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To dip or not to dip? The unique relationship between different blood pressure patterns and cardiac function and structure

Abstract

Dipping and nondipping blood pressure (BP) patterns are associated with different levels of target organ damage and cardiovascular risk. The aim of our investigation was to determine the relationship between different BP patterns (dipping, nondipping, extreme dipping and reverse dipping type) and cardiac structure, and function in hypertensive patients. This cross-sectional study included 376 hypertensive patients. All subjects underwent 24-h ambulatory BP monitoring, and complete two-dimensional, pulsed and tissue Doppler echocardiography. Most of the parameters of the left ventricular (LV) diastolic function (E/A, e′/a′, E/e′) significantly and progressively deteriorated from the extreme dippers to the dippers and nondippers, and finally to the reverse dippers. In contrast, LV structural parameters (IVS, RWT, LV mass index) showed a statistically important difference only by comparing the dippers and the extreme dippers with the rest of the patients. Simultaneously, the right ventricular (RV) structural parameter (RVT, right ventricular thickness), and most RV diastolic parameters significantly and progressively worsened from the extreme dippers, over the dippers and the nondippers, to the reverse dippers. Daytime and night time systolic BP, nocturnal systolic BP fall, and the nondipping and the reverse dipping status were independently associated with LV and RV structure, as well as with diastolic function. LV and RV structure, and diastolic function were significantly more impaired with the nondippers and the reverse dippers compared with others.

Introduction

Ambulatory blood pressure monitoring (ABPM) has been proved to be a very useful and valuable method in the determination of cardiovascular risk and target organ damage. O’Brien et al.1 were the first to show that patients with an abnormal circadian BP profile with a lack of nocturnal BP decrease had a higher prevalence of stroke. O’Brien and colleagues introduced the terms ‘dipping’ and ‘nondipping’ as main BP patterns. The usage of ABPM revealed another, more precise, BP model, which divided the nocturnal blood pressure pattern into four subtypes: dipping, nondipping, extreme dipping and reverse dipping. Growing evidence indicates that dipping and nondipping BP patterns were associated with different levels of target organ damage and cardiovascular risk in hypertensive patients, and that nondipper subjects have a worse cardiovascular outcome than that of the dippers.2, 3, 4 Consensus on the impact of nocturnal BP fall on target organ damage and cardiovascular morbidity and mortality has not been established yet.5, 6 The subtle differences in cardiovascular damage and outcome between four BP patterns (the dipping, nondipping, extreme dipping and reverse dipping type) still remain controversial due to the limited number of studies.4, 7, 8

Our study was designed to investigate the relationship between different BP patterns (the dipping, nondipping, extreme dipping and reverse dipping type)and structure and function of the left and right ventricle in hypertensive patients.

Materials and methods

Our cross-sectional study included 376 consecutive subjects mostly untreated for hypertension (69%). The study was conducted at Cardiology Clinic, Clinical Centre of Serbia, between January 2007 and December 2010. The inclusion criteria were office systolic blood pressure (SBP) values 140 mm Hg and/or diastolic blood pressure (DBP) 90 mm Hg in three separate measurements, and 24-h BP 125/80 mm Hg or orderly treated hypertensive patients with short history of hypertension (<3years). Patients with clinical BP>180/100 mm Hg, as well as patients who were treated for arterial hypertension longer than 3 years, subjects with >3 antihypertensive drugs in therapy and patients with white-coat hypertension were excluded from the study. Subjects with heart failure, coronary artery disease, previous cerebrovascular insult, atrial fibrillation, congenital heart disease, valvular heart disease, obesity (BMI30 kg m−2), neoplastic disease, cirrhosis of the liver, kidney failure, renovascular and renoparenchymal disease, sleeping disorders or endocrinological diseases including type 2 diabetes mellitus, Cushing's and Conn's syndrome, and pheochromocytoma were also excluded from the study.

The anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, uric acid, total cholesterol, low and high-density lipoprotein cholesterol, triglycerides and serum creatinine) were taken from all the subjects included in the study.

