CORONARY BLOOD FLOW

Dr. P. PRANEETH

Myocardial contraction is closely connected to coronary flow and oxygen delivery, the balance between oxygen supply and demand is a critical determinant of the normal beat-to-beat function of the heart.

A knowledge of the regulation of coronary blood flow, determinants of myocardial oxygen consumption, and relationship between ischemia and contraction is essential for understanding the pathophysiologic basis and management of many cardiovascular disorders.

Determinants of myocardial oxygen consumption Autoregulation

Determinants of coronary vascular resistance Extravascular compressive resistance Resistance within microcirculation

Structure and funtion Intraluminal regulation

Myogenic regulation Flow mediated resistance artery control

Metabolic regulation Neural control of resistance and conduit arteries

MYOCARDIAL OXYGEN CONSUMPTION

In contrast to most other vascular beds, myocardial oxygen extraction is near-maximal at rest, averaging approximately 75% of arterial oxygen content.

Increases in myocardial oxygen consumption are primarily met by proportional increases in coronary flow and oxygen delivery.

In addition to coronary flow, oxygen delivery is directly determined by arterial oxygen content (Pao2).

Fick equation and the relationship between heart rate (HR)–systolic pressure (SBP) double product and myocardial oxygen consumption . A, Increases in are primarily met by increases in coronary flow and linearly related to the double product. Twofold increases in HR, SBP, or contractility each result in approximately 50% increases in myocardial oxygen consumption.

The major determinants of myocardial oxygen consumption are heart rate, systolic pressure (or myocardial wall stress), and left ventricular (LV) contractility.

A twofold increase in any of these individual determinants of oxygen consumption requires an approximately 50% increase in coronary flow.

The basal myocardial oxygen requirements needed to maintain critical membrane function are low and the cost of electrical activation is trivial when mechanical contraction ceases during diastolic arrest and diminishes during ischemia.

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.

This phenomenon is termed

autoregulation

Autoregulatory relationship under basal conditions and following metabolic stress Following stress (right panel), tachycardia increases the compressive determinants of coronary resistance by decreasing the time available for diastolic perfusion and thus reduces maximum vasodilated flow. In addition, increases in myocardial oxygen demand or reductions in arterial oxygen content increase resting flow. These changes reduce coronary flow reserve, the ratio between dilated and resting coronary flow, and cause ischemia to develop at higher coronary pressures.

Resting coronary blood flow under normal hemodynamic conditions averages 0.7 to 1.0 mL/min/g and can increase between four- and fivefold during vasodilation.

The ability to increase flow above resting values in response to pharmacologic vasodilation is termed

coronary reserve.

Flow in the maximally vasodilated heart is dependent on coronary arterial pressure.

Maximum perfusion and coronary reserve are reduced when the diastolic time available for subendocardial

perfusion is decreased (tachycardia) or the compressive determinants of diastolic perfusion

(preload) are increased. anything that increases resting flow, including increases

in the hemodynamic determinants of oxygen consumption (systolic pressure, heart rate, contractility) and reductions in arterial oxygen supply (anemia, hypoxia).

Thus, circumstances can develop that precipitate subendocardial ischemia in the presence of normal coronary arteries

Subendocardial flow primarily occurs in diastole and begins to decrease below a mean coronary pressure of 40 mm Hg.

In contrast, subepicardial flow occurs throughout the cardiac cycle and is maintained until coronary pressure falls below 25 mm Hg.

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.

Transmural variations in coronary autoregulation and myocardial metabolism

The transmural difference in the lower autoregulatory pressure limit results in vulnerability of the subendocardium to ischemia in the presence of a coronary stenosis.

Endothelium-Dependent Modulation of Coronary Tone

Epicardial arteries do not normally contribute significantly to coronary vascular resistance,

arterial diameter is modulated by a wide variety of paracrine factors that can be released from platelets, as well as circulating neurohormonal agonists, neural tone, and local control through vascular shear stress.

Endothelium-dependent control of vascular tone.

CORONARY VASCULAR RESISTANCE The resistance to coronary blood flow can be

divided into three major components, R1 - epicardial conduit artery resistance

R2 - resistance secondary to metabolic and autoregulatory adjustments in flow and occurs in arterioles and resistance arteries

R3 - time-varying compressive resistance that is higher in subendocardial than subepicardial layers

R1:Under normal circumstances, there is no measurable pressure drop in the epicardial arteries, indicating negligible conduit resistance.

