ABSTRACT
Objective
This study aimed to explore whether circadian rhythm of blood pressure is associated with brachial-ankle pulse wave velocity (baPWV) and brachial artery flow-mediated dilation (FMD) in patients with essential hypertension.
Method
This cross-sectional study included 4,217 patients with essential hypertension who completed 24-hour ambulatory blood pressure monitoring, baPWV, and FMD. BaPWV and FMD were measured to evaluate arterial stiffness and endothelial dysfunction. Participants were divided into dipper, non-dipper, and reverse dipping groups according to the nocturnal systolic blood pressure dipping percentage.
Results
In this study, baPWV was highest in the reverse dipping groups, followed by non-dipper and dipper groups (1667.11 ± 327.90 vs. 1613.88 ± 325.11 vs. 1577.45 ± 306.15 cm/s, P < .001) and FMD gradually increased (4.41 ± 2.87 vs. 4.70 ± 2.84 vs. 4.92 ± 2.79%, P = .001). baPWV and FMD were significantly associated with declining nocturnal systolic blood pressure (SBP). Interestingly, FMD (β = 0.042, P = .014) was only positively associated with a drop in nocturnal SBP decline in patients <65 years of age. Whereas baPWV was consistently negatively associated with nocturnal SBP decline regardless of age (β = -0.065, P < .001, age <65 years; β = -0.149, P = .002, age ≥ 65). Receiver operating characteristics (ROC) curves analysis showed areas under the curve (AUC) of baPWV/FMD for predicting circadian rhythm of blood pressure are 0.562/0.554 with a sensitivity of 51.7%/53.9% and specificity of 56.4%/53.4.
Conclusion
Impairment of baPWV and FMD were correlated with abnormal circadian rhythm of blood pressure in essential hypertension, suggesting a decrease in nighttime SBP may associate with endothelial function and arterial stiffness.
Introduction
Hypertension is one of the most common cardiovascular (CV) diseases. In addition, it is a significant risk factor for developing other CV diseases and mortality (Citation1–3). Over recent years, hypertension has significantly increased, probably due to increased life expectancy worldwide. Therefore, monitoring blood pressure (BP) through different methods, including 24-hour ambulatory BP monitoring, is particularly important.
Ambulatory BP monitoring provides a unique opportunity to assess circadian BP, which has been studied extensively since it was discovered in 1988 (Citation4). Normal circadian rhythm of blood pressure means blood pressure increases on waking in the morning and decreases during sleeping at night, which is defined dipper. Another pattern is non-dipper, which means the nighttime decrease is absent or blunted. Earlier evidence highlighted that non-dipping BP patterns are closely associated with larger left ventricular mechanics (Citation5), left ventricular dilatation (Citation6,Citation7), left atrial function (Citation8), and increased carotid wall thickness (Citation9). Consequently, abnormal dipping patterns of BP increase the risk of CV events, including stroke, myocardial infarction (MI), and sudden cardiac death (Citation10–16). Moreover, it has been described that non-dipper or reverse-dipping hypertensives have more significant vascular damage in the carotid arteries (Citation17) and higher CV morbidity (Citation18,Citation19). Interestingly, substantial evidence indicates that arterial stiffness and endothelial dysfunction promote the physiological hardening of the arterial system and contribute to the pathogenesis of hypertension (Citation20,Citation21).
Endothelial dysfunction and arterial stiffness involve vascular damage’s pathogenesis and are surrogate markers for impaired vascular function and structure. With the advancement in clinical studies, different parameters have been used to determine endothelial damage and systemic arterial stiffness. Among the many parameters, brachial artery flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) are commonly used (Citation20). However, to the extent of our knowledge, the association between BP circadian rhythms and FMD and baPWV parameters has yet to be tested in large-scale epidemiological studies. Therefore, elucidating the association between circadian rhythms of BP and the parameters of endothelial dysfunction and arterial stiffness is significant.
Owing to abnormal patterns of circadian rhythms of BP can lead to an increased clinical burden of CVDs and mortality, this study sought to (i) compare the parameters of vascular endothelial function and systemic arterial stiffness in dipper, non-dipper and reverse dipping essential hypertensive patients, and (ii) explore the association between parameters of nocturnal systolic blood pressure (SBP) decline and endothelial dysfunction (FMD) and arterial stenosis (baPWV) in patients with essential hypertension.
