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Common carotid artery stiffness, cardiovascular function and lipid metabolism after menopause
Life Sciences 78 (2006) 1696 – 1701 www.elsevier.com/locate/lifescie
Common carotid artery stiffness, cardiovascular function and lipid metabolism after menopause Shun-ichiro Izumi *, Takayo Muano, Akira Mori, Goh Kika, Shinji Okuwaki Department of Obstetrics and Gynecology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan Received 5 January 2005; accepted 4 August 2005
Abstract While cardiovascular disease is a major cause of death in elderly women, relatively little is known regarding the influence of menopause on atherogenesis. We tried to characterize postmenopausal changes in the arterial properties. A group of 72 postmenopausal women were classified into subgroups based on duration of the postmenopausal period (PMP): Group PM1 (1 – 2 years; n = 16), PM4 (2 – 6 years; n = 16), PM8 (6 – 10 years; n = 25), and PM12 (10 – 15 years; n = 15). The control group consisted of 24 volunteers with regular menstruation (PM0). The diameter pulse waveform and intima-media thickness (IMT) of the common carotid artery (CCA) was measured using a phase-locked echo tracking system coupled with B-mode ultrasonography. The stiffness index was calculated from the waveform and the systemic blood pressure. The cardiac contractile force and the cerebral perfusion were also estimated using the maximum incremental velocity (MIV) and the calculated blood flow, as well as the fasting lipid profile. When compared to control, significant and progressive increases were noted in total cholesterol and low density lipoprotein (PM1, PM4, PM8, PM12), IMT (PM8, PM12), and SI (PM1, PM4, PM8, PM12). Further significant and progressive reductions were noted in pulse amplitude of CCA diameter (PM1, PM4, PM8, PM12) and MIV and cerebral perfusion (PM8, PM12). The postmenopausal increase in CCA stiffness as well as lipid profile occurs earlier than the increase in IMT and may be a more sensitive predictor of disorder on arterial property. D 2005 Elsevier Inc. All rights reserved. Keywords: Aging; Arteriosclerosis; Diagnosis; Lipids; Ultrasonics; Women; Estrogen
Introduction Cardiovascular disease is the leading cause of morbidity and mortality in elderly women. Thus, strategies to reduce atherosclerosis are critical to elevate quality of life in modern society, particularly in the context of increasing population of elderly women. While the incidence of atherosclerosis in women increases significantly after menopause (Bugliosi et al., 1995), a recent large-scale clinical trial of hormone replacement therapy was discontinued because of concerns regarding an increased risk of stroke and coronary heart disease (CHD) (Wassertheil-Smoller et al., 2003; Pradhan et al., 2002). Although an atherogenesis is dependent on multiple factors, including changes in lipid profile, endothelial function, and alteration in blood flow patterns (Willeit and Kiechl, 2000),
there have been few reports that tried to analyze these multiple factors simultaneously. We previously developed a method of measuring the vessel wall stiffness using a phase-locked echo tracking system coupled with B-mode ultrasonography, and used this technique to establish a change of fetal circulation as an initial event in fetal growth restriction (Mori et al., 2000). In the present study, we tried to characterize arterial properties using this technique after menopause, and investigate the consequence of menopausal duration/length on these variables simultaneously with lipid profile, while in young people the parameters of metabolic syndrome were reported to overlap but be partly independent to greater arterial stiffness (Ferreira et al., 2005). Subjects and methods Effect of menopause
* Corresponding author. Tel.: +81 463 93 1121x2394, 2395; fax: +81 463 92 8015 (direct), +81 463 91 4343 (OB/GYN). E-mail address: [email protected] (S. Izumi). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.08.006
Subjects included 72 postmenopausal women that were enrolled from the outpatient clinic of our department. A group
S. Izumi et al. / Life Sciences 78 (2006) 1696 – 1701
of 72 postmenopausal women were classified into different subgroups based on the duration of the postmenopausal period (PMP) as follows: Group PM1 (1 –2 years; n = 16), PM4 (2 –6 years; n = 16), PM8 (6 –10 years; n = 25), and PM12 (10 –15 years; n = 15), with the digit number label of the group name corresponding the median year of postmenopausal duration. The control group consisted of 24 volunteers with regular menstruation (PM0). Written informed consent was obtained from all participants, and the institutional review board of our hospital approved all protocols. There was no history of diabetes mellitus, hypertension, thromboembolic disease, cancer, or other chronic illnesses in any of the participants. Following an overnight fast, blood was obtained from participants for assessment of total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), triglycerides (TG), lipoproteins, and apolipoproteins. Two atherogenic indices (AIs) were calculated from the lipid parameters, as previously described (Dobiasova, 2004; Goran et al., 2001): AIc was calculated as [TC HDLC] / HDLC, and AIap was calculated as [apolipoprotein B] / [apolipoprotein A1]. To investigate arterial adaptation to the metabolic changes after menopause, we evaluated the arterial properties and circulatory parameters listed below.
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diastolic phase, D s is the arterial diameter in the systolic phase, and DD is the pulse diameter (= D s D d). Regarding the parameters of circulatory function, cardiac contractile force and the cerebral perfusion were also assessed. Maximum incremental velocity (MIV, mm/s), which was calculated from the first derivatives of the diameter waveform of CCA, was utilized as a reflection of cardiac contractile force. Further, blood flow was measured by color Doppler ultrasonography for 10 consecutive stable cardiac cycles, and cerebral blood flow was calculated by multiplying the full vessel lumen velocity and the vessel diameter, as previously described (Handa et al., 1990): ½ flow volume; ðml=sÞ ¼
Z
t
½flow velocityI½ vessel areadt
o
where t is the period of one heart beat ([vessel area] = ([vessel diameter] / 2)2k. Statistical analysis One way ANOVA was used for comparisons, with the Bonferroni test as post hoc comparison when necessary. A p value of less than 0.05 was considered statistically significant.
