This document summarizes key concepts regarding coronary blood flow and myocardial ischemia from Braunwald's Heart Disease, 12th edition. It discusses how coronary blood flow is regulated and the determinants of myocardial oxygen demand. When oxygen supply and demand are disrupted by diseases affecting coronary blood flow, a vicious cycle of ischemia can result. Knowledge of coronary flow regulation, oxygen demand factors, and the relationship between ischemia and contraction is essential to understanding myocardial ischemia.

1. Braunwald’s Heart Disease, 12th ed, Chapter 36
Coronary Blood Flow
and Myocardial
Ischemia
Dirk J. Duncker, John M. Canity Jr.

2. “
◦ The heart is responsible for generating the arterial pressure
that is required to perfuse the systemic circulation and yet,
at the same time, has its own perfusion impeded during the
systolic phase of the cardiac cycle
◦ When the balance between oxygen supply and demand is
acutely disrupted by diseases affecting coronary blood flow,
the resulting imbalance can immediately precipitate a
vicious cycle
◦ Knowledge of the regulation of coronary blood flow,
determinants of myocardial oxygen consumption, and the
relation between ischemia and contraction is essential
Introduction

3. Control of Coronary
Blood Flow

4. Control of Coronary Blood Flow
◦ Variation exists between
coronary artery and venous flow
between systole and diastole
◦ During systolic contraction:
◦ Tissue pressure increase 
perfusion redistributed from
subendocardium to epicardium 
coronary arterial inflow impeded
◦ Reduced diameter of
intramyocardial microcirculatory
vessels  increased coronary
venous outflow

5. Determinants of Myocardial
Oxygen Consumption
◦ In contrast to most other vascular beds, myocardial oxygen
extraction is near-maximal at rest, averaging 70% to 80% of
arterial oxygen content.
◦ Coronary venous oxygen tension (PvO2) can only decrease
from 25 mm Hg to approximately 15 mm Hg
◦ Increases in myocardial oxygen consumption are primarily
met by proportional increases in coronary flow and oxygen
delivery
◦ Major determinants: heart rate, systolic pressure (or
myocardial wall stress), and left ventricular (LV) contractility

6. “

7. Coronary Autoregulation
◦ Regional coronary blood flow remains constant as
coronary artery pressure is reduced below aortic
pressure over a wide range when the
determinants of myocardial oxygen consumption
are kept constant
◦ Coronary flow reserve  The ability to increase
flow above resting values in response to
pharmacologic vasodilation

8. “

9. Coronary flow reserve…
◦ … is reduced when:
◦ diastolic time available for subendocardial perfusion is
decreased (tachycardia)
◦ compressive determinants of diastolic perfusion (preload) are
increased
◦ Also, by anything that increases resting flow:
◦ Increases in the hemodynamic determinants of oxygen
consumption (systolic pressure, heart rate, and contractility)
◦ Reductions in arterial oxygen supply (anemia and hypoxia)
◦ Thus, circumstances can develop that precipitate subendocardial
ischemia in the presence of normal coronary arteries

10. Transmural variations in coronary
autoregulation
◦ Subendocardial
flow occurs
primarily in
diastole and
begins to decrease
below a mean
coronary pressure
of 40 mmHg
◦ Subepicardial flow
occurs throughout
the cardiac cycle
and is maintained
until coronary
pressure falls
below 25 mm Hg

11. …continued
◦ This difference arises from increased oxygen
consumption in the subendocardium, requiring a
higher resting flow level, as well as the more
pronounced effects of systolic contraction on
subendocardial vasodilator reserve
◦ The transmural difference in the lower autoregulatory
pressure limit results in vulnerability of the
subendocardium to ischemia in the presence of a
coronary stenosis

