This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yokoyama, I. Articles by Omata, M. Search for Related Content PubMed PubMed Citation Articles by Yokoyama, I. Articles by Omata, M.

(Circulation. 1996;94:3232-3238.)
© 1996 American Heart Association, Inc.

Articles

Reduced Coronary Flow Reserve in Hypercholesterolemic Patients Without Overt Coronary Stenosis

Ikuo Yokoyama, MD; Tohru Ohtake, MD; Shin-ichi Momomura, MD; Junichi Nishikawa, MD; Yasuhito Sasaki, MD; Masao Omata, MD

the Second Department of Internal Medicine (I.Y., S.M., J.N., M.O.) and the Department of Radiology (T.O., J.N., Y.S.), University of Tokyo (Japan).

Correspondence to Ikuo Yokoyama, MD, The Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients.

Methods and Results Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and ¹³N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3±31.4) and SH (70.0±20.7) patients was not different from that in control subjects (75.0±34.9). However, MBF during dipyridamole loading was significantly lower in FH patients (129±19.1) than in control subjects (322±174, P<.01) and SH patients (210±71.2, P<.01). CFR in FH patients (1.59±0.41) was also significantly lower compared with both control subjects (4.22±1.42, P<.01) and SH patients (3.00±0.96, P<.01). CFR in SH patients was also significantly lower than that in control subjects (P<.05). CFR correlated significantly with both plasma total cholesterol (r=.67, P<.01) and LDL cholesterol concentrations (r=.69, P<.01).

Conclusions CFR was decreased even in anatomically normal coronary arteries in hypercholesterolemic patients. This abnormality was more prominent in FH patients.

Key Words: hypercholesterolemia • stenosis • blood flow • tomography

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
It has been widely accepted that CFR decreases according to the severity of coronary stenosis.¹ However, recent clinical investigations have demonstrated that CFR is reduced in a variety of diseases such as hypertrophic cardiomyopathy,² dilated cardiomyopathy,³ diabetes associated with hypertension,⁴ and diabetes not accompanied by hypertension⁵ as well as in normal segments in patients with myocardial infarction without overt coronary stenosis.⁶ Previously, reduced CFR in patients with FH who had no evidence of ischemia was reported.⁷ The same result was also shown in patients with SH.⁸ However, it remained uncertain whether the reduced CFR in hypercholesterolemic patients was due to overt coronary stenosis.

FH is a well-known, dominantly inherited disease caused by a mutation of the LDL receptor gene.⁹ The important clinical characteristics of FH are a high incidence of CAD and subsequent high mortality as the result of CAD and reduced longevity.^{10 11 12 13 14 15 16 17} Therefore, early detection of coronary arterial abnormality and prevention of CAD are important in the management of this disease. In patients with SH, the etiologic background is different from that in FH patients. For example, SH is more affected by lifestyle, including diet, exercise, and so forth. The duration of the hypercholesterolemic state also differs between FH and SH patients because the former is usually of juvenile onset, whereas the latter is usually of adult onset. Coronary circulatory dynamics, including CFR, may well be different between patients with FH and those with SH.

The aims of this study were first, to clarify whether CFR can be decreased even in anatomically normal coronary arteries in FH or in SH, and second, to compare CFR between the two conditions.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
Twenty-two hypercholesterolemic patients (15 men and 7 women) and 11 control subjects (9 men and 2 women) were involved in this study. Of the 22 patients, 11 had FH and 11 had SH. In 22 hypercholesterolemic patients, 19 were complicated with CAD (8 FH, 11 SH). Of 19 hypercholesterolemic patients with CAD, 7 had OMI (4 FH, 3 SH). All patients underwent coronary cineangiography and were proven to have either normal coronary arteries or one- or two-vessel disease (Table 1). In 7 patients with no vessel disease, 2 had received percutaneous transluminal angioplasty, 2 had chest pain syndrome, and 3 were asymptomatic. At the time of PET, 11 patients (8 were FH patients and 3 were SH patients) were taking oral lipid-lowering agents, but the total plasma cholesterol level was not normalized in any of the hypercholesterolemic patients at this time. Caffeine intake was prohibited for 24 hours before the PET study. In this study, we focused on those myocardial segments perfused by normal coronary arteries (0% stenosis). The diagnosis of coronary arterial lesion was made by 3 independent specialists without knowledge of PET data. Coronary arteries having stenoses were excluded whether or not they were significant. The diagnosis of FH was made according to the following two criteria: (1) hypercholesterolemic patients with an Achilles tendon thickness >10 mm or (2) hypercholesterolemic patients with a family history of hypercholesterolemia in a first-degree relative.¹¹ Hypercholesterolemic patients who did not meet the above criteria were considered to have SH. Total plasma cholesterol level of >5.7 mmol/L (220 mg/dL) was diagnostic of hypercholesterolemia. Eleven normolipemic, normoglycemic, asymptomatic subjects without any history of heart disease were selected as control subjects. In our control subjects, resting ECG and symptom-limited treadmill test were normal; those with typical chest pain or abnormal ECG indicating myocardial ischemia were not used as control. The general characteristics of our study subjects are summarized in Table 2. There were no significant differences in age, sex, body weight, height, body mass index, blood pressure, smoking, and hemoglobin A_1c (HbA_1c) among the 3 groups. Four hypertensive patients were included (2 with FH, 2 with SH). Of the 4 hypertensive patients, 2 had diabetes mellitus (1 with FH and 1 with SH). Two normotensive diabetic patients were also included (1 with FH and 1 with SH). All diabetic patients had a mild diabetic condition (HbA_1c <7%). Of the 11 FH patients, 8 were normotensive and normoglycemic, as were 8 of 11 SH patients. Before the initiation of the study, the nature of the study was explained to all subjects, who then agreed to participate in the protocol, which was approved by the local Ethics Committee.

