Physiology of Coronary Blood Flow Dr Sandeep Mohanan, Department of Cardiology, Medical College, Calicut.

OUTLINE Physiologic assessment of CAD- noninvasively and invasively Introduction Coronary microcirculation, resistance beds & autoregulation Endothelium dependent vasodilation CBF during exercise Physiology of CBF across a stenosis Measurement of CBF Physiologic assessment of CAD- noninvasively and invasively Coronary collateral circulation CBF abnormalities with ‘normal’ coronary vessels

INTRODUCTION The resting coronary blood flow ~250ml/min (0.8ml/min/g myocardium=5% of COP) Myocardial oxygen consumption --- balance between supply and demand According to Fick’s principle, oxygen consumption in an organ is equal to the product of regional blood flow and oxygen extraction capacity. The heart is unique in having a maximal resting O2 extraction (~70-80%) So, MVO2 = CBF * CaO2 Thus, when systemic oxygenation is stable, the oxygen supply is determined by the coronary blood flow Adolf Eugene Fick – German physician and phsiologist GREGG effect : Where an increase in coronary blood flow can independently increase the MVO2 (by increasing end-diastolic diameter)

 The coronary blood flow is unique: Helps generate the systole (cardiac output) & simultaneously gets impeded by the systole it generates. At systole – Arterial flow is minimum: directed from the subendocardium to the subepicardium; and the coronary venous outflow is maximum Diastole – The coronary inflow is maximum  

BASIC PHYSICS OF FLOW Bernoulli’s principle Daniel Bernoulli (Swiss scientist) studied fluid dynamics and postulated in his book, Hydrodynamica, that for an inviscid flow an increase in the speed of the fluid occurs simultaneously with a decrease in pressure or a decrease in the fluid's potential energy. LAW OF CONSERVATION OF ENERGY {Total energy = Kinetic energy + Potential(Pressure) energy} - May explain in part the increase in flow during diastole 1738

Hagen-Poisseuilles equation: -Gives the pressure drop for a viscous liquid( in laminar flow) as it flows through a long cylindrical pipe -Corresponds to the Ohms law for electrical circuits (V=IR) -Thus halving the radius of the tube increases the resistance by 16 times Principles were also extended to turbulent flow and helped derived the Darcy-Weisbach equation and the Reynolds number

DETERMINANTS OF CORONARY RESISTANCE Flow is determined by the segmental resistance and therefore an understanding of the resistance beds is necessary: 3 resistance beds R1 R2 R3

R2( Microcirculatory resistance) – 20- 200µm Small arteries and arterioles Capillaries: ~ 20% of R2 ( even if capillary density doubles, perfusion increases by only 10%) R3( Compressive resistance) - time varying - Increased in heart failure In the subendocardium R3increases but R2 decreases. So, transmural flow is normally uniform.

Coronary driving pressure = Aortic root pressure – LVEDP Broadly 2 compartments of coronary resistance: 1) Epicardial conduit vessels – no pressure loss 2) Resistance vessels -- < 300μm -- gradually dissipating pressure till 20-30 mmHg Coronary driving pressure = Aortic root pressure – LVEDP The interactions of coronary driving pressure and the coronary resistance are coordinated so as to maintain a constant flow for a given workload. ---- CORONARY AUTOREGULATION

CORONARY AUTOREGULATION Maintenance of a constant regional coronary blood flow over a wide range of coronary arterial pressures when determinants of myocardial oxygen consumption are kept constant. Below the lower limit: flow becomes pressure dependent Under optimal circumstances this lower threshold is a mean pressure of 40mmHg. Sub-endocardial flow compromise: <40mmHg Sub-epicardial flow compromise: <25mmHg -Due to higher resting blood flow in subendocardium and effects of systole on subendocardial coronary reserve

The threshold increases with increased determinants of oxygen consumption. Even as constant flow is maintained at a constant work load; -- As the workload increases, the oxygen consumption proportionately increases. -- The increase in MvO2( Demand) needs a proportionate increase in coronary flow ( Supply). -- This increase in CBF is directed by endothelium related flow mediated dilatation as well as by various mediators that decrease coronary resistance.

