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(Circulation. 1995;91:1375-1380.)
© 1995 American Heart Association, Inc.

Articles

Increased Prevalence of Coronary Ectasia in Heterozygous Familial Hypercholesterolemia

Krishnankutty Sudhir, MD, PhD; Thomas A. Ports, MD; Thomas M. Amidon, MD; Jeffrey J. Goldberger, MD; Vikas Bhushan, MD; John P. Kane, MD, PhD; Paul Yock, MD; Mary J. Malloy, MD

From the Cardiovascular Research Institute, University of California, San Francisco.

Correspondence to Mary J. Malloy, MD, Box 0130, University of California at San Francisco, San Francisco, CA 94143.

	Abstract

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Background Although coronary atherosclerosis most commonly produces clinical effects as a result of stenosis, aneurysmal disease also occurs. We have found an increased prevalence of ectasia and aneurysmal disease in familial hypercholesterolemia (FH) suggesting a link between plasma lipoproteins and coronary aneurysms.

Methods and Results In 197 asymptomatic subjects with FH, we examined the prevalence of ectasia and its association with coronary risk factors. An ectatic segment was defined as one with a luminal diameter >1.5 times that of the adjacent normal segment, excluding poststenotic dilation. Among subjects with FH, 15% had ectasia compared with 2.5% of an age- and sex-matched control group of 198 subjects without FH pre- senting for coronary angiography (P<.001). These control patients had significantly more severe coronary atherosclerosis than patients with FH. Ectasia was 3 times more common in men than women (P<.025). Neither age nor hypertension was predictive. Although in part reflecting the striking sex differential, ectasia was strongly associated with a lower HDL cholesterol level (P=.003), a higher LDL/HDL ratio (P=.003), and to a lesser extent, a higher LDL cholesterol level (P=.07). No association was found with plasma triglycerides or very low-density lipoprotein cholesterol levels. Among FH patients, ectasia was strongly associated with an overall index of occlusive atherosclerotic disease, based on quantitative angiography (P=.004). Intracoronary ultrasound interrogation of aneurysmal segments revealed circumferential intimal thickening.

Conclusions Coronary ectasia is more prevalent in patients with FH than in other patients with coronary atherosclerosis and shows a strong inverse association with HDL cholesterol levels. This suggests that disordered lipoprotein metabolism in FH may predispose patients to aneurysmal coronary artery disease.

Key Words: hypercholesterolemia • lipoproteins • aneurysm • risk factors • angiography

	Introduction

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Coronary ectasia is an uncommon angiographic finding, with estimates of its incidence varying from 0.3%¹ to 4.7%.² Its clinical significance is unclear, and there is some dispute regarding its relation to occlusive coronary artery disease. In various reports, ectasia has been described either as an isolated congenital lesion³ or in association with coronary atherosclerosis,^{4 5} syphilis,⁶ congenital heart disease,⁷ scleroderma,⁸ polyarteritis nodosa,⁹ Ehlers-Danlos syndrome,¹⁰ bacterial infections,¹¹ and Kawasaki syndrome.¹² In some studies, a higher incidence of systemic hypertension was found in patients with aneurysmal disease.^{13 14} Coronary ectasia has been described in one patient with homozygous familial hypercholesterolemia (FH).¹⁵ It was also observed in 18% of a small group of Japanese patients with heterozygous FH, but no association with age, plasma lipoproteins, or coronary stenosis was found.¹⁶ In the present study, we examined the prevalence of coronary ectasia, its anatomic distribution and extent in the coronary arterial tree, and its association with coronary risk factors in 197 asymptomatic patients with heterozygous FH. We observed an increased prevalence of ectasia in these patients (15%) compared with 2.5% in our patient population without FH presenting for coronary angiography. We found significant differences in sex distribution, lipoprotein profiles, and coronary artery stenosis between the FH patients with coronary ectasia (n=29) and the FH patients without ectasia (n=168).

	Methods

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Patient Selection
Data were analyzed from 197 consecutive asymptomatic patients with heterozygous FH recruited from the Lipid Clinic at the University of California, San Francisco. To be included, patients had to have tendon xanthomas, mean LDL cholesterol levels >200 mg/dL (5.17 mmol/L), and total triglyceride levels <275 mg/dL (3.1 mmol/L) while they were consuming a diet restricted in saturated fats and cholesterol. Patients without tendon xanthomas were included if they had an LDL cholesterol level >250 mg/dL (6.46 mmol/L) or an LDL cholesterol level >200 mg/dL (5.17 mmol/L) and a first-degree relative with tendon xanthomas. Patients with previous angioplasty, coronary bypass surgery, or multiple infarcts were excluded, as were patients with systemic diseases other than atherosclerosis or hypertension. Patients with disorders known to produce secondary hyperlipidemia and those homozygous for apolipoprotein E-2 also were excluded.

