Download Coronary Physiology

Matthew Schumaecker, MD
 To
understand:
• Determinants of myocardial oxygen
•
•
•
•
consumption
Determinants of coronary vascular resistance
Regulation of coronary blood flow
Coronary flow reserve
Physiologic consequences of ischemia
Physical Principle #1
Pin - Pout
Q=
R
Physical Principle #2
“When multiple resistors are connected
in series, their combined resistance is
equal to the individual resistances added
together.”
R1
R2
R3
Resistance total = R1 + R2 + R3
 Inotropy
 Chronotropy
 HR
x BP is clinically referred to as double
product and is used as a surrogate
marker for myocardial oxygen demand
Epicardial Arteries

Vascular tone of R1 vessels is
controlled by:
1.
2.
3.
4.
Nitric oxide causes vasodilation in
response to shear stress.
Endothelium-derived
hyperpolarizing factor.
Sympathetic β-dilation (i.e., during
exercise)
Sympathetic α1-constriction
Epicardial Arteries




Due to their size, there is
normally no pressure drop across
epicardial arteries.
Therefore, epicardial contribution
to coronary vascular resistance is
negligible in the normal heart.
With hemodynamically
significant lesions, fixed stenosis
begins to contribute to total
resistance.
Severely narrowed arteries may
reduce resting flow.
Coronary Microvasculature



Dynamic resistance occurs from
arteriolar network (20 to 200μm)
Changes in response to multiple
physical, metabolic, paracrine
and neural effectors.
Approximate contribution to
resistance:
25% - vessels > 200μm
• 20% - vessels 100-200μm
• 55% - vessels < 100 μm
•
Compressive
Resistance



Extravascular tissue pressure in
the myocardium is determined by
myocardial tension at that given
point in the cardiac cycle.
During systole, tissue pressure =
SBP in the subendocardium while
it falls to pleural pressure in the
subepicardium.
This decreases driving pressure
for coronary blood flow.
Compressive
Resistance


It is because of compressive
resistance that there is no
significant coronary blood flow
during systole.
i.e., Pin ≈ Pout
Increase in LV diastolic pressure
increases compressive resistance
and decreases flow during
diastole.
1.
2.
3.
Myogenic Regulation
Flow-Induced Vasodilation
Direct Metabolic Effectors
• Vascular smooth muscle opposes change in
•
•
•
•
arteriolar diameter
i.e., vessels relax when distending pressure is
decreased and constrict when it is elevated.
Likely secondary to stretch-activated calcium
channels
Most active in small vessels
Postulated to play a role in regulated
precapillary tissue exchange
Am J Phys 273:H257 1997
 Three
major affectors:
1. Nitric oxide (mostly in vessels > 100 μm)
2. Endothelium-dependent hyperpolarizing
factor.
3. Prostacyclin PGI2
NO is a crucial signaling molecule in vascular biology
Produced in endothelial cells
Indirectly catalyzes intracellular cGMP formation from GTP
cGMP acts a secondary messenger, ultimately causing the
relaxation of endothelial smooth muscle by decreasing
intracellular Ca2+ concentration and a decrease in the
contractile sensitivity to extracellular Ca2+ .
 This causes a vasodilatory effect in vessels > 100 μm (i.e., R1
and large R2 vessels)
 In patients with CAD, nitric oxide no longer plays a role in flowmediated vasodilation.




Carvajal, et al. J. Cell. Physiol. 184:409-420, 2000.





