Clinical Investigation and Reports
Improvement of Impaired Myocardial Vasodilatation Due toDiffuse Coronary Atherosclerosis in Hypercholesterolemics
After Lipid-Lowering Therapy
Ikuo Yokoyama, MD; Shin-ichi Momomura, MD; Tohru Ohtake, MD; Katsunori Yonekura, MD;
Weidong Yang, MD; Naoshi Kobayakawa, MD; Teruhiko Aoyagi, MD; Seiryo Sugiura, MD;
Nobuhiro Yamada, MD; Kuni Ohtomo, MD; Yasuhito Sasaki, MD;
Masao Omata, MD; Yoshio Yazaki, MD
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 patientshad .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 (263633.8) than in controls(195616.6), and it normalized after lipid-lowering therapy (197619.9). Baseline MBF (ml z min21 z 100 g21) was
comparable among hypercholesterolemics (both before and after therapy) and controls. MBF during dipyridamoleloading was significantly lower in hypercholesterolemics before therapy (189675.4) than in controls (2996162,
P,0.01). However, MBF during dipyridamole loading significantly increased after therapy (226684.7; P,0.01).
MVD significantly improved after therapy in hypercholesterolemics (2.7761.35 after treatment [P,0.05] versus
2.0260.68 before treatment [P,0.01]), but it remained significantly higher in controls (3.6961.13, 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 (r520.61, P,0.05).
Conclusions—Diminished MVD of anatomically normal coronary arteries in hypercholesterolemics can be reversed after
lipid-lowering therapy. (Circulation. 1999;100:117-122.)
Key Words: cholesterol n hyperlipidemia n lipid-lowering therapy n blood flow reserve n tomography,
emission-computedM

yocardial 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 haveevidence of ischemia.2– 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). Lipidlowering therapy has been associated with risk reduction inpatients with CAD and hypercholesterolemia9,10 and withincreases in the diameter of stenotic coronary arteries(proven by angiography).11–14 Recovery of altered MVD ofstenotic coronary arteries has been reported in hypercho-

lesterolemics after short- or long-term risk factor–modification therapy15,16 and in asymptomatic subjects at highrisk 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.

Received August 7, 1998; revision received April 12, 1999; accepted April 22, 1999.
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.
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

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TABLE 1.

July 13, 1999

CAG Findings in Study PatientsCAG Findings
No diseased vessels
No diseased vessels after PTCA

No. of Study Patients(n527)
11
5

PTCA to LAD

4PTCA to LCX

1PTCA to RCA

0

No diseased vessels after CABG

4CABG to LAD and LCX

2

CABG to LAD

1

CABG to LCX and RCA

11-vessel disease

3

LAD

0

LCX

0

RCA

3

2-vessel disease

4

LAD1LCX

1

LAD1RCA0

LCX1RCA

3

PTCA indicates percutaneous transluminal coronary angioplasty; CABG,
coronary artery bypass grafting; CAG, coronary cineangiography; LAD, left
descending coronary artery; LCX, left circumflex coronary artery; and RCA, rightcoronary artery.

This study aimed to clarify whether the altered MVD in
hyperlipidemics can be reversed by relatively long-term
lipid-lowering therapy.

Materials and Methods
Study Population
A total of 27 hypercholesterolemics (17 men, 10 women) and 16
control subjects (12 men, 4 women) were studied. Among thepatients, 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 ofan 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 patientare shown in Table 2. Thirteen normolipidemic, normoglycemic,
asymptomatic subjects without a history of heart disease or longterm 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, bloodpressure, 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.

Positron Emission Tomography
Regional myocardial blood flow (MBF, ml z min21 z 100 g21) at restand during dipyridamole loading was measured using positronemission tomography (PET) and 13N-ammonia before and 8 to 15
months after the initiation of lipid-lowering therapy (mean durationof follow-up, 11.962.3 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, orDaisaikotou (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 theadministration 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 mCi/ml for direct and cross planes,
respectively. Twenty-four hours before the PET study, all medications and caffeine intake were discontinued. No smoking wasallowed the day of the PET scans.
We acquired transmission data over a period of 8 minutes tocorrect 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 13Nammonia), 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
13
N-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 suchsegments 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 bothmyocardial and left ventricular radioactivity were influenced by eachother. Details are provided in our previous publications.2,7All data were corrected for dead-time effects to reduce error to lessthan 1%. To avoid the influence of the partial volume effectassociated with the object’s size, recovery coefficients obtained fromexperimental phantom studies in our laboratory were used. The

Yokoyama et al
TABLE 2.

