Abstract
We investigate the impact of dipper status on cardiac structure with cardiovascular magnetic resonance (CMR). Ambulatory blood pressure monitoring and 1.5T CMR were performed in 99 tertiary hypertension clinic patients. Subgroup analysis by extreme dipper (n = 9), dipper (n = 39), non‐dipper (n = 35) and reverse dipper (n = 16) status was performed, matched in age, gender and BMI. Left ventricular (LV) mass was significantly higher for extreme dippers than dippers after correction for covariates (100 ± 6 g/m2 vs 79 ± 3 g/m2, P = .004). Amongst extreme dippers and dippers (n = 48), indexed LV mass correlated positively with the extent of nocturnal blood pressure dipping (R = .403, P = .005). On post‐hoc ANCOVA, the percentage of nocturnal dip had significant effect on indexed LV mass (P = .008), but overall SBP did not (P = .348). In the tertiary setting, we found a larger nocturnal BP drop was associated with more LV hypertrophy. If confirmed in larger studies, this may have implications on nocturnal dosing of anti‐hypertensive medications.
Keywords: ambulatory blood pressure, hypertrophy, myocardial strain, nocturnal dip
1. INTRODUCTION
The global burden of systemic hypertension is immense, affecting an estimated 25% of the worldwide adult population and the prevalence of the disease is estimated to reach 1.56 billion by 2025.1 24‐hour ambulatory blood pressure monitoring (ABPM) is an important tool for risk stratification of individuals with arterial hypertension.2 The pattern of nocturnal blood pressure (BP) relative to diurnal BP on ABPM can be categorized into (1) dipper (≥10% reduction in average systolic blood pressure [SBP] at night) and (2) non‐Dipper (<10% reduction in SBP at night) groups. Within the dipper group, there is a subset of patients with exaggerated nocturnal BP dip (>20% reduction in SBP at night), termed extreme dippers. Likewise, there is a further subgroup within the non‐dippers who demonstrate an increase in SBP overnight and these patients are known as reverse dippers.3 The nocturnal BP subtypes are associated with different levels of cardiovascular risk in hypertension, with non‐dipper status conferring the worse prognosis.4, 5 However, there remains debate about the impact of dipper status on target organ damage. For example, there is increasing evidence that extreme dipper status may result in increased cerebrovascular morbidity; extreme dippers had increased prevalence of ischaemic stroke in one study6 and increased risk of intracerebral haemorrhage in another.7 Studies assessing differences in cardiovascular structure and function have not yielded consistent results.8 To date, the effect of dipper status subtypes on cardiac target damage has not been comprehensively investigated with cardiovascular magnetic resonance imaging (CMR), which is the current non‐invasive gold‐standard investigation to assess left ventricular (LV) volumes, mass, and systolic function.9 Consequently, we aimed to investigate the impact of nocturnal dipper status on cardiac structure and function using a comprehensive multi‐parametric CMR protocol, assessing LV volumes and mass, burden of myocardial replacement fibrosis, and myocardial deformational strain parameters. We hypothesized that non‐dipper status would be associated with the most adverse cardiac remodeling/hypertrophy.
2. MATERIALS AND METHODS
2.1. Study population
This was a prospective observational study. Inclusion criteria were consecutive patients being treated for hypertension referred for CMR with contemporaneous ABPM from the Bristol Heart Institute tertiary hypertension clinic between February 2012 and April 2015. The local research ethics committee confirmed that the study conformed to the governance arrangements for research ethics committees. Subjects provided written consent. Baseline demographic and clinical characteristics were recorded, including prevalence of obstructive sleep apnea and a number of nocturnal anti‐hypertensive medications. Patients with any concomitant myocardial pathology that may confound the cardiac remodeling/hypertrophy were excluded. Exclusion criteria (Figure 1) were, any evidence of moderate‐to‐severe valvular heart disease, acquired or inherited cardiomyopathy and suspected athlete's heart (on the basis of clinical and International imaging consensus guidelines),10 and a severely decreased estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. A history of myocardial ischaemia or infarction was not considered an exclusion criterion because both symptomatic and silent myocardial ischaemic are common in hypertensive patients with left ventricular hypertrophy, even in the absence of epicardial coronary artery disease, and LVH itself is a recognized cause of myocardial ischaemia.11, 12, 13, 14
Figure 1.
