© 1998 American Heart Association, Inc.
Original Contributions |
Altered Myocardial Vasodilatation in Patients With Hypertriglyceridemia in Anatomically Normal Coronary Arteries
From the Second Department of Internal Medicine (I.Y., S.M., K.Y., N.K., T.A., S.S., M.O.) and the Department of Radiology (T.O., Y.S.), University of Tokyo, Japan.
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Abstract |
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Abstract—Reduced myocardial vasodilatation (MVD) in hypercholesterolemics without overt coronary stenosis has been reported. However, the status of MVD in hypertriglyceridemics has not yet been clarified. The aim of this study was to investigate whether MVD is impaired in patients with hypertriglyceridemia without overt coronary stenosis. Twenty-three hypertriglyceridemics (10 normocholesterolemic hypertriglyceridemics [HTGs] and 13 mixed combined hyperlipidemics [MCHLs]) and 13 age-matched controls were studied. All patients were proven to have more than one normal coronary artery, as diagnosed by coronary angiography, and those segments that were perfused by anatomically normal coronary arteries were used in the study. Myocardial blood flow (MBF) during dipyridamole (DP) loading and baseline MBF were measured by using positron emission tomography and [13N]ammonia, after which MVD was calculated. Baseline MBF (mL · min-1 · 100 g-1) was comparable among HTG (76.0±26.1), MCHL (77.0±26.1), and controls (80.3±38.5). However, MBF during DP loading was significantly lower in MCHL (159±52.5) than in control subjects (292±166, P<.01), while it was comparable in HTG (202±104) and controls. MVD was significantly reduced in both HTG (2.70±1.09, P<.05) and MCHL (2.07±.70, P<.01) compared with controls (3.73±1.14). MVD in MCHLs tended to be reduced compared with that in HTGs, but the difference was statistically insignificant (P=.08). There was a significant relationship between MVD and both plasma triglycerides (r=-.47, P<.01) and plasma total cholesterol (r=-.55, P<.01). When controls and HTGs were combined, the relationship between MVD and plasma total triglycerides became more prominent (r=-.55, P<.05), and the significant relationship between cholesterol level and MVD disappeared. Multivariate regression analysis has revealed that the triglyceride level (F=5.2, P<.05) was independently related to MVD (r=.69, P<.01). In conclusion, MVD was reduced in hypertriglyceridemics in anatomically normal coronary arteries. Hypertriglyceridemia is an independent factor for this abnormality.
Key Words: hyperlipidemia • hypertriglyceridemia • atherosclerosis • myocardial vasodilatation • PET
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Introduction |
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Reduced MVD has been thought to be a factor in coronary stenosis.1 It has been shown that MVD can be altered without evidence of ischemia in hypercholesterolemics2 3 4 and that there is a significant inverse relationship between MVD and plasma TG levels in hyperlipidemics without evidence of ischemia.3 5 In fact, alterations in MVD without overt coronary stenosis have been indicated in a variety of conditions; for example, hypertrophic cardiomyopathy,6 dilated cardiomyopathy,7 and diabetes with and without associated hypertension,8 9 10 and in normal segments in patients with myocardial infarction.11 We have reported a reduced MVD without overt coronary stenosis in patients with hypercholesterolemia.12 However, most recent studies, including our own, involved patients with pure hypercholesterolemia or mixed combined hyperlipidemia. The specific role of hypertriglyceridemia in MVD in angiographically normal coronary arteries remains uncertain.
The first aim of this study was to clarify whether MVD in hypertriglyceridemics is reduced in segments perfused by angiographically normal coronary arteries and the second was to compare MVD between HTG and MCHL subjects.
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Methods |
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Study Population
Twenty-three hypertriglyceridemic patients (18 males, 5 females) and 13 normolipidemic, normoglycemic asymptomatic control subjects without a history of heart disease or chronic disease (8 males, 5 females) were involved in this study. Two female patients (1 MCHL, 1 HTG) and 1 female control subject were premenopausal. Of the 23 hypertriglyceridemics, 10 were HTG, as defined by a total TG level >200 mg/dL and TC <220 mg/dL with a longer than 14-hour fast, and 13 were MCHL, as defined by a total TG level >200 mg/dL and TC >220 mg/dL under the same fasting condition. No subject had received lipid-lowering agents before the study. All of the hypertriglyceridemics had atypical chest pain, typical angina, or old myocardial infarction occurring more than 6 months before the PET and had undergone CAG, which confirmed one or two normal coronary arteries within the three major branches, as diagnosed by three independent specialists (zero percent stenosis). Details of CAG findings are shown in Table 1
. General characteristics of our study
subjects are summarized in Table 2. There
were no significant differences among the three groups in the
parameters that include sex, body weight, height, body mass
index, blood pressure, smoking, and HbA1c level; there was a
significant difference in age, however. All subjects were informed of
the nature of the study, after which they agreed to participate in the
protocol, which was approved by the local ethics committee.