Improvement of Vasodilatation in Hypercholesterolemics

119

Lipid-Lowering Therapy

Case No.

Sex

Age

DiseaseTreatment for Hyperlipidemia

1

M

58

FH2

SVT (10 mg)1PRB (250 mg)1EPA (1200 mg)

2

M

60

FH2

PVT (20 mg)1EPA (1200 mg)

3

M

61

FH

BZR (400 mg)3PVT (10 mg)1PRB (250 mg)

4

F

62

FH2

Diet

5

F

51

FH2

SVT (10 mg)1EPA (1200 mg)

6

M

49

FH

SVT (10 mg)1EPA (1200 mg)1DSK (9 g)

7

M

75

FH2

SVT (10 mg)1EPA (1200 mg)1DSK (9 g)

8

M

51

FH2

PVT (10 mg)

9

F

64

FH

SVT (10 mg)1EPA (1200 mg)

10

M

50

FH2

SVT (10 mg)1EPA (1200 mg)

11

F

62

FH

SVT (10 mg)

12

F

58

FH

SVT (10 mg)

13

F

61

FH2

SVT (10 mg)1DSK (9 g)

14

M

67

FH

SVT (10 mg)1EPA (1200 mg)

15

F

61

FH2

BZR (400 mg)

16

M

51

FH2

SVT (10 mg)1EPA (1200 mg)

17

F

56

FH2

SVT (5 mg)

18

M

48

FH

PVT (5 mg)

19

M

67

FH2

PVT (10 mg)

20

M

76

FH

PVT (20 mg)1LDL aferesis

21

M

66

FH2

SVT (10 mg)

22

M

49

FH2

PVT (20 mg)

23

M

63

FH

PVT (10 mg)

24

M

47

FH2

Diet

25

M

55

FH2

PVT (10 mg)

26

F

66

FH

PVT (10 mg)

27

F

60

FH2

PVT (10 mg)

FH2 indicates non-familial hypercholesterolemia; EPA, ethyl icosapentate (fish oil); SVT, simvastatin; PVT, pravastatin; PRB; probucol, BZR, bezafibrate; and DSK, Daisaikotou.

recovery coefficient was 0.8 when myocardial wall thickness was
10 mm. To correct the partial volume effect, wall thickness wasmeasured 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 ontransaxial images. To obtain input function, these regions wereplaced on the left ventricular cavity of each slice. We then determined the MVD as follows:
MVD5MBF during dipyridamole administration/baseline MBF

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 mean6SD. P,0.05
was considered significant.

Results
Hemodynamic and ECG Responses to
Dipyridamole Infusion
SBP at rest and during dipyridamole loading and the ratepressure 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 dipyridamoleloading, typical chest pain or chest oppression was observed inall 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 tothose in controls; plasma LDL cholesterol levels were alsosignificantly reduced (P,0.01). Total plasma triglyceride
levels were significantly reduced to the levels of controls, but

120

Circulation

TABLE 3.

July 13, 1999

General Characteristics of Study Subjects
Hypercholesterolemics

Control

BeforeTherapy

After
Therapyn (M/F)

16 (12/4)

27 (17/10)

NAAge, y54.569.62

56.866.43

NABW, kg64.667.95

62.0610.5

NA
NA

Height, cm

16467.36

16166.87

BMI, kg/m2

24.762.00

24.563.01

NA

SBP at rest, mm Hg

12669.20

142623.0126611.9†

DBP at rest, mm Hg

76.267.00

82.2616.1

73.869.09†

HR at rest, bpm

68.3612.2

65.069.12

57.868.17*

RPP at rest

860661512

940462312

725761300*

HBA1c, %5.3860.27

5.7861.05

NA

Smoking, no. ofcigarettes/day

12.2616.9

11.0610.5

NATC

192617.2

263633.8

197619.9†

LDL

122618.4

173634.8

123623.0†

HDL

48.9613.5

57.8635.9

56.5615.9†

TG119638.0

162670.7118651.0†

SBP with DP, mm Hg

122616.5

131616.8

125611.4*

DBP with DP, mm Hg

75.666.5

79.2610.3

67.867.41*

HR with DP

82.5619.0

76.5613.6

76.3614.3

RPP with DP

10 06861667

991462870

916962043

BW indicates body weight; BMI, body mass index; SBP, systolic bloodpressure; DPB, diastolic blood pressure; HR, heart rate; RPP, rate pressure
products; HBA1c, hemoglobin A1c; TG, triglycerides; DP, dipyridamole; and NA,
not applicable.
*P,0.05 vs values before therapy; †P,0.01 vs values after therapy.

