© 1996 American Heart Association, Inc.
Articles |
Improvement of Atherosclerosis and Stiffness of the Thoracic Descending Aorta With Cholesterol-Lowering Therapies in Familial Hypercholesterolemia
the Second Department of Internal Medicine and Clinical Laboratory Science, Yamaguchi University School of Medicine, Yamaguchi, Japan. Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
Correspondence to Masunori Matsuzaki, MD, PhD, The Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi 755, Japan.
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Abstract |
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The thoracic aorta is frequently involved in atherosclerotic lesions associated with familial hypercholesterolemia (FH). Transesophageal echocardiography (TEE) allows quantitative evaluation of the wall properties of the thoracic aorta. Using TEE, we tested whether atherosclerosis of the thoracic aorta in FH could be improved by cholesterol-lowering therapies. The subjects investigated were 22 FH patients and 22 age-matched normal subjects. The descending aorta (DA) was divided into four longitudinal portions of equal length. Atheromatous lesions of each portion of the DA were scored by character and extension of lesions by biplane two-dimensional TEE. The scores of atheromatous lesions from all four portions of the DA were added together to give the total atheromatous score (TAS). We also measured instantaneous dimensional changes of the DA in a cardiac cycle by M-mode TEE and blood pressure by a cuff method and calculated the stiffness parameter ß (ln[SBP/DBP]/[Dmax-Dmin]/Dmin), where SBP is the systolic arterial blood pressure, DBP is the diastolic arterial blood pressure, Dmax is the maximum aortic dimension during the ejection period, and Dmin is the minimum aortic dimension during the preejection period. TAS was higher in FH (3.70±1.32) than normal (0.62±0.54, P<.0001) subjects. ß in FH (10.35±4.87) was greater than in normal (5.10±1.25, P<.0001) subjects, but there were no significant differences of DA dimensions between the groups. In both normal subjects and FH patients, ß correlated with age (r=.52, P<.02 and r=.59, P<.005, respectively). In FH patients, ß and TAS correlated well with pretreatment total cholesterol levels (r=.43, P<.05 and r=.60, P<.005, respectively). In 12 of 22 FH patients, strict cholesterol-lowering therapies with diet and cholesterol-lowering drugs (pravastatin and probucol) were undertaken for 13 months. Cholesterol levels were significantly decreased from 333±45 to 219±39 mg/dL (P<.0001); this was associated with significant decreases in ß and TAS (from 9.88±5.03 to 7.88±3.92, P<.005, and from 3.61±1.50 to 2.94±1.22, P<.0005, respectively). In FH patients, the incidence and severity of morphological and physiological atherosclerosis of the DA were significantly higher than in age-matched normal subjects. A significant regression of atherosclerosis was achieved by strict cholesterol-lowering therapies in relatively young FH patients.
Key Words: transesophageal echocardiography • atherosclerosis • thoracic descending aorta • familial hypercholesterolemia • cholesterol-lowering therapy
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Introduction |
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The lipoprotein disorder FH is inherited in an autosomal-dominant manner and is characterized by an abnormally high level of LDL-C in plasma from birth.1 2 3 Acquired atherosclerotic lesions of the coronary artery and aortic wall appear to be a frequent complication in the younger population with FH.4 5 6 The aorta is frequently involved in atherosclerotic lesions associated with FH to a particularly high degree.
Atherosclerosis was previously regarded as a combination of two major features of two separate diseases, atherosis and sclerosis. In 1904, Marchand7 recognized the consistent association of fatty degeneration and vessel stiffness and introduced the term atherosclerosis to indicate this combination. The standard methodology of diagnosis is sensitive to the atheromatous component but does not adequately evaluate the sclerotic component. However, arterial elasticity measurements in atherosclerotic animal models8 9 and humans10 confirm the coexistence of atherosis and sclerosis.11
TEE was developed in our department approximately 17 years ago,12 and it has been in wide clinical use in recent years. TEE allows not only the diagnosis of cardiovascular disease but also quantitative evaluation of the wall propers ties of the thoracic aorta and itdistensibility.13 14
In the present study, we assessed semiquantitative analysis of morphological atheromatous lesions (atherosis) of the thoracic aorta in normal subjects and FH patients by 2D TEE. At the same time, we used M-mode echocardiography to assess physiological aortic stiffness (sclerosis), a vascular characteristic that is difficult to assess using other methods.
