© 1999 American Heart Association, Inc.
Original Contributions |
Large-Artery Elastic Properties in Young Men
Relationships to Serum Lipoproteins and Oxidized Low-Density Lipoproteins
From the Departments of Clinical Physiology (J.O.T., J.J.H., O.T.R.), Radiology (P.N.), and Medicine (J.S.A.V.), Turku University Central Hospital, Finland; and the MCA Research Laboratory, Department of Physiology (M.A.), and the Cardiorespiratory Research Unit (H.N.), University of Turku, Finland.
Correspondence to Jyri O. Toikka, Department of Clinical Physiology, Turku University Hospital, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland. E-mail jyri.toikka{at}utu.fi
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Abstract |
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Abstract—Measures of arterial elasticity have been proposed as surrogate markers for asymptomatic atherosclerosis. We investigated the relations of serum lipoproteins, oxidized low-density lipoprotein (ox-LDL), and familial hypercholesterolemia (FH) to arterial elasticity among young men. As a marker of arterial elasticity we measured compliance in the thoracic aorta by using magnetic resonance imaging and in the common carotid artery by using ultrasound. LDL diene conjugation was used as a marker of ox-LDL. In study I, 25 healthy men (aged 29 to 39) were classified into 2 extreme groups according to previously measured high-density lipoprotein cholesterol to total cholesterol ratio (HDL-C/TC ratio). In study II, the healthy men were used as controls for 10 age matched asymptomatic patients with FH. In healthy men, the group with low HDL-C/TC ratio had decreased carotid artery compliance (2.3±0.4% versus 1.9±0.5%/10 mm Hg, P=0.034). In univariate analysis, the compliance of the carotid artery associated with ox-LDL (r =-0.49, P=0.016) and HDL-C/TC ratio (r=0.41, P=0.040). In multivariate regression analyses, ox-LDL was the only independent determinant for compliance of the carotid artery (P=0.016). Aortic elasticity was not related to standard lipid variables, but the compliance of the ascending aorta associated with ox-LDL (r=-0.44, P=0.030). In FH patients, arterial elasticity was similar to that in controls. We conclude that elasticity of the common carotid artery is affected by serum lipid profile in young men. The current study demonstrates for the first time an in vivo association between ox-LDL and arterial elasticity suggesting that oxidative modification of LDL may play a role in the alteration of arterial wall elastic properties.
Key Words: arteries • lipoproteins, LDL • hypercholesterolemia, familial
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Introduction |
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Atherosclerosis begins in childhood, and advanced atherosclerotic lesions may appear already in young adulthood.1 Postmortem studies have shown that several risk factors related to clinically significant coronary heart disease in adults are also associated with the prevalence and extent of arterial lesions in the young.2 3 Although the atherogenic process begins early in life, there is a long latent period before the appearance of the first clinical signs of arterial disease, such as angina or myocardial infarction. Detection of early changes of atherosclerosis would allow early treatment and prevention of cardiovascular diseases. In addition, noninvasive quantification of atherosclerosis in asymptomatic subjects would be useful for evaluating the effects of risk factor modifications.
Atherosclerosis and its risk factors can alter vascular wall properties and thereby distensibility.4 5 Arterial distensibility can be studied noninvasively in vivo and measures of arterial stiffness have been proposed as surrogate markers for atherosclerosis.6 7 It is well established that arterial distensibility decreases with aging.4 Furthermore, it has been shown that subjects with advanced coronary artery disease or hypertension have more rigid arteries than healthy controls.4 However, there is a lack of data concerning arterial distensibility in asymptomatic young adults. Furthermore, reports concerning serum lipoproteins in the context of arterial stiffness have been controversial. Some investigations have reported positive associations between serum cholesterol concentration and aortic distensibility6 8 9 ; some, negative associations10 11 ; and others, no association.12 13
In the current study, we investigated the elastic properties of large arteries in the ascending and descending parts of the thoracic aorta by using magnetic resonance imaging (MRI) and in the extracranial common carotid artery by using high-resolution ultrasound. The primary purpose was to study the association between the HDL cholesterol/total cholesterol (HDL-C/TC) ratio and arterial elasticity in healthy young men. We also studied the relationships between LDL oxidation and elasticity, and furthermore, we assessed the effect of familial hypercholesterolemia (FH) on arterial distensibility.
