CLINICAL STUDIES: ENDOTHELIAL FUNCTION
Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia
Philipp A. Kaufmann, MD*  ,1,
Tomaso Gnecchi-Ruscone, MD*,
Klaus P. Schäfers, MSc*,
Thomas F. Lüscher, MD, FACC, FESC, FRCP and
Paolo G. Camici, MD, FACC, FESC, FRCP*
* MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
Cardiology, University Hospital, Zürich, Switzerland
Manuscript received September 2, 1999;
revised manuscript received December 30, 1999,
accepted February 28, 2000.
Reprint requests and correspondence: Prof. Paolo G. Camici, MRC Cyclotron Unit, Hammersmith Hospital, London W12 ONN, United Kingdom
paolo.camici{at}csc.mrc.ac.uk
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Abstract
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OBJECTIVES
The present study evaluates the impact of total cholesterol (TC) and its subfractions on coronary flow reserve (CFR), an index of the integrated function of the coronary circulation, in asymptomatic subjects.
BACKGROUND
Endothelial dysfunction of the coronary microcirculation has been reported in asymptomatic subjects with hypercholesterolemia.
METHODS
Using oxygen-15-labeled water and positron emission tomography, myocardial blood flow (MBF, in ml/min per g) was measured at rest and during intravenous adenosine (140 µg/kg body weight per min) in 80 asymptomatic nonsmoking men: group 1 (n = 61; age 45 ± 7 years) had normal TC ( 6.5 mmol/liter or 250 mg/dl) and group 2 (n = 19; age 48 ± 10 years) had elevated TC.
RESULTS
Total cholesterol were 5.1 ± 0.8 and 7.2 ± 0.7 mmol/liter in groups 1 and 2 (p < 0.0005), respectively; low density lipoprotein (LDL) cholesterol levels were 3.2 ± 0.8 and 4.9 ± 0.7 mmol/liter (p < 0.0005); high density lipoprotein (HDL) cholesterol levels were 1.1 ± 0.3 and 1.0 ± 0.4 mmol/liter (p = NS); and triglyceride levels were 1.8 ± 1.3 and 3.0 ± 1.8 mmol/liter (p < 0.005). Groups 1 and 2 did not differ with regard to MBF at rest (0.87 ± 0.14 vs. 0.84 ± 0.14), MBF during adenosine (3.63 ± 1.02 vs. 3.30 ± 0.86) or CFR (4.23 ± 1.29 vs. 3.95 ± 0.93). A significant but weak correlation was found between CFR and HDL in group 1 (r = 0.29, p < 0.05), but not in group 2. In contrast, a significant inverse correlation between LDL and CFR was found in group 2 (r = –0.61, p < 0.05), but not in group 1.
CONCLUSIONS
Low density lipoprotein cholesterol but not TC correlated inversely with CFR in hypercholesterolemic subjects. Thus, LDL-induced coronary microvascular dysfunction could play an important role in the pathogenesis of coronary artery disease and its complications.
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Abbreviations and Acronyms
| | CFR | = coronary flow reserve | | ECG | = electrocardiogram | | H215O | = oxygen-15-labeled water | | HDL | = high density lipoprotein | | LDL | = low density lipoprotein | | MBF | = myocardial blood flow | | PET | = positron emission tomography | | TC | = total cholesterol |
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In angiographically normal coronary arteries, hypercholesterolemia impairs endothelial-mediated coronary dilation (1,2). This is, at least in part, reversible by L-arginine infusion (3,4) and therapy with lipid-lowering drugs (5–8) or calcium channel blockers (9). Similarly, by using positron emission tomography (PET), a reduction in coronary flow reserve (CFR) has been documented in hypercholesterolemic asymptomatic subjects with normal coronary arteries (10,11), as well as its reversibility with the use of cholesterol-lowering strategies (12–14). However, from results obtained in vitro, endothelial dysfunction has been specifically attributed to attenuation of nitric oxide release or the initiation of superoxide anion production by oxidized low density lipoprotein (LDL) cholesterol (15,16), or both, rather than by an increase in total cholesterol (TC). In fact, single LDL apheresis in humans has been shown to improve endothelium-dependent vasodilation in hypercholesterolemic patients (17). Thus, the aim of the present study was to evaluate the correlation between TC, including each lipid subfraction, and CFR as assessed with PET.
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Methods
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Study group.
