HHS Public Access Author manuscript Hypertension. Author manuscript; available in PMC 2017 August 01.

Transcription

1 Masked Hypertension and Cardiovascular Disease Events in a Prospective Cohort of African Americans: the Jackson Heart Study John N. Booth III, MS a, Keith M. Diaz, PhD b, Samantha Seals, PhD c, Mario Sims, PhD c, Joseph Ravenell, MD d, Paul Muntner, PhD a, and Daichi Shimbo, MD b a University of Alabama at Birmingham, Birmingham, Alabama b Columbia University Medical Center, New York, New York c University of Mississippi Medical Center, Jackson, Mississippi d New York University School of Medicine, New York, New York Abstract HHS Public Access Author manuscript Published in final edited form as: Hypertension August ; 68(2): doi: /hypertensionaha Masked hypertension, defined as non-elevated clinic blood pressure (BP) with elevated out-ofclinic BP, has been associated with increased cardiovascular disease (CVD) risk in Europeans and Asians. Few data are available on masked hypertension and CVD and mortality risk among African Americans (AAs). We analyzed data from the Jackson Heart Study, a prospective cohort study of AAs. Analyses included participants with clinic-measured systolic/diastolic BP (SBP/DBP)<140/90mmHg who completed ambulatory BP monitoring (ABPM) following the baseline exam in (n=738). Masked daytime (10:00am 8:00pm) hypertension was defined as mean ambulatory SBP/ DBP 135/85mmHg. Masked nighttime (midnight-6:00am) hypertension was defined as mean ambulatory SBP/DBP 120/70mmHg. Masked 24-hour hypertension was defined as mean SBP/ DBP 130/80mmHg. CVD events (nonfatal/fatal stroke, nonfatal myocardial infarction or fatal coronary heart disease) and deaths identified through December 2010 were adjudicated. Any masked hypertension (masked daytime, nighttime or 24-hour hypertension) was present in 52.2% of participants; 28.2%, 48.2% and 31.7% had masked daytime, nighttime and 24-hour hypertension, respectively. There were 51 CVD events and 44 deaths over a median follow-up of 8.2 and 8.5 years, respectively. CVD rates per 1,000 person-years (95% CI) in participants with and without any masked hypertension were 13.5 ( ) and 3.9 ( ), respectively. The multivariable adjusted hazard ratio (95% CI) for CVD was 2.49 ( ) for any masked hypertension and 2.86 ( ), 2.35 ( ) and 2.52 ( ) for masked daytime, nighttime and 24-hour hypertension, respectively. Masked hypertension was not associated with all-cause mortality. Address Correspondence and Reprint Requests: Daichi Shimbo, Columbia University Medical Center, 622 West 168 th Street, PH New York, NY 10032; Phone/Fax: (212) /(646) ; ds2231@columbia.edu. Conflicts of Interest Disclosures: PM received an institutional grant from Amgen Inc. unrelated to the topic of the current manuscript. There are no other potential conflicts of interest.

2 Booth et al. Page 2 Masked hypertension is common and associated with increased risk for CVD events in AAs. Keywords ambulatory blood pressure monitoring; masked hypertension; cardiovascular disease; mortality Introduction Methods Study population Ambulatory blood pressure monitoring (ABPM) is used to quantify out-of-office blood pressure (BP), typically over a 24-hour period. 1 Currently, ABPM is recommended primarily to confirm the diagnosis of hypertension in individuals with elevated clinic-measured BP, typically defined as systolic BP (SBP) 140 mmhg or diastolic BP (DBP) 90 mmhg. 2 4 ABPM can also be used in individuals with non-elevated clinic-measured BP, SBP<140 mmhg and DBP<90 mmhg, to identify masked hypertension. 1, 5, 6 The most widely used definition of masked hypertension, clinic-measured SBP<140 mmhg and DBP<90 mmhg with daytime ambulatory SBP 135 mmhg or DBP 85 mmhg, was proposed by Pickering in Studies have also used elevated 24-hour BP instead of daytime BP to define masked hypertension. 8 Recently, the 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) position paper on ABPM incorporated elevated nighttime BP into the definition for masked hypertension. 5 The prevalence of masked hypertension has been reported to be 15% to 30% when defined by elevated daytime or 24-hour BP and as high as 60% when nighttime BP is included in the definition. 8, 9 Studies of European and Japanese participants have reported masked hypertension to be associated with increased risk for cardiovascular disease (CVD). 5, 8 Data are scarce on the prognostic significance of masked hypertension among African Americans (AA), a population with substantially higher risk for hypertension-related outcomes compared with whites Studying masked hypertension in AAs may be particularly important as a high prevalence in this population would indicate the need to identify out-of-office hypertension and poorly controlled BP. Using data from the Jackson Heart Study (JHS), a large cohort comprised exclusively of AAs, we determined the prevalence of masked hypertension and its association with CVD events and all-cause mortality. Additionally, we evaluated whether this association differed when defining masked hypertension using daytime BP, nighttime BP, or 24-hour BP. The JHS, a population-based prospective cohort study, was designed to evaluate CVD risk among AAs ( 13 Briefly, the JHS enrolled 5,301 non-institutionalized AAs, aged 21 years, between 2000 and 2004 from the Atherosclerosis Risk in the Community (ARIC) site in Jackson, Mississippi, and a representative sample of urban and rural Jackson, Mississippi metropolitan tri-county (Hinds, Madison and Rankin counties) residents, volunteers, randomly contacted individuals and secondary family members. 14 The current analysis was restricted to JHS participants who underwent ABPM

