(Circulation. 1999;100:117-122.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Improvement of Impaired Myocardial Vasodilatation Due to Diffuse Coronary Atherosclerosis in Hypercholesterolemics After Lipid-Lowering Therapy
From the Departments of Cardiovascular Medicine (I.Y., S.M., K.Y., W.Y., N.K., T.A., S.S., K.O., Y.Y.), Metabolic Diseases (N.Y.), Radiology (T.O., Y.S.), and Gastroenterology (M.O.), University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
Correspondence and reprint requests to Ikuo Yokoyama, MD, Department of Cardiovascular Medicine, The Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655.
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Abstract |
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Background—Diminished myocardial vasodilatation (MVD) in hypercholesterolemics without overt coronary stenosis has been reported. However, whether the diminished MVD of angiographically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy is not known.
Methods and Results—A total of 27 hypercholesterolemics and 16 age-matched controls were studied. All patients had >1 normal coronary artery, and those segments that were perfused by anatomically normal coronary arteries were studied. Myocardial blood flow (MBF) was measured during dipyridamole loading and at baseline using positron emission tomography and 13N-ammonia, after which MVD was calculated before and after lipid-lowering therapy. Total cholesterol was significantly higher in hypercholesterolemics (263±33.8) than in controls (195±16.6), and it normalized after lipid-lowering therapy (197±19.9). Baseline MBF (ml · min-1 · 100 g-1) was comparable among hypercholesterolemics (both before and after therapy) and controls. MBF during dipyridamole loading was significantly lower in hypercholesterolemics before therapy (189±75.4) than in controls (299±162, P<0.01). However, MBF during dipyridamole loading significantly increased after therapy (226±84.7; P<0.01). MVD significantly improved after therapy in hypercholesterolemics (2.77±1.35 after treatment [P<0.05] versus 2.02±0.68 before treatment [P<0.01]), but it remained significantly higher in controls (3.69±1.13, P<0.01). There was a significant relationship between the percent change of total cholesterol and the percent change of MVD before and after lipid-lowering therapy (r=-0.61, P<0.05).
Conclusions—Diminished MVD of anatomically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy.
Key Words: cholesterol • hyperlipidemia • lipid-lowering therapy • blood flow reserve • tomography, emission-computed
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Introduction |
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Myocardial vasodilatation (MVD) occurring in response to hyperemic stress can decrease with the severity of coronary stenosis.1 However, recent investigations have shown that MVD can also be reduced in hyperlipidemics who do not have evidence of ischemia.2 3 4 5 6 Furthermore, reduced MVD in angiographically normal coronary arteries (ANCAs) was reported in hyperlipidemics.7 8 These results strongly suggest that decreased MVD can be an early manifestation of coronary atherosclerosis before progression to coronary artery disease (CAD). Lipid-lowering therapy has been associated with risk reduction in patients with CAD and hypercholesterolemia9 10 and with increases in the diameter of stenotic coronary arteries (proven by angiography).11 12 13 14 Recovery of altered MVD of stenotic coronary arteries has been reported in hypercholesterolemics after short- or long-term risk factor–modification therapy15 16 and in asymptomatic subjects at high risk for CAD after short-term adherence to a low-fat diet.17 However, the therapeutic effect of lipid-lowering drugs on MVD in hypercholesterolemics remains controversial. For instance, short-term lipid-lowering therapy using pravastatin influenced the recovery of endothelial function (EDF) but not that of MVD.18 Because impaired EDF and diffuse macrovascular atherosclerosis can be factors in the reduced MVD of ANCA in hypercholesterolemics, relatively long-term lipid-lowering therapy may produce a different effect on abnormal MVD than short-term therapy. Whether the altered MVD of ANCAs can be reversed after relatively long-term lipid-lowering therapy remains uncertain.
This study aimed to clarify whether the altered MVD in hyperlipidemics can be reversed by relatively long-term lipid-lowering therapy.