Angiography and Analysis of Angiograms
Coronary angiography was done via the femoral arterial approach using 7F catheters (US Catheter Instrument Co). Cineangiograms were filmed at 60 frames per second through a lens with a focal length of 135 mm, with an x-ray field of 15 cm. Multiple pairs of perpendicular views of the left and right coronary arteries were obtained for biplane quantitative analysis.¹⁷

Films were viewed at x5 magnification (Vanguard Instruments). An ectatic segment was defined as one with a luminal diameter >1.5 times that of the adjacent normal segment.¹⁸ Poststenotic dilation was excluded from this analysis. Ectatic segments were classified as localized when they involved a discrete portion of the artery with adjacent normal vessel within that segment and diffuse when the entire segment was ectatic with no normal vessel within that segment. Measurements were made using a calibration device placed perpendicular to the artery of interest, and in each instance, an ectasia ratio (diameter of ectatic segment/diameter of the adjacent normal segment) was calculated.

In 141 patients with FH, percent cross-sectional area stenosis was computed using quantitative angiography.¹⁷ As an index of severity of coronary artery disease, a coronary stenosis score was also calculated in each patient as the sum of all percent area coronary stenoses. Angiograms were also analyzed for percent diameter stenosis and number of lesions. In addition, angiograms from 198 patients from our catheterization laboratory, matched for age and sex with the FH population, were analyzed for evidence of coronary ectasia and for percent diameter stenosis and number of lesions.

Measurement of Lipids and Lipoproteins
Close to the time of angiographic evaluation, blood was drawn from patients after a 10- to 16-hour fast. Serum was separated at room temperature for determination of cholesterol and triglyceride concentrations.¹⁹ Cholesterol and triglyceride concentrations were measured as very low-density lipoproteins (VLDL), low-density lipoproteins, and high-density lipoproteins after separation by preparative ultracentrifugation.¹⁹ Cholesterol and triglyceride analyses were standardized against reference material supplied by the Standardization of the National Center for Disease Control.

Intravascular Ultrasound Imaging
In two subjects with ectasia, intravascular ultrasound imaging was performed as previously described²⁰ to examine the characteristics of the arterial wall in the ectatic segment. In brief, a 4.3F, 30-MHz, two-dimensional ultrasound imaging catheter (Cardiovascular Imaging Systems) was introduced over a 0.014-in. guide wire into the arterial segment of interest. Two-dimensional ultrasound images were obtained using a commercially available imaging system (CVIS, Cardiovascular Imaging Systems). The ultrasound catheter (4.3F) has a fixed, 30-MHz transducer and a rotating mirror assembly. Images were displayed on a video monitor; axial resolution was approximately 150 µm and lateral resolution approximately 250 µm. Gain, contrast, and reject settings were adjusted by the operator to yield a well-balanced gray scale appearance on the video display. Real-time images were stored on high-quality super VHS videotape for subsequent off-line studies.

Statistical Analysis
The prevalence of ectasia in FH patients was compared with those without FH using a 2x2 ² analysis. Tests of normality were applied, and since most of the data were found not to be normally distributed, nonparametric comparisons were applied. Coronary risk factors between FH patients with ectasia and FH patients without ectasia were compared using the Mann-Whitney U test. Sex and ethnic distributions and prevalence of hypertension and smoking in the FH groups with and without ectasia were compared using a 2x2 ² analysis. Potential correlations between coronary risk factors and the degree of ectasia were examined using the Kendall correlation test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Prevalence of Ectasia and Sex Distribution
Patients with FH had a prevalence of ectasia of 15% (29 subjects) compared with 2.5% (5 subjects) in an age- and sex-matched control population (n=198) without FH catheterized in our laboratory (²=14.37, P<.001). Whereas the study population with FH had nearly equal numbers of men (n=95) and women (n=102), ectasia was about 3 times as common in men with FH (21 men, 8 women, ²=4.99, P=.025).

Age, Hypertension, Smoking, and Ethnicity
There was no apparent relation of ectasia to age, hypertension, smoking, or ethnicity. Mean age in the FH group with ectasia was 42.5±1.8 years and 42.6±0.9 in the group without ectasia. There was one hypertensive patient in the FH group with ectasia and 15 in the FH group without ectasia (²=0.99, P=NS). There were 10 smokers among the group with ectasia (only 2 were current smokers) and 57 among the FH patients without ectasia (10 current) (²=0.003, P=NS). The majority of patients in both groups were white (ectasia, 59%; no ectasia, 69%), and ethnic distributions in the two groups were similar.

