Accepted Article

White coat effect and masked uncontrolled hypertension in treated hypertensivediabetic patients: prevalence and target organ damage1 Running Title: White-coat and masked hypertension and diabetes Liana F. LEIRIA1, Mateus D. SEVERO2, Priscila S. LEDUR2, Alexandre D. BECKER2, Fernanda M. AGUIAR3, Daniela MASSIERER1, Valéria C. FREITAS1, Beatriz D. SCHAAN2, Miguel GUS1.

1

Cardiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil,

2

Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil,

and 3Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.

Supported by: Fundo de Incentivo à Pesquisa e Eventos (FIPE) of the Hospital de Clínicas de Porto Alegre; Grant 11-0059, Conselho Nacional de Desenvolvimento Científico

e

Tecnológico

(CNPq);

Grant

472792/2009-1,

Coordenação

de

Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

Corresponding author: Miguel Gus, M.D., Ph.D. Serviço de Cardiologia Hospital de Clínicas de Porto Alegre Ramiro Barcelos, 2350 90.035-003, Porto Alegre, RS, Brazil Phone/FAX: + 5551-316-8420; FAX = + 5551-333-1541 E-mail: [email protected]

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1753-0407.12231

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Abstract

Objective: The association between hypertensive phenotypes of controlled

hypertension (CH), white-coat effect (WCE), masked uncontrolled hypertension (MUH) and sustained hypertension (SH) with target organ damage have not been clearly established in diabetic hypertensive treated patients. The present study aims to evaluate the prevalence of the four phenotypes considering the current cut-off points for office and 24h-ambulatory blood pressure monitoring (ABPM) and the association with left ventricle hypertrophy (LVH), diastolic function and nephropathy. Methods: Cross-sectional study with 304 patients on anti-hypertensive treatment

aged 57.6 ± 6.1 years, who were submitted to ABPM and echocardiography. They were classified into CH (normal office BP and ABPM), WCE (high office BP and normal ABPM), MUH (normal office BP and high ABPM), and SH (high office BP and ABPM).

Results: Median HbA1c and diabetes duration were 7.9% (6.8-9.2), and 10 years

(5-16), respectively. Prevalences of CH, WCE, MUH and SH were 27.3%, 17.1%, 18.8%, and 36.8%. MUH prevalence was higher than previously described. There was a significant increasing trend across the four groups in variables related to LVH (P< 0.001 for trend). There was not a clear “dose-response” relationship of the four hypertensive

phenotypes with nephropathy and diastolic function. Conclusion: The use of ABPM beyond the traditional cardiovascular risk

stratification tools has limitations, but is still useful in high-risk patients. Longitudinal studies could better evaluate the role of the use of ABPM in this scenario. Cut-off points for normality of office and ABPM influence the prevalences of WCH and MUH.

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Significant findings of the study: The variables related to LVH progressively increased from the CH to the SH group (P for trend < 0.001).

What this study adds: The role of hypertensive phenotypes in diabetic hypertensive treated patients and its relationship to target organ damage was not clearly established previously. The use of ABPM beyond the traditional cardiovascular risk stratification tools is still useful in high-risk diabetic patients.

Keywords: Echocardiography, Masked hypertension, Type 2 diabetes mellitus, White-

coat hypertension.

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Introduction Hypertension is often associated with type 2 diabetes mellitus (DM2) and

hypertensive diabetic patients have twice the risk of cardiovascular events as compared to nondiabetic patients1 and reduction in cardiovascular risk can be achieved by blood pressure reduction2,3. Blood pressure (BP) measurements at physician’s office may not accurately

reflect the usual BP levels in up to half of all cases4. Twenty-four-hour ambulatory BP

monitoring (ABPM) in patients with treated hypertension is a better predictor of cardiovascular events, regardless of office BP monitoring and other cardiovascular risk factors5,6. The simultaneous use of office BP monitoring and ABPM in treated hypertensive patients permits the identification of four different profiles:7 1. Controlled