3 Booth et al. Page 3 Data Collection following the baseline exam (n=1,148). Participants who did not meet the International Database on ABPM in relation to Cardiovascular Outcomes (IDACO) criteria for a complete ABPM (n=102; described below) or were missing clinic-measured BP (n=5) or information on antihypertensive medication use (n=58) were excluded. 15 As masked hypertension can only be present among individuals without elevated clinic-measured BP, we excluded participants with SBP 140 mm Hg or DBP 90 mmhg during the baseline study clinic visit (n=245) leaving 738 participants for the current analyses. The Institutional Review Board governing human subjects research approved the JHS protocol and current analysis. All participants provided written informed consent. Data were collected during an in-home interview, clinic examination and through ABPM. During the in-home interview, trained staff administered questionnaires to collect selfreported information on socio-demographics, health behaviors, prior diagnosed co-morbid conditions, snoring and breathing cessation during sleep and daytime tiredness. During the clinic examination, trained technicians measured height, weight, neck circumference and BP, collected blood samples and recorded the names of prescription and over the counter medications taken in the two weeks prior to the study visit. After the clinical examination, participants were given the opportunity to complete ABPM. Using a modified Baecke questionnaire, the duration, frequency and intensity of physical activity during active living, work, home life and sport were recorded and summed to calculate a total physical activity score. 16 Higher scores represent more daily physical activity. Current smoking was defined by affirmative responses to the questions Have you smoked more than 400 cigarettes in your lifetime? and Do you now smoke cigarettes? Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Antihypertensive medication use and history of myocardial infarction (MI) and stroke were self-reported. Total and high-density lipoprotein (HDL) cholesterol were quantified by an oxidase method. 17 High-sensitivity C-reactive protein (CRP) was calculated using the latex particle immunoturbidimetric assay method. The use of statins was determined by pill bottle review. Urinary albumin and creatinine were quantified from a 24- hour urine collection or from a spot urine sample using the nephalometric immunoassay and enzymatic methods, respectively. 17 Albuminuria was defined as a urinary-albumin-tourinary-creatinine ratio (ACR) 30 mg/g. Estimated glomerular filtration rate (egfr) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 18 Reduced egfr was defined as <60 ml/min/1.73 m 2. Diabetes was defined as a fasting ( 8 hours) serum glucose 126 mg/dl or hemoglobin A1c 6.5% or use of insulin or oral hypoglycemic medications within 2 weeks prior to the clinic examination. Sleep apnea risk was calculated using available components that comprise the validated STOP BANG screening tool, which identifies individuals with a high risk for sleep apnea. 19 There are 8 components that assess the following attributes: snoring loudly, breathing cessation during sleep, tiredness during the daytime, hypertension status (i.e., mean clinic SBP 140 mmhg or DBP 90 mmhg or self-reported use of antihypertensive medication), BMI >35 kg/m 2, being aged >50 years, having a neck circumference > 40 cm and being male. Individuals with 3 attributes described above are categorized as high risk for obstructive sleep apnea. 19

4 Booth et al. Page 4 Clinic-measured BP was obtained following a standardized protocol. Participants were asked to avoid caffeine, eating, heavy physical activity, and smoking and alcohol intake for 12 hours prior to the visit. After participants had sat for at least 5 minutes in an upright position with their back and arms supported, feet flat on the floor and legs uncrossed, trained staff conducted two BP measurements in the right arm. One minute elapsed between the two measurements. A random zero sphygmomanometer (Hawksley and Sons Ltd) and appropriate cuff size, determined from an arm circumference measurement, was used. 13, 20 The JHS Coordinating Center conducted quality control by monitoring digit preference for each technician and by comparing mean BP measurements within and between trained technicians. The two clinic-measured BP measurements were averaged for analysis. Nonelevated clinic-measured BP was defined as a mean clinic SBP<140 mmhg and DBP<90 mmhg. Ambulatory blood pressure monitoring Following the baseline exam, participants were fitted with an ABPM device (Spacelabs 90207) on their non-dominant arm. Ambulatory BP (ABP) was recorded every 20 minutes. After 24-hours, participants returned to the clinic and the device was removed. Data were evaluated for quality and processed with Medifacts International s Medicom software (Rockville, MD). IDACO criteria were used to define whether the ABPM measurement was complete. Specifically, participants were considered to have a complete ABPM if they had 10 daytime (10am to 8pm) and 5 nighttime (midnight to 6am) SBP and DBP measurements. 15 Daytime hypertension was defined as a mean SBP 135 mmhg or mean DBP 85 mmhg based on measurements between 10am and 8pm. 5 Nighttime hypertension was defined by a mean SBP 120 mmhg or mean DBP 70 mmhg based on measurements between midnight and 6am, and 24-hour hypertension was defined as mean SBP 130 mmhg or mean DBP 80 mmhg using all available BP measurements from ABPM. 5 Since the current analysis was restricted to participants with non-elevated clinic-measured BP, those with daytime, nighttime and 24- hour hypertension were categorized as having masked daytime, masked nighttime and masked 24-hour hypertension, respectively. Additionally, participants with masked daytime, nighttime or 24-hour hypertension were categorized as having any masked hypertension. Non-dipping BP status, defined as mean nighttime to daytime SBP ratio >90%, was also determined for each participant. Outcomes The primary outcome was CVD events. All-cause mortality was examined as a secondary outcome. Adjudication procedures for these outcomes have been described previously. 21 Briefly, living participants or their proxies were contacted annually via telephone to assess potential CVD events and vital status. Hospital discharge lists with specific diagnosis criteria were also obtained from the Jackson, Mississippi tri-county area hospitals. Death certificates were requested from the Mississippi State Department of Health for JHS participants as needed. When a CVD-related hospitalization or a death was identified, medical records were retrieved and abstracted. Trained clinicians adjudicated events following published guidelines using the information available about the circumstance surrounding an event. 21 For the current analysis, definite or probable CVD events (i.e., coronary heart disease [CHD], nonfatal MI or acute CHD death or stroke defined as non-carotid embolic or thrombotic brain infarction, brain hemorrhage or