View this table: [in this window] [in a new window]   Table 1. Coronary Cineangiography Findings in Study Subjects

View this table: [in this window] [in a new window]   Table 2. General Characteristics, Plasma Lipids, and Complications in Study Subjects

Positron Emission Tomography
Regional MBF (mL/min per 100 g) at rest and during dipyridamole loading was measured with the use of PET scanning and ¹³N-ammonia. Myocardial flow images were obtained with the use of 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 (FWHM), and the z-axial resolution is 9.5 mm at FWHM. Effective in-plane resolution was 7 mm after a smoothing filter was used. The sensitivity of the Headtome IV scanners is 14 and 24 kilocounts per second (kcps) (1 µCi/mL) for direct and cross planes, respectively.

After transmission data were acquired 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, followed by static PET scanning for 8 minutes. After waiting 45 minutes to allow for decay of the radioactivity of ¹³N-ammonia, dipyridamole (0.56 mg/kg) was loaded intravenously. Five minutes after dipyridamole loading, 15 to 20 mCi of ¹³N-ammonia was injected and a second dynamic PET scanning was performed for 2 minutes, immediately followed by static PET scanning for 8 minutes. The dynamic PET scanning was performed every 15 seconds (eight times) in the 2-minute period, and dynamic data were obtained for 7 slices. Only one-channel ECG monitoring in limb leads was made during the PET study.

Determination of Myocardial Blood Flow and Coronary Flow Reserve
Regional MBF was calculated according to the two-compartment ¹³N-ammonia tracer kinetic model demonstrated by Krivokapitch et al.¹⁸ The time-activity curve of the left ventricular cavity was used as an input function. Tracer spillover was corrected by least squares nonlinear regression analysis on our program to calculate the MBF, with an assumption that both myocardial and left ventricular radioactivity were influenced by each other. Specifically, true radioactivity of the left ventricular cavity at the time of t[Ca (t)_true] was expressed as

where Ca(t)_PET is radioactivity of the left ventricular cavity measured by PET, Cm(t)_true is a true radioactivity of the cardiac muscle, and C₁ is the spillover factor that is expressed as a percentage, with the assumption that C₁(%) of the true radioactivity of the cardiac muscle was added to the radioactivity of the left ventricular cavity measured by PET. Similarly, true radioactivity of cardiac muscle at the time of t[Cm(t)_true] is expressed as

where Cm(t)_PET is myocardial radioactivity measured by PET, Ca(t)_true is the true radioactivity of the left ventricular cavity, and C₂ is the spillover factor that is expressed as a percentage, with the assumption that C₂(%) of the true radioactivity of the left ventricular cavity was added to the myocardial radioactivity measured by PET.

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 to determine MBF.

CFR was determined by the ratio of MBF during dipyridamole loading to baseline MBF. As shown in Fig 1, each transaxial image was divided into 8 segments. Segments S1, S2, A1, and A2 on the midventricular transaxial slice and S3, S4, A3, and A4 on the lower slice were defined as the left descending coronary artery region. Segments L1 and L2 on the middle slice and L3 and L4 on the lower slice were defined as the left circumflex coronary artery region. Segments P1 and P2 on the middle slice and P3 and P4 on the lower slice were defined as the right coronary artery region. To obtain input function, regions of interest were placed on the left ventricular cavity of each slice.

View larger version (54K): [in this window] [in a new window]   Figure 1. Schematic representation of placement of regions of interest (ROI) and anatomic orientation of each segment on the transaxial images; ROIs were placed on the transaxial images as follows. To each slice, the anteroapical pole (AAP) was determined visually, and the tangent (T) to the anteroapical pole was drawn. Then, a perpendicular line to the tangent to the antero-apical pole (PA line) was drawn from the AAP. The J line was drawn from the junction of right ventricular wall to septum (RVSJ) to the PA line at an angle of 45°. On the basis of the PA line and J line, the left ventricle was divided equally into 8 segments. Septal segments were obtained from the middle transaxial (#S1, #S2) and the lower slices (#S3, #S4); anterior segments were obtained from the middle (#A1, #A2) and lower slices (#A3, #A4). Anteroseptal segments were defined as the left descending coronary artery region. The lateral wall segment was obtained from the middle (#L1, #L2) and lower slices (#L3, #L4). Lateral segments were defined as the left circumflex coronary artery region. The inferoposterior wall segment was obtained from the middle (#P1, #P2) and lower slices (#P3, #P4). When #P1 or #P2 on the middle slice was not large enough to place an ROI, those segments were excluded in the data analysis. Inferoposterior segments were defined as the right coronary artery region.

