From the Department of Medicine, Division of Cardiology, University of
Minnesota Medical School, Minneapolis.
Correspondence to Robert J. Bache, MD, Division of Cardiology, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail bache001{at}maroon.tc.umn.edu
Assessment of coronary artery
stenosis severity depends on either determination of the
anatomic dimensions of the stenosis by angiographic techniques
or assessment of the functional significance of the stenosis by
measurement of its effect on blood flow. Measurement of myocardial
blood flow during maximal pharmacological vasodilation (vasodilator
reserve) has been used to examine the functional consequences of a
stenosis on perfusion of the dependent region of
myocardium. In experimental animals, flow reserve measured
with an electromagnetic flowmeter during pharmacological
coronary vasodilation corresponds closely to quantitative
coronary angiographic measurements of stenosis
geometry.1 Studies using PET imaging with
[13N]ammonia to measure coronary flow
reserve in patients with coronary artery disease also
demonstrated an inverse correlation between stenosis severity
and flow reserve, but the relationship exhibited a greater degree of
scatter than that obtained in animal models.2 It
is not surprising that the correlation between stenosis
severity and flow reserve would be less precise in patients with
coronary disease, because atherosclerosis
introduces potential variability in the behavior of both the epicardial
stenotic segment and the coronary resistance vessels.
Thus, a coronary stenosis in a patient with
atherosclerosis may not produce a fixed degree of
anatomic narrowing of the epicardial artery, and the resistance vessels
may not predictably undergo maximal vasodilation in response to
pharmacological vasodilators. Consequently, interpretation of
coronary vasodilator reserve requires consideration of the
dynamic characteristics of both the epicardial artery segment and the
coronary resistance vessels.
Epicardial Arteries
Lundmer et al3 demonstrated that
intracoronary acetylcholine caused vasodilation in patients
with atypical chest pain and angiographically normal coronary
vessels but produced vasoconstriction in patients with
atherosclerosis and angina pectoris. Furthermore,
blockade of nitric oxide (NO) synthesis with intracoronary
NG-monomethyl-L-arginine
(L-NMMA) caused a decrease in basal epicardial artery lumen
diameter in patients with normal coronary
arteriograms,4 demonstrating that NO normally
contributes to maintenance of basal coronary
vasodilator tone. Vita et al5 subsequently
reported that acetylcholine can cause coronary vasoconstriction
in patients with risk factors for atherosclerosis even
with angiographically smooth coronary vessels. Data from both
experimental animals and patients undergoing coronary
angiography have demonstrated that normal epicardial arteries undergo
vasodilation in response to increases of blood
flow.6 7 This response is dependent on an intact
endothelium, because removal of the
endothelium abolished the flow-mediated
vasodilation.6 Flow-mediated epicardial
coronary artery dilation has been demonstrated in
angiographically normal human coronary arteries by infusion of
adenosine or papaverine distal to the site of measurement of
coronary diameter, thereby avoiding exposure of the proximal
artery to the direct effects of the pharmacological
vasodilator.7 In patients with angiographically
normal coronary arteries, metabolic vasodilation of
the coronary resistance vessels during exercise or cardiac
pacing also results in flow-mediated vasodilation of the epicardial
arteries.4 8 9 In contrast, in patients with
atherosclerotic disease, exercise caused no change or coronary
artery constriction.8 9 After blockade of NO
synthesis with L-NMMA, coronary dilation during pacing was
similar in patients with and without risk factors, supporting the
concept that vasodilation in response to pacing in patients without
risk factors was the result of increased NO
production.4
Coronary Artery Stenosis
Autopsy studies of stenotic coronary artery
segments have demonstrated that
Microvascular Impairment of Flow Reserve
Although vasodilator reserve was initially devised to
quantify limitation of flow caused by an epicardial
coronary stenosis, maximal flow rates can also be
influenced by alterations at the microvascular level. Increased
extravascular forces secondary to elevation of left
ventricular diastolic pressure or
tachycardia act to compress the intramyocardial
microvasculature and limit peak flow rates.12
Structural abnormalities of the small vessels in hypertension,
diabetes, and hypertrophic cardiomyopathy can limit
vasodilation, thereby impairing maximal flow
rates.13 14 In addition,
hyperlipidemia has been found to impair
endothelium-dependent resistance vessel dilation. Thus,
in patients with hypercholesterolemia, the
increases of coronary artery flow in response to
intracoronary acetylcholine measured with a Doppler
catheter were less than normal in patients with
hypercholesterolemia, and the response was
improved after 6 months of cholesterol-lowering therapy
with pravastatin.15 These findings
indicate that hyperlipidemia causes impairment of
endothelium-dependent vasodilator responses not only in
epicardial arteries but also in the coronary resistance
vessels.