With the development of hemodynamically significant epicardial artery narrowing (more than 50% diameter reduction), the fixed conduit artery resistance begins to contribute an increasing component to total coronary resistance and, when severely narrowed (more than 90%), may reduce resting flow.

R2:The second component of coronary resistance is dynamic and primarily arises from microcirculatory resistance arteries and arterioles.

This is distributed throughout the myocardium across a broad range of microcirculatory resistance vessel size (20 to 200 μm in diameter) and changes in response to physical forces (intraluminal pressure and shear stress), as well as the metabolic needs of the tissue.

There is normally little resistance contributed by coronary venules and capillaries and their resistance remains fairly constant during changes in vasomotor tone.

R3: The third component, or compressive resistance, varies with time throughout the cardiac cycle and is related to cardiac contraction and systolic pressure development within the left ventricle.

In heart failure, compressive effects from elevated ventricular diastolic pressure also impede perfusion via passive compression of microcirculatory vessels by elevated extravascular tissue pressure during diastole.

Increases in preload effectively raise the normal back pressure to coronary flow above coronary venous pressure levels.

Extravascular Compressive Resistance (R3) During systole, cardiac contraction raises extravascular

tissue pressure to values equal to LV pressure at the subendocardium.

This declines to values near pleural pressure at the subepicardium.

The increased effective backpressure during systole produces a time-varying reduction in the driving pressure for coronary flow that impedes perfusion to the subendocardium.

Transmural Variations in Minimum Coronary Resistance (R2) and Diastolic Driving Pressure

The subendocardial vulnerability to compressive determinants of vascular resistance is partially compensated for by a reduced minimal resistance from an increased arteriolar and capillary density.

Coronary vascular resistance in the maximally vasodilated heart is also pressure-dependent, reflecting passive distention of arterial resistance vessels.

Thus, the instantaneous vasodilated value of coronary resistance obtained at a normal coronary distending pressure will be lower than that at a reduced pressure.

Structure and Function of the Coronary Microcirculation

Epicardial arteries (>400 μm in diameter) serve a conduit artery function, with diameter primarily regulated by shear stress, and contribute little pressure drop (<5%) over a wide range of coronary flow.

Coronary resistance vessels can be divided into resistance arteries (100 to 400 μm), which regulate their tone

in response to local shear stress and luminal pressure changes (myogenic response), and

arterioles (>100 μm), which are sensitive to changes in local tissue metabolism and directly control perfusion of the low-resistance coronary capillary bed.

Capillary density of the myocardium averages 3500/mm2, resulting in an average intercapillary distance of 17 μ m, and is greater in the subendocardium than the subepicardium.

Transmural distribution of coronary resistance vessels—major vasodilatory and vasoconstrictor mechanisms in epicardial conduit arteries and different sites of the microcirculation

Under resting conditions, most of the pressure drop in the microcirculation arises in resistance arteries between 50 and 200 μm in size, with little pressure drop occurring across capillaries and venules at normal flow levels.

Following pharmacologic vasodilation with dipyridamole, resistance artery vasodilation minimizes the precapillary pressure drop in arterial resistance vessels.

At the same time, there is an increased pressure drop and redistribution of resistance to venular vessels, in which smooth muscle relaxation is limited and the already low resistance is fairly fixed.

Microcirculatory pressure profile and local resistance changes to physiologic stimuli in subepicardial vessels

Heterogeneous arterial microvessel response during autoregulation. A reduction in pressure to 38 mm Hg elicited dilation in arterioles smaller than 100 um, whereas larger arteries tended to constrict passively from the reduction in distending pressure.

Homogeneous vasodilation of resistance arteries during increases in myocardial oxygen consumption.

There is dilation in all microvascular resistance arteries that is greatest in vessels smaller than 100 um.

There is considerable heterogeneity in microcirculatory vasodilation during physiologic adjustments in flow.

For example, as pressure is reduced during autoregulation, dilation is primarily accomplished by arterioles smaller than 100 um, whereas larger resistance arteries tend to constrict because of the reduction in perfusion pressure.

In contrast, metabolic vasodilation results from a more uniform vasodilation of resistance vessels of all sizes.

Similar inhomogeneity in resistance vessel dilation occurs in response to endothelium-dependent agonists and pharmacologic vasodilators.

A unique component of subendocardial coronary resistance vessels are the transmural penetrating arteries that course from the epicardium to the subendocardial plexus.