Statistics
MBF at rest, MBF during dipyridamole loading, CFR, body weight, systolic blood pressure, diastolic blood pressure, height, body mass index, and plasma lipid parameters in the three groups were compared with the use of ANOVA; individual data then were analyzed by two-tailed Student's t test. Values are expressed as mean±SD. A value of P<.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Plasma Lipid Levels
Plasma concentration of total cholesterol was significantly higher in FH patients compared with control subjects and SH (Table 3). Likewise, the plasma concentration (mmol/L) of LDL cholesterol was significantly higher in the FH group compared with control subjects and SH patients (Table 3). The plasma concentration of HDL cholesterol was about the same among the three groups (Table 3). The plasma triglyceride concentration was also about the same among the three groups (Table 3).

View this table: [in this window] [in a new window]   Table 3. Comparison of Plasma Lipid Concentrations

Hemodynamic and ECG Responses to Dipyridamole Loading
There were no significant differences in systolic blood pressure at rest and during dipyridamole loading and rate-pressure product among the 3 groups (Table 4). During dipyridamole loading, typical chest pain or chest oppression occurred in all of the hypercholesterolemic patients who had significant coronary stenoses and in 2 patients with FH who did not have ischemic heart disease accompanied by ECG change. Atypical chest pain, chest discomfort, or dyspnea were observed in the other 4 non–ischemic heart disease patients without abnormal ECG change. Because of a difficulty in recording the ECG in the precordial leads on the PET study, a detailed description of ECG response to dipyridamole was not possible in this study by limb leads.

View this table: [in this window] [in a new window]   Table 4. Hemodynamic Response to Dipyridamole Loading

Myocardial Blood Flow at Rest and During Dipyridamole Loading
There was no significant difference in baseline MBF in segments perfused by angiographically normal coronary arteries among the three groups (Table 5). However, the MBF during dipyridamole loading was significantly lower in the FH group compared with both control subjects and SH patients (Table 5).

View this table: [in this window] [in a new window]   Table 5. Comparison of Myocardial Blood Flow at Rest and During Dipyridamole Loading and CFR Among Control Subjects, FH Patients, and SH Patients

Coronary Flow Reserve
CFR was significantly lower in the FH group compared with control subjects and the SH group (Table 5). CFR in SH patients was also significantly lower compared with control subjects (Table 5).

Seven patients with OMI were included in this study. When OMI patients were excluded, CFR in patients with FH was also significantly reduced compared with control subjects and patients with SH (Table 6). CFR in patients with SH who did not have OMI was also significantly reduced compared with control subjects (Table 6). There was no significant difference in CFR in segments perfused by normal coronary arteries between FH patients with OMI and those without. In SH patients, there was no significant difference in CFR between patients who had OMI and those who did not have OMI (Table 6).

View this table: [in this window] [in a new window]   Table 6. Influence of OMI on CFR in Normal Coronary Arteries in Hypercholesterolemic Patients

There was no significant difference in CFR in segments perfused by normal coronary arteries between patients with no vessel disease (n=7, 2.0±0.58) and patients with one- or two-vessel disease (n=15, 2.48±1.1).

Furthermore, in the FH group, 2 patients had hypertension. Therefore, we further investigated whether or not hypertension influenced the CFR value. CFR in normotensive hypercholesterolemic patients (2.64±0.79) was significantly lower compared with control subjects (4.22±1.42, P<.01). In FH patients, CFR was comparable between normotensive patients (1.58±0.43) and hypertensive patients (1.41±0.29). CFR in normotensive FH patients (1.58±0.43) was significantly lower compared with both control subjects (P<.01) and normotensive SH patients (3.49±0.87, P<.01). Again, in SH patients, CFR was slightly reduced even in normotensive patients (3.49±0.87) compared with control subjects (4.22±1.42), but this difference was not statistically significant. In the SH group, CFR tended to be reduced in hypertensive patients (2.19±0.12) compared with normotensive patients (3.49±0.87), but again this difference was not statistically significant.

When we further excluded hypertensive and diabetic patients, CFR was significantly reduced in the FH group (n=7, 1.61±0.51) compared with control subjects and normotensive normoglycemic SH patients (n=8, 3.65±0.83). In normotensive nondiabetic SH patients, CFR was comparable to that of control subjects.

The Relationship Between Plasma Lipid Fractions
When the three groups were combined, there was a significant relationship between CFR and both the plasma total cholesterol concentration (r=.67, P<.01, Fig 2) and the plasma LDL cholesterol concentration (r=.69, P<.01, Fig 2). On the other hand, there were no significant relationships between the plasma HDL cholesterol concentration and the plasma triglyceride concentration.