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Methods |
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Subjects
In study I, healthy men were enrolled from the Special Turku Coronary Risk Factor Intervention Project for Babies (STRIP) baby investigation, which is an ongoing study aimed at assessing the effects of dietary fat–oriented intervention on risk factors in young children.14 Young (age <40 years), lean (body mass index <27 kg/m2), normotensive (blood pressure <150/90 mm Hg), nonsmoking, and nondiabetic men (fathers, n=1022) were included in the current study. From these men, 2 groups of subjects were formed using earlier lipid measurements taken on 2 previous occasions
2 years apart. Group 1 included men who were in
the highest age-specific quartile for HDL-C/TC ratio in both
examinations (n=33), and group 2 included men who were in the lowest
quartile in both examinations (n=31). From these men, the 2 study
groups were further matched according to age and body mass index. Forty
subjects were selected for the study (20 subjects from each group). A
total of 25 subjects volunteered for the study (12 from group 1, 13
from group 2). In study II, groups 1 and 2 were pooled and used as a healthy control group (FH-) for 10 age-matched, nonsmoking FH patients (FH+) with no clinical history or evidence of coronary artery disease or any other cardiac disease, diabetes, or systemic hypertension. All FH patients had at least 1 first-degree relative with hypercholesterolemia. The diagnosis of FH was ensured by lymphocyte testing in 2 men. Five men had a positive finding of tendon xanthomata by ultrasound scan of the Achilles tendon. Three men have at least 1 first-degree relative with hypercholesterolemia and tendon xanthomata. Seven patients had been on cholesterol lowering medication for several years. Five patients were on lovastatin, 1 on lovastatin in combination with colestipol, and 1 on lovastatin in combination with acipimox. Three patients were on only diet therapy.
Magnetic Resonance Imaging
MRI was performed with the method previously described by
Mohiaddin et al15 using a commercial 1.5-T whole-body
scanner (Siemens Magnetom 63 SP), body coil, and ECG triggering. A
single transaxial slice at the level of the main pulmonary
artery was selected to obtain cross-sections of ascending and
descending aorta simultaneously. We used a gradient echo
sequence with repetition time of 21 ms and echo time of 5 ms. Up to 30
phases were obtained per cardiac cycle. Slice thickness was 10 mm
and the field of view, 350 mm. The images were acquired on a
128x256 matrix and transformed to a 256x256 matrix. After imaging,
the blood pressure was measured from the brachial artery by
sphygmomanometer with subjects supine. The quality of images from the
ascending aorta of 2 FH patients was inadequate and were excluded.
An on-screen analysis program (NIH-image) was used to measure the changes in aortic diameter from diastole to systole. The diastolic diameter was calculated from the smallest lumen area and systolic diameter from the largest lumen area as 2xsquare root (aortic area/3.1415).
To assess the repeatability of serial magnetic resonance examinations, aortic imaging was performed twice on on the same day in 19 healthy men measured. The coefficient of variation between the 2 examinations was 2.1±1.3% (mean±SD) for the diastolic diameter of ascending aorta, 2.8±2.4% for the diastolic diameter of descending aorta, 13.4±6.8% for the pulsative diameter change in the ascending aorta, and 19.4±14.2% for the pulsative diameter change in the descending aorta. To assess the repeatability of measuring analyzing magnetic resonance images, data from 8 studies were analyzed twice in a blinded manner. The coefficient of variation between the 2 analyses was 1.1±0.6% for the diastolic diameter of ascending aorta, 2.5±2.0% for the diastolic diameter of descending aorta, 7.7±6.7% for the pulsative diameter change in the ascending aorta, and 13.4±13.6% for the pulsative diameter change in the descending aorta. These values were in agreement with those of a previous report.9
Ultrasound Imaging
All measurements were performed by Acuson 128XP/10 (Acuson
Inc) ultrasonography with a 7-MHz scanning frequency linear
array transducer. All scans were performed by the same operator, who
was not involved in the image analysis. Left common carotid
artery diameter was scanned approximately 1 cm proximal to the carotid
bulb by M-mode. Blood pressure was measured in brachial artery of the
nondominant arm by sphygmomanometer.
