Association of Isolated Systolic, Isolated Diastolic, and Systolic-Diastolic Masked Hypertension With Carotid Artery Intima-Media Thickness

ORIGINAL PAPER Association of Isolated Systolic, Isolated Diastolic, and Systolic-Diastolic Masked Hypertension With Carotid Artery Intima-Media Thickness Efstathios Manios, MD; 1 Fotios Michas, MD; 1 Kimon Stamatelopoulos, MD; 1 Eleni Koroboki, MD; 1 Konstantinos Stellos, MD; 2 Iliana Tsouma, MD; 1 Konstantinos Vemmos, MD; 1 Nikolaos Zakopoulos, MD 1 From the Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece; 1 and Department of Cardiology, Goethe University Frankfurt, Frankfurt am Main, Germany 2 Masked hypertension (MH) is associated with advanced target organ damage. However, patients with MH constitute a group of individuals with heterogeneous characteristics concerning their ambulatory blood pressure (BP) status. The aim of this study was to evaluate the association of isolated systolic MH, isolated diastolic MH, and systolic/diastolic MH with carotid artery intima-media thickness (CIMT). A total of 101 patients with MH underwent carotid artery ultrasonographic measurements. The patients were divided into three groups according to office and daytime BP values: isolated systolic MH, isolated diastolic MH, and systolic/diastolic MH. Patients with isolated systolic (n=36) (0.771 mm) and systolic/diastolic MH (n=37) (0.775 mm) had significantly (P<.05) higher CIMT values than those with isolated diastolic MH (n=28) (0.664 mm), even after adjustment for baseline characteristics and risk factors. Patients with isolated systolic and systolic/diastolic MH presented significantly higher CIMT values compared with patients with isolated diastolic MH. J Clin Hypertens (Greenwich). 2015;17:22 26. ª 2014 Wiley Periodicals, Inc. The increasing use of ambulatory blood pressure (BP) monitoring and home BP monitoring over the past decades has allowed the identification of different BP conditions such as sustained normotension, sustained hypertension, white-coat hypertension, and masked hypertension (MH). The term masked hypertension was firstly introduced by Professor Pickering and is defined as normal office BP with elevated ambulatory or home BP values. 1 Its prevalence lies between 10% and 30% according to the characteristics of the population examined and the diagnostic criteria used to identify this condition. 2 4 It is now well established that MH is associated with advanced target organ damage and poor cardiovascular prognosis 5 9 and also that patients with MH have a similar cardiovascular risk as do patients with sustained hypertension. 10 However, patients with MH constitute a group of individuals with heterogeneous characteristics as far as their ambulatory BP status is concerned. More specifically, patients with MH could be divided into three subgroups according to the elevated ambulatory BP component (systolic BP [SBP] and/or diastolic BP [DBP]): those with isolated systolic MH, those with isolated diastolic MH, and those with both systolic and diastolic MH. So, the question that arises is whether the aforementioned masked hypertensive groups ran the same cardiovascular risk and have the same extent of target organ damage development. Address for correspondence: Efstathios Manios, MD, Vasilisis Sofias 80, Athens 11528, Greece E-mail: stathismanios@yahoo.gr Manuscript received: August 6, 2014; revised: September 3, 2014; accepted: September 4, 2014 DOI: 10.1111/jch.12430 The aim of our study was to evaluate the association of isolated systolic MH, isolated diastolic MH, and systolic/diastolic MH with common carotid artery intima-media thickness (CIMT). PATIENTS AND METHODS A consecutive series of 622 patients who were referred for evaluation to the Hypertension Center of our department between January 2009 and January 2012 underwent office BP measurements, 24-hour ambulatory BP monitoring, and CIMT measurements. The study population fulfilled the following inclusion criteria: (1) no history or clinical evidence of hypertensionrelated complications (coronary artery disease, heart failure, cerebrovascular disease, renal insufficiency, or peripheral artery disease); (2) no clinical signs or laboratory evidence of secondary causes of arterial hypertension; and (3) no previous antihypertensive treatment. Risk factors such as diabetes mellitus, hypercholesterolemia, smoking, and body mass index were recorded. A total of 101 individuals presented with normal office and elevated daytime ambulatory BP values and were defined as having MH. These patients were referred to our laboratory by their primary physicians for evaluation of previous office BP alterations or symptoms suggesting possible abnormal BP variations such as headache, tinnitus, dizziness, fainting, and epistaxis. Patients with MH were divided into three subgroups according to office and daytime ambulatory SBP and DBP levels: isolated systolic MH (office SBP <140 and DBP <90 mm Hg), (daytime SBP 135 mm Hg and DBP <85 mm Hg), isolated diastolic MH (office SBP <140 mm Hg and DBP <90 mm Hg), (daytime SBP <135 mm Hg and DBP 85), systolic/diastolic MH (office SBP <140 mm Hg and DBP <90 mm Hg), 22 The Journal of Clinical Hypertension Vol 17 No 1 January 2015