5 Booth et al. Page 5 subarachnoid hemorrhage) and all-cause mortality were available through December 31, Role of the funding source Statistical analysis The funding source had no role in the study design, collection, analysis, interpretation, or drafting of the manuscript or in the decision to submit the manuscript for publication. Characteristics were calculated for participants with and without any masked hypertension. The prevalence of any masked hypertension and masked daytime, nighttime or 24-hour hypertension was calculated, overall, and for participants taking and not taking antihypertensive medication, separately. The incidence rates of CVD were calculated for participants with and without daytime, nighttime, 24-hour and any masked hypertension. Using Cox proportional hazards regression, the hazard ratios (HR) and 95% confidence intervals (CI) for CVD associated with masked daytime, nighttime, and 24-hour hypertension, and any masked hypertension were calculated. HRs were calculated after age and sex adjustment (Model 1) and after additional adjustment for clinic-measured SBP and DBP and antihypertensive medication use (Model 2) and a CVD risk score (Model 3). Risk scores are a useful approach for controlling for confounders when there are a limited number of outcomes. 22 The CVD risk score was created in the full JHS population with clinic-measured SBP<140 mmhg and DBP<90 mmhg (n=3,797 and 201 incident CVD events) by determining the 10-year predicted probabilities for CVD from a Cox regression model with age, sex, education, smoking status, physical activity, BMI, history of MI and stroke, diabetes, total and HDLcholesterol, CRP, statin use, reduced egfr, albuminuria and antihypertensive medication use as independent variables. To account for variables in the CVD risk score with missing data Table S1), multiple imputation was performed using chained equations and 10 data sets. 23 Two additional models included adjustment for the variables in Model 3 plus nondipping BP status (Model 4) and, separately, adjustment for high sleep apnea risk (Model 5). Analyses were repeated in subgroups defined by antihypertensive medication use and, separately, after restricting the analytic sample to participants without a history of MI or stroke at the baseline exam. Participants were then divided into tertiles based on the distribution of daytime, 24-hour and nighttime SBP and, separately, DBP. CVD incidence rates were calculated by tertile of each BP measure and the HRs for CVD associated with the upper two tertiles, separately, compared with the lowest tertile of each BP measure. Next, the HRs for outcomes associated with daytime, nighttime and 24-hour SBP and DBP, modeled as continuous variables, expressed per standard deviation higher level, were calculated in all participants and subgroups defined by antihypertensive medication use. Five levels of adjustment were performed as described above. Using all-cause mortality as a secondary outcome, the above analyses were repeated. A mortality risk score was created in the full JHS population with clinic-measured SBP<140 mmhg and DBP<90 mmhg (n=3,797 with n=282 deaths) and included as a covariate in

6 Booth et al. Page 6 Results Model 3. Similar to the analysis for CVD events, two additional models adjusted for the variables in Model 3 plus non-dipping BP status (Model 4) and, separately, for high sleep apnea risk (Model 5). P-values <0.05 were considered statistically significant. All data analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC) or Stata version 13.1 (Stata Inc., College Station, TX). Participant characteristics Compared to participants without masked daytime, nighttime or 24-hour hypertension, those with any masked hypertension were older, more likely to be male and have less than a high school education, smoke cigarettes, have diabetes, a reduced egfr and albuminuria and use antihypertensive medication (Table 1). Participants with any masked hypertension also had a higher predicted 10-year CVD risk score and clinic and ambulatory BP levels. Overall, 52.2% of participants with non-elevated clinic-measured BP had any masked hypertension (Figure 1). Any masked hypertension and masked daytime, nighttime, and 24- hour hypertension were each more common among participants taking versus not taking antihypertensive medication. Masked nighttime hypertension was the most common type of masked hypertension followed by masked 24-hour and daytime hypertension, respectively. Masked hypertension and cardiovascular disease Over a median follow-up of 8.2 years (maximum: 10.2 years), there were 51 CVD events (13 events among participants not taking antihypertensive medication and 38 events among participants taking antihypertensive medication). CVD incidence rates were higher among participants with compared to without any masked hypertension and masked daytime, nighttime, and 24-hour hypertension, separately (Table 2, Panel A). Any masked hypertension and each type of masked hypertension was associated with increased CVD risk after further adjustment for the variables in Model 3, Model 4 and Model 5. Each type of masked hypertension was associated with CVD incidence among participants taking antihypertensive medication (Table 2, Panel B). In those not taking antihypertensive medication, any masked hypertension and each type of masked hypertension were associated with higher incidence of CVD, but only masked 24-hour hypertension was associated with CVD risk after multivariable adjustment (Table 2, Panel C). Among participants without a history of CVD at baseline, CVD incidence rates were higher in those with versus without any masked hypertension and each type of masked hypertension (Table S2). After further adjustment for CVD risk score in Model 3, the HR for CVD was 2.05 (95% CI ), 2.30 (95% CI ), 1.89 (95% CI ) and 1.73 (95% CI ) for those with any, daytime, nighttime and 24-hour masked hypertension, respectively. The results were similar after further adjustment for non-dipping BP status (Model 4) and having high risk for sleep apnea (Model 5). Ambulatory blood pressure and cardiovascular disease Higher tertiles of daytime, nighttime and 24-hour SBP were associated with increased CVD risk, before and after multivariable adjustment (Table 3, Panel A). The highest tertile of