A flow chart showing the study exclusions. (HOCM = hypertrophic obstructive cardiomyopathy. AR, moderate aortic regurgitation; AVR, aortic valve replacement; DCM, dilated cardiomyopathy mod; LVNC, LV non‐compaction cardiomyopathy; *, artifact from implantable loop recorder. Representative examples of the multi‐parametric CMR protocol: (A) Steady‐state free precession left ventricular short‐axis mid‐cavity cines images at end‐diastole with bloodpool threshold detection software analysis to define endocardial contours (red line) and manual definition of epicardial contours (green line) to estimate LV mass, LV volumes, and LV ejection fraction (every other image shown for illustrative purposes). (B) Voxel tracking software analysis that is applied in a post‐processing step to steady‐state free precession images to derive estimates of longitudinal strain, circumferential strain, and radial strain. (C) Inversion‐recovery late gadolinium enhancement left ventricular short‐axis mid‐cavity image at end‐diastole demonstrating a cases of subtle replacement fibrosis at the right ventricular insertion points (solid white arrows)
2.2. Ambulatory blood pressure monitoring
Non‐invasive 24‐hour ABPM was performed during a weekday on the nondominant arm with an automatic device.15 The device obtained BP readings by the oscillometric method every 30 minutes for 24 hours. The patients were instructed to conduct their usual daily activities but remain still at the time of BP measurement. The International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome (IDACO) criteria were used (10 daytime measurements, 5 nighttime measurements) to determine satisfactory ABPM.16 Nocturnal BP was defined as the mean BP readings from the time the patient went to bed until the time they got out of bed, with the remainder of the readings constituting the day time values. The ABPM data were analyzed with automated software to obtain mean overall/daytime/nighttime systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP). Dipper status was defined3 as either:
Dipper (≥10% and ≤20% reduction in average systolic blood pressure [SBP] at night)
Extreme dipper (>20% reduction in SBP at night)
Non‐dipper (0%‐10% reduction in SBP at night)
Reverse dipper (<0% reduction in SBP at night [ie, nocturnal increase in SBP])
2.3. CMR cine protocol and analysis
CMR was performed at 1.5T. Short‐axis steady‐state free precession (SSFP) cines with whole left ventricular (LV) coverage (8 mm slice thickness, no slice gap, temporal resolution 38.1 ms, echo time 1.07 ms, in‐plane pixel size 1.5 × 0.8 mm) were used for the estimation LV mass (LVM) and volumes, and indexed to body surface area as previously described.17 In accordance with the Society of CMR guidelines,18 a validated19 threshold‐detection software package was used to measure LVM, including papillary musculature and trabeculae in LVM estimation (Figure 1). LVH was defined as indexed LVM > 95th percentile of established CMR reference ranges (men: 89‐93 g/m2 and women: 77‐78 g/m2, depending on age).17 LV mass‐to‐volume ratio (M/V), akin to relative wall thickness on echocardiography, was calculated and an increased M/V that was defined as >95th gender‐specific percentile (men: >1.12 g/mL and women: >1.14 g/mL) from healthy volunteers, as previously described.20 LV dilatation was defined as indexed EDV > 95th percentile of the age‐ and gender‐specific reference ranges. Left ventricular ejection fraction (LVEF) was reduced if <5th percentile of the same reference range. The CMR analysis was performed by an experienced CMR reader, blind to the ABPM data and CMR strain data.
2.4. Defining patterns of left ventricular remodeling and hypertrophy
Four patterns (Figure 2) of LV remodeling/hypertrophy were defined previously21: (1) normal = normal indexed LVM, normal indexed end‐diastolic volume (EDV), and normal mass to volume ratio (M/V); (2) LV remodeling = normal indexed LVM, but increased M/V; (3) concentric hypertrophy = increased indexed LVM, increased M/V; and (4) eccentric hypertrophy = increased LVM, increased indexed EDV, normal M/V, and normal or reduced LVEF.
Figure 2.
Different patterns of left ventricular remodeling and hypertrophy
2.5. CMR late gadolinium protocol and analysis
Replacement myocardial fibrosis was assessed by late gadolinium enhancement (LGE) (Figure 1). An inversion‐recovery fast gradient recall echo sequence performed 10 to 15 minutes following injection of 0.1 mmol/kg intravenous gadobutrol, as previously described.22 The inversion time was personalized to achieve optimal myocardial nulling in each subject. LGE was visually assessed as a consensus between 2 expert CMR readers, blinded to the remodeling/hypertrophy, CMR strain, and ABPM data.
2.6. CMR strain imaging
Strain imaging was performed off‐line using 4‐chamber, 2‐chamber, and short‐axis stack SSFP cine images with voxel‐tracking software, as previously described23 (Figure 1). The software defines the position of each myocardial voxel at end‐diastole and tracks their location of the cardiac cycle in 2D. It is based on a previously described algorithm.24, 25 Briefly, endocardial and epicardial end‐diastolic borders were defined excluding papillary muscles and trabeculae. The end‐diastolic mitral valve annular plane was defined. Global longitudinal strain was the averaged strain from 4‐chamber and 2‐chamber analysis. Circumferential strain was calculated as a mean value of mid myocardial segments from the short‐axis cine 2D strain model, in order to minimize partial‐volume averaging and through‐plane motion at the base and apex. All strain analysis was performed by an experienced CMR reader blinded to the ABPM data and other CMR data.