View larger version (30K): [in this window] [in a new window]   Figure 2. Top, Significant negative relationship between coronary flow reserve (CFR) and total cholesterol (TC) level. FH indicates familial hypercholesterolemia; SH, secondary hypercholesterolemia; and C; control. Bottom, Significant negative relationship between CFR and LDL cholesterol level.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Decreased Coronary Flow Reserve in Patients With Hyperlipidemia Without Overt Coronary Atherosclerosis
Recent clinical investigations have demonstrated that CFR can decrease even in patients with anatomically normal coronary arteries in a variety of diseases.^{2 3 4 5 6} Previously, we reported a reduced CFR in FH patients without evidence of myocardial ischemia.⁷ Similar observations were demonstrated by Dayanikli et al⁸ in hyperlipidemic subjects. Although these data suggest that CFR can decrease without evidence of ischemia in hypercholesterolemic patients, it is not clear whether this abnormality occurs in normal coronary arteries in hyperlipidemic subjects. Recently, Seiler et al¹⁹ demonstrated abnormal vasomotion during exercise stress testing in angiographically normal coronary arteries in hypercholesterolemic patients. Although the presence of coronary flow regulatory abnormality in hypercholesterolemic patients was suggested, Seiler and colleagues only investigated the percent changes in coronary diameter during exercise stress testing, which do not reflect CFR. Therefore, it remained uncertain whether CFR does decrease even in FH or SH patients who have normal coronary arteries. In our previous study in FH patients without ischemia, coronary cineangiography was not performed. However, in this present study, myocardial segments perfused by angiographically normal coronary arteries in hypercholesterolemic patients with ischemic heart disease were investigated, and we found a significant decrease in CFR both in FH and SH patients. Comparing our present results with those of recent similar studies, we found that CFR in the myocardial segments perfused by normal coronary arteries in FH patients was comparable to that of FH patients without evidence of ischemia, as previously reported by us,⁷ and the difference in CFR between normal subjects and SH patients was almost the same as that reported by Dayanikli et al.⁸ However, when data from hypertensive subjects were excluded from the analysis, a significant difference in CFR did not exist between SH patients and control subjects in the present study. These results may be related to the fact that patients with FH have the highest risk of death as the result of CAD among the diseases associated with a hyperlipidemic state.¹⁷ Since this disease develops in infancy, atherosclerotic abnormalities caused by hypercholesterolemia would be more strikingly presented in FH patients than in SH patients. Our data are consistent with these speculations. The severity of hypercholesterolemia may correlate with the decrease of CFR in segments perfused by angiographically normal coronary arteries.

Possible Mechanism for Reduced Coronary Flow Reserve in Patients With Hypercholesterolemia Without Overt Coronary Stenosis
Diffuse but undetectable coronary atherosclerosis could be a factor for the reduced CFR in hypercholesterolemic patients, as could be microcirculation abnormalities. A reduced coronary microvascular bed may be another factor for the reduced CFR observed in hypercholesterolemic patients, as is sometimes proposed in diabetic patients.⁴ Another mechanism, abnormal coronary flow regulation in hypercholesterolemia, should be discussed. There have been several reports that suggested impaired endothelial function in hypercholesterolemic patients without overt atherosclerosis in the large vessels.^{20 21 22 23 24 25} Recent investigation has demonstrated that the vasodilating action of dipyridamole may be associated with increased production of nitric oxide resulting from the inhibition of phosphodiesterase activity.²⁶ It is therefore possible that abnormal endothelial function may be partially related to the reduction of CFR in FH or SH. On the other hand, the endothelium-independent vasodilatory action of dipyridamole also should be considered as a possible mechanism leading to these results. Atheromatous plaques that may not cause angiographically significant stenosis may mechanically impair vasodilatory function in hypercholesterolemic patients. Further investigation should be addressed in the abnormality in the endothelium-independent vasodilatory function in patients with hypercholesterolemia.

Czernin et al²⁷ recently demonstrated that CFR was more significantly reduced in healthy elderly subjects than in young healthy subjects. In this study, there was no significant difference in age among patients with FH or SH and control subjects. Therefore, our results could not be attributed to such an age-related reduction in CFR.

Since approximately two thirds of hypercholesterolemic patients have significant coronary stenoses in one or two major vessels, the influence of coexisting coronary stenosis on CFR in segments perfused by normal coronary arteries in hypercholesterolemic patients should be addressed. However, in our study there was no significant difference in CFR in segments perfused by normal coronary arteries between patients with no vessel disease and patients with one- or two-vessel disease. Therefore, our findings of decreased CFR in angiographically normal coronary arteries in hypercholesterolemic patients is not thought to be influenced by coronary stenosis in other branches.

Gender-Specific Variance of Coronary Flow Reserve in Patients With FH
The incidence of CAD in FH patients is significantly high,^{9 10 11 12 13 14 15 16 17} and 70% of FH patients die as the result of CAD.^{10 11} However, the incidence of CAD is much lower, and longevity is higher for women than for men with FH.^{10 11 17} Our previous data on asymptomatic FH patients with no evidence of ischemia showed a significant difference in CFR between men and women.⁷ However, in this study we could not find gender-specific differences because of the relatively small number of patients involved in the study. Further investigation is needed to clarify this point.