Figure 1. Significant relationship between % change of plasma
TC and % change of MVD (r520.61; P,0.01).

change of MVD in patients treated with pravastatin (n510,
52.0634.2%) was comparable to that of those treated withsimvastatin (n513, 39.0654.4%). The percent change of
MVD in patients with (n516, 44.3648.8%) and without
CAD (n511, 36.9651.1%) was comparable.
There was a significant relationship between percent
change of TC and percent change of MVD before and after
lipid-lowering therapy (r520.61, P,0.01; Figure 1). This
relationship was observed in both patients with (r520.69,
P,0.01; Figure 2) and without FH (r520.56, 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 (r520.625, P,0.01), as did
the Kendall rank correlation coefficient test (t520.447,
P,0.01).

Discussion
MVD in Hypercholesterolemics

plasma HDL cholesterol levels in hypercholesterolemics did
not change after therapy.

Myocardial Blood Flow at Rest and During
Dipyridamole Loading

Baseline MBF (ml z min21 z 100 g21) in hyperlipidemics did
not differ before and after therapy (88.8614.9 versus
83.1611.6), nor did it differ from that in controls(79.9633.6). MBF during dipyridamole loading in hypercholesterolemics significantly increased after therapy (226684.7
versus 189675.4; P,0.01), but it was statistically comparable with that in controls (2996162; P50.09).

Our results showed that impaired MVD in ANCAs can bereversed after long-term lipid-lowering therapy in hyperlipidemics. Because both impaired EDF in hypercholesterolemics23–25 and an indirect effect of dipyridamole on endothelium-dependent vasodilatation26 have been reported, theimprovement of EDF by lipid-lowering therapy may be afactor 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

Myocardial Vasodilatation
MVD in hypercholesterolemics before therapy (20260.68)
was significantly lower than in controls (3.6961.13;
P,0.001). It increased significantly after therapy(2.7761.33), 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 (3.2761.69 after therapy
versus 2.2560.777 before therapy; P,0.01) to a level comparable to that in controls. Furthermore, when data on the 5diabetics were excluded, improvement of MVD after lipidlowering therapy was also more apparent (2.1460.67 before
treatment versus 3.2261.78 after treatment). The percent

Figure 2. Significant relationship between % change of TC and% change of MVD in patients with FH (r520.69; P,0.05).

Yokoyama et al

Improvement of Vasodilatation in Hypercholesterolemics

Figure 3. Significant relationship between % change of TC and% change of MVD in patients without FH (r520.56, P,0.05).

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 toarterial wall fibrosis, and/or atheromatous plaque and abnormal smooth muscle cell proliferation), the presence anddegree of severity of any of these factors might delay therecovery of MVD after lipid-lowering therapy. Furthermore,in the study by Egashira et al,18 pravastatin was used and theeffect 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 associatedwith 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 andsystemic vascular tone. Slightly reduced baseline MBF can bea factor in the improvement of MVD. Our results wereconsistent 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 canalter MVD29 –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 withthat in controls. Therefore, inclusion of those with hypertension or diabetes may account for the observed variation inreactivity to the therapy or the lack of normalization of MVD.
Thus, when such patients were excluded, results indicatedthat 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 thesearteries by PET perfusion imaging and studied the effects oflipid-lowering therapy on such arteries. Our findings sug-

121

gested 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 withand without FH. These results indicate that even in patientswith 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 andwithout 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, longerlasting hypercholesterolemic state than patients without FH,
which might alter their response to therapy. Furthermore, thecoexistence of coronary risk factors other than hypercholesterolemia should be considered because they might alter
therapeutic results.

Conclusions
Impaired MVD in ANCAs in hypercholesterolemics can bereversed by lipid-lowering therapy. Our results also indicatethat in hypercholesterolemics, ANCAs are not normal but
have diffuse atherosclerosis.

