24-h Ambulatory blood pressure in patients with ECG ... - Nature

Journal of Human Hypertension (2004) 18, 391–396 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

24-h Ambulatory blood pressure in patients with ECG-determined left ventricular hypertrophy: left ventricular geometry and urinary albumin excretion—a LIFE substudy N Wiinberg1, LE Bang2, K Wachtell3, J Larsen2, MH Olsen3, C Tuxen1, PR Hildebrandt1, J Rokkedal3, H Ibsen3 and RB Devereux4 1

Frederiksberg University Hospital, Frederiksberg, Denmark; 2Næstved Hospital, Næstved, Denmark; Glostrup University Hospital, Glostrup Denmark; 4Weill Medical College of Cornell University, New York, NY, USA

3

This study was undertaken to evaluate the relationships among left ventricular (LV) geometric patterns and urinary albumin excretion in patients with hypertension and electrocardiographic (ECG) LV hypertrophy. In 143 patients with stage II–III hypertension, 24-h ambulatory blood pressure (BP) monitoring, single urine albumin determination, and echocardiography were performed after 14 days of placebo treatment. Mean age was 6877 years, 35% were women, body mass index was 2875 kg/ m2, LV mass index (LVMI) was 125726 g/m2, and 24% had microalbuminuria. The mean office BP was 176715/ 9978 mmHg and the mean daytime ambulatory BP was 161718/92712 mmHg. Ambulatory BP, but not office BP, was higher among albuminuric compared to normoalbuminuric patients. In patients with established hypertension, daytime pulse pressure and office BP were different in the four patterns of LV geometry, with the highest pressure in those with abnormal geometry. Furthermore, microalbuminuria was more frequent in hypertensive patients with LV hypertrophy than in those

with either normal geometry or concentric remodelling. White coat hypertensives (10%) showed lower LVMI and no microalbuminuria compared to patients with established hypertension. There were no differences in the prevalence of nondippers (26%) among the four LV geometric patterns or in microalbuminuria. In conclusion, increased daytime pulse pressure and office BP were associated with increased prevalence of abnormal LV geometry. Microalbuminuria was more frequent in groups with concentric and eccentric LV hypertrophy. Ambulatory BP, but not office BP, was higher in albuminuric than normoalbuminuric patients. With regard to the relationship among BP, LV geometric patterns, and urine albumin excretion in this population, 24-h ambulatory BP did not provide additional information beyond the office BP. Journal of Human Hypertension (2004) 18, 391–396. doi:10.1038/sj.jhh.1001717 Published online 1 April 2004

Keywords: left ventricular hypertrophy; ambulatory blood pressure; microalbuminuria; white coat hypertension; LIFE

substudy

Introduction 1

Left ventricular (LV) hypertrophy and increased urinary albumin excretion2 have been shown to be strong predictors of morbidity and mortality in patients with essential hypertension. The office Correspondence: N Wiinberg, Department of Clinical Physiology and Nuclear Medicine, Frederiksberg University Hospital, DK-2000 Frederiksberg, Denmark. E-mail: [email protected] The study was funded in parts by grants from Merck & Co., Inc., West Point, PA, USA, and Editor, Mr and Mrs Anders Kaarsens Foundation, Copenhagen, Denmark Published online 1 April 2004

blood pressure (BP), especially the systolic BP, has been shown to relate to LV hypertrophy3 and microalbuminuria,4 but closer relations have been observed using ambulatory BP.5 LV hypertrophy is a result of increased BP load on the heart, resulting in development of various patterns of LV geometry shown by echocardiography.6 Furthermore, studies have shown additional risk associated with abnormal LV geometry beyond the simple LV mass increase.7,8 Whether the BP load determined by 24-h ambulatory BP is related to specific LV geometric patterns determined by echocardiography and urinary albumin excretion remains unclear.9

