Carotid Artery Disease
The Association of Elevated HDL Levels With Carotid Atherosclerosis in Middle-Aged Women With Untreated Essential Hypertension
Angiology 2015, Vol. 66(10) 904-910 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319715572679 ang.sagepub.com
Helen Triantafyllidi, MD, PhD1, George Pavlidis, MD1, Paraskevi Trivilou, MD1, Ignatios Ikonomidis, MD, PhD1, Stavros Tzortzis, MD, PhD1, Iosif Xenogiannis, MD1, Antonios Schoinas, MD1, and John Lekakis, MD, PhD1
Abstract High-density lipoprotein cholesterol (HDL-C), a negative risk factor, is positively associated with a decreased risk of coronary heart disease. We investigated the association between high HDL-C levels and target organ damage (TOD) in never treated women with hypertension. We measured HDL-C levels in 117 women followed by estimation of TODs, that is, pulse wave velocity, microalbuminuria, left ventricular mass index, coronary flow reserve, and carotid intima–media thickness (cIMT). Women were divided into 2 groups (HDLH and HDLL), regarding HDL-C quartiles (upper quartile vs the first 3 lower quartiles). In HDLH group (HDL 70 mg/dL), cIMT was nonindependently, negatively related to HDL-C (r ¼ .42, P < .05). Using receiver –operating characteristic curve (ROC) analysis in the HDLH group, we concluded that the cutoff value of HDL 76.5 mg/dL moderately predicted the absence of carotid atherosclerosis (area under the curve: 0.77, P ¼ .02; confidence interval: 0.57-0.97; sensitivity 73% and specificity 67%). Increased HDL-C may predict the absence of carotid atherosclerosis in middle-age women with untreated essential hypertension and consequently contribute to total cardiovascular risk estimation and treatment planning. Keywords HDL, hypertension, target organ damage, carotid intima–media thickness, atheromatosis
Introduction Large-scale epidemiological studies have shown that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular (CV) risk.1-3 Furthermore, almost all available risk assessment tools including the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) assume that high HDL-C is a favorable CV risk factor.4 Regarding the general population without known CV disease (CVD), high HDL-C levels are inversely related to coronary events, ischemic stroke, and carotid atherosclerosis even after adjustment for lipid and nonlipid risk factors.5,6 Moreover, the appearance of coronary artery disease (CAD) is being delayed by 3 to 5 years in those patients with increased HDL-C compared to patients with low or normal HDL-C levels. Unfortunately, this favorable profile changes when CAD is diagnosed, since patients with elevated HDL-C develop similar cardiac events as do other cardiac patients.7 High-density lipoprotein cholesterol seems to have a greater impact in women. In the Framingham study, the risk of developing myocardial infarction associated with a low HDL-C
concentration was far greater in women than in men,8 while an increase in HDL-C produced a greater CV benefit in women than in men.9 Arterial hypertension is a major risk factor for CVD leading to subclinical organ involvement, target organ damage (TOD), a stage in the continuum of vascular disease as well as an important determinant of CV.10 The TOD should be thoroughly investigated in patients with hypertension. The TOD includes left ventricular (LV) hypertrophy (expressed as left ventricular mass index [LVMI]), reduced coronary flow reserve (CFR), increased carotid intima–media thickness (cIMT), elevated levels of microalbuminuria (MAU), and impaired aortic stiffness, which can be estimated noninvasively by measuring carotid– 1
Second Department of Cardiology, Medical School, University of Athens, ATTIKON Hospital, Athens, Greece
Corresponding Author: Helen Triantafyllidi, Second Cardiology Department, Attikon Hospital, Medical School, University of Athens, 83, Agiou Ioannou Theologou, Holargos, 155 61 Athens, Greece. Email: [email protected]
Downloaded from ang.sagepub.com at CMU Libraries - library.cmich.edu on November 3, 2015
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femoral pulse wave velocity (PWV); the velocity of the pulse wave traveling between 2 sites in the arterial system.10 High-density lipoprotein cholesterol exhibits an inverse association with the prevalence of CVD in Spanish women with hypertension.11 There is general acceptance that elevated HDL-C is protective, but there are no data regarding any relationship between elevated HDL-C levels and TOD indices in newly diagnosed and untreated women with hypertension. The purpose of the current study was to investigate relationships between increased HDL-C and TOD indices (cIMT, PWV, LVMI, MAU, and CFR) in first diagnosed and middle-aged untreated women with hypertension.
Material and Method Study Population We studied 117 women with hypertension visiting our outpatient clinic, from April 2005 until December 2013, with recently diagnosed and never-treated stage I-II essential hypertension according to the 2007, 2009, and 2013 guidelines of the European Society of Hypertension.10,12,13 All patients were subjected to the following examinations within 2 weeks: (1) 3 office blood pressure (BP) measurements in each 1 of the 3 subsequent visits in the hypertension outpatient clinic, (2) blood and urine sampling for routine blood (lipid profile included) and urine chemistry examination, (3) standard 12-lead electrocardiogram, (4) 24-hour ambulatory BP monitoring (ABPM) was performed in order to confirm the diagnosis of hypertension based on clinic repeated BP measurements, (5) transthoracic echocardiogram in order to evaluate LVMI and CFR of left anterior descending artery, (6) carotid–femoral PWV to evaluate arterial stiffness, (7) MAU in 24 hours urine collection, and (8) carotid ultrasonography to measure IMT. Informed consent was obtained during the initial visit of the study, which was approved by the ethical committee of the hospital. Patients with secondary hypertension, congestive heart failure, previous myocardial infarction, stroke, cardiac valve diseases, history of coronary artery intervention and/or bypass grafting, atrial fibrillation, renal insufficiency, overt proteinuria, diabetes mellitus, under medication for hyperlipidemia, non-CVDs, or hormone replacement treatment as well as those involved in a structured exercise program, defined as more than three 30-minute workouts per week, were excluded from the study. Participants in our study did not have any concomitant disorders, and they did not receive any cardiometabolic medications. Due to the above-mentioned major limitations in order to have a homogenous group (ie, women with never treated essential hypertension and no other concomitant disorders), the recruitment period of our study lasted about 8½ years.
