(Circulation. 1995;91:2916-2923.)
© 1995 American Heart Association, Inc.
Articles |
Reduced Epicardial Coronary Vasodilator Capacity in Patients With Left Ventricular Hypertrophy
From the Department of Internal Medicine, Cardiology, University Hospital, Zurich, Switzerland.
Correspondence to Otto M. Hess, MD, Cardiology, University Hospital, Raemistrasse 100, 8091 Zurich, Switzerland.
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Abstract |
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Background Enlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow.
Methods and Results Vasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 µg intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2±2.2 mm) than in control subjects (8.6±1.5 mm; P<.001); after 100 µg intracoronary nitroglycerin, it increased to 12.9±2.2 mm (6±5%) in those with LV hypertrophy and to 10.3±1.5 mm (21±8%; P<.001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (r=-.71, P<.001).
Conclusions Vasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.
Key Words: vasodilation • hypertrophy • nitroglycerin • stenosis • ventricles
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Normal as well as stenotic coronary arteries have been shown to change their size with different pharmacological interventions and physiological stress.1 2 Changes in blood flow and arterial diameter are closely correlated, ie, an increase in flow is accompanied by an increase in vascular diameter, and vice versa.3 4 An enlargement of the coronary arteries has been reported in patients with left ventricular (LV) hypertrophy due to valvular heart disease,5 6 7 hypertension,8 and cardiomyopathy.9 The purpose of the present study was to assess epicardial coronary artery size at rest and after nitroglycerin administration and to determine the vasodilator capacity of the large coronary arteries in patients with LV hypertrophy.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
Forty-four patients with normal coronary arteries were included in the present analysis. In a dose-response study (study A), 14 patients were examined with increasing doses of intracoronary nitroglycerin. Seven patients (age, 63±9 years) had severe aortic stenosis, and 7 healthy subjects (age, 54±8 years), who were examined because of atypical chest pain, served as the control group.
In a second study (study B), 30 patients were examined with a maximal vasodilating dose of 100 µg intracoronary nitroglycerin. Fifteen patients (age, 63±13 years) had LV hypertrophy secondary to valvular heart disease: 9 of them had aortic stenosis, 3 had aortic regurgitation, and 3 had severe mitral regurgitation. Fifteen patients (age, 48±6 years) with atypical chest pain served as control subjects. Mean body surface area was similar in patients with LV hypertrophy (1.81±0.28 m2) and control subjects (1.85±0.32 m2). Coronary arteriography was performed in all patients for diagnostic purposes. Patients with LV hypertrophy were selected for the study when the following inclusion criteria were fulfilled: severe valve lesion (preoperative evaluation), normal coronary arteries, and adequate opacification of the coronary arteries for quantitative evaluation.
Cardiac Catheterization
Informed consent to undergo cardiac
catheterization and coronary
angiography was obtained from all patients. Premedication consisted of
10 mg oral chlordiazepoxide administered 1 hour before catheterization.
Vasoactive substances were withheld for at least 24 hours before
catheterization. LV and aortic pressures were measured with an 8F
pigtail catheter introduced retrogradely from the right femoral artery
in patients with aortic and mitral regurgitation and in control
subjects. In patients with aortic stenosis, transeptal catheterization
was carried out, and systolic pressure gradient was calculated from
simultaneous LV and aortic pressure measurements. LV angiograms were
recorded simultaneously in the right and left anterior oblique
projections at a filming rate of 50 frames per second.10
LV volume and ejection fraction were calculated using the
"area–length" method.11 Aortic and mitral
regurgitation fraction was determined from LV angiography and cardiac
output (Fick). LV muscle mass was obtained according to the method of
Rackley et al.12 Selective left coronary arteriography was
carried out from the right femoral artery (Judkins technique, 8F
catheters) using multiple views for optimal visualization of the
coronary arteries.