hypertension (CH) - normal office BP and ambulatory BP; 2. White-coat effect (WCE) significant differences between office BP and ambulatory BP in systolic and diastolic BP (in many cases the ABPM are within normal values); 3. Masked uncontrolled hypertension (MUH) - normal office BP and high ambulatory BP; and 4. Sustained hypertension (SH) - high office BP and high ambulatory BP. Several studies have reported the prevalence of WCE and MUH in patients who are already being treated8,9,10 and the possible association between these hypertensive phenotypes and target organ damage (left ventricular hypertrophy - LVH and microalbuminuria) has been investigated11. However, such investigations in diabetic patients are scarce12,13, and the few available studies have been conducted in small populations. Thus, much of data are derived from subgroup analyses8. Given the dearth of literature on this topic, it remains

unknown whether hypertensive diabetic patients on antihypertensive drugs are more likely to have WCE or MUH, or whether the latter is underdiagnosed among these patients as compared to hypertensive-only individuals. Moreover, recent guidelines

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recommend cut-off values for ABPM which could modify the previously described prevalences of the four hypertensive phenotypes7 . The aims of this study were to determine the prevalence rates of WCE and MUH

in diabetic patients on antihypertensive treatment considering the recent definitions of normality for ABPM and office measurements for diabetic patients7,14,15 investigate

a

possible

association

of

these

hypertensive

and to

phenotypes

with

echocardiographic variables (of LVH and diastolic function) and microalbuminuria in a high-risk sample.

Methods

This cross-sectional study was conducted at the outpatient clinic of the Hospital

de Clínicas de Porto Alegre (Porto Alegre, RS, Brazil), a tertiary teaching hospital, from April 2010 to December 2011. Our data came from a larger study assessing cardiovascular risk in hypertensive diabetic patients using noninvasive methods. The study was approved by the Research Ethics Committee of the hospital, and all patients signed an informed consent before entering the study. The study population was selected from a consecutive sample of 2,342 screened

patients. The patients included in the study were drawn from general and specialist outpatient clinics of hypertension or diabetes, had a previous diagnosis of DM2 and hypertension, were being treated for both conditions, and were younger than 65. The exclusion criteria were: body mass index (BMI) higher than 35 kg/m2, chronic diseases and arrhythmias (e.g., atrial fibrillation) that could interfere with BP measurements, and ABPM recordings of fewer than 8 nighttime measures and 16 daytime measures16.

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Baseline demographic and clinical data of patients who met the inclusion criteria

and agreed to participate were collected. Blood samples were collected for laboratory analysis and were performed office BP measurement, direct ophthalmoscopy and evaluation for the presence of autonomic neuropathy. Details of the protocol are published17. BP was measured at 2 times, during the clinical evaluation, always performed by the same investigators, after 15 min of rest, in the sitting position, using an automatic sphygmomanometer (OMRON Comfort III Visomat Incoterm, Germany) and cuff size appropriate to the participant's arm circumference. Diabetic nephropathy was defined as presence of microalbuminuria, macroalbuminuria, or protein in qualitative urine analyses. High office BP levels were defined as BP ≥ 140/90 mmHg according to guidelines to diabetic patients15. Evaluations (clinical, ABPM, and echocardiographic), were performed over a maximum period 4 months (approximately 75% of patients had full evaluation within 30 days). Ambulatory blood pressure monitoring was performed during a normal working

day (Spacelabs 90207, Spacelabs, Redmond, WA), up to four months after the initial evaluation.

Details of the protocol are published17. High 24h-ABPM levels were

defined as BP ≥ 130/80 mmHg7. Echocardiography was performed by a single investigator, usually on the same

day of the ABPM. Images were obtained using a commercially available instrument (GE Healthcare VIVID 7, equipped with a 4 MHz transducer), according to the recommendations of the American Society of Echocardiography18, using three

consecutive cardiac cycles. Standard parasternal and apical views were obtained with subjects in the partial left decubitus position. Left ventricular volumes and ejection fraction were calculated using Simpson’s rule. Ventricular mass was calculated according to the American Society of Echocardiography formula18: 0.8 x [1.04 x

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{(septum thickness + left ventricular internal dimension+ posterior wall thickness) – left