Diagnostic Workup Office BP measurement. Morning office BP was measured in the hospital outpatient clinic, approximately at the same morning hour of the day, by the same cardiologist with a mercury sphygmomanometer (first and fifth phases of Korotkoff sounds taken
as systolic [SBP] and diastolic BP [DBP], respectively) after the patients had rested for a period of 5 to 10 minutes in the sitting position. Three measurements were taken at 1-minute intervals, and the average was used to define office SBP and DBP. Office pulse pressure (PP) was calculated as SBP minus DBP, while mean BP was defined as DBP plus one-third of the PP. Hypertension was diagnosed as a SBP >140 mm Hg and/or DBP >90 mm Hg. Patients were advised to avoid smoking or coffee at least for 2 hours before examination. Ambulatory BP monitoring. Ambulatory BP monitoring was carried out on the nondominant arm using a valid recorder, Spacelab 90207 (Spacelab, Redmont, California). The ABPM device was set to obtain BP readings at 15-minute intervals during the day (07.00-23.00) and at 20-minute intervals during the night (23.00-07.00). The time of application and the type of the device were the same in all patients. The patients were instructed to attend their usual day-to-day activities but to keep still at the times of measurements. Although BP monitoring was obtained during working days (Monday-Friday), patients were asked to go to bed not later than 23.00 and to stay in bed until 07.00. Recordings were analyzed to obtain 24 hours, daytime, and nighttime average SBP, DBP, and heart rates as well as 24 hours PP. Systolic readings >260 or 150 or 75% of successful readings. Transthoracic echocardiography. Studies were performed using a Vivid 7 (GE Medical Systems, Horten, Norway) ultrasound system. All studies were digitally stored in a computerized station (Echopack GE, Horten, Norway) and were analyzed by 3 observers blinded to clinical and laboratory data. All patients had adequate images for analysis. Both LV mass and LVMI were measured in all patients using the Devereux formula according to the Penn Convention Protocol. The presence of LV hypertrophy was defined as LVMI index >134 g/m2 in men and >110 g/m2 in women.14 Carotid–femoral PWV. Arterial stiffness was estimated by an automatic carotid–femoral PWV measurement using a Complior SP (Artech Medical, France), a computerized device that permits automatic calculation of PWV. Time delay between the recorded carotid and femoral arterial waves was recorded, while distance separating the transducers was superficially measured resulting in a PWV calculation as the average of at least 10 cardiac cycles. The same examiner, who was blinded to the patient’s history, performed all measurements. Patients were advised to avoid smoking or coffee at least for 2 hours before examination. The PWV 10 m/s was consider as normal.10,15 Coronary flow reserve. Coronary flow velocity profiles were obtained using color-guided pulse-wave Doppler from longaxis apical projections using a 7-MHz transducer. We measured velocity–time integral of the diastolic coronary waveform at rest and after adenosine infusion (140 mg/kg/min) for 3 minutes.
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Measurements from 3 cardiac cycles were averaged. The CFR was calculated as the ratio of hyperemic to resting diastolic velocity–time integral according to standard Doppler methodology. The CFR values >2.5 were considered as normal.10,16 Microalbumin levels in 24 hours urine collection. Microalbuminuria (MAU) was analyzed by nephelometry (Immunochemical assay, BN, Prospec; Dade Behring, Marburg, Germany). Patients were classified as normoalbuminuric when MAU levels were 76.5 mg/dL with a moderate sensitivity and specificity. Finally, among the usual hypertensive
TOD indices (CFR, MAU, PWV, LVMI, and cIMT), cIMT in our study was the most sensitive index in the hypertensive disease process positively related to increased HDL-C levels. The protective role of HDL, expect from participating in reverse cholesterol transport, is based on antioxidant, anti-inflammatory, and antithrombotic properties as well as endothelial-repaired processes that protect against the development of atherosclerosis and CAD.17,18 Although HDL has anti-inflammatory properties in the absence of inflammation, it can become proinflammatory in the presence of atherosclerosis.19 It seems that HDL particles might be highly heterogenous as well as functionally diverse.20 Evidence from the literature supports the view that HDL is inversely associated with the risk of stroke and carotid atherosclerosis, but it is also clear that more data are needed to firmly establish this association.21 Additionally, findings further suggest a synergistic role of low-HDL and inflammation on the atherosclerotic
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Figure 1. Relationship between carotid intima–media thickness (cIMT; mm) and HDL (mg/dL) in the increased HDL (HDLH) group. Data in the 1.1/72, 1.2/73, 0.9/75, and 0.8/77 positions are in bold since they each represent 2 patients with identical cIMT/HDL-C measurements. HDL-C indicates high-density lipoprotein cholesterol.