2.7. Statistical analysis
Statistical analysis was performed using SPSS Version 21. Normally distributed continuous variables were expressed as mean ± standard deviation and compared using one‐way analysis of variance with Bonferroni post‐hoc correction. Categorical variables were expressed as percentages and analyzed using the Fisher's exact test. Multiple linear regression was used to control for covariates of age, gender, body mass index, diabetes, daytime SBP, daytime DBP, and daytime MAP with Bonferroni correction for multiple post‐hoc comparisons. To determine the relative impact of daytime blood pressure levels and degree of nocturnal dip on indexed LV mass amongst dippers, linear regression analysis, controlling for daytime systolic blood pressure, was performed. Statistical significance was set at two‐sided P < .05.
3. RESULTS
3.1. Study population
One hundred and eleven hypertensive patients were screened, 12 patients were excluded due to concomitant cardiac pathology or inadequate CMR study (Figure 1), resulting in a final sample size of 99. The demographics and baseline clinical characteristics are displayed in Table 1. Dipper, extreme dipper, non‐dipper, and reverse dipper subgroups were matched in terms of age, gender, and BMI.
Table 1.
Demographic and ambulatory blood pressure data for dipper subgroups
| All patients (n = 99) | (n = 39) | Extreme dippers (n = 9) | Non‐dippers (n = 35) | Reverse dippers (n = 16) | P ‐value | |
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Age (y) | 51 ± 14 | 48 ± 15 | 50 ± 16 | 52 ± 13 | 56 ± 14 | |
| Gender n (% male) | 49 (49) | 20 (51) | 6 (67) | 14 (40) | 9 (56) | |
| BMI (kg/m2) | 30 ± 5 | 30 ± 6 | 30 ± 5 | 31 ± 6 | 29 ± 4 | |
| Diabetes n (%) | 12 (12) | 3 (8) | 1 (11) | 8 (23) | 0 (0) | |
| Ischaemic Heart Disease n (%) | 16 (16) | 2 (5) | 3 (33) | 6 (17) | 5 (31) | |
| Obstructive sleep apnea n (%) | 16 (16) | 8 (21) | 1 (11) | 5 (14) | 2 (13) | |
| ACEi/ARB n (%) | 76 (76) | 25 (64) | 6 (67) | 28 (80) | 16 (100) | a |
| No. anti‐hypertensives | 3 ± 2 | 2 ± 2 | 3 ± 2 | 3 ± 2 | 4 ± 2 | a |
| No. nocturnal hypertensive | 1 ± 1 | 1 ± 1 | 1 ± 1 | 0 ± 1 | 0 ± 1 | |
| Ambulatory blood pressure | ||||||
| Noctural dip (%) | 9 ± 8 | 14 ± 3 | 22 ± 2 | 5 ± 3 | −4 ± 4 | b |
| Overall SBP (mm Hg) | 152 ± 21 | 145 ± 18 | 153 ± 20 | 161 ± 23 | 151 ± 23 | c |
| Overall DBP (mm Hg) | 89 ± 14 | 88 ± 14 | 92 ± 16 | 92 ± 15 | 84 ± 14 | |
| Overall MAP (mm Hg) | 106 ± 16 | 102 ± 15 | 110 ± 18 | 111 ± 16 | 101 ± 14 | |
| Daytime SBP (mm Hg) | 156 ± 21 | 152 ± 18 | 162 ± 21 | 163 ± 23 | 150 ± 22 | |
| Daytime DBP (mm Hg) | 92 ± 15 | 92 ± 14 | 99 ± 18 | 94 ± 16 | 84 ± 13 | |
| Daytime MAP (mm Hg) | 108 ± 16 | 108 ± 15 | 117 ± 19 | 111 ± 15 | 101 ± 15 | |
| Nighttime SBP (mm Hg) | 143 ± 23 | 130 ± 16 | 127 ± 14 | 155 ± 23 | 156 ± 23 | c , d , e , f |
| Nighttime DBP (mm Hg) | 81 ± 15 | 76 ± 13 | 74 ± 11 | 87 ± 16 | 81 ± 15 | c |
| Nighttime MAP (mm Hg) | 98 ± 17 | 90 ± 14a , b | 90 ± 13a , c | 107 ± 17 | 102 ± 12 | c , e |
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.
One‐way ANOVA with Bonferroni for post‐hoc multiple comparisons: aDippers vs Reverse dippers; P < .05. bAll subgroup comparisons; P < .01. cDippers vs Non‐dippers; P < .05. dDippers vs Reverse dippers; P < .01. eExtreme dippers vs Non‐dippers; P < .05. fExtreme dippers vs Reverse dippers; P < .05.
3.2. Blood pressure in dipper subgroups
When all patients with nocturnal dip <10% (non‐dippers and reverse dippers, n = 51) were compared with all patients with nocturnal dip ≥10% (dippers and extreme dippers, n = 48), the combined non‐dipper and reverse dipper cohort had significantly higher mean overall ABPM SBP (157 ± 23 mm Hg vs 147 ± 19 mm Hg, P = .008) and nocturnal ABPM SBP (155 ± 23 mm Hg vs 130 ± 15 mm Hg, P < .0001) compared to the combined dipper and extreme dipper cohort. However, when the individual dipper subgroups were compared, it was only the dipper subgroup (with nocturnal dip ≥10% and <20%) that exhibited significantly lower overall ABPM SBP compared to the non‐dipper subgroup (with nocturnal dip 0%‐10%; 145 ± 18 mm Hg vs 161 ± 23 mm Hg, P = .009; Table 1). The extreme dipper subgroup showed no significant difference in overall and daytime ABPM SBP compared with non‐dipper and reverse dipper subgroups, respectively.
3.3. Cardiac structure and function in dipper subgroups
When all patients with nocturnal dip <10% (non‐dippers and reverse dippers, n = 51) were compared with all patients with nocturnal dip ≥10% (dippers and extreme dippers, n = 48), there was no significant difference in indexed LV mass (nocturnal dip ≥10%: 83 ± 20 g/m2 vs nocturnal dip <10%: 89 ± 25 g/m2, P = .208; Figure 3). Contrary to the hypothesis, it was the extreme dippers whom demonstrated the highest prevalence of concentric LVH (67%) and had the highest indexed LV mass (103 ± 29 g/m2; Table 2), despite the non‐dippers and reverse dippers having similar overall and daytime ABPM SBP and significantly higher nighttime ABPM DBP (Table 1). Within the subgroup of patients with preserved nocturnal dip ≥10%, the extreme dipper cohort had significantly higher indexed LV mass than the dipper cohort (103 ± 29 g/m2 vs dippers: 78 ± 15 g/m2, P = .021; Table 2). However, there were no significant differences in systolic function in terms of LVEF, longitudinal strain, and circumferential strain between the cohorts (Table 2; Figure 3). The prevalence of myocardial replacement fibrosis was not significantly different between the subgroups (Table 2).
Figure 3.
Summary of key findings, including deformational strain (circumferential strain, longitudinal strain and radial strain) vs time graphs for the different dipper subgroups. *1One‐way ANCOVA correction for covariates of age, gender, BMI, diabetes mellitus, daytime SBP, daytime DBP, and daytime MAP. *2Linear regression analysis
Table 2.
Cardiovascular magnetic resonance for all patients, dipper, and non‐dippers
| All patients (n = 99) | Dippers (n = 39) | Extreme dippers (n = 9) | Non‐dippers (n = 35) | Reverse dippers (n = 16) | P ‐value | |
|---|---|---|---|---|---|---|
| CMR volumetrics | ||||||
| LVEF (%) | 69 ± 9 | 69 ± 8 | 69 ± 8 | 69 ± 9 | 67 ± 9 | |
| Indexed LV mass (g/m2) | 86 ± 23 | 78 ± 15a | 103 ± 29 | 89 ± 25 | 88 ± 27 | a |
| Indexed EDV (mL/m2) | 77 ± 16 | 76 ± 13 | 76 ± 12 | 78 ± 18 | 80 ± 22 | |
| Indexed ESV (mL/m2) | 25 ± 10 | 24 ± 8 | 24 ± 7 | 24 ± 11 | 28 ± 15 | |
| Indexed SV (mL/m2) | 53 ± 9 | 52 ± 8 | 53 ± 9 | 52 ± 10 | 54 ± 11 | |
| Cardiac output (L/min) | 7.5 ± 1.9 | 7.9 ± 1.8 | 7.1 ± 1.9 | 7.5 ± 1.9 | 6.7 ± 2.2 | |
| Mass: Volume ratio (g/mL) | 1.15 ± 0.32 | 1.06 ± 0.24 | 1.37 ± 0.35 | 1.20 ± 0.35 | 1.13 ± 0.34 | |
| Subendocardial LGE n (%) | 8 | 5 | 11 | 9 | 13 | |
| Patterns of LV remodeling/hypertrophy | ||||||
| Normal n (%) | 48 (48) | 24 (62) | 3 (33) | 14 (40) | 7 (44) | |
| Concentric LV remodeling n (%) | 13 (13) | 6 (15) | 0 (0) | 5 (14) | 2 (13) | |
| Concentric LVH n (%) | 24 (24) | 5 (13) | 6 (67)b , c | 10 (29) | 3 (19) | b , c |
| Eccentric LVH n (%) | 14 | 4 (10) | 0 (0) | 6 (17) | 4 (25) | |
| Myocardial strain and strain rate | ||||||
| Peak longitudinal strain (%) | −17 ± 3 | −17 ± 3 | −15 ± 4 | −16 ± 3 | −17.3 | |
| Peak circumferential strain (%) | −16 ± 3 | −17 ± 3 | −15 ± 3 | −16 ± 3 | −15 ± 4 | |
EDV, end‐diastolic volume; ESV, end‐systolic volume; LGE, late myocardial gadolinium enhancement (ie, myocardial scar/fibrosis); LV, left ventricle; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; SV, stroke volume; TPR, total peripheral resistance.
