Influence of circadian blood pressure patterns and cardiopulmonary functional capacity in hypertensive patients
Abstract
We sought to assess functional capacity in recently diagnosed untreated hypertensive patients with different 24-hour blood pressure (BP) patterns (dipping, non-dipping, extreme dipping, and reverse dipping). This cross-sectional study involved 164 untreated hypertensive patients who underwent 24-hour ambulatory BP monitoring and cardiopulmonary exercise testing. Our findings showed that 24-hour and daytime BP values did not differ between four groups. Nighttime BP significantly and gradually increased from extreme dippers to reverse dippers. There was no significant difference in BPs at baseline and at the peak of exercise among four observed groups. Peak oxygen consumption (peak VO2) was significantly lower in reverse dippers than in dippers and extreme dippers. Heart rate recovery was significantly lower among reverse dippers than in dippers and extreme dippers. Ventilation/carbon dioxide slope (VE/VCO2) was significantly higher in reverse dippers and non-dippers in comparison with dippers and extreme dippers. Non-dipping BP pattern (non-dippers and reverse dippers together) was independently and negatively associated lower heart rate recovery in the first minute and peak VO2. Reverse dipping BP pattern was independently associated not only with heart rate recovery in the first minute and peak VO2, but also with VE/VCO2. In conclusion, untreated hypertensive patients with reverse dipping BP patterns showed significantly worse functional capacity than those with dipping and extreme dipping BP patterns. Circadian BP rhythm is related with functional capacity and should be taken into account in the risk assessment of hypertensive patients.
1 INTRODUCTION
Exercise capacity has been accepted as a very important predictor of all-cause mortality in hypertensive population.1, 2 The investigators even showed inverse relationship between exercise capacity and progression from prehypertension to hypertension.3 Studies that involved assessment of functional capacity by cardiopulmonary exercise test in patients with arterial hypertension are less frequent. Our study group showed that untreated hypertensive patients and those patients with uncontrolled hypertension had significantly lower peak oxygen consumption (peak VO2) than controls and well-controlled hypertensive patients.4 Furthermore, we showed significant negative correlation between blood pressure (BP) and peak VO2, as well as between left ventricular remodeling and peak VO2.4 The mechanisms of the relationship between BP and functional capacity are still largely speculative.5
Circadian BP patterns are extensively investigated in last three decades, since O'Brien et al presented them for the first time.6 The authors introduced dipping and non-dipping BP pattern using the percentage of nocturnal BP reduction (>10% for dippers and <10% for non-dippers), and soon afterward studies showed negative impact of non-dipping on morbidity and mortality.7-9 Not all authors agree about the negative impact of non-dipping BP pattern on target organ damage.10 Gkaliagkousi et al recently reported that non-dipping was accompanied by microvascular, yet not macrovascular and endothelial dysfunction in early-stage hypertension.11 Moreover, dippers with elevated nighttime systolic BP (SBP) had higher cardiovascular risk than those with lower nighttime SBP.11
More recently two new BP patterns were presented—reverse dipping and extreme dipping, and their importance has not been established yet. Large meta-analysis showed that reverse dipping was a predictor of total cardiovascular events, coronary events and strokes.9 Extreme dipping pattern was not predictor of any of these events.9 Our pooled data analysis showed that extreme dipping was not related with cardiac remodeling—left ventricular remodeling.12 However, the question that arises is whether excessive nighttime BP drop in extreme dippers could increase risk of stroke. This has been reported in studies that investigated hypertensive elderly patients.13, 14
Data regarding the association between circadian BP rhythm and functional capacity are scarce. Ritvo et al15 showed no difference in exercise capacity between dippers and non-dippers. However, the authors showed significant correlation between exercise capacity and dipping BP pattern.15
The aim of this study was to investigate functional capacity in untreated hypertensive patients with different circadian BP patterns and to determine the possible association between BP patterns and functional capacity indices.
