Regulation of Coronary Blood Flow

Regulation of Coronary Blood Flow for the Interventionalists Bernard De Bruyne Cardiovascular Center Aalst Belgium

ABC of Coronary Physiology For the Interventionalist 1. About Pressure, flow, mass, resistance, etc,... 2. Epicardial vs microvascular compartments 3. Flow-function relationship 4. Coronary autoregulation

Extravascular Compressive Forces Pressure Aorta LV

Extravascular Compressive Forces Pressure Aorta LV LAD FLOW

Extravascular Compressive Forces Pressure Aorta Coronary LV LAD FLOW

Extravascular Compressive Forces Pressure Aorta RV LAD FLOW RCA FLOW

Cross-Sectional Lumenal Area (cm²) www.cardio-aalst.be Relation between Vessel Size and Myocardial Mass 0.3 Normals 0.25 0.2 CAD 0.15 0.1 0.05 0 0 100 200 300 400 500 Regional Myocardial Mass (g) C. Seiler et al Circulation 1992

About Pressure, Flow, Resistance, and Vessel Size BASE APEX 100 % of value at the ostium Diameter Mass Pressure Flow Distance from the ostium

About Pressure, Flow, Resistance, and Vessel Size

About Pressure, Flow, Resistance, and Vessel Size 5 Ref Diam (mm) 4 < 4 mm² = significant stenosis? 3 2 50 % Stenosis for an Cross Sectional Area of 4 mm² 25 0

Anatomy vs Physiology: the Chimeric Link IVUS OCT Waksman et al. JACC 2013 Guagliumi et al EuroInterv 2013 DS CCT Angio Sarno et al JACC 2009 FFR Toth et al EHJ 2014 Statistical (mechanistic) relation but little clinical relation

ABC of Coronary Physiology For the Interventionalist 1. About Pressure, flow, resistance, etc,... 2. Epicardial vs microvascular compartments 3. Flow-function relationship 4. Coronary autoregulation

Two-Compartment Model of the Coronary Circulation The coronary angiogram detects only 5% of the total coronary tree

Two-Compartment Model of the Coronary Circulation Epicardial Artery Microvasculature FFR IMR CFR

Two-Compartment Model of the Coronary Circulation Conductance Arteries Resistance Arteries >500 µ <500 µ Microvasculature P a 100 MACRO MICRO

Pressure and Flow Velocity in Normal Coronary Arteries Adenosine FFR = 0.98 CFR = 4.15

Conductance Arteries Focal Stenosis >500 µ Resistance Arteries <500 µ Microvasculature P a 100 MACRO MICRO

Conductance Arteries >500 µ Resistance Arteries <500 µ Microvasculature Stent P a 100 MACRO MICRO

Conductance Arteries Focal Stenosis >500 µ Resistance Arteries <500 µ Microvasculature P a 100 Diffuse Atherosclerosis MACRO MICRO

Conductance Arteries >500 µ Resistance Arteries <500 µ Microvasculature Stent P a 100 Diffuse Atherosclerosis MACRO MICRO

Conductance Arteries >500 µ Resistance Arteries <500 µ Microvasculature P a 100 Diffuse Atherosclerosis MACRO MICRO

Endothelial Control of Coronary Blood Flow ACh Blood Flow Shear Stress Bradykinine Endotheline Normal Endothelium L-Arginine enos NO PGI 2 EDHF Vascular Smooth Muscle Cell Guanyl Cyclase cgmp Dilatation

Endothelial Control of Coronary Blood Flow ACh Blood Flow Shear Stress Bradykinine Endotheline Abnormal Endothelium L-Arginine enos NO Vascular Smooth Muscle Cell Guanyl Cyclase cgmp Constriction

Importance of Maximal Vasodilation Epicardial = Conductance Arteries > 550 µ Microvasculature = Resistance Arteries < 550 µ Nitrates Vasospasm Adenosine Autoregulation

Endothelial Control of Coronary Blood Flow Effects of Mental Stress on the Diameter of Stenosed, Irregular, and Smooth Epicardial Coronary-Artery Segments. Effect of Mental Stress on the Diameter of Coronary Arteries Yeung AC et al. N Engl J Med 1991;325:1551-1556.

% Reduction in Subendocardial Function www.cardio-aalst.be Flow-Function Relationship % Reduction in Subendocardial Flow 0-20 -40-100 - 80-60 -40-20 0-60 - 80-100 -120-140 -160-180 -200 S. Vatner Circ Res 1980;47:201

Flow-Function Relationship 100 LV Wall Thickening (% of control value) Arterial saturation = 98 % Cor sinus saturation = 20 % 0 0 100 Resting Coronary Flow (% of control value) J. Canty Circ Research 1988;63:821-836

LV Wall Thickening (% of control value) www.cardio-aalst.be Flow-Function Relationship 100 0 0 100 Resting Coronary Flow (% of control value)

Flow-Function Relationship

The Control of Myocardial Blood Flow Neuro-humoral factors α 1 α 2 Metabolic factors Noradrenaline Adrenaline β 1 β 2 NO PGI 2 EDHF A 2 adenosine Acethylcholine M M α 2 PO 2 Arterial Pressure Coronary pressure RAP, LVDP and P f=0 TXA 2 5-HT TXA 2 NO PGI 2 EDHF 5-HT P 2 Endothelium P 2 B H 1 2 NO PGI 2 EDHF ET B H 2 ET AT 1 ET A ET B PCO 2, H +, K + Angiotensine II H 1 Histamine Systolic compression Diastolic compression Bradykinine Physical factors Endo- and paracrine factors Adapted from D.J.G.M. Duncker