12. Determinants of Coronary Vascular Resistance
Conduit resistance (R1)  negligible
◦ may contribute to increasing vascular resistance at
hemodynamically significant (>50%) stenosis
◦ may reduce resting flow in severely narrowed (>90%)
arteries
Microcirculatory resistance (R2)  dynamic
◦ distributed across a broad range of microcirculatory
vessel sizes
◦ changes in response to physical forces (intraluminal
pressure and shear stress) as well as the metabolic
needs of the tissue
Extravascular compressive resistance (R3)  varies with
time throughout the cardiac cycle
◦ related to cardiac contraction and systolic pressure
development within the left ventricle
◦ also affected by elevated ventricular diastolic pressure
in heart failure

13. Effects of extravascular tissue
pressure on transmural perfusion
◦ Cardiac contraction raises extravascular
tissue pressure to values equal to LV
pressure at the subendocardium
◦ However, this does not account for
accelerated venous outflow
◦ Concept of intramyocardial pump 
microcirculatory vessels are compressed,
producing a capacitive discharge of blood
that accelerates flow to the coronary venous
system

14. Endothelium-dependent
Modulation of Coronary Tone
◦ Arterial diameter is modulated by a wide variety of paracrine
factors  many are dependent on a functional endothelium
◦ Example:
◦ Acetylcholine normally dilates arteries through an
endothelium-dependent relaxing factor (NO)
◦ NO increases cyclic GMP  relaxes vascular smooth
muscle  vasodilation
◦ In the absence of a functional endothelium  muscarinic
vascular smooth muscle contraction  vasoconstriction

15. Endothelium-dependent
Biochemical Pathways
◦ Nitric Oxide
◦ Produced by the enzymatic conversion of L-arginine to citrulline
via type III or endothelial nitric oxide synthase (eNOS)
◦ Binds to guanylyl cyclase  increasing cGMP production 
relaxation through a reduction in intracellular calcium
◦ In CAD  oxidative stress  generation of superoxide anion 
inactivation of NO
◦ Endothelium- Dependent Hyperpolarizing Factor (EDHF)
◦ Hyperpolarizes vascular smooth muscle and dilates arteries by
opening calcium activated potassium channels (KCa)
◦ Prostacyclin
◦ Endothelin  potent vasoconstrictor

16. Paracrine Vasoactive Mediators
◦ Serotonin
◦ Thromboxane A2
◦ Adenosine diphosphate (ADP)
◦ Thrombin

17. Coronary Vasospasm
◦ Most frequently occurs in the setting of a coronary
stenosis
◦ Results in transient functional occlusion of a coronary
artery that is reversible with nitrate vasodilation
◦ Impaired endothelium- dependent is not causal, and a
trigger is required (e.g., thrombus formation,
sympathetic activation)

18. Pharmacologic Vasodilation
Nitroglycerin
◦ Dilates epicardial conduit arteries and small coronary resistance arteries
◦ Transient arteriolar vasodilation is overcome by autoregulatory escape 
does not increase coronary blood flow
◦ Improves the distribution of perfusion to the subendocardium when
flow-mediated NO-dependent vasodilation is impaired.
CCBs
◦ Induce vascular smooth muscle relaxation  coronary vasodilators
◦ Submaximally vasodilate coronary resistance vessels  sometimes
precipitate subendocardial ischemia in the presence of a critical stenosis
(coronary steal)

19. Pharmacologic Vasodilation
Adenosine
◦ Dilates coronary arteries through activation of A2 receptors independent
of endothelium
◦ Direct effects related to resistance vessel size and restricted primarily to
vessels smaller than 100 μm  larger arteries dilate through NO-
dependent mechanism
Dipyridamole
◦ Inhibits reuptake of adenosine  similar mechanism of action
Papaverine
◦ Inhibits phosphodiesterase and increases cyclic adenosine
monophosphate (cAMP)

20. Structure and Function of the Coronary
Microcirculation
◦ Individual coronary resistance arteries are a
longitudinally distributed network
◦ Considerable spatial heterogeneity of specific
resistance vessel control mechanisms
◦ This can be accomplished independently of metabolic
signals by
◦ Sensing physical forces such as intraluminal flow
(shear stress–mediated control); or
◦ Intraluminal pressure changes (myogenic control).