7 Booth et al. Page 7 daytime, nighttime and 24-hour DBP were associated with increased CVD incidence rates and after age and sex adjustment (Table 3, Panel B). After further multivariable adjustment, daytime but not nighttime or 24-hour DBP was associated with increased CVD risk. Modeled as continuous variables, daytime, nighttime and 24-hour SBP and DBP were associated with increased CVD risk, in the overall population and among participants taking antihypertensive medication (Table S3, Panel A for SBP and Panel B for DBP). Among participants not taking antihypertensive medication, daytime, nighttime and 24-hour SBP and DBP were associated with CVD risk after age and sex adjustment. After further multivariable adjustment, only higher nighttime DBP was associated with an increased CVD risk. Masked hypertension and all-cause mortality Discussion Over a median follow-up of 8.5 years (maximum: 10.2 years), there were 44 deaths (28 and 16 deaths among participants taking and not taking antihypertensive medication, respectively). All-cause mortality rates were higher among participants with versus without masked hypertension (Table S4). Masked hypertension (any, and for daytime, nighttime and 24-hour, separately) was not associated with all-cause mortality after age and sex adjustment or further multivariable adjustment in the overall sample, and in those taking and not taking antihypertensive medication evaluated separately. In this population-based sample of AAs without elevated clinic-measured BP, the prevalence of masked hypertension was high. Masked hypertension regardless of whether it was defined using daytime, nighttime or 24-hour BP, was associated with an increased risk for CVD. These associations were present in the overall population, among participants taking and not taking antihypertensive medication, and in those without history of CVD at baseline. Higher tertiles of daytime, nighttime, and 24-hour SBP were associated with an increased risk for CVD events. Also, high daytime DBP was associated with increased risk for CVD events. In contrast, masked hypertension was not associated with all-cause mortality. Several large European, Asian and South American population-based studies (>500 participants) have previously examined the prevalence of masked hypertension among those with non-elevated clinic BP (Table 4). 8, 9, Most of these studies reported the prevalence of masked daytime hypertension, whereas fewer studies reported the prevalence of masked nighttime or 24-hour hypertension. Further, few studies examined the prevalence of masked hypertension stratified by antihypertensive medication use. Overall, the prevalence of any masked hypertension and masked daytime, nighttime and 24-hour hypertension was higher in the current study compared with European, Asian and South American populations. Prior studies of masked hypertension on CVD outcomes have had limited representation of AAs and no population-based studies included AAs. Two small studies (each <100 participants), which included middle-aged AAs, have reported a prevalence of masked hypertension exceeding 40%. 32, 33 Also, in the African American Study of Kidney Disease (AASK) Cohort Study, which included 691 AAs with established kidney disease, 70% of

8 Booth et al. Page 8 participants had masked daytime or nighttime hypertension. 30 In the current study, approximately 30% of AAs had masked daytime and 24-hour hypertension. Furthermore, more than 50% of participants had any masked hypertension or nighttime hypertension. One important issue is whether the thresholds for masked daytime, nighttime hypertension and 24-hour hypertension are relevant for AAs. Although the SBP/DBP thresholds used in the current study (daytime: 135/85 mmhg, nighttime: 120/70 mmhg, 24-hour: 130/80 mmhg) are present in several guidelines and position papers, these thresholds were derived in European, Asian, and South American samples. Future studies should determine ambulatory BP thresholds in AAs. In studies primarily from Europe, Asia and South America, masked hypertension has been reported to be associated with an increased risk for CVD outcomes overall and in adults taking and not taking antihypertensive medications. 26, A meta-analysis of 7,961 adults from 7 studies estimated the risk for CVD (i.e., MI, stroke, and peripheral vascular events) to be 2.09 (95% CI: ) times higher in those with masked daytime hypertension compared to normotensive adults. 35 Among 2,024 Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study participants aged years without elevated clinicmeasured BP, the HR was 2.75 (95% CI: ) comparing masked 24-hour hypertension with clinic-measured SBP/DBP <120/80 mmhg. 24, 34 In the current study, we extend prior studies by reporting a strong association between masked hypertension and CVD in AAs. Further, these results were consistent across higher tertiles of ambulatory BP. The association between masked hypertension and all-cause mortality has been investigated previously. The HR (95% CI) for mortality associated with masked daytime hypertension was 1.23 ( ) and with masked 24-hour hypertension was 1.25 ( ) in a pooled cohort of 12 population-based studies including 8,237 participants not taking antihypertensive medication. 27 Additionally, the HR (95% CI) for the association between masked nighttime hypertension and death was 1.29 ( ). 27 Data on this association in AAs are limited. Reported herein, the HR ranged from 1.15 (any masked hypertension) to 1.38 (masked 24-hour hypertension) but it was not statistically significant. However, the association between masked hypertension and mortality in AAs needs further investigation since few deaths occurred during follow-up. There is ongoing debate about whether home BP monitoring or ABPM is more useful for assessing CVD risk. 37, 38 The high prevalence of masked nighttime hypertension along with the magnitude of the HR for CVD events associated with this phenotype in the current study supports the use of ABPM since home BP monitoring is unable to assess nighttime BP. The presence of an association in participants taking antihypertensive medication suggests that ABPM may also be useful for targeting treatment to achieve normal ambulatory BP. As such, ABPM provides an opportunity to identify, treat and control masked hypertension in AAs and may help to reduce racial disparities in CVD. Published recommendations for using ABPM in the clinic setting are available, but few mention using ABPM to identify masked hypertension. 2 5 The Canadian Education Program in Hypertension (CEPH) recommends assessment with ABPM in adults without