2 METHODOLOGY
This cross-sectional study included 164 untreated hypertensive subjects referred to the outpatient clinic of University Clinical Hospital Center “Dr Dragisa Misovic—Dedinje”, Belgrade, Serbia, for 24-hour ambulatory BP monitoring. Inclusion criteria were untreated arterial hypertension and age ≥18 years. Subjects with heart failure, known coronary artery disease, atrial fibrillation or ventricular arrhythmia, congenital heart disease, more than mild valve heart disease, renal failure, morbid obesity, or diabetes mellitus were excluded from the further analysis. Basic anthropometric measures and laboratory analyses were taken from all study subjects. Body mass index (BMI) was calculated for each patient. The local Ethics Committee approved study, and all participants signed the informed consent.
2.1 BP measurement
Clinic BP values were obtained in the morning hours by measuring the average value of the three consecutive measurements in the sitting position taken 5 minutes apart. BP was obtained in at least two separate occasions. All the participants underwent a 24-hour BP monitoring. The noninvasive 24-hour ambulatory BP monitoring was performed by Schiller BR-102 plus system (Schiller AG) according to current guidelines.16 BP was measured at 20-minute intervals during the day (07:00-23:00 o'clock) and at 30-minute intervals during the night (23:00-07:00 o'clock). The patients were asked to diary of their daily activities including the time when they wake up and when they go to bed. Nighttime BP was defined as the average of BPs from the time when the patients went to bed until the time they got out of the bed, and daytime BP as the average of BPs recorded during the rest of the day. The recording was analyzed to obtain a 24-hour, daytime and nighttime average SBP, diastolic BP (DBP), and heart rates.
Arterial hypertension was defined by 24 hours SBP ≥130 mm Hg and/or DBP ≥80 mm Hg in 24-hour ambulatory pressure monitoring.16
The nocturnal dipping was defined as a reduction in average SBP <20% at night ≥10% and <20% compared with average daytime values; the extreme nocturnal dipping existed if the reduction in average SBP at night was ≥20%. The non-dippers had a nocturnal reduction in average SBP <10%, and the reverse dippers were the patients with higher nocturnal average SBP in comparison with diurnal values.16
2.2 Cardiopulmonary exercise testing
All study participants underwent a maximum symptom-limited treadmill exercise test according to a modified Bruce ramp protocol (adding to the standard Bruce protocol stage 3 minutes; 1.7 km/h, at 5% grading). The patients were stimulated to continue with the test as long as their respiratory exchange ratio exceeded 1. The peak oxygen uptake (peak VO2) was assessed by a breath-by-breath gas analysis (Schiller, CARDIOVIT CS-200 Ergospiro system). Peak VO2 was defined as an average value within the last 20 seconds of exercise and expressed as mL/kg/min. The ventilation/carbon dioxide slope, which showed the linear increase of ventilation relative to carbon dioxide production, was computed automatically by the Schiller computer system. Blood pressure and heart rate were measured before, during the exercise test, and during the recovery period (after first, second, and third minute). Heart rate recovery was calculated as the difference between peak heart rate achieved during the exercise and heart rate after first, second, and third minute of recovery.
2.3 Statistical analysis
Continuous variables were presented as mean ± standard deviation showed normal distribution, and they were compared by the analysis of equal variance (ANOVA). Tukey post hoc analysis was used for the comparison between different groups. Differences in proportions were compared by the chi-square test. Univariate and multivariate linear regression analyses were used for determination of association between demographic and clinical parameters with indices obtained during cardiopulmonary exercise testing. The P-value <.05 was considered statistically significant.
3 RESULTS
The observed groups were of similar age, gender distribution, BMI, fasting glucose, cholesterol, triglycerides, and creatinine levels (Table 1). Clinic, 24-hour and daytime BPs did not differ between groups (Table 2). Nighttime systolic and DBP significantly and gradually increased from extreme dippers to reverse dippers (Table 2). By definition, the percentage reduction in SBP and DBP gradually and significantly decreased from extreme dippers, throughout dippers and non-dippers to reverse dippers (Table 2). There was no difference between the groups in 24-hour heart rate. However, daytime heart rate was lower in extreme and reverse dippers than in non-dippers (Table 2). Nighttime heart rate was higher in reverse dippers than in dippers and extreme dippers (Table 2).