Accepted Article

3

ventricular internal dimension }] + 0.6 g and adjusted both for body surface area as 3

indexed for body height to the power of 2.7. Relative wall thickness (RWT) was defined as (septum + posterior wall thickness) / (left ventricular diastolic diameter). Diastolic function was evaluated based upon mitral inflow Doppler measurements (early peak flow velocity in diastolic E-wave and late peak flow velocity in diastolic A-wave). Early peak (E’) and late peak (A’) tissue Doppler velocities were assessed at the mitral annulus, with values being determined as the average of septal and lateral wall measurements. The following variables were used for categorical analyses on the prevalence of LVH: septal and posterior wall thickness, RWT, and left ventricular mass index. We used the reference values proposed by the American Society of Echocardiography for these variables18. Hypertrophy was defined as the presence of at least two abnormal variables.

Statistical analysis Sample size calculation was based upon the mean differences found in the two

echocardiographic variables (LVH and diastolic function) between the CH and MUH groups. Considering the 2:1 proportion in CH and MUH patients19, a standard deviation (SD) of 0.15, an alpha error of 5%, and power of 80% to detect a 15% increase in the posterior wall thickness20, the sample size estimation was 45 patients (30 and 15 patients in the CH and MUH groups, respectively). For the E/E´ ratio21, we considered a SD of 2, the same proportion and difference between the CH and MUH groups. According to this estimation, the sample size was 102 patients (68 and 34 in the CH and

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MUH groups, respectively). Considering the prevalence of WCE and SH, 20 and 30%, respectively, a sample of 204 patients would be required. The groups were defined according to the BP levels obtained by the two

different methods of measurement (office and ABPM) as CH (normal office and ambulatory BP), WCE (high office BP and normal ambulatory BP), MUH (normal office BP and high ambulatory BP), and SH (high office and ambulatory BP). Student’s t, χ2, ANOVA, and Kruskal-Wallis tests were used, as appropriate, to

compare the characteristics of the groups. P values < 0.05 (two-tailed) were considered to be statistically significant. Results showing overall significant differences in ecocardiographic variables between groups were subjected to post-hoc Tukey's test and P values < 0.05 were considered significant. The variations of ecocardiographic variables across the four groups were analyzed by Jonckheere trend test and P ≤ 0.001 was considered significant for trend. Results are expressed as mean ± SD or median and interquartile range. Logarithmic transformation was applied to microalbuminuria before parametric tests were performed. The Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA), version 18.0, was used for the analyses.

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Results According to the inclusion criteria, 349 patients were included and 304 patients

underwent both ABPM and echocardiography evaluation (Figure 1). Their mean age was 57.6 ± 6.1 years, 193 (64%) were women, and 209 (69%) were Caucasian. The median HbA1c and diabetes duration were 7.9% (6.8- 9.2) and 10 years (5-16), respectively. Previous cardiovascular disease, defined by coronary angioplasty and/or coronary revascularization surgery and/or acute myocardial infarction, was present in 73 patients (24%), and 138 (46%) were either smokers or former smokers (any tobacco intake). Most of these subjects had a BMI > 30 (52%). Approximately 20% of the sample was drawn from a general outpatient clinic, while the others were from a specialist outpatient clinic. Office BP levels < 140/90 mmHg was found in 45% of whole sample. Good metabolic control (HbA1c < 7.0%) was observed only in 92 (31%) patients.

The distribution of BP phenotype groups according to office BP and 24h ABMP

is shown in Figure 2. The majority of the subjects had uncontrolled BP on antihypertensive treatment. The clinical characteristics of the patients are shown in Table 1. Metabolic

control, which was determined by plasma glucose, HbA1c, and lipid profile, was similar in the four groups. The use of beta-blockers was more prevalent in the WCE group as compared to the SH group. Most patients (55%) were being treated with three or more antihypertensive drugs. This condition, as expected, was more prevalent in the WCE group, because it is associated with pseudo-resistant hypertension. Most patients (83%) were treated with angiotensin II-receptor antagonists or angiotensin-converting enzyme inhibitors, with no difference between the groups. The use of antidiabetic drugs was similarly distributed between the groups, and almost half (47%) of the patients were on

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insulin. Statins and antiplatelet drugs were also similarly used by all the groups. The prevalence of autonomic neuropathy was 28.8%, but there was no difference in terms of its prevalence in the groups. Microalbuminuria was higher (P = 0.001) in the SH group as compared to the CH group. As shown in figure 3, the prevalence of diabetic nephropathy was higher in the SH group as compared to CH (P=0.006), but we neither found a “dose-response” relationship between the prevalence of nephropathy and the BP phenotypes, nor a significant higher prevalence as compared to the WCE group (P=0.96).