A more surprising finding has been the recent demonstration that
hyperlipidemia can impair coronary resistance
vessel dilation in response to
non–endothelium-dependent dilators. Several
investigators have reported that maximal myocardial blood flow rates
measured with positron emission tomography using
[13N]ammonia or
15O-labeled water during intravenous
infusion of adenosine or dipyridamole are
impaired in patients with hyperlipidemia and
angiographically normal coronary arteries or normal exercise
stress tests.16 17 18 19 Impaired resistance vessel
dilation in response to endothelium-independent
vasodilators in patients with lipid abnormalities can probably be
explained by studies demonstrating size-related differences in
vasodilator responses of the coronary small vessels. Studies in
which coronary microvessels were directly visualized in beating
hearts have shown that metabolic vasodilation occurs
principally in arterioles <100 µm in
diameter.20 Adenosine and
dipyridamole also produce their vasodilator effects
mainly in vessels of this size. However, up to 40% of total
coronary resistance resides in small arteries 100 to 400
µm in diameter.21 Although these small arteries
are not under metabolic control, they have the potential to
influence maximal coronary flow rates importantly. In the
normal heart, vasomotor tone in these small arteries is indirectly
coupled to myocardial metabolic needs through
endothelium-dependent flow-mediated NO
production. Thus, when vasodilation of the arterioles causes an
increase in blood flow, the resultant increase in
endothelial shear will cause increased NO
production and vasodilation of the small
arteries.20 22 In this way, arteriolar
vasodilation also leads to dilation of the small resistance arteries.
However, in the setting of hyperlipidemia,
endothelium-dependent shear-mediated vasodilation of
the small arteries may be impaired or lost. In this situation,
adenosine or dipyridamole would be expected to
produce a subnormal increase in blood flow, because these agents dilate
only the arterioles but not the small arteries. Absence of
flow-mediated vasodilation of the small arteries could impair minimum
vascular resistance, because substantial resistance to blood flow
resides at the level of these small arteries.
Response to Lipid-Lowering Therapy
Several investigators have reported that short-term
lipid-lowering therapy can cause improvement of
endothelium-dependent vasodilator responses in both
epicardial coronary arteries and coronary resistance
vessels. Egashira et al15 reported that in
patients with hypercholesterolemia,
pravastatin treatment over an 8-month interval had a
beneficial effect on the response of the epicardial arteries (measured
with quantitative angiography) as well as the resistance-vessel
dilation produced by intracoronary acetylcholine. A regimen of
lipid lowering in conjunction with cardiovascular
conditioning of 6 weeks' duration has been reported to improve flow
reserve during intravenous infusion of
dipyridamole in patients with elevated
cholesterol, some of whom were known to have occlusive
coronary artery disease.17 Intensive
lipid-lowering therapy for 12 weeks in patients with documented
coronary artery disease and hyperlipidemia
caused a decrease in the size and severity of myocardial perfusion
abnormalities measured with [13N]ammonia PET
imaging during dipyridamole
administration.23 It is reasonable to conclude
that the improved flow reserve in these studies was principally the
result of a functional improvement of
endothelium-dependent vasodilator responses, because
the interval of treatment was too brief to expect atheroma
regression.24
In this issue of Circulation, Huggins and
associates25 report the effect of 4 months of
lipid-lowering therapy with simvastatin on the
coronary vasodilator response to intravenous
adenosine using PET [13N]ammonia in
patients with ischemic heart disease. Although coronary
angiography was not performed, the investigators reasoned that it
should be possible to distinguish between myocardial regions perfused
by a stenotic coronary artery and regions without a
stenosis by the response of flow during vasodilation with
adenosine before therapy is begun. According to this construct,
myocardial segments were classified as normal (flow >2 mL ·
min-1 · g-1 during
adenosine before simvastatin therapy) or abnormal