Influence of Myocardial Infarction on Coronary Flow Reserve in Segments Perfused by Anatomically Normal Coronary Arteries
Recently, reduced CFR in normal segments in patients with myocardial infarction was demonstrated by Uren et al.⁶ Thus, to clarify whether our results in hypercholesterolemic patients were influenced by this abnormality in patients with myocardial infarction, we further investigated CFR in hypercholesterolemic patients without OMI and found a significantly reduced CFR in hypercholesterolemic patients who did not have OMI. This reduction in CFR was more prominent in FH than in SH patients even when OMI patients were excluded. Furthermore, there was not a significant difference in CFR in hypercholesterolemic patients between patients with and without OMI whether or not these patients had FH. Therefore, our results were not attributed to mechanisms specifically relating to OMI.

Influence of Hypertension and Diabetes Mellitus
In our study patients, two SH patients and two FH patients also had hypertension. To estimate the influence of hypertension on CFR, comparison was made between hypertensive and normotensive subjects. We found that CFR was comparable between hypertensive FH patients and normotensive FH patients. However, CFR in normotensive FH patients was significantly lower than that in control subjects. Therefore, the influence of hypertension on the decrease of CFR in patients with FH was small in our study. While a significant difference in CFR was not observed between normotensive patients with SH and control subjects, coexistence of hypertension and hypercholesterolemia in SH might accelerate the reduction in CFR in these patients. The reason for the small decrease in CFR observed in SH patients probably was because hyperlipidemia is less severe and of shorter duration in Japanese patients with SH than in those with FH.

The influence of diabetes on CFR was negligible in the present study, but the diabetes in these patients was of a mild degree (HbA_1c<7%). In our laboratory, no significant reduction of CFR was observed in less severe diabetics whose HbA_1c was <7% (unpublished data, 1996).

Measurement of Myocardial Blood Flow
We used the two-compartment ¹³N-ammonia tracer kinetic model (dynamic PET and ¹³N-ammonia) to determine MBF.¹⁹ There are several problems with this two-compartment tracer kinetic model, including (1) the need for the correction of the partial volume effect, (2) avoidance of the negative influence of tracer spillover, and (3) difficulty in estimating the myocardial segment corresponding to the right coronary artery on the transaxial image. In our study, to address these concerns, correction of the partial volume effect was made by consideration of the wall thickness measured by two-dimensional echocardiography by experienced specialists. Because wall thickness corrected by two-dimensional echocardiography did not completely coincide with that of PET emission transaxial images, there remains some uncertainty about MBF values obtained by this method. However, our major interest is that the CFR value can negate the influence of partial volume effect because CFR is a ratio of MBF during stress loading to baseline MBF. So our results on CFR cannot be modified by the uncertainty of the correction of the partial volume effect by two-dimensional echocardiography. Second, since the input function was obtained from the time-activity curve of the left ventricular cavity and spillover from the left ventricular cavity to the cardiac muscle is large during the first several minutes, tracer spillover should be taken into consideration. Therefore, tracer spillover was considered in the method using the two-compartment model by Krivokapitch et al,¹⁸ and details were reported by Kuhle et al.²⁸ Using their method but with small changes, including the estimation of spillover from the blood pool to the myocardium, we avoided the influence of spillover on the determination of MBF, using nonlinear regression algorithm. Therefore, certainty of the time-activity curve of the left ventricular cavity as an input function was confirmed. The third problem may be solved by making short-axial dynamic images, as was also demonstrated by Kuhle et al.²⁸ However, it was difficult to obtain good short-axis images from the transaxial images during the first 60 seconds of PET data acquisition because of the small tracer distribution to the heart during such periods. This may be a limitation of the two-compartment tracer kinetic model, whose accuracy remains valid only during the first 90 seconds. However, 6 of our patients (5 FH, 1 SH) had significant right coronary arterial stenosis. Actually, results were the same when we excluded those 6 patients and those who had only normal right coronary arteries; CFR in FH patients (1.57±0.51, n=5) was significantly lower compared with both normal control subjects and SH patients (3.41±0.99, n=7). Therefore, analytical error by misreading the right coronary arterial perfusion area was negligible in this study.

Recently, Hutchins et al²⁹ developed another precise model to measure MBF using PET and ¹³N-ammonia, the so-called three-compartment tracer kinetic model that considers myocardial metabolism of ¹³N-ammonia. Because this model requires a complicated program and data sampling, we did not use it. One of the major problems in calculating MBF is whether or not myocardial metabolism of ¹³N-ammonia should be considered between the two models. However, since we calculated MBF using dynamic PET scan data during the first 90 seconds after ¹³N-ammonia injection, the negative influence of metabolites of ¹³N-ammonia on MBF measurement might be negligible. Furthermore, Hutchins et al have also shown that the CFR calculated from the two-compartment model did not differ from that calculated from the three-compartment model.²⁹ In this study, CFR was slightly lower than that of Hutchins et al (4.2±1.4 versus 4.8±1.3).²⁹ This difference may be simply due to the difference in age between the patient groups and not to the method used. As shown by Czernin et al,²⁷ CFR decreases in accordance with age, so it is acceptable that CFR in control subjects in our study was relatively lower than reported by Hutchins et al.²⁹ Moreover, there was no apparent difference in the % coefficients of variance of normal CFR between the results of the present study and these by Hutchins et al (34.1 versus 27.1). Iida et al³⁰ conducted a collaborative study on MBF and CFR in normal Japanese subjects and found a greater degree of variability in CFR (3.82±2.12) than did our study. Therefore, the SD in our findings related to normal CFR is not high compared with data from other institutions.