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PET
Regional MBF (mL · min-1 ·
100 g-1) at rest and during DP loading was
measured using PET and[13N]ammonia. Myocardial
flow images were obtained using a Headtome IV PET scanner (Shimadzu
Corp). This PET scanner has seven imaging planes; in-plane resolution
is 4.5 mm at full width at half maximum and the z-axial
resolution is 9.5 mm at full width at half maximum. Effective
in-plane resolution was 7 mm after using a smoothing filter. The
sensitivity of the Headtome IV scanners is 14 and 24 kcps (µCi/mL)
for direct and cross planes, respectively.
After acquiring transmission data over 8 minutes to correct for photon attenuation before obtaining the PET emission images, 15 to 20 mCi of [13N]ammonia was injected, and dynamic PET scanning was performed for 2 minutes and static PET scanning for 8 minutes. Fifty-five minutes after the injection of [13N]ammonia (to allow for decay of the radioactivity of [13N]ammonia), DP (0.56 mg/kg) was administrated intravenously over 4 minutes. Five minutes after the end of DP infusion, 15 to 20 mCi of [13N]ammonia was injected and, at exactly the same time, a second dynamic PET scan was performed for 2 minutes and a static PET scan for 8 minutes. The dynamic PET scan was performed every 15 seconds (eight times) during the 2-minute period. Dynamic data were obtained for seven slices. Only one channel ECG monitoring in limb leads was made during the PET study. ECG monitoring was performed but was not satisfactory because the precordial ECG record could not be monitored due to technical difficulty; therefore, there was the possibility that ECG data would be unreliable.
Determination of MBF
Regional MBF was calculated according to the two-compartment
[13N]ammonia tracer kinetic
model.13 14 The time activity curve of the left
ventricular cavity was used as an input function. The
tracer spillover was corrected by least-squares nonlinear
regression analysis on our program to calculate MBF, with the
assumption that myocardial and left ventricular
radioactivity were influenced by each other. Details are provided in
our previously published studies.2 12
All data were corrected for dead-time effects to reduce error to <1%. To avoid the influence of the partial-volume effect associated with the object's size, recovery coefficients obtained from experimental phantom studies in our laboratory were used. The recovery coefficient was 0.8 when myocardial wall thickness was 10 mm. For the correction of partial-volume effect, wall thickness was measured with two-dimensional echocardiography by specialists in our hospital. The recovery coefficient was taken into consideration in our program to measure MBF.
As we reported previously,12 each transaxial image was divided into eight segments. Anteroseptal segments on the midventricular transaxial slice and the lower slice were defined as the left descending coronary artery region. Lateral segments on the middle slice and the lower slice were defined as the left circumflex coronary artery region. Inferoposterior segments on the middle slice and the lower slice were defined as the right coronary artery region. When there was not enough space to place regions of interest, those segments were excluded to obtain MBF. Only those segments that were perfused by anatomically normal coronary arteries (zero percent stenosis) were used in this study. Segments perfused by coronary arteries after percutaneous transluminal angioplasty were not included in this study, even if those coronary arteries were diagnosed as zero percent stenosis. To obtain input function, regions of interest were placed on the left ventricular cavity of each slice. Static [13N]ammonia images were also obtained from the PET study and analyzed visually by three independent specialists who had no other information on the patients. We then determined the MVD value as MVD=MBFDP/MBFR, where MBFDP is the MBF during DP loading and MBFR is the MBF at rest.
Statistical Analysis
The MBF at rest, MBF during DP loading, MVD, body weight,
systolic blood pressure, diastolic blood pressure,
height, body mass index, and lipid parameters in the three
groups were compared using analysis of variance. Individual
data were analyzed by the two-tailed Student's t
test. Simple linear regression analysis was done between MVD
and plasma lipid fractions, using the least-squares method. Then
multivariate regression analysis was undertaken
between MVD and factors considered using the least-squares method to
examine which factors were independently related to MVD. Factors
considered were TC, plasma TG level, HDL cholesterol, LDL
cholesterol, systolic blood pressure,
diastolic blood pressure, smoking habits, HbA1c, sex, and
age. Two-tailed Student's t test was done to determine
whether the regression coefficient was significantly different from
zero. Values are expressed as the mean±SD. A value of
P<.05 was considered significant.