Arterial properties and circulatory parameters To evaluate arterial properties, the diameter pulse waveform and the intima-media thickness (IMT) of the right common carotid artery (CCA) was measured at 2 cm beneath the carotid bifurcation using a phase-locked echo tracking system coupled to a B-mode ultrasonic imager. This apparatus allows continuous measurement of the arterial vessel wall movement non-invasively through use of an ultrasonic probe (7.5 MHz) with simultaneous ECG recording. For further high-frequency (3 kHz) analysis, an analog to digital converter was equipped to the echo-tracking system, as described previously (Mori et al., 2000). The CCA stiffness index (SI) was calculated from pulsatile changes of arterial diameter and systemic blood pressure of the brachial artery, as described by Handa et al. (1990): ½ stiffness index ðSIÞ ¼ lnðPs =Pd ÞIðDd =DDÞ; where, ln is the natural logarithm, P s is the systolic pressure, P d is the diastolic pressure, D d is the arterial diameter in the
Results Participant demographics are summarized in the upper part of Table 1. There was no difference in body mass index (BMI) when comparing the groups. Difference in serum lipid parameters is shown in Fig. 1. Serum TC, and LDLC levels increased significantly ( p < 0.05, and p < 0.01, respectively) beginning at PM1, but the increase in TG and decrease in HDLC did not reach the level of statistical significance. These early increases continued up to PM12, with a significant decrease in HDLC noted at PM8 ( p < 0.05). Both AIs increased significantly at PM1. Systolic and diastolic blood pressures were significantly elevated beginning at PM4 ( p < 0.05), while arterial diameters of CCA in both systole and diastole increased beginning at PM8 (shown in the lower part of Table 1). Fig. 2 shows that the pulse blood pressure was significantly elevated beginning at PM4, and pulse amplitude was significantly reduced beginning at PM1. The
Table 1 General profile and circulatory data of enrolled subjects Group name Years after menopause n Age (years) Body mass index (kg/m2) Systolic pressure (mm-Hg) Diastolic pressure (mm-Hg) Systolic diameter (mm) Diastolic diameter (mm) All values are expressed as mean T SD. * = p < 0.05, . = p < 0.01 vs. PM0.
PM0
PM1
PM4
PM8
PM12
24 45.5 + 1.9 21.7 + 0.4 115.2 + 13.7 69.2 + 8.2 7.50 + 0.87 6.91 + 0.75
1.4 + 0.3 16 48.7 + 0.7 22.0 + 0.5 120.4 + 16.21 73.9 + 11.6 7.68 + 0.65 7.19 + 0.68
4.0 + 0.6 16 52.2 + 0.8 21.9 + 0.6 25.5 + 14.9* 75.2 + 9.6* 7.79 + 0.82 7.33 + 0.82
8.1 + 0.9 25 57.1 + 1.2 22.0 + 0.5 129.5 + 13.4. 79.7 + 11.3. 8.19 + 0.59* 7.79 + 0.77.
11.6 + 1.1 15 61.5 + 1.8 21.7 + 1.2 133.7 + 9.8. 80.4 + 10.6. 8.41 + 0.76. 8.08 + 0.79.
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Fig. 1. Difference of lipids parameters in postmenopausal group. Data of lipid parameters were designated as mean T SD along with post menopausal periods. Blood was obtained from participants following an overnight fast for assessment of total cholesterol (TC), triglycerides (TG), [Panel a]; high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) [Panel b]; and lipoproteins and apolipoproteins. Two atherogenic indices (AIs) were calculated from the lipid parameters [Panel c]: AIc was calculated as [TC HDLC] / HDLC, and AIap was calculated as [apolipoprotein B] / [apolipoprotein A1]. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
increase in IMT became statistically significantly ( p < 0.05) at PM12 (the upper panel of Fig. 3), whereas the SI showed a significant increase beginning at PM1 ( p < 0.05; the lower panel). As shown in Fig. 4, MIV significantly decreased after PM8 ( p < 0.05; the lower panel), which resulted in a simultaneous decrease in cerebral perfusion at PM8 (the upper panel). Discussion A goal of the present study was to characterize changes in arterial properties after menopause. While atherosclerosis may
be mediated by decreased estrogen action on the vascular wall (Mukherjee et al., 2003), the alteration in lipid metabolism has been accepted as a major risk factor for atherosclerotic disease (Dalal and Robbins, 2002; Despres et al., 2000). Within 2 years after menopause, TC increased by ¨10% LDLC increased by ¨20% and HDLC decreased by ¨10%. Further, atherogenic indices (AIc and AIap), which represent the relative atherogenic risk associated with altered lipid profiles, were elevated after menopause. Increased arterial stiffness leads to systolic blood pressure elevation and left ventricular hypertrophy and may contribute to development of coronary heart disease and stroke (Laurent et
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Fig. 2. Difference of pulse pressure and amplitude in postmenopausal group. The pulse blood pressure (upper panel) and the pulse amplitude of arterial diameter (lower panel) were designated as mean T SD along with post menopausal periods. The pulse amplitude equals the systolic diameter minus the diastolic diameter. Refer to the text for precise description. *, indicates p < 0.05 vs. group PM0.