Clinical arterial blood pressure values were obtained by using a conventional sphygmomanometer in the morning hours by measuring the average value of the three consecutive measurements in the sitting position, taken within an interval of 5 min after the subject had rested at least for 5 min in that position. Prior to the study, informed consent was obtained from all the patients.

All patients underwent routine abdominal ultrasound with vascular colour Doppler ultrasound due to exclusion of renovascular and reno-parenchymal disease or enlargement of adrenal glands. In patients with characteristic clinical signs, laboratory findings or with enlargement of adrenal glands, we excluded the possibility of Cushing's and Conn's syndrome and pheochromocytoma. Patients with suspected secondary endocrine hypertension (n=15) were referred to the Clinic of Endocrinology, Clinical Centre of Serbia, where they underwent imaging examinations and assessment of necessary hormones. After endocrinological examination, three patients were excluded from the study; one patient because of Conn's syndrome and two patients because of Cushing's syndrome.

Clinical BP measurement and 24-h ambulatory BP monitoring

Noninvasive 24-h ABPM was performed on the non-dominant arm using Schiller BR-102 plus system (SCHILLER AG, Baar, Switzerland). The device was programmed to obtain BP readings at 15-min intervals during the day (0700–2300 hours) and at 20-min intervals during the night (2300–0700 hours). The patients were asked to attend to their usual daily activities, but to keep still at the times of measurement. Night time BP was defined as the average of BPs from the time the patients went to bed until the time they got out of bed, and daytime BP as the average of BPs recorded during the rest of the day. The ABPM was always performed during a working day (Monday–Friday). The recording was then analysed to obtain 24-h daytime and night time average SBP, DBP, mean arterial pressure and heart rates. When the readings exceeded at least 80% of the total readings programmed for the testing period, the recording was considered as valid and satisfactory. The nocturnal dipping was defined as a reduction in average SBP and DBP at night, which was 10% and <20%, respectively, compared with average daytime values; the extreme nocturnal dipping existed if the reduction in average SBP and DBP at night was 20%. The nondippers had a nocturnal reduction in average SBP and DPB <10%, and the reverse dippers were the patients with a higher nocturnal average SBP and DPB in comparison with diurnal values.1

Echocardiography

The echocardiographic examination was performed on the Acuson Sequoia 256 ultrasound system (Siemens AG, Erlangen, Germany) by using a 2–4-MHz transducer. The values of all the echocardiographic parameters were obtained as the average value of five consecutive cardiac cycles. The left ventricular (LV) end-systolic (LVESD) and end-diastolic diameters (LVEDD), the left ventricular free wall (PWT) and septum thickness (IVS) were determined according to the recommendations of the American Society of Echocardiography.9 End-systolic and end-diastolic volumes and parameters of the systolic function (ejection fraction and fractional shortening) were estimated by using the Teicholz formula. Relative wall thickness (RWT) was calculated as (2 × PWT)/LVEDD.

The left ventricular mass (LVmass) was calculated by using the Penn's formula.9 The left ventricular hypertrophy was defined as the left ventricular mass index (LVmass/Ht2.7) 51 g m−2.7 for men and 49.5 g m−2.7 for women.10

The transmitral inflow velocities were analysed using pulsed Doppler in the apical four-chamber view, with the sample volume placed at the mitral valve leaflet tips.11 Measurements included the transmitral early diastolic peak flow velocity (Em), late diastolic flow velocity (Am), their ratio (E/A)m and deceleration time (DTm).11

Tissue Doppler imaging was used to obtain the LV myocardial velocities in the apical four-chamber view with a 2-mm sample volume placed at the septal segment of the mitral annulus during early diastole (e′).11 The E/e′ ratio was determined by using previously estimated values of E and e′ flow velocity during the early diastole obtained by pulsed Doppler and tissue Doppler. Diagnosis of LV diastolic dysfunction was based on the recommendations of the European and the American Society of Echocardiography.12