and (daytime SBP 135 mm Hg and DBP 85 mm Hg). The study was approved by the local scientific committee and all participants provided informed consent. Office and Ambulatory BP Measurements Office BP was measured in both arms using a clinically validated automated sphygmomanometer (Omron 705IT; Omron Healthcare, Kyoto, Japan) by a physician. An appropriate cuff was then applied around the nondominant arm and three BP measurements taken at a 1-minute interval were averaged to obtain a single systolic and diastolic office BP value. During the measurements, the participants remained seated with the arm supported and placed at the level of the heart. All patients underwent 24-hour ambulatory BP monitoring on a usual working day. They were instructed to act and work as usual and to keep their nondominant arm still and relaxed at the side during measurements. Ambulatory BP was recorded using oscillometric Spacelabs 90207 equipment (SpaceLabs, Redmond, WA). Readings were obtained automatically at 15-minute intervals throughout the 24-hour study period. Daytime was defined as the interval between 9 AM and 9 PM and nighttime was the interval between 1 AM and 6 AM. For each patient, we computed mean 24-hour, daytime, and nighttime SBP and DBP. Pulse pressure (PP) was estimated as the difference between SBP and DBP. According to the SBP nocturnal fall, patients were divided into two groups: dippers (SBP nocturnal fall >10 mm Hg) and nondippers (SBP nocturnal fall <10 mm Hg). All patients were instructed to rest and sleep during the nighttime and to maintain their usual activities during the day. None of the study participants were bedridden or hospitalized during ambulatory BP monitoring. Carotid Ultrasonographic Measurements The left and right common carotid arteries were examined in the anterolateral, posterolateral, and mediolateral directions with a high-resolution ultrasound Doppler system (Vivid 7; GE, Fairfield, CT), equipped with an 8- to 14-MHz linear array transducer. Patients were examined in the supine position, with the head turned 45 from the site being scanned. Both carotid arteries were scanned longitudinally to visualize the CIMT in the far wall of the artery. The best images of the far wall that could be obtained were used to determine the CIMT. Measurements were made on frozen images, magnified to standard size online. The CIMT value was defined as the mean of the right and left intima-media thickness of the common carotid arteries, calculated from 10 measurements on each side, taken 10 mm proximal to the carotid bifurcation. The lumen/intima leading edge (I line) to media/adventitia leading edge (M line) method, which has been previously validated anatomically, was used. 11 The longitudinal B-scan frames were digitized and analyzed using a computerized image analysis by two investigators blinded to the BP recordings. The intraobserver coefficient of variation of this method in our laboratory was 7.5%. Statistical Analyses Statistical comparisons were performed between the three subgroups in terms of baseline characteristics, office BP values, ambulatory BP monitoring parameters, and CIMT values. Dichotomous variables were compared using the X 2 test, and continuous variables were compared using 1-way analysis of variance. Bonferroni correction for multiple comparisons was applied as appropriate. The CIMT (after adjustment for age and risk factors) was also compared among the three subgroups by means of analysis of covariance. The covariate adjusted mean values were computed and are presented with their corresponding 95% confidence interval (CI). Simple and multiple linear regression analyses were performed to assess which factors are independently associated with CIMT in masked hypertensive patients. Baseline characteristics and office and ambulatory BP values were selected as independent variables; CIMT was the dependent variable. The CIMT data were entered as continuous values in the model. In the initial simple regression analyses, a threshold of