9 Booth et al. Page 9 Perspectives macrovascular target-organ damage, diabetes or chronic kidney disease when SBP is between 140 and 180 mmhg or DBP is between 90 and 110 mmhg during two consecutive clinic visits. 4 The US Preventive Services Task Force (USPSTF) recommends using ABPM to confirm a clinic-measured SBP 140 mmhg or DBP 90 mmhg to prevent misdiagnosing and over-treating adults with isolated clinic hypertension. 39 The United Kingdom National Institute for Health and Care Excellence (UK NICE) guidelines recommend ABPM in adults with a clinic-measured SBP 140 mmhg or DBP 90 mmhg to confirm clinic-diagnosed hypertension. 3 The 2013 ESH/ESC position paper on ABPM recommends performing ABPM when masked daytime or nighttime hypertension is suspected. 5 However, this position paper does not clearly define which populations should be screened with ABPM to detect masked hypertension. Empirical data on which populations should be screened with ABPM to detect masked hypertension are limited. There are several possible screening approaches: (1) use ABPM in all adults with non-elevated clinic-measured BP, (2) offer ABPM to adults with BP levels in the prehypertension range (i.e., clinic-measured SBP/DBP /80 89 mmhg) due to the substantial overlap that exists between prehypertension and masked hypertension 40, 41, (3) screen adults with clinic-measured BP in the upper range of prehypertension (i.e., clinic SBP mmhg or clinic DBP mmhg) since the prevalence of masked hypertension is very high in this range 9, 40, 42 and (4) use a prediction equation that incorporates clinic-measured BP and other/clinical characteristics to identify those with a higher probability of having masked hypertension. 43 These approaches were compared by Booth et. al. who calculated test characteristics (i.e., sensitivity, specificity, positive and negative predictive value) and estimated the number of US adults who were not taking antihypertensive medications that would need to be screened with ABPM. 43 The results indicated that screening all adults with clinic-measured BP in the prehypertension range may provide the most efficient approach (sensitivity: 82.5%, specificity: 61.5%). 43 The current study has a number of strengths. The JHS is among the few population-based investigations that have performed ABPM in AAs. Additionally, ABPM and clinic-measured BP were conducted following standardized protocols. JHS had a broad scope of data collection which allowed us to control for several potential confounders. Also, the JHS actively followed participants to identify CVD events and all-cause mortality, which were subsequently adjudicated following a standardized approach. Further, the study was able to examine the contributions of daytime BP, nighttime BP, and separately 24-hour BP to CVD risk and mortality. Despite these strengths, several limitations should be considered when interpreting the results from the current analysis. ABPM was only conducted in a subset of JHS participants. Differences were present in demographic and clinical characteristics of JHS participants who volunteered those who did not volunteer to complete ABPM. 9 Also, only a limited number of CVD events and deaths occurred. Despite few events occurring, we were able to control for multiple confounders using a risk score. In the current study, masked hypertension was common among AAs without elevated clinicmeasured BP. The prevalence of any masked hypertension exceeded 50% and masked

10 Booth et al. Page 10 hypertension was associated with an increased risk for CVD events. This association was consistent for daytime, nighttime and 24-hour masked hypertension. The results herein highlight the potential importance of assessing out-of-clinic BP over a 24-hour period among individuals with non-elevated clinic-measured BP. Supplementary Material Refer to Web version on PubMed Central for supplementary material. Acknowledgments References None. Funding Sources: The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (N01- HC-95170); University of Mississippi Medical Center (N01-HC-95171); and Touglaoo College (N01-HC-95172) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Center on Minority Health and Health Disparities (NCMHD) at the National Institute of Health (NIH). The current study is also supported by R01 HL from the NHLBI. JNB III receives support through F31 HL from the NHLBI. KMD receives support through R01 HL S1 from the NHLBI. SS and MS receive support through P60MD and U54MD from the NCMHD. DS receives support through R01 HL and K24- HL from the NHLBI. PM receives research support from Amgen, Inc. 1. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. The New England Journal of Medicine. 2006; 354: [PubMed: ] 2. Redon J, Lurbe E. Ambulatory blood pressure monitoring is ready to replace clinic blood pressure in the diagnosis of hypertension: Con side of the argument. Hypertension. 2014; 64: [PubMed: ] 3. Hypertension: The clinical management of primary hypertension in adults: update of clinical guidelines 18 and 34. London: Hackam DG, Quinn RR, Ravani P, et al. Canadian Hypertension Education P. The 2013 canadian hypertension education program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. The Canadian Journal of Cardiology. 2013; 29: [PubMed: ] 5. O Brien E, Parati G, Stergiou G, et al. European Society of Hypertension Working Group on Blood Pressure M. European society of hypertension position paper on ambulatory blood pressure monitoring. Journal of Hypertension. 2013; 31: [PubMed: ] 6. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of H, European Society of C 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). Journal of Hypertension. 2007; 25: [PubMed: ] 7. Pickering TG, Davidson K, Gerin W, Schwartz JE. Masked hypertension. Hypertension. 2002; 40: [PubMed: ] 8. Peacock J, Diaz KM, Viera AJ, Schwartz JE, Shimbo D. Unmasking masked hypertension: Prevalence, clinical implications, diagnosis, correlates and future directions. Journal of Human Hypertension. 2014; 28: [PubMed: ] 9. Diaz KM, Veerabhadrappa P, Brown MD, Whited MC, Dubbert PM, Hickson DA. Prevalence, determinants, and clinical significance of masked hypertension in a population-based sample of african americans: The jackson heart study. American Journal of Hypertension. 2015; 28: [PubMed: ]