The parameters necessary for calculating the Tei index were obtained by using the tissue Doppler in the apical four-chamber view. A 2-mm sample volume was placed at the lateral corner of the mitral/tricuspid annulus. Isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) were measured from the end of the mitral/tricuspid annular velocity pattern to the onset of the systolic wave and from the end of the systolic wave to the onset of the mitral/tricuspid annular velocity pattern, respectively. The ejection time (ET) was defined as the duration of the left/right ventricular outflow–Doppler velocity profile. The Tei indexes were calculated according to the formula Tei index=(IVCT+IVRT)/ET.13

The right ventricular (RV) internal end-diastolic diameter and RV end-diastolic thickness were measured in M-mode in the parasternal long-axis view at the outflow tract level.13 The right longitudinal atrial diameter was measured in the apical four-chamber view at the ventricular end-systole.14 Tricuspid flow velocities were achieved by the standard pulsed Doppler technique in the apical four-chamber view. The following parameters were determined: early diastolic peak flow velocity (Et), late diastolic flow velocity (At), their ratio (E/A)t and deceleration time (DTt).

RV global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE), which was measured as the difference between the distance among the tricuspid annulus and RV apex at the end-diastole and end-systole of the same cardiac cycle.14

Tissue Doppler imaging was used to obtain the right ventricular myocardial velocities in the apical four-chamber view with a 2-mm sample volume placed at the septal segment of the tricuspid annulus during the early diastole (et).14 (E/e′)t ratio of the right ventricle was determined by using previously estimated Doppler values.

Assessment of the right ventricular systolic or diastolic dysfunction, along with the global function, was based on the recommendations of the American and European Society of Echocardiography for 2010.14 RV hypertrophy was defined by RV end-diastolic thickness at the outflow tract (6 mm in men and 5.5 mm in women).15

Statistical analysis

Continuous variables were presented as mean± (s.d.), and the analysis of equal variance with Bonferroni post hoc analysis was used to detect differences between the groups, as they showed normal distribution. Differences in proportions were compared by using the χ2 or Fisher's exact test, where appropriate. Pearson's correlation coefficient was used to determine the correlation between different demographic, clinical and echocardiographic parameters and LV mass index, E/e′ mitral ratio, RV wall thickness and E/e′ tricuspid ratio. The variables that showed a P-value 0.10 were included in the stepwise multiple regression analyses. P-values <0.05 was considered statistically significant.

Results

The study included 376 hypertensive patients who were divided into four subgroups according to 24-h ABPM: 173 dippers (46%), 125 nondippers (33%), 45 extreme dippers (12%) and 33 reverse dippers (9%). The different groups were of similar age, gender and BMI distribution (Table 1). There were no significant differences in laboratory analyses, prevalence of smokers or frequency of untreated patients (Table 1). Analyses showed that the pharmacological treatment of hypertension and the number of antihypertensive drugs per patient was similar between different groups (Table 1).

Table 1 Demographic characteristics and clinical parameters of study population

Clinical BP, 24-h and daytime average systolic, diastolic and mean arterial BP were similar between the groups (Table 2). On the other hand, average systolic, diastolic and mean arterial BP were significantly different among the groups. The lowest values were recorded in the extreme dippers, followed by the dippers and the nondippers, and the highest values were, as expected, found in the reverse dippers (Table 2). There was a statistically significant and gradual increase from the extreme dippers to the reverse dippers not only in the night time SBP, DBP and mean BP, but also in the nocturnal BP change (Table 2). The same results were obtained for the treated patients who showed satisfactory BP regulation. The 24-h SBP (121±12 vs 123±12 vs 124±13 vs 127±14 mm Hg; P=0.186) as well as 24-h DBP (73±5 vs 73±6 vs 74±7 vs 76±7 mm Hg; P=0.075), in treated patients, gradually increased from the extreme dippers to the reverse dippers.