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Materials and Methods |
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Study Population
A total of 27 hypercholesterolemics (17 men, 10 women) and 16 control subjects (12 men, 4 women) were studied. Among the patients, 12 had hypercholesterolemia (fasting plasma total cholesterol [TC] >220 mg/dL) and 15 had mixed combined hypercholesterolemia (fasting total triglycerides over 14 hours >153 mg/dL and TC >220 mg/dL). Of these 27 patients, 10 had familial hypercholesterolemia (FH) and 17 did not. FH was diagnosed on the basis of an Achilles tendon thickness of
10
mm or a history of hypercholesterolemia in a
first-degree relative.19 All patients had >1 normal
coronary artery within the 3 major branches (diagnosed by 3
independent specialists; 0% stenosis). Of the 27 patients, 16
had CAD and 11 did not. Twenty patients had no diseased vessels:
2 were asymptomatic, 9 had atypical chest pain syndrome
without CAD, 5 had undergone percutaneous transluminal
angioplasty, and 4 had undergone coronary artery bypass
grafting. Of the remaining 7 patients, 3 had single vessel
disease and 4 had well-controlled 2-vessel disease. Table 1
summarizes the results of
coronary arteriography. A total of 25 patients were treated
with medication and a low-cholesterol diet, and 2 were
treated by diet therapy alone. Sixteen patients had well-controlled
hypertension; 3 of these patients also had diabetes. There were also 2
diabetics among the normotensive subjects. Medications were not changed
during the follow-up period. Medication details and relevant
information for each patient are shown in Table 2. Thirteen normolipidemic,
normoglycemic, asymptomatic subjects without a history of
heart disease or long-term disease were selected as controls.
Characteristics of study subjects are summarized in Table 3. There were no significant differences
in age, sex, body weight, height, body mass index, blood pressure,
amount of smoking, or hemoglobin A1c levels between the 2 groups. All
study subjects were informed of the nature of the study and agreed to
participate in the protocol, which was approved by the local Ethics
Committee.
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Positron Emission Tomography
Regional myocardial blood flow (MBF, ml ·
min-1 · 100 g-1)
at rest and during dipyridamole loading was measured
using positron emission tomography (PET) and
13N-ammonia before and 8 to 15 months after the
initiation of lipid-lowering therapy (mean duration of follow-up,
11.9±2.3 months). All patients underwent PET before therapy and were
followed prospectively for more than 8 months except 1. In that 1 case,
the first PET scan was done after the initiation of medication that was
ineffective, and the second PET scan was performed 6 months after the
addition of twice-monthly plasma LDL apheresis to the treatment. Plasma
lipid fractions were measured 2 or 3 times monthly. When TC decreased
to <220 mg/dL or was reduced more than 20% from the baseline and the
decrease was maintained for more than 1 month, a second PET scan was
performed. If TC did not reach the target value 3 months after the
initiation of diet therapy, anticholesterol agents
(pravastatin, simvastatin, or bezafibrate) were
added. If TC did not meet the above criteria 3 to 6 months after the
initiation of the first medication, additional medications, such as
ethyl icosapentate, probucol, or Daisaikotou (scientifically
well-established traditional Chinese medicine for
hypercholesterolemia), or ethyl icosapentate in
combination with either probucol or Daisaikotou, were tried. In 1 case,
bezafibrate was replaced by simvastatin 3 months after the
initiation of therapy. When the effectiveness of therapy was confirmed
and TC remained constant, a second PET scan was performed 6 months
after the administration of the second medication. During this study
period, antianginal regimens were not changed.
Myocardial flow images were obtained using a Headtome IV scanner (Shimadzu Corp) with 7 imaging planes; the in-plane resolution was 4.5 mm at full width at half-maximum, and the z-axial resolution was 9.5 mm at full width at half-maximum. The effective in-plane resolution was 7 mm after using a smoothing filter. Sensitivities were 14 and 24 µCi/ml for direct and cross planes, respectively. Twenty-four hours before the PET study, all medications and caffeine intake were discontinued. No smoking was allowed the day of the PET scans.
We acquired transmission data over a period of 8 minutes to correct for photon attenuation before obtaining PET images; after that, 15 to 20 mCi of 13N-ammonia was injected. Dynamic PET scanning was performed for 2 minutes and static PET scanning for 8 minutes. A total of 55 minutes after the injection of 13N-ammonia (time chosen to allow for the decay of the radioactivity of 13N-ammonia), dipyridamole (0.56 mg/kg) was administrated intravenously over a 4-minute period. Five minutes after the end of dipyridamole 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 (8 times) during the 2-minute period. Dynamic data were obtained for 7 slices. Only 1-channel ECG monitoring in limb leads was done during the PET scans.
Determination of MBF
Regional MBF was calculated according to the 2-compartment
13N-ammonia tracer kinetic
model.20 21 Only segments that were perfused by
ANCAs were used; segments perfused by coronary artery bypass
grafts were excluded because diminished MVD in such segments has been
reported.22 Segments pefused by coronary arteries after
percutaneous transluminal angioplasty were also excluded. The time
activity curve of the left ventricular cavity was used as
an input function. Tracer spillover was corrected by least-square
nonlinear regression analysis to calculate MBF with the
assumption that both myocardial and left ventricular
radioactivity were influenced by each other. Details are provided in
our previous publications.2 7
All data were corrected for dead-time effects to reduce error to less than 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. To correct the partial volume effect, wall thickness was measured with 2D echocardiography by specialists in our hospital. The recovery coefficient was taken into consideration when measuring MBF.