Of the 199 patients evaluated for diabetic retinopathy (n= 50, 34, 40 and 75 in

groups CH, WCE, MUH and SH, respectively), no differences were found in prevalence rates between groups. Of the 349 individuals selected, 307 (88%) underwent ABPM. Table 2 shows

the distribution of office and 24h ambulatory BP levels between the groups. As expected, there were differences according to BP profiles. Among the 349 patients, 92% (n=322) underwent echocardiography. The

majority of

the

sample

had

echocardiographic

evidence

of

LVH

(54%).

Echocardiographic parameters are shown in Tables 3 and 4. Table 3 shows the echocardiographic variables related to cardiac chamber size and the echocardiographic variables related to LVH. The SH group had higher RWT and posterior wall thickness as compared to the CH and WCE groups, and higher septum thickness as compared to the other groups. For these three variables we found a significant trend for increase across the four groups (P < 0.001 for trend). Left ventricular mass did not differ between the four groups. Table 4 shows the echocardiographic variables related to diastolic function. All variables were similar between the groups.

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Discussion In a sample of hypertensive diabetic outpatients treated at a tertiary center, we

found that most individuals’ BP levels were not adequately controlled. As expected,

there was an association between SH and some echocardiographic variables related to left ventricular hypertrophy and we found a significant trend across the four phenotypes of hypertension. This “dose-response” relationship was not found for other organ

damage variables such as diastolic function or nephropathy. Sustained hypertension was present in 36.8% of the patients. This is higher than

previously reported in population-based studies (15-28%) that used daytime ABPM and office BP as the measurement method11. Fagard et al., using daytime ABPM to evaluate patients treated with antihypertensive drugs, reported a prevalence of SH of 29.2%. However, only 10% of their sample included diabetic subjects22. In our study we defined the hypertensive phenotypes considering the current cut-off point for ABPM recommended by the last European Guidelines7,14, which is lower than the traditionally recommended. Therefore, as expected, our results should show lower prevalences for CH and WCE and higher for MUH and SH. Previous reports involving diabetic patients reported higher prevalence rates for

WCE (40 to 55%)12,23 and masked hypertension (30 to 47%)13,20,24, but these studies were conducted in patients who were not in use of antihypertensive medication at the time of measurement of BP. White-coat effect and MUH were detected in 17.1% and 18.8% of our sample, respectively. In a large cohort of treated elderly hypertensive patients, where home BP was used, the prevalences of WCE with truly controlled BP and MUH was 13.3% and 9.3%, respectively25. In the IDACO registry26, that analyzed 9691 subjects, the hypertensive phenotypes were defined in accordance with the daytime ABPM  135/85 mmHg. In the sub-group of 254 treated hypertensive diabetic

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participants the prevalence of MUH was 14.5%, which is slightly lower than our findings27. Therefore, as expected, the prevalence of hypertensive phenotypes are directly determined by studies’ samples, ambulatory methods and by the cut-off points. Few studies have previously reported the association of 24-hour ABPM with

target organ damage in diabetic patients. Eguchi described association of the 24-hour BP average with silent brain infarcts and LVH28. Masked hypertension and SH have been described as having a similar impact on target organ damage11, while white coat hypertension (not WCE, since these patients were not in anti-hypertensive treatment) was a condition closer to CH29. Krammer et al. studied diabetic patients who were not

using antihypertensive treatment and described an association of white coat hypertension with microvascular complications (retinopathy and microalbuminuria)30. Several studies have shown that patients with masked hypertension have a

higher prevalence of LVH, increased septal thickness, posterior wall thickness, and RWT8,13,31. Microalbuminuria has also been shown to be more prevalent in these patients, although few studies have been conducted in diabetic patients8,32-34. However, there is scarce literature on an association between subclinical diastolic dysfunction assessed by echocardiography and WCE or masked hypertension12,23,35. We could not

find any studies considering these issues in diabetic subjects on antihypertensive treatment, reinforcing the importance of the present data. We found a “dose-response” relationship between the four BP phenotypes (CH,