Methods
Study participants
We conducted a cross-sectional study among hospitalized patients with essential hypertension between January 2015 and October 2020 at the First Affiliated Hospital of Dalian Medical University (FAHDMU). Blood pressure was measured with an HBP-1100 professional blood pressure monitor (OMRON HEALTHCARE Co., Ltd., Tokyo, Japan) three times on the first day of admission to the hospital after a rest of at least 10 minutes, and the average systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded. The hospitalized patients aged >18 years and SBP ≥140 mm Hg, DBP ≥90 mm Hg, or use of antihypertensive drugs as defined in the 2013 European Society of Cardiology and European Society of Hypertension (ESC/ESH) guidelines (Citation22) were enrolled. Patients with secondary hypertension(N = 104), severe arrhythmia (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, type-II 2nd or 3rd-degree atrioventricular block and sick sinus syndrome, N = 105), moderate to severe kidney dysfunction (estimated glomerular filtration rate [eGFR] ≤60 mL/min/1.73 m2, N = 132), left ventricular systolic dysfunction (left ventricular ejection fraction < 50%, N = 38), severe valvular heart disease(N = 26), ankle-brachial index < 0.9(N = 32), acute myocardial infarction or unstable angina pectoris(N = 117) were excluded. Secondary hypertension was defined based on the 2013 ESC/ESH guidelines. All patients had records for plasma aldosterone and renin, and aldosterone: renin ratio, thyroid function tests, duplex renal artery Doppler or CT angiography or MR angiography, adrenal Doppler or CT angiography and renal Doppler if necessary; if the patients had a history of snoring or obesity, a polysomnographic evaluation was retrieved, which aimed to exclude the patients with obstructive sleep apnea, renal parenchymal disease, renovascular disease (includes atherosclerotic renovascular disease and fibromuscular dysplasia), endocrine causes (include Primary Aldosteronism, Phaeochromocytoma, Cushing’s syndrome, e.t.c). Those subjects with missing baPWV, FMD, and ambulatory BP testing (N = 167) were also excluded, resulting in 4,217 patients ().
Figure 1. The overview of the selection of study participants.
The research was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the FAHDMU. All procedures listed here were carried out in compliance with the approved guidelines. Furthermore, the institutional review board waived the requirement for informed consent as the data was utilized from the electronic medical record database of FAHDMU.
Explanatory variables
The participants’ demographic and clinical characteristics, including age, sex, height, weight, smoking status, CV disease, and use of oral antihypertensive drugs and statins, were extracted from the electronic health record database FAHDMU. Smoking status was classified into never smoker (<100 cigarettes in a lifetime), former smoker (≥100 cigarettes in lifetime and none in the past year), or current smoker (≥100 cigarettes in a lifetime and at least one cigarette in the last year). Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Data on biochemical parameters, including total cholesterol (TC), triglycerides (TG), High-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol (LDL-C), and creatinine (Cre) were also retrieved from the FAHDMU, and all these biochemical parameters were performed using the standard protocols. The eGFR was calculated according to the equation suggested by the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration (Citation23). DM was defined as fasting plasma glucose ≥7.0 mmol/L, 2-hour postprandial blood glucose ≥11.1 mmol/L, or a history of DM.
Measurement of baPWV
Patients were requested to lie supine, and their baPWV was measured and recorded using a volume-plethysmography device (VP-1000; Omron, Tokyo, Japan). The brachial and posterior tibial artery pressure waveforms were measured using an oscillometric method. The distance between the upper arm and ankle was determined based on height, and baPWV was calculated using time-phased analysis. BaPWV was obtained from the right and left measurements, and the higher of the two readings was used for analysis.
Measurement of FMD
Participants were informed about fasting for at least six hours before the examination. They were also advised not to smoke, exercise physically, or consume caffeine and alcohol twenty-four hours before the test. In addition, before the examination, the patient should remain supine for at least ten minutes. An automated sphygmomanometer (Dinamap device) was placed in the forearm arm to monitor BP and pulse at 5-minute intervals throughout the examination. Next, we positioned a standard BP cuff around the arm, 2 cm below the antecubital fossa, and measured the arterial pressure 5 to 9 cm above it. Imaging of the brachial artery was made using a linear array multifrequency transducer operating at 9 MHz (GE Logiq 700 Device; GE Healthcare). For about 5 minutes, the cuff was inflated to 50 mm Hg above the participant’s SBP. Serial images of the brachial artery were captured continuously for 30 seconds before cuff inflation and for 2 minutes immediately before cuff deflation to document the vasodilator response. In addition, images of brachial artery diameter were captured in diastole (gated with electrocardiograph R wave). The semiautomated readings of these digitized images generated the baseline and maximum diameters of the brachial artery from which the %FMD was computed.
Blood pressure and ambulatory BP monitoring
Ambulatory blood pressure was monitored by an FDA-approved device (ABPM50, CONTEC Medical System LTD, Qinhuangdao, China). The other details of the 24-hour ambulatory BP monitoring methodology are described in our previous study (Citation8). Briefly, the mean 24-hour, daytime, and nighttime SBP, diastolic blood pressure (DBP), and heart rate (HR) were recorded. In addition, nocturnal SBP reductions were calculated as continuous variables using the equation:
Nocturnal SBP decline = [(Daytime mean SBP - nighttime mean SBP)/daytime mean SBP] × 100%
as previously described (Citation24).