Ultrasound scans were recorded on super-VHS videotape for later analysis. Images were digitized with videograbber for personal computer and analyzed with custom-made analysis software. The carotid diameter was measured in end-diastole and end-systole in at least 3 different cardiac cycles. The mean of the measurements was used as the end-diastolic or the end-systolic diameter.
Arterial compliance [%/10 mm Hg] was calculated as ([Ds-Dd]/Dd)/(Ps-Pd) where Dd is diastolic diameter; Ds, systolic diameter; Ps, systolic blood pressure; and Pd, diastolic blood pressure. Mean blood pressure was calculated as Pd+(Ps-Pd)/3.
Serum Lipids, Lipoproteins, LDL Oxidation, and Insulin
Blood was collected from the antecubital vein after an overnight
fast. All lipid determinations were done in the laboratory of Turku
University Central Hospital. Serum TC, HDL-C, and
triglyceride concentrations were measured using standard
enzymatic methods (Boehringer Mannheim GmbH) with a fully
automated analyzer (Hitachi 704; Hitachi Ltd). HDL-C
concentration was measured after polyethyleneglycol (final
concentration, 10%) precipitation.16 LDL-C concentration
was calculated using Friedewald's equation.17 Ox-LDL was
measured by determining the level of LDL diene conjugation by use of a
method that has been recently validated and reported in
detail.18 In brief, serum LDL-C was isolated by
precipitation with buffered heparin. The amount of peroxidized lipids
in samples was determined by degree of conjugated diene double bonds.
Lipids were extracted from the samples by a mixture of chloroform and
methanol (2:1), dried under nitrogen, redissolved in cyclohexane, and
analyzed spectrophotometrically at 234 nm. Serum insulin
concentration was measured by radioimmunoassay kit (Pharmacia,
Uppsala). Apolipoprotein AI and apolipoprotein B concentrations
were measured by the immunonephelometric method (Behring BNA). The
serum levels of lipoprotein(a) were determined using a commercially
available solid-phase 2-site immunoradiometric assay kit (Mercodia
apo(a) RIA, Mercodia AB).
Statistical Methods
Results are expressed as mean±SD unless stated otherwise.
Comparisons among groups were conducted by using Student's
t test. For correlation analysis, Pearson's
correlation coefficients were calculated. The data on serum
triglyceride, insulin, and lipoprotein(a) levels were
skewed into high values and were included as their logarithms in the
analysis. Stepwise linear regression models were used to study
the independent predictors of arterial elasticity
variables. Variables with univariate linear
regression P<0.15 were included in stepwise linear
regression model. All statistical tests were performed with the
Statistical Analysis System, SAS.19
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Results |
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Characteristics of Subjects
The average HDL-C/TC ratio was 0.37±0.05 and 0.18±0.04 in groups 1 and 2, respectively. The average mean arterial blood pressure was 96±9 and 98±7 mm Hg in groups 1 and 2, respectively (nonsignificant). The characteristics of subjects are shown in Table 1
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Arterial Compliance in Healthy Men With Different
HDL-C/TC Ratio
The compliance in the ascending and descending aorta and in the
carotid artery between the study groups of healthy men are shown in
Table 2. The group with a low HDL-C/TC
ratio (group 2) had less compliant carotid arteries compared with the
group with a high HDL-C/TC ratio (group 1) (2.3±0.4% versus
1.9±0.5%/10 mm Hg, P=0.034). No differences were
seen in the aortic compliance between the study groups.