al., 2001; Zureik et al., 2003). In contrast, with the early change in lipid profile, IMT, which is considered to be sensitive indicator for actual atherosclerosis, showed a significant increase at approximately 10 years after menopause. However, postmenopausal women had a significantly lower CCA distensibility within 2 years after menopause, as indicated by the change in SI. SI is computed from the stress –strain constitutive law of blood vessel and may be a more efficient and functional parameter for atherosclerosis than the pulse wave velocity
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(Hayashi et al., 1974). Since this index was calculated from the pulse amplitude (vessel caliber change) and the pulse pressure change, it is necessary to measure the precise diameter of blood vessel with arterial pulsation. For that purpose, we performed high frequency data sampling (3 kHZ) using ultrasonic wave echo tracking equipment (Mori et al., 2000). Since the aorta or CCA show earlier atherosclerotic change that the cerebral or coronary arteries (Van der Meer et al., 2004; Hollander et al., 2003; Shimizu et al., 2003), measurements of the CCA, which incidentally may be easier than measurement of other vessels in the outpatient setting, were used in the present study. In the present study, the SI showed an increase relatively early in the postmenopausal state. Blood pressure increased by 5– 10% and by 10 – 15% in diastole and systole, respectively, at approximately 5 years after menopause compared with the premenopausal group, resulting in an increase in the pulse pressure. In contrast, arterial diameters of CCA increased by 10– 15% and by 5 – 10% in diastole and systole, respectively, at the same time-point, resulting in a decrease of the pulse amplitude of the arterial diameter. Thus, the increase in the SI may serve as a sensitive functional marker for disordered arterial properties, whereas the relatively late increase in IMT may be insufficient for this purpose. To discuss the change of arterial property, there should be clarified conceptual aspect between arteriosclerosis and atherosclerosis. As Dr. O’Rourke summarized, ‘‘atherosclerosis is a primarily intimal disease that is patchy in location and causes narrowing of arteries and therefore interference with blood supply to tissues downstream. Arteriosclerosis is a primarily medial degenerative condition that is generalized throughout the thoracic aorta and larger central elastic arteries. It causes dilatation and stiffening, with impaired cushioning function, with an increased load on the left ventricle upstream’’ (O’Rourke, 1995). Thus atherosclerosis and arterial stiffness (i.e., arteriosclerosis) are two different and separate conditions. In our study, SI and IMT, those are representative for atherosclerosis and arteriosclerosis, respectively, were individually elevated in older women, where SI changed earlier than IMT. In this context, it might be not surprising that the risk factor (lipid profile) also occurs earlier than atherosclerosis
Fig. 3. Difference of intima-media thickness (IMT) and stiffness index (SI) in postmenopausal group. The intima-media thickness (IMT) and the stiffness index (SI) of the right common carotid artery (CCA) were designated as mean T SD along with post menopausal periods. Refer to the text for precise description. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
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Fig. 4. Cerebral perfusion and the maximum incremental velocity (MIV) in postmenopausal group. Calculated cerebral perfusion (upper panel) and MIV (lower panel) were designated as mean T SD along with post menopausal periods. The cerebral perfusion was estimated by multiplying the full vessel lumen velocity measured by color-Doppler ultrasonography and the vessel diameter, calculated by the diameter waveform of the common carotid artery (CCA). MIV reflects the cardiac contractile force and was calculated from the first derivatives of the diameter waveform of the CCA. Refer to the text for precise description. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
(IMT), which might be slower and more metabolically complicated disorder than arteriosclerosis. In the present study, the SI is calculated based on the change in (carotid) arterial diameter with blood pressure measured in the brachial artery, not in CCA. As proposed by van Bortel et al., the values could be reliably adjusted by comparing CCA and brachial waveform (Van Bortel et al., 2001). Utilizing this adjustment, the arterial stiffness was recently investigated for its association of the parameters of metabolic syndrome in young people and reported about their partly independence (Ferreira et al., 2005). Since not all data of ours include the simultaneously measured brachial waveform, we tried to convert some data of ours into the adjusted SI according to the above mentioned method and confirmed the tendency of earlier change of SI than IMT. For further investigation, we should record the simultaneous brachial waveform and try to obtain the accurate assessment for arterial property. However, our present data may be still reliable to evaluate the changes of arterial property after menopause in comparison of SI with IMT. Recent studies have demonstrated that estrogen produces various effects, including inhibition of vascular smooth muscle cells proliferation in vitro, induction of vascular extension, and modulation of vascular tone by production of nitric oxide (Iwakura et al., 2003). These data, taken together with studies that show that estrogen inhibits medial thickening (Lobo, 1991), suggest that estrogen supports endothelial cell function and exerts an anti-atherogenic effect and that absence of estrogen results in promotion of atherosclerosis (McGrath et al., 1998). Further, the selective estrogen modulator, tamoxifen, has a favorable influence on the postmenopausal arterial stiffness (Simon et al., 2002). However WHI study was discontinued because of an increased risk of stroke and CHD as described in ‘‘Introduction’’, there will still be controversial discussions about IMT of CCA and the beneficial/adverse effect(s) of estrogen therapy on CHD risk. The EPAT trial