In study A, the dose-response relation of intracoronary nitroglycerin was determined from biplane coronary arteriograms in the right and left anterior oblique projections. First, a control run was performed; then, 10, 30, 90, and 150 µg intracoronary nitroglycerin were administered with an interval of 5 minutes between the different steps. Heart rate and mean aortic pressure were recorded before and after each injection.
In study B, a maximal vasodilating dose of 100 µg intracoronary nitroglycerin was administered, and coronary angiography was repeated immediately after injection.
Quantitative Coronary Arteriography
Quantitative evaluation
of the coronary angiograms was performed
with a semiautomatic computer system.13 14 The system
is
based on a 35-mm film projector (Tagarno 35 CX), a slow-scan CCD camera
(image digitization) that has been developed at the Institute for
Biomedical Engineering in Zurich, and a computer work station (Apollo
DN 3000) for image storage and processing. Contour detection was
carried out using a geometric-densitometric edge-detection algorithm
(Fig 1
). The methodology for computerized analysis
of coronary angiograms has been described
previously.15 16
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The proximal cross-sectional
area of the left anterior descending and
the left circumflex coronary arteries, defined as the vessel segments
immediately beyond the bifurcation of the left main coronary artery
over the length of approximately 1 cm, was measured using one to three
end-diastolic cine-frames. The computer traced these
segments automatically and calculated their mean cross-sectional area
(Fig 1
). Calibration was performed automatically using either
the
isocenter technique13 or the tip of the 8F Judkins
catheter. Vasodilator capacity was defined as circumferential length
after nitroglycerin minus circumferential length at rest divided by
resting length multiplied by 100.
Statistical Analysis
Statistical comparisons of hemodynamic
and angiographic data
between control subjects and patients with LV hypertrophy were
performed with an unpaired Student's t test, whereas a
paired Student's t test was used for comparisons of
angiographic data before and after nitroglycerin administration. The
analysis of the dose-response relation in the two groups was
carried out with a two-way ANOVA for repeated measurements. If the
analysis was significant, the Scheffé procedure was applied.
An exponential regression analysis between coronary circumferential
length at rest and its percent increase after nitroglycerin
administration was performed using the least-squares method.
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Results |
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Clinical Data
Patients' characteristics in studies A and B are summarized in Table 1
. In study A, 1 patient with aortic stenosis
was in New York Heart Association (NYHA) functional class I, 3 were in
class II, and 3 were in class III. In study B, 2 patients with valvular
heart disease were in NYHA functional class I, 8 were in class II, and
5 were in class III. Mean physical working capacity (in percent of the
age-, sex-, and height-corrected normal values17 ) was
95±19% in control subjects and 71±14% (P<.01) in
patients with LV hypertrophy. Seven of 44 patients (3 control subjects
and 4 patients with LV hypertrophy) were receiving long-acting
nitrates, and 6 were receiving angiotensin-converting enzyme inhibitors
before catheterization. Cardiovascular medication is summarized in
Table 1.
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Hemodynamic and Ventriculographic Data
In study A, mean
systolic pressure gradient was 57±9 mm Hg
(range, 44 to 68 mm Hg), and the opening area of the aortic valve was
0.7 cm2 (range, 0.5 to 0.9 cm2) in patients
with aortic stenosis. LV muscle mass index was 142±21 g/m2
in these patients and 82±11 g/m2 (P<.01) in
control subjects (upper limit of normal, 118
g/m210 ). Heart rate and mean aortic pressure
after each dose of intracoronary nitroglycerin in the two groups are
shown in Table 2.
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The hemodynamic data of study B are
summarized in Table 3. Mean systolic pressure gradient was
61±24 mm Hg in
patients with pure or predominant aortic stenosis and 28±21 mm Hg in
patients with predominant aortic regurgitation. Aortic regurgitant
fraction was 24±14% in patients with predominant aortic stenosis and
59±10% in those with predominant aortic regurgitation. Mitral
regurgitant fraction was 67±5% in patients with mitral regurgitation
and 21±15% in patients with aortic valve disease. LV muscle mass
index was 145±23 g/m2 in patients with LV hypertrophy and
85±12 g/m2 (P<.01) in control subjects.