These vessels are removed from the metabolic stimuli that develop when ischemia is confined to the subendocardium.

As a result, local control from altered shear stress and myogenic relaxation to local pressure become very critical determinants of diameter in this “upstream” resistance segment.

Even during maximal vasodilation, this segment creates an additional longitudinal component of coronary vascular resistance that must be traversed before the arteriolar microcirculation is reached.

Because of this greater longitudinal pressure drop, the microcirculatory pressures in subendocardial coronary arterioles are lower than in the subepicardial arterioles.

Intraluminal Physical Forces Regulating Coronary Resistance

Myogenic Regulation- the ability of vascular smooth muscle to oppose changes in coronary arteriolar diameter.

Thus, vessels relax when distending pressure is decreased and constrict when distending pressure is elevated

Although the cellular mechanism is uncertain, it is dependent on vascular smooth muscle calcium entry, perhaps through stretch-activated L-type Ca2+ channels, eliciting cross-bridge activation.

The resistance changes arising from the myogenic response tend to bring local coronary flow back to the original level.

Myogenic regulation has been postulated to be one of the important mechanisms of the coronary autoregulatory response and, in vivo, appears to occur primarily in arterioles smaller than 100 um

Effects of physical forces on coronary diameter in isolated human coronary resistance arteries. As distending pressure is reduced from 100 mm Hg, there is progressive vasodilation consistent with myogenic regulation.

Flow-Mediated Resistance Artery Control Originally demonstrated by Kuo and colleagues. They found this to be endothelium-dependent

and mediated by NO, because it could be abolished with an l-arginine analogue.

Flow-mediated vasodilation in cannulated human resistance arteries. As the pressure gradient across the isolated vessel is increased, intraluminal flow rises and causes progressive dilation that is abolished by removing the endothelium. Similar flow-mediated dilation occurs in most arterial vessels, including the coronary conduit arteries.

Metabolic Mediators of Coronary Resistance

Adenosine ATP-Sensitive K+ Channels Hypoxia Acidosis

Neural Control of Coronary Conduit and Resistance Arteries

Cholinergic Innervation

In normal arteries, acetylcholine elicits vasodilation but there is vasoconstriction in the atherosclerotic artery, which is particularly pronounced in the stenosis.

Sympathetic innervation

Activation of sympathetic tone normally leads to net epicardial dilation but there is vasoconstriction in irregular and stenotic coronary segments in patients with atherosclerosis.

PHYSIOLOGICAL ASSESSMENT OF CORONARY ARTERY STENOSES

STENOSES PRESSURE FLOW RELATIONSHIP The relationship between pressure drop across a

stenosis and coronary flow for stenoses between 30% and 90% diameter reduction can be described using the Bernoulli principle.

The total pressure drop across a stenosis is governed by three hydrodynamic factors— viscous losses, separation losses, and turbulence

Fluid mechanics of a stenosis. The pressure drop across a stenosis can be predicted by the Bernoulli equation. It is inversely related to the minimum stenosis cross-sectional area and varies with the square of the flow rate as stenosis severity increases. An = area of the normal segment; As = area of the stenosis; f1 = viscous coefficient; f2 = separation coefficient; L = stenosis length; ΔP = pressure drop; = flow; u = viscosity of blood; ρ = density of blood.

The single most important determinant of stenosis resistance for any given level of flow is the minimum lesional cross-sectional area within the stenosis.[32]

Resistance is inversely proportional to the square of the cross-sectional area.

Separation losses determine the curvilinearity or steepness of the stenosis pressure-flow relationship.

Stenosis length and changes in cross-sectional area distal to the stenosis are relatively minor determinants.

Stenosis resistance increases exponentially as minimum lesional cross-sectional area decreases.

It is also flow dependent and varies with the square of the flow or flow velocity.

As a result, the instantaneous stenosis resistance increases during vasodilation.

Curvilinearity of the pressure-flow relationship as stenosis severity increases. The relationship between pressure drop across the stenosis and flow for diameter narrowing of 30%, 50%, 70%, 80%, and 90% is calculated on the basis of a proximal reference internal diameter of 3 mm (area, 7.1 mm2). Measurements in parentheses are minimal lesional cross-sectional areas. Instantaneous resistance is the slope of the pressure-flow curve (dashed red line) and, for a given stenosis, increases as flow rate rises. At levels of resting flow (dashed vertical line), the stenosis resistance increases exponentially as stenosis severity rises (solid red line in inset)

Interrelationship Among Distal Coronary Pressure, Flow, and Stenosis Severity

Coronary autoregulation Coronary blood flow reserve

Interrelationship among stenosis flow reserve

Very little increase in epicardial conduit artery resistance (R1) develops until stenosis severity reaches a 50% diameter reduction.