Eighty asymptomatic male volunteers were included in the present analysis. Sixty-one subjects who had normal cholesterol (<6.5 mmol/liter or 250 mg/dl) served as the control group (group 1; age 45 ± 7 years). Nineteen subjects with elevated cholesterol ( 6.5 mmol/liter or 250 mg/dl; according to the inclusion criteria in West Of Scotland COronary Prevention Study (WOSCOPS) [18]) comprised group 2 (age 48 ± 10 years). None of the subjects had a history of cardiovascular disease or coronary risk factors (except for hypercholesterolemia). Entry criteria included a normal heart rate, blood pressure, electrocardiogram (ECG) and two-dimensional echocardiogram, as well as a low clinical probability for coronary artery disease (19).
In addition, all subjects were carefully instructed to refrain from intake of caffeine-containing beverages within 24 h before the study. A screening test for caffeine was performed on a blood sample taken immediately before the PET scan from each subject. Caffeine was not detectable in any of the blood samples.
Positron emission tomography.
Scanning was performed with an ECAT 931-08/12, 15-slice tomograph giving a 10.5-cm axial field of view (CTI/Siemens, Knoxville, Tennessee), the characteristics of which have been reported previously (20,21). Myocardial blood flow was measured using oxygen-15-labeled water (H215O), as reported elsewhere (22,23). Briefly, H215O (700 to 900 MBq) was injected as an intravenous bolus over 20 s at an infusion rate of 10 ml/min, and the venous line was then flushed for another 2 min with saline. The following acquisition frame times were used: 14 x 5, 3 x 10, 3 x 20 and 4 x 30 s.
To define regions of interest, myocardial and blood pool images were then generated directly from the dynamic H215O study, as reported previously (24). Subsequently, regions of interest were drawn within the left atrium and ventricular myocardium on consecutive image planes. These were projected onto the dynamic H215O images to generate blood and tissue time-activity curves. These curves were fitted to a single tissue-compartment tracer kinetic model to give values of myocardial blood flow (ml/g per min), as previously described (25). For the measurement of MBF, the entire left ventricle was involved to obtain a value representing the global left ventricle myocardial flow. The reproducibility of this technique has been documented recently (26).
The study protocol was approved by the Research Ethics Committee of Hammersmith Hospital, and radiation exposure was licensed by the U.K. Administration of Radioactive Substances Advisory Committee (ARSAC). All patients gave written, informed consent before the study.
Coronary flow reserve.
Myocardial blood flow was measured at rest and during pharmacologically induced hyperemia using IV adenosine at a rate of 140 µg/kg body weight per min (27). Arterial blood pressure was recorded with an automatic cuff sphygmomanometer at 1-min intervals, and the ECG was monitored continuously throughout the procedure. A 12-lead ECG was recorded at baseline and every minute during adenosine administration.
Coronary flow reserve was calculated as the ratio of hyperemic to baseline MBF. To account for the variability of coronary driving pressure, coronary resistance (mm Hg/ml per min per g) was also calculated as the ratio of mean arterial pressure to MBF.
Statistical analysis.
Intergroup comparisons of hemodynamic and PET data at rest and during adenosine were carried out by two-way analysis of variance (ANOVA) for continuous variables, followed by the Scheffé F test when the ANOVA test was significant (p < 0.05). Univariate analysis of the influence of cholesterol and its subfractions on CFR was performed with the use of linear regression. Data are reported as the mean value ± SD.
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Results
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All procedures were well tolerated, apart from the common side effects caused by adenosine, such as flushing and chest tightness.
Subject characteristics.
Gender distribution (all men), age and risk factors for coronary artery disease were comparable between the two groups (except for hypercholesterolemia). Because of the selection criteria, total serum and LDL cholesterol levels, as well as triglyceride levels, were significantly lower in control subjects than in hypercholesterolemic subjects (Table 1).
Hemodynamic data.
Heart rate and mean arterial blood pressure were similar in control subjects and hypercholesterolemic subjects both at rest and during adenosine. The rate–pressure product did not differ between the two groups, neither at rest nor during adenosine (Table 2).
Myocardial blood flow and CFR.