Table 2 Clinical and ambulatory blood pressure measurements

LV diameters and systolic function (EF) were completely preserved and did not differ among the groups. Interestingly, most of the parameters of LV diastolic function (E/A, e′/a′, E/e′) and the parameter of global LV function (Tei index), significantly and progressively, deteriorated from the extreme dippers to the dippers and the nondippers, and finally to the reverse dippers. In contrast, all LV structural parameters (IVS, RWT, LV mass index) and the left atrium showed a statistically important difference only by comparing the dippers and the extreme dippers on the one hand, and the nondippers and the reverse dippers on the other (Table 3). However, the prevalence of LV hypertrophy and LV diastolic dysfunction was significantly higher in the reverse dippers compared with the dippers and the extreme dippers (Table 3).

Table 3 Echocardiographic parameters of left and right ventricular structure and function in study population

RV and RA diameters, and parameters of RV systolic function (tricuspid annular plane systolic excursion, right ventricular ejection fraction (RVEF)) were similar between the groups. RV structural parameter (RVT), almost all RV diastolic parameters and RV global function indicator (RV Tei index) significantly and progressively worsen from the extreme dippers, over the dippers and the nondippers, to the reverse dippers (Table 3). Similar to LV, the prevalence of RV hypertrophy and biventricular hypertrophy was significantly higher in the reverse dippers compared with the dippers and the extreme dippers (Table 3). The prevalence of RV diastolic dysfunction was higher in the reverse dipper pattern group compared with the dipper and the nondipper pattern groups (Table 3).

Univariate analysis showed that BMI, daytime and night time SBP and DBP, nocturnal SBP and DBP fall, and nondipping and reverse dipping status correlated with LV structure (LV mass index) (Table 4) and RV structure (RV wall thickness) (Table 5). Multivariate analysis revealed daytime and night time SBP, nocturnal SBP fall, and nondipping and reverse dipping statuses as independent predictors of LV and RV structure (Tables 4 and 5, respectively).

Table 4 Demographic, clinical and echocardiographic predictors of left ventricular mass index and mitral E/e′ in study group (correlation and multivariate regression analyses)
Table 5 Demographic, clinical and echocardiographic predictors of right ventricular wall thickness and tricuspid E/e′ in study group (correlation and multivariate regression analyses)

BMI, daytime and night time SBP and DBP, nocturnal SBP and DBP fall, and nondipping and reverse dipping status correlated with LV and RV diastolic function (E/e′ mitral and E/e′ tricuspid; (Tables 4 and 5, respectively). However, daytime and night time SBP, nocturnal SBP fall, and nondipping and reverse dipping status were independently associated with LV and RV diastolic function (Tables 4 and 5, respectively).

Discussion

Our study investigated the impact of different nocturnal BP patterns (dipping, nondipping, extreme dipping and reverse dipping) on LV and RV structure and function with hypertensive patients. It provided new evidence about the relationship between night time BP fall and functional and structural cardiac changes. First, we showed that LV diastolic function and structure were more impaired in the reverse dippers and the nondippers than in the rest of the hypertensives. Second, the results also confirmed the impairment in RV function. Third, the analyses revealed that LV and RV function together with RV structure gradually and progressively deteriorated, starting from the extreme dippers to the dippers and the nondippers, and to the reverse dippers in the last place, whereas LV structure statistically did not show this step-by-step kind of impairment.

Our results showed that the patients with different BP patterns had similar demographic and clinical characteristics, which was also found in previous investigations regarding concerned four different BP patterns,7, 8 as well as in those studies that stressed on only two main BP pattern types.16, 17, 18, 19, 20, 21 This is a very interesting topic because it would be expected to find some kind of metabolic imbalance in non-dipper and reverse dipper patients due to a higher sympathetic activity that is often mentioned as the main reason for greater impairment of the target organ in these patients.7 Seo et al7 showed that urea and serum creatinine were increased in non-dippers, although all other parameters including the level of microalbuminuria, were similar between groups. The possible reasons could be older age and longer duration of hypertension in these patients (the authors did not specify the average duration of hypertension).22

Values obtained by 24-h ABPM revealed that the average SBP and DBP during 24h as well as daytime BP were similar between the four BP patterns, whereas night time BP gradually increased from the extreme dippers to the reverse dippers, which coincides with the results of other authors.7, 8 Studies on the two main BP patterns mostly agree with our results.6, 21, 22, 23 On the other hand, there are interesting studies in which the average daytime and night time BP are remarkably increased in non-dippers but there is no difference in average 48-h BP between the dippers and the nondippers.17