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Associations Between Arterial Distensibility and Risk
Factors in Healthy Men
In the pooled data for healthy men (groups 1 and 2 combined),
carotid compliance correlated significantly with ox-LDL
(r=-0.49, P=0.016) (Figure 1) and HDL-C/TC ratio (r=0.41,
P=0.040) and tended to correlate with HDL-C
(r=0.38, P=0.058),
log10-transformed insulin (r=-0.39,
P=0.053), LDL-C (r=-0.35, P=0.085),
and apolipoprotein B (r=-0.36, P=0.078). In
stepwise multivariate regression analysis, the
only independent determinant for the compliance of the common carotid
artery was ox-LDL (P=0.016).
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The compliance of the ascending aorta correlated with ox-LDL (r=-0.44, P=0.030). The compliance of the descending aorta correlated with log10 transformed insulin (r=-0.41, P=0.040). No significant correlations were seen between aortic or carotid compliance and either systolic or diastolic blood pressure.
Effect of FH on Arterial Compliance
The comparison of FH men (FH+) and healthy controls (FH-)
is shown in Table 1
. No differences were seen in the aortic or
carotid compliances between FH+ and controls. In FH+, the
compliance of the carotid artery correlated with age
(r=-0.69, P=0.029) (Figure 2), body mass index (r=-0.66,
P=0.037), ox-LDL (r=-0.70, P=0.037),
apolipoprotein B (r=-0.70, P=0.024), and
apolipoprotein A-I (r=-0.77, P=0.009) and tended
to correlate LDL-C (r=-0.55, P=0.097) and
log10 transformed triglycerides
(r=-0.62, P=0.056).
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Discussion |
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Arterial atherosclerotic fatty streak involvement is inversely related to HDL-C level and directly to TC level.3 In epidemiological studies, HDL-C/TC ratio has been a better marker of coronary heart disease risk than either TC or HDL-C levels alone.20 In the current study, we tested the hypothesis that the burden of subclinical atherosclerosis would be different in young healthy men with either constantly high or low HDL-C/TC ratio level and that these groups would therefore have differences in vascular elastic properties. The comparison of 2 groups of carefully matched men with different HDL-C/TC ratio did not reveal differences in aortic elasticity but showed decreased carotid distensibility in the group with low HDL-C/TC ratio. Diminished carotid elasticity has been demonstrated previously in healthy children and adolescents with elevated serum TC and blood pressure levels.21 The realization that changes in arterial elasticity can be detected noninvasively in young asymptomatic subjects and that they are influenced by coronary risk factors implies that elastic indices may be used as markers of arterial function in primary prevention, eg, when evaluating the effects of lipid lowering diet or drug therapy on vascular wall properties.
The novel observation in the current study was that a marker of ox-LDL was associated with decreased arterial elasticity among healthy men, as well as FH patients. Furthermore, the relationship between ox-LDL and decreased elasticity remained after adjustment for age, blood pressure, and other lipid risk markers, suggesting that oxidative modification of LDL particles may be an important mechanism behind the association observed between arterial stiffness and serum lipoproteins. Oxidation of LDL may play a central role in the development of atherosclerosis. Recent investigations suggest that ox-LDL interacts with normal arterial vasodilatory function.22 23 Our group previously has shown altered coronary reactivity in normal subjects with high ox-LDL levels.24 Ox-LDL may influence vessel wall elasticity by enhancing vasoconstriction via increasing the intracellular calcium concentration in smooth muscle cells, by inducing endothelial dysfunction, or by promoting smooth muscle cell proliferation.23 25 26 27 28 A recent study by Ramsey et al29 showed that arterial distensibility is controlled by normal endothelium in healthy subjects.
It is well established that arterial distensibility is inversely related to age, coronary artery disease, and blood pressure.4 However, reports concerning serum lipoproteins in the context of arterial elasticity have been controversial. Most studies have shown an inverse association between arterial elasticity and total cholesterol concentration and a direct association between elasticity and HDL-concentration.11 30 31 32 However, some investigators have also reported increased arterial elasticity associated with elevated serum cholesterol levels. For example, Lehmann et al8 reported increased aortic elasticity in adolescent FH patients (mean age 15 years). They hypothesized that the increased elasticity in the early phases of atherosclerosis may be due to enhanced intake of lipids into vessel wall and formation of foam cells.33 The initial increase in elasticity associated with early atherosclerotic lesions has also been observed in animals such as cockerels and monkeys that have been fed an atherogenic diet.34 35 As vascular wall develops sclerotic component and the content of fibrous tissue increases, the artery becomes less distensible. However, the precise mechanisms by which serum lipids influence arterial distensibility are largely unknown.