P<.1 was used to identify candidate variables for inclusion in the final model (because of the risk of type II error due to low statistical power in such an analysis). The multiple regression analyses were performed using the backward procedure and statistical significance was achieved with TABLE I. Demographic Characteristics and Blood Pressure Parameters of the Study Population Variables Isolated Systolic MH (n=36) Isolated Diastolic MH (n=28) Systolic- Diastolic MH (n=37) Baseline characteristics Age, y 60 (12) a,b 50 (9) c 54 (9) c Male sex, % 47 68 60 Body mass index, kg/m 2 29 (5) a 26 (3) b,c 29 (5) a Diabetes mellitus, % 6 8 3 Hypercholesterolemia, % 34 31 38 Smoking, % 29 54 43 Blood pressure parameters Office SBP, mm Hg 125 (9) 121 (7) b 128 (9) a Office DBP, mm Hg 78 (7) 80 (5) 80 (7) Daytime SBP, mm Hg 138 (5) a,b 130 (3) b,c 144 (8) a,c Daytime DBP, mm Hg 80 (3) a,b 88 (2) b,c 92 (6) a,c Daytime PP, mm Hg 59 (5) a,b 42 (3) b,c 52 (6) a,c Nighttime SBP, mm Hg 124 (13) a 113 (9) b,c 126 (12) a Nighttime DBP, mm Hg 68 (8) b 72 (8) b 78 (9) a,c Nighttime PP, mm Hg 56 (7) a,b 41 (5) b,c 48 (7) a,c Nondippers, % 53 39 43 Abbreviations: DBP, diastolic blood pressure; MH, masked hypertension; PP, pulse pressure; SBP, systolic blood pressure. a P<.05 vs isolated diastolic MH. b P<.05 vs systolic-diastolic MH. c P<.05 vs isolated systolic MH. 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TABLE II. Carotid Ultrasonographic Measurements of the Subtypes of Masked Hypertension Variables Isolated Systolic MH (n=36) Isolated Diastolic MH (n=28) Systolic-Diastolic MH (n=37) Ultrasonographic measurements CIMT, mm 0.777 (0.731 0.824) a 0.668 (0.624 0.712) b,c 0.781 (0.728 0.833) a Model 1 CIMT, mm d 0.753 (0.707 0.798) a 0.693 (0.642 0.744) b,c 0.785 (0.742 0.828) a Model 2 CIMT, mm e 0.771 (0.726 0.815) a 0.664 (0.611 0.717) b,c 0.775 (0.731 0.820) a Abbreviations: CIMT, intima-media thickness of common carotid artery; MH, masked hypertension. a P<.05 vs isolated diastolic MH. b P<.05 vs isolated systolic MH. c P<.05 vs systolic-diastolic MH. d Model 1: adjustment for age. e Model 2: adjustment for age, sex, body mass index, diabetes mellitus, hypercholesterolemia, and smoking. a two-tailed value of P<.05. To confirm the robustness of multiple regression models, all analyses were repeated using a forward-selection procedure. The associations between CIMT and the other variables are presented by means of linear regression coefficients with their corresponding 95% CI. All covariates included in the final models were tested for interactions with each other. Because the tolerance values for each covariate were >0.5, no correction for the collinearity of the data was necessary. SPSS version 18.0 for Windows (SPSS Inc; IBM, Armonk, NY) was used for statistical analyses. RESULTS Our study population consisted of 36 patients with isolated systolic MH, 28 with isolated diastolic MH, and 37 with systolic/diastolic MH. Demographics, cardiovascular risk factors, and BP parameters of the study population are presented in Table I. Patients with isolated systolic MH (60 years) were significantly older than those with isolated diastolic (50 years) and systolic/diastolic MH (54 years). Body mass index was significantly greater in patients with isolated systolic and systolic/diastolic MH compared with those with isolated diastolic MH. The three groups did not differ significantly regarding sex, prevalence of diabetes mellitus, hypercholesterolemia, smoking, and dipping status. The carotid ultrasonographic measurements are presented in Table II. Patients with isolated systolic (0.777 mm) and systolic/diastolic MH (0.781 mm) presented with significantly (P<.05) higher CIMT values than those with isolated diastolic MH (0.668 mm) (Figure). After adjustment for age, sex, body mass index, diabetes mellitus, hypercholesterolemia, and smoking, patients with isolated systolic (0.771 mm) and systolic/diastolic MH (0.775 mm) had significantly (P<.05) greater CIMT values than those with isolated diastolic MH (0.664 mm). FIGURE. Common carotid artery intima-media thickness in masked hypertension subgroups. 24 The Journal of Clinical Hypertension Vol 17 No 1 January 2015

