Center Aalst OLV-Clinic Aalst, Belgium

ETP April 24-26, 2014 Why?

1. General concept of stress test (as opposed to “rest test”)

2. Standardized measurements (as opposed to “moving target”)

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3. All clinical outcome data are based on hyperemic data - www.cardio

ETP April 24-26, 2014 General concept of stress test Mild Aortic Stenosis

Rest

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P = 17 mm Hg

ETP April 24-26, 2014 General concept of stress test Mild Aortic Stenosis

Rest Dobutamine CO 4.8 L/min 40 µg/kg/min

CO 8.1 L/min

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P = 17 mm Hg P = 21 mm Hg

ETP April 24-26, 2014 General concept of stress test Aortic Stenosis

Cardiac output 3.8 L.min-1 Cardiac output 8.6 L.min-1 Aortic Gradient 26 mm Hg Aortic Gradient 58 mm Hg

Aortic Valve Area 0.77 cm² Aortic Valve Area 1.1 cm²

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ETP April 24-26, 2014 General concept of stress test Diabetes Oral Glucose Tolerance Test: 75 g of sugar to be drunk within 5 minutes

Mg/dL Mg/dL 200 Normal 200 Diabetes 180 180 160 160 140 140

120 120

aalst.be - 100 100 80 80 60 60 www.cardio 40 40 20 20 0 0 Fasting 2 hours 4 Hours Fasting 2 hours 4 Hours

ETP April 24-26, 2014 General concept of stress test

The Wind Tunnel

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ETP April 24-26, 2014 Why?

1. General concept of stress test (as opposed to “rest test”)

2. Standardized measurements (as opposed to “moving target”)

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3. All clinical outcome data are based on hyperemic data (FFR) - www.cardio

ETP April 24-26, 2014 The Control of Resting Myocardial Blood Flow

Neuro-humoral Metabolic

factors α1 α2 factors Adenosine Noradrenaline A Adrenaline β1 β 2 2 NO PGI EDHF 2 PO α2 2 Acethylcholine M M + + PCO2, H , K TXA2 TXA2 NOEndothelium ETA ET 5-HT PGI 2 ETB Arterial Pressure 5-HT EDHF ETB Coronary pressure P2 H AT1 Angiotensine II RAP, LVDP and Pf=0 B2 1 P2 NO PGI2 EDHF H2 H1 Histamine

Systolic compression aalst.be Diastolic compression Bradykinine -

Physical Endo- and paracrine

factors factors www.cardio The “resting state” in biology is wishful thinking of biologists

„Rest‟ is almost never „steady state‟

ETP April 24-26, 2014 The Control of

Resting Myocardial Blood Flow

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ETP April 24-26, 2014 Why?

1. General concept of stress test (as opposed to “rest test”)

2. Standardized measurements (as opposed to “moving target”)

3. All clinical outcome data are based on hyperemic data (FFR) aalst.be

- www.cardio

ETP April 24-26, 2014

How?

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“Keep it Simple and Standardized” - www.cardio The KISS principle

ETP April 24-26, 2014 Maximal Vasodilation

Epicardial Microvasculature = Conductance = Resistance

Arteries > 550 µ Arteries < 550 µ

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ETP April 24-26, 2014 Maximal Vasodilation

1. Nitrates  Epicardial arteries

2. Adenosine  Microvasculature

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www.cardio  IC: 100 – 200 µg in bolus

ETP April 24-26, 2014 Maximal Vasodilation

1. Nitrates  Epicardial arteries

2. Adenosine  Microvasculature

aalst.be 3. Papaverine inhibition of phosphodiesterase  cyclic adenosine MP ↑ - 4. Regadenoson precursor of adenosine 5. Apadenoson precursor of adenosine 6. Binodenoson precursor of adenosine 7. Nitroprusside NO pathways direct non-selective vasodilator www.cardio 8. Nicorandil ↑ guanylate cyclase to increase formation of cyclic GMP - 9. Dopamine ß1 agonist ↑ O2 consumption  adenosine ↑ 10. Exercise Adren stimulation ↑ O2 consumption Adenosine ↑ 11. Coronary occlusion Ischemia  release of adenosine

ETP April 24-26, 2014 Adenosine: Mechanisms of Action

Target organs Receptors (A1, A2A, A2B, A3)

- Coronary arteriolar smooth muscle cells A 2A - Renal arteries (organ level) A1 - Peripheral and central nervous system A1 A2A - Myocardium A3 - Cardiac Conduction system A1 - Respiratory tract A1 - Fibroblast, Adipocytes, Immune System A 2B