We also used TEE to examine the influence of serum cholesterol level and age on the incidence of atherosclerotic lesions and whether regression of atherosclerotic lesions of the thoracic aorta was induced by strict long-term cholesterol-lowering therapies in FH patients.
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Methods |
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Study Patients
A total of 22 patients (9 men and 13 women) were studied. The patient characteristics that were examined are summarized in Table 1
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Criteria for the diagnosis of FH were serum TC >270 mg/dL before treatment and the presence of phenotype IIa or IIb hypercholesterolemia according to the World Health Organization classification. Another criterion was the detection of Achilles tendon xanthomas >10 mm thick on the lateral view by computed radiography (Fuji Corp Ltd). It was also necessary that each patient had at least one parent, sibling, or child who had hypercholesterolemia accompanied by tendon xanthomas. The other 22 subjects, aged 36 to 60 years, who presented without hypertension, hyperlipidemia, diabetes, or organic heart disease, served as normal subjects. All the subjects were free from severe cardiac dysfunction (left ventricular ejection fraction <50% by radionuclide ventriculography) and significant valvular diseases as confirmed by color Doppler echocardiography.
The study was approved by the Institutional Review Board of Yamaguchi University School of Medicine, and informed consent was obtained from all patients before the study.
TEE
We used biplane TEE to assess atherosclerotic lesions of the DA. The biplane probe (UST-SSD870 P2-5 or P2-6, Aloka Corp Ltd) consisted of two adjacent 5.0-MHz transducer arrays of 48 elements attached to the tip of a flexible shaft (9 mm in diameter and 100 cm long). The probe provided for longitudinal as well as transverse scanning planes and was connected to a commercially available echocardiograph (SSD870, Aloka Corp Ltd). 2D images of the thoracic aorta were recorded on ½-inch videotape for subsequent playback and evaluation, and M-mode images of the DA were recorded on a strip-chart recorder simultaneously with a lead II electrocardiogram and phonocardiogram.
The procedure that we used for inserting the transesophageal transducer in our laboratory has been reported.13 14 15 16 17 The examination was performed with all patients in the left lateral decubital position. The transesophageal transducer was passed voluntarily into the esophagus, and the location of the transducer during imaging was determined as the distance to the incisor.
Measurements of Morphological Atheromatous Lesions (Evaluation of Atherosis)
Fig 1 shows a diagram of biplane images of the thoracic aorta obtained by biplane 2D TEE. Except for the blind portion caused by the bifurcation of the trachea (shaded area in Fig 1), all portions of the thoracic aorta were satisfactorily imaged. Cross-sectional views of the DA at four equally sized segments (D1 through D4) located four regions that extended from 25 to approximately 45 cm, ie, from the incisors to the diaphragm level; these were assessed by biplane (transverse and longitudinal views) 2D TEE.
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The natural process of the formation of atheromatous lesions of the aorta is believed to be the occurrence of fatty streaks that progress to intimal thickening and finally to raised plaques.18 Calcification might occur as a terminal process of atheromatous lesions. Therefore, we classified atheromatous lesions of the DA into four categories and scored each segment according to the severity of atheromatous lesions on the 2D images as 0 through 3 (Fig 2). Atheromatous point 0 indicated that a fine and smooth intimal-medial complex echo was visualized at the center of the sector where the ultrasonic beam was perpendicular to the aortic wall (Fig 2A). Atheromatous point 1 indicated that diffuse intimal thickening produced irregular and dense echoes around the surface of the intima without raised plaque (thickness of intimal-medial complex <3 mm; Fig 2B). Atheromatous point 2 indicated the presence of significant raised plaque, cystic lesion, or ulcer formation (thickness of intimal-medial complex 
3 mm; Fig 2C). Atheromatous point 3 indicated that calcified plaque produced a marked increase in echo intensity together with acoustic shadowing behind the lesion (Fig 2D).
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We observed 360° of sector scan of the DA by rotating the transducer in all cases examined in the study (Fig 3). However, it was rare to find considerable atheromatous lesions of the DA in the half closer to the transducer. The incidence of atheromatous lesions is always much higher in the posterior wall of the DA (ie, the half of the aorta that is farther from the transducer) than the anterior half, probably because the affected area may be coincident with a low-shear region in the thoracic aorta.19 We therefore used the farther half of the circular transverse echo image of the DA for semiquantitative evaluation of atheromatous lesions.