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Results |
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Hemodynamic and ECG Responses to DP Infusion
There were no significant differences in systolic blood pressure at rest and during DP loading and rate pressure product among the three groups (Table 2
). During DP loading, typical chest pain
or chest oppression was observed in all of the patients with
hypertriglyceridemia. Due to difficulty in
recording ECG in the precordial leads on the PET study,
detailed description of ECG response to DP was not possible in this
study.
MBF at Rest and During DP Loading
Baseline MBF (mL · min-1 ·
100 g-1 weight heart) in HTGs (76.0±26.1) did
not differ from that in control subjects (80.3±38.5) and MCHLs
(77.0±9.30). MBF during DP loading in HTGs (202±104) was comparable
with that in control subjects (292±166, P=.153), but in
MCHLs (154±54.0) was significantly lower than that in control subjects
(P<.01).
MVD
When the hypertriglyceridemic subjects
were considered as one group, MVD (2.30±0.99, n=23) was significantly
lower than that in control subjects (3.73±1.14, P=.0048).
When these groups were considered separately, MVD in HTGs (2.69±1.09,
n=10) was significantly lower than that in control subjects
(P=.038), as was MVD in MCHLs (1.99±0.73, n=13;
P=.0038). In comparing the two
hypertriglyceridemic groups, MVD in MCHLs
tended to be lower than that in HTGs, but not to a statistically
significant degree (P=.08). There was no significant
difference in MVD between patients with myocardial infarction
(2.07±0.78) and those without (2.36±1.01). Because of the small
number of study patents, there were not sufficient data for comparisons
of sex variance.
Relationship Between Plasma Lipid Fractions
When the three groups were combined, there was a significant
relationship between MVD and both plasma total TG concentration
(r=-.47, P<.01; Fig 1, top) and
plasma TC concentration (r=-.55, P<.01; Fig 1, bottom). When only the control and HTG groups were considered together,
the relationship between MVD and plasma total TG became more prominent
(r=-.55, P<.05; Fig 2, top), whereas the relationship between
MVD and TC became insignificant (Fig 2, bottom). There was no
significant relationship between MVD and plasma HDL
cholesterol concentration.
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Multivariate regression analysis revealed that
only plasma TG concentration (F=5.2, P<.05) was
independently related to MVD (r=.69, P<.05)
among TC, LDL cholesterol, HDL cholesterol, TG,
systolic blood pressure, diastolic blood pressure,
HbA1c, smoking habits, and age (Table 3).
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Discussion |
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Reduced MVD in Hypertriglyceridemia
One of the aims of the present work was to determine whether MVD in subjects with hypertriglyceridemia would be reduced in segments perfused by coronary arteries that had been proved to be normal by angiography. Results of this study did indeed show such a reduction, and furthermore, multivariate regression analysis showed that plasma TG concentration was independently related to the reduced MVD in these arteries. There are several possible explanations for this result. The diffuse but angiographically undetectable balanced macrovascular atherosclerosis that has been detected by intravascular ultrasound15 can be a factor for the reduction in MVD revealed in our study. Microcirculation abnormalities may also play a role in the observed reduction, as has been proposed in diabetic patients.8 9 10 The impairment in blood flow–mediated vasodilatation indicating endothelial dysfunction, as was suggested in hypercholesterolemics,16 17 18 19 20 21 22 may also be a factor. Although the principal pharmacological action of DP is acknowledged to be endothelium independent, it has been proposed that endothelial function partially contributes to the vasodilating action of DP.23 Therefore, impaired endothelial function may be involved in the reduced MVD in hypertriglyceridemics. Although a risk of CAD has been cited in hypertriglyceridemics,24 25 26 27 it is not yet clear whether endothelial function is impaired in hypertriglyceridemics independent of hypercholesterolemia.