Our study, like many others, showed that the lack of nocturnal BP fall increased LV structural damage in hypertensive patients.3, 8, 16, 17, 22 These findings, on the other hand, do not agree with some other investigations.5, 6 However, the comparison between the four different BP patterns regarding LV structure is relatively new. Recently, Muxfeldt et al.8 showed that the LV mass index gradually increased from the extreme dippers to the dippers and the nondippers, and were followed by the reverse dippers, which matched with our results, although both studies showed a statistically significant difference only when comparing the nondippers and the reverse dippers on one side and the rest of hypertensive patients on the other. Besides the LV mass index, we also compared IVS and relative wall thickness between the observed groups as additional parameters of LV structure, and revealed significant differences in LV structural remodelling among groups. LV hypertrophy prevalence was higher in the reverse dipping group in comparison with the extreme dipping and the dipping groups. The high prevalence of LV hypertrophy (31%) despite the relatively low average 24-h BP could be explained by the fact that about one-third of the patients were orderly treated for hypertension, and by the fact that we did not know for how long hypertension was actually present in the patients included in our study. Hypertension had been recently discovered in our patients, but we could not exclude the possibility that our patients had undiagnosed hypertension for years.

This investigation showed that LV diastolic function progressively deteriorated from the extreme dippers towards the reverse dippers. Previous studies mostly failed to prove the impairment of LV diastolic function in the nondippers, which could have been the consequence of the small sample or the technique (pulsed Doppler).6, 17, 23 However, Ferrara et al,18 by using pulsed Doppler, demonstrated that the nondippers had a greater impairment of LV diastolic function compared with the dippers. More recently, other authors succeeded in demonstrating more prominent LV diastolic dysfunction in hypertensive nondippers by using a more accurate diagnostic tool (tissue Doppler).22, 24 Our study confirmed that LV systolic function was completely preserved not only in the nondippers but also in the reverse dippers, as Muxfeldt et al.8 previously reported. Global LV function estimated by the Tei index progressively and gradually deteriorated from the extreme dippers to the reverse dippers, which could be explained by similar changes in LV diastolic function. LV diastolic dysfunction was more prevalent in the reverse dipping group in comparison with the extreme dipping and dipping groups.

Our results concerning RV structure and function also revealed a different level of its impairment between the observed groups. Sokmen et al.23 were one of the few authors who found the impact of the nondipping status on RV function (actually only on RV Tei index and RV systolic myocardial velocity) in hypertensive patients. Other authors did not find any correlation, which was probably the consequence of a small number of examinees. Our results for the RV are quite similar to those that we presented for the LV. Structural changes (RVT) showed greater impairment in the reverse dippers and the nondippers in comparison with other hypertensive patients with stepwise type of deterioration (from the extreme dippers to the reverse dippers). The incidence of RV and biventricular hypertrophy was higher in the reverse dippers, in contrast to the extreme dipping and the dipping hypertensive patients. Systolic RV function (RVEF, tricuspid annular plane systolic excursion) remained preserved in all the four groups. RV diastolic function deteriorated gradually from the extreme dippers to the reverse dippers, similar to RV global function estimated by RV Tei index. The prevalence of RV diastolic dysfunction was higher in the reverse dippers in comparison with the extreme dippers and the dippers.