Mean values of MBF and CFR for both groups are summarized in Table 3. Rest and hyperemic MBF values were similar in control subjects and hypercholesterolemic subjects, resulting in a similar CFR in both groups (4.23 ± 1.29 vs. 3.95 ± 0.93, relative values; p = NS), with no correlation with TC or LDL cholesterol (Fig. 1). There was a significant, although weak, correlation between CFR and high density lipoprotein (HDL) cholesterol in normocholesterolemic (r = 0.29, p < 0.05; Fig. 2) but not in hypercholesterolemic subjects (Fig. 3). In contrast, there was a significant inverse correlation between CFR and LDL cholesterol in hypercholesterolemic (r = –0.61, p < 0.01; Fig. 3) but not in normocholesterolemic subjects (Table 4 and Fig. 2). Coronary resistance was comparable in both groups at rest and during adenosine (Table 3).
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Discussion
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In contrast to previous studies in small patient groups, we found no difference in either rest or hyperemic MBF or CFR based on TC. There was a weak correlation between CFR and HDL cholesterol for all subjects, but not between CFR and LDL cholesterol. However, in hypercholesterolemic subjects, CFR was inversely related to the LDL subfraction (–0.61, p < 0.01), supporting a pathogenic role for this lipid subfraction in dysfunction of the coronary microcirculation. This is in line with an increasing body of evidence indicating that LDL cholesterol, particularly its oxidized form, specifically impairs endothelium-dependent vasodilation by reducing nitric oxide synthesis or initiating superoxide anion production, or both (15,16,28–30).
Our findings are in agreement with previous results from Dayanikli et al. (10) and Yokoyama et al. (11,31), who demonstrated a significant inverse correlation between CFR and lipid variables, including LDL cholesterol. In contrast to our results and the results of Guethlin et al. (14), however, they also found a negative correlation between TC and CFR. The discrepancies could be explained by different patient selection, smaller study groups with a narrow, nonrepresentative range of cholesterol and concomitant medical therapy in the previous studies. For example, Dayanikli et al. (10) studied 16 hypercholesterolemic men, all of whom had a family history; three were smokers and 12 were being treated with lipid-lowering agents. Yokoyama et al. (31) found a significantly reduced CFR in patients with familial hypercholesterolemia. However, this must not necessarily be attributed to coronary dysfunction, because the systemic hemodynamic response to dipyridamole was largely blunted in patients with familial hypercholesterolemia as compared with control subjects. Indeed, although dipyridamole increased the rate–pressure product by >30% in control subjects, it induced an increase of only 10% in hypercholesterolemic patients. This is in contrast to a report from Kavey et al. (32), who found an exaggerated blood pressure response to exercise in patients with increased LDL cholesterol. It seems that secondary and familial hypercholesterolemia do not necessarily have the same impact on endothelial function, as the latter could represent an epiphenomenon whereby the primary disease would directly affect the vascular bed. In fact, Pitkänen et al. (33) recently found a correlation between TC and CFR in patients with familial combined hyperlipidemia and the phenotype IIB, but not in those with the phenotype IIA, despite increased total serum cholesterol in both groups. Recent data from the same group provided the first evidence of linkage to a subchromosomal region (1q21-23) in familial combined hyperlipidemia (34). Thus, they convincingly concluded that genetic factors behind familial combined hyperlipidemia may cause endothelial or smooth muscle dysfunction, or both, by mechanisms unrelated to lipid metabolism (33).
Yokoyama et al. (11) also reported decreased CFR in patients with secondary hypercholesterolemia. However, after exclusion of the hypertensive subjects from their analysis, they found no significant difference in CFR between hypercholesterolemic patients and control subjects (11). Hypertension was an exclusion criterion in our study, because it is a well-known confounding factor for endothelial dysfunction (35).
Determinants of CFR.
Coronary flow reserve, defined as the ratio of near maximal to basal MBF, has been proposed as an indirect variable to evaluate the function of the coronary circulation (36). It is an integrated measure of coronary flow through both the large epicardial coronary arteries and the microcirculation. Therefore, abnormal CFR can be caused by either narrowing of the epicardial arteries (22) or dysfunction of the microcirculation (37), even in the absence of detectable epicardial stenoses. Although, for ethical reasons, coronary angiography could not be performed on asymptomatic volunteers, the probability of relevant coronary stenosis was very low in our study group, according to the clinical assessment (19). Dysfunction of the microcirculation can be caused by 1) structural changes (38) (i.e., vascular remodeling with a reduced lumen/wall ratio; 2) functional alterations, which may involve neurohumoral factors (39–41) and/or endothelial dysfunction (1); 3) alteration of autonomic innervation (42–45); and 4) changes in extravascular resistance (e.g., increased intramyocardial pressure).