11 Booth et al. Page Mozaffarian D, Benjamin EJ, Go AS, et al. American Heart Association Statistics C, Stroke Statistics S. Heart disease and stroke statistics-2015 update: A report from the american heart association. Circulation. 2015; 131:e29 e322. [PubMed: ] 11. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E, McCormack P, Staessen JA, O Brien E. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: The dublin outcome study. Hypertension. 2005; 46: [PubMed: ] 12. Muntner P, Lewis CE, Diaz KM, Carson AP, Kim Y, Calhoun D, Yano Y, Viera AJ, Shimbo D. Racial differences in abnormal ambulatory blood pressure monitoring measures: Results from the coronary artery risk development in young adults (cardia) study. American Journal of Hypertension. 2015; 28: [PubMed: ] 13. Taylor HA Jr, Wilson JG, Jones DW, Sarpong DF, Srinivasan A, Garrison RJ, Nelson C, Wyatt SB. Toward resolution of cardiovascular health disparities in african americans: Design and methods of the jackson heart study. Ethnicity & Disease. 2005; 15:S Wilson JG, Rotimi CN, Ekunwe L, Royal CD, Crump ME, Wyatt SB, Steffes MW, Adeyemo A, Zhou J, Taylor HA Jr, Jaquish C. Study design for genetic analysis in the jackson heart study. Ethnicity & Disease. 2005; 15:S Thijs L, Hansen TW, Kikuya M, et al. Investigators I. The international database of ambulatory blood pressure in relation to cardiovascular outcome (idaco): Protocol and research perspectives. Blood Pressure Monitoring. 2007; 12: [PubMed: ] 16. Bell EJ, Lutsey PL, Windham BG, Folsom AR. Physical activity and cardiovascular disease in african americans in atherosclerosis risk in communities. Medicine and Science in Sports and Exercise. 2013; 45: [PubMed: ] 17. Carpenter MA, Crow R, Steffes M, Rock W, Heilbraun J, Evans G, Skelton T, Jensen R, Sarpong D. Laboratory, reading center, and coordinating center data management methods in the jackson heart study. The American Journal of the Medical Sciences. 2004; 328: [PubMed: ] 18. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, Ckd EPI. A new equation to estimate glomerular filtration rate. Annals of Internal Medicine. 2009; 150: [PubMed: ] 19. Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, Khajehdehi A, Shapiro CM. Stop questionnaire: A tool to screen patients for obstructive sleep apnea. Anesthesiology. 2008; 108: [PubMed: ] 20. Barker MH, Erlanger J, Meakins J, Schneider R Jr, S BS, White HUPD, Wiggers C, Wright I. Standard method for taking and recording blood pressure readings. Journal of the American Medical Association. 1939; 113: Keku E, Rosamond W, Taylor HA Jr, Garrison R, Wyatt SB, Richard M, Jenkins B, Reeves L, Sarpong D. Cardiovascular disease event classification in the jackson heart study: Methods and procedures. Ethnicity & Disease. 2005; 15:S [PubMed: ] 22. Arbogast PG, Kaltenbach L, Ding H, Ray WA. Adjustment for multiple cardiovascular risk factors using a summary risk score. Epidemiology. 2008; 19: [PubMed: ] 23. White IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Statistics in Medicine. 2011; 30: [PubMed: ] 24. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure. Hypertension. 2006; 47: [PubMed: ] 25. Banegas JR, Ruilope LM, de la Sierra A, de la Cruz JJ, Gorostidi M, Segura J, Martell N, Garcia- Puig J, Deanfield J, Williams B. High prevalence of masked uncontrolled hypertension in people with treated hypertension. European Heart Journal. 2014; 35: [PubMed: ] 26. Ohkubo T, Kikuya M, Metoki H, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognosis of masked hypertension and white-coat hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the ohasama study. Journal of the American College of Cardiology. 2005; 46: [PubMed: ]

12 Booth et al. Page Asayama K, Thijs L, Li Y, et al. International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes I. Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population. Hypertension. 2014; 64: [PubMed: ] 28. Bjorklund K, Lind L, Zethelius B, Andren B, Lithell H. Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation. 2003; 107: [PubMed: ] 29. Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C. Ambulatory blood pressure monitoring and risk of cardiovascular disease: A population based study. American Journal of Hypertension. 2006; 19: [PubMed: ] 30. Pogue V, Rahman M, Lipkowitz M, Toto R, Miller E, Faulkner M, Rostand S, Hiremath L, Sika M, Kendrick C, Hu B, Greene T, Appel L, Phillips RA. African American Study of Kidney D, Hypertension Collaborative Research G. Disparate estimates of hypertension control from ambulatory and clinic blood pressure measurements in hypertensive kidney disease. Hypertension. 2009; 53: [PubMed: ] 31. Franklin SS, Thijs L, Hansen TW, et al. International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes I. Significance of white-coat hypertension in older persons with isolated systolic hypertension: A meta-analysis using the international database on ambulatory blood pressure monitoring in relation to cardiovascular outcomes population. Hypertension. 2012; 59: [PubMed: ] 32. Veerabhadrappa P, Diaz KM, Feairheller DL, Sturgeon KM, Williamson ST, Crabbe DL, Kashem AM, Brown MD. Endothelial-dependent flow-mediated dilation in african americans with maskedhypertension. American Journal of Hypertension. 2011; 24: [PubMed: ] 33. Larsen TR, Gelaye A, Waanbah B, Assad H, Daloul Y, Williams F, Williams M, Steigerwalt S. Prevalence of masked hypertension in african americans. Journal of Clinical Hypertension. 2014; 16: [PubMed: ] 34. Angeli F, Reboldi G, Verdecchia P. Masked hypertension: Evaluation, prognosis, and treatment. American Journal of Hypertension. 2010; 23: [PubMed: ] 35. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: An updated meta analysis. American Journal of Hypertension. 2011; 24: [PubMed: ] 36. Boggia J, Li Y, Thijs L, et al. International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes i. Prognostic accuracy of day versus night ambulatory blood pressure: A cohort study. Lancet. 2007; 370: [PubMed: ] 37. Parati G, Omboni S, Bilo G. Why is out-of-office blood pressure measurement needed? Hypertension. 2009; 54: [PubMed: ] 38. Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. Home blood pressure measurements will not replace 24-hour ambulatory blood pressure monitoring. Hypertension. 2009; 54: [PubMed: ] 39. Siu AL, Force USPST. Screening for high blood pressure in adults: U.S. Preventive services task force recommendation statement. Annals of Internal Medicine. 2015; 163: [PubMed: ] 40. Shimbo D, Newman JD, Schwartz JE. Masked hypertension and prehypertension: Diagnostic overlap and interrelationships with left ventricular mass: The masked hypertension study. American Journal of Hypertension. 2012; 25: [PubMed: ] 41. Elliott WJ, Black HR. Prehypertension. Nature Clinical Practice Cardiovascular Medicine. 2007; 4: Pickering TG. The natural history of hypertension: Prehypertension or masked hypertension? Journal of Clinical Hypertension. 2007; 9: [PubMed: ] 43. Booth JN, Muntner P, Diaz KM, Viera AJ, Bello NA, Schwartz JE, Shimbo D. Evaluation of criteria to detect masked hypertension. The Journal of Clinical Hypertension (Greenwich). 2016:1 9.