One‐way ANOVA with Bonferroni for post‐hoc multiple comparisons. aDipper vs Extreme Dipper; P < .05. bExtreme Dipper vs Dipper; P < .01. cExtreme Dipper vs Reverse Dipper; P < .05.
3.4. Dipper vs extreme dipper
To determine whether the increased indexed LV mass observed amongst the extreme dipper cohort compared to the dipper cohort was simply due to the association with higher daytime SBP, a one‐way analysis of covariance (ANCOVA) was performed to assess for persistent differences in indexed LV mass between extreme dipper and dippers, controlling for covariates of age, gender, BMI, diabetes, daytime SBP, daytime DBP, and daytime MAP (Table 3). Extreme dippers still demonstrated a significantly higher indexed LV mass compared to dippers (100 ± 6 g/m2 vs 79 ± 3 g/m2, P = .004) even after correcting for these covariates (Figure 3).
Table 3.
Subgroup analysis of patients with dipper status with correction for covariates
| Dippers (n = 39) | Extreme dippers (n = 9) | P value | |
|---|---|---|---|
| Indexed LV mass (g/m2) | 79 ± 3 | 100 ± 6 | .004 |
| Peak longitudinal strain (%) | −17 ± 1 | −15 ± 1 | .09 |
| Peak circumferential strain (%) | −17 ± 1 | −15 ± 1 | .12 |
Multiple linear regression controlling for covariates of age, gender, body mass index, diabetes, daytime SBP, daytime DBP, and daytime MAP with Bonferroni correction for multiple post‐hoc comparisons. Data are mean ± standard error of mean.
Amongst dippers (n = 48), indexed LV mass correlated positively with percentage of nocturnal dip (R = .403, P = .005). Linear regression analysis was performed to assess the relationship between percentage nocturnal dip amongst dippers and indexed LV mass, controlling for daytime systolic blood pressure. A significant relationship persisted between indexed LV mass and percentage nocturnal dip (β = .371, 95th confidence intervals: 0.479‐3.477, P = .011), but not between indexed LV mass and daytime systolic blood pressure (β = .131, 95th confidence intervals: −0.164‐0.450, P = .352). Essentially, the exaggerated swing in SBP between daytime and nighttime is more likely the reason for more advanced LV hypertrophic responses in extreme dippers compared to dippers, than higher daytime SBP.
Significant positive correlations with demonstrated between percentage nocturnal dip and: (1) peak circumferential strain (r = .412, P = .004) and (2) peak longitudinal strain (r = .345, P = .016), but not with peak radial strain (r = −.161, P = .276). Essentially, the greater the nocturnal dip, the worse the circumferential and longitudinal deformation, as these are negative indices by convention. Linear regression analysis was also performed to assess the relationship between LV strain indices and indexed LV mass, controlling for daytime systolic blood pressure. A significant relationship persisted between (1) peak circumferential strain (β = .393, 95th confidence intervals: 0.099‐0.599, P = .007) and (2) peak longitudinal strain (β = .321, 95th confidence intervals: 0.025‐0.489, P = .031) with percentage nocturnal dip, but not with daytime systolic blood pressure in either of the statistical models, respectively (β = .078, 95th confidence intervals: −0.037‐0.065, P = .581; β = .097, 95th confidence intervals: −0.32‐0.063, P = .504). After correcting for daytime systolic blood pressure, there was no significant relationship between peak radial strain and percentage nocturnal dip (β = −.215, 95th confidence intervals: −3.821‐0.626, P = .155). Essentially, the exaggerated swing in SBP between daytime and nighttime is more likely to be the reason for circumferential and longitudinal strain impairment in extreme dippers compared to dippers, rather than higher overall SBP.
4. DISCUSSION
4.1. Summary of results
We investigated the impact of dipper status on cardiac structure and function using CMR. We show that in the tertiary setting, extreme dippers exhibit the highest indexed LV mass, after correction for covariates of age, gender, BMI, diabetes, and daytime SBP/DBP/MAP. Larger nocturnal drops in BP are associated with more advanced myocardial hypertrophy, independent of daytime SBP.
4.2. Hypertensive LVH and dipper status
The extreme dipper subgroup had the highest indexed LV mass and the highest prevalence of concentric LVH. There is heterogeneity in the literature regarding LV mass and dipper status. Importantly, it is only relatively recent that dipping profiles have been subdivided into extreme dipper and reverse dipper subgroups. Ivanoic et al looked at all 4 dipper subgroups and demonstrated the highest prevalence of LVH in reverse dippers.26 However, 69% of this cohort were untreated and LV mass was indexed to height, which has been shown to systematically misclassify patients regarding LVH presence.27 The effect of drug treatment on the relationship of dipper status and cardiac function may be an important variable. For example, Muxfeldt et al showed no significant differences in LV mass indexed to BSA amongst dipper, non‐dipper, reverse dipper, and extreme dipper subgroups in the context of resistant hypertension using echocardiography.28 The current study differs from the previous studies by at least one of the following variables: (1) imaging modality for measuring LV mass (CMR), (2) definition of LVH (CMR specific cut‐offs for age and gender indexed to BSA), (3) treatment status of patients (on treatment), and (4) type of patient (recruited from tertiary setting). Consequently, the current findings apply to a specific, but important, cohort of hypertensive patients.