Anatomic Distribution and Type of Ectasia in the Coronary Arteries
Twenty-one patients had ectasia in the right coronary artery (13 diffuse, 8 localized), 16 had ectasia involving the left anterior descending coronary artery (10 localized, 6 diffuse), 13 had ectasia of the circumflex coronary artery (9 diffuse, 4 localized) (Figs 1 and 2), and 2 had ectasia involving the left main coronary artery (both diffuse).

View larger version (76K): [in this window] [in a new window]   Figure 1. Coronary angiograms from a 56-year-old man with familial hypercholesterolemia (A) and a 41-year-old man with familial hypercholesterolemia (B) in the right anterior oblique projection, showing diffuse ectasia of the left anterior descending and circumflex coronary arteries.

View larger version (115K): [in this window] [in a new window]   Figure 2. Coronary angiograms from a 43-year-old man with familial hypercholesterolemia (A) and a 37-year-old man with familial hypercholesterolemia (B) in the left anterior oblique projections, showing localized ectasia of the right coronary artery. Arrows indicate ectatic regions.

Lipoprotein Levels: Association With Coronary Ectasia
HDL cholesterol levels were significantly lower (ectasia, 47.2±2.6; no ectasia, 55.8±1.2 mg/dL; P=.003), LDL cholesterol levels higher (ectasia, 322.3±14.6; no ectasia, 296.3±5.5 mg/dL; P=.07), and LDL/HDL ratios significantly higher (ectasia, 7.4±0.5; no ectasia, 5.9±0.2; P=.003) in FH patients with ectasia (Fig 3). There was no significant difference between groups in total cholesterol (ectasia, 406.8±15.1; no ectasia, 395.9±5.8 mg/dL), total triglycerides (ectasia, 128.1±12.3; no ectasia, 132.0±8.2 mg/dL), LDL triglycerides (ectasia, 41.7±3.4; no ectasia, 42.6±1.6 mg/dL), HDL triglycerides (ectasia, 13.3±1.0; no ectasia, 13.9±0.5 mg/dL), VLDL cholesterol (ectasia, 22.8±2.9; no ectasia, 23.7±1.8 mg/dL), or VLDL triglycerides (ectasia, 69.0±9.1; no ectasia, 69.0±6.6 mg/dL).

View larger version (26K): [in this window] [in a new window]   Figure 3. Plots showing higher LDL levels (P=.07), lower HDL levels (P=.003), and higher LDL/HDL ratios (P=.003) in familial hypercholesterolemia patients with ectasia compared with those without ectasia. Data are presented as box plots: Upper bound of the rectangle is the upper quartile, lower bound is the lower quartile, and the line between them is the median; the two small horizontal lines at the ends of the vertical lines projecting above and below the rectangle indicate the 90th and 10th percentiles, respectively. Circles indicate extreme values lying above the 90th percentile or below the 10th percentile.

Whereas LDL cholesterol levels were similar in men and women in our FH study population (men, 299.5±7.0; women, 300.7±7.7 mg/dL), HDL cholesterol levels were significantly higher in women (men, 47.9±1.4; women, 60.6±1.6; P<.001). This no doubt partially accounts for our finding of lower HDL cholesterol levels in FH patients with ectasia, where the male-to-female ratio was almost 3:1. However, women with ectasia also had lower HDL cholesterol levels (52.9±7.6 mg/dL) than women without ectasia (61.3±1.6 mg/dL) (P=.07). Men with ectasia, too, showed a trend toward lower HDL cholesterol levels (45.1±2.1 mg/dL) compared with men without ectasia (48.7±1.6 mg/dL), but this difference did not reach statistical significance in our limited sample. The degree of ectasia (defined as the ratio of the ectatic segment to the adjacent nonectatic segment) ranged from 1.5 to 4.4 in patients with FH and did not correlate significantly with age or lipoprotein concentrations.

The 5 control subjects with ectasia had a mean total cholesterol level of 203±6.5 mg/dL, suggesting that none of these subjects had FH.