(flow <2 mL · min-1 ·
g-1). The investigators note that even the
"normal" segments had decreased peak flow rates in comparison with
truly normal individuals. This was not unexpected, in light of previous
data demonstrating that the response to
endothelium-independent vasodilators is impaired in the
setting of
hyperlipidemia.15 16 17 18 19 23 Heart
rate and arterial pressure, variables that can affect
flow reserve, were similar before and after treatment. Furthermore,
other factors that impair flow reserve at the microvascular level, such
as hypertension or myocardial hypertrophy, should influence
flow reserve in regions perfused by normal or stenosed epicardial
arteries equally. In normal segments, simvastatin treatment
caused no change in myocardial blood flow during basal conditions and
no change in the response to adenosine. In abnormal segments,
in contrast, blood flow during high-dose adenosine was on
average 47% greater after lipid-lowering therapy. Because
lipid-lowering therapy did not improve the response to
adenosine in normal segments, the investigators concluded that
the effect of simvastatin in abnormal segments could not be
the result of an effect on the microvasculature but rather resulted
from augmented dilation of stenotic epicardial conduit vessels,
most likely as the result of improved flow-mediated vasodilation. In a
previous report, Czernin et al17 found that in
patients with hyperlipidemia, several of whom had known
coronary artery disease, peak flow rates during
dipyridamole infusion were modestly but significantly
improved after a 6-week program of low-fat diet and
cardiovascular conditioning. The peak flow rates before
treatment reported by Czernin et al were intermediate between the
normal and abnormal regions in the study by Huggins et
al,25 suggesting that the myocardial regions
studied were not identical in these 2 reports. Huggins et al suggest
that failure to find an improvement in regions designated as normal
after lipid-lowering therapy may be related to longer duration and more
extensive disease in their patients with manifest ischemic
heart disease. An additional factor that might have affected the
results of Huggins et al is that at the time the flow measurements were
made, a number of patients were taking nitrates or calcium blockers,
agents that are known to be active in the coronary vasculature.
This may be especially important for nitrates, because these agents act
by generating NO and consequently might obscure impaired
endogenous endothelial production
of NO in the measurements made before
treatment.26 A functional interaction between
endogenous NO and calcium blockers is less likely but
cannot be entirely excluded.
The finding by Huggins and associates25 that
simvastatin improved the vasodilator response in the
segments with the lowest pretreatment flow reserve is of therapeutic
importance, because these are the regions most vulnerable to developing
ischemia during exercise or other stress. The conclusion by the
authors that this effect resulted from recovery of flow-mediated
vasodilation of stenotic coronary artery segments after
lipid lowering is consonant with previous data demonstrating that
normal coronary arteries exhibit flow-mediated
vasodilation7 8 and that coronary
stenoses can dilate in response to exogenous
nitrates.10 Nevertheless, in the absence of
coronary angiography, it is possible that other alterations of
coronary anatomy could have contributed to the observed
responses. For example, flow reserve is impaired in myocardial regions
perfused by collateral channels and most likely would be
indistinguishable from stenotic regions by PET imaging.
Furthermore, endothelium-dependent small-vessel
responses are impaired in small vessels perfused through collateral
channels even in the absence of lipid
abnormalities.27 Whether
hyperlipidemia has an additional effect on small
vessels in collateral-dependent regions is unknown but will be an
important area for study, especially because of the current interest in
promoting coronary angiogenesis, an intervention that will
increase the myocardial dependency on collateral vessels.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Gould KL, Kirkeeide RL, Buchi M. Coronary
flow reserve as a physiologic measure of stenosis severity.
J Am Coll Cardiol. 1990;15:459–474.[Abstract]
2.