TABLE III. Simple and Multiple Linear Regression Analyses of Factors Associated With Common Carotid Artery Intima-Media Thickness in Patients With Masked Hypertension Simple Linear Regression Analysis Multiple Linear Regression Analysis Factor Regression Coefficient (95% CI) P Value Regression Coefficient (95% CI) P Value Age a 0.052 (0.028 0.076) <.001 0.047 (0.024 0.071) <.001 Male sex 0.049 ( 0.008 to 0.107).093 0.060 (0.009 0.111).021 Body mass index 0.001 ( 0.006 to 0.006).989 Smoking 0.016 ( 0.044 to 0.076).599 Diabetes mellitus 0.018 ( 0.116 to 0.153).788 Hyperlipidemia 0.061 (0.001 0.122).049 0.044 ( 0.008 to 0.096).096 Office SBP b 0.024 ( 0.010 to 0.056).159 Office DBP b 0.052 ( 0.099 to 0.006).029 0.010 ( 0.052 to 0.032).652 Daytime SBP b 0.067 (0.034 0.100) <.001 0.068 (0.034 0.102) <.001 Daytime DBP b 0.014 ( 0.059 to 0.031).533 Nighttime SBP b 0.022 (0.001 0.044).056 0.006 ( 0.028 to 0.015).558 Nighttime DBP b 0.009 ( 0.022 to 0.041).556 Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. a Per 10-year increase. b Per 10-mm Hg increase. The factors associated with CIMT in all patients with MH were determined by means of univariate and multivariate linear regression models. The variables included in the initial univariate analyses are presented in Table III. Age, male sex, hypercholesterolemia, office DBP, and daytime and nighttime SBP were significantly associated with CIMT in the univariate analyses. Daytime and nighttime PP were also significantly associated with CIMT; however, they were not included in the multivariate model for collinearity reasons. The multivariate linear regression analyses showed significant and independent associations of CIMT with the following factors: daytime SBP (b=0.068; 95% CI, 0.034 0.102; P<.001), age (b=0.047; 95% CI, 0.024 0.071; P<.001), and male sex (b=0.060; 95% CI, 0.009 0.111; P=.021). The predicted model accounted jointly for 42.3% of the variation in CIMT (R 2 =0.358). DISCUSSION To the best of our knowledge, this is the first study to classify MH according to systolic and\or diastolic ambulatory BP values and evaluate the association of the three subgroups with CIMT. The results of our study demonstrate that patients with isolated systolic and systolic/diastolic MH presented with significantly higher CIMT values compared with those with isolated diastolic MH, even after adjustment for age and traditional risk factors. The relationship between MH and target organ damage development is indisputable. Many recent studies demonstrated that MH is strongly associated with carotid atherosclerosis, left ventricular hypertrophy, and microalbouminouria both in the general population and in smaller subgroups being examined. 5,12 15 Furthermore, the degree of target organ damage in patients with MH was similar to that in patients with sustained hypertension, 10 which explains why patients with MH ran approximately the same cardiovascular risk as patients with sustained hypertension. However, given that patients with MH form a heterogeneous group of patients, according to the elevated ambulatory BP component, it should be addressed whether both MH subgroups develop target organ damage at the same degree and consequently run the same cardiovascular risk. The results of our study demonstrate that isolated systolic and systolic/diastolic MH is associated with increased CIMT values compared with isolated diastolic MH. A possible explanation of our findings is that patients with isolated systolic and systolic/diastolic MH were significantly older than those with isolated diastolic MH. It is well-known that older age is associated with increased CIMT values. However, the difference between MH subgroups regarding CIMT retained its statistical significance after adjustment for age and other risk factors. Our study indicates that the main component that leads to increased CIMT in MH is systolic ambulatory BP. Several studies in hypertensive patients demonstrated that SBP was associated with CIMT. The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS) showed that in 508 hypertensive patients, only SBP and PP were associated with significant CIMT alterations. 16 Furthermore, the findings of the PHYLLIS study confirmed observations of a previous epidemiological survey, the European Lacidipine Study on Atherosclerosis (ELSA) study, which demonstrated similar results. 17 It is well-known that subclinical atherosclerotic changes manifesting on arterial walls involve thickening of the CIMT and decreased vascular elasticity. The assessment of CIMT is a valid method to define early atherosclerosis and to predict eventual cardiovascular events in the general population. 18 Of course, the increased CIMT values do not directly represent the extent of vascular stiffness, but, nevertheless, subclinical atherosclerosis contributes to the impairment of the The Journal of Clinical Hypertension Vol 17 No 1 January 2015 25