disease progression from subclinical lesions to clinical events.19,22 It is interesting that in our study, 26% of the women with hypertension had HDL-C levels 70 mg/dL. Indeed, people living in Mediterranean areas have higher concentrations of HDL-C probably related to their dietary habits.23 Women have higher plasma HDL-C concentrations than men,24 while the pattern of lipoprotein changes with age is different between males and females. In women, HDL-C increases at the time of adolescence and remains elevated in comparison with men. Although this may be true cross-sectionally, the protection of the higher level of HDL-C may diminish over time among women who are free of symptomatic CAD. Indeed, HDL seems protective against progression of carotid atherosclerosis in middleaged men; antiatherogenic effects of HDL may diminish in women around the age of menopause.20 The cIMT reflects structural arterial wall changes. In patients with hypertension, cIMT is usually increased, reflecting an early generalized vascular damage.25,26 The cIMT can detect morphological changes in the carotid artery, consisting of both an intimal atherosclerotic process and a medial hypertrophy.27 Increased cIMT correlates with most conventional CV factors,28 with atherosclerotic lesions at other sites of the arterial tree,29 as well as with the presence and severity of CAD30 and endothelial dysfunction in patients with atherosclerosis.31 Studies have also addressed the importance of CRP in the prediction of carotid lesions in patients with newly diagnosed hypertension; however, further studies are needed to evaluate the therapeutic modulation of CRP levels in highrisk patients for CVD prevention.32 Thus, cIMT may be used as a cumulative vascular marker of the atherogenetic process, reflecting vascular structural changes in the arterial wall. In the risk of stroke in women with hypertension study (RIMHA study), a cross-sectional study that included 11042
Spanish women with hypertension aged 55 years, the prevalence of total CVD, heart disease, myocardial infarction, angina, and heart failure was lowest in the higher quintile of HDL (>66 mg/dL) compared with the lowest one (0.9 mm but 1.6 mm. However, our results not only conclude that an inverse relationship between increased HDL-C levels and cIMT exists but they also provide evidence that a cutoff value of HDL-C 76.5 mg/dL almost predicts the absence of carotid atherosclerosis (cIMT 0.9 mm) in untreated middle-aged women with hypertension. However, increased HDL-C levels might mislead physicians to underdiagnose CV events, especially in women. When HDL-C is elevated and the patient presents with atypical symptoms, physicians might underestimate a female’s CV risk based on the expected HDL protection for CVD.36 Careful evaluation of both symptoms and laboratory results also taking into account any favorable CV risk markers should lead to correct diagnosis. Several limitations should be considered concerning this study. The first is its cross-sectional nature, which prevents establishing a cause–effect relation between the associations found. The second limitation is the relatively small number of patients overall and in each study group. Since hypertension has a high prevalence, a greater number of patients should be necessary in order to generalize the results of this study both in untreated and treated patients with hypertension. Another limitation refers to HDL-C measurements that were not performed in a central laboratory, but this reflects everyday
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clinical practice. However, we cannot rule out the possibility of a certain degree of variability in the measurements or that this might have influenced the results. Again regarding HDL-C measurements, we were not able to assess the size of HDL particles, especially the large ones, which might not be protective against atherosclerosis. However, our results are based on the existing inverse relationship between HDL-C levels and carotid atherosclerosis only in women with increased HDL-C. Another limitation refers to the cutoff of cIMT, which we used in our study. The Reference Values for Arterial Measurements Collaboration37 shows that the 0.90-mm cIMT cutoff we used is approximately equal to the 97th centile for healthy men and is above that centile for healthy women. The cIMT for patients with CVD was approximately 0.68 + 0.1 mm for men and women.37 However, we chose to follow the recent recommendations of European Society of Hypertension,10 which propose a cIMT cutoff of 0.90 mm. Another limitation is the nonhomogenous status of menopause in the total population, since half of the females were at the age of menopause or even younger while the rest of them was at postmenopausal age. However, this situation was similar in both study groups diminishing any consequences of postmenopause in reducing HDL-C levels. Finally, HDL-C levels in our study group ranged between 31 and 98 mg/dL. If the beneficial association between high HDL-C levels and cIMT still exists at levels of HDL-C 100 mg/dL has to be further investigated in future studies. In conclusion, a nonindependent, inverse relationship exists between increased levels of HDL-C (70 mg/dL) and carotid atherosclerosis in middle-age women with untreated essential hypertension, which might consequently contribute to total CV estimation and treatment planning. This association becomes more pronounced at HDL-C 76.5 mg/dL, which actually predicts the absence of carotid atherosclerosis. Authors’ Note Helen Triantafyllidi contributed to the conception and design, acquisition, analysis and interpretation of data, drafting and revising the article, and gave the final approval of the version to be published. George Pavlidis, Paraskevi Trivilou, Stavros Tzortzis, Iosif Xenogiannis, and Antonios Schoinas contributed to acquisition of data, drafting the article, and gave the final approval of the version to be published. Ignatios Ikonomidis contributed to the acquisition and analysis and interpretation of data, drafting the article, and gave the final approval of the version to be published. John Lekakis contributed to analysis and interpretation of data, drafting the article, and gave the final approval of the version to be published. This article was accepted and presented at a poster session at the ESC 2013 meeting (Amsterdam, the Netherlands).