DiCarli M, Czernin J, Hoh CK, Gerbaudo VH, Brunken RC,
Huang SC, Phelps ME, Schelbert HR. Relation among stenosis
severity, myocardial blood flow, and flow reserve in patients with
coronary artery disease. Circulation. 1995;91:1944–1951.
3.
Ludmer PL, Selwyn AP, Shook THL, Wayne RR, Mudge GH,
Alexander RW, Ganz P. Paradoxical vasoconstriction induced by
acetylcholine in atherosclerotic coronary arteries.
N Engl J Med. 1986;315:1046–1051.[Abstract]
4.
Quyyumi AA, Dakak N, Andrews NP, Gilligan DM, Panza
JA, Cannon RO. Contribution of nitric oxide to metabolic
coronary vasodilation in the human heart.
Circulation. 1995;92:320–326.
5.
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish
RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary
vasomotor response to acetylcholine relates to risk factors for
coronary artery disease. Circulation. 1990;81:491–497.
6.
Holtz J, Giesler M, Bassenge E. Two dilatory
mechanisms of anti-anginal drugs on epicardial coronary
arteries in-vivo: indirect, flow-dependent,
endothelium-mediated dilation and direct smooth muscle
relaxation. Z Kardiol. 1983;72(suppl 3):98–106.
7.
Cox DA, Vita JA, Treasure CB, Fish RD, Alexander RW,
Ganz P, Selwyn AP. Atherosclerosis impairs
flow-mediated dilation of coronary arteries in humans.
Circulation. 1989;80:458–465.
8.
Gage JE, Hess OM, Murakami T, Ritter M, Grimm J,
Krayenbuehl HP. Vasoconstriction of stenotic coronary
arteries during dynamic exercise in patients with classic angina
pectoris: reversibility by nitroglycerin.
Circulation. 1986;73:865–876.
9.
Gordon JB, Ganz P, Nabel EG, Fish RD, Zebeda J, Mudge
GH, Alexander RW, Selwyn AP. Atherosclerosis influences
the vasomotor response of epicardial coronary arteries to
exercise. J Clin Invest. 1989;83:1946–1952.
10.
Brown BG, Bolson EL, Dodge HT. Dynamic mechanisms in
human coronary stenosis. Circulation. 1984;70:917–922.
11.
Schwartz JS, Bache RJ. Effect of arteriolar dilation on
coronary artery diameter distal to coronary
stenoses. Am J Physiol. 1985;249:H981–H988.
12.
Duncker D, Zhang J, Bache R. Coronary
pressure-flow relationship in left ventricular
hypertrophy: importance of changes in back pressure versus
changes in minimum resistance. Circ Res. 1993;72:579–587.
13.
Schwartzkopff B, Motz W, Frenzel H, Vogt M, Knauer S,
Strauer BE. Structural and functional alterations of the
intramyocardial coronary arterioles in patients with
arterial hypertension. Circulation. 1993;88:993–1003.
14.
Nahser PJ Jr, Brown RE, Oskarsson H, Winniford MD,
Rossen JD. Maximal coronary flow reserve and
metabolic coronary vasodilation in patients with
diabetes mellitus. Circulation. 1995;91:635–640.
15.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S,
Inou T, Takeshita A. Reduction in serum cholesterol with
pravastatin improves endothelium-dependent
coronary vasomotion in patients with
hypercholesterolemia. Circulation. 1994;89:2519–2524.
16.
Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M,
Schwaiger M. Early detection of abnormal coronary flow reserve
in asymptomatic men at high risk for coronary
artery disease using positron emission tomography.
Circulation. 1994;90:808–817.
17.
Czernin J, Barnard RJ, Sun KT, Krivokapich J, Nitzsche
E, Dorsey D, Phelps ME, Schelbert HT. Effect of short-term
cardiovascular conditioning and low-fat diet on
myocardial blood flow and flow reserve. Circulation. 1995;92:197–204.
18.