(Hodis et al., 2001) found a beneficial effect of estrogen therapy and baseline IMT was 0.764 mm while adverse effects were found in HERS and the baseline CAIMT was 1.193 mm. We presented the basal date of the relationship of years postmenopausal to stage of IMT and this might have important implications concerning the time of initiating estrogen and/or hormone therapy, which might be investigated further. The present study described cerebral perfusion as the product of blood velocity and vessel cross-sectional area. This technique requires simultaneous measurement of blood velocity waveform by the color-Doppler method and vessel diameter pulsation waveform by an ultrasonic echo-tracking method. This method takes into account the vessel pulsation to determine the actual blood flow volume. The pressure and resistance of any fluid traveling through a tubular system can be expressed by the Poiseuille equation (Giles and Trudinger, 1986; Thompson and Trudinger, 1990): Flow ¼ Pressure=Resistance; i:e: DPkr 4=8 gl; where DP is the pressure gradient, r is the vessel radius, g is the viscosity of the fluid and l is the vessel length. The influence of viscosity on flow in much less important in large arteries than in small vessels. Indeed, the inertial forces moving a column of blood during pulsatile flow are more important in large arteries. Since the arteries characterized in the present study have a diameter of more than 5 mm, viscosity could be theoretically expected to be less important in determining flow. Therefore, the Poiseulle equation provides a useful expression of the relationship between pressure and resistance. Based on this analysis, we demonstrated that cerebral perfusion declined after 8 years of PMP. In the present study, MIV was used as a reflection of cardiac contractile force and correlated well with aortic flow acceleration. It seems reasonable to assume that the rate of increase in aortic diameter in early systole is closely linked to the rate of
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ejection of blood from the heart (i.e., the aortic flow acceleration (AFA)). Since AFA is a sensitive measure of cardiac inotropy, this correlation demonstrates that changes in MIV could be used to estimate the direction of change of the cardiac contractile force. In this study, MIV was calculated from the waveform of CCA. The elastic recoil of the CCA during diastole is dependent on the pressure gradient, since the radial stretching of the aorta is almost linearly related to the pressure gradient. Based on this analysis, we demonstrated that MIV declined after 8 years of PMP. Conclusion To characterize postmenopausal changes in the arterial properties, 72 postmenopausal and 24 volunteers with regular menstruation underwent assessment of diameter pulse waveform and intima-media thickness (IMT) of the common carotid artery (CCA), stiffness index and maximum incremental velocity (MIV) of cardiac contractile force. Since postmenopausal increases in CCA stiffness and lipid profile occurred earlier than the increase in IMT, SI may be more sensitive as a predictor for disorder on arterial property. References Bugliosi, R., Caratozzolo, V., Caratozzolo, A., 1995. Hyperlipidemia, hypertension and atherosclerosis in women. Reality and perspectives. LaClinica Terapeutica 146, 503 – 518. Dalal, D., Robbins, J.A., 2002. Management of hyperlipidemia in the elderly population: an evidence-based approach. The Southern Medical Journal 95, 1255 – 1261. Despres, J.P., Lemieux, I., Dagenais, G.R., Cantin, B., Lamarche, B., 2000. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study. Atherosclerosis 153, 263 – 272. Dobiasova, M., 2004. Atherogenic index of plasma [log(triglycerides / HDLcholesterol)]: theoretical and practical implications. Clinical Chemistry 50, 1113 – 1115. Ferreira, I., Henry, R.M., Twisk, J.W., van Mechelen, W., Kemper, H.C., Stehouwer, C.D., 2005. The metabolic syndrome, cardiopulmonary fitness, and subcutaneous trunk fat as independent determinants of arterial stiffness: the Amsterdam growth and health longitudinal study. Archives of Internal Medicine 25, 875 – 882. Giles, W.B., Trudinger, B.J., 1986. Umbilical cord whole blood viscosity and the umbilical artery flow velocity time waveforms: a correlation. British Journal of Obstetrics and Gynaecology 93, 466 – 470. Goran, W., Ingmar, J., Ingar, H., Are, H.A., Werner, K., Eugen, S., 2001. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 358, 2026 – 2033. Handa, N., Matsumoto, M., Maeda, H., Hougaku, H., Ogawa, S., Fukunaga, R., Yoneda, S., Kimura, K., Kamada, T., 1990. Ultrasonic evaluation of early carotid atherosclerosis. Stroke. A Journal of Cerebral Circulation 21, 1567 – 1572. Hayashi, K., Sato, M., Handa, H., Moritake, K., 1974. Biomechanical study of the constitute laws of vascular walls. Experimental Mechanics 14, 440 – 444. Hodis, H.N., Mack, W.J., Lobo, R.A., Shoupe, D., Sevanian, A., Mahrer, P.R., Selzer, R.H., Liu, Cr. C.R., Liu, Ch. C.H., Azen S.P., Estrogen in the Prevention of Atherosclerosis Trial Research Group, 2001. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebocontrolled trial. Annals of Internal Medicine 135, 939 – 953. Hollander, M., Hak, A.E., Koudstaal, P.J., Bots, M.L., Grobbee, D.E., Hofman, A., Witteman, J.C., Breteler, M.M., 2003. Comparison between measures of
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atherosclerosis and risk of stroke: the Rotterdam study. Stroke. A Journal of Cerebral Circulation 34, 2367 – 2372. Iwakura, A., Luedemann, C., Shastry, S., Hanley, A., Kearney, M., Aikawa, R., Isner, J.M., Asahara, T., Losordo, D.W., 2003. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrowderived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 108, 3115 – 3121. Laurent, S., Tropeano, A.I., Lillo-Lelouet, A., Jondeau, G., Laloux, B., Boutouyrie, P., 2001. Local pulse pressure is a major determinant of large artery remodelling. Clinical and Experimental Pharmacology and Physiology 28, 1011 – 1014. Lobo, R.A., 1991. Effects of hormonal replacement on lipids and lipoproteins in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism 73, 925 – 930. McGrath, B.P., Liang, Y.L., Teede, H., Shiel, L.M., Cameron, J.D., Dart, A., 1998. Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy. Arteriosclerosis, Thrombosis, and Vascular Biology 18, 1149 – 1156. Mori, A., Iwabuchi, M., Makino, T., 2000. Fetal haemodynamic changes in fetuses during fetal development evaluated by arterial pressure pulse and blood flow velocity waveforms. BJOG: An International Journal of Obstetrics and Gynaecology 107, 669 – 677. Mukherjee, T.K., Nathan, L., Dinh, H., Reddy, S.T., Chaudhuri, G., 2003. 17epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression. The Journal of Biological Chemistry 278, 11746 – 11752. O’Rourke, M., 1995. Mechanical principles in arterial disease. Hypertension 26, 2 – 9. Pradhan, A.D., Manson, J.E., Rossouw, J.E., Siscovick, D.S., Mouton, C.P., Rifai, N., Wallace, R.B., Jackson, R.D., Pettinger, M.B., Ridker, P.M., 2002. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. The Journal of the American Medical Association 288, 980 – 987. Shimizu, Y., Kitagawa, K., Nagai, Y., Narita, M., Hougaku, H., Masuyama, T., Matsumoto, M., Hori, M., 2003. Carotid atherosclerosis as a risk factor for complex aortic lesions in patients with ischemic cerebrovascular disease. Circulation Journal: Official Journal of the Japanese Circulation Society 67, 597 – 600. Simon, T., Boutouyrie, P., Simon, J.M., Laloux, B., Tournigand, C., Tropeano, A.I., Laurent, S., Jaillon, P., 2002. Influence of tamoxifen on carotid intimamedia thickness in postmenopausal women. Circulation 106, 2925 – 2929. Thompson, R.S., Trudinger, B.J., 1990. Doppler waveform pulsatility index and resistance, pressure and flow in the umbilical placental circulation: an investigation using a mathematical model. Ultrasound in Medicine and Biology 16, 449 – 458. Van Bortel, L.M., Balkestein, E.J., van der Heijden-Spek, J.J., Vanmolkot, F.H., Staessen, J.A., Kragten, J.A., Vredeveld, J.W., Safar, M.E., Struijker, Boudier, H.A., Hoeks, A.P., 2001. Non-invasive assessment of local arterial pulse pressure: comparison of applanation tonometry and echo-tracking. Journal of Hypertension 19, 1037 – 1044. Van der Meer, I.M., Bots, M.L., Hofman, A., del Sol, A.I., van der Kuip, D.A., Witteman, J.C., 2004. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam study. Circulation 109, 1089 – 1094. Wassertheil-Smoller, S., Hendrix, S.L., Limacher, M., Heiss, G., Kooperberg, C., Baird, A., Kotchen, T., Curb, J.D., Black, H., Rossouw, J.E., Aragaki, A., Safford, M., Stein, E., Laowattana, S., W.H.I. Investigators, 2003. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. The Journal of the American Medical Association 289, 2673 – 2684. Willeit, J., Kiechl, S., 2000. Biology of arterial atheroma. Cerebrovascular Diseases (Basel, Switzerland) 10 (Suppl 5), 1 – 8. Zureik, M., Bureau, J.M., Temmar, M., Adamopoulos, C., Courbon, D., Bean, K., Touboul, P.J., Benetos, A., Ducimetiere, P., 2003. Echogenic carotid plaques are associated with aortic arterial stiffness in subjects with subclinical carotid atherosclerosis. Hypertension 41, 519 – 527.
Common carotid artery stiffness, cardiovascular function and lipid metabolism after menopause Shun-ichiro Izumi *, Takayo Muano, Akira Mori, Goh Kika, Shinji Okuwaki Department of Obstetrics and Gynecology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan Received 5 January 2005; accepted 4 August 2005
Abstract While cardiovascular disease is a major cause of death in elderly women, relatively little is known regarding the influence of menopause on atherogenesis. We tried to characterize postmenopausal changes in the arterial properties. A group of 72 postmenopausal women were classified into subgroups based on duration of the postmenopausal period (PMP): Group PM1 (1 – 2 years; n = 16), PM4 (2 – 6 years; n = 16), PM8 (6 – 10 years; n = 25), and PM12 (10 – 15 years; n = 15). The control group consisted of 24 volunteers with regular menstruation (PM0). The diameter pulse waveform and intima-media thickness (IMT) of the common carotid artery (CCA) was measured using a phase-locked echo tracking system coupled with B-mode ultrasonography. The stiffness index was calculated from the waveform and the systemic blood pressure. The cardiac contractile force and the cerebral perfusion were also estimated using the maximum incremental velocity (MIV) and the calculated blood flow, as well as the fasting lipid profile. When compared to control, significant and progressive increases were noted in total cholesterol and low density lipoprotein (PM1, PM4, PM8, PM12), IMT (PM8, PM12), and SI (PM1, PM4, PM8, PM12). Further significant and progressive reductions were noted in pulse amplitude of CCA diameter (PM1, PM4, PM8, PM12) and MIV and cerebral perfusion (PM8, PM12). The postmenopausal increase in CCA stiffness as well as lipid profile occurs earlier than the increase in IMT and may be a more sensitive predictor of disorder on arterial property. D 2005 Elsevier Inc. All rights reserved. Keywords: Aging; Arteriosclerosis; Diagnosis; Lipids; Ultrasonics; Women; Estrogen
Introduction Cardiovascular disease is the leading cause of morbidity and mortality in elderly women. Thus, strategies to reduce atherosclerosis are critical to elevate quality of life in modern society, particularly in the context of increasing population of elderly women. While the incidence of atherosclerosis in women increases significantly after menopause (Bugliosi et al., 1995), a recent large-scale clinical trial of hormone replacement therapy was discontinued because of concerns regarding an increased risk of stroke and coronary heart disease (CHD) (Wassertheil-Smoller et al., 2003; Pradhan et al., 2002). Although an atherogenesis is dependent on multiple factors, including changes in lipid profile, endothelial function, and alteration in blood flow patterns (Willeit and Kiechl, 2000),
there have been few reports that tried to analyze these multiple factors simultaneously. We previously developed a method of measuring the vessel wall stiffness using a phase-locked echo tracking system coupled with B-mode ultrasonography, and used this technique to establish a change of fetal circulation as an initial event in fetal growth restriction (Mori et al., 2000). In the present study, we tried to characterize arterial properties using this technique after menopause, and investigate the consequence of menopausal duration/length on these variables simultaneously with lipid profile, while in young people the parameters of metabolic syndrome were reported to overlap but be partly independent to greater arterial stiffness (Ferreira et al., 2005). Subjects and methods Effect of menopause
* Corresponding author. Tel.: +81 463 93 1121x2394, 2395; fax: +81 463 92 8015 (direct), +81 463 91 4343 (OB/GYN). E-mail address: [email protected] (S. Izumi). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.08.006
Subjects included 72 postmenopausal women that were enrolled from the outpatient clinic of our department. A group
S. Izumi et al. / Life Sciences 78 (2006) 1696 – 1701
of 72 postmenopausal women were classified into different subgroups based on the duration of the postmenopausal period (PMP) as follows: Group PM1 (1 –2 years; n = 16), PM4 (2 –6 years; n = 16), PM8 (6 –10 years; n = 25), and PM12 (10 –15 years; n = 15), with the digit number label of the group name corresponding the median year of postmenopausal duration. The control group consisted of 24 volunteers with regular menstruation (PM0). Written informed consent was obtained from all participants, and the institutional review board of our hospital approved all protocols. There was no history of diabetes mellitus, hypertension, thromboembolic disease, cancer, or other chronic illnesses in any of the participants. Following an overnight fast, blood was obtained from participants for assessment of total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), triglycerides (TG), lipoproteins, and apolipoproteins. Two atherogenic indices (AIs) were calculated from the lipid parameters, as previously described (Dobiasova, 2004; Goran et al., 2001): AIc was calculated as [TC HDLC] / HDLC, and AIap was calculated as [apolipoprotein B] / [apolipoprotein A1]. To investigate arterial adaptation to the metabolic changes after menopause, we evaluated the arterial properties and circulatory parameters listed below.
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diastolic phase, D s is the arterial diameter in the systolic phase, and DD is the pulse diameter (= D s D d). Regarding the parameters of circulatory function, cardiac contractile force and the cerebral perfusion were also assessed. Maximum incremental velocity (MIV, mm/s), which was calculated from the first derivatives of the diameter waveform of CCA, was utilized as a reflection of cardiac contractile force. Further, blood flow was measured by color Doppler ultrasonography for 10 consecutive stable cardiac cycles, and cerebral blood flow was calculated by multiplying the full vessel lumen velocity and the vessel diameter, as previously described (Handa et al., 1990): ½ flow volume; ðml=sÞ ¼
Z
t
½flow velocityI½ vessel areadt
o
where t is the period of one heart beat ([vessel area] = ([vessel diameter] / 2)2k. Statistical analysis One way ANOVA was used for comparisons, with the Bonferroni test as post hoc comparison when necessary. A p value of less than 0.05 was considered statistically significant.
Arterial properties and circulatory parameters To evaluate arterial properties, the diameter pulse waveform and the intima-media thickness (IMT) of the right common carotid artery (CCA) was measured at 2 cm beneath the carotid bifurcation using a phase-locked echo tracking system coupled to a B-mode ultrasonic imager. This apparatus allows continuous measurement of the arterial vessel wall movement non-invasively through use of an ultrasonic probe (7.5 MHz) with simultaneous ECG recording. For further high-frequency (3 kHz) analysis, an analog to digital converter was equipped to the echo-tracking system, as described previously (Mori et al., 2000). The CCA stiffness index (SI) was calculated from pulsatile changes of arterial diameter and systemic blood pressure of the brachial artery, as described by Handa et al. (1990): ½ stiffness index ðSIÞ ¼ lnðPs =Pd ÞIðDd =DDÞ; where, ln is the natural logarithm, P s is the systolic pressure, P d is the diastolic pressure, D d is the arterial diameter in the
Results Participant demographics are summarized in the upper part of Table 1. There was no difference in body mass index (BMI) when comparing the groups. Difference in serum lipid parameters is shown in Fig. 1. Serum TC, and LDLC levels increased significantly ( p < 0.05, and p < 0.01, respectively) beginning at PM1, but the increase in TG and decrease in HDLC did not reach the level of statistical significance. These early increases continued up to PM12, with a significant decrease in HDLC noted at PM8 ( p < 0.05). Both AIs increased significantly at PM1. Systolic and diastolic blood pressures were significantly elevated beginning at PM4 ( p < 0.05), while arterial diameters of CCA in both systole and diastole increased beginning at PM8 (shown in the lower part of Table 1). Fig. 2 shows that the pulse blood pressure was significantly elevated beginning at PM4, and pulse amplitude was significantly reduced beginning at PM1. The
Table 1 General profile and circulatory data of enrolled subjects Group name Years after menopause n Age (years) Body mass index (kg/m2) Systolic pressure (mm-Hg) Diastolic pressure (mm-Hg) Systolic diameter (mm) Diastolic diameter (mm) All values are expressed as mean T SD. * = p < 0.05, . = p < 0.01 vs. PM0.
PM0
PM1
PM4
PM8
PM12
24 45.5 + 1.9 21.7 + 0.4 115.2 + 13.7 69.2 + 8.2 7.50 + 0.87 6.91 + 0.75
1.4 + 0.3 16 48.7 + 0.7 22.0 + 0.5 120.4 + 16.21 73.9 + 11.6 7.68 + 0.65 7.19 + 0.68
4.0 + 0.6 16 52.2 + 0.8 21.9 + 0.6 25.5 + 14.9* 75.2 + 9.6* 7.79 + 0.82 7.33 + 0.82
8.1 + 0.9 25 57.1 + 1.2 22.0 + 0.5 129.5 + 13.4. 79.7 + 11.3. 8.19 + 0.59* 7.79 + 0.77.
11.6 + 1.1 15 61.5 + 1.8 21.7 + 1.2 133.7 + 9.8. 80.4 + 10.6. 8.41 + 0.76. 8.08 + 0.79.
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Fig. 1. Difference of lipids parameters in postmenopausal group. Data of lipid parameters were designated as mean T SD along with post menopausal periods. Blood was obtained from participants following an overnight fast for assessment of total cholesterol (TC), triglycerides (TG), [Panel a]; high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) [Panel b]; and lipoproteins and apolipoproteins. Two atherogenic indices (AIs) were calculated from the lipid parameters [Panel c]: AIc was calculated as [TC HDLC] / HDLC, and AIap was calculated as [apolipoprotein B] / [apolipoprotein A1]. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
increase in IMT became statistically significantly ( p < 0.05) at PM12 (the upper panel of Fig. 3), whereas the SI showed a significant increase beginning at PM1 ( p < 0.05; the lower panel). As shown in Fig. 4, MIV significantly decreased after PM8 ( p < 0.05; the lower panel), which resulted in a simultaneous decrease in cerebral perfusion at PM8 (the upper panel). Discussion A goal of the present study was to characterize changes in arterial properties after menopause. While atherosclerosis may
be mediated by decreased estrogen action on the vascular wall (Mukherjee et al., 2003), the alteration in lipid metabolism has been accepted as a major risk factor for atherosclerotic disease (Dalal and Robbins, 2002; Despres et al., 2000). Within 2 years after menopause, TC increased by ¨10% LDLC increased by ¨20% and HDLC decreased by ¨10%. Further, atherogenic indices (AIc and AIap), which represent the relative atherogenic risk associated with altered lipid profiles, were elevated after menopause. Increased arterial stiffness leads to systolic blood pressure elevation and left ventricular hypertrophy and may contribute to development of coronary heart disease and stroke (Laurent et
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Fig. 2. Difference of pulse pressure and amplitude in postmenopausal group. The pulse blood pressure (upper panel) and the pulse amplitude of arterial diameter (lower panel) were designated as mean T SD along with post menopausal periods. The pulse amplitude equals the systolic diameter minus the diastolic diameter. Refer to the text for precise description. *, indicates p < 0.05 vs. group PM0.
al., 2001; Zureik et al., 2003). In contrast, with the early change in lipid profile, IMT, which is considered to be sensitive indicator for actual atherosclerosis, showed a significant increase at approximately 10 years after menopause. However, postmenopausal women had a significantly lower CCA distensibility within 2 years after menopause, as indicated by the change in SI. SI is computed from the stress –strain constitutive law of blood vessel and may be a more efficient and functional parameter for atherosclerosis than the pulse wave velocity
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(Hayashi et al., 1974). Since this index was calculated from the pulse amplitude (vessel caliber change) and the pulse pressure change, it is necessary to measure the precise diameter of blood vessel with arterial pulsation. For that purpose, we performed high frequency data sampling (3 kHZ) using ultrasonic wave echo tracking equipment (Mori et al., 2000). Since the aorta or CCA show earlier atherosclerotic change that the cerebral or coronary arteries (Van der Meer et al., 2004; Hollander et al., 2003; Shimizu et al., 2003), measurements of the CCA, which incidentally may be easier than measurement of other vessels in the outpatient setting, were used in the present study. In the present study, the SI showed an increase relatively early in the postmenopausal state. Blood pressure increased by 5– 10% and by 10 – 15% in diastole and systole, respectively, at approximately 5 years after menopause compared with the premenopausal group, resulting in an increase in the pulse pressure. In contrast, arterial diameters of CCA increased by 10– 15% and by 5 – 10% in diastole and systole, respectively, at the same time-point, resulting in a decrease of the pulse amplitude of the arterial diameter. Thus, the increase in the SI may serve as a sensitive functional marker for disordered arterial properties, whereas the relatively late increase in IMT may be insufficient for this purpose. To discuss the change of arterial property, there should be clarified conceptual aspect between arteriosclerosis and atherosclerosis. As Dr. O’Rourke summarized, ‘‘atherosclerosis is a primarily intimal disease that is patchy in location and causes narrowing of arteries and therefore interference with blood supply to tissues downstream. Arteriosclerosis is a primarily medial degenerative condition that is generalized throughout the thoracic aorta and larger central elastic arteries. It causes dilatation and stiffening, with impaired cushioning function, with an increased load on the left ventricle upstream’’ (O’Rourke, 1995). Thus atherosclerosis and arterial stiffness (i.e., arteriosclerosis) are two different and separate conditions. In our study, SI and IMT, those are representative for atherosclerosis and arteriosclerosis, respectively, were individually elevated in older women, where SI changed earlier than IMT. In this context, it might be not surprising that the risk factor (lipid profile) also occurs earlier than atherosclerosis
Fig. 3. Difference of intima-media thickness (IMT) and stiffness index (SI) in postmenopausal group. The intima-media thickness (IMT) and the stiffness index (SI) of the right common carotid artery (CCA) were designated as mean T SD along with post menopausal periods. Refer to the text for precise description. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
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Fig. 4. Cerebral perfusion and the maximum incremental velocity (MIV) in postmenopausal group. Calculated cerebral perfusion (upper panel) and MIV (lower panel) were designated as mean T SD along with post menopausal periods. The cerebral perfusion was estimated by multiplying the full vessel lumen velocity measured by color-Doppler ultrasonography and the vessel diameter, calculated by the diameter waveform of the common carotid artery (CCA). MIV reflects the cardiac contractile force and was calculated from the first derivatives of the diameter waveform of the CCA. Refer to the text for precise description. *, and . indicate p < 0.05, and p < 0.01 vs. group PM0, respectively.