Diagnosis of Coronary Arterial Stenosis
In this study, diagnosis of CAD was made with visual inspection by three independent specialists. Application of other methods such as quantitative coronary artery arteriography could identify a diffuse CAD, as was used in the experimental study reported by Seiler et al.³¹ The differential diagnosis of diffuse CAD by such methods could possibly clarify the mechanism for the reduced CFR in hypercholesterolemic patients. Although quantitative methods usually present difficulties in establishing good automated software to exclude uncertainties with this type of analysis, the potential limitation of visual estimation of coronary arterial lesions in this study should be taken into account. Further investigation to compare CFR measured by PET and coronary stenosis determined by computer-assisted quantitative analysis should be done.

Limitations of the Study
It should be considered whether the CFR in our normal control subjects actually corresponds to the CFR in age-matched healthy subjects. In other words, can we say whether a noninvasively evaluated normal human actually has normal coronary arteries? It is a difficult problem because coronary angiography should not be performed in such asymptomatic normal humans. That is one limitation of this study. To our knowledge, there has been no demonstration of impaired function or advanced atherosclerosis in coronary arteries in healthy asymptomatic humans without coronary risk factors. Rozanski et al³² demonstrated that subjects with angiographically normal coronary arteries often had abnormal ventriculographic responses, whereas such abnormality was rarely seen in subjects with low probability of cardiac disease. Therefore, cardiac normality in control subjects was not confirmed by cardiac catheterization but by the low probability of cardiac disease. Therefore, we believe that our control subjects with a low probability of cardiac disease are appropriate as normal control even if coronary cineangiography was not undertaken. Furthermore, given the high diagnostic accuracy of myocardial PET imaging for CAD, it is possible to assume that in asymptomatic normal subjects without coronary risk factors or chronic disease, the anatomy and function of the coronary arteries would be normal.

Conclusions
CFR decreased even in patients with hypercholesterolemia who had anatomically normal coronary arteries. This decrease was more prominent in FH than in SH patients. Both the plasma concentration of total cholesterol and the duration of the hypercholesterolemic state appear to contribute to this decrease in CFR. Noninvasive assessment of CFR by ¹³N-ammonia PET is useful to detect abnormal coronary flow regulation both in patients with FH and SH.

	Selected Abbreviations and Acronyms

 

CAD = coronary artery disease CFR = coronary flow reserve FH = familial hypercholesterolemia MBF = myocardial blood flow OMI = old myocardial infarction PET = positron emission tomography SH = secondary hypercholesterolemia

	Acknowledgments

 
We are grateful to Dr Hirohide Iida (Research Institute for Brain and Blood Vessels Akita) for his technical advice on PET measurement. We also thank Tamotsu Yada and Dr Yoshio Kojima for their technical assistance in preparation of ¹³N-ammonia. We also thank Drs Katsu Takenaka, Junichi Suzuki, Tsutomu Igarashi, and Fuminori Watanabe (The Second Department of Internal Medicine, University of Tokyo) for their technical assistance in the measurement of two-dimensional echocardiography.

Received May 28, 1996; revision received July 15, 1996; accepted July 30, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol. 1974;34:48-55.[Medline] [Order article via Infotrieve]
   
2. Camici PG, Chiriatti G, Lorenzoni R, Bellina RC, Gistri R, Italiani G. Coronary vasodilation is impaired in both hypertrophied and non-hypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol. 1991;17:879-886.[Abstract]
   
3. Inoue T, Sasaki Y, Morooka S, Hayashi T, Takayanagi K, Yamanaka T, Kakoki H, Takabatake Y. Coronary flow reserve in patients with dilated cardiomyopathy. Am Heart J. 1993;125:93-98.[Medline] [Order article via Infotrieve]
   
4. 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.[Abstract]
   
5. Nahser PJ Jr, Brown RE, Oskarsson H, Winnifold MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation. 1995;91:635-640.[Abstract/Free Full Text]
   
6. Uren NG, Crake T, Leffery DC, Silva R, Gavies GJ, Maseri A. Reduced coronary vasodilator function in infarcted and normal myocardium after myocardial infarction. N Engl J Med. 1994;331:222-227.[Abstract/Free Full Text]
   
7. Yokoyama I, Ohtake T, Murakami T, Momomura S, Nishikawa J, Sasaki Y, Omata M. Reduced coronary flow reserve in familial hypercholesterolemia. J Nucl Med. In press.
   