WCE, MUH, and SH) and echocardiographic variables related to LVH. As expected, the SH group had more pronounced changes. However, this was not the case for variables related with diastolic function. In contrast to our findings, studies that analyzed the echocardiographic diastolic parameters in hypertensive diabetic subjects without previous antihypertensive treatment demonstrated a higher prevalence of

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diastolic dysfunction in white coat hypertension, MUH, and SH groups as compared to normotensive subjects12,23,35. We interpret that these results were different from the present study because those were described in lower risk samples. On the contrary, half of our sample had a DM2 diagnosis for longer than 10 years, and nearly half of those were already using insulin. Moreover, only 30.5% had an adequate metabolic control (HbA1c < 7%)36. Most of our patients were using three or more antihypertensive drugs, but only 45% had an office BP at the accepted levels. Considering all these factors, and taking into account that most participants of the present study were selected from a tertiary hospital outpatient clinic, it is worth mentioning that our sample consisted of patients at a high cardiovascular risk. Furthermore, more than half of our patients already had echocardiographic

findings related to LVH, while the prevalence of LVH in the adult U.S. population is 15-20%37. Thus, we can speculate that contrary to general population or to lower-risk samples, in a high-risk setting, the use of ABPM to stratify all the target organ damage according to hypertensive phenotypes has limitations. This might be in accordance with other unpublished negative studies38. The lack of association between MUH and cardiovascular risk was also described in the IDACO registry26 in the analysis of the

sub-group of diabetic-treated hypertensive patients27. Cardiovascular risk associated with masked hypertension in diabetic patients without antihypertensive treatment was greater than in normotensive group and equivalent to stage 1 hypertension, and the authors suggest that the term “masked hypertension” should be used with caution in the

presence of anti-hypertensive therapy27. Our study did not clearly support the use of

ABPM in this context, and the traditional risk-stratification variables within the traditional tools (such as UKPDS Risk Engine and Framingham Score39,40) may still be

the main guides to cardiovascular prevention in such high risk patients.

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As previously reported in nonhypertensive diabetic patients, we also observed a

higher albuminuria excretion in SH group as compared with CH group, as expected12,32. But we also did not find a clear “dose-response” relationship between the prevalence of nephropathy and the four BP phenotypes. This was also the case for other target organ damage variables such as retinopathy and neuropathy. Some limitations of our study deserve to be mentioned. The external validity of

our findings should be questioned because our results may not be applicable to a lower risk hypertensive diabetic population. Furthermore, echocardiographic variables are surrogate endpoints, and the capacity of ABPM to help in the risk stratification of high risk hypertensive diabetic patients might be better evaluated in studies with hard endpoints. Moreover, it is possible that the study findings might have been slightly distorted by changes in antihypertensive treatments of patients, although the intervals between assessments of study were smaller than the intervals between medical consultations with their own physicians. And finally, our results were derived from a cross-sectional design that has its own methodological limitations. Ideally, longitudinal studies with hard cardiovascular endpoints including high risk hypertensive diabetic patients could better analyze the usefulness of ABPM in risk stratification. In conclusion, our results showed that in hypertensive diabetic patients with a

high-risk cardiovascular profile the prevalence rates of WCE, and especially of MUH, are influenced by the lower cut-off point for ABPM that is currently recommended by the more recent guidelines. Moreover, we found a “dose-response” association between

the four hypertensive phenotypes with echocardiographic variables related with hypertrophy but not for other target-organ damage variables. Thus, even considering the methodological limitations of the present study, the use of ABPM beyond the traditional cardiovascular risk stratification tools may have limitations but is still useful in high-

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risk patients. Longitudinal studies could better evaluate the role of the use of ABPM in this scenario.