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Dose-Response Relation of Intracoronary Nitroglycerin
Percent
increase in coronary artery size was significantly less at
each intracoronary nitroglycerin dose in patients with aortic stenosis
than in control subjects (Fig 2). In both groups, the
dose-response relation was curvilinear, leveling off after a dose of 30
µg. Mean increase in coronary circumferential length after 150 µg
intracoronary nitroglycerin was 21±4% in control subjects and
10±6%
(P<.001) in patients with aortic stenosis. After a dose of
90 µg nitroglycerin, 96% of the respective increase was reached in
both groups. The dose-response curve in patients with aortic stenosis
appeared to be shifted to the right compared with that of control
subjects. Because coronary flow has not been measured in the
present study but has been previously shown to increase
proportionately with LV mass, LV muscle mass has been used to correct
for dilution effects caused by increased flow in LV hypertrophy. After
normalization for LV muscle mass, the rightward shift of the
dose-response curve was no longer seen.
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L indicates increase in coronary circumferential
length (%; mean±1 SEM); C, control subjects (n=7); and AS,
aortic
stenosis (n=7). Rightward shift of the curve in the patients with AS is
no longer present after normalization for LMM.
Coronary Artery Size and Vasodilating Capacity
Circumferential length of the left anterior descending and
circumflex coronary arteries in the patients of study B is shown in Fig
3. At baseline, it was significantly higher in
patients with LV hypertrophy (12.2±2.2 mm) compared with control
subjects (8.6±1.5 mm; P<.001). After intracoronary
nitroglycerin administration, coronary circumference increased to
12.9±2.2 mm in patients with LV hypertrophy and to 10.3±1.5 mm
in
control subjects (P<.001 versus baseline in both groups).
Thus, the percent increase in coronary circumference was significantly
less in patients with LV hypertrophy (6±5%) than in control subjects
(21±8%; P<.001). Interestingly, coronary artery size
after nitroglycerin administration in control subjects was still lower
than the baseline values of patients with LV hypertrophy. An
exponential relation (r=-.71, P<.001)
between
coronary circumferential length at baseline and its percent change
after nitroglycerin was found in the study population as a whole (Fig
4).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The modulation of coronary vascular tone allows the heart to match for changes in metabolic demands by adjusting coronary blood flow. Many studies on chronic LV hypertrophy in experimental animals18 19 20 21 22 23 24 25 and in patients with aortic valve disease,26 27 28 29 30 31 hypertension,32 or hypertrophic cardiomyopathy33 have shown that coronary flow per unit mass is normal in the basal state. Parallel to the increase in flow, an increase in coronary artery size has been described in patients with valvular heart disease.5 6 7 The exact mechanism responsible for the growth of the vessels, however, is not known, although increased coronary blood flow has been postulated to be the major growth stimulus. Several other factors might be involved in the enlargement of the coronary arteries, such as perfusion pressure, the endothelium-derived relaxing factor,34 35 36 circulating neurohormones, and local growth factors.36 37 38
Vasodilator Capacity of Epicardial Coronary Arteries in LV
Hypertrophy
The major finding of the present study is that the
vasodilator
capacity of the large coronary arteries is reduced in patients with LV
hypertrophy. This concept has not yet been evaluated in humans. Recent
data39 40 41 from healthy subjects are
comparable to our
results showing an increase in coronary circumferential length of 21%
(increase in cross-sectional area, 40%) after administration of 100
µg intracoronary nitroglycerin. In patients with coronary artery
disease, Brown et al42 found an increase in the
cross-sectional area of 18% after administration of 0.4 mg
nitroglycerin SL in angiographically normal coronary artery
segments.