Ambulatory blood pressure in left ventricular hypertrophy N Wiinberg et al 392

This study was undertaken to evaluate the relationship among LV geometric patterns, urinary albumin excretion and 24-h ambulatory BP in patients with stage II–III hypertension and electrocardiographic (ECG) LV hypertrophy. This investigation is a substudy of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.10 LIFE was a double-blind, randomized study in hypertensive patients with ECG-documented LV hypertrophy that compared the effects of atenolol vs losartan on cardiovascular mortality and morbidity.11

Methods Patients

This study was a substudy of the LIFE echocardiography substudy.12,13 Hypertension was defined as sitting office systolic BP 160–200 mmHg and/or diastolic BP 95–115 mmHg (average of two measurements using a mercury sphygmomanometer) after 2 weeks on placebo. ECG criteria for LV hypertrophy were either gender-specific Cornell voltage-duration and/or Sokolow–Lyon voltage criteria. The Cornell voltage duration criterion was (RaV1 þ SV3 ( þ 6 mV for women)) QRS duration X2.440 mV ms and the Sokolow–Lyon criterion was SV1 þ RV5/ RV6438 mV.14 Further inclusion criteria included age 55–80 years, no myocardial infarction or stroke within 6 months, absence of current congestive heart failure, angina requiring beta-blockade, ejection fraction 440%, overt renal insufficiency (serum creatinine 4160 mmol/l or 1.8 mg/dl), or significant hepatic disorder. After a run-in period that documented eligible BP levels during 14 days of placebo treatment, patients underwent baseline evaluation. Self-reported daily smoking habits were registered and routine blood samples were measured. The patients were asked to provide an early morning urine sample, the first voided specimen on arising. In 143 Danish patients, 24-h ambulatory BP monitoring and echocardiograms were performed and morning urine was sampled at the baseline visit after 14 days of placebo treatment. At this visit, office BP was obtained as the average of two measurements using a mercury sphygmomanometer in sitting position. 24-h ambulatory BP measurements

All 143 hypertensive patients had their ambulatory BP monitored for 24 h using an A&D TM2421 device (A&D Co., Ltd, Tokyo, Japan) or a QuietTrak device (Welch Allyn, Tycos, USA). The equipment has been found to be acceptable for clinical purposes.15,16 The average number of accepted measurements through 24 h was 62720. Ambulatory BP monitoring was Journal of Human Hypertension

conducted on days with daily routine activities. There were no shift workers among the patients. All recordings contained at least 20 useful measurements, including five or more measurements at night.17 White coat hypertension was defined as daytime systolic BP o137 mmHg and daytime diastolic BP o87 mmHg.18 Nondippers were defined as a decrease from day to night in both systolic and diastolic BP less than 10%.19 ECG measurements

ECG procedures for this study have been previously described.12,13 LV internal dimension, and septal and posterior wall thickness were measured at enddiastole and end-systole by American Society of Echocardiography recommendations.20 When optimal orientation of the M-mode cursor could not be obtained, correctly oriented two-dimensional linear dimension measurements were made by the leadingedge American Society of Echocardiography convention.21 Calculation of derived variables

End-diastolic LV dimensions were used to calculate LV mass by an anatomically validated formula (r ¼ 0.90. vs necropsy LV mass) (22). LV mass showed excellent interstudy reliability (r ¼ 0.93)22 in a separate study of 183 hypertensive patients.23 Relative wall thickness (RWT) was calculated as posterior wall thickness in diastole/LV internal radius.23 LV hypertrophy was considered present when LV mass/body surface area exceeded 116 g/m2 for men and 104 g/m2 for women.13 Increased RWT was present when 40.43, which represents the 97.5th percentile in normal subjects.24 Normal geometry was present when LV mass index (LVMI) and RWT were normal. Increased RWT and normal LVMI was classified as concentric remodelling, increased LVMI but normal RWT identified eccentric LV hypertrophy, and increases of both variables identified concentric LV hypertrophy.7 Urine analysis