Acknowledgement
This work was supported by a Research Grant for Cardiovascular
Disease (8A-5) from the Ministry of Health and Welfare in Japan.

References
1. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow
reserve and resistance. Am J Cardiol. 1974;34:48 –54.
2. Yokoyama I, Ohtake T, Murakami T, Momomura S, Nishikawa J, Sasaki
Y, Omata M. Reduced coronary flow reserve in familial hypercholesterolemia. J Nucl Med. 1996;37:1937–1942.
3. Dayanikli F, Grambow D, Muzil O, Mosca L, Rubenfire M, Schwaiger
M. Early detection of abnormal coronary flow reserve in asymptomaticmen at high risk for coronary artery disease using positron emission
tomography. Circulation. 1994;90:808 – 817.
4. Pitkanen OP, Raitakari OT, Ninikoshi H, Nuutila P, Iida H, Voipio-Pulkki
LM, Haerkoenen R, Wegelius U, Roennemaa T, Viikari J, Kunuuti J.
Coronary flow reserve is impaired in young men with familial hypercholesterolemia. J Am Coll Cardiol. 1996;28:1705–1711.
5. Raitakari OT, Pitkanen OP, Lehtimaki T, Lahdenpera S, Iida H, YlaHerttuala S, Luoma J, Mattila K, Nikkari T, Taskinen MR, Viikari JS,
Knuuti J. In vivo low density lipoprotein oxidation relates to coronary
reactivity in young men. J Am Coll Cardiol. 1997;30:97–102.
6. Yokoyama I, Ohtake T, Momomura S, Yonekura K, Nishikawa J, Sasaki
Y, Omata M. Impaired myocardial vasodilation during hyperemic stresswith dipyridamole in hypertriglyceridemia. J Am Coll Cardiol. 1998;31:
1568 –1574.
7. Yokoyama I, Ohtake T, Momomura S, Nishikawa J, Sasaki Y, Omata M.
Reduced coronary flow reserve in hypercholesterolemic patients without
overt coronary stenosis. Circulation. 1996;94:3232–3238.
8. Yokoyama I, Ohtake T, Momomura S, Yonekura K, Kobayakawa N,
Aoyagi T, Sugiura S, Nishikawa J, Sasaki Y, Omata M. Altered myocardial vasodilatation in patients with hypertriglyceridemia in anatomically normal coronary arteries. Arterioscler Thromb Vasc Biol. 1998;18:
294 –299.
9. Scandinavian Simvastatin Survival Study Group. Randomised trial ofcholesterol lowering in 4444 patients with coronary heart disease. Lancet.
1993;344:1383–1389.
10. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW,
Mckillop JH, Packard CJ. Prevention of coronary artery disease withpravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:
1301–1307.

122

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July 13, 1999

11. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP,
Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin
therapy on coronary atherosclerosis and coronary venous bypass grafts.
JAMA. 1987;257:3233–3240.
12. Ornish DM, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports
TA, McLanhan SM, Krirkeeide RL, Brand RJ, Gould KL. Can lifestylechanges reverse atherosclerosis? Lancet. 1990;336:129 –133.
13. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ.
Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA. 1990;264:3007–3012.
14. Gould KL, Ornish D, Kirkeeide R, Brown S, Stuart Y, Buchi M, Billings
JH, Armstrong W, Ports T, Scherwitz L. Improved stenosis geometry by
quantitative coronary arteriography after vigorous risk factor modification. Am J Cardiol. 1992;69:845– 853.
15. Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP, Latifi R,
Dudick SJ. Short-term cholesterol lowering decreases size and severity of
perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease: a potential noninvasive
marker of healing coronary endothelium. Circulation. 1994;89:1530 –1538.
16. Gould KL, Ornish D, Scherwitz L, Shirley B, Patterson E, Hess MJ,
Mullani N, Bolomey L, Dobbs F, Armstrong WT, Merritt T, Ports T,
Sparler S, Billings J. Changes in myocardial perfusion abnormalities by
positron emission tomography after long term, intense risk factor modification. JAMA. 1995;274:894 –901.
17. Czernin J, Barnard RJ, Sun KT, Krivokapitch J, Nitzsche E, Dorsey D,
Phelps ME, Schelbert HR. Effect of short term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve.
Circulation. 1995;92:197–204.
18. 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.
19. Mabuchi H, Koizumi J, Shimizu M, Takeda R, Hokuriku FH, for the
CHD Study Group. Development of coronary heart disease in familial
hypercholesterolemia. Circulation. 1989;89:225–232.
20. Krivokapitch J, Smith GT, Huang SC, Hoffmen EJ, Raitib O, Phelps ME,
Schelbert HR. 13N-ammonia myocardial imaging at rest and with exercise
in normal volunteers. Circulation. 1989;80:1328 –1337.
21. Kuhle WG, Porenta G, Huang SC, Buxton DB, Gambhir SS, Hansen H,
Phelps ME, Schelbert HR. Quantification of regional myocardial bloodflow using 13N-ammonia and reoriented dynamic positron emission
tomography. Circulation. 1992;86:1004 –1017.
22. Campisi R, Czernin J, Karpman HL, Schelbert HR. Coronary vasodilatory capacity and flow reserve in normal myocardium supplied bybypass grafts late after surgery. Am J Cardiol. 1997;80:27–31.