CORONARY MICROCIRCULATION A longitudinally distributed network with considerable spatial heterogeneity of control mechanisms. Each resistance vessel needs to dilate in an orchestrated fashion.

Resistance As (100 -400μm) - shear stress + myogenic Arterioles (<100 μm) –metabolic Capillaries- 3500/mm2 ΔP (Pressure drop) occurs b/w 50 - 200μm

Heterogeneity of microcirculatory auto-regulation: When driving pressure decreases, Autoregulation causes arterioles<100μm dilate where as larger resistance arteries tend to constrict due to a decrease in perfusion pressure. However metabolic vasodilation which is triggered shows a homogenous response. FIGURES>>>>>

Transmural penetrating arteries: Not influenced by metabolic stimuli. Blood flow driven by coronary driving pressure, flow mediated vasodilation and myogenic regulation. Significantly influences the subendocardial blood flow

MEDIATORS OF CORONARY RESISTANCE PHYSICAL FORCES METABOLIC MEDIATORS NEURALCONTROL PARACRINE FACTORS

Physical forces Myogenic regulation: These are intraluminal forces: Ability of the vascular smooth muscle to oppose changes in coronary arteriolar diameter Probably due to stretch activated L-type Ca channels Primarily in <100microm Significant role in coronary autoregulation

2) Flow mediated vasodilatation: Coronary diameter regulation in response to changes in local shear stress. Kuo et al Endothelium mediated- NO, EDHF Occurs in both conduit (?hyperpolarisation) as well as resistance arteries (NO mediated)

Metabolic mediators Adenosine: - Cardiac myocytes during ischemia ( ATP hydrolysis) T-half of 10sec A2a receptors - cAMP : Ca2+ activated K-channels Direct action on <100µm vessels Indirectly on resistance arteries and conduit arteries : endothelium-dependent Hypoxia Exercise –induced myocardial ischemia A1 – decrease heart rate A2a- coronary artery vasodilation A2b- bronchospasm A3- cardiac muscle relaxation, cardioprotective during ischemia

Acidosis and arterial hypercapnoea: K+-ATP channels - Contributes to resting coronary tone - It is actually a common effector pathway of several other mediators Hypoxia - However a direct vasodilatory mechanism is lacking Acidosis and arterial hypercapnoea:

NEURAL CONTROL- Cholinergic innervation -Endothelium dependent and flow mediated vasodilatory effects also NORMAL CORONARIES ATHEROSCLEROSIS RESISTANCE ARTERIES DILATION ATTENUATED DILATION CONDUIT ARTERIES NET MILD DILATION (Muscarinic constrictive + Endo-dep & flow mediated vasodilatory) CONSTRICTION

NEURAL CONTROL- Sympathetic innervation - Sympathetic denervation does not affect resting flow NORMAL CORONARIES ATHEROSCLEROSIS RESISTANCE ARTERIES NET DILATION (β2 dilation+ α1 constriction + β1 consumption) ATTENUATED DILATION CONDUIT ARTERIES (β2 dilation + endo-dep & flow mediated dilation+ α1 constriction) CONSTRICTION Therefore exercise induced feed-forward increased blood flow. However beta blockade causes coronary vasoconstriction and decrease flow…but this is offset by an increased oxygen extraction and a decreased oxygen demand

PARACRINE MEDIATORS Released from epicardial arterial thrombi following plaque rupture NORMAL CORONARIES ATHEROSCLEROSIS Conduit Resistance SEROTONIN constriction dilation THROMBOXANE A2 ADP attenuated THROMBIN BRADYKININ HISTAMINE SUBSTANCE P Dilatory effects are all secondary endothelium dependent NO and prostacyclin effects

