Regulation of Coronary Blood Flow

24-04-2104 Dirk J. Duncker

ETP April 24-26, 2014 Regulation of Coronary Blood Flow

• Introduction • Control of Coronary Resistance Vessels • Autoregulation: Pressure Flow Relation • Hemodynamic Effects of a Coronary Stenosis

Duncker & Bache Physiol Rev 2008 Van de Hoeff et al J Mol Cell Cardiol 2012 Laughlin, …., Duncker Compr Physiol 2012 Canty & Duncker Braunwald’s Heart Disease 2014 ETP April 24-26, 2014 Cyclic Compression of the Coronary Microvasculature Systole Diastole Systole 120 Ao Pressure (mmHg) 80 LV

40 RV

120 LAD flow (ml/min) 60

Courtesy of Harold Laughlin 0

20 RCA flow (ml/min) 10

160 GCV flow (ml/min) 80

0.0 0.4 0.8 1.2 ETP April 24-26, 2014 Duncker & Merkus 2004 Time (s) Unique aspects of the coronary circulation

• Cyclic compression of the vasculature • High resting myocardial metabolic rate Cardiac muscle 1 ml/min/g flow Skeletal muscle 0.1 ml/min/g flow

 High capillary density Cardiac muscle 3000-4000/mm2 Skeletal muscle 500-1000/mm2  High oxygen extraction Cardiac muscle 60-80% Skeletal muscle 20-30% Myocardial O2 balance during exercise CBF Hct 3.0 Coronary Flow Hematocrit * * 50 * *

2.5 (%) * 40 2.0 ArtSO * 100 2

1.5 * (%) 90

(ml/min/g) 1.0 30 CVSO2 20 0.5 (%) * 10 * * 0.0 0 *

0.0 0.2 0.4 0.6 0.0 0.2 0.4 0.6 MVO (ml/min/g) MVO (ml/min/g) Myocardial2 O2 consumption (ml/min/g)2

ETP April 24-26, 2014 Von Restorff et al Pfluegers Arch 1977 Myocardial O2 balance during exercise

60% Heart Rate 60% 100% Contraction 20% Contractility

O demand 2 LV work 20% Basal metabolism ~0% Myocardial

O2 balance 80% Coronary flow 80%

O2 supply

[O ] - [O ] 20% 2 ART 2 CV

DunckerETP April 24& -Bache26, 2014 Physiol Reviews 2008 Duncker & Bache Physiol Reviews 2008 Metabolic Vasodilation Exercise

LVMBF = LV Myocardial Blood Flow

ETP April 24-26, 2014 Laughlin, Davis,…., Bache, Merkus, Duncker Compr Physiol 2012 Laws of Hemodynamics

• Darcy’s law ΔP = Flow x R ΔP P P ΔP 1 2 Flow = P = pressure R  Flow    R = resistance R

• Poiseuille’s law R = 8 h L L 4  r L = length h r r = radius h = viscosity R = resistance

ETP April 24-26, 2014 JR Levick An Introduction to Cardiovascular Physiology 2010 Regulation of Coronary Blood Flow

• Introduction • Control of Coronary Resistance Vessels • Autoregulation: Pressure Flow Relation • Hemodynamic Effects of a Coronary Stenosis

Duncker & Bache Physiol Rev 2008 Van de Hoeff et al J Mol Cell Cardiol 2012 Laughlin, …., Duncker Compr Physiol 2012 Canty & Duncker Braunwald’s Heart Disease 2014 ETP April 24-26, 2014 Distribution of Resistance in Coronary Microcirculation

Chilian et al Am J Physiol 1989 μ

Davis et al APS Handbook of Physiology 2008 Zhang, …, Chilian APS Handbook of Physiology 2008 Control of tissue blood flow

“Blood goes where it is needed” John Hunter 1794

“He must have wondered how blood “knows” where it is needed?” LB Rowell JAP 2004

ETP April 24-26, 2014 The ultimate cardiac challenge Exercise

Rest Exercise at 5 km/h

100 MAP (mmHg) 50

100 LVP (mmHg) 50

5000 L S 1 2 3 4 5 LV dP/dt Hg/s) (mm 2500 Exercise (km/h) 0

-2500

150 CBF (ml/min) 100

Duncker et al. Circ Res 1998 Duncker & Merkus J Physiol 2007 Duncker & Bache Physiol Rev 2008 ETP April 24-26, 2014 Laughlin, …, Duncker Compr Physiol 2012 Control of Coronary Microvascular Tone

Neurohumoral influences Extravascular influences

compression

NE Endo- en Paracrine influences ACh ANG II histamine

PCO , H+, K+ 2 bradykinin adenosine Endothelial influences

PO2

Metabolic influences

Platelets ETP April 24-26, 2014 Erythrocytes Duncker & Bache Physiol Reviews 2008 NO shear stress TXA 5HT ATP 2 O2