Coronary Artery Stenosis: Association With Ectasia
In 141 FH patients (ectasia, 16; no ectasia, 125) whose angiograms were analyzed for coronary stenosis by quantitative angiography, composite within-patient coronary stenosis scores correlated significantly with age (P<.001), total cholesterol (P=.04), LDL cholesterol (P=.04), and LDL/HDL cholesterol ratios (P=.03). There was a significantly higher coronary stenosis score in FH patients with ectasia (ectasia, 148±17; no ectasia, 103±5; P=.004), and there was a significant correlation between the coronary stenosis score and the number of ectatic vessels (P=.003).

Overall, patients with FH had less severe coronary artery disease than the control population. The average number of lesions in patients with FH was 5.8±0.4, with a mean percent diameter stenosis of 34±2%; control patients without ectasia had a mean of 6.2±0.3 lesions, with a mean percent diameter stenosis of 51±1.4%.

Intravascular Ultrasound Imaging Studies
In two patients with ectasia, the ectatic segment also was examined using two-dimensional intravascular ultrasound imaging. Despite angiographic evidence of increase in lumen size, the ectatic segments showed circumferential intimal thickening (Fig 4), with a mean intimal thickness of 900 µm. This value for intimal thickness is considerably in excess of the normal range (<178 µm) previously reported from our laboratory.²¹

View larger version (70K): [in this window] [in a new window]   Figure 4. A, Coronary angiogram in a 52-year-old man with familial hypercholesterolemia showing an ectatic segment in the left anterior descending artery. B, Two-dimensional intravascular ultrasound image of the ectatic segment showing circumferential intimal thickening. Calibration marks are 0.5 mm apart.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Coronary ectasia has been described as an uncommon manifestation of atherosclerosis.²² The present study demonstrates that there is an increased prevalence of coronary ectasia in FH related to higher levels of LDL cholesterol, lower levels of HDL cholesterol, and hence, a higher LDL/HDL ratio. Coronary ectasia also is associated with more extensive coronary stenosis. Thus, our findings would suggest that in FH, coronary ectasia is a consequence of more abnormal lipoprotein profiles and more extensive coronary atherosclerosis. The association of hypertension with coronary ectasia is debated^{2 13 14} ; in the present study, however, coronary ectasia in FH was unrelated to age, hypertension, smoking, or ethnicity.

Coronary ectasia was 3 times more frequent in men than in women in our study. Men are known to have a lower HDL cholesterol than women; hence, the association of a lower HDL in FH patients with ectasia may have been caused by a higher male-to-female ratio among patients with ectasia in our study. However, HDL cholesterol levels were lower among our female FH patients with coronary ectasia and tended to be lower in male FH patients with ectasia as well. There was no difference in LDL cholesterol levels between men and women among our FH patients. Hence, our observation of higher LDL levels in FH patients with ectasia was unlikely to have been biased by the increased number of male FH patients with ectasia. Our findings differ from those of Genda et al,¹⁶ who found no association of ectasia with lipoprotein levels or coronary stenosis.

Our observation that ectasia of the coronary arteries correlated with the severity of stenotic coronary lesions (in within-patient studies) suggests that stenosis and ectasia have pathophysiological mechanisms in common. In fact, thinning of the vascular media has been associated with advanced atherosclerosis.^{23 24} Because we systematically excluded ectatic regions that were juxtaposed to stenotic lesions, the phenomenon we have observed is not due to poststenotic dilation. Glagov and his associates²⁵ have described compensatory dilation in human coronary arteries at sites where plaques have begun to diminish the cross-sectional area of the lumen. This involves an increase in the area inscribed by the internal elastic lamina, indicating that this structure is somehow capable of expansion at the site of the lesion. Observations in animal models suggest that this phenomenon is related to increased velocity of flow in the vicinity of the plaque.^{26 27} Whatever the mechanism, the capacity for compensatory dilation appears to be limited, ceasing when plaque volume reaches about 40% of the area within the internal elastic lamina.²⁵ Schwartz et al have shown that age itself appears to produce significant dilation of both the coronary arteries²⁸ and the aorta,²⁹ perhaps reflecting long-term mechanical effects on elastic tissue elements. The dilation associated with age, however, is uniform in its distribution and limited to an increase of about twofold in luminal diameter, in contrast with the focal, often saccular, aneurysms that we describe. Thus, if a commonality of mechanism is involved with the phenomenon of dilation with age, it is markedly aggravated in patients with FH.