13 Booth et al. Page 13 What is new? Novelty and Significance While masked hypertension has been associated with increased risk for cardiovascular disease (CVD) events in European and Japanese population-based samples, there are no published outcome data in African Americans, a population with high CVD risk. There are few published data on the associations of masked nighttime and 24-hour hypertension with CVD events. What is relevant? The prevalence of any masked hypertension exceeded 50% among African Americans. Nearly 50% of African Americans with any masked hypertension had masked nighttime hypertension which was the most common subtype. There was a strong association of masked daytime, nighttime and 24- hour hypertension and any masked hypertension with CVD events in African Americans. Summary Clinic-measured blood pressure may be inadequate for identifying many African Americans with increased blood pressure-related CVD risk. The results reported herein suggest the potential importance of using ABPM for CVD risk stratification in African Americans with nonelevated clinic BP.

14 Booth et al. Page 14 Figure 1. Prevalence of daytime, nighttime, 24-hour and any masked hypertension for Jackson Heart Study participants with non-elevated clinic-measured blood pressure overall and by antihypertensive medication use (n=738). Any masked hypertension: the presence of daytime hypertension, nighttime hypertension, or 24-hour hypertension. Masked daytime hypertension: mean daytime systolic or diastolic ambulatory blood pressure 135 or 85 mmhg. Masked nighttime hypertension: mean nighttime systolic or diastolic ambulatory blood pressure 120 or 70 mmhg. Masked 24-hour hypertension: mean 24-hour systolic or diastolic ambulatory blood pressure 130 or 80 mmhg.

15 Booth et al. Page 15 Table 1 Baseline characteristics for Jackson Heart Study participants with non-elevated clinic-measured blood pressure by any masked hypertension (n=738). Parameters Participant characteristics Any masked hypertension No (n=353) Yes (n=385) p-value Age, years 56.9 ± ± 10.5 <0.001 Male, % <0.001 Less than high school education, % Physical activity score *, exercise units 8.5 ± ± Body mass index, kg/m ± ± Current smoking, % Diabetes, % <0.001 HsCRP > 3.0 mg/l Total cholesterol, mg/dl ± ± HDL cholesterol, mg/dl 55.1 ± ± Statin use, % egfr < 60 ml/min/m 2, % ACR 30 mg/g, % <0.001 History of myocardial infarction, % History of stroke, % year CVD risk score, % 7.2 ± ± 12.9 <0.001 Sleep apnea risk score 3 (high risk), % Antihypertensive medication use, % <0.001 Clinic SBP, mmhg ± ± 10.1 <0.001 Clinic DBP, mmhg 73.8 ± ± 8.5 <0.001 Daytime SBP, mmhg ± ± 10.8 <0.001 Daytime DBP, mmhg 72.5 ± ± 8.7 <0.001 Nighttime SBP, mmhg ± ± 12.4 <0.001 Nighttime DBP, mmhg 61.0 ± ± 8.5 < hour SBP, mmhg ± ± 10.1 < hour DBP, mmhg 67.9 ± ± 7.7 <0.001 Nocturnal non-dipping status, % <0.001 Numbers in the table are percentages or mean ± standard deviation. Any Masked hypertension was defined by the presence of daytime hypertension (mean daytime systolic or diastolic ambulatory blood pressure 135 or 85 mmhg), nighttime hypertension (mean nighttime systolic or diastolic ambulatory blood pressure 120 or 70 mmhg) or 24-hour hypertension (mean 24-hour systolic or diastolic ambulatory blood pressure 130 or 80 mmhg). HsCRP: high-sensitivity c-reactive protein. HDL: high-density lipoprotein cholesterol. SBP: systolic blood pressure. DBP: diastolic blood pressure.

16 Booth et al. Page 16 egfr: estimated glomerular filtration rate. ACR: albumin-to-creatinine ratio. CVD: cardiovascular disease. * Higher score is equivalent to more physical activity. Determined using chi square and t-tests, as appropriate.