According to the nocturnal SBP decline, circadian BP pattern was used to be classified into dipper (mean nocturnal SBP decline ≥ 10% in nocturnal SBP relative to daytime), non-dipper (mean nocturnal SBP decline ≥ 0% and < 10% in nocturnal SBP relative to daytime) and reverse dipper (mean nocturnal SBP decline < 0% in nocturnal SBP relative to daytime).
Statistical analysis
All statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY). The Kolmogorov-Smirnov test was used to test the normality of distribution. Normally distributed continuous variables are expressed as mean ± SD, and non-normally distributed parameters are presented as the median (interquartile range). Categorical data are presented as counts and percentages. Differences among groups were compared using the variance (ANOVA), χ2 test, or Mann-Whitney U test, depending on the nature of the data. We conducted post-hoc (Bonferroni) analysis to further examine the differences among groups. As aging is considered a determinant factor for vascular function23, we further stratified participants into two categories (<65 years and ≥65 years). Multiple linear regression analysis was carried out to evaluate the association between nocturnal SBP decline and baPWV and FMD in three models: Model 1 was unadjusted; Model 2 was adjusted for age and sex; and Model 3 was adjusted for age, sex, BMI, heart rate, SBP, smoking history, eGFR, use of statins, DM, and stable angina. Receiver operator characteristics (ROC) curve analysis was used to evaluate the productive power of baPWV and FMD for circadian rhythm of blood pressure.All statistical analyses were 2-sided, and a P-value of < 0.05 was considered statistically significant.
Results
Baseline characteristics
A total of 4217 hypertensive patients, including 1460 dippers (34.6%), 2177 non-dippers (51.6%), and 580 reverse dippers (13.8%), were involved in the present study. Compared with dippers, the non-dippers, and reverse dippers were more likely to be female (39.9% vs. 48.0% vs. 58.8%, P < .001) and older (51.44 ± 13.83 vs. 54.23 ± 13.65 vs. 61.11 ± 13.21 years, P < .001). Moreover, patients in non-dipper and reverse dipper groups were more likely to suffer from DM (21.5% vs. 29.0% vs. 17.3%, P < .001) and stable angina (16.1% vs. 24.0% vs. 10.9%, P < .001) compared with dippers. In addition, non-dippers and reverse dipper groups were more likely to receive statins (57.3% vs. 69% vs. 52.0%, P < .001). There were no significant differences in BMI, current smoking, TC, TG, HDL-C, LDL-C, and the use of calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, or diuretics (all P > .05). Baseline characteristics of the dipper, non-dipper, and reverse dipper groups are summarized in .
Table 1. Baseline characteristics of the subjects according to circadian rhythm of blood pressure.
The comparison of the ambulatory BP parameters among dipper, non-dipper, and reverse dipper group
There was a significant difference in nocturnal mean SBP, nocturnal mean DBP, and nocturnal heart rate among the dippers, non-dippers, and reverse dippers. The nocturnal mean SBP, nocturnal mean DBP, and nocturnal heart rate were significantly higher in non-dippers and reverse dippers than in dippers (All P < .05). The 24-hour mean DBP (87.51 ± 13.06 vs. 86.6 ± 13.17 vs. 82.93 ± 13.16 mm Hg), 24-hour heart rate (71.35 ± 9.36 vs. 70.63 ± 9.42 vs. 68.74 ± 9.27 bpm), mean daytime SBP (145.09 ± 16.97 vs. 141.53 ± 16.87 vs. 137.82 ± 17.65 mm Hg) , daytime mean DBP and the nocturnal SBP decline (14.46 ± 3.69% vs. 5.34 ± 2.84% vs. -5.06 ± 4.34) were gradually decreased from dipper, non-dipper and reverse dipper groups. The 24-hour SBP was similar among the three groups (P = .169). The comparison of the ambulatory BP parameters is summarized in .
Table 2. Comparison of ambulatory blood pressure between dippers and non-dippers.
Comparison of baPWV and FMD in the dipper, non-dipper, and reverse dipper hypertension
As shown in , baPWV was highest in reverse dipping groups, followed by non-dipper and dipper groups (1667.11 ± 327.90 vs. 1613.88 ± 325.11 vs. 1577.45 ± 306.15 cm/s, P < .001). On the other hand, FMD gradually increased (4.41 ± 2.87 vs. 4.70 ± 2.84 vs. 4.92 ± 2.79%, P = .001). The comparison of FMD among the three groups is demonstrated in .