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707-714. 2. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986; 256(20):2835-2838. 3. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104(10):1108-1113. 4. Grundy SM, Becker D, Clark LT, et al. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA. 2001;285(19):2486-2497. 5. Di Angelantonio E, Sarwar N, Perry P, et al. Emerging risk factors collaboration, major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993-2000. 6. Yokokawa H, Yasumura S, Tanno K, et al. Serum low-density lipoprotein to high-density lipoprotein ratio as a predictor of future acute myocardial infarction among men in a 2.7-year cohort study of a Japanese northern rural population. J Atheroscler Thromb. 2011;18(2):89-98. 7. Sbrana F, Puntoni M, Bigazzi F, et al. High density lipoprotein cholesterol in coronary artery disease: when higher means later. J Atheroscler Thromb. 2013;20(1):23-31. 8. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction: the Framingham Study. Atherosclerosis. 1988;8: 207-211. 9. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79(1):8-15. 10. Mancia G, Fagard R, Narkiewicz K, et al. ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159-2219. 11. Coca A, Cea-Calco L, Lozano JL, et al. High-density lipoprotein cholesterol and cardiovasular disease in Spanish hypertensive women. The RIMHA study. Rev Esp Cardiol. 2009;62(9): 1022-1031. 12. Mancia G, Laurent S, Agabiti-Rosei E, et al. European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27(11):2121-2158. 13. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105-1187.
Downloaded from ang.sagepub.com at CMU Libraries - library.cmich.edu on November 3, 2015
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14. Devereux R, Reichek N. Echocardiographic assessment of left ventricular mass in man. Circulation. 1977;55(4):613-618. 15. Van Bortel LM, Laurent S, Boutouyrie P, et al. Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30(3): 445-448. 16. Stavros Tzortzis, Ignatios Ikonomidis, John Lekakis, et al. Incremental predictive value of carotid intima–media thickness to arterial stiffness for impaired coronary flow reserve in untreated hypertensives. Hypertens Res. 2010;33(4):367-373. 17. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res. 2006;98(11):1352-1364. 18. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95(8):764-772. 19. Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Prediction of cardio- and cerebro-vascular events in patients with subclinical carotid atherosclerosis and low HDL-cholesterol. Atherosclerosis. 2008;200(2):389-395. 20. Fan AZ, Dwyer JH. Sex differences in the relation of HDL cholesterol to progression of carotid intima-media thickness: the Los Angeles Atherosclerosis Study. Atherosclerosis. 2007;195(1): e191-196. 21. Amarenco P, Labreuche J, Touboul PJ. High-density lipoproteincholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis. 2008;196(2):489-496. 22. Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res. 2012;51(4):314-324. 23. Estruch R, Martı´nez-Gonza´lez MA, Corella D, et al. PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145(1):1-11. 24. Williams CM. Lipid metabolism in women. Proc Nutr Soc. 2004; 63(1):153-160. 25. Kobayashi K, Akishita M, Yu W, Hashimoto M, Ohni M, Toba K. Interrelationship between non-invasive measurements of atherosclerosis: flow-mediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity. Atherosclerosis. 2004;173(1):13-18. 26. Chambless L, Heiss G, Folsom A, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study,1987–1993. Am J Epidemiol. 1997;146(6):483-494. Juonala M, Viikari J, Laitinen T, et al. Interrelations between brachial endothelial function and carotid intima media thickness in young adults. The Cardiovascular Risk in Young Finns Study. Circulation. 2004;110(18):2918-2923. Folsom AR, Eckfeldt JH, Weitzman S, et al. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity: Atherosclerosis Risk in Communities (ARIC) Study investigators. Stroke. 1994;25(1): 66-73. Bots M, Iglesias del Sol A, Grobbee D. Carotid intima-media thickness measurements in observational and intervention studies. Curr Res Vasc Dis. 1998;3:274-283. O’Leary D, Polak J, Kronmal R, Manolio T, Burke G, Wolfson S. Carotid intima and media thickness as a risk factor for myocardial infarction and stroke in older subjects. N Engl J Med. 1999; 340(1):14-22. Hashimoto M, Eto M, Akishita M, et al. Correlation between flow-mediated vasodilatation of the brachial artery and intima– media thickness in the carotid artery in men. Arterioscler Thromb Vasc Biol. 1999;19(11):2795-2800. Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Association of elevated fibrinogen and C-reactive protein levels with carotid lesions in patients with newly diagnosed hypertension or type II diabetes. Arch Med Res. 2006;37(8):1004-1009. De Michele M, Iannuzzi A, Panico S, et al. Effect of high-density lipoprotein cholesterol levels on carotid artery geometry in a Mediterranean female population. Eur J Cardiovasc Prev Rehabil. 2004;11(5):403-407. Keidar S, Bogner I, Gamliel-Lazarovich A, Leiba R, Fuhrman B, Kouperberg E. High plasma high-density lipoprotein levels, very low cardiovascular risk profile, and subclinical carotid atherosclerosis in postmenopausal women. J Clin Lipidol. 2009;3(5): 345-350. van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. JACC. 2008;51(6):634-642. Baron AA1, Baron SB. High levels of HDL cholesterol does not predict protection from cardiovascular disease in women. Prev Cardiol. 2007;10(3):125-127. Engelen L, Ferreira I, Stehouwer CD, Boutourie P, Laurent S. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J. 2013;34(30):2368-2380.