8. Dayanikli F, Grambow D, Muzil O, Mosca L, Rubenfire M, Schwaiger M. Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography. Circulation. 1994;90:808-817.[Abstract/Free Full Text]
   
9. Goldstein JL, Dana SE, Brunschede GY, Brown MS. Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutation affecting functions of low-density lipoprotein receptor. Proc Natl Acad Sci U S A. 1975;72:1092-1096.[Abstract/Free Full Text]
   
10. Mabuchi H, Tanami R, Haba T, Ueda K, Oota M, Takeguchi T, Wakasugi T, Takeda R. Cause of death in patients with familial hypercholesterolemia. Atherosclerosis. 1986;61:1-6.[Medline] [Order article via Infotrieve]
    
11. Mabuchi H, Koizumi J, Shimizu M, Takeda R, Hokuriku FH, CHD Study Group. Development of coronary heart disease in familial hypercholesterolemia. Circulation. 1989;79:225-232.[Abstract/Free Full Text]
    
12. Heiberg A. The risk of atherosclerotic vascular disease in subjects with xanthomatosis. Acta Med Scand. 1975;198:249-261.[Medline] [Order article via Infotrieve]
    
13. Beaumont V, Jacotot B, Beaumont JL. Ischemic disease in men and women with familial hypercholesterolemia and xanthomatosis: a comparative study of genetic and environmental factors in 274 heterozygous cases. Atherosclerosis. 1976;24:441-450.[Medline] [Order article via Infotrieve]
    
14. Jensen J, Blankenhorn DH, Kornerup V. Coronary artery disease in familial hypercholesterolemia. Circulation. 1967;36:77-82.[Abstract/Free Full Text]
    
15. Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with type II hyperlipoproteinemia. Circulation. 1974;49:476-488.[Abstract/Free Full Text]
    
16. Kwiterovich PO Jr, Levy RI, Fredrickson DS. Neonatal diagnosis of familial type II hyperlipoproteinemia. Lancet. 1973;1:118-121.[Medline] [Order article via Infotrieve]
    
17. Slach J. Risk of ischemic heart disease in familial hyperlipoproteinaemic states. Lancet. 1969;2:1380-1383.[Medline] [Order article via Infotrieve]
    
18. 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.[Abstract/Free Full Text]
    
19. Seiler C, Hess OM, Buechi H, Suten TM, Krayenbuehl HP. Influence of serum cholesterol and other coronary risk factors in vasomotion of angiographically normal coronary arteries. Circulation. 1993;88:2139-2148.[Abstract/Free Full Text]
    
20. Osborne JA, Siegman MJ, Sedar AW, Mooers SU, Lefer AM. Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am J Physiol. 1989;256:C591-C597.[Abstract/Free Full Text]
    
21. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet. 1991;338:1546-1549.[Medline] [Order article via Infotrieve]
    
22. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991;83:391-401.[Abstract/Free Full Text]
    
23. Drexler H, Zeiher AM. Endothelial function in human coronary arteries in vivo: focus on hypercholesterolemia. Hypertension. 1991;18(suppl II):II-90-II-99.
    
24. Sellke FW, Armstrong ML, Harrison DG. Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic patients. Circulation. 1990;81:1586-1593.[Abstract/Free Full Text]
    
25. Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA. The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation. 1993;88:2541-2547.[Abstract/Free Full Text]
    
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.[Medline] [Order article via Infotrieve]
    
27. Czernin J, Muller P, Chan S, Brunken RC, Porenta GP, Krivokapitch J, Chen K, Chan A, Phelps ME, Schelbert HR. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation. 1993;88:62-69.[Abstract/Free Full Text]
    
28. Kuhle WG, Porenta G, Huang SC, Buxton DB, Gambhir SS, Hansen H, Phelps ME, Scherbert HR. Quantification of regional myocardial blood flow using 13N-ammonia and reoriented dynamic positron emission tomography. Circulation. 1992;86:1004-1017.[Abstract/Free Full Text]
    
29. Hutchins G, Schwaiger M, Rosenspire KC, Krivokapitch J, Schelbert HR, Kuhl DE. Noninvasive quantification of regional myocardial blood flow with N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol. 1990;15:1032-1042.[Abstract]
    
30. Iida H, Tamaki N. Cardiac PET Working Group, Japan: quantitative assessment of regional myocardial blood flow using O-15 water and PET. J Nucl Med. 1995;36:78P. Abstract.
    
31. Seiler C, Kirkeeide K, Gould KL. Basic structure-function relationship of the epicardial coronary tree: basis of quantitative coronary arteriography for diffuse coronary artery disease. Circulation. 1992;85:1987-2003.[Abstract/Free Full Text]
    
32. Rozanski A, Diamond GA, Forrester JS, Berman DS, Morris D, Swan JC. Alternative referent standard for cardiac normality: implication for diagnostic testing. Ann Intern Med. 1984;101:164-171.
    