23. Sellke FW, Armstrong ML, Harrison DG. Endothelium-dependent
vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic patients. Circulation. 1990;81:1586 –1593.
24. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Modulation of coronary
vasomotor tone in humans: progressive endothelial dysfunction withdifferent early stages of coronary atherosclerosis. Circulation. 1991;83:391– 401.
25. Drexler H, Zeiher AM. Endothelial function in human coronary arteries invivo: focus on hypercholesterolemia. Hypertension. 1991;18:II-90 –II-99.
26. Bult H, Fret HRL, Jordeans FH, Herman AG. Dipyridamole potentiates
the anti-aggregating and vasodilator activity of nitric oxide. Eur
J Pharmacol. 1991;199:1– 8.
27. Raitakari OT, Toikka J, Pitakanen OP, Laine H, Viikari JSA, Nuutila P,
Knuuti J. Influence of subclinical atherosclerosis on coronary flow
reserve in young men. Circulation. 1998;98(suppl I):I-94. Abstract.
28. Yokoyama I, Ohtake T, Momomura S, Yonekura K, Fujita H,
Kobayakawa N, Aoyagi T, Sugiura S, Ohtomo K. Improvement of myocardial flow reserve in patients with non-insulin dependent diabetes after
successful treatment of chronic hyperglycemia. Circulation. 1998;
98(suppl 1):I-95. Abstract.
29. Nitenberg A, Valensi P, Sachs R, Dalim M, Aptecar E, Attali JR.
Impairment of coronary vascular reserve and Ach-induced coronary vasodilation in diabetic patients with angiographically normal coronary
arteries and normal ventricular systolic function. Diabetes. 1993;32:
1017–1023.
30. Nahser PJ Jr, Brown RE, Oskarsson H, Winnifold MD, Rossen JD.
Maximal coronary flow reserve and metabolic coronary vasodilation inpatients with diabetes mellitus. Circulation. 1995;91:635– 640.
31. Yokoyama I, Ohtake T, Momomura S, Yonekura K, Nishikawa J, Sasaki
Y, Omata M. Reduced myocardial flow reserve in patients with noninsulin dependent diabetes mellitus. J Am Coll Cardiol. 1997;30:
1472–1477.
32. Yokoyama I, Ohtake T, Momomura S, Yonekura K, Nishikawa J, Sasaki
Y, Omata M. Hyperglycemia rather than insulin resistance is related tocoronary flow reserve in patients with non-insulin dependent diabetes
mellitus. Diabetes. 1998;47:119 –124.
33. Pitkanen OP, Nuutila P, Raitakari OT, Ronnemaa T, Koskinen PJ, Iida H,
Lehtimaki TJ, Laine HK, Takala T, Viikari JS, Knuuti J. Coronary flow
reserve is reduced in young men with IDDM. Diabetes. 1998;47:248 –54.
34. Motz W, Strauer BE. Improvement of coronary flow reserve after longterm therapy with enalapril. Hypertension. 1996;27:1031–1038.
35. Laine H, Raitakari OT, Niinikoski H, Pitkanen OP, Iida H, Viikari J,
Nuutila P, Knuuti J. Early impairment of coronary flow reserve inyoung men with borderline hypertension. J Am Coll Cardiol. 1998;
32:147–153.