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The Association of Elevated HDL Levels With Carotid Atherosclerosis in Middle-Aged Women With Untreated Essential Hypertension
Angiology 2015, Vol. 66(10) 904-910 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319715572679 ang.sagepub.com
Helen Triantafyllidi, MD, PhD1, George Pavlidis, MD1, Paraskevi Trivilou, MD1, Ignatios Ikonomidis, MD, PhD1, Stavros Tzortzis, MD, PhD1, Iosif Xenogiannis, MD1, Antonios Schoinas, MD1, and John Lekakis, MD, PhD1
Abstract High-density lipoprotein cholesterol (HDL-C), a negative risk factor, is positively associated with a decreased risk of coronary heart disease. We investigated the association between high HDL-C levels and target organ damage (TOD) in never treated women with hypertension. We measured HDL-C levels in 117 women followed by estimation of TODs, that is, pulse wave velocity, microalbuminuria, left ventricular mass index, coronary flow reserve, and carotid intima–media thickness (cIMT). Women were divided into 2 groups (HDLH and HDLL), regarding HDL-C quartiles (upper quartile vs the first 3 lower quartiles). In HDLH group (HDL 70 mg/dL), cIMT was nonindependently, negatively related to HDL-C (r ¼ .42, P < .05). Using receiver –operating characteristic curve (ROC) analysis in the HDLH group, we concluded that the cutoff value of HDL 76.5 mg/dL moderately predicted the absence of carotid atherosclerosis (area under the curve: 0.77, P ¼ .02; confidence interval: 0.57-0.97; sensitivity 73% and specificity 67%). Increased HDL-C may predict the absence of carotid atherosclerosis in middle-age women with untreated essential hypertension and consequently contribute to total cardiovascular risk estimation and treatment planning. Keywords HDL, hypertension, target organ damage, carotid intima–media thickness, atheromatosis
Introduction Large-scale epidemiological studies have shown that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular (CV) risk.1-3 Furthermore, almost all available risk assessment tools including the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) assume that high HDL-C is a favorable CV risk factor.4 Regarding the general population without known CV disease (CVD), high HDL-C levels are inversely related to coronary events, ischemic stroke, and carotid atherosclerosis even after adjustment for lipid and nonlipid risk factors.5,6 Moreover, the appearance of coronary artery disease (CAD) is being delayed by 3 to 5 years in those patients with increased HDL-C compared to patients with low or normal HDL-C levels. Unfortunately, this favorable profile changes when CAD is diagnosed, since patients with elevated HDL-C develop similar cardiac events as do other cardiac patients.7 High-density lipoprotein cholesterol seems to have a greater impact in women. In the Framingham study, the risk of developing myocardial infarction associated with a low HDL-C
concentration was far greater in women than in men,8 while an increase in HDL-C produced a greater CV benefit in women than in men.9 Arterial hypertension is a major risk factor for CVD leading to subclinical organ involvement, target organ damage (TOD), a stage in the continuum of vascular disease as well as an important determinant of CV.10 The TOD should be thoroughly investigated in patients with hypertension. The TOD includes left ventricular (LV) hypertrophy (expressed as left ventricular mass index [LVMI]), reduced coronary flow reserve (CFR), increased carotid intima–media thickness (cIMT), elevated levels of microalbuminuria (MAU), and impaired aortic stiffness, which can be estimated noninvasively by measuring carotid– 1
Second Department of Cardiology, Medical School, University of Athens, ATTIKON Hospital, Athens, Greece
Corresponding Author: Helen Triantafyllidi, Second Cardiology Department, Attikon Hospital, Medical School, University of Athens, 83, Agiou Ioannou Theologou, Holargos, 155 61 Athens, Greece. Email: [email protected]
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femoral pulse wave velocity (PWV); the velocity of the pulse wave traveling between 2 sites in the arterial system.10 High-density lipoprotein cholesterol exhibits an inverse association with the prevalence of CVD in Spanish women with hypertension.11 There is general acceptance that elevated HDL-C is protective, but there are no data regarding any relationship between elevated HDL-C levels and TOD indices in newly diagnosed and untreated women with hypertension. The purpose of the current study was to investigate relationships between increased HDL-C and TOD indices (cIMT, PWV, LVMI, MAU, and CFR) in first diagnosed and middle-aged untreated women with hypertension.
Material and Method Study Population We studied 117 women with hypertension visiting our outpatient clinic, from April 2005 until December 2013, with recently diagnosed and never-treated stage I-II essential hypertension according to the 2007, 2009, and 2013 guidelines of the European Society of Hypertension.10,12,13 All patients were subjected to the following examinations within 2 weeks: (1) 3 office blood pressure (BP) measurements in each 1 of the 3 subsequent visits in the hypertension outpatient clinic, (2) blood and urine sampling for routine blood (lipid profile included) and urine chemistry examination, (3) standard 12-lead electrocardiogram, (4) 24-hour ambulatory BP monitoring (ABPM) was performed in order to confirm the diagnosis of hypertension based on clinic repeated BP measurements, (5) transthoracic echocardiogram in order to evaluate LVMI and CFR of left anterior descending artery, (6) carotid–femoral PWV to evaluate arterial stiffness, (7) MAU in 24 hours urine collection, and (8) carotid ultrasonography to measure IMT. Informed consent was obtained during the initial visit of the study, which was approved by the ethical committee of the hospital. Patients with secondary hypertension, congestive heart failure, previous myocardial infarction, stroke, cardiac valve diseases, history of coronary artery intervention and/or bypass grafting, atrial fibrillation, renal insufficiency, overt proteinuria, diabetes mellitus, under medication for hyperlipidemia, non-CVDs, or hormone replacement treatment as well as those involved in a structured exercise program, defined as more than three 30-minute workouts per week, were excluded from the study. Participants in our study did not have any concomitant disorders, and they did not receive any cardiometabolic medications. Due to the above-mentioned major limitations in order to have a homogenous group (ie, women with never treated essential hypertension and no other concomitant disorders), the recruitment period of our study lasted about 8½ years.