Unidentified vasoactive substance
Mediates flow-induced vasodilation, particular in CAD
EDHF activates K+ channels, leading to
hyperpolarization and vasodilation.
Strong evidence suggests that it is a metabolite of
arachidonic acid derived from cytochrome P450
Contribution of EDHF to vasodilation increases as
vessel size decreases.
Miura et al. Circulation 2001;103:1992-1998
• Platelet factors:
 Thrombin
 ADP
• Bradykinin
• Histamine
• Substance P
 These
exert their actions almost
exclusively on the R2 vessels (i.e.,
arterioles and microvasculature)
 Adenosine
 Tissue
pO2
 Tissue pCO2
 Tissue pH
 Adenosine
• Released by myocytes when ATP hydrolysis exceeds
•
•
•
•
•
synthesis during ischemia.
Powerful vasodilator which exerts action upon R2
vessels via A2A receptors agonism.
A2A receptor activation increases cAMP levels,
thereby activating calcium-activated KATP channels.
Direct vasodilation occurs primarily in vessels
<100μm
Indirect vasodilation occurs in larger arteries
because of increase in shear stress as arteriolar
resistance falls
Continuously produced by local metabolism and
removed by reentry into cardiomyocytes.
A1 Decrease heart rate, AV nodal block
A2A Coronary arteriolar vasodilation
A2B Unclear physiology – found on mast
cells
A3 Bronchial smooth muscle constriction,
 Hypoxia
• Local decrease in pO2 is a potent vasodilator.
• Unclear mechanism.
 Acidosis
• Local increase in pCO2 produces vasodilation.
• Unclear mechanism
 Sympathetic
nervous system
• α-receptor – mediated vasoconstriction
 Not active during normal states. Become active during
pathological states
 In the epicardial arteries, α1 predominates
 In the microvasculature, α2 predominates
• β2-receptor – mediated vasodiliation
 β2-receptor is responsible for ~25% coronary flow increase in
exercise.1
1Tune
et. al. Ex Bio Med 2002;227:238-250
• Adenosine
 As previously mentioned
• Dipyridamole
 Inhibits myocyte reuptake of adenosine.
• Regadenoson, binadeson
 A2A – specific agonist
• Papaverine
 Causes more prolonged vasodilation than adenosine
via inhibiting phosphodiesterase and increasing
cAMP
• Nitroglycerin
 Direct vasodilatory action
Definition:
“The process by which coronary blood
flow is kept constant in the face of
decreasing coronary blood pressure.”


In the resting state,
regional coronary
flow is kept stable
over a wide range of
coronary pressures.
Vasodilation allows
four to five fold
increase in coronary
flow at normal
arterial pressures
Vasodilation
Increased MVO2
Coronary
Flow
Flow reserve
~40mmHg
Autoregulation
Constant MVO2
PRA
Coronary Pressure

Stress states such as
tachycardia, anemia
and hypertension,
decrease:
1.
2.
3.