As we reported previously, regions of interest were placed at
the septum, anterior wall, lateral wall, and inferoposterior wall on
transaxial images. To obtain input function, these regions were placed
on the left ventricular cavity of each slice. We then
determined the MVD as follows:
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Statistical Analysis
Baseline MBF, MBF during dipyridamole
administration, MVD, body weight, systolic blood pressure
(SBP), diastolic blood pressure (DBP), height, body mass
index, and lipid parameters in the 2 groups were compared
using ANOVA. Individual data were analyzed by the 2-tailed
Student's t test. Values are expressed as mean±SD.
P<0.05 was considered significant.
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Results |
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Hemodynamic and ECG Responses to Dipyridamole Infusion
SBP at rest and during dipyridamole loading and the rate-pressure product (RPP) did not differ significantly between controls and hypercholesterolemics before therapy (Table 3
). However, baseline SBP in
hypercholesterolemics was significantly reduced after
therapy (P<0.01), as were baseline DBP (P<0.01)
and baseline RPP (P<0.05) (Table 3). SBP during
dipyridamole administration after therapy was
significantly reduced compared with levels before therapy
(P<0.05), as was DBP during dipyridamole
administration (P<0.01, Table 3). However, RPP
during dipyridamole administration was comparable
between the 2 groups (Table 3). During
dipyridamole loading, typical chest pain or chest
oppression was observed in all hyperlipidemic subjects
before therapy. After therapy, chest pain disappeared in 7 patients.
Because of difficulties in recording ECG in the precordial
leads in the PET study, a detailed description of ECG response to
dipyridamole was not possible.
Plasma Lipid Fractions Before and After Lipid-Lowering
Therapy
The mean TC in hypercholesterolemics was
significantly reduced after lipid-lowering therapy to levels comparable
to those in controls; plasma LDL cholesterol levels were
also significantly reduced (P<0.01). Total plasma
triglyceride levels were significantly reduced to the
levels of controls, but plasma HDL cholesterol levels in
hypercholesterolemics did not change after therapy.
Myocardial Blood Flow at Rest and During Dipyridamole
Loading
Baseline MBF (ml · min-1 ·
100 g-1) in hyperlipidemics did
not differ before and after therapy (88.8±14.9 versus 83.1±11.6), nor
did it differ from that in controls (79.9±33.6). MBF during
dipyridamole loading in
hypercholesterolemics significantly increased after
therapy (226±84.7 versus 189±75.4; P<0.01), but it was
statistically comparable with that in controls (299±162;
P=0.09).
Myocardial Vasodilatation
MVD in hypercholesterolemics before therapy
(202±0.68) was significantly lower than in controls (3.69±1.13;
P<0.001). It increased significantly after therapy
(2.77±1.33), although it still remained significantly lower than in
controls (P<0.05). When data on hypertensive patients were
excluded, MVD in hypercholesterolemics improved
significantly after therapy (3.27±1.69 after therapy versus
2.25±0.777 before therapy; P<0.01) to a level
comparable to that in controls. Furthermore, when data on the 5
diabetics were excluded, improvement of MVD after lipid-lowering
therapy was also more apparent (2.14±0.67 before treatment versus
3.22±1.78 after treatment). The percent change of MVD in
patients treated with pravastatin (n=10, 52.0±34.2%) was
comparable to that of those treated with simvastatin
(n=13, 39.0±54.4%). The percent change of MVD in patients with
(n=16, 44.3±48.8%) and without CAD (n=11, 36.9±51.1%) was
comparable.
There was a significant relationship between percent change of TC and
percent change of MVD before and after lipid-lowering therapy
(r=-0.61, P<0.01; Figure 1). This relationship was observed in
both patients with (r=-0.69, P<0.01; Figure 2) and without FH (r=-0.56,
P<0.05; Figure 3). The
Spearman rank correlation coefficient test showed a significant
relationship between percent change of MVD and percent change of TC
(r=-0.625, P<0.01), as did the Kendall rank
correlation coefficient test (
=-0.447, P<0.01).