Diagnostic Workup Office BP measurement. Morning office BP was measured in the hospital outpatient clinic, approximately at the same morning hour of the day, by the same cardiologist with a mercury sphygmomanometer (first and fifth phases of Korotkoff sounds taken
as systolic [SBP] and diastolic BP [DBP], respectively) after the patients had rested for a period of 5 to 10 minutes in the sitting position. Three measurements were taken at 1-minute intervals, and the average was used to define office SBP and DBP. Office pulse pressure (PP) was calculated as SBP minus DBP, while mean BP was defined as DBP plus one-third of the PP. Hypertension was diagnosed as a SBP >140 mm Hg and/or DBP >90 mm Hg. Patients were advised to avoid smoking or coffee at least for 2 hours before examination. Ambulatory BP monitoring. Ambulatory BP monitoring was carried out on the nondominant arm using a valid recorder, Spacelab 90207 (Spacelab, Redmont, California). The ABPM device was set to obtain BP readings at 15-minute intervals during the day (07.00-23.00) and at 20-minute intervals during the night (23.00-07.00). The time of application and the type of the device were the same in all patients. The patients were instructed to attend their usual day-to-day activities but to keep still at the times of measurements. Although BP monitoring was obtained during working days (Monday-Friday), patients were asked to go to bed not later than 23.00 and to stay in bed until 07.00. Recordings were analyzed to obtain 24 hours, daytime, and nighttime average SBP, DBP, and heart rates as well as 24 hours PP. Systolic readings >260 or 150 or 75% of successful readings. Transthoracic echocardiography. Studies were performed using a Vivid 7 (GE Medical Systems, Horten, Norway) ultrasound system. All studies were digitally stored in a computerized station (Echopack GE, Horten, Norway) and were analyzed by 3 observers blinded to clinical and laboratory data. All patients had adequate images for analysis. Both LV mass and LVMI were measured in all patients using the Devereux formula according to the Penn Convention Protocol. The presence of LV hypertrophy was defined as LVMI index >134 g/m2 in men and >110 g/m2 in women.14 Carotid–femoral PWV. Arterial stiffness was estimated by an automatic carotid–femoral PWV measurement using a Complior SP (Artech Medical, France), a computerized device that permits automatic calculation of PWV. Time delay between the recorded carotid and femoral arterial waves was recorded, while distance separating the transducers was superficially measured resulting in a PWV calculation as the average of at least 10 cardiac cycles. The same examiner, who was blinded to the patient’s history, performed all measurements. Patients were advised to avoid smoking or coffee at least for 2 hours before examination. The PWV 10 m/s was consider as normal.10,15 Coronary flow reserve. Coronary flow velocity profiles were obtained using color-guided pulse-wave Doppler from longaxis apical projections using a 7-MHz transducer. We measured velocity–time integral of the diastolic coronary waveform at rest and after adenosine infusion (140 mg/kg/min) for 3 minutes.
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Measurements from 3 cardiac cycles were averaged. The CFR was calculated as the ratio of hyperemic to resting diastolic velocity–time integral according to standard Doppler methodology. The CFR values >2.5 were considered as normal.10,16 Microalbumin levels in 24 hours urine collection. Microalbuminuria (MAU) was analyzed by nephelometry (Immunochemical assay, BN, Prospec; Dade Behring, Marburg, Germany). Patients were classified as normoalbuminuric when MAU levels were 76.5 mg/dL with a moderate sensitivity and specificity. Finally, among the usual hypertensive
TOD indices (CFR, MAU, PWV, LVMI, and cIMT), cIMT in our study was the most sensitive index in the hypertensive disease process positively related to increased HDL-C levels. The protective role of HDL, expect from participating in reverse cholesterol transport, is based on antioxidant, anti-inflammatory, and antithrombotic properties as well as endothelial-repaired processes that protect against the development of atherosclerosis and CAD.17,18 Although HDL has anti-inflammatory properties in the absence of inflammation, it can become proinflammatory in the presence of atherosclerosis.19 It seems that HDL particles might be highly heterogenous as well as functionally diverse.20 Evidence from the literature supports the view that HDL is inversely associated with the risk of stroke and carotid atherosclerosis, but it is also clear that more data are needed to firmly establish this association.21 Additionally, findings further suggest a synergistic role of low-HDL and inflammation on the atherosclerotic
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Figure 1. Relationship between carotid intima–media thickness (cIMT; mm) and HDL (mg/dL) in the increased HDL (HDLH) group. Data in the 1.1/72, 1.2/73, 0.9/75, and 0.8/77 positions are in bold since they each represent 2 patients with identical cIMT/HDL-C measurements. HDL-C indicates high-density lipoprotein cholesterol.