Acknowledgments

Supported by Fundo de Incentivo à Pesquisa e Eventos (FIPE) of the Hospital de Clínicas de Porto Alegre; Grant 11-0059, Conselho Nacional de Desenvolvimento Científico

e

Tecnológico

(CNPq);

Grant

472792/2009-1,

Coordenação

de

Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

Disclosure

The authors don’t have any disclosure of conflict of interest.

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for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci (Lond) 2001; 101: 671-9.

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Accepted Article

Figure legends

Figure 1. Participants’ flow diagram.

Figure 2: Distribution of patients into four groups based on 24h ambulatory blood pressure and office blood pressure. The cutoff points applied are 130/80 mmHg for 24h-ABPM and 140/90 mmHg for office BP. Figure 3: Distribution of patients into four groups according to presence of diabetic nephropathy (spot urine albumin concentration > 17 mg/L or presence of protein in qualitative urine analyses). This analysis was performed for the 273 patients who had had this measurement performed. * P= 0.006 vs CH group.

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Accepted Article

Table 1. Characteristics of the patients studied, according to their office blood pressure and daytime

ambulatory blood pressure monitoring. Controlled hypertension (CH, n= 83)

White- coat effect (WCE, n=52)

Age (years)

57.3 ± 6.3

58.3 ± 5.8

Masked uncontrolled hypertension (MUH, n= 57) 57.0 ± 6.6

Sustained hypertension (SH, n=112)

P

Women

64 (77.1)

36 (69.2)

36 (63.2)

60 (53.6)

0.001

Caucasian

59 (71.1)

38 (73.1)

38 (66.7)

74 (67.3)

0.89

Diabetes Duration (years)

8 (5- 16)

11.5 (5- 17.5)

10 (4- 15.5)

10 (5- 18)

0.50

56.8 ± 6.1

0.52

Smoking

0.35

Never Smoked

48 (57.8)

30 (60.0)

28 (50.0)

57 (50.9)

Current Smoker

7 (8.4)

5 (10.0)

12 (21.4)

14 (12.5)

Former Smoker

28 (33.7)

15 (30.0)

16 (28.6)

41 (36.6)

27 (32.9)

16 (32.0)

13 (23.2)

32 (28.8)

0.64

Metformin

77 (92.8)

45 (86.5)

51 (91.1)

97 (86.6)

0.49

Sulfonylureas

31 (37.3)

20 (38.5)

21 (37.5)

35 (31.3)

0.73

Insulin

39 (47.0)

31 (59.6)

19 (33.9)

54 (48.2)

0.07

Diuretics

65 (78.3)

45 (86.5)

46 (82.1)

87 (78.4)

0.47

ACEI and/or ARA2

63 (75.9)

43 (82.7)

50 (89.3)

94 (84.7)

0.19

Calcium channel blockers

29 (34.9)

15 (28.8)

14 (25.0)

42 (37.8)

0.34

Beta-blockers

43 (51.8)

40 (76.9)

29 (51.8)

46 (41.4)

0.001

Antiplatelets

54 (65.1)

35 (67.3)

38 (67.9)

71 (64.0)

0.95

Statins

59 (71.1)

40 (76.9)

38 (67.9)

73 (66.4)

0.57

≥ 3 antihypertensive drugs

41 (49.4)

38 (73.1)

29 (52.7)

58 (52.3)

0.04

BMI (kg/ m2)

30.0 ± 4.8

30.5 ± 4.2

29.7 ± 2.3

30.0 ± 4.2

0.78

Plasma glucose (mg/dL)

147.8 ± 60.9

183.8 ± 87.7

154.9 ± 68.6

156.6 ± 68.9

0.06

HbA1c (%)

8.0 ± 1.8

8.6 ± 2.0

8.3 ± 2.1

8.1 ± 1.8

0.40

Previous cardiovascular disease Medications in use

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173.6 ± 39.2

179.0 ± 43.0

178.6 ± 37.9

182.3 ± 47.8

0.64

HDL-cholesterol (mg/dL)

41.0 ± 9.7

43.1 ± 10.0

44.0 ± 16.8

41.1 ± 10.8

0.38

Triglycerides (mg/dL)