mechanical properties of the vascular wall and consequently to vascular stiffness. Furthermore, the increased PP that comes along with isolated systolic hypertension stands as an additional aggravating factor that is also responsible for the increased cardiovascular risk of patients with isolated systolic hypertension. STUDY LIMITATIONS The present study has certain limitations. We have to acknowledge that our results were based on data collected from a rather small group of patients (n=101). However, taking into consideration the prevalence of MH, the number of patients with nevertreated MH seems to be sufficient. In addition, the patients with isolated systolic MH were significantly older than those with isolated diastolic and systolic/ diastolic MH. However, our results retained significance after adjustment for age. Finally, we have to acknowledge that the present findings were derived from crosssectional data on the basis of one-time examination of 24-hour ambulatory BP monitoring and carotid ultrasonographic measurements. CONCLUSIONS Our study demonstrated that patients with isolated systolic and systolic/diastolic MH presented with significantly higher CIMT values compared with patients with isolated diastolic MH, independently of age and other risk factors. Our findings support the notion that patients with isolated systolic and systolic/diastolic MH should alert physicians to perform a more thorough evaluation of the cardiovascular profile of such patients. However, prospective studies are needed in order to confirm the clinical usefulness of our findings. Disclosures: The authors have no conflicts of interest or funding sources to disclose. References 1. Pickering TG, Davidson K, Gerin W, et al. Masked hypertension. Hypertension. 2002;40:795 796. 2. Stergiou GS, Salgami EV, Tzamouranis DG, et al. Masked hypertension assessed by ambulatory blood pressure versus home blood pressure monitoring: is it the same phenomenon? Am J Hypertens. 2005;18:772 778. 3. Verberk WJ, Kessels AG, de Leeuw PW. Prevalence, causes and consequences of masked hypertension: a meta-analysis. Am J Hypertens. 2008;21:969 975. 4. Angeli F, Reboldi G, Verdecchia P. Masked hypertension: evaluation, prognosis and treatment. Am J Hypertens. 2010;23:941 948. 5. Liu JE, Roman MJ, Pini R, et al. Cardiac and arterial target organ damage in adults with elevated ambulatory and normal office blood pressure. Ann Intern Med. 1999;131:564 572. 6. Bjorklund K, Lind L, Zethelius B, et al. Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation. 2003;107:1297 1302. 7. Clement DL, De Buyzere ML, De Bacquer DA, et al. Prognostic value of ambulatory blood pressure recordings in patients with treated hypertension. N Engl J Med. 2003;348:2407 2415. 8. Bobrie G, Chatellier G, Genes N, et al. Cardiovascular prognosis of masked hypertension detected by blood pressure selfmeasurement in elderly treated hypertensive patients. JAMA. 2004;291:1342 1349. 9. Ohkubo T, Kikuya M, Metoki H, et al. Prognosis of masked hypertension and white-coat hypertension detected by 24-h ambulatory blood pressure monitoring: ten-year follow-up from the Ohasama study. J Am Coll Cardiol. 2005;46:508 515. 10. Tomiyama M, Horio T, Yoshii M, et al. Masked hypertension and target organ damage in treated hypertensive patients. Am J Hypertens. 2006;19:880 886. 11. Meller MG, Fisher CM, Nicolaides AN, et al. Measurement of the ultrasonic intima-media complex thickness in normal subjects. J Vasc Surg. 1993;17:719 725. 12. Hara A, Ohkubo T, Kikuya M, et al. Detection of carotid atherosclerosis in subjects with masked hypertension and whitecoat hypertension by self-measured blood pressure at home: The Ohasama study. J Hypertens. 2007;25:321 327. 13. Sega R, Trocino G, Lanzarotti A, et al. Alterations of cardiac structure in patients with isolated office, ambulatory, or home hypertension: data from the general population (Pressioni Arteriose Monitorate E Loro Associazioni [PAMELA] Study). Circulation. 2001;104:1385 1392. 14. Lurbe E, Torro I, Alvarez V, et al. Prevalence, persistence, and clinical significance of masked hypertension in youth. Hypertension. 2005;45:493 498. 15. Cuspidi C, Meani S, Fusi V, et al. Isolated ambulatory hypertension and changes in target organ damage in treated hypertensive patients. J Hum Hypertens. 2005;19:471 477. 16. Zanchetti A, Crepaldi G, Gene Bond M, et al. Systolic and pulse pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study. J Hypertens. 2001;19: 79 88. 17. Zanchetti A, Bond MG, Hennig M, et al. Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J Hypertens. 1998;16:949 961. 18. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008;21:93 111. 26 The Journal of Clinical Hypertension Vol 17 No 1 January 2015