The present dose-response study showed a reduced dilation of
the
coronary arteries in response to intracoronary nitroglycerin in
patients with aortic stenosis (Fig 2). The dose-response curve
flattened off after 30 µg nitroglycerin in both the control subjects
and the patients with aortic stenosis, indicating that a dose of 100
µg is adequate to induce maximal vasodilation. However, a rightward
shift of the dose-response curve was found in patients with
aortic stenosis compared with control subjects. This finding suggests
either a reduced sensitivity of the smooth muscle to nitroglycerin or a
greater dilution of the injected nitroglycerin because of the increased
coronary blood flow in patients with aortic
stenosis.26 27 28 29
In the present study, arterial blood concentrations of
nitroglycerin were not determined since coronary flow measurements were
not carried out. However, previously data26 from our group
have demonstrated that coronary blood flow is proportional to LV muscle
mass in patients with aortic stenosis and, thus, LV muscle mass has
been used for normalization purposes (Fig 2). The rightward
shift of
the dose-response curve in the aortic stenosis group was abolished when
the nitroglycerin dose was divided by LV muscle mass. This observation
suggests a similar sensitivity of the coronary arteries to
nitroglycerin in control subjects and in patients with aortic stenosis,
although maximum vasodilator response was reduced in LV
hypertrophy.
Functional and Structural Factors Determining Epicardial Coronary
Vasodilating Capacity
Data from the present study do not allow
differentiation
between functional and structural factors responsible for the decrease
of coronary vasodilator capacity in patients with LV hypertrophy. From
a theoretical point of view, the following two mechanisms are
possible.
Functional Factors
In the absence of vascular
remodeling, each smooth muscle cell is
expected to elongate to the same extent in response to nitroglycerin
(Fig 5). In control subjects, nitroglycerin leads to
an increase in coronary circumferential length of 21% (1.7/8.8 mm),
whereas the increase is only 6% (0.7/12.2 mm) in patients with LV
hypertrophy. Because baseline length was different in the two groups,
an increase of 21% in control subjects is equal to an increase of 14%
(1.7/12.2 mm) in patients with LV hypertrophy. However, the observed
increase is clearly less than this predicted value. Thus, the reduced
coronary vasodilator capacity in LV hypertrophy cannot be explained by
functional factors alone but suggests the occurrence of vascular
remodeling.
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Because coronary flow is increased in LV hypertrophy,18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 flow-mediated vasodilation can be expected as a result of the enhanced release of the endothelium-derived relaxing factor.36 43 44 45 46 47 This release is mediated by the shear stress of the streaming blood48 as well as by local and circulating agonists, such as acetylcholine, bradykinin, and serotonin.43 Therefore, the increased blood flow in LV hypertrophy leads to a "predilation" of the large coronary artery and reduces its functional vasodilator capacity. Predilation of the coronary arteries tends to normalize coronary flow velocity and, thus, shear stress, resulting in a reduced release of the endothelium-derived relaxing factor.
In the present study, however, the
maximally dilated coronary
arteries in control subjects were not as large as the coronary arteries
in patients with LV hypertrophy under baseline conditions (Fig
3). This
suggests structural enlargement of the coronary arteries in patients
with LV hypertrophy and, thus, true vascular remodeling.
Structural Factors
In the presence of vascular
remodeling, a variable elongation of
the smooth muscle cells occurs in response to nitroglycerin (Fig
5). An
increase in coronary artery size in hypertrophic hearts has been
reported in necropsy studies more than 30 years
ago.49 50 51
Further evidence of vascular remodeling has been provided by
histological examination of intramyocardial coronary arteries in
patients with hypertension52 53 54 or
hypertrophic
cardiomyopathy.52 A parallel increase
in LV muscle mass and carotid artery wall thickness has been reported
in hypertensive patients.55 Langille and
O'Donnell4 observed a 21% decrease in vascular diameter
2 weeks after a 70% reduction in blood flow through the rabbit carotid
artery. This effect was believed to be due to vascular remodeling after
long-term changes in flow rather than to a sustained contraction of the
vascular smooth musculature, since papaverine did not attenuate this
response.