| Dippers (n = 67) | Non-dippers (n = 47) | Extreme dippers (n = 30) | Reverse dippers (n = 20) | P | |
|---|---|---|---|---|---|
| Age (years) | 50 ± 11 | 52 ± 10 | 52 ± 11 | 54 ± 11 | .467 |
| Male (%) | 35 (52) | 25 (54) | 16 (53) | 12 (60) | .944 |
| BMI (kg/m2) | 26.0 ± 3.7 | 26.7 ± 3.9 | 26.2 ± 3.5 | 27.3 ± 4.2 | .523 |
| Plasma glucose (mmol/L) | 5.4 ± 1.2 | 5.1 ± 1.4 | 5.3 ± 1.6 | 5.5 ± 1.5 | .623 |
| Total cholesterol (mmol/L) | 5.6 ± 1.6 | 6.0 ± 1.9 | 5.1 ± 1.7 | 5.7 ± 2.0 | .187 |
| Triglycerides (mmol/L) | 1.8 ± 0.8 | 2.0 ± 0.9 | 1.9 ± 0.8 | 2.1 ± 1.0 | .457 |
| Serum creatinine (mmol/L) | 87 ± 20 | 91 ± 24 | 90 ± 20 | 93 ± 22 | .641 |
- Abbreviations: BMI, body mass index; BP, blood pressure.
| Dippers (n = 67) | Non-dippers (n = 47) | Extreme dippers (n = 30) | Reverse dippers (n = 20) | P | |
|---|---|---|---|---|---|
| Clinic | |||||
| SBP (mm Hg) | 150 ± 15 | 148 ± 16 | 147 ± 16 | 148 ± 15 | .809 |
| DBP (mm Hg) | 93 ± 10 | 94 ± 10 | 93 ± 9 | 91 ± 10 | .727 |
| 24-h | |||||
| SBP (mm Hg) | 135 ± 12 | 139 ± 14 | 132 ± 11 | 137 ± 14 | .110 |
| DBP (mm Hg) | 81 ± 10 | 82 ± 10 | 78 ± 9 | 83 ± 10 | .254 |
| Heart rate (beat/min) | 71 ± 9 | 75 ± 10 | 70 ± 9 | 71 ± 9 | .067 |
| Daytime | |||||
| SBP (mm Hg) | 140 ± 14 | 141 ± 16 | 139 ± 15 | 135 ± 16 | .501 |
| DBP (mm Hg) | 84 ± 10 | 83 ± 9 | 83 ± 10 | 82 ± 9 | .851 |
| Heart rate (beat/min) | 74 ± 10 | 78 ± 10 | 72 ± 9a | 71 ± 9b | .014 |
| Nighttime | |||||
| SBP (mm Hg) | 119 ± 11 | 134 ± 15 | 105 ± 9 | 142 ± 16 | <.001* |
| DBP (mm Hg) | 72 ± 8 | 78 ± 8 | 62 ± 7 | 87 ± 9 | <.001** |
| Heart rate (beat/min) | 62 ± 7 | 67 ± 8c | 60 ± 7e | 70 ± 9d, f | <.001 |
| ∆Day-night (%) | |||||
| SBP | 15.2 ± 3.7 | 5.0 ± 2.3 | 24.3 ± 3.3 | −5.2 ± 2.7 | <.001** |
| DBP | 14.7 ± 3.3 | 5.6 ± 2.4 | 25.0 ± 3.7 | −6.2 ± 2.6 | <.001** |
- Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
- a P < .05 for non-dippers vs extreme dippers.
- b P < .05 for non-dippers vs reverse dippers.
- c P < .01 for dippers vs non-dippers.
- d P < .01 for dippers vs reverse dippers.
- e P < .01 for non-dippers vs extreme dippers.
- f P < .01 for non-dippers vs reverse dippers.
- * For all comparisons P < .05.
- ** For all comparisons P < .01.
3.1 Cardiopulmonary exercise testing
Heart rates and BP before and at the peak of cardiopulmonary exercise testing were similar between four observed groups (Table 3). Percentage of predicted heart rate was lower in extreme dippers than in non-dippers, but any other difference between groups was not noticed (Table 3).
| Dippers (n = 67) | Non-dippers (n = 47) | Extreme dippers (n = 30) | Reverse dippers (n = 20) | P | |
|---|---|---|---|---|---|
| Rest | |||||
| Heart rate at rest (beats/min) | 78 ± 12 | 80 ± 11 | 79 ± 11 | 81 ± 12 | .697 |
| Systolic BP (mm Hg) | 143 ± 16 | 146 ± 15 | 142 ± 16 | 144 ± 17 | .690 |
| Diastolic BP (mm Hg) | 82 ± 11 | 84 ± 10 | 81 ± 11 | 80 ± 10 | .457 |
| Maximum exercise | |||||
| Heart rate (beats/min) | 161 ± 12 | 164 ± 13 | 158 ± 12 | 160 ± 13 | .209 |
| Systolic BP (mm Hg) | 188 ± 20 | 195 ± 21 | 193 ± 21 | 194 ± 20 | .290 |
| Diastolic BP (mm Hg) | 99 ± 9 | 100 ± 10 | 102 ± 9 | 100 ± 9 | .542 |
| Percentage of predicted heart rate (%) | 95 ± 4 | 97 ± 5 | 94 ± 5a | 96 ± 5 | .030 |
| Recovery heart rate | |||||
| Heart rate in 1.min of recovery (beats/min) | 141 ± 14 | 149 ± 16e | 139 ± 12a | 147 ± 15 | .006 |
| Heart rate in 2.min of recovery (beats/min) | 120 ± 13 | 128 ± 14b | 115 ± 11d | 130 ± 15c, f | <.001 |
| Heart rate in 3.min of recovery (beats/min) | 109 ± 12 | 115 ± 13e | 105 ± 10d | 118 ± 14f, g | <.001 |
| Δ Heart rate after 1.min (beats/min) | 20 ± 7 | 15 ± 5b | 19 ± 6a | 13 ± 5c, f | <.001 |
| Δ Heart rate after 2.min (beats/min) | 41 ± 11 | 36 ± 10 | 43 ± 11a | 30 ± 9c, f | <.001 |
| Δ Heart rate after 3.min (beats/min) | 52 ± 13 | 49 ± 12 | 53 ± 14 | 42 ± 12g, h | .012 |
| Recovery BP | |||||
| Systolic BP recovery in 1.min (mm Hg) | 165 ± 18 | 168 ± 18 | 167 ± 17 | 170 ± 20 | .682 |
| Diastolic BP recovery in 1.min (mm Hg) | 91 ± 8 | 92 ± 9 | 90 ± 9 | 95 ± 10 | .221 |
| Systolic BP recovery in 3.min (mm Hg) | 143 ± 14 | 145 ± 15 | 141 ± 14 | 151 ± 17 | .102 |
| Diastolic BP recovery in 3.min (mm Hg) | 84 ± 7 | 86 ± 7 | 81 ± 6a | 89 ± 9c, f | .001 |
| Respiratory exchange ratio | 1.13 ± 0.07 | 1.16 ± 0.08 | 1.15 ± 0.10 | 1.19 ± 0.10g | .029 |
| Peak oxygen uptake (mL/kg/min) | 25.7 ± 3.8 | 23.1 ± 4.0b | 25.5 ± 4.2a | 22.3 ± 3.4c, h | <.001 |
| Ventilation/carbon dioxide slope | 24.7 ± 2.7 | 26.8 ± 2.9b | 24.0 ± 2.5d | 27.9 ± 3.3c, f | <.001 |
- BP, blood pressure.
- a P < .05 for non-dippers vs extreme dippers.
- b P < .01 for dippers vs non-dippers.
- c P < .01 for dippers vs reverse dippers.
- d P < .01 for non-dippers vs extreme dippers.
- e P < .05 for dippers vs non-dippers.
- f P < .01 for extreme dippers vs reverse dippers.
- g P < .05 for dippers vs reverse dippers.
- h P < .05 for extreme dippers vs reverse dippers.
Heart rate recovery in the first, second, and third minute was significantly lower in reverse dippers than in dippers and extreme dippers (Table 3). There was no difference between non-dippers and reverse dippers. BP recovery in the first minute did not differ between four groups (Table 3). The same was found for SBP in the third minute of recovery, whereas DBP in the third minute of recovery was higher in reverse dippers than in extreme dippers and dippers (Table 3). Respiratory exchange ratio was higher in reverse dippers than in dippers, whereas there was no difference between other observed groups. Peak VO2 was significantly lower in reverse dippers than in dippers and extreme dippers (Table 3). There was no significant difference between non-dippers and reverse dippers. On the other hand, ventilation/carbon dioxide slope was significantly increased reverse dippers and non-dippers than in the other two groups of hypertensive patients (Table 3).
3.2 Correlation and regression analyses
24-hour SBP and non-dipping BP pattern correlated with heart rate recovery in the first minute (Table 4). Both parameters were independently of age, sex, and BMI associated with heart rate recovery in the first minute. Non-dipping pattern included non-dippers and reverse dippers.
| Δ Heart rate recovery in 1.min (beats/min) | Peak oxygen uptake (mL/kg/min) | Ventilation/carbon dioxide slope | ||||
|---|---|---|---|---|---|---|
| Correlation | Multivariate regression | Correlation | Multivariate regression | Correlation | Multivariate regression | |
| r | β | r | β | r | β | |
| Age | −.085 | −0.070 | −.179* | −0.112 | .059 | 0.066 |
| Sex (male) | −.105 | −0.094 | .207* | −0.140 | .091 | 0.072 |
| BMI (kg/m2) | −.076 | −0.089 | −.129 | −0.088 | .117 | 0.103 |
| 24−h SBP (mm Hg) | −.305** | −0.228* | −.455** | −0.378** | .320** | 0.275** |
| Non-dipping statusa | −.215* | −0.187* | −.305** | −0.196* | .208** | 0.129 |
| r 2 | .231 | .340 | .274 | |||
- a Non-dippers and reverse dippers together.
- * P < .05.
- ** P < .01.
Age, male sex, 24-hour SBP, and non-dipping BP pattern correlated with peak VO2 (Table 4). However, only 24-hour SBP and non-dipping BP pattern were independently related with peak VO2.
24-hour SBP and non-dipping BP pattern correlated with ventilation/carbon dioxide slope, but only non-dipping BP pattern was independently associated with VE/VCO2 slope (Table 4).
Somewhat different results were obtained when reverse dipping pattern was considered separately to another BP patterns (extreme dipping, dipping, and non-dipping). Reverse dipping BP pattern was associated with heart rate recovery in the first minute (β = −0.246, P < .001), peak VO2 (β = −0.359, P < .001) and VE/VCO2 slope (β = 0.205, P = .011), independently of age, male sex, and 24-hour SBP in all three models.
4 DISCUSSION
The present investigation revealed several important findings: (a) peak oxygen consumption was significantly lower in hypertensive patients with reverse dipping than in those with dipping and extreme dipping BP patterns; (b) heart rate recovery during the first three minutes was significantly lower in reverse dippers than in extreme dippers and extreme dippers: (c) ventilation/carbon dioxide slope was significantly higher in reverse dippers than in dippers and extreme dippers; and (d) reverse dipping was the only BP pattern associated with functional capacity indices independently of age, sex, and 24-hour SBP.
In our study, peak VO2 was significantly lower in reverse dippers than in dippers and extreme dippers. Additionally, reverse dippers were the only BP pattern that was independently associated with peak VO2, heart rate recovery, and ventilation/carbon dioxide slope. This indicated that reverse dipping represented the most unfavorable type of 24-hour BP patterns. Our analysis of pooled data showed that the risk of nonfatal and fatal cardiovascular events in reverse dippers was 2.5-fold greater than in dippers and 2.1-fold higher than in non-dippers.17 Meta-analysis that involved 17 312 hypertensive patients also demonstrated that reverse dipping was predictor of all-cause and cardiovascular mortality.9 Our previous investigation showed that reverse dippers had significantly more pronounced left and right ventricular structural and functional remodeling than dippers and extreme dippers.18 Cardiac remodeling might be one of the most important mechanisms that could explain the relationship between BP patterns and oxygen kinetics in hypertensive patients.
Decreased heart rate recovery in reverse dippers in comparison with dippers and extreme dippers indicated abnormal cardiac autonomic function in these patients. Heart rate recovery graded after exercise represents one of the most commonly used methods for assessment of cardiac autonomic function and predicts cardiovascular events and mortality.19 Normally, exercise is related with elevated sympathetic and reduced parasympathetic activity, whereas the recovery period after maximum exercise implies a combination of sympathetic deprivation and parasympathetic reactivation. Decrease of heart rate recovery in reverse dippers might correspond with increased sympathetic activity that could not be deprived after exercise. Previous study showed significantly higher sympathetic activation among reverse dippers comparing with other BP patterns.20 This might explain the lack of heart rate reduction during whole recovery period.
Ventilation/carbon dioxide slope was significantly higher in reverse dippers than in dippers and extreme dippers. Moreover, reverse BP dipping pattern was positively associated with increased ventilation/carbon dioxide. This might be explained by changes in pulmonary vasculature and cardiac dysfunction induced by arterial hypertension.5 Studies showed that ventilation/carbon dioxide slope was the strongest predictor of mortality and severe complications after lung resection,21 and superior predictor to the oxygen uptake efficiency slope in patients with heart failure.22
The pathophysiological mechanisms underlying the possible association between circadian BP patterns and functional capacity in hypertensive population are largely speculative. Hypotheses included sympathetic overactivity, changed baroreceptor sensitivity, increased salt sensitivity or renal dysfunction, sleeping disorders, hyperaldosteronism status, increased arterial stiffness, endothelial dysfunction, cardiac remodeling, chronic low-grade inflammation, and daytime orthostatic hypotension.23
There are several important clinical implications of the current study. Our findings emphasized the importance of 24-hour ambulatory BP monitoring because home and office BP measurements could not detect this type of BP pattern. Hypertensive patients with reverse dipping BP pattern should be particularly followed and controlled due to increased risk of decreased functional capacity and cardiac remodeling.
4.1 Limitations
This study showed some limitations. All the patients with common comorbidities have been excluded from the study, which limits the potential generalization of the present findings. Circadian BP patterns were classified by SBP, which also could have an impact on the results. A single 24-hour BP monitoring was used for determination of BP patterns. This type of monitoring has somewhat lower reproducibility in comparison with a 48-hour BP monitoring. There was no normotensive group for comparison with hypertensive patients with different BP patterns.
5 CONCLUSION
Oxygen kinetics was significantly more deteriorated in recently diagnosed hypertensive patients with reverse dipping than in patients with dipping and extreme dipping BP patterns. Heart rate kinetics during recovery was also significantly more affected in reverse dippers than in extreme dippers and dippers. Considering the fact that heart rate kinetics during recovery reflect the autonomic nervous system and primarily vagal function during early recovery, this makes the hypothesis regarding the association between the autonomic nervous system, BP patterns and functional capacity more reasonable. Further longitudinal investigations with a larger number of hypertensive patients are required to investigate the impact of interaction between 24-hour BP patterns and functional capacity on outcome in hypertensive population.
CONFLICT OF INTEREST
The authors have nothing to disclose.
AUTHOR CONTRIBUTIONS
MT was responsible for design of the study and its methodology. MT and VV performed echocardiographic examinations. JSL, VV, and OI performed cardiopulmonary exercise testing, MT performed the LA phasic analysis on the dedicated software offline, MT and CS performed statistical analysis, MT wrote the article, and CC, VC, and VDj revised it carefully and gave a significant scientific contribution to its content.