Pitkanen O-P, Raitakari OT, Niinikoski H, Nuutila P,
IIda H, Voipio-Pulkki L-M, Harkonen R, Wegelius U, Ronemaa T, Viikari
J, Knuuti J. Coronary flow reserve is impaired in young men
with familial hypercholesterolemia.
J Am Coll Cardiol. 1996;28:1705–1711.[Abstract]
19.
Yokoyama I, Ohtake T, Momomura S-I, Nishikawa J, Sasaki
Y, Omata M. Reduced coronary flow reserve in
hypercholesterolemic patients without overt
coronary stenosis. Circulation. 1996;94:3232–3238.
20.
Komaru T, Lamping KG, Eastham CL, Dellsperger KC. Role
of ATP-sensitive potassium channels in coronary microvascular
autoregulatory responses. Circ Res. 1991;69:1146–1151.
21.
Chilian WM, Eastham CL, Marcus ML. Microvascular
distribution of coronary vascular resistance in beating left
ventricle. Am J Physiol. 1986;251:H779–H788.
22.
Ishibashi Y, Duncker DJ, Zhang J, Bache RJ.
ATP-sensitive K+ channels, adenosine, and
nitric oxide-mediated mechanisms account for coronary
vasodilation during exercise. Circ Res. 1998;82:346–359.
23.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP,
Latifi R, Dudrick SJ. Short-term cholesterol lowering
decreases size and severity of perfusion abnormalities by positron
emission tomography after dipyridamole in patients with
coronary artery disease. Circulation. 1994;89:1530–1538.
24.
Brown BG, Zhao X-Q, Sacco DE, Albers JJ. Lipid lowering
and plaque regression. Circulation. 1993;87:1781–1791.
25.
Huggins GS, Pasternak RC, Alpert NM, Fischman AJ,
Gewirtz H. Effect of short term treatment of
hyperlipidemia on coronary vasodilator function
and myocardial perfusion in regions having substantial impairment of
baseline dilator reserve. Circulation. 1998;98:1291–1296.
26.
Harrison DG, Bates JN. The nitrovasodilators: new ideas
about old drugs. Circulation. 1993;87:1461–1467.
27.
Sellke FW, Quillen JE, Brooks LA, Harrison DG.
Endothelial modulation of the coronary
vasculature in vessels perfused via mature collaterals.
Circulation. 1990;81:1938–1947.
© 1998 American Heart Association, Inc.
Editorial
Vasodilator Reserve
A Functional Assessment of Coronary Health
Key Words: Editorials • cholesterol • coronary disease • endothelium • nitric oxide • vasodilation
75% of atheromas are
eccentric in location, leaving part of the arterial wall
uninvolved.10 The existence of a relatively
uninvolved segment of vessel probably explains the finding that
coronary artery stenoses often do not behave as fixed
narrowings but have some degree of compliance and some ability to
undergo active vasomotion.10 Thus, sympathetic
nervous system activation, serotonin, and ergonovine can
produce constriction at the site of an eccentric atherosclerotic
lesion, whereas nitroglycerin can cause dilation of
coronary stenoses.8 10 The latter
observation demonstrates that stenotic coronary
segments are responsive to the vasodilating effects of NO. The
intra-arterial pressure within a stenotic segment
opposes the arterial wall elasticity and vasomotor tone,
which act to collapse the vessel. For this reason, a compliant
stenosis can undergo passive changes in lumen area secondary to
changes in aortic pressure.10 Furthermore,
interactions between the stenotic segment and the distal
vasculature can also result in passive changes in severity of
stenosis. Vasodilation of the resistance vessels will cause an
increase in blood flow and therefore an increase in blood velocity
(kinetic energy) within the stenotic segment; the increased
velocity causes a proportionate decrease in pressure (potential energy)
acting to distend the stenosis. As the intraluminal distending
pressure decreases with increasing flow, both active vasomotor tone and
the arterial wall elasticity will tend to collapse the
stenosis and worsen the degree of
narrowing.11 With severe stenoses, these
effects can be sufficient to cause a paradoxical decrease in blood flow
in response to administration of vasodilators such as adenosine
or dipyridamole, which act principally at the level of
the resistance vessels.10 11
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