P2Y TXA2 5HT M α2 H1 B2 Endothelium ECE eNOS COX-1 CYP450 • - O2 bET-1 ET-1 L-Arg NO PGI2 AA EDHF ACE ETB

ANG I ANG II IP AT 5HT 1 ETA H2O2 TXA2 ETB cGMP cAMP O M Smooth Muscle 2 ß2 ACh α1 α A NE NE 2 2 KV H1 H P K K 2 2X K ATP K Ca Ca KCa ATP

adenosine CO2

ATP ADP

Cardiomyocyte O2 Neurohumoral influences Extravascular influences

compression

NE Endo- en Paracrine influences ACh ANG II histamine

PCO , H+, K+ 2 bradykinin adenosine Endothelial influences

PO2

Metabolic influences Control of Coronary Microvascular Tone

Platelets Erythrocytes NO shear stress TXA 5HT ATP 2 O2

P2Y TXA2 5HT M α2 H1 B2 Endothelium ECE eNOS COX-1 CYP450 • - O2 bET-1 ET-1 L-Arg NO PGI2 AA EDHF ACE ETB

ANG I ANG II IP AT 5HT 1 ETA H2O2 TXA2 ETB cGMP cAMP O M Smooth Muscle 2 ß2 ACh α1 α A NE NE 2 2 KV H1 H P K K 2 2X K ATP K Ca Ca KCa ATP

adenosine CO2

ATP ADP

Cardiomyocyte O2

ETP April 24-26, 2014 Duncker & Bache Physiol Reviews 2008 Regulation of Coronary Blood Flow

• Introduction • Control of Coronary Resistance Vessels • Autoregulation: Pressure Flow Relation • Hemodynamic Effects of a Coronary Stenosis

The ability of the heart to maintain flow constant

in the face of a change in perfusion pressure aalst.be

without the intervention of any other external mechanism - www.cardio

ETP April 24-26, 2014 (Courtesy of Bernard De Bruyne) Coronary Autoregulation 200

175

150

125

100 aalst.be 75 -

50 www.cardio

25 Coronary Blood Flow Blood (mL/min) Flow Coronary

0 25 50 75 100 125 150 175 200 Coronary Perfusion Pressure (mm Hg)

ETP April 24-26, 2014 (Courtesy of Bernard De Bruyne) Rubio and Berne, Prog CV Disease 1975 Autoregulatory Range

200

175

150

125

100 aalst.be 75 -

50 www.cardio

25 Coronary(mL/min) Blood Flow

0 25 50 75 100 125 150 175 200 Coronary Perfusion Pressure (mm Hg)

ETP April 24-26, 2014 (Courtesy of Bernard De Bruyne) Rubio and Berne, Prog CV Disease 1975 μ

Davis et al APS Handbook of Physiology 2008

μ Zhang, Rogers, Merkus, … Chilian APS Handbook of Physiology 2008 Coronary Pressure-Flow Relation

ΔP = Flow x R

Rmin = ΔP/Flowmax Cmax = 1/Rmin = Flowmax/ΔP

P = pressure R = resistance C = conductance

ETP April 24-26, 2014 Canty & Duncker Braunwald’s Heart Disease 2014 Coronary Pressure-Flow Relation

ETP April 24-26, 2014 Canty & Duncker Braunwald’s Heart Disease 2014 Coronary Pressure-Flow Relation Subendocardial Vulnerability

ETP April 24-26, 2014 Canty & Duncker Braunwald’s Heart Disease 2014 Coronary Flow-Function Relation Subendocardial vulnerability

ETP April 24-26, 2014 Canty Circ Res 1988; Canty et al Circulation 1990 Regulation of Coronary Blood Flow

• Introduction • Control of Coronary Resistance Vessels • Autoregulation: Pressure Flow Relations • Hemodynamic Effects of a Coronary Stenosis

ETP April 24-26, 2014 Canty & Duncker Braunwald’s Heart Disease 2014 Stenosis

PDISTAL

PAORTA

ETP April 24-26, 2014 Pressure Derived Fractional Flow Reserve, FFR

FFR= Pd/Pao = 105/133 = 0.78 Aortic (Pao)

Coronary (Pd)

Coronary velocity

CFR= 2.2

Adenosine

ETP April 24-26, 2014 Assessment of Coronary Reserve

Flow velocity wire

PET/MRI/CT Perfusion

Pressure wire

Canty & Duncker Braunwald’s Heart Disease 2014 Regulation of Coronary Blood Flow

• Introduction • Control of Coronary Resistance Vessels • Autoregulation: Pressure Flow Relations • Hemodynamic Effects of a Coronary Stenosis

Duncker & Bache Physiol Rev 2008 Van de Hoeff et al J Mol Cell Cardiol 2012 Laughlin, …., Duncker Compr Physiol 2012 Canty & Duncker Braunwald’s Heart Disease 2014 ETP April 24-26, 2014 Coronary Pressure-Flow Relation Influence of Coronary Microvascular Disease

ETP April 24-26, 2014 Canty & Duncker Braunwald’s Heart Disease 2014