17 Booth et al. Page 17 Table 2 Incidence rates and hazard ratios for cardiovascular disease associated with any masked hypertension and masked daytime, nighttime, 24-hour hypertension among Jackson Heart Study participants with non-elevated clinic-measured blood pressure overall (Panel A) and by antihypertensive medication use (Panels B and C). Incidence rate (95% CI) * Hazard Ratio (95% CI) Model 1 Model 2 Model 3 Model 4 Model 5 Masked hypertension status Events/n at risk Panel A Overall Any masked hypertension No 11/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 40/ ( ) 2.75 ( ) 2.64 ( ) 2.52 ( ) 2.26 ( ) 2.52 ( ) Masked daytime hypertension No 22/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 29/ ( ) 2.83 ( ) 2.85 ( ) 2.89 ( ) 3.19 ( ) 2.78 ( ) Masked nighttime hypertension No 13/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 38/ ( ) 2.61 ( ) 2.53 ( ) 2.38 ( ) 2.06 ( ) 2.40 ( ) Masked 24-hour hypertension No 20/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 31/ ( ) 2.70 ( ) 2.73 ( ) 2.57 ( ) 2.48 ( ) 2.55 ( ) Panel B Taking antihypertensive medication (n=407) Any masked hypertension No 7/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 31/ ( ) 2.09 ( ) 1.77 ( ) 2.77 ( ) 2.45 ( ) 2.78 ( ) Masked daytime hypertension No 16/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 22/ ( ) 2.68 ( ) 2.33 ( ) 2.82 ( ) 3.18 ( ) 2.68 ( )

18 Booth et al. Page 18 Incidence rate (95% CI) * Hazard Ratio (95% CI) Model 1 Model 2 Model 3 Model 4 Model 5 Masked hypertension status Events/n at risk Masked nighttime hypertension No 9/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 29/ ( ) 2.32 ( ) 2.02 ( ) 2.39 ( ) 2.00 ( ) 2.43 ( ) Masked 24 hour hypertension No 15/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 23/ ( ) 3.14 ( ) 2.79 ( ) 2.34 ( ) 2.23 ( ) 2.31 ( ) Panel C Not taking antihypertensive medication (n=331) Any masked hypertension No 4/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 9/ ( ) 2.91 ( ) 2.95 ( ) 2.24 ( ) 2.12 ( ) 2.23 ( ) Masked daytime hypertension No 6/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 7/ ( ) 2.74 ( ) 2.80 ( ) 2.89 ( ) 3.50 ( ) 2.93 ( ) Masked nighttime hypertension No 4/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 9/ ( ) 2.58 ( ) 2.65 ( ) 3.13 ( ) 2.81 ( ) 3.09 ( ) Masked 24-hour hypertension No 5/ ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) Yes 8/ ( ) 2.43 ( ) 2.54 ( ) 4.30 ( ) 4.74 ( ) 4.49 ( ) Any masked hypertension: the presence of daytime hypertension, nighttime hypertension, or 24-hour hypertension. Masked daytime hypertension: mean daytime systolic or diastolic ambulatory blood pressure 135 or 85 mmhg. Masked nighttime hypertension: mean nighttime systolic or diastolic ambulatory blood pressure 120 or 70 mmhg. Masked 24-hour hypertension: mean 24-hour systolic or diastolic ambulatory blood pressure 130 or 80 mmhg.

19 Booth et al. Page 19 * Crude incidence rate per 1,000 person years (95% confidence interval). Model 1: Adjustment for age and sex. Model 2: Adjustment for age, sex, clinic systolic blood pressure, clinic diastolic blood pressure. Model 3: Adjustment for variables in Model 2 and the 10-year cardiovascular disease risk score.

20 Booth et al. Page 20 Table 3 Incidence rates and hazard ratios for cardiovascular disease associated with tertile of daytime, nighttime or 24-hour systolic (Panel A) and diastolic (Panel B) ambulatory blood pressure among Jackson Heart Study participants with non-elevated clinic-measured blood pressure (n=738). Tertile of blood pressure Events/n at risk Incidence rate (95% CI) * Hazard Ratio (95% CI) Model 1 Model 2 Model 3 Model 4 Model 5 Panel A Systolic blood pressure Tertile of daytime SBP, mm Hg < / ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) to / ( ) 1.15 ( ) 1.16 ( ) 0.96 ( ) 1.05 ( ) 1.00 ( ) / ( ) 2.66 ( ) 2.73 ( ) 2.35 ( ) 2.70 ( ) 2.38 ( ) P-trend < Tertile of nighttime SBP, mm Hg < / ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) to / ( ) 1.93 ( ) 1.93 ( ) 1.73 ( ) 1.51 ( ) 1.79 ( ) / ( ) 3.46 ( ) 3.41 ( ) 2.97 ( ) 2.38 ( ) 3.11 ( ) P-trend < Tertile of 24-hour SBP, mm Hg < / ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) to / ( ) 2.26 ( ) 2.36 ( ) 2.13 ( ) 2.12 ( ) 2.31 ( ) / ( ) 4.64 ( ) 5.00 ( ) 4.51 ( ) 4.27 ( ) 4.74 ( ) P-trend <0.001 <0.001 < Panel B Diastolic blood pressure Tertile of daytime DBP, mm Hg < / ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 72.7 to / ( ) 0.83 ( ) 0.83 ( ) 0.72 ( ) 0.76 ( ) 0.70 ( ) / ( ) 2.32 ( ) 2.23 ( ) 2.17 ( ) 2.39 ( ) 2.10 ( ) P-trend Tertile of nighttime DBP, mm Hg < / ( ) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 62.8 to / ( ) 1.35 ( ) 1.33 ( ) 1.24 ( ) 1.03 ( ) 1.20 ( )