ENDOTHELIUM DEPENDENT MODULATION OF CORONARY TONE A functional endothelium is the major determinant in the normal physiological effects of physical, metabolic, neural and paracrine factors on the coronary tone. Nitric oxide (NO) Endothelium dependent Hyperpolarising factor (EDHF) Prostacyclins Endothelins

Nitric Oxide “Molecule of the year” in 1992 Robert F. Furchgott, Louis J. Ignarro and Ferid Murad received Nobel prize for Physiology/Medicine in 1998 L-arginine + 3/2 NADPH + H+ + 2 O2 = citrulline + NITRIC OXIDE + 3/2 NADP+ Action: It increases cGMP levels : Decreased i.c Ca levels -Its effects are enhanced by increased shear stress of flow Exercise : Chronic upregulation of NO synthase CVD risk factors – Increase oxidative stress(superoxide) – inactivates NO

EDHF Shear stress induced vasodilation Opens K+ channels – vasodilation Probably metabolites of arachidonic acid by the CYP pathway ? Epoxyeicosatrienoic acid ? Endothelium derived hydrogen peroxide

PROSTACYCLIN: -Arachidonic acid metabolism via cycloxygenase pathway Important in collateral vascular resistance ENDOTHELINS: - prolonged vasoconstictor response ETa and ETb receptors Regulates blood flow only in pathophysiological states.

VARYING SENSITIVITIES OF THE MICROCIRCULATION TO STIMULI

Pharmacological Vasodilation Nitroglycerin: Vasodilation in conduit and resistance arteries No effect in nomal coronary arteries due to autoregulatory mechanisms Improves subendocardial perfusion: Compensates for impaired endo-dependent mechanisms Dilates collateral vessels Reduces LV end-diastolic pressure

Calcium Channel blockers: Vasodilation of conduit and submaximal action on resistance vessels ( Therefore rarely precipitate subendocardial ischemia ) Adenosine & agonists : Regadenoson (A2) Dipyridamole Papaverine: 1st agent used for coronary vasodilation Increases cAMP by inhibiting phosphodiesterase

A newer mechanism for coronary blood flow Davies et al (Circulation 2006) : “Pushing waves and Suction waves” Pushing waves : Proximal to distal push- forward - pushes blood till the conduit vessels Suction waves: Distal to proximal suction effect - backward - main determinant of diastolic flow

CBF DURING EXERCISE ACUTE EXERCISE: Increases afterload, contractility, LV wall stress, tachycardia and oxygen demand Proportional increase in myocardial blood flow (2 to 4 fold) mainly through a decrease in R2 and flow mediated dilation. However in presence of a coronary stenosis the increase in R1 overruns the decrease in R2 above a threshold, causing stress induced ischemia.

PROLONGED EXERCISE TRAINED HEART: The CBF is maintained or increases

PHYSIOLOGY OF CBF ACROSS A CORONARY STENOSIS Consequence of a coronary obstruction due to CAD: 1) Increased resistance in an epicardial artery due to stenosis 2) Abnormal microcirculatory control

The flow across a stenosis is determined by the P-Q relationship Perfusion of territory distal to a stenosis ------------ DISTAL CORONARY PRESSURE In normal coronaries : R2> R3>> R1 In CAD : R1 > R3 > R2 R1 increases with stenosis severity and impairs flow

Ideal stenosis P-Q relationship According to Bernoullis principle and law of conservation of energy. The total energy = KE + PE; i.e  E ∝ V2 + PE The flow across a stenosis (Flow= A * mean velocity) Thus V ∝ 1/D2 …. -Therefore in 50% stenosis, V- 4 times and KE- 16times. - The PE proportionately decreases and is lost as (ΔP) DISTAL PRESSURE LOSS Post stenosis: V comes back to normal …Therefore KE decreases to pre-stenosis values… PE thus becomes (prestenotic PE)- ΔP i.e =Pd

ΔP= Viscous losses + Separation losses + Turbulence Viscous losses = f1 Q , f1 (Viscous coefficient = 8πμL/ As2 ) (Hagen-Poiseuille equation) Separation losses= f2 Q2, f2 (Separation coefficient= ρ/2[1/As-1/An]2 ) μ - viscosity of blood ρ - density of blood L - length of stenosis As - CSA of stenotic segment An - CSA of normal segment Flow to distal territory = Pd- venous pressure

Resistance is also flow dependent ( α square of flow) Thus the pressure drop across a stenosis varies directly with the length of the stenosis and inversely with fourth power of the diameter. Therefore overall resistance and thus distal pressure is determined mainly by cross sectional area of the stenosis – increases exponentially Resistance is also flow dependent ( α square of flow) Abluminal outward remodelling : No effect on P-Q characteristics Inward remodelling : Significant longitudinal pressure drop Instantaneous resistance increases during vasodilation

MEASUREMENT OF CORONARY BLOOD FLOW Earlier microsphere radionuclide techniques were considered gold standard. Presently, regional myocardial blood flow can be quantitated non-invasively equally accurately using MRI, CT and PET. Resting CBF – 0.7-1ml/min/g However a resting CBF gives little information This may be normal in HCM, CAD, DCMP etc due to inherent “adjusting mechanisms”. It is the CBF in a “stressed” heart that brings out the true quality of the coronary vasculature. “STRESS” – Pharmacological / Physiological

Noninvasive flow measurements MRI, Doppler echo and Dynamic PET (Nuclear Perfusion studies) Require measurements of the myocardial tissue tracer concentrations and its kinetics.

FUNCTIONAL ASSESSMENT OF CAD - Noninvasive Vasodilator stress: - Adenosine 140µg/kg/min for 4 min( Dypiridamole 560µg/kg/min) Induces hyperemia and makes CBF dependent on driving pressure and the residual resistance 3 to 5 times flow (2-4ml/min/g) Exposes the minimum coronary vascular resistance of the system Noninvasive methods may measure either the relative flow (compared to normal regions)or the absolute flow The concept of Coronary flow reserve pioneered by Lance Gould is central to the functional assessment of CBF across a stenosis. Lance Gould-relationship b/w the anatomic severity of a stenosis and flow resistance

Coronary reserve : Ability to increase CBF above resting value by maximum pharmacologic vasodilation (4 to 5 fold) Parameters that may affect CFR: - HR - preload - afterload - contractility - systemic oxygen supply Flow in the maximally vasodilated heart is pressure dependent. Thus CFR indirectly shows the consistency of the driving coronary pressure uptill the distal territory

Relative Flow Reserve = Regional perfusion of a segment/ Perfusion in normal segment during maximal pharmacological vasodilation/exercise Compares under same hemodynamic conditions Independent of HR and MAP More lesion specific than the AFR --- correlates with FFR Limitations: - Requires a normal reference segment--- ? Diffuse CAD Low sensitivity – requires relatively large differences in regional flow The uptake of nuclear tracers may not be proportionate in both regions Not much prognostic data available

Absolute Flow Reserve = Maximal vasodilated flow in a region of interest/ Resting flow of same region. - Normal AFR ~ 4-5 Clinically significant impairment if <2 AFR incorporates functional importance of a stenosis + microcirculatory dysfunction Limitations: - Altered by factors affecting resting flow also (Hb, HCM, Hemodynamics etc) Instantaneous hemodynamic conditions of the values are different Cannot specify the importance of the epicardial lesion alone Correlation with stenosis severity decreases with more extensive CAD

Rb-82 quantitativePET scan before and after dipyridamole stress in a patient with significant triple vessel disease- showing inferior and inferolateral ischemia

- Vasodilator stressing is also dependent on the changes in extravascular resistive forces (HR, contractility,SBP) --- Thus exercise induced vasodilation causes a lesser flow increase than pharmacological -- Endothelium mediated vasodilation contributes significantly to pharmacological vasodialtion (eNOS inhibition causes ~ 18% decrease in flow reserve & a 21% decrease in vasodilatory capacity)

2) Positive inotropic stress : Dobutamine infusion Similar to exercise induced mechanisms Around 200 to 300% increase in flow 3) Sympathetic stress : Cold pressor test - Targets endothelium mediated determinants of resistance Adrenergically mediated vasoconstrictor effects are balanced by endothelium-related vasodilator forces affecting both the microvasculature and the epicardial vessels. ~ 38% increase in MVO2 (rate-pressure product) & ~30% increase in CBF. In early CAD causes actually a decrease in CBF due to unopposed vasoconstrictor responses ( Highly sensitive)

Limitations of CAD assessment by noninvasive testing: Conceptual limitations: Suboptimal accuracy in assessing intermediate epicardial lesions Limited spatial resolution ( esp in complex lesions) ?Several stenosis within same artery ? Multivessel disease Uncertainty about exact perfusion territory Practical limitations: Needs referral to another department and related delays Not possible when an immediate on-table decision is required Number of acute presentations increasing Additional financial commitments

Functional assessment of CAD- Invasive AFR and RFR can also be derived by invasive measurements Fractional Flow Reserve(FFR) Brought forward by Pijls et al who demonstrated that “it is the maximum hyperemic distal coronary pressure that determines the ischemic potential of a lesion”. The FFR is the fraction of maximal CBF that goes through the stenotic vessel, expressed as a percentage of blood flow through the same artery in the theoretical absence of the stenosis. FFR = Pd – Pv/ Pa – Pv = Pd/ Pa, when Pv is taken as 0. Normal value for FFR= 1

FFR Measurement Pressure wire with a sensor 3 cm from from tip of a 0.014inch guide wire Maximum hyperemia is a prerequisite Adenosine IV infusion(140ug/Kg/min) or Intra coronary (60ug for left coronary and 30ug for right coronary)

Clinical equivalence of FFR Idea is to measure pressures to assess blood flow An FFR of 0.9 = Only 90% of maximal CBF is able to cross the lesion An FFR of 0.71 = 71% of maximal CBF crosses lesion When a PTCA has changed the FFR from a baseline of 0.5 to 0.9, there has been an additional 40% increase in maximal CBF

Clinical significance of FFR

Need for FFR in addition to CAG?

Decision making for intermediate lesions Decision regarding mutivessel PCI Serial lesions Diffuse disease Ostial or distal LM and ostial RCA lesions Side branch lesions ISR Prior MI Assess PCI results

FFR for assessing PCI results Eg: PCI for RCA serial stenosis

AFR vs RFR vs FFR

Advantages of FFR - Independent of HR, SBP & driving pressure. - A lesion specific index and independent of status of microcirculation Independent of contribution by collateral flow Highly reproducible when compared to AFR Superior to quantitative CAG and IVUS in physiological assessment. Offers excellent physiological correlates in a world of coronary anatomy

Limitations of CFR assessment Maximum hyperemia is mandatory for assessment Assumptions : 1) Coronary venous pressure is 0, 2) P-Q relationship is linear FFR cut-off of 0.75 is derived from a stable population with SVD and normal LV function – not universally applicable to all scenarios. “Pitfalls” of pressure measurement need to be avoided Wedging of the guide catheter (0.16mm2 ) may alter absolute pressure measurements in critical stenosis Limited data for acute MI

Clinical validation of invasive measurement - comparison with noninvasive sress testing

DEFER study ( JACC 2010)

FAME study (JACC 2010)

FAME 2 trial (NEJM 2012)) Bruyne, Pijls et al FFR-guided PCI vs Medical therapy in stable CAD FFR guided PCI +OMT vs OMT significantly decreased the need for urgent revascularisation In patients with FFR>0.8 best outcomes were attained with OMT alone.

IVUS vs FFR comparison IVUS- best anatomical information of a lesion FFR- best physiological information of a lesion One cannot be a substitute for the other for in-depth assessment of complex lesions Takagi et al demonstrated that an IVUS minimal lumen area <3.0 mm2 and an area stenosis <60% had 100% predictive accuracy for a FFR < 0.75. (Circulation.1999;100:250 –255) Hanekamp et al found IVUS and FFR>0.94 had 91% concordance in the identification of optimal stent apposition and deployment. (Circulation. 1999;99:1015–1021)

CORONARY COLLATERAL CIRCULATION Collaterals develop as a result of arteriogenesis promoted by a chronic coronary occlusion that causes a pressure gradient between the proximal and distal beds in a serial direction Shear stress acts on preexisting collaterals < 200µm Growth factors (VEGF) – NO mediated Capillaries in ischemic region proliferate– little impact on perfusion Tremendous individual variability in the development and function of collaterals. A sudden thrombosis developing in a chronic critical stenosis may still be minimally destructive – RECRUITABLE COLLATERALS

Collateral Flow Index (CFI) = FFR beyond a lesion after full occlusion (balloon); CFI > 0.25 have a better prognosis -Collateral resistance is tonically regulated by NO and prostaglandins

ABNORMAL CBF WITH NORMAL CORONARY ARTERIES MICROCIRCULATORY IMPAIRMENT As discussed earlier the CFR decreases with 1)Tachycardia (decreased diastolic time), 2) Increased preload ( compressive determinants) 3) Increased afterload 4) Increased contractility 5) Decreased Oxygen supply ( anaemia, hypoxia) 6) Abnormal endothelium (DM, HTN, DLP, CTDs)

CONDUIT VESSEL DYSFUNCTION: - A longitudinal perfusion gradient develops from base to apex ( Base flows ~ 20% more than apex) - Endothelial dysfunction, Vessel stiffness, Outward vascular remodelling and diffuse luminal narrowing ANGINA with NORMAL CORONARIES Risk factor reduction has been found to significantly improve the CFR in several studies

Thank you

Multiple Choice Questions 1) The oxygen extraction ratio of the myocardium is : 100% 90% 80-90% 70-80% 60-70%

2) A 75% simple stenosis in a coronary blood vessel would increase the flow resistance by: a) 24 times b) 48 times c) 64 times d) 128 times e) 256 times

3) Subepicardial coronary flow becomes compromised at coronary pressures less than: 20mmHg 25mmHg 30mmHg 35mmHg 40mmHg

4)Microcirculatory vasodilation in response to increased flow requirements chiefly occur at vessels: a)<50micm b)50-200micm c)200-400micm d)>400micm e) Similar contributions at all levels

5) One of the following mediator has a significant endothelium independent vasodilatory effect on normal coronary vasculature: a)Bradykinin b) Cholinergic innervation c) ADP d) Adenosine e) Thrombin

6) The Hagen-Poiseuille equation focuses on the effect of: Pressure conservation as total energy is conserved Total pressure lost as potential energy Pressure drop due to viscous losses Pressure drop due to separation losses Pressure drop due to turbulence losses

7) Flow to the distal territory of a stenosis is determined by: Pa-Pd Pa-Pv Pd-Pv Pa only Pv only

8)Main advantage of FFR over AFR in physiological assessment of CAD is: It gives anatomical data as well as physiological data It correlates better with the severity of CAD It has a better prognostic value It is lesion specific It provides information on microcirculation also

9) FAME 2 strategy (conclusion) in managing a epicardial lesion in CSA patients is a) PTCA to patients with >70% stenosis improves mortality b) PTCA based on FFR values has a mortality benefit compared to that based on angiographic criteria alone. c) PTCA based on FFR values decreases urgent revascularisation compared to based on angio criteria alone d) PTCA by FFR guided vs angio-criteria alone showed no significant differences

10) Based on available data, the best results following POBA and PTCA based on FFR criteria are when they are respectively greater than: o.75 and 0.90 0.90 and 0.94 0.94 and 0.90 0.90 and 0.75 0.75 each