Urine albumin/creatinine was determined by standard methods and is described previously.25 Patients were classified as having microalbuminuria when albumin/creatinine excretion was 43.5 mg/mmol and macroalbuminuria when albumin/creatinine was 435.0 mg/mmol.25 Statistical analyses

The SPSS 10.1 statistical software (SPSS, Inc, Chicago, IL, USA) was used for statistical analysis. The results are mean7s.d., or percent. Differences in continuous variables between two groups were


assessed by Student’s t-test for parametric data, and, where appropriate, either w2-analysis or Fisher’s exact test for categorical data. Comparisons among multiple groups were performed by ANOVA with the Scheffe´ post hoc test. Owing to the skewed distribution of urine albumin/creatinine data, they were log transformed before univariate relationships were assessed as partial correlations. Independent correlates of continuous measures of LV geometric patterns, and systolic and diastolic LV function were identified by multiple linear regression analysis using an enter procedure with assessment of colinearity diagnostics. Two-tailed Po0.05 was considered statistically significant.

Results The mean age of the 143 patients was 6877 years, 35% were women, body mass index (BMI) was 27.574.6 kg/m2, and 27% of patients were current smokers. Office BP (Table 1) was moderately to severely elevated, similar to the levels in the entire LIFE population.11 As expected, the daytime ambulatory BP was on average 15/7 mmHg lower than the office BP, and night-time BP was lower than daytime BP. A majority (74%) of the 143 patients had a dipping diurnal BP pattern. White coat hypertension was presented in 14 patients (10%). On average, LVMI was in the hypertrophied range. Serum creatinine level was normal, while three in 10 patients had either micro- or macroalbuminuria.

Table 1 Patient characteristics Number of patients Systolic BP—office (mmHg) Diastolic BP—office (mmHg) Pulse pressure—office (mmHg) Heart rate—office (min1) Systolic BP—day (mmHg) Diastolic BP—day (mmHg) Pulse pressure—day (mmHg) Heart rate—day (min1) Systolic BP–nighta (mmHg) Diastolic BP–nighta (mmHg) Pulse pressure–nighta (mmHg) Heart rate-nighta (min1) Nondippers (%) White coat hypertension LV mass/body surface areab (g/m2) RWT (%) Serum creatininec (mmol/l) Microalbuminuriad (%) Macroalbuminuriad (%) Diabetics (%) History of coronary artery disease (%) History of cerebral vascular disease (%) History of peripheral vascular disease (%) a

143 176715 9978 77716 71712 161718 92712 70714 7479 146721 80714 66715 64710 37 (26) 14 (10) 125726 41.576.6 86719 26 (24) 7 (6) 23 (16) 18 (12) 17 (12) 5 (4)

n ¼ 140 patients. n ¼ 132 patients. n ¼ 136 patients. d n ¼ 110 patients. Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; LVMI, left ventricular mass indexed by body surface area. b c

Five patients (4%) previously received centralacting antihypertensive drugs, 49 (34%) received diuretics, 26 (18%) received beta-blockers, 47 (33%) received calcium-blockers, 37 (26%) received either angiotensin-converting enzyme or angiotensin II receptor blockers, and 36 (25%) of patients did not receive any prior antihypertensive medication. The patients who received prior antihypertensive medication were, on average, 3 years older (7077 vs 6777.5, Po0.05), but had the same prevalence of women, current smokers and non-dippers (data not shown). There were no differences between previously treated and untreated patients in office BP; ambulatory daytime, night-time or 24-h BP; or pulse pressure. There were no differences in baseline heart rate, LV mass, prevalence of LV hypertrophy, or micro- or macroalbuminuria. LV hypertrophy