(IMT), which might be slower and more metabolically complicated disorder than arteriosclerosis. In the present study, the SI is calculated based on the change in (carotid) arterial diameter with blood pressure measured in the brachial artery, not in CCA. As proposed by van Bortel et al., the values could be reliably adjusted by comparing CCA and brachial waveform (Van Bortel et al., 2001). Utilizing this adjustment, the arterial stiffness was recently investigated for its association of the parameters of metabolic syndrome in young people and reported about their partly independence (Ferreira et al., 2005). Since not all data of ours include the simultaneously measured brachial waveform, we tried to convert some data of ours into the adjusted SI according to the above mentioned method and confirmed the tendency of earlier change of SI than IMT. For further investigation, we should record the simultaneous brachial waveform and try to obtain the accurate assessment for arterial property. However, our present data may be still reliable to evaluate the changes of arterial property after menopause in comparison of SI with IMT. Recent studies have demonstrated that estrogen produces various effects, including inhibition of vascular smooth muscle cells proliferation in vitro, induction of vascular extension, and modulation of vascular tone by production of nitric oxide (Iwakura et al., 2003). These data, taken together with studies that show that estrogen inhibits medial thickening (Lobo, 1991), suggest that estrogen supports endothelial cell function and exerts an anti-atherogenic effect and that absence of estrogen results in promotion of atherosclerosis (McGrath et al., 1998). Further, the selective estrogen modulator, tamoxifen, has a favorable influence on the postmenopausal arterial stiffness (Simon et al., 2002). However WHI study was discontinued because of an increased risk of stroke and CHD as described in ‘‘Introduction’’, there will still be controversial discussions about IMT of CCA and the beneficial/adverse effect(s) of estrogen therapy on CHD risk. The EPAT trial
(Hodis et al., 2001) found a beneficial effect of estrogen therapy and baseline IMT was 0.764 mm while adverse effects were found in HERS and the baseline CAIMT was 1.193 mm. We presented the basal date of the relationship of years postmenopausal to stage of IMT and this might have important implications concerning the time of initiating estrogen and/or hormone therapy, which might be investigated further. The present study described cerebral perfusion as the product of blood velocity and vessel cross-sectional area. This technique requires simultaneous measurement of blood velocity waveform by the color-Doppler method and vessel diameter pulsation waveform by an ultrasonic echo-tracking method. This method takes into account the vessel pulsation to determine the actual blood flow volume. The pressure and resistance of any fluid traveling through a tubular system can be expressed by the Poiseuille equation (Giles and Trudinger, 1986; Thompson and Trudinger, 1990): Flow ¼ Pressure=Resistance; i:e: DPkr 4=8 gl; where DP is the pressure gradient, r is the vessel radius, g is the viscosity of the fluid and l is the vessel length. The influence of viscosity on flow in much less important in large arteries than in small vessels. Indeed, the inertial forces moving a column of blood during pulsatile flow are more important in large arteries. Since the arteries characterized in the present study have a diameter of more than 5 mm, viscosity could be theoretically expected to be less important in determining flow. Therefore, the Poiseulle equation provides a useful expression of the relationship between pressure and resistance. Based on this analysis, we demonstrated that cerebral perfusion declined after 8 years of PMP. In the present study, MIV was used as a reflection of cardiac contractile force and correlated well with aortic flow acceleration. It seems reasonable to assume that the rate of increase in aortic diameter in early systole is closely linked to the rate of
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ejection of blood from the heart (i.e., the aortic flow acceleration (AFA)). Since AFA is a sensitive measure of cardiac inotropy, this correlation demonstrates that changes in MIV could be used to estimate the direction of change of the cardiac contractile force. In this study, MIV was calculated from the waveform of CCA. The elastic recoil of the CCA during diastole is dependent on the pressure gradient, since the radial stretching of the aorta is almost linearly related to the pressure gradient. Based on this analysis, we demonstrated that MIV declined after 8 years of PMP. Conclusion To characterize postmenopausal changes in the arterial properties, 72 postmenopausal and 24 volunteers with regular menstruation underwent assessment of diameter pulse waveform and intima-media thickness (IMT) of the common carotid artery (CCA), stiffness index and maximum incremental velocity (MIV) of cardiac contractile force. Since postmenopausal increases in CCA stiffness and lipid profile occurred earlier than the increase in IMT, SI may be more sensitive as a predictor for disorder on arterial property. References Bugliosi, R., Caratozzolo, V., Caratozzolo, A., 1995. Hyperlipidemia, hypertension and atherosclerosis in women. Reality and perspectives. LaClinica Terapeutica 146, 503 – 518. Dalal, D., Robbins, J.A., 2002. Management of hyperlipidemia in the elderly population: an evidence-based approach. The Southern Medical Journal 95, 1255 – 1261. Despres, J.P., Lemieux, I., Dagenais, G.R., Cantin, B., Lamarche, B., 2000. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study. Atherosclerosis 153, 263 – 272. Dobiasova, M., 2004. Atherogenic index of plasma [log(triglycerides / HDLcholesterol)]: theoretical and practical implications. Clinical Chemistry 50, 1113 – 1115. Ferreira, I., Henry, R.M., Twisk, J.W., van Mechelen, W., Kemper, H.C., Stehouwer, C.D., 2005. The metabolic syndrome, cardiopulmonary fitness, and subcutaneous trunk fat as independent determinants of arterial stiffness: the Amsterdam growth and health longitudinal study. Archives of Internal Medicine 25, 875 – 882. Giles, W.B., Trudinger, B.J., 1986. Umbilical cord whole blood viscosity and the umbilical artery flow velocity time waveforms: a correlation. British Journal of Obstetrics and Gynaecology 93, 466 – 470. Goran, W., Ingmar, J., Ingar, H., Are, H.A., Werner, K., Eugen, S., 2001. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 358, 2026 – 2033. Handa, N., Matsumoto, M., Maeda, H., Hougaku, H., Ogawa, S., Fukunaga, R., Yoneda, S., Kimura, K., Kamada, T., 1990. Ultrasonic evaluation of early carotid atherosclerosis. Stroke. A Journal of Cerebral Circulation 21, 1567 – 1572. Hayashi, K., Sato, M., Handa, H., Moritake, K., 1974. Biomechanical study of the constitute laws of vascular walls. Experimental Mechanics 14, 440 – 444. Hodis, H.N., Mack, W.J., Lobo, R.A., Shoupe, D., Sevanian, A., Mahrer, P.R., Selzer, R.H., Liu, Cr. C.R., Liu, Ch. C.H., Azen S.P., Estrogen in the Prevention of Atherosclerosis Trial Research Group, 2001. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebocontrolled trial. Annals of Internal Medicine 135, 939 – 953. Hollander, M., Hak, A.E., Koudstaal, P.J., Bots, M.L., Grobbee, D.E., Hofman, A., Witteman, J.C., Breteler, M.M., 2003. Comparison between measures of
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