disease progression from subclinical lesions to clinical events.19,22 It is interesting that in our study, 26% of the women with hypertension had HDL-C levels 70 mg/dL. Indeed, people living in Mediterranean areas have higher concentrations of HDL-C probably related to their dietary habits.23 Women have higher plasma HDL-C concentrations than men,24 while the pattern of lipoprotein changes with age is different between males and females. In women, HDL-C increases at the time of adolescence and remains elevated in comparison with men. Although this may be true cross-sectionally, the protection of the higher level of HDL-C may diminish over time among women who are free of symptomatic CAD. Indeed, HDL seems protective against progression of carotid atherosclerosis in middleaged men; antiatherogenic effects of HDL may diminish in women around the age of menopause.20 The cIMT reflects structural arterial wall changes. In patients with hypertension, cIMT is usually increased, reflecting an early generalized vascular damage.25,26 The cIMT can detect morphological changes in the carotid artery, consisting of both an intimal atherosclerotic process and a medial hypertrophy.27 Increased cIMT correlates with most conventional CV factors,28 with atherosclerotic lesions at other sites of the arterial tree,29 as well as with the presence and severity of CAD30 and endothelial dysfunction in patients with atherosclerosis.31 Studies have also addressed the importance of CRP in the prediction of carotid lesions in patients with newly diagnosed hypertension; however, further studies are needed to evaluate the therapeutic modulation of CRP levels in highrisk patients for CVD prevention.32 Thus, cIMT may be used as a cumulative vascular marker of the atherogenetic process, reflecting vascular structural changes in the arterial wall. In the risk of stroke in women with hypertension study (RIMHA study), a cross-sectional study that included 11042
Spanish women with hypertension aged 55 years, the prevalence of total CVD, heart disease, myocardial infarction, angina, and heart failure was lowest in the higher quintile of HDL (>66 mg/dL) compared with the lowest one (0.9 mm but 1.6 mm. However, our results not only conclude that an inverse relationship between increased HDL-C levels and cIMT exists but they also provide evidence that a cutoff value of HDL-C 76.5 mg/dL almost predicts the absence of carotid atherosclerosis (cIMT 0.9 mm) in untreated middle-aged women with hypertension. However, increased HDL-C levels might mislead physicians to underdiagnose CV events, especially in women. When HDL-C is elevated and the patient presents with atypical symptoms, physicians might underestimate a female’s CV risk based on the expected HDL protection for CVD.36 Careful evaluation of both symptoms and laboratory results also taking into account any favorable CV risk markers should lead to correct diagnosis. Several limitations should be considered concerning this study. The first is its cross-sectional nature, which prevents establishing a cause–effect relation between the associations found. The second limitation is the relatively small number of patients overall and in each study group. Since hypertension has a high prevalence, a greater number of patients should be necessary in order to generalize the results of this study both in untreated and treated patients with hypertension. Another limitation refers to HDL-C measurements that were not performed in a central laboratory, but this reflects everyday
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clinical practice. However, we cannot rule out the possibility of a certain degree of variability in the measurements or that this might have influenced the results. Again regarding HDL-C measurements, we were not able to assess the size of HDL particles, especially the large ones, which might not be protective against atherosclerosis. However, our results are based on the existing inverse relationship between HDL-C levels and carotid atherosclerosis only in women with increased HDL-C. Another limitation refers to the cutoff of cIMT, which we used in our study. The Reference Values for Arterial Measurements Collaboration37 shows that the 0.90-mm cIMT cutoff we used is approximately equal to the 97th centile for healthy men and is above that centile for healthy women. The cIMT for patients with CVD was approximately 0.68 + 0.1 mm for men and women.37 However, we chose to follow the recent recommendations of European Society of Hypertension,10 which propose a cIMT cutoff of 0.90 mm. Another limitation is the nonhomogenous status of menopause in the total population, since half of the females were at the age of menopause or even younger while the rest of them was at postmenopausal age. However, this situation was similar in both study groups diminishing any consequences of postmenopause in reducing HDL-C levels. Finally, HDL-C levels in our study group ranged between 31 and 98 mg/dL. If the beneficial association between high HDL-C levels and cIMT still exists at levels of HDL-C 100 mg/dL has to be further investigated in future studies. In conclusion, a nonindependent, inverse relationship exists between increased levels of HDL-C (70 mg/dL) and carotid atherosclerosis in middle-age women with untreated essential hypertension, which might consequently contribute to total CV estimation and treatment planning. This association becomes more pronounced at HDL-C 76.5 mg/dL, which actually predicts the absence of carotid atherosclerosis. Authors’ Note Helen Triantafyllidi contributed to the conception and design, acquisition, analysis and interpretation of data, drafting and revising the article, and gave the final approval of the version to be published. George Pavlidis, Paraskevi Trivilou, Stavros Tzortzis, Iosif Xenogiannis, and Antonios Schoinas contributed to acquisition of data, drafting the article, and gave the final approval of the version to be published. Ignatios Ikonomidis contributed to the acquisition and analysis and interpretation of data, drafting the article, and gave the final approval of the version to be published. John Lekakis contributed to analysis and interpretation of data, drafting the article, and gave the final approval of the version to be published. This article was accepted and presented at a poster session at the ESC 2013 meeting (Amsterdam, the Netherlands).