Daytime and 24-h systolic BP, day and night pulse pressure, and ambulatory BP correlated significantly to ECG LVMI (r values up to 0.19). Office BP did not correlate to ECG LVMI. No relation was found between BP indices and RWT. LVMI was significantly lower in white coat hypertensives (109726 vs 126726 g/m2, Po0.05). Eccentric and concentric LV hypertrophy were the most common abnormal geometric patterns; whereas, fewer than 20% had normal LV geometry (Table 3). Office systolic, diastolic and pulse pressures and daytime pulse pressure were different in the geometric LV groups, with highest pressure in the abnormal geometric groups (Table 3). No differences existed among the geometric groups in gender, age, BMI, diabetes, current smoking, white coat hypertension, and nondipping status. Urine albumin/creatinine ratio and LVMI did not significantly correlate (r ¼ 0.12). Urine albumin/ creatinine ratio did not differ in the four LV geometric groups. However, microalbuminuria was more frequent in groups with eccentric and concentric LV hypertrophy. No differences were seen for macroalbuminuria. Albuminuria

There was no significant correlation (r ¼ 0.08) between systolic/diastolic office BP and the albumin/creatinine ratio. Correlation coefficients between ambulatory BP and albumin/creatinine were in the range of 0.27–0.45, with the highest values for systolic BP. Corrections were made for diabetes mellitus and smoking. White coat hypertensive patients had lower excretion of albumin in the urine than established hypertensives (0.670.7 vs 11731, Po0.001) and none of the 14 white coat hypertensive patients had macro- or microalbuminuria. Percentages of patients with micro- and macroalbuminuria were similar in nondipper and dipper Journal of Human Hypertension


Table 2 Differences in pressures between hypertensive patients with normal or abnormal albumin excretion Normal albumin/creatinine ratio n ¼ 78

Microalbuminuria n ¼ 26

Macroalbuminuria n¼6

ANOVA P-value

66.777.2 27 (35) 28.074.9 23 (30) 123726 41.376.3 23 (31) 170721 94712 158716 91713 67713 75710 142719 79713 64713 65710

68.377.8 10 (39) 26.573.5 5 (19) 127724 43.677.9 6 (23) 177719 92710 171714*** 9479 78714** 7479 152717* 81712 72715* 6677

68.178.3 2 (33) 29.475.0 2 (33) 140729 44.776.5 3 (50) 175721 9179 179721 9976* 80722* 7977 170731* 95725** 75721 7176

NS NS NS NS NS NS NS NS NS o0.001 NS 0.001 NS 0.001 o0.05 o0.05 NS

Age (years) Women (%) Body mass Index (kg/m2) Current smokers (%) LVMI (g/m2) Relative wall thickness (%) Nondipper (%) Systolic BP—office (mmHg) Diastolic BP—office (mmHg) Systolic BP—day (mmHg) Diastolic BP—day (mmHg) Pulse pressure—day (mmHg) Heart rate—day (min1) Systolic BP—night (mmHg) Diastolic BP—night (mmHg) Pulse pressure—night (mmHg) Heart rate—night (min1)

Post hoc testing significant difference between normal albumin/creatinine ratio and microalbuminuria: *Po0.05, **Po0.01, ***Po0.001 between normal and micro- or macroalbuminuria. NS ¼ nonsignificant.

Table 3 BP and urine albumin in 132 hypertensive patients according to LV geometric patterns

Number (%) Systolic BP—office (mmHg) Diastolic BP—office (mmHg) Pulse pressure—office (mmHg) Pulse pressure—day (mmHg) Log Urine—albumin/creatinine ratioa Microalbuminuriaa (%) Macroalbuminuriaa (%)

Normal

Concentric remodelling

Eccentric hypertrophy

Concentric hypertrophy

P-value

24 (18) 170713 95711 75716 66715 1.671.2 2 (8) 0 (0)

17 (13) 177714 10276 68719 66715 26.9763.5 0 (0) 2 (1)

63 (47) 180714 10078 78715 69713 9.4725.0 14 (22) 2 (0.3)

28 (21) 176715 9878 82714 75715 10.5724.2 9 (32) 2 (1)

0.03 0.02 0.03 0.03 NS 0.04 NS

BP: blood pressure, NS: nonsignificant. a n ¼ 103 patients.

groups. Patients with either micro- or macroalbuminuria were similar in age, prevalence of women, BMI, smoking, LV mass, RWT, and heart rate (Table 2). However, albuminuric patients had higher day systolic and pulse pressure, as well as higher night systolic, diastolic, and pulse pressure than normoalbuminuric patients. In patients with established hypertension 30% were current smokers, whereas there were no smokers in the white coat hypertension group (P ¼ 0.001).