Epidemiological studies have indicated that serum insulin level is a risk factor for atherosclerosis.36 In the current study, we found an inverse association between serum insulin level and compliance of the descending aorta. Similarly, some previous studies have shown an inverse association between insulin levels and arterial elasticity.5 9 31 The mechanisms by which insulin level may effect arterial distensibility are not well elucidated but may include the effects of insulin, promoting vascular wall smooth muscle hypertrophy37 and collagen tissue synthesis.
FH is a monogenic and dominantly inherited disease characterized by LDL-receptor defect, markedly elevated serum LDL concentrations, and premature coronary artery disease. Earlier observations have suggested that FH patients may have increased arterial distensibility in childhood and young adulthood, but they develop increased arterial stiffness with advancing age earlier than normal controls.4 8 We found no differences in aortic distensibility between FH patients and controls. Similarly, Dart et al6 found no differences in aortic elastic properties between isolated hypercholesterolemia patients and controls who were 30 years of age. Furthermore, the studies of Tomochika et al11 using transesophageal echocardiography have suggested that in FH patients, aortic compliance begins to decrease only after the age of 30. Thus, the findings of the current study are in line with these earlier observations and indicate that elastic indices of aorta or carotic artery do not discriminate between FH patients and normal controls aged of 30 years. Nevertheless, within the FH group, increased carotid stiffness was more closely associated with increasing age, elevated serum cholesterol concentration, and increased ox-LDL level compared with healthy men, suggesting differences in risk factor-vessel wall interactions between normal subjects and FH patients.
Limitations of Study
The current study included a relatively small number of
participants and only males. However, with respect to lipid risk
factors, the study groups were well characterized and in a narrow age
range. Thus, although the results may not be applicable to the
population at large, they nevertheless provide insight into the effects
of lipid risk factors on large artery properties in young adult
males.
Blood pressure was measured from the brachial artery by a noninvasive method, and this result was used as aortic or carotid blood pressure. The use of brachial pressures may overestimate pulse pressure in these arteries.38 The increase in pulse pressure in peripheral arteries is a consequence of pulsewave reflection from the periphery, which augments the peak of the pressure wave close to the reflection sites.38 Pulse wave velocity is closely related to age. Therefore, the difference between central and peripheral pulse pressure is likely to be similar between study subjects within a narrow age range, as in our study. Another potential limitation of the blood pressure measurement was that pressure was measured only once during the MRI and ultrasound studies, either immediately before or after the arterial diameter measurement. Using continuous blood pressure monitoring during the arterial scanning and including the average of several measurements in the calculations would probably result in more reliable estimates of arterial elasticity.13 32
In the current study, we measured the compliance by using two different kinds of imaging methods, MRI and ultrasound, that use entirely different physics in their imaging technique. Furthermore, the other target artery, the aorta, is located deep within the thoracic tissue, while the common carotid artery lies superficially. Because of these differences in methodology and location of the target artery, it is likely that the compliance values acquired with these 2 imaging modalities are not similar and, as such, not entirely comparable with each other. Therefore, in lack of specific knowledge about comparability of the compliance values obtained by either MRI or ultrasound, the results of the current study must be interpreted cautiously. For example, the comparison of the absolute compliance values between the aorta and the carotid artery may not be possible.
Conclusions
The current study demonstrates for the first time an in vivo
association between ox-LDL and arterial distensibility and
suggests that oxidative modification of LDL may have an essential role
in the alteration of arterial wall elastic properties in
the early stages of atherosclerosis. In addition, our
findings confirm those of others showing that large-artery elastic
properties are related to age and standard lipid risk factors in
asymptomatic young men.
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Acknowledgments |
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The authors thank the Emil Aaltonen Foundation, the Ida Montin Foundation, the Yrjö Jahnsson Foundation, the Foundation of Turku University, the Academy of Finland, and Turku University Central Hospital Research Foundation for financial support of the study.