Endothelium-dependent and -independent coronary hyperemic response to adenosine.
Until recently, the vasodilator effect of adenosine was thought to be based solely on direct stimulation of A2-adenosine receptors on vascular smooth muscle cells, which mediate an increase in the second messenger cyclic adenosine monophosphate by stimulating adenylate cyclase. Therefore, this agent has been used frequently in animal as well as human studies to evaluate endothelium-independent vasodilation (46). However, in the last decade, it has been appreciated that adenosine also acts as an endothelial-dependent vasodilator (47), both through flow-mediated dilation (48) and by directly stimulating A1-adenosine (49) and other purinergic (50) receptors on endothelial cells. Therefore, impaired CFR, as assessed with PET in response to adenosine or dipyridamole, has been suggested as a surrogate measure of subclinical coronary disease, providing an integrated measure of vascular endothelial function and smooth muscle relaxation (10,33). In fact, CFR assessed during adenosine-induced hyperemia has been found to relate to endothelium-dependent vasodilation (51–53). Thus, our results reflect, at least in part, endothelial function.
Mechanisms of LDL-induced coronary dysfunction.
Endothelial dysfunction has been found to be caused by several coronary risk factors, such as hypercholesterolemia (54), essential hypertension (35), diabetes mellitus (55) and smoking (56). We found a significant inverse correlation between CFR and LDL cholesterol in hypercholesterolemic patients. Several mechanisms of LDL-associated vascular dysfunction have been reported. Reduced endothelial nitric oxide bioactivity has been demonstrated in hypercholesterolemic animals and attributed to increased LDL cholesterol (15,57). The oxidized form of LDL is markedly more effective than native LDL cholesterol in causing endothelial (29) and microcirculatory dysfunction (16) by reducing nitric oxide synthesis (16). In addition, LDL cholesterol has been shown to increase vascular production of superoxide anion (16,58,59), which can inactivate nitric oxide rapidly (60). Dietary correction of hypercholesterolemia (61), long-term antioxidant therapy (62,63) and polyethylene glycol superoxide dismutase (64) improve endothelium-dependent vasodilation by normalizing endothelium superoxide anion production. Oxidized LDL cholesterol, per se, has been shown to cause endothelial dysfunction in vitro (65) and to decrease endothelium-dependent vasodilation in ex vivo experiments (29,66). Oxidized LDL may also impair the signal transduction pathways that link endothelial cell surface receptors with nitric oxide production (67,68) and inhibit nitric oxide synthase activity (69). Recently, enhanced endothelin immunoreactivity (70) in the coronary and systemic circulation and elevated plasma levels (71) of endothelin have been reported in humans with endothelial dysfunction, suggesting the possibility that increased endothelin may also contribute to endothelial dysfunction.
Clinical implications.
Although we found no difference in MBF and CFR based on TC, the LDL cholesterol subfraction correlated inversely with CFR in hypercholesterolemic subjects who where otherwise normal and totally asymptomatic. This supports a pathogenetic role for the LDL subfraction in coronary dysfunction. Our in vivo results are in agreement with the previous observations identifying the LDL subfraction as a cause of endothelial dysfunction, and extend these findings to the coronary microcirculation in humans. This provides pathophysiologic support for the clinical strategy (72) that it is more appropriate to treat the entire lipid profile rather than to target TC reduction alone. In fact, risk assessment without taking LDL subfraction into account seems to provide unreliable results (73). In this context, it is of particular importance to remember that the benefits of treating any risk factor depend not only on the absolute risk of future disease but also on the degree to which the risk factor in question contributes to this risk (74). The measurement of CFR with PET in hypercholesterolemic patients may not only help to identify those asymptomatic subjects at highest risk, but also provide a "target" to assess the functional effectiveness of lipid-lowering treatment.
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Acknowledgments
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We are grateful to Flemming Hermansen for the use of his software and to the staff of the MRC Cyclotron Unit, especially the radiographers Andy Blyth and Hope McDevitt, for their excellent technical assistance.
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Footnotes
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1 Dr. Kaufmann was funded by a grant from the Swiss National Science Foundation (SCORE B, Grant no. 3232-055002.98). 
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