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707-714. 2. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986; 256(20):2835-2838. 3. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104(10):1108-1113. 4. Grundy SM, Becker D, Clark LT, et al. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA. 2001;285(19):2486-2497. 5. Di Angelantonio E, Sarwar N, Perry P, et al. Emerging risk factors collaboration, major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993-2000. 6. Yokokawa H, Yasumura S, Tanno K, et al. Serum low-density lipoprotein to high-density lipoprotein ratio as a predictor of future acute myocardial infarction among men in a 2.7-year cohort study of a Japanese northern rural population. J Atheroscler Thromb. 2011;18(2):89-98. 7. Sbrana F, Puntoni M, Bigazzi F, et al. High density lipoprotein cholesterol in coronary artery disease: when higher means later. J Atheroscler Thromb. 2013;20(1):23-31. 8. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction: the Framingham Study. Atherosclerosis. 1988;8: 207-211. 9. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79(1):8-15. 10. Mancia G, Fagard R, Narkiewicz K, et al. ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159-2219. 11. Coca A, Cea-Calco L, Lozano JL, et al. High-density lipoprotein cholesterol and cardiovasular disease in Spanish hypertensive women. The RIMHA study. Rev Esp Cardiol. 2009;62(9): 1022-1031. 12. Mancia G, Laurent S, Agabiti-Rosei E, et al. European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27(11):2121-2158. 13. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105-1187.
Downloaded from ang.sagepub.com at CMU Libraries - library.cmich.edu on November 3, 2015
910
Angiology 66(10)
14. Devereux R, Reichek N. Echocardiographic assessment of left ventricular mass in man. Circulation. 1977;55(4):613-618. 15. Van Bortel LM, Laurent S, Boutouyrie P, et al. Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30(3): 445-448. 16. Stavros Tzortzis, Ignatios Ikonomidis, John Lekakis, et al. Incremental predictive value of carotid intima–media thickness to arterial stiffness for impaired coronary flow reserve in untreated hypertensives. Hypertens Res. 2010;33(4):367-373. 17. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res. 2006;98(11):1352-1364. 18. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95(8):764-772. 19. Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Prediction of cardio- and cerebro-vascular events in patients with subclinical carotid atherosclerosis and low HDL-cholesterol. Atherosclerosis. 2008;200(2):389-395. 20. Fan AZ, Dwyer JH. Sex differences in the relation of HDL cholesterol to progression of carotid intima-media thickness: the Los Angeles Atherosclerosis Study. Atherosclerosis. 2007;195(1): e191-196. 21. Amarenco P, Labreuche J, Touboul PJ. High-density lipoproteincholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis. 2008;196(2):489-496. 22. Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res. 2012;51(4):314-324. 23. Estruch R, Martı´nez-Gonza´lez MA, Corella D, et al. PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145(1):1-11. 24. Williams CM. Lipid metabolism in women. Proc Nutr Soc. 2004; 63(1):153-160. 25. Kobayashi K, Akishita M, Yu W, Hashimoto M, Ohni M, Toba K. Interrelationship between non-invasive measurements of atherosclerosis: flow-mediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity. Atherosclerosis. 2004;173(1):13-18. 26. Chambless L, Heiss G, Folsom A, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study,1987–1993. Am J Epidemiol. 1997;146(6):483-494. Juonala M, Viikari J, Laitinen T, et al. Interrelations between brachial endothelial function and carotid intima media thickness in young adults. The Cardiovascular Risk in Young Finns Study. Circulation. 2004;110(18):2918-2923. Folsom AR, Eckfeldt JH, Weitzman S, et al. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity: Atherosclerosis Risk in Communities (ARIC) Study investigators. Stroke. 1994;25(1): 66-73. Bots M, Iglesias del Sol A, Grobbee D. Carotid intima-media thickness measurements in observational and intervention studies. Curr Res Vasc Dis. 1998;3:274-283. O’Leary D, Polak J, Kronmal R, Manolio T, Burke G, Wolfson S. Carotid intima and media thickness as a risk factor for myocardial infarction and stroke in older subjects. N Engl J Med. 1999; 340(1):14-22. Hashimoto M, Eto M, Akishita M, et al. Correlation between flow-mediated vasodilatation of the brachial artery and intima– media thickness in the carotid artery in men. Arterioscler Thromb Vasc Biol. 1999;19(11):2795-2800. Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Association of elevated fibrinogen and C-reactive protein levels with carotid lesions in patients with newly diagnosed hypertension or type II diabetes. Arch Med Res. 2006;37(8):1004-1009. De Michele M, Iannuzzi A, Panico S, et al. Effect of high-density lipoprotein cholesterol levels on carotid artery geometry in a Mediterranean female population. Eur J Cardiovasc Prev Rehabil. 2004;11(5):403-407. Keidar S, Bogner I, Gamliel-Lazarovich A, Leiba R, Fuhrman B, Kouperberg E. High plasma high-density lipoprotein levels, very low cardiovascular risk profile, and subclinical carotid atherosclerosis in postmenopausal women. J Clin Lipidol. 2009;3(5): 345-350. van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. JACC. 2008;51(6):634-642. Baron AA1, Baron SB. High levels of HDL cholesterol does not predict protection from cardiovascular disease in women. Prev Cardiol. 2007;10(3):125-127. Engelen L, Ferreira I, Stehouwer CD, Boutourie P, Laurent S. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J. 2013;34(30):2368-2380.
Downloaded from ang.sagepub.com at CMU Libraries - library.cmich.edu on November 3, 2015