21. 21

22. Myogenic Response
◦ The ability of vascular
smooth muscle to oppose
changes in coronary arterial
diameter
◦ ↓Distending pressure 
relaxation, vice versa
◦ Depends on vascular smooth
muscle calcium entry,
perhaps through stretch-
activated L- type Ca2+
channels
Flow-Mediated Vasodilation
◦ Regulate their diameter in response to
changes in local shear stress
◦ Endothelium dependent, mediated by NO

23. Physiologic Assessment
of Coronary Artery
Stenoses

24. Stenosis Pressure-Flow Relation
◦ The total pressure drop across a
stenosis is governed by three
hydrodynamic factors:
◦ Viscous losses;
◦ Separation losses; and
◦ Turbulence
◦ The most important determinant 
minimum lesional crosssectional
area within the stenosis

25. 25
◦ No significant pressure
drop across a stenosis
(ΔP) until stenosis
severity exceeds 50%
◦ As stenosis severity
exceeds 50%, the
pressure flow relation
becomes curvilinear
◦ Because of coronary
autoregulation, resting
flow remains constant as
stenosis severity
increases

26. Flow- and Pressure- Derived Indices of
Coronary Reserve
◦ The development of invasive approaches to assess distal
coronary pressure and flow using transducers placed on
coronary guidewires have led to indices of coronary
stenosis severity based on coronary flow reserve and
resting and vasodilated distal coronary pressure
◦ Leading to more complete understanding of the role of
epicardial coronary stenoses versus the coronary
microcirculation in limiting myocardial perfusion

27. Absolute Flow Reserve
◦ The ratio of maximally vasodilated flow to the corresponding
resting flow value in a specific region of the heart
◦ Altered by factors that affect maximal coronary flow and the
corresponding resting flow value
Relative Flow Reserve
◦ Relative differences in regional perfusion (per gram of tissue)
assessed during maximal pharmacologic vasodilation
◦ Fairly insensitive to variations in mean arterial pressure, heart
rate, and preload
Perfusion/Flow-based Indices

28. Fractional Flow Reserve
◦ Based on the principle that the distal coronary pressure
measured during vasodilation is directly proportional to
maximum vasodilated perfusion
◦ An indirect index  driving pressure for microcirculatory
flow distal to the stenosis relative to the coronary driving
pressure available in the absence of a stenosis
Instantaneous Wave-free Ratio
◦ The ratio of distal coronary pressure to aortic pressure
averaged throughout mid-diastole (i.e., the “wave- free
period”)
◦ Free of the compressive effects of systole and phasic
coronary flow and the stenosis diastolic pressure gradient
are maximal
Pressure-based Indices

29. Pathophysiologic States Affecting
Microcirculatory Coronary Flow Reserve
Left Ventricular Hypertrophy
◦ Resting flow per gram of myocardium
remains constant, increase in the
absolute level of resting flow
◦ Pathologic hypertrophy does not
result in appreciable vascular
proliferation
◦ The increase in LV mass in the
absence of vascular proliferation
reduces the maximum perfusion per
gram of myocardium

30. Pathophysiologic States Affecting
Microcirculatory Coronary Flow Reserve
Microvascular Dysfunction
◦ Flow per gram of
myocardium will be normal
at rest and reduced during
pharmacologic vasodilation
◦ Absolute flow remains
normal at rest in
microvascular disease, and
the absolute vasodilated
flow is reduced

31. 31
Endothelial Dysfunction and Coronary
Flow Reserve
• NO inactivation associated
with risk factors for CAD
 abnormal control of
local resistance vessel
through impaired
endothelium-dependent
vasodilation
• Reversed with L-arginine

32. Coronary Collateral
Circulation

33. Arteriogenesis and Angiogenesis
◦ Proliferation of coronary collaterals occurs in response to
repetitive stress-induced ischemia and the development of
transient interarterial pressure gradients  arteriogenesis
◦ In contrast to de novo vessel growth  angiogenesis 
sprouting of smaller, capillary-like structures from preexisting
blood vessels
◦ Progressive enlargement of collaterals happen through a
process dependent on physical forces and growth factors 
VEGF, mediated by NOS
◦ Thus, patients with impaired NO-mediated vasodilation may
have a limited ability to develop coronary collaterals

34. Regulation of Collateral Resistance
◦ Collateral blood flow is governed by a series resistance
arising from interarterial collateral anastomoses 
major determinant of perfusion
◦ Collaterals constrict when NO synthesis is blocked,
which aggravates myocardial ischemia  overcome by
nitroglycerin

35. Metabolic And Functional
Consequences
of Ischemia

36. Irreversible Injury and Myocyte Death
◦ Irreversible myocardial injury begins after 20 minutes of
coronary occlusion in the absence of significant collaterals
◦ Starts in the subendocardium and progresses as a wavefront
over time, to the subepicardial layers.

37. Cardioprotection from Local and
Remote Conditioning
◦ Brief reversible ischemia preceding a prolonged coronary occlusion
reduced infarct size, a phenomenon termed acute preconditioning
◦ Myocardial postconditioning  the ability to engage cardiac
protection by producing intermittent ischemia or administering
pharmacologic agonists at reperfusion
◦ Remote conditioning is particularly attractive because it can be easily
implemented using a blood pressure cuff and has been shown to
experimentally reduce infarct size
◦ Nevertheless, large randomized clinical trials of postconditioning and
remote conditioning have failed to translate these into measurable
impacts on clinical end points or infarct size

38. 38

39. Reversible Ischemia and Perfusion-
Contraction Matching
◦ Reductions in subendocardial flow are closely related to
reductions in regional contractile function of the heart

40. Functional Consequences of
Reversible Ischemia
◦ Late consequences of ischemia have been
documented after normal myocardial perfusion is
reestablished
◦ In the most chronic state, they result in hibernating
myocardium  characterized by chronic contractile
dysfunction and regional cellular mechanisms that
downregulate contractile and metabolic function of
the heart so as to protect it from irreversible injury

41. Stunned Myocardium
◦ Myocardial function normalizes
rapidly after single episodes of
ischemia lasting less than 2 minutes
◦ Regional myocardial function
remains depressed for up to 6 hours
after resolution of ischemia
following a 15- minute occlusion 
myocardial stunning
◦ Function remains depressed while
resting  dissociation of the usual
close relation between
subendocardial flow and function

42. Chronic Hibernating
Myocardium
◦ Viable dysfunctional myocardium 
any myocardial region in which
contractile function improves after
coronary revascularization
◦ Chronically stunned  When resting
flow relative to a remote region is
normal in dysfunctional myocardium
distal to a stenosis
◦ Hibernating myocardium  When
relative resting flow is reduced in
the absence of symptoms or signs of
ischemia

43. Cellular Responses in
Hibernating Myocardium
Apoptosis, Myocyte Loss, and Myofibrillar Loss
◦ Approximately 30% regional myocytes undergo apoptosis
Cell Survival and Antiapoptotic Program in Response to Repetitive Ischemia
◦ Upregulation of antiapoptotic proteins in patients without HF
Metabolism and Energetics in Hibernating Myocardium
◦ Once adapted, the metabolic and contractile response of hibernating myocardium
appears to be dissociated from external determinants of workload
Inhomogeneity in Sympathetic Innervation, Beta- Adrenergic Responses,
and Sudden Death
◦ The contractile response of hibernating myocardium is blunted 
regional downregulation in beta- adrenergic adenylyl cyclase coupling
43

44. 44
Conclusion and Future Directions
• The major factors determining myocardial perfusion and
oxygen delivery have been incorporated into the current
management of angina and have withstood the test of time
• Important gaps remain in basic knowledge and in the
translation of this knowledge to clinical care
• Our understanding of the physiologic and cellular mechanisms
responsible for microvascular dysfunction is limited
• Continued bench-to-bedside translational investigation in
these and other areas is needed

45. Thank You