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Measurements of atheromatous lesions of the DA, which represents the morphological properties in the aortic wall, are shown in Fig 4. Scoring of atheromatous lesions of the DA was done as follows. In each section of the whole DA, which was equally divided into four portions (D1 through D4) along the longitudinal direction, measurement was made of the sector angles of the most serious atheromatous lesions on the transverse scan images. The given sector angles decided by 180 degrees were then multiplied by referred points. The atheromatous scores (AS) from each of the four portions were added to obtain the TAS of the DA. TAS was defined as 
where
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1, 2, and 3 are sector angles of intimal thickening, atheroma, and calcification, respectively.
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Measurements of Physiological Aortic Stiffness (Evaluation of Sclerosis)
For the assessment of aortic stiffness, we measured instantaneous dimensional variables of the DA. While displaying a transverse 2D echogram of the DA at a depth 
35 cm from the incisors, the dimensional changes of the sites with almost normal intimal echo (atheromatous point 0 or 1) were simultaneously recorded on a strip-chart recorder during cardiac cycles by M-mode TEE. At the same time, BP was determined by a cuff method (Fig 5).
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We measured minimum aortic dimension during the preejection period (Dmin), maximum aortic dimension during the ejection period (Dmax), and systolic distension (
D=Dmax-Dmin); measurements were made in millimeters. A stiffness parameter, ß, was used to represent the physiological stiffness of the aortic wall. ß was calculated from the relation between systemic BP and the diameter of the DA by using20 21
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Cholesterol-Lowering Therapies and Follow-up
For the FH patients, management and clinical data including serum cholesterol level were observed only by F.O. Thus, the authors who performed TEE (N.T. and I.T.) and measured TAS and ß (Y.T. and Y.W.) were blinded to the results of these data. Additionally, the two echographers and two measurers did not know if the patients they examined were treated or untreated.
Intraobserver and interobserver variability of the ultrasound measurements was determined by remeasuring TAS and ß without knowledge of the previous values, serum cholesterol levels, or other clinical data during both the pretreatment and treatment periods. The second set of measurements was obtained 1 month after the first set. Linear regression analysis was applied to determine intraobserver (Y.T.) and interobserver (Y.T. and Y.W.) compatibility, presenting the correlation coefficient (r) and its SEE.
After the first TEE examination, all FH patients began a strict cholesterol-lowering therapy that included diet and the cholesterol-lowering agents probucol (1000 mg/d) and pravastatin (20 mg/d). In 12 of 22 FH patients, a repeat examination by TEE was undertaken 13±7 months later. At the repeat examination, 2D echocardiographic images and M-mode echograms of the DA were recorded at sites that were as close as possible to the sites used in the first examination. The sites were also confirmed by referring to the previously used distance from the incisor. The cholesterol-lowering therapies were continued without change until the second TEE examination.
Statistical Analysis
Continuous variables are expressed as mean±SD and were compared by using the unpaired Student's t test. The effects of the treatments were assessed by paired t test. We also calculated the best-fit linear regression equation by the least-squares method and the correlation coefficient for the pairs of data. Statistical significance was recognized when P<.05.
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Results |
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Reproducibility of Results
There was a highly significant correlation between the measurements of TAS and ß obtained by the same or different observers. All the paired measurements obtained by one of the observers revealed a correlation coefficient of r=.97 (P<.01) with SEEs of 0.52 and 1.35 for TAS and ß, respectively. The interobserver variability test for TAS and ß yielded correlation coefficients of r=.92 (SEE=0.76) and r=.96 (SEE=1.84), respectively (both P<.01). Therefore, we used the average values of both parameters obtained by two independent observers.
Morphological Analysis (Atheromatous Score) of Atheromatous Lesions
In all FH patients examined in the present study, the 2D echocardiographic evaluation of atheromatous lesions of the DA designated each portion of the DA as at least 1. Scores from each portion were significantly higher in FH patients (D1, 0.99±0.49; D2, 0.93±0.39; D3, 0.99±0.55; D4, 0.81±0.43; TAS, 3.70±1.32) than in normal subjects (TAS: 0.62±0.54, P<.0001; Table 2). There were no significant differences among FH patients between the atheromatous scores of any of the portions of the DA.