4.3. Mechanisms for LVH in extreme dippers
Why extreme dippers develop the most LVH is not clear. Extreme dippers had comparable overall SBP levels compared to non‐dippers and reverse dippers, suggesting a complex relationship beyond absolute BP level.
An excessive early morning BP surge is associated with increased cardiovascular events.29 The level of morning surge in BP has been demonstrated to be significantly associated with cardiovascular remodeling, independent of 24 hour BP level, daytime BP variability, and nocturnal BP decline in patients >60 years old on antihypertensive medications.30 Extreme dippers may be most prone to exhibit early morning surge in BP, which may account for the fact that extreme dipping has been associated with increased cardiovascular events6, 7 A potential unifying explanation for these observations is that early morning surge may be a result of increased morning sympathetic activity.29 Elevated daytime sympathetic nerve activity may result in not only daytime BP increases, but also directly stimulate the myocardium, potentially directly inducing LVH itself.31
Equally, the exaggerated fall in SBP at night may contribute to LVH in extreme dippers. Recently, we demonstrated that increased cerebrovascular resistance and reduced cerebral blood flow were present before the onset of increased muscle sympathetic nerve activity in the borderline hypertensive patients, suggesting cerebral hypoperfusion may be a factor in triggering and exacerbating hypertension.32 The exaggerated nocturnal drop in BP in extreme dippers could theoretically aggravate nocturnal cerebral perfusion and result in rebound increases in neurogenically‐mediated sympathetic nerve activity. This relative nocturnal hypoperfusion may also help account for the increased cerebrovascular pathology identified in extreme dippers in some studies6, 7
Extreme dipping may have direct cardiac effects. Theoretically, relative nocturnal hypotension may result in reduced myocardial perfusion pressure. If this were to fall below a critical threshold, it may trigger subclinical hypoperfusion/hypoxemia, which itself will trigger low level myocardial inflammation and hypertrophy of the myocardium. Indeed, Kotsis et al33 previously demonstrated a significantly higher Gensini score (a computerized scoring system of coronary artery disease severity that depends on the degree of luminal narrowing, the geographic importance of each stenosis, the ejection fraction, and possible collateral circulation of coronary arteries) in extreme dippers. Excessive sympathetic activity to the heart, for example via the aforementioned selfish brain hypothesis, may cause coronary vasoconstriction and potentially compound cardiac hypoperfusion during dipping.
4.4. Clinical implications
The post‐hoc analysis of the current study suggests that it is the actual exaggerated nocturnal dip response that is associated with advanced LVH and not simply a higher daytime SBP. If the findings are validated in larger scale studies, this may have implications for anti‐hypertensive regimens. It is common practice to suggest patients take their anti‐hypertensive medications at night if they are developing pre‐syncopal symptoms during the day. Whilst several antihypertensive medications have appropriate pharmacodynamics and pharmacokinetics to allow single dosing, if the medications are taken at night, they may actually contribute to a larger nocturnal dip that could have pathological implications to the brain and heart as discussed above. More insight into this may be gained when the Hellenic Anglo Research into Morning Or Night antihypertensive drug deliverY (HARMONY) trial, a randomized cross‐over trial of 100 participants comparing daytime and evening dosing of antihypertensive medications, reports its findings. Therefore, it is proposed that ABPM is performed to define whether dipping occurs and to assess its extent and the impact of long‐acting and/or nocturnal anti‐hypertensive regimens.
5. LIMITATIONS
There are several limitations of this study. First, the sample size is small. However, the increased precision, accuracy, and reliability of CMR over 2‐dimensional echocardiography increases the statistical power, reducing the sample size required to detect a statistically significant change in LV mass of 10 g with 90% power (1‐β error) by 6‐fold.34 There is a relatively low prevalence of extreme and reverse dippers in our cohort, but the proportions of these subgroups to the overall study size are comparable to previous echocardiographic studies.26, 28 However, one of the relative strengths of this study, in our opinion, is the real‐world data captured by the study design, which was a prospectively maintained clinical database of consecutive hypertensive patients referred for CMR. The low prevalence of extreme dipper subgroups reflects our real world practice. It represents a small, but clinically important, subgroup of patients with nocturnal dip >10%. We performed additional analyses looking at nocturnal blood pressure dip as a continuous variable, in addition to looking at predefined dipper subgroups. These findings provide further support to the notion that percentage of nocturnal dip is an important variable that mitigates against, but does not completely exclude, a type 1 error.