As a result, there is no significant pressure drop across a stenosis or stenosis-related alteration in maximal myocardial perfusion until stenosis severity exceeds a 50% diameter reduction (75% cross-sectional area)

the stenosis pressure-flow relationship

As stenosis severity increases further, the curvilinear coronary pressure-flow relationship steepens and increases in stenosis resistance are accompanied by concomitant increases in the pressure drop (ΔP) across the stenosis.

This reduces distal coronary pressure, the major determinant of perfusion to the microcirculation, and maximum vasodilated flow decreases.

Above a value of 70% diameter reduction, small increases in stenosis severity are accompanied by further increases in stenosis pressure drop that reduce distal coronary pressure and result in progressive reductions in maximal vasodilated perfusion of the microcirculation.

Autoregulation

A critical stenosis, one in which subendocardial flow reserve is completely exhausted at rest, usually develops when stenosis severity exceeds 90%.

Under these circumstances, pharmacologic vasodilation of subepicardial resistance vessels results in a reduction in distal coronary pressure that actually redistributes flow from the subendocardium, leading to a transmural steal phenomenon.

Concept of Maximal Perfusion and Coronary Reserve

GOULD originally proposed the concept of coronary reserve.

There are currently three major indices used to quantify coronary flow reserve— absolute, relative, and fractional

Absolute flow reserve It is expressed as the ratio of maximally vasodilated flow

to the corresponding resting flow value in a specific region of the heart and quantifies the ability of flow to increase above the resting value.

Clinically important reductions in maximum flow correlating with stress-induced ischemia on SPECT are generally associated with absolute flow reserve values below 2

Absolute flow reserve is altered not only by factors that affect maximal coronary flow but also by the corresponding resting flow value.

Resting flow can vary with hemoglobin content, baseline hemodynamics, and the resting oxygen extraction.

As a result, reductions in absolute flow reserve can arise from inappropriate elevations in resting coronary flow and from reductions in maximal perfusion.

Absolute flow reserve can be quantified using intracoronary Doppler velocity or thermodilution flow measurements, as well as by quantitative approaches to image absolute tissue

perfusion based on PET

In the absence of diffuse atherosclerosis or LV hypertrophy, absolute flow reserve in conscious humans is similar to measurements in animals, with vasodilated flow increasing four to five times the value at rest.

There is also fairly good reduplication of the idealized relationship between stenosis severity and absolute flow reserve in patients with isolated one- or two-vessel CAD with intracoronary vasodilation.

In contrast, in patients with risk factors such as hypercholesterolemia and no significant coronary luminal narrowing, values of absolute flow reserve using PET are lower than in normals, reflecting microcirculatory impairment in flow or attenuated vasodilator responsiveness.

Abnormalities in the coronary microcirculation and uncertainty in stenosis geometry or diffuse atherosclerosis lead to considerably more variability of the observed relationship between stenosis severity and absolute flow reserve in patients with more extensive disease.

A significant limitation of absolute flow reserve measurements is that the importance of an epicardial stenosis cannot be dissociated from changes caused by functional abnormalities in the microcirculation that are common in patients(e.g., hypertrophy, impaired endothelium-dependent vasodilation).

Relative Flow Reserve Measured using nuclear perfusion imaging .

In this approach, relative differences in regional perfusion are assessed during maximal pharmacologic vasodilation or exercise stress and expressed as a fraction of flow to normal regions of the heart.

This compares relative perfusion under the same hemodynamic conditions and thus is relatively insensitive to variations in mean arterial pressure and heart rate.

An alternative invasive approach uses absolute flow reserve measurements and derives relative flow reserve by dividing measurements in a stenotic vessel by those in remote normally perfused territories.

Limitations: First, conventional SPECT imaging requires a normal

reference segment within the left ventricle for comparison. Because of this, relative flow reserve measurements

cannot accurately quantify stenosis severity when diffuse abnormalities in flow reserve related to balanced multivessel CAD or impaired microcirculatory vasodilation are present.

