Transcript Physiology of Coronary Blood Flow - calicutcardiosr.in

Dr Sandeep Mohanan,
Department of Cardiology,
Medical College, Calicut.
OUTLINE
 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
 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
 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.
 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.
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
 These are intraluminal forces:
1) Myogenic regulation:
-
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
1) Hypoxia
2) Exercise –induced myocardial ischemia
 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
CONSTRICTION
(Muscarinic constrictive +
Endo-dep & flow mediated
vasodilatory)
NEURAL CONTROL- Sympathetic innervation
- Sympathetic denervation does not affect resting flow
NORMAL
CORONARIES
ATHEROSCLEROSIS
RESISTANCE
ARTERIES
NET DILATION
ATTENUATED
DILATION
CONDUIT ARTERIES
NET DILATION
(β2 dilation+ α1 constriction
+ β1 consumption)
(β2 dilation + endo-dep &
flow mediated dilation+ α1
constriction)
CONSTRICTION
PARACRINE MEDIATORS
Released from epicardial arterial thrombi following plaque rupture
NORMAL CORONARIES
ATHEROSCLEROSIS
Conduit
Resistance
Conduit
Resistance
SEROTONIN
constriction
dilation
constriction
constriction
THROMBOXANE
A2
constriction
constriction
constriction
constriction
ADP
dilation
dilation
attenuated
attenuated
THROMBIN
dilation
dilation
constriction
constriction
BRADYKININ
dilation
dilation
attenuated
attenuated
HISTAMINE
dilation
dilation
attenuated
attenuated
SUBSTANCE P
dilation
dilation
attenuated
attenuated
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:
1) Compensates for impaired endo-dependent
mechanisms
2) Dilates collateral vessels
3) 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
 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
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
1) 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.
 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 :
a) 100%
b) 90%
c) 80-90%
d) 70-80%
e) 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:
a) 20mmHg
b) 25mmHg
c) 30mmHg
d) 35mmHg
e) 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:
a) Pressure conservation as total energy is conserved
b) Total pressure lost as potential energy
c) Pressure drop due to viscous losses
d) Pressure drop due to separation losses
e) Pressure drop due to turbulence losses
 7) Flow to the distal territory of a stenosis is determined
by:
a) Pa-Pd
b) Pa-Pv
c) Pd-Pv
d) Pa only
e) Pv only
 8)Main advantage of FFR over AFR in physiological
assessment of CAD is:
a) It gives anatomical data as well as physiological data
b) It correlates better with the severity of CAD
c) It has a better prognostic value
d) It is lesion specific
e) 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:
a) o.75 and 0.90
b) 0.90 and 0.94
c) 0.94 and 0.90
d) 0.90 and 0.75
e) 0.75 each