FH is associated with the highest levels of LDL among the more common forms of genetic hyperlipidemia. Therefore, the marked increase that we have observed in the incidence of coronary ectasia among patients with FH and its positive correlation with LDL cholesterol levels in this study suggest that lipoproteins may be directly involved in this process, perhaps reducing the tensile strength of the artery wall. Thompson et al³⁰ reported improvement in coronary ectasia after plasma exchange in a patient with FH, lending support to an association between plasma lipoproteins and ectasia. Interestingly, lipid abnormalities have been described in Kawasaki syndrome,³¹ which is associated with coronary artery abnormalities including aneurysms.¹² The abnormal lipid profile includes depressed total and HDL cholesterol concentrations during the acute phase and a persistence of low HDL for many years.³¹ The association of these abnormalities with coronary ectasia in Kawasaki syndrome has not been studied.

Physical interaction between lipoprotein-like particles and both elastin and collagen fibers can be demonstrated by scanning electron microscopy.³² Apolipoprotein (apo) B, the principal protein of LDL, can be detected immunochemically in the vicinity of collagen and elastin fibers in the intima. Furthermore, it has long been recognized that about half of the apo B–containing lipoproteins of the artery wall are released only after collagenase treatment. LDL has been shown to bind to both elastin³³ and collagen³⁴ in vitro, and lipoprotein-derived lipids can themselves bind to collagen.³⁵ In fact, this process may be an integral part of the formation of foam cells because it has been shown that interaction of LDL with collagen and with elastin increases endocytosis by macrophages and smooth muscle cells.^{36 37} In this respect, it is interesting that the binding of LDL to collagen may induce conformational changes in apo B that facilitate its binding to collagen-like domains of the scavenger receptor.³⁸ Furthermore, oxidation of LDL, now thought to be a critical process in atherogenesis,³⁹ increases binding of LDL to collagen,⁴⁰ raising the possibility of damage to collagen or elastin fibers mediated by free radicals derived from lipid hydroperoxides and other reactive intermediaries. A further mechanism by which collagen could be chemically modified is the covalent cross-linking of apo B to arterial type III procollagen by transglutaminase.⁴¹

In addition to the possibility that structural weakening of connective tissue elements in the artery wall may result from interaction with LDL, active lysis of elastin or collagen also may be a consequence of foam cell formation. Fuster et al⁴² and Schwartz et al⁴³ have pointed out the inflammatory nature of the atheroma. In particular, unstable angina and infarction are now clearly established consequences of the weakening of the connective tissue scaffolding underlying the endothelium over an atheromatous plaque.^{42 44} The frequent appearance of layers of fibrin incorporated into complex lesions suggests that such events are commonplace, contributing to the mass of atheroma as a result of subclinical fissuring. A direct link between foam cells and possible weakening of arterial wall connective tissue is already at hand. Macrophages elaborate several proteases, including collagenase activity, as part of the inflammatory response. Furthermore, it is now established that macrophages secrete elastase activity in response to the endocytosis of modified LDL.⁴³ Endothelial injury also could contribute to this effect because platelet activating factor released by endothelial cells stimulates secretion of elastase activity by macrophages.⁴⁵ Thus, coronary ectasia may be an exaggeration of the remodeling process. Our findings of circumferential intimal thickening at the ectatic site, on intracoronary ultrasound, is consistent with this model.

Although coronary ectasia has been reported in association with a variety of pathological conditions (see introduction), the most common association in Western populations is with atherosclerotic coronary artery disease.¹⁸ It is unlikely, however, that the greater prevalence of ectasia simply reflects greater severity of coronary artery disease because FH patients actually had less severe disease than the control population. The prognosis of patients with coronary ectasia is unclear. One study reported an increased mortality in association with ectasia,¹³ presumably from thrombosis secondary to nonlaminar blood flow in a dilated vessel. In that study, however, there was a higher incidence of three-vessel disease, which may have accounted for increased mortality. More recent studies² have shown no increase in mortality for aneurysmal coronary artery disease. In the present study, ectasia in FH patients is associated with a more abnormal lipoprotein profile and with more severe atherosclerosis and thus would predict a higher risk of mortality. Further follow-up of these patients is required to reveal the pathophysiological significance of this entity.

	Acknowledgments

 
This study was funded through grants from the National Institutes of Health (HL-14237, Arteriosclerosis Specialized Center of Research, and HL-50779-01), the University of California Tobacco Related Disease Research Program (2RT172), and the General Clinical Research Center, University of California at San Francisco (5-M01-RR00079). Dr Sudhir was funded as a C.J. Martin Fellow by the National Health and Medical Research Council of Australia and as a Postdoctoral Fellow by the American Heart Association, California Affiliate.

	Footnotes

 
Dr Yock is a consultant with an equity position at Cardiovascular Imaging Systems.

Received December 22, 1993; revision received September 30, 1994; accepted October 10, 1994.

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