Received October 14, 1997; accepted July 10, 1998.
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C. M. McEniery, S. Wallace, I. S. Mackenzie, B. McDonnell, Yasmin, D. E. Newby, J. R. Cockcroft, and I. B. Wilkinson Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans Hypertension, October 1, 2006; 48(4): 602 - 608. [Abstract] [Full Text] [PDF]
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 M. J. Haller, M. Samyn, W. W. Nichols, T. Brusko, C. Wasserfall, R. F. Schwartz, M. Atkinson, J. J. Shuster, G. L. Pierce, and J. H. Silverstein Radial Artery Tonometry Demonstrates Arterial Stiffness in Children With Type 1 Diabetes Diabetes Care, December 1, 2004; 27(12): 2911 - 2917. [Abstract] [Full Text] [PDF]
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I. B. Wilkinson, S. S. Franklin, and J. R. Cockcroft Nitric Oxide and the Regulation of Large Artery Stiffness: From Physiology to Pharmacology Hypertension, August 1, 2004; 44(2): 112 - 116. [Full Text] [PDF]
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A. M. Dart, C. D. Gatzka, J. D. Cameron, B. A. Kingwell, Y.-L. Liang, K. L. Berry, C. M. Reid, and G. L. Jennings Large Artery Stiffness Is Not Related to Plasma Cholesterol in Older Subjects with Hypertension Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 962 - 968. [Abstract] [Full Text]
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 M. J. Jarvisalo, M. Raitakari, J. O. Toikka, A. Putto-Laurila, R. Rontu, S. Laine, T. Lehtimaki, T. Ronnemaa, J. Viikari, and O. T. Raitakari Endothelial Dysfunction and Increased Arterial Intima-Media Thickness in Children With Type 1 Diabetes Circulation, April 13, 2004; 109(14): 1750 - 1755. [Abstract] [Full Text] [PDF]
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L. Jartti, T. Ronnemaa, J. Kaprio, M.J. Jarvisalo, J.O. Toikka, J. Marniemi, N. Hammar, L. Alfredsson, M. Saraste, J. Hartiala, et al. Population-Based Twin Study of the Effects of Migration From Finland to Sweden on Endothelial Function and Intima-Media Thickness Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 832 - 837. [Abstract] [Full Text] [PDF]
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 A. Makin, S.H. Silverman, and G.Y.H. Lip Peripheral vascular disease and Virchow's triad for thrombogenesis QJM, April 1, 2002; 95(4): 199 - 210. [Full Text] [PDF]
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 I. B. Wilkinson, K. Prasad, I. R. Hall, A. Thomas, H. MacCallum, D. J. Webb, M. P. Frenneaux, and J. R. Cockcroft Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1005 - 1011. [Abstract] [Full Text] [PDF]
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I. B. Wilkinson, I. R. Hall, H. MacCallum, I. S. Mackenzie, C. M. McEniery, B. J. van der Arend, Y.-E. Shu, L. S. MacKay, D. J. Webb, and J. R. Cockcroft Pulse-Wave Analysis: Clinical Evaluation of a Noninvasive, Widely Applicable Method for Assessing Endothelial Function Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 147 - 152. [Abstract] [Full Text] [PDF]
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 J. Westerbacka, A. Seppala-Lindroos, and H. Yki-Jarvinen Resistance to Acute Insulin Induced Decreases in Large Artery Stiffness Accompanies the Insulin Resistance Syndrome J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5262 - 5268. [Abstract] [Full Text] [PDF]
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A. M. Dart and B. A. Kingwell Pulse pressure--a review of mechanisms and clinical relevance J. Am. Coll. Cardiol., March 15, 2001; 37(4): 975 - 984. [Abstract] [Full Text] [PDF]
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 Y.-X. Wang, M. Halks-Miller, R. Vergona, M. E. Sullivan, R. Fitch, C. Mallari, B. Martin-McNulty, V. da Cunha, A. Freay, G. M. Rubanyi, et al. Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H428 - H434. [Abstract] [Full Text] [PDF]
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