A possible reason for these results could lie in the fact that the different BP patterns are associated with a different sympathetic activity.7 Grassi et al.7 reported that the reverse dipper hypertensive patients have a higher sympathetic activity than the other hypertensives, but the authors also found a difference in sympathetic activity between the dipper, nondipper and extreme dipper hypertensive patients, which did not show statistically significant difference, probably as a consequence of a small sample. A greater sympathetic activation is followed by a reduced probability for nocturnal BP decrease, which leads to minor nocturnal BP fall or even night time BP increase. The other possibility is the relationship between insulin resistance state and alterations in the dipping state. Some authors claimed that insulin resistance was associated with the nondipping and reverse dipping status.7, 25 A very important cause of cardiac remodelling in the reverse dippers and the nondippers might also be the renin—angiotensin–sympathetic interaction,26 which is responsible for cardiomyocyte hypertrophy, myocardial fibrosis, apoptosis, endothelial dysfunction, vasoconstriction and increased nocturnal sodium retention. All these changes could result in functional and structural impairment of LV and RV equally. A higher activity of sympathetic system in the reverse dipper and the nondipper hypertensives leads to an increased reaction of the rennin–angiotensin–aldosterone system, which altogether results in a greater damage of cardiac function and structure.

The multivariate analysis of our results revealed daytime and night time SBP, nocturnal SBP fall, and nondipping and reverse dipping status as independent predictors of LV and RV diastolic function and structure. There are different opinions concerning independent predictors of LV mass index. Some authors found a correlation with daytime SBP and DBP;5 others did not find a correlation with BP, but found a relation with daytime/night time BP ratio or night time SBP and DBP fall19, 20 whereas some other authors found correlation with both daytime and night time SBP and DBP.17 The data about LV diastolic function predictors in different BP patterns are poor. Investigators22, 23 reported a correlation between the nondipping status and LV diastolic function (E/e′ or e′/a′), which agrees with our results. It is very interesting that the systolic component of daytime and night time BP, similar to the nocturnal systolic BP fall, had a dominant role in LV and RV structure and function in our patients. Similar findings had been recently reported by Syrseloudis et al.27 The finding of independent predictors of RV diastolic function and structure regarding different BP patterns is new, because we did not find any similar analysis in the available literature.

Limitations

This study has some potential limitations. First, our study population included uncomplicated, mostly untreated mild hypertensive patients, which could be the reason why our findings cannot be generalized, especially when taking into account patients with more severe or long-lasting hypertension, older age and concomitant comorbidities such as diabetes and cardiovascular diseases. Second, in our study 31% of patients were treated for hypertension, which certainly could influence the results of the study. However, there was no difference in medical treatment between the observed groups, which decreases, but does not exclude, the possibility of treatment's influence on LV and RV structural and functional changes. Third, the classification of the circadian BP pattern with a single ABPM could be inaccurate because of its low reproducibility. Studies that diagnosed nondipping status according to two sessions of ABPM showed a stronger correlation of nondipping status with cardiovascular target organ damage.17, 20, 27 However, other authors using a single ABPM also demonstrated a relationship between nondipping status and target organ damage.4, 6, 19, 22 Fourth, different authors use different conditions to classify the circadian BP patterns of SBP and/or DBP, which also could have an impact on the results. Fifth, the quality of sleep as well, may cause difficulties in assessing the nondipping BP pattern.

Conclusions

Our study shows that the extreme dipping and reverse dipping status among mild-to–moderate, mostly untreated hypertensive patients is a rather common phenomenon, which is relatively often seen in everyday clinical practice. Our study extensively investigated LV and RV structure, and diastolic and global function in four different BP patterns with a wide range of echocardiographic parameters and revealed that LV and RV structure, and diastolic and global functions were significantly impaired in the nondippers and the reverse dippers compared with the dippers and the extreme dippers. The daytime and night time SBP, nocturnal SBP fall, and nondipping and the reverse dipping statuses were defined as independent predictors of LV and RV diastolic function and structure. Further investigations with usage of other methods besides echocardiography, for example microalbuminuria, carotid ultrasound or pulse wave velocity measurements, are needed to complete the complex puzzle of relationships between different BP patterns and target organ damage.

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Correspondence to B A Ivanovic.

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Ivanovic, B., Tadic, M. & Celic, V. To dip or not to dip? The unique relationship between different blood pressure patterns and cardiac function and structure. J Hum Hypertens 27, 62–70 (2013). https://doi.org/10.1038/jhh.2011.83

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Keywords

  • ambulatory blood pressure monitoring
  • blood pressure patterns
  • cardiac structure
  • cardiac function

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