125.0

145.0

155.0

178.0

0.09

(88.5- 201.5)

(107.0- 225.0)

(118.0- 241.5)

(104.0- 239.5)

GFR (mL/min/1.73m2)

89.0 ± 23.8

93.1 ± 31.2

89.7 ± 32.0

82.0 ± 24.2

UAE (mg/mL)

6.0 (0.0-11.9)

9.7 (0.8- 42.6)

7.3 (0.0- 17.2)

12.9 (4.7- 66.0)* 0.001

CRP

3.0 (1.0- 7.8)

4.9 (1.6- 8.3)

2.4 (0.8- 4.2)

3.1 (0.6- 8.0)

0.13

Autonomic neuropathy

15 (18.3)

14 (28.6)

20 (37.0)

36 (31.6)

0.08

Diabetic retinopathy

13 (26.0)

12 (35.3)

11 (27.5)

26 (34.7)

0.67

Accepted Article

Total cholesterol (mg/dL)

0.11

Continuous variables are expressed as mean ± standard deviation or median (interquartile range). Categorical variables are expressed as number (%). ARA2: angiotensin receptor antagonist 2; ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; US CRP: C-reactive protein; GFR: glomerular filtration rate calculated by the MDRD equation; UAE: urinary albumin excretion; Previous cardiovascular disease: previous coronary angioplasty and/or coronary revascularization surgery and/or acute myocardial infarction; Current and former smoking: any tobacco intake. Kruskal- Wallis test for CRP and UAE analysis, for others, ANOVA test and X 2test, Tukey test for post hoc analysis. *P= 0.001 vs. CH.

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Accepted Article

Table 2. Blood pressure levels according to hypertensive phenotypes. Controlled Hypertension (CH, n=83)

White-coat Effect (WCE, n= 52)

Masked uncontrolled Hypertension (MUH, n= 57)

Sustained Hypertension (SH, n= 112)

P

Systolic BP

128.7 ± 8.9

153.6 ± 10.5*

129.0 ± 7.8

158.3 ± 15.5*

< 0.001

Diastolic BP

75.5 ± 6.6

85.3 ± 8.5*

76.8 ± 7.2

88.0 ± 10.3*

< 0.001

Systolic BP

117.2 ± 13.9

120.4 ± 10.2

136.5 ± 12.1**

142.5 ± 13.3**

< 0.001

Diastolic BP

70.4 ± 5.7

70.7 ± 6.5

81.3 ± 9.0**

81.5 ± 8.3**

< 0.001

Systolic BP

121.9 ± 9.4

123.4 ± 10.7

139.3 ± 11.7**

144.7 ± 14.2**

< 0.001

Diastolic BP

73.3 ± 7.1

72.7 ± 8.7

84.1 ± 8.9**

83.9 ± 8.9**

< 0.001

Systolic BP

110.1 ± 9.9

112.5 ± 10.7

130.8 ± 17.3**

136.3 ± 16.9**

< 0.001

Diastolic BP

62.9 ± 6.4

62.8 ± 7.2

75.3 ± 11.5**

74.9 ± 10.0**

< 0.001

Office

24 h ABPM

Daytime ABPM

Nigthtime ABPM

Data are expressed as mean ± standard deviation. BP: blood pressure. 24h ABPM: 24-hour arterial blood pressure monitoring. *Vs. CH and MH groups, **vs. CH and WCE groups. ANOVA test, post hoc Tukey test.

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Accepted Article

Table 3. Echocardiographic variables related to cardiac chamber diameters and left ventricular hypertrophy according to hypertensive phenotypes.