Discussion The mean age of this population was relatively high, which could explain the high systolic BP and pulse pressure in the patient population. Beyond high systolic BP, the subjects were, on average, men, elderly, overweight, with high prevalences of diabetes and microalbuminuria—all factors indicating a high risk for cardiovascular disease.26 There was a Journal of Human Hypertension

relative low prevalence of smokers compared to the Danish population in general in this age group.27 The 24-h ambulatory BP correlated significantly but weakly to LVMI where no correlation was observed to office BP. These results confirm those of other studies.28 Only the office BP differed among the geometric LV groups (with highest pressure in the abnormal geometric groups), but ambulatory BP (except daytime pulse pressure) showed no differences among LV geometric groups. In this highly selected population, one would not expect a strong correlation between BP and indices of LV mass because patients with both very high and normal BP or without ECG evidence of LV hypertrophy were excluded. All above-mentioned correlations and P-values explain only up to 4% of variations in patients with manifest LV hypertrophy and high BP. This could indicate that in a group of hypertensive patients who already have developed LV hypertrophy an increase in BP has minor influence on further development of LV hypertrophy.


We found a high (18%) prevalence of normal LV geometry in this hypertensive group with ECGdocumented LV hypertrophy (Table 3), which is in accord with predictions made on the basis of the known performance characteristics of the ECG criteria.13,29 We did not find a significant relation between urine albumin/creatinine ratio and LVMI or LV geometric patterns. This observation contrasts with other studies where higher albuminuria was found in patients with severe LV hypertrophy30,31 and with findings in the entire LIFE echocardiography substudy population, which had greater power due to its larger sample size. Compared to normoalbuminuric patients those with albuminuria had no differences in age, prevalence of women, BMI, smoking, LV mass, RWT or heart rate (Table 2). We observed higher BP among albuminuric patients than in normoalbuminuric patients using ambulatory BP measurements; this was not the case for office BP. Using a partition value instead of a continuous variable, we found microalbuminuria more frequently in those patients with eccentric and concentric hypertrophy. This could not be explained by smoking because there was no difference in smoking among the four geometric groups. Urine albumin/creatinine correlated to ambulatory BP, especially systolic BP. This was not observed for office BP.32 We found a surprisingly high percentage (10%) of patients with white coat hypertension in this hypertensive population despite the fact that our participants had ECG LV hypertrophy.33 Our results show no macro-or microalbuminuria in the white coat group, confirming one large study.34 Among our patients with white coat hypertension, we found echocardiographic LV hypertrophy in six of 14 (46%), three each with concentric and eccentric hypertrophy. In other studies, white coat hypertensive patients seem to be more like normotensives than hypertensives with regard to target organ damage.35 A likely explanation could be that our population was selected by ECG LV hypertrophy, and not only by BP. The number of nondippers was similar to that in other studies in hypertension (30–40%).36 Nondipping may be associated with increased target organ damage,35 but we were not able to confirm this, in that nondipping was similarly prevalent in groups defined by albuminuria or LV geometric status in our study. In summary, increased daytime pulse pressure and office BP were associated with increased prevalence of abnormal LV geometry. Microalbuminuria was more frequent in groups with concentric and eccentric LV hypertrophy. Ambulatory BP, but not office BP, was higher in albuminuric than normoalbuminuric patients. With regard to the relationship among BP, LV geometric patterns, and urine albumin excretion in this population, 24-h

ambulatory BP did not provide additional information beyond office BP.

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