The Control of Myocardial Blood Flow Metabolic factors Endothelium Physical factors Neuro-humoral factors Endo- and paracrine factors Multiple, interacting, cumulative, nonlinear mechanisms Coronary Autoregulation Adapted from D.J.G.M. Duncker

Autoregulation The ability of the heart of maintaining flow constant in case of change of perfusion pressure without the intervention of any other external mechanism

Coronary Blood Flow (ml/min) www.cardio-aalst.be Coronary Autoregulation 200 175 150 125 100 75 50 25 0 25 50 75 100 125 150 175 200 Coronary Perfusion Pressure (mm Hg) Rubio and Berne, Prog CV Disease 1975

Coronary Blood Flow (ml/min) www.cardio-aalst.be Autoregulatory Range 200 175 150 125 100 75 50 25 0 25 50 75 100 125 150 175 200 Coronary Perfusion Pressure (mm Hg) Rubio and Berne, Prog CV Disease 1975

Coronary Blood Flow (ml/min) www.cardio-aalst.be Autoregulatory Range 200 175 150 125 Initial Pressure 100 75 50 25 0 25 50 75 100 125 150 175 200 Coronary Perfusion Pressure (mm Hg) Rubio and Berne, Prog CV Disease 1975

% Control Flow www.cardio-aalst.be Flow, Pressure, and Resistance R myo P a F R epi P v 100 75 50 25 F = P R epi + R myo 0 25 50 75 100 % Area Stenosis K. Lance Gould, 1974

% Control Flow www.cardio-aalst.be Flow, Pressure, and Resistance R myo P a F R epi P v 100 75 50 25 P F = R epi + R myo 0 25 50 75 100 % Area Stenosis K. Lance Gould, 1974

Autoregulation Proximal LAD stenosis (n = 26) Normal LV systolic function PET fow measurements ( 15 O-labeled water) at rest 5 4 3 2 1 0 30 40 50 60 70 80 90 100 110 120 130 Distal Coronary Pressure (mm Hg) De Bruyne et al, 1996

Hyperemic Coronary Blood Flow ( % of Normal ) www.cardio-aalst.be Pressure-Flow Relationship During Maximal Vasodilation 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Hyperemic Coronary Perfusion Pressure ( % of normal )

People who wish to treat patients with CAD without coronary physiology must settle for a suboptimal treatment

Fractional Flow Reserve FFR = ratio of hypermic flow in the stenotic vessel to hyperemic flow in the same vessel but in the absence of the stenosis FFR = extent to which (%) maximal myocardial flow is limited by the epicardial stenosis P a S Q max FFR = = N Q max P d P a P d During maximal hyperemia (i.e. during maximal transstenotic flow)

Fractional Flow Reserve FFR = ratio of hypermic flow in the stenotic vessel to hyperemic flow in the same vessel but in the absence of the stenosis FFR = extent to which (%) maximal myocardial flow is limited by the epicardial stenosis P a FFR = Q s max max Q N P d FFR =? P d P a (at hyperemia)

Definition Fractional Flow Reserve is the ratio of maximal myocardial flow In the stenotic territory to normal maximal myocardial flow max Q N P a 100 P d 100 P v 0 FFR = FFR = Q s max Q N (P d -P v ) / R S (P a -P v ) / R N max max max P a 100 P d 70 P v 0 Hyperemia R s =R N max Q s P v <<< P a and P d FFR = P d P a

Hyperemic Coronary Blood Flow ( % of Normal ) www.cardio-aalst.be Pressure-Flow Relationship During Maximal Vasodilation P a 100 P d 100 P v 0 100 Q N max 90 80 70 60 50 P a 100 P d 70 P v 0 40 30 Q s max 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Hyperemic Coronary Perfusion Pressure ( % of normal )

Non-Linearity of the Pressure-Resistance Relationship? Spaan, J. A.E. et al. Circulation 2006

Diameter Normalized to the Passive Diameter at 100 mm Hg www.cardio-aalst.be 1.1 Non-Linearity of the Pressure-Resistance Relationship? 1.05 1 0.95 0.9 0.85 0.8 0.75 0.7 30 50 70 90 110 Pressure (mm Hg) Adapted from Spaan, J. A.E. et al. Circulation 2006

Diameter Normalized to the Passive Diameter at 100 mm Hg www.cardio-aalst.be 1.2 Non-Linearity of the Pressure-Resistance Relationship? 1 0.8 0.6 0.4 0.2 0 30 50 70 90 110 Pressure (mm Hg) Adapted from Spaan, J. A.E. et al. Circulation 2006

The relation between P d /P a and Q S /Q N is LINEAR during HYPEREMIA Pijls NHJ et al, Circulation,1993;86:1354

The relation between P d /P a and Q S /Q N is LINEAR during HYPEREMIA 22 Patients with an isolated proximal LAD stenosis H 2 15 O PET maximal flow in LAD vs normal territories FFR within 24 hours De Bruyne B et al, Circulation,1994;89:1013

FFR: Physiologic Meaning S Q max FFR = = N Q max P d P a During maximal hyperemia (i.e. during maximal transstenotic flow) FFR has a well defined physiologic meaning (in sharp contrast to other indices like the ΔP, resting P d /P a, ifr, FFR diast )

People who wish to treat patients with CAD without coronary physiology must settle for a suboptimal treatment