Large differences in relative vasodilated flow are required to detect SPECT perfusion differences because nuclear tracers become diffusion-limited and their myocardial uptake fails to increase proportionally with increases in vasodilated flow. As a result, differences in tracer deposition underestimate

the actual relative difference in perfusion. This limitation can be overcome with PET tracers of

perfusion and appropriate kinetic modeling.

Finally, whereas prognostic data related to the perfusion deficit size are available, there are no imaging studies evaluating the quantitative severity of the stress or vasodilated flow reduction as a continuous outcome measure.

Fractional Flow Reserve This technique, pioneered by PIJLS, is based on the

principle that the distal coronary pressure measured during vasodilation is directly proportional to maximum vasodilated perfusion

Fractional flow reserve (FFR) is an indirect index determined by measuring the driving pressure for microcirculatory flow distal to the stenosis (distal coronary pressure minus coronary venous pressure) relative to the coronary driving pressure available in the absence of a stenosis (mean aortic pressure minus coronary venous pressure).

The approach assumes linearity of the vasodilated pressure-flow relationship, which is known to be curvilinear at reduced coronary pressure, and usually assumes that coronary venous pressure is zero.

This results in the simplified clinical FFR index of mean distal coronary pressure/mean aortic pressure (Pd/Pao).

Although derived, the measurements are conceptually similar to those of relative coronary flow reserve because they rely only on minimum mean coronary pressure measurements during intracoronary vasodilation and compare stenotic with normal regions (assumed to equal 1) under similar hemodynamic conditions.

They are attractive in that they can immediately assess the physiologic significance of an intermediate stenosis to help guide decisions regarding coronary intervention and are unaffected by alterations in resting flow.

Similarly, because they only require vasodilated coronary pressure measurements, FFR can be used to assess the functional effects of a residual lesion after PCI.

Conclusions Routine measurement of FFR in patients with

multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year.

Conclusions As an initial management strategy in patients

with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.

Conclusions In patients with stable coronary artery disease and

functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization.

In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone.

• Fractional Flow Reserve, calculated from coronary pressure measurement, is an accurate, invasive, and lesion-specific index to demonstrate or exclude whether a particular coronary stenosis can cause reversible ischemia.

• FFR can be determined easily, in the cath-lab, immediately prior to a planned intervention

DEFER study: background

FFR based strategy for PCI in equivocal stenosis( DEFER – Study)

The DEFER Study: Objectives

• to test safety of deferring PCI of stenoses

not responsible for inducible ischemia as indicated by FFR > 0.75 ( “outcome” )

Secondary objective

• to compare quality of life in such patients, whether or not treated by PCI (CCS-class, need for anti-anginal drugs) (“symptoms”)

Primary objective

DEFER Group REFERENCE Group PERFORM Group

The DEFER Study: Flow ChartPatients scheduled for PCI without

Proof of Ischemia (n=325)

performance of PTCA (158)deferral of PTCA (167)

FFR 0.75 (91)

No PTCA

FFR 0.75(90)

PTCA

FFR < 0.75(76)

PTCA

FFR < 0.75(68)

PTCA

Randomization

No. at risk

Defer group 90 85 82 74 73 72Perform group 88 78 73 70 67 65

Reference gr 135 105 103 96 90 88

78.872.764.4

0 1 2 3 4 50

25

50

75

100

Defer

Perform

Reference(FFR < 0.75)

p=0.52

p=0.17p=0.03

Years of Follow-up

event – free survival (%)

Cardiac Death And Acute MI After 5 Years

3.3

7.9

15.7

0

5

10

15

20 %

P=0.20

P< 0.03

P< 0.005

DEFER PERFORM REFERENCE

FFR > 0.75 FFR < 0.75

0%

20%

40%

60%

80%

100%

baseline 1month 1 year 2 year 5 year

Defer group Perform group Reference group

freedom from chest pain

FFR > 0.75 FFR > 0.75 FFR < 0.75

* *

* *

* **

*

Conclusions : Five-year outcome after deferral of PCI of an

intermediate coronary stenosis based on FFR 0.75 is excellent.

The risk of cardiac death or myocardial infarction related to this stenosis is <1% per year and not decreased bystenting

LIMITATIONS: It can only assess the functional significance of

epicardial artery stenoses and cannot assess physiologic contributions caused by abnormalities in microcirculatory flow reserve in resistance vessels.

The measurements are also critically dependent on achieving maximal pharmacologic vasodilation.