This article has been cited by other articles:

				H Oe, T Hozumi, E Murata, H Matsuura, K Negishi, Y Matsumura, S Iwata, K Ogawa, K Sugioka, Y Takemoto, et al. Arachidonic acid and docosahexaenoic acid supplementation increases coronary flow velocity reserve in Japanese elderly individuals Heart, March 1, 2008; 94(3): 316 - 321. [Abstract] [Full Text] [PDF]

				M. Saglam, O. Karakaya, I. Barutcu, A. M. Esen, M. Turkmen, R. Kargin, O. Esen, N. Ozdemir, and C. Kaymaz Identifying Cardiovascular Risk Factors in a Patient Population With Coronary Artery Ectasia Angiology, January 1, 2008; 58(6): 698 - 703. [Abstract] [PDF]

				L. Wang, T. Y. Wong, A. R. Sharrett, R. Klein, A. R. Folsom, and M. Jerosch-Herold Relationship Between Retinal Arteriolar Narrowing and Myocardial Perfusion: Multi-Ethnic Study of Atherosclerosis Hypertension, January 1, 2008; 51(1): 119 - 126. [Abstract] [Full Text] [PDF]

				A. T. Sezgin, I. Barutcu, N. Sezgin, H. Gullu, A. M. Esen, N. Acikgoz, E. Topal, and R. Ozdemir Contribution of Plasma Lipid Disturbances to Vascular Endothelial Function in Patients With Slow Coronary Flow Angiology, January 1, 2007; 57(6): 694 - 701. [Abstract] [PDF]

				P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]

				S. J. Nicholls, E. M. Tuzcu, T. Crowe, I. Sipahi, P. Schoenhagen, S. Kapadia, S. L. Hazen, C.-C. Wun, M. Norton, F. Ntanios, et al. Relationship Between Cardiovascular Risk Factors and Atherosclerotic Disease Burden Measured by Intravascular Ultrasound J. Am. Coll. Cardiol., May 16, 2006; 47(10): 1967 - 1975. [Abstract] [Full Text] [PDF]

				L. Wang, M. Jerosch-Herold, D. R. Jacobs Jr, E. Shahar, and A. R. Folsom Coronary Risk Factors and Myocardial Perfusion in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) J. Am. Coll. Cardiol., February 7, 2006; 47(3): 565 - 572. [Abstract] [Full Text] [PDF]

				C. L. Heaps, D. L. Tharp, and D. K. Bowles Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H568 - H576. [Abstract] [Full Text] [PDF]

				P. A. Kaufmann and P. G. Camici Myocardial Blood Flow Measurement by PET: Technical Aspects and Clinical Applications J. Nucl. Med., January 1, 2005; 46(1): 75 - 88. [Full Text] [PDF]

				I. Yokoyama, Y. Inoue, T. Moritan, K. Ohtomo, and R. Nagai Impaired myocardial vasodilatation during hyperaemic stress is improved by simvastatin but not by pravastatin in patients with hypercholesterolaemia Eur. Heart J., April 2, 2004; 25(8): 671 - 679. [Abstract] [Full Text] [PDF]

				H. Paiva, J. Laakso, H. Laine, R. Laaksonen, J. Knuuti, and O. T. Raitakari Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1241 - 1247. [Abstract] [Full Text] [PDF]

				R. Campisi, L. Nathan, M. H. Pampaloni, H. Schoder, J. W. Sayre, G. Chaudhuri, and H. R. Schelbert Noninvasive Assessment of Coronary Microcirculatory Function in Postmenopausal Women and Effects of Short-Term and Long-Term Estrogen Administration Circulation, January 29, 2002; 105(4): 425 - 430. [Abstract] [Full Text] [PDF]

				K. Hirata, K. Shimada, H. Watanabe, T. Muro, M. Yoshiyama, K. Takeuchi, T. Hozumi, and J. Yoshikawa Modulation of coronary flow velocity reserve by gender, menstrual cycle and hormone replacement therapy J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1879 - 1884. [Abstract] [Full Text] [PDF]

				S.-J. Rim, H. Leong-Poi, J. R. Lindner, K. Wei, N. G. Fisher, and S. Kaul Decrease in Coronary Blood Flow Reserve During Hyperlipidemia Is Secondary to an Increase in Blood Viscosity Circulation, November 27, 2001; 104(22): 2704 - 2709. [Abstract] [Full Text] [PDF]

				P. Poredos State-of-the-Art Review: Endothelial Dysfunction in the Pathogenesis of Atherosclerosis Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 276 - 280. [Abstract] [PDF]

				J. Taki, S. Fujino, K. Nakajima, I. Matsunari, H. Okazaki, T. Saga, H. Bunko, and N. Tonami 99mTc-Sestamibi Retention Characteristics During Pharmacologic Hyperemia in Human Myocardium: Comparison with Coronary Flow Reserve Measured by Doppler Flowire J. Nucl. Med., October 1, 2001; 42(10): 1457 - 1463. [Abstract] [Full Text] [PDF]

				M Fujiwara, T Tamura, K Yoshida, K Nakagawa, M Nakao, M Yamanouchi, N Shikama, T Himi, and Y Masuda Coronary flow reserve in angiographically normal coronary arteries with one-vessel coronary artery disease without traditional risk factors Eur. Heart J., March 2, 2001; 22(6): 479 - 487. [Abstract] [PDF]

P. A. Kaufmann, T. Gnecchi-Ruscone, K. P. Schafers, T. F. Luscher, and P. G. Camici Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholester