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

2. 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

3. 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)

4.  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

5. 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

6. 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

7. 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

8. 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.

9. 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 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

10. 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

13. 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.

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

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

16. 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>>>>>

17. 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

18. MEDIATORS OF CORONARY RESISTANCE
PHYSICAL FORCES
METABOLIC MEDIATORS
NEURALCONTROL
PARACRINE FACTORS

19. 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

20. 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)

21. 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

22. 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:

23. 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

24. 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

25. 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

26. 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

27. 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

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

29. 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.

30. VARYING SENSITIVITIES OF THE MICROCIRCULATION TO STIMULI

31. 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

32. 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

33. 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

34. 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.

35. PROLONGED EXERCISE TRAINED HEART: The CBF is maintained or increases

36. 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

38. 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

40. 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

42. 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

43. 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

45. 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

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

47. 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

48. 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

49. 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

50. 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

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

52. - 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)

53. 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)

54. 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

55. 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

58. 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)

60. 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

61. Clinical significance of FFR

62. Need for FFR in addition to CAG?

63. 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

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

66. AFR vs RFR vs FFR

67. 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

68. 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

69. Clinical validation of invasive measurement - comparison with noninvasive sress testing

70. DEFER study ( JACC 2010)

72. FAME study (JACC 2010)

74. 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.

75. 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 < (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)

76. 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

77. 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

78. 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)

79. 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

80. Thank you

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

82. 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

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

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

85. 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

86. 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

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

88. 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

89. 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

90. 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