Aorta (cm)

Controlled Hypertension (CH, n= 83) 3.2 ± 0.4

White-Coat Hypertension (WCE, n= 52) 3.2 ± 0.3

Masked Hypertension (MUH, n= 57) 3.2 ± 0.4

Sustained Hypertension (SH, n=112) 3.1 ± 0.3

P

0.83

Left Atrium (cm)

3.8 ± 0.5

3.9 ± 0.5

3.8 ± 0.4

3.8 ± 0.4

0.52

LVSD (cm)

2.9 ± 0.4

2.9 ± 0.4

2.9 ± 0.3

2.9 ± 0.4

0.59

LVDD (cm)

4.6 ± 0.4

4.6 ± 0.5

4.6 ± 0.5

4.6 ± 0.5

0.92

RigthVentricle (cm)

2.1 ± 0.3

2.1 ± 0.3

2.1 ± 0.3

2.2 ± 0.2

0.42

LVEF (%)

64.8 ± 5.6

64.1 ± 5.6

64.8 ± 5.3

64.8 ± 5.0

0.88

RWT

0.41 ± 0.07

0.41 ± 0.06

0.43 ± 0.06

0.45 ± 0.08*

0.001

Septum thickness (cm)

0.96 ± 0.18

0.98 ± 0.16

1.01 ± 0.17

1.04 ± 0.16**

0.01

PW thickness (cm)

0.92 ± 0.14

0.93 ± 0.14

0.94 ± 0.14

0.99 ± 0.15***

0.001

LVMI (g/m2)

94.4 ± 29.9

98.3 ± 30.9

97.5 ± 30.3

103.1 ± 30.2

0.26

LVMI (g/h2,7)

47.5 ± 14.4

48.5 ± 14.9

48.7 ± 14.7

51.3 ± 16.0

0.37

LAVI (mL/m2)

28.5 ± 11.2

30.3 ± 10.8

26.8 ± 8.2

29.9 ± 9.6

0.20

Data are expressed as mean ± standard deviation. LVSD: Left ventricular systolic diameter; LVDD: Left ventricular diastolic diameter; LVEF: left ventricular ejection fraction. RWT: relative wall tickness; PW: posterior wall; LVMI: left ventricular mass index; LAVI: left atrial volume index. *P= 0.001 vs. CH group and P= 0.02 vs. WCE group. **P=0.01 vs. CH group. ***P= 0.00 vs. CH group and P=0.04 v.s WCE group. ANOVA test, post hoc Tukey test.

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Table 4. Echocardiographic variables related diastolic dysfunction according to hypertensive phenotypes.

Controlled Hypertension (CH, n=83)

White-coat Effect (WCE, n=52)

E wave velocity (m/s)

0.77 ± 0.19

0.79 ± 0.21

Masked uncontrolled Hypertension (MUH, n=57) 0.75 ± 0.19

Sustained Hypertension (SH, n=112)

P

A wave velocity (m/s)

0.82 ± 0.23

0.81 ± 0.25

0.77 ± 0.24

0.85 ± 0.22

0.19

E wave DT (m/s)

240.7 ± 41.7

223.4 ± 52.7

232.4 ± 36.5

238.9 ± 44.5

0.11

A wave length (cm/s)

178.2 ± 44.2

177.8 ± 42.1

178.4 ± 43.5

180.3 ± 41.3

0.99

E/A ratio (m)

0.95 ± 0.29

1.00 ± 0.34

0.96 ± 0.30

0.91 ± 0.30

0.33

E’ wavevelocity (m/s)

0.08 ± 0.02

0.07 ± 0.02

0.07 ± 0.02

0.07 ± 0.02

0.25

A’ wave velocity (m/s)

0.10± 0.02

0.09 ± 0.02

0.09± 0.02

0.10 ± 0.02

0.33

E/E’ratio

10.7 ± 3.3

11.7± 5.0

11.1 ± 3.4

11.2 ± 3.2

0.54

0.74 ± 0.15

0.41

E/E’ratio

0.77

≤8

21 (25.9)

12 (23.1)

12 (21.1)

23 (20.9)

9-14

52 (64.2)

31 (59.6)

35 (61.4)

74 (67.3)

≥ 15

07 (9.9)

09 (17.3)

13 (17.5)

13 (11.8)

IVRT (m/s)

108.8 ± 19.2

108.9 ± 19.9

108.8 ± 16.3

110.0 ± 16.9

0.96

Data are expressed as mean ± standard deviation and n (percentage). IVTR: isovolumetric relaxation time; DT: E wave deceleration time. ANOVA test and X2 test.

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JDB_12231_F1

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JDB_12231_F2

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JDB_12231_F3

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