Several growth or angiogenic factors, such as platelet- and monocyte-derived growth factors, as well as fibroblast growth factors56 and transforming growth factor-ß136 37 38 possibly promote this vascular remodeling. Shear stress itself enhances the proliferation of coronary smooth muscle cells57 via the release of the platelet-derived growth factor.58 On the other hand, nitric oxide inhibits both mitogenesis and proliferation of vascular smooth muscle cells59 as well as the production of excessive matrix molecules. Angiotensin II is a bifunctional vascular smooth muscle cell growth modulator capable of inducing hypertrophy or inhibiting mitogen-stimulated DNA synthesis.37
Thus, a complex balance exists between proliferative and antiproliferative stimuli that modulate the growth response of vascular smooth muscle cells to LV hypertrophy. This interplay between functional and structural factors in the adaptation of the arterial wall to long-term hemodynamic changes appears to be important for the reduced coronary vasodilator capacity in patients with LV hypertrophy.
Study Limitations
Coronary blood flow was not measured in the
present study and,
thus, no conclusion on the effect of blood flow on coronary vasomotion
can be made. However, because an increased coronary flow can be assumed
in the presence of severe LV
hypertrophy,18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
arterial
blood concentration of nitroglycerin can be expected to be reduced in
these patients. Therefore, data from control subjects and patients with
LV hypertrophy are not really comparable with respect to arterial blood
concentration of nitroglycerin.
Control subjects and patients with LV hypertrophy were not perfectly matched with respect to medication before catheterization. Although all drugs were discontinued at least 24 hours before the intervention, some residual pharmacological effects cannot be completely ruled out, especially from ß-blockers or angiotensin-converting enzyme inhibitors. However, only 4 patients were receiving ß-blockers, and 6 were receiving angiotensin-converting enzyme inhibitors. Because 3 control subjects but only 1 patient with LV hypertrophy was receiving ß-blockers, a potential bias would have caused an underestimation of vasodilator capacity in control subjects but not in patients with LV hypertrophy and, thus, would not have affected our conclusions. Seven of the 44 patients were receiving long-acting nitrates. Although tachyphylaxis to nitrates is possible, it is unlikely to have significantly modified our results, since a drug-free interval of 24 hours was respected and the number of patients receiving nitrates was relatively small; furthermore, the two groups of patients were well balanced in this regard.
Control injections with saline have not been performed in the present study. However, repeated injections of nonionic contrast agents have shown only minor effects on coronary vasomotion with variations in vessel diameter of less than 5% of the control value.60
Because our analysis was not blinded, some observer-dependent bias cannot be ruled out, although the differences in coronary artery size between the two groups were quite large compared with changes observed after other pharmacological interventions.
Factors other than muscle
mass may also influence coronary artery size,
such as age, sex, body size, and physical working capacity. Variable
effects of age on the size of the left coronary artery have been
described.61 62 63 In the present study,
age was higher
in patients with LV hypertrophy than in control subjects, but no
correlation was found between age and coronary artery size at baseline
(r=.31; P=NS). Body size may also influence
coronary artery size. Because body surface area was similar in control
subjects and in patients with LV hypertrophy (see Table 1),
this factor
appears to have no influence on the results of the present
study.
Physical working capacity may also affect coronary artery size. In fact, a recent study41 reported an increased coronary vasodilator capacity in marathon runners. In study B, a difference in physical working capacity between control subjects (95±19% of the age-, sex-, and height-corrected normal value17 ) and patients with LV hypertrophy (71±14%; P<.05) has been observed; however, this difference can probably not account for the marked decrease in vasodilator capacity in the patients with LV hypertrophy since there was no correlation between these two factors (r=.28, P=NS).
In conclusion, vasodilator capacity of the large coronary arteries is reduced in patients with LV hypertrophy, probably due to a flow-mediated decrease in coronary tone and a structural remodeling of the vascular wall with long-term vessel enlargement.
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Acknowledgments |
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This study was supported by the Swiss National Science Foundation, Berne, Switzerland. We thank Hetty van Hoeven and the cardiac catheterization team for their excellent technical assistance.
Received October 5, 1994; revision received December 14, 1994; accepted December 27, 1994.
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