ADO 40 µg bolus in Renal Artery ADO 40 µg bolus in LAD

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ETP April 24-26, 2014 Half Life = 4 to 10 s Maximal Vasodilation

1. Nitrates  Epicardial arteries

2. Adenosine  Microvasculature

aalst.be  IV: 140 µg/kg/min -

www.cardio  IC: 100 – 200 µg in bolus

ETP April 24-26, 2014

Adenosine IV

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ETP April 24-26, 2014 Specificities of IV Adenosine (140 µg/kg/min)

1. Preferred route when a pressure pull back is needed

2. Induces a brief increase in systemic pressure followed by a decrease in systemic pressure by 10-20%

3. Is almost uniformly accompanied by a burning aalst.be - sensation

www.cardio 4. Fluctuation of the Pd/Pa ratio are observed in some cases

5. A-V blocks are relatively frequent, always transient

ETP April 24-26, 2014 Adenosine IV 140 µg/kg/min

STOP

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ETP April 24-26, 2014 FAQ

Useful to increase the dose of IV ado > 140 µg/kg/min ?

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ETP April 24-26, 2014 Increasing the dose above 140 µg/kg/min decreases

systematic BP and increases the thoracic pain

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ETP April 24-26, 2014

Adenosine IC

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ETP April 24-26, 2014 Specificities of IC Adenosine (100-200 µg)

1. Can be used in the vast majority of lesions

2. Short half live

3. Rare AV blocks, always transient

aalst.be - 4. Extremely reproducible: do it twice or more!

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ETP April 24-26, 2014

Adenosine ic dose-response curve

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ETP April 24-26, 2014

Adenosine ic dose-response curve

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ETP April 24-26, 2014

IC Adenosine ... Not that shortlasting

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12 beats

ETP April 24-26, 2014

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ETP April 24-26, 2014 Specificities of IC Adenosine (100-200 µg)

1. Can be used in the vast majority of lesions

2. Short half live

3. Rare AV blocks, always transient

aalst.be - 4. Extremely reproducible: do it twice (or more!)

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ETP April 24-26, 2014 IC Adenosine: reproducible but shortlasting

ADO IC 1 ADO IC 2 ADO IC 3

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FFR = 0.53 FFR = 0.53 FFR = 0.54

ETP April 24-26, 2014

Regadenosone aalst.be

IV peripheral - www.cardio

ETP April 24-26, 2014

Regadenoson ( = Rapiscan ® ) Regadenoson as single peripheral i.v. bolus 400 µg

• maximum hyperemia within 60 sec and lasting for aalst.be at least 30 seconds (sufficient for pull-back recording) -

• can be safely repeated after 10 min www.cardio

• hyperemia completely comparable to i.v. adenosine

ideal in radial procedures or ad-hoc FFR

ETP April 24-26, 2014 Van Nunen et al, TCT 2013

Regadenoson vs Adenosine (N=100)

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• Mean Difference 0.00 ± 0.01

ETP April 24-26, 2014 Van Nunen et al, TCT 2013 Quality of the Pressure Recordings

• Recording of 12 beats steady state at rest

• Very short (1-2 s) injections of ado

• Total recording of 45-60 s

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ETP April 24-26, 2014

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ETP April 24-26, 2014 Tips and Tricks

Full Scale

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± 60 s

ETP April 24-26, 2014

Tips and Tricks

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ETP April 24-26, 2014

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Rest or Hyperemia ?

ETP April 24-26, 2014

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ETP April 24-26, 2014

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ETP April 24-26, 2014

When Pd/Pa at rest > 0.90, hyperemia ?

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Pd/Pa = 0.96 FFR = 0.62

ETP April 24-26, 2014

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ETP April 24-26, 2014 Conclusive Remarks

1. Hyperemia is mandatory to “interrogate” a lesion properly

2. Can be obtained very easily, safely, cheaply, ... aalst.be -

3. Provided it is standardized in each laboratory www.cardio

ETP April 24-26, 2014 FAQ

 When Pd/Pa at rest > 0.90, do we have to induce hyperemia ?  When Pd/Pa at rest < 0.80, do we have to induce hyperemia ?  Useful to increase the dose of IV ado > 140 µg/kg/min ?

 Useful to increase the dose of IC ado > 200 µg (bolus) ?

 Is the burning sensation related to ischemia ? aalst.be  Are some patients resistant to Adenosine ? -  Can Papaverine be used instead of Adenosine ?

 Is hyperemia expensive ? www.cardio  What to do with radial procedures ?  Interference with some medications ?  Is adenosine contraindicated in patients with lung disease? ETP April 24-26, 2014 FAQ

When Pd/Pa at rest > 0.90, do we have to induce hyperemia ?