This study was conducted in a specialist hypertension clinic. Therefore, we can only conclude that the findings are applicable in this tertiary setting. Further study is required to determine whether the same findings occur in, for example, untreated/newly diagnosed patients with hypertension in the primary care or community setting.
Due to the prolonged subclinical course of the disease, it was not possible to accurately correct for the duration of subclinical and established hypertension. Finally, the dipper status of our patients was only confirmed on a single ABPM reading, rather than two contemporaneous ABPM investigations. In addition, routine clinical CMR is likely to be inferior to echocardiography at assessing diastolic dysfunction and this has been previously investigated.35
6. CONCLUSIONS
In the tertiary hypertension setting, extreme dippers with nocturnal dip >20% exhibit the most advanced hypertrophic response which appears to be independent of daytime BP and related to the relative swings in sympathetic activity and BP from night to day. This was contrary to the original hypothesis that non‐dipper status would be associated with the most adverse cardiac remodeling/hypertrophy. If confirmed in larger studies, this may have implication on the recommendation of nocturnal dosing of anti‐hypertensive medications.
CONFLICT OF INTEREST
None.
ACKNOWLEDGMENTS
We thank Mr Christopher Lawton, superintendent radiographer, and his team of specialist CMR radiographers from the Bristol Heart Institute for their expertise in performing the CMR studies. This work was supported by the NIHR Bristol Cardiovascular Biomedical Research, Bristol Heart Institute. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health. Dr Jonathan C L Rodrigues is funded by the Clinical Society of Bath Postgraduate Research Bursary and Royal College of Radiologists Kodak Research Scholarship. Dr Emma C Hart is funded by BHF, grant number IBSRF FS/11/1/28400
Rodrigues JCL, Amadu AM, Ghosh Dastidar A, et al. Noctural dipping status and left ventricular hypertrophy: A cardiac magnetic resonance imaging study. J Clin Hypertens. 2018;20:784–793. 10.1111/jch.13235
Funding information
This work was supported by the NIHR Bristol Cardiovascular Biomedical Research, Bristol Heart Institute. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health. Dr Jonathan C L Rodrigues is funded by the Clinical Society of Bath Postgraduate Research Bursary and Royal College of Radiologists Kodak Research Scholarship. Dr Emma C Hart is funded by BHF, grant number IBSRF FS/11/1/28400.
REFERENCES
- 1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217‐223. [DOI] [PubMed] [Google Scholar]
- 2. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC 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). Eur Heart J. 2013;34:2159‐2219. [DOI] [PubMed] [Google Scholar]
- 3. O'Brien E, Sheridan J, O'Malley K. Dippers and non‐dippers. Lancet. 1988;2:397. [DOI] [PubMed] [Google Scholar]
- 4. Ben‐Dov IZ, Kark JD, Ben‐Ishay D, Mekler J, Ben‐Arie L, Bursztyn M. Predictors of all‐cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension. 2007;49:1235‐1241. [DOI] [PubMed] [Google Scholar]
- 5. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension. 1994;24:793‐801. [DOI] [PubMed] [Google Scholar]
- 6. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension. 2001;38:852‐857. [DOI] [PubMed] [Google Scholar]
- 7. Metoki H, Ohkubo T, Kikuya M, et al. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the ohasama study. Hypertension. 2006;47:149‐154. [DOI] [PubMed] [Google Scholar]
- 8. Cuspidi C, Giudici V, Negri F, Sala C. Nocturnal nondipping and left ventricular hypertrophy in hypertension: an updated review. Expert Rev Cardiovasc Ther. 2010;8:781‐792. [DOI] [PubMed] [Google Scholar]
- 9. Pennell DJ. Ventricular volume and mass by CMR. J Cardiovasc Magn Reson. 2002;4:507‐513. [DOI] [PubMed] [Google Scholar]
- 10. Galderisi M, Cardim N, D'Andrea A, et al. The multi‐modality cardiac imaging approach to the Athlete's heart: an expert consensus of the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:353. [DOI] [PubMed] [Google Scholar]
- 11. Dunn FG, Pringle SD. Left ventricular hypertrophy and myocardial ischemia in systemic hypertension. Am J Cardiol. 1987;60:19I‐22I. [DOI] [PubMed] [Google Scholar]
- 12. Salcedo EE, Marwick TH, Korzick DH, Goormastic M, Go RT. Left ventricular hypertrophy sensitizes the myocardium to the development of ischaemia. Eur Heart J. 1990;11(Suppl G):72‐78. [DOI] [PubMed] [Google Scholar]
- 13. Yurenev AP, DeQuattro V, Devereux RB. Hypertensive heart disease: relationship of silent ischemia to coronary artery disease and left ventricular hypertrophy. Am Heart J. 1990;120:928‐933. [DOI] [PubMed] [Google Scholar]