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Discussion |
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MVD in Hypercholesterolemics
Our results showed that impaired MVD in ANCAs can be reversed after long-term lipid-lowering therapy in hyperlipidemics. Because both impaired EDF in hypercholesterolemics23 24 25 and an indirect effect of dipyridamole on endothelium-dependent vasodilatation26 have been reported, the improvement of EDF by lipid-lowering therapy may be a factor in MVD improvement. However, because short-term (6 months) lipid-lowering therapy using pravastatin improved only EDF but not MVD,18 the improvement in MVD found in our study cannot be solely attributed to improved EDF. Recently it was reported that angiographically undetectable, diffuse, balanced, macrovascular coronary atherosclerosis played a large role in reduced MVD in hypercholesterolemics.27 In addition, because MVD is altered by several complex factors (including endothelial-dependent and independent vasodilatory function, diffuse atherosclerosis due to arterial wall fibrosis, and/or atheromatous plaque and abnormal smooth muscle cell proliferation), the presence and degree of severity of any of these factors might delay the recovery of MVD after lipid-lowering therapy. Furthermore, in the study by Egashira et al,18 pravastatin was used and the effect of simvastatin on MVD remained undetermined. In another study, however, MVD also improved after simvastatin therapy.28
Hemodynamic Effects and MVD Improvement
Our results showed that MVD improvement was associated with
hemodynamic changes, such as DBP, SBP, and decreased
RPP, after lipid-lowering therapy. Baseline MBF tended to be reduced
after therapy. These results suggest that lipid-lowering therapy can
alter coronary vascular tone and systemic vascular tone.
Slightly reduced baseline MBF can be a factor in the improvement of
MVD. Our results were consistent with those reported by Gould
et al.15 16
Influence of Hypertension and Diabetes
MVD after lipid-lowering therapy in
hypercholesterolemics did not reach the level of that
in controls. The study group included 16 patients with hypertension and
5 with diabetes. It has been reported that essential hypertension or
diabetes can alter MVD29 30 31 32 33 34 35 ; they may also influence the
effect of therapy on MVD. In fact, when such hypertensive patients or
diabetics were excluded, MVD after therapy was comparable with that in
controls. Therefore, inclusion of those with hypertension or diabetes
may account for the observed variation in reactivity to the therapy or
the lack of normalization of MVD. Thus, when such patients were
excluded, results indicated that the reduced MVD in ANCAs of patients
with only hypercholesterolemia can be
normalized by lipid-lowering therapy.
Clinical Implications
Previously we reported impaired MVD in ANCAs in
hypercholesterolemics, suggesting that such ANCAs are
not normal in
hypercholesterolemics.7 Therefore,
we assessed these arteries by PET perfusion imaging and studied the
effects of lipid-lowering therapy on such arteries. Our findings
suggested that lipid-lowering therapy could successfully reverse
impaired MVD in hyperlipidemics. Moreover, a
significant relationship was observed between the percent of change in
MVD and the percent of change in TC in both patients with and without
FH. These results indicate that even in patients with ANCAs and
hypercholesterolemia, there is the potential
for abnormalities, such as diffuse coronary
atherosclerosis, abnormal EDF, or both. However,
nonuniform response to the therapy was noted, perhaps because the
patient population was nonuniform. First, including patients both with
and without CAD would alter MBF response to
dipyridamole. Second, including patients who do or do
not have FH might account for a nonuniform responsive to lipid-lowering
therapy. Also, patients with FH have a more severe, longer-lasting
hypercholesterolemic state than patients without FH,
which might alter their response to therapy. Furthermore, the
coexistence of coronary risk factors other than
hypercholesterolemia should be considered
because they might alter therapeutic results.
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Conclusions |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Impaired MVD in ANCAs in hypercholesterolemics can be reversed by lipid-lowering therapy. Our results also indicate that in hypercholesterolemics, ANCAs are not normal but have diffuse atherosclerosis.
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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 in Japan.
Received August 7, 1998; revision received April 12, 1999; accepted April 22, 1999.
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References |
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Laine H, Raitakari OT, Niinikoski H, Pitkanen OP,
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coronary flow reserve in young men with borderline
hypertension. J Am Coll Cardiol. 1998;32:147–153.Using 13N-ammonia positron emission
tomography, we investigated whether the reduced myocardial
vasodilatation (MVD) of anatomically normal coronary arteries
in hypercholesterolemics can be reversed by
lipid-lowering therapy. MVD in segments perfused by normal
coronary arteries was significantly decreased in
hypercholesterolemics, both before and after therapy,
when compared with controls, although there was no significant
difference in baseline myocardial blood flow between the 2 groups. The
reduced MVD of anatomically normal coronary arteries in
hypercholesterolemics was significantly reversed after
lipid-lowering therapy, indicating the value of lipid-lowering therapy
in such patients.
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