In addition, ignoring the backpressure to coronary flow by assuming that venous pressure is equal to zero and ignoring curvilinearity of the diastolic pressure-flow relationship will cause the FFR to underestimate the physiologic significance of a stenosis. This is particularly problematic at low coronary

pressures and when assessing the functional significance of coronary collaterals where venous pressure needs to be accounted for.

Finally, inserting the guidewire across a stenosis can artifactually overestimate stenosis severity caused by the reduction in effective intralesional area when there is diffuse disease, when it is placed in small branch vessels, or in assessing a severe stenosis.

Despite these limitations and its invasive nature, FFR is currently the most direct way to assess the physiologic significance of individual coronary lesions.

Pathophysiologic States Affecting Microcirculatory Coronary Flow Reserve

Abnormalities in coronary flow reserve and endothelium-dependent vasodilation are common in women with insignificant coronary disease and can be accompanied by metabolic ischemia, assessed by magnetic resonance spectroscopy and they negatively affect prognosis.

The two most common factors affecting microcirculatory resistance control independently of coronary stenosis severity in patients are LV hypertrophy and impaired NO-mediated resistance vessel vasodilation.

Left Ventricular Hypertrophy

Effects of left ventricular hypertrophy (LVH) on maximal coronary flow

The effects of hypertrophy on coronary flow reserve are complex and need to be thought of in terms of the absolute flow level as well as the flow per gram of myocardium.

With acquired hypertrophy, resting flow per gram of myocardium remains constant, but the increase in LV mass necessitates an increase in the absolute level of resting flow through the coronary artery.

In terms of maximal perfusion, acquired hypertrophy does not result in vascular proliferation and coronary resistance vessels remain unchanged.

Because maximum absolute flow remains unchanged, maximum perfusion per gram of myocardium falls.

The net effect is that coronary flow reserve at any given coronary arterial pressure is reduced and inversely related to the change in LV mass

Some degree of LV hypertrophy is common in patients with CAD and it likely contributes to reductions in coronary flow reserve that are independent of stenosis severity.

The actual coronary flow reserve in hypertrophy will be critically dependent on the underlying cause of hypertrophy and its effects on coronary driving pressure.

A similar degree of hypertrophy caused by untreated systemic hypertension will have a higher coronary flow reserve than in aortic stenosis, in which mean arterial pressure remains normal.

Similarly, when hypertrophy is from systolic hypertension and increased pulse pressure caused by reduced aortic compliance, the accompanying reduction in diastolic pressure can lower coronary reserve

Impaired Endothelium-Dependent Vasodilation

Measurements of coronary flow reserve in humans with risk factors for atherosclerosis are systematically lower than normals without coronary risk factors and underscore the importance of abnormalities in microvascular control in determining coronary flow reserve.

KUO and colleagues have demonstrated that experimental hypercholesterolemia markedly attenuates the dilation of coronary arterioles in response to shear stress and pharmacologic agonists that stimulate NOS in the absence of epicardial stenoses.

This was reversed with l-arginine, suggesting that it reflects impaired NO synthesis or availability.

Although resting blood flow is not altered, there is a marked increase in the coronary pressure at which intrinsic autoregulatory adjustments become exhausted, with flow beginning to decrease at a distal coronary pressure of 60 versus 45 mm Hg, approximately similar to the shift occurring in response to a twofold increase in heart rate.

In vivo microcirculatory studies have demonstrated that there is an inability of resistance arteries to dilate maximally in response to shear stress.

This likely reflects excess resistance in the transmural penetrating arteries, which are upstream of metabolic stimuli for vasodilation and extremely dependent on shear stress as a stimulus for local vasodilation.

These abnormalities amplify the functional effects of a coronary stenosis, resulting in the development of subendocardial ischemia at a lower workload

Impaired microcirculatory control with abnormal NO-mediated endothelium-dependent resistance artery dilation

Transmural perfusion before and after blocking NO-mediated dilation with LNNA in exercising dogs subjected to a coronary stenosis

These observations in animals with impaired NO production appear to be relevant to pathophysiologic states associated with impaired endothelium-dependent vasodilation in humans.

For example, coronary flow reserve is markedly reduced in the absence of a coronary stenosis in familial hypercholesterolemia, and improving endothelial function by lowering elevated LDL levels with statins produces a delayed improvement in coronary flow reserve in normal and stenotic arteries and also ameliorates clinical signs of myocardial ischemia.

Impaired NO-mediated vasodilation likely affects the regulation of myocardial perfusion in other disease states in which endothelium-dependent vasodilation is impaired.

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