- 14. Pringle SD, Dunn FG, Tweddel AC, et al. Symptomatic and silent myocardial ischaemia in hypertensive patients with left ventricular hypertrophy. Br Heart J. 1992;67:377‐382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. O'Brien E, Beevers G, Lip GY. ABC of hypertension. Blood pressure measurement. Part III‐automated sphygmomanometry: ambulatory blood pressure measurement. BMJ. 2001;322:1110‐1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Thijs L, Hansen TW, Kikuya M, et al. The International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome (IDACO): protocol and research perspectives. Blood Press Monit. 2007;12:255‐262. [DOI] [PubMed] [Google Scholar]
- 17. Maceira A, Prasad S, Khan M, Pennell D. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2006;8:417‐426. [DOI] [PubMed] [Google Scholar]
- 18. Schulz‐Menger J, Bluemke DA, Bremerich J, et al. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson. 2013;15:35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Childs H, Ma L, Ma M, et al. Comparison of long and short axis quantification of left ventricular volume parameters by cardiovascular magnetic resonance, with ex‐vivo validation. J Cardiovasc Magn Reson. 2011;13:40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Buchner S, Debl K, Haimerl J, et al. Electrocardiographic diagnosis of left ventricular hypertrophy in aortic valve disease: evaluation of ECG criteria by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2009;11:1‐11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Rodrigues JCL, Amadu AM, Dastidar AG, et al. Comprehensive characterisation of hypertensive heart disease left ventricular phenotypes. Heart. 2016;102:1671‐1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Rodrigues JCL, Amadu AM, Dastidar AG, et al. Prevalence and predictors of asymmetric hypertensive heart disease: insights from cardiac and aortic function with cardiovascular magnetic resonance. Eur Heart J Cardiovasc Imaging. 2015;17:1405‐1413. [DOI] [PubMed] [Google Scholar]
- 23. Rodrigues JCL, Amadu AM, Ghosh Dastidar A, et al. ECG strain pattern in hypertension is associated with myocardial cellular expansion and diffuse interstitial fibrosis: a multi‐parametric cardiac magnetic resonance study. Eur Heart J Cardiovasc Imaging. 2016;18:441‐450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Bistoquet A, Oshinski J, Skrinjar O. Left ventricular deformation recovery from cine MRI using an incompressible model. IEEE Trans Med Imaging. 2007;26:1136‐1153. [DOI] [PubMed] [Google Scholar]
- 25. Bistoquet A, Oshinski J, Skrinjar O. Myocardial deformation recovery from cine MRI using a nearly incompressible biventricular model. Med Image Anal. 2008;12:69‐85. [DOI] [PubMed] [Google Scholar]
- 26. Ivanovic BA, Tadic MV, Celic VP. To dip or not to dip? The unique relationship between different blood pressure patterns and cardiac function and structure. J Hum Hypertens. 2013;27:62‐70. [DOI] [PubMed] [Google Scholar]
- 27. Chirinos JA, Segers P, De Buyzere ML, et al. Left ventricular mass: allometric scaling, normative values, effect of obesity, and prognostic performance. Hypertension. 2010;56:91‐98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Muxfeldt ES, Cardoso CRL, Salles GF. Prognostic value of nocturnal blood pressure reduction in resistant hypertension. Arch Intern Med. 2009;169:874. [DOI] [PubMed] [Google Scholar]
- 29. Biaggioni I. Circadian clocks, autonomic rhythms, and blood pressure dipping. Hypertension. 2008;52:797‐798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Yano Y, Hoshide S, Inokuchi T, et al. Association between morning blood pressure surge and cardiovascular remodeling in treated elderly hypertensive subjects. Am J Hypertens. 2009;22:1177‐1182. [DOI] [PubMed] [Google Scholar]
- 31. Rodrigues JCL, Dastidar AG, Paton JFR, MacIver DH. Precursors of hypertensive heart phenotype develop in healthy adults: an alternative explanation. JACC Cardiovasc Imaging. 2016;9:762‐763. [DOI] [PubMed] [Google Scholar]
- 32. Warnert EAH, Rodrigues JCL, Burchell AE, et al. Is high blood pressure self‐protection for the brain? Circ Res. 2016;119:e140‐e151. [DOI] [PubMed] [Google Scholar]
- 33. Kotsis V, Pitiriga V, Stabouli S, et al. Carotid artery intima‐media thickness could predict the presence of coronary artery lesions. Am J Hypertens. 2005;18:601‐606. [DOI] [PubMed] [Google Scholar]
- 34. Myerson SG, Bellenger NG, Pennell DJ. Assessment of left ventricular mass by cardiovascular magnetic resonance. Hypertension. 2002;39:750‐755. [DOI] [PubMed] [Google Scholar]
- 35. Cuspidi C, Michev I, Meani S, et al. Non‐dipper treated hypertensive patients do not have increased cardiac structural alterations. Cardiovasc Ultrasound. 2003;1:1. [DOI] [PMC free article] [PubMed] [Google Scholar]