Coronary perfusion
time
Maximum vasodilated
flow
Coronary flow reserve
Ischemia therefore
develops at higher
coronary pressures
Vasodilation
Increased MVO2
~60mmHg
Coronary
Flow
Autoregulation
Constant MVO2
PRA
Coronary Pressure
Reduced
flow reserve
~40mmHg
Subendocardium
~25mmHg
Subepicardium
Coronary Pressure
Autoregulation is exhausted at a higher pressure in the subendocardium
This increases the sensitivity of the subendocardium to systolic compressive effects.
ΔP
Q
Q
As
length
An
ml/min
ΔP = f1( 1/As2, length, Q) + f2( 1/As2, 1/An2 , Q2)
viscous
separation
Redrawn from Germano and Beman Clinical Gated Cardiac Spect, p.12
 Reductions
in post-stenotic pressure are
modest for stenoses < 70%
 70-90% stenoses - microcirculatory
vasodilation can maintain resting flow at
normal level.
 >90% stenosis - compensatory
mechanisms are exhausted
 Ratio
of blood flow in a maximally
vasodilated vessel to that same vessel in
a basal, autoregulated state.
 Principle
determinants of CFR are:
1. Vessel stenoses
2. Inability to achieve optimal vasodilation (i.e.,
“endothelial dysfunction”)
Stenosis
Reduction in MVDF
50%
20%
70%
40%
80%
60%
>90%
Loss of flow reserve
Klock FJ JACC 1990,16:763-769
 R2
vessels in the subendocardium are
more vasodilated in the basal state than
R2 vessels in the subepicardium.
 This is to account for the transmural
gradient in the effect of compressive
resistance (i.e., R3).
 Therefore, the subendocardium has less
coronary reserve than the
subepicardium.
Epicardial
Vessels
Subepicardium: R2>>>R3
Decreasing Coronary
Flow Reserve
Subendocardium: R3>>>R2
R3
Left Ventricle
 Absolute
Flow Reserve
 Relative Flow Reserve
 Fractional Flow Reserve
Absolute Flow Reserve
 Amount of increase in flow with ischemic
dilation (transient occlusion) or with
pharmacologic dilation.
 Can be quantified using doppler,
thermodilution or PET
 Flow-dependent as well as perfusiondependent (i.e., anemia, increased VO2).
 Normal values are 4-5
 Clinically significant < 2
Relative Flow Reserve
 Cornerstone physiologic concept behind
nuclear perfusion imaging.
 Relative differences in regional perfusion
are assessed in response to exercise or
pharmacologic vasodilation and
expressed as a fraction of flow to normal
regions of the heart.
Relative Flow Reserve - Advantages
 Compares
perfusion differences under
identical hemodynamic conditions (i.e.,
HR, BP, Hg, VO2).
 Well
suited to cardiac imaging.
Relative Flow Reserve - Disadvantages
 Requires a normal reference segment.
This may not be present in:
1. States of impaired microcirculatory
vasodilation.
2. Diffuse multivessel CAD (“balanced
ischemia”)
Myocardial uptake of nuclear tracers
fail to increase proportionally to
coronary flow beyond a certain
threshold
Ideal Tracer
Tracer Uptake

Thallium
Sestamibi
Tetrofosmin
T
Low
Normal Rest
Exercise (2-3x)
Pharmacologic Stress (4-5x)
Myocardial Blood Flow

Large differences in relative vasodilated flow are
necessary to detect perfusion differences.

Differences in tracer deposition underestimate
underlying differences in regional coronary flow.
Tracer Uptake
Ideal Tracer (O15)
Thallium
Sestamibi
Tetrofosmin
T
Low
Normal Rest
Exercise (2-3x)
Pharmacologic Stress (4-5x)
Myocardial Blood Flow
Fractional Flow Reserve
 Distal
coronary pressure measured during
vasodilation is directly proportional to
maximum vasodilated flow.
 Technique
1.
2.
3.
Pressure distal to a stenosis is measured with a transducer during
infusion of adenosine.
This is indexed to mean aortic pressure (Pd/Pao)
Limited data show that values of > 0.75 are associated with good
outcomes without intervention.
Fractional Flow Reserve –
Clinical Limitations
 Cannot
assess abnormalities in microvascular
flow reserve.
 Dependent upon inducing maximum
vasodilation.
 Ignores back pressure to coronary flow and
assumes that coronary venous pressure is zero.
 The wire itself can worsen the stenosis in small
vessels
German G and Berman D Clinical Gated Cardiac SPECT Blackwell Futura,
2006
DiCarli M, et. al. (1997). "Effects of cardiac sympathetic innervation of
coronary blood flow." New England Journal of Medicine 336: 1208-1215.
Jorge A. Carvajal, e. a. (2000). "Molecular mechanism of cGMP-mediated
smooth muscle relaxation." Journal of Cellular Physiology 184(3): 409-420.
Miura H, W. R., Liu Y, et al. (2001). "Flow-induced diliation of human coronary
arterioles: important role of Ca2+-activated K+ channels." Circulation 103:
1992-1998.
Quyyumi AA, D. M., Andrews NP, Gilligan DM, Panz JA, Cannon RO III. (1995).
"Contribution of nitric oxide to metabolic coronary vasodilation in the
heart.”