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Physiological Analysis of Aortic Stiffness (ß)
Measurements of the dimensional variables of the DA by M-mode echocardiography and the stiffness parameter ß are summarized in Table 3. Dimensional change of the DA throughout a cardiac cycle (D) was significantly less (P<.0001) in FH patients (1.12±0.45 mm) than normal subjects (1.72±0.27 mm). Accordingly, ß was significantly higher (P<.0001) in FH patients (10.35±4.87) than normal subjects (5.10±1.25), although there were no significant differences in Dmin, Dmax, and ln(SBP/DBP) between both groups, indicating augmented aortic stiffness in the FH patients.
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Relationships of TAS and ß With TC Level or Age
TAS in FH patients was highly correlated with TC level at pretreatment (r=.60, P<.005; Fig 6). The regression analysis between age and TAS in FH was significant though weak (r=.43, P<.05; Fig 6).
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ß in FH patients was significantly correlated with TC level (r=.43, P<.05; Fig 7). Fig 7 also shows the relationships between ß and age in normal subjects and FH patients. Although there were significant correlations between age and ß in both groups (FH patients: r=.59, P<.005; control subjects: r=.52, P<.02), the regression line of FH patients was much steeper than that of normal subjects.
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) and FH patients (
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Effect of Cholesterol-Lowering Therapies
In 12 of 22 FH patients, strict cholesterol-lowering therapies were undertaken for approximately 13 months. Table 4 shows changes in serum lipid levels, TAS, and ß between pretreatment and after cholesterol-lowering therapies. Although TG and HDL-C levels were not significantly changed during this period, significant reductions in TC and LDL-C levels (from 333±45 to 219±39 mg/dL and from 264±49 to 149±22 mg/dL, respectively, P<.0001) were associated with significant decreases in TAS (from 3.61±1.50 to 2.94±1.22, P<.0005) and ß (from 9.88±5.03 to 7.88±3.92, P<.005).
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Regression of atherosclerosis was much more common than expected. Figs 8 and 9 represent the regression of atherosclerotic lesions of the DA.
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Discussion |
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FH is inherited in an autosomal-dominant manner, and the incidence of this disease is thought to be high.1 2 3 Cutaneous and tendon xanthomas are unique clinical findings of FH. However, considering its pathology, atherosclerosis is the most important complication of the disease. In homozygous FH, coronary heart disease often begins in childhood and frequently causes death from myocardial infarction before the age of 20 years.
Atherosclerotic lesions in FH patients involve not only the coronary artery but also the aortic valves, aorta, and peripheral arteries. In this study, we assessed the semiquantitative analysis of morphological atheromatous lesions in the thoracic aorta in FH patients by TEE. At the same time, we used this technique to assess physiological aortic stiffness, which is difficult to assess by using a transthoracic ultrasound approach or any other method available. The use of the biplane transesophageal probe enables us to clearly visualize the features of intimal atherosclerotic lesions,18 a characteristic sign of lipid metabolism disorders, on the transverse scan images. Moreover, simultaneous display of the longitudinal image permitted us to observe the details of intimal lesions on a serial image. Echocardiograms of the thoracic aorta revealed normal intima in nearly all the normal subjects, except for those in whom intimal thickening was detected. In marked contrast, the echographic images of all the FH patients age-matched with the normal subjects disclosed intimal and medial atheromatous lesions.
Assessment of Atherosis
It is generally known that along with hypertension and smoking, hypercholesterolemia is one of the major risk factors of atherosclerosis. Strong et al23 have studied the relationship between the incidence of coronary intimal atherosclerotic lesions and age at onset of hypercholesterolemia in autopsied cases. According to their report the incidence increased with age, often beginning at 30 years of age and reaching a peak at 50 to 60 years. However, the incidence of so-called fatty streaks, ie, early atherosclerotic lesions, increased from 10 years of age, reaching a peak by 30 years. Risk factors such as hypercholesterolemia apparently play an important role in the development of early atherosclerotic lesions. FH patients are believed to be at increased risk of developing atherosclerosis due to exposure to high cholesterol levels from an early age. According to some reports,24 25 serum TC level alone has no direct correlation with the incidence of ischemic heart disease or the severity of coronary atherosclerotic lesions. However, cholesterol level does show a significant correlation with atherosclerosis when many risk factors are present concurrently with hypercholesterolemia. Our examination of the thoracic aorta by TEE revealed that the serum cholesterol level before treatment significantly correlated with aortic stiffness and the severity of intimal atheromatous lesions.