YES

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Pd/Pa = 0.96 FFR = 0.62

ETP April 24-26, 2014 FAQ

When Pd/Pa at rest < 0.80, do we have to induce hyperemia ?

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ETP April 24-26, 2014

When Pd/Pa at rest < 0.80, do we have to induce hyperemia ?

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Pd/Pa = 0.56 FFR = 0.42 ETP April 24-26, 2014 FAQ

Useful to increase the dose of IV ado > 140 µg/kg/min ?

aalst.be

- www.cardio

ETP April 24-26, 2014 Increasing the dose above 140 µg/kg/min decreases

systematic BP and increases the thoracic pain

aalst.be

- www.cardio

ETP April 24-26, 2014 FAQ Useful to increase the dose of IC ado > 200 µg (bolus) ?

Blood Pressure Pd / Pa

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N=46 www.cardio

720 µg decreases Pd/Pa a bit further w/o any decrease in BP, any increase in HR and no heart blocks ???? ETP April 24-26, 2014 De Luca et al JACC Interv 2011 FAQ

Is the burning sensation related to ischemia ?

Adenosine is an algesic substance which stimulates the aalst.be same nerves than those resposnsible for angina ... - which is also due to the local release of adenosine

during ischemia www.cardio

ETP April 24-26, 2014 Sylven C. Cardiovasc Drugs Ther 1993;7:745 FAQ

Are some patients resistant to Adenosine ?

NO,

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Resistance to exogenous Adenosine does not exist - www.cardio

ETP April 24-26, 2014 FAQ

Can Papaverine be used instead of Adenosine ?

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ETP April 24-26, 2014 Papaverine IC

16 mg IC in LCA 12 mg IC in RCA

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ETP April 24-26, 2014 Papaverine IC 16 mg IC in LCA 12 mg IC in RCA

NO PULLBACK Sensor left in the distal LAD

PULLBACK from distal to proximal LAD aalst.be

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ETP April 24-26, 2014 Van Belleghem Rene (22.10.2001) Papaverine IC

16 mg IC in LCA 12 mg IC in RCA

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ETP April 24-26, 2014 Papaverine IC

16 mg IC in LCA 12 mg IC in RCA

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ETP April 24-26, 2014 FAQ

Is hyperemia expensive ?

... NOT REALLY:

aalst.be 0.12 € / bolus of 100 µg IC; 0.24 € / bolus of 200 µg -

1.34 € / syringe needed for approx 15 minutes of IV administration www.cardio

ETP April 24-26, 2014 FAQ

What to do with radial procedures ?

IC BOLUS

IV adenosine INFUSION

aalst.be IV Regadenosone BOLUS -

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ETP April 24-26, 2014 FAQ Some medications interfere with Adenosine

Beta-blockers Alpha-blockers Caffeine Ticagrelor

ACE-inhibitors aalst.be -

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ETP April 24-26, 2014 Effect of Caffeine on FFR

0.76 0.75

0,5

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0 Before Caffeine After Caffeine

ETP April 24-26, 2014 Aqel RA et al Am J Cardiol. 2004 Beta-Adrenergic Blockade and Myocardial Flow

15 Changes in Rest Myocardial 10 Blood Flow Hypermia

aalst.be - Carvedilol Metoprolol -5

-10 www.cardio

-15

ETP April 24-26, 2014 Koepli P et al J Nucl Med 2004 Effect of α-Blockers on Diameter and FFR

PHENTOLAMINE URAPIDIL SALINE

p=NS A p=NS B p=NS C 2,75 2,75 2,75 2,50 2,50 2,50 2,25 2,25 2,25 2,00 2,00 2,00 MLD 1,75 1,75 1,75 (mm) 1,50 1,50 1,50 1,25 1,25 1,25

1,00 1,00 1,00

0,75 0,75 0,75

0,50 0,50 0,50

aalst.be - p=0.03 D p=0.0001 E p=NS F 1,00 1,00 1,00

0,90 0,90 0,90

FFR 0,80 0,80 0,80 www.cardio

0,70 0,70 0,70

0,60 0,60 0,60

0,50 0,50 0,50

Pre Post Pre Post Pre Post

ETP April 24-26, 2014 E. Barbato et al EHJ 2004 FAQ Is adenosine contraindicated in all patients with lung disease ?

1. Adenosine is strictly contra indicated in asthma aalst.be -

2. Adenosine is NOT contra indicated in COPD www.cardio

ETP April 24-26, 2014

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ETP April 24-26, 2014