Comparison of Hypercholesterolemia and
Hypertriglyceridemia
Similar to our finding of reduced MVD in
hypercholesterolemics without overt coronary
stenosis,12 reduced MVD was seen in
hypertriglyceridemia in angiographically
normal coronary arteries. Although both
hypertriglyceridemia and
hypercholesterolemia appear to alter MVD, it is
not clear whether the mechanisms are the same. As to this issue,
several epidemiological investigations have shown that
hypertriglyceridemia can be a risk factor
for CAD24 25 26 27 28 ; furthermore, the concept of
insulin resistance has emerged as a common cause underlying several
risk factors for CAD.28 Since insulin resistance
is usually associated with
hypertriglyceridemia, the importance of
hypertriglyceridemia as a risk factor for
CAD has been cited, especially in relation to insulin
resistance.29 30 Recent experiments on
hypertriglyceridemic mice showed that
severe atherosclerosis was seen in transgenic mice with
a higher expression of the human apolipoprotein C-III gene compared
with that in a relatively lower expression
group.31 If one considers that reduced MVD in
angiographically normal coronary arteries is an early
manifestation of coronary atherosclerosis,
those reports imply that the mechanism of the reduction of MVD
associated with hypertriglyceridemia may be
different from that in
hypercholesterolemia.
Our results showed that MVD was significantly reduced in HTG, as well as in MCHL subjects. Furthermore, MVD in MCHL tended to be reduced compared with HTG subjects, with marginal significance. It is suggested that coexistence of hypercholesterolemia and hypertriglyceridemia would severely impair MVD. Of interest is that our result is similar to epidemiological data indicating that hypertriglyceridemia is an important risk factor in subjects with elevated cholesterol and results of recent animal experiments demonstrating more severe atherosclerosis in hypertriglyceridemic mice with lower expression of human apolipoprotein C-III gene that were fed a high-cholesterol diet as opposed to those who were not.32
Influence of Age and Sex Variance on MVD
Although a significantly reduced MVD in older normal subjects
compared with that in young normal subjects was
reported,33 there was no significant relationship
between age and MVD in our study. With the narrow range of age among
our subjects, it is natural that such an age-related variation would
not occur. Previously, sex-specific variance of MVD in familial
hypercholesterolemics2 and
diabetics10 was shown. Because we selected our
subjects purely on the parameters outlined previously
rather than on family history, we cannot be certain of the duration of
the hypertriglyceridemic state, although we
can speculate that the duration of that state may not have been
sufficient for sex variations to become apparent. Further investigation
should be done on this point in relation to familial
hypertriglyceridemia.
Measurement of MBF Using PET and [13N]Ammonia
We used the two-compartment [13N]ammonia
tracer kinetic model to determine MBF, using dynamic PET and
[13N]ammonia,13 14
because this model has been well validated and frequently used in the
assessment of MBF or MVD.2 5 10 12 33 34 35 36 37 38 39 40
Recently, Hutchins et al41 developed a
three-compartment model as another model to measure MBF, using PET and
[13N]ammonia. The main difference between the
two models is whether or not myocardial metabolism of
[13N]ammonia should be addressed. Because
myocardial metabolism of
[13N]ammonia can be negligible within the first
90 seconds after its administration, accuracy in measuring MBF is
assured.
Diagnosis of Coronary Arterial Stenosis
In this study, diagnosis of CAD or normal coronary
arteries was made by visual inspection by three independent
specialists, which is a conventionally acceptable practice. However,
this means may not allow the diagnosis of a minor degree of diffuse
coronary atherosclerosis with certainty, as has
been reported by Mintz et al.15 Application of
quantitative coronary artery
arteriography42 or intravascular ultrasound would
be more helpful to identify whether reduced MVD is due to a minor
degree of diffuse coronary atherosclerosis or
another cause. Quantitative methods usually present difficulties in
establishing good automated software to exclude uncertainties with this
type of analysis. Therefore, it would appear that intravascular
ultrasound should be the more useful means to address this question,
and further studies should address this point.
Cardiac Normality in Control Subjects
It is difficult to justify the performance of CAG on
asymptomatic normal subjects. For this reason, we assessed
cardiac normality on the basis of absence of risk factors for CAD
rather than on results of cardiac catheterization, as
discussed by Rozanski et al.43 Therefore, even if
CAG was not undertaken, we consider our control subjects to be
appropriate. Furthermore, given the high diagnostic
accuracy of static myocardial PET imaging for
CAD,44 it can be concluded that normal results of
PET imaging would indicate normal anatomy and function of
coronary arteries in asymptomatic subjects without
coronary risk factors or chronic disease.
Conclusion
MVD was decreased in patients with
hypertriglyceridemia without overt
coronary stenosis.
Hypertriglyceridemia was independently
related to this abnormality.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a research grant for cardiovascular disease (8A-5) from the Ministry of Health and Welfare, Japan. We thank Tamotsu Yada and Yoshio Kojima for their technical support in preparing [13N]ammonia.
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Footnotes |
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Reprint requests to Ikuo Yokoyama, MD, Second Department of Internal Medicine, University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113.
Received August 5, 1997; accepted October 25, 1997.
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