Assessment of Sclerosis
Hayashi et al20 21 have analyzed the mechanical behavior of human arterial walls by observing changes in external radii due to distending pressure. They demonstrated that the stiffness parameter ß is the slope of the exponential function between the logarithm of the relative arterial pressure and the distension ratio of the artery. This parameter characterizes the entire deformation behavior of the vascular wall and is independent of the intramural pressure within the physiological range. Some investigators26 27 28 have evaluated sclerosis of the carotid artery and abdominal artery in humans by using ultrasonography. We evaluated aortic wall stiffness by using ß in FH patients as assessed by M-mode TEE. ß was significantly higher in FH patients than in age-matched normal subjects. ß of FH patients was assessed when the intima was either normal or showed mild intimal thickening as determined by 2D echocardiography. This result suggests that aortic wall stiffness increases before the formation of severe intimal atheromatous lesions.
Cardiovascular complications associated with atherosclerosis progress with advancing age,29 and Kawasaki et al27 have demonstrated the age-related changes in ß of major branches of human arteries. An increase in the stiffness of arteries with advancing age is related to structural and anatomic changes such as an increased ratio of collagen to elastin, qualitative deficiency of the wall elements, and augmented relative wall thickness due to the increase in caliber and wall thickness.30 In other words, aging is one of the most important risk factors for sclerosis. Our previous studies12 13 using TEE proved that aortic wall distensibility significantly decreases with age even in subjects without atherogenic risk factors. In the present study, we observed a high correlation between age and ß. In FH patients the relationship between both parameters was much steeper than in normal subjects. The correlation between age and TAS was also significant though weak. These findings suggest that the serum cholesterol level may play a more direct role than age in the severity of morphological atheromatous lesions, even though physiological aortic stiffness may progress with age.
Regression of Aortic Atherosclerosis
Extensive research has been conducted into methods of regressing atherosclerosis. Lowering serum cholesterol level, particularly LDL-C, is known to be essential in retarding the atheromatous lesion development process. In recent years, animal experiments and clinical data have suggested that cholesterol-lowering therapy reversed lipid accumulation, the main feature of atheromatous lesions.
Wissler and Vesselinovitch31 used an atherogenic diet to produce aortic atherosclerotic lesions in the monkey and examined the effects of cholestyramine, probucol, or a combination of both on these lesions. Their study revealed that probucol produced a marked regression of atheromatous lesions. Kita et al32 report that the administration of probucol to Watanabe heritable hyperlipidemic rabbits possibly prevents the progression of atheromatous lesions of the aorta. In addition, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase33 34 has been reported to be effective in preventing the progression of aortic lesions in Watanabe heritable hyperlipidemic rabbits with hyperlipidemia loads. In the present study, we also administered probucol and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin to relatively younger patients with heterozygous FH. The results showed a significant reduction of cholesterol level associated with a significant morphological and physiological regression of atherosclerotic lesions of the DA.
The inhibitory effects of antilipotropic drugs on the progression of coronary atherosclerotic lesions have been widely reported.35 36 37 38 Epidemiological studies reveal that a reduction of serum cholesterol level markedly decreases the incidence of ischemic heart disease. Recent developments in coronary angiography39 40 41 and intravascular ultrasound42 now make it possible to evaluate coronary atheromatous lesions and the effectiveness of antilipotropic drugs on the lesion. However, atherosclerosis is not confined to the coronary arteries, and frequently occurs in the aorta or peripheral arteries as well. We concentrated our investigations on the thoracic aorta, which has thus far proven difficult to examine clinically. TEE, however, can be performed repeatedly because it is seminoninvasive. Its greatest advantage is that it permits simultaneous and quantitative diagnosis of the morphological and physiological properties of the thoracic aorta.
Conclusion
Pignoli43 and Pignoli et al44 have reported that the thickness of the intimal-medial complex as measured by carotid ultrasonography significantly correlates with that measured at the pathological examination. The comparison of TEE atheromatous findings with pathological findings is considered to be valuable. We intend to systematically compare echocardiographic findings with histological findings in a future study.
TEE was used for the accurate evaluation of morphological and physiological atherosclerotic lesions of the thoracic aorta in patients with atherogenic factors. This method thus seems capable of providing the diagnosis of the early stage of atherosclerotic lesions, leading to immediate initiation of strict cholesterol-lowering therapy and ultimately producing regression of existing atherosclerosis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was partly supported by a Research Grant for Cardiovascular Disease (3A-7) from the Ministry of Health and Welfare, Japan.
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Footnotes |
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Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
Received March 21, 1995;
revision received March 13, 1996;
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