Figure 2. Comparison of baPWV/FMD between dipper, non-dipper, and reverse dipper groups. (a). BaPWV between dipper, non-dipper, and reverse dipper groups. (b). FMD between dipper, non-dipper, and reverse dipper groups. baPWV, brachial-ankle pulse wave velocity; FMD, flow-mediated dilation. **indicates P < .05, *** indicates P < .001.
Relationship between the percentage of nocturnal SBP decline and baPWV/FMD
We used multiple linear regressions to examine the association between the percentage of nocturnal SBP decline and baPWV/FMD (). The percentage of nocturnal SBP decline was not associated with baPWV in the unadjusted model (β = -0.049, P = .069). In contrast, this relationship was inversely associated after we adjusted the model for the potential confounding factors (β = -0.079, P < .001). Conversely, the drop in nocturnal SBP was positively associated with FMD in the univariate model (β = 0.079, P < .001) and multivariate model (β = 0.030, P = .034).
Table 3. The relationships between percentage of nocturnal -SBP decline and baPWV and FMD parameters in the entire cohort.
Relationship between the percentage of nocturnal SBP decline and baPWV/FMD in different age groups
There are 3199 participants <65 years of age. As shown in , we observed a significant association between the nocturnal SBP decline and baPWV (Model 1: β = -0.119, P < .001; Model 2: β = -0.111, P < .001; Model 3: β = -0.065, P < .001) and FMD (Model 1: β = 0.064, P < .001; Model 2: β = 0.052, P = .003; Model 3: β = 0.042, P = .014).
Table 4. The relationships between percentage of nocturnal -SBP decline and baPWV and FMD parameters in <65 years of age, (N = 3199).
indicates the relationship between the percentage of nocturnal SBP decline and baPWV/FMD in the group of ≥65 years (N = 1018). However, we only observed a positive association between the nocturnal SBP decline and baPWV in participants ≥65 years of age. Therefore, the β in the fully adjusted model was (β = -0.149, P = .002).
Table 5. The relationships between percentage of nocturnal -SBP decline and baPWV and FMD parameters in ≥65 years of age, (N = 1018).
3. ROC curve for prediction of circadian rhythm of blood pressure with baPWV and FMD
ROC analysis was used to evaluate the availability of baPWV or FMD to predict circadian rhythm of blood pressure (). We regrouped patients according to dipping (nocturnal SBP decline ≥ 10%) and non-dipping (nocturnal SBP decline < 10%). The areas under the curve (AUC) of the baPWV predicted circadian rhythm of blood pressure were 0.562. The sensitivity and specificity of baPWV at the cutoff of 1531.75 cm/s were 51.7% and 56.4%. Moreover, the AUC of FMD predicted circadian rhythm of blood pressure were 0.554. The sensitivity and specificity of FMD at the cutoff of 4.45% were 53.9% and 53.4%.
Figure 3. Receiver operating characteristic (ROC) curve for blood pressure circadian rhythms prediction with baPWV and FMD. A. ROC curve for prediction of blood pressure circadian rhythms with baPWV. B. ROC curve for prediction of blood pressure circadian rhythms with FMD. baPWV, brachial-ankle pulse wave velocity; FMD, flow-mediated dilation; AUC, the area under the curve.
Discussion
In this retrospective study, we assessed vascular function using baPWV and FMD in patients with essential hypertension with different BP dipping patterns. Compared to dippers, baPWV was significantly higher in non-dippers and reverse dippers. Whereas FMD gradually decreased from the dipper, non-dippers to reverse dippers. Notably, the nocturnal SBP decline was significantly associated with decreased baPWV and elevated FMD in patients with essential hypertension, and this association remained consistent even after adjusting for potential confounders. These findings suggested that a drop in nocturnal SBP is associated with endothelial dysfunction and arterial stiffness.
The main mechanisms of an abnormal nighttime BP dip aggravating blood vessel damage may involve dysregulation of the sympathetic nervous system and renin-angiotensin-aldosterone system (Citation25–27). Cuspidi et al (Citation26). investigated the association between nocturnal BP patterns and sympathetic drive in essential hypertensive patients and found that a stepwise increase in sympathetic nerve activation occurred from normotensive controls to extreme dipper, dipper, non-dipper, and reverse dipper hypertensive patients. Another study reported that non-dippers were characterized by reduced nighttime decreases in norepinephrine and epinephrine and heightened alpha 1-adrenergic receptor responsiveness compared with dippers. Arterial compliance is also influenced by sympathetic neural activity; therefore, sympathetic nervous system activity may represent a link between vessel damage and nighttime BP dipping (Citation28). Second, increasing nocturnal natriuresis plays an essential role in the elevation of nocturnal BP (Citation29,Citation30). This condition activates the renin-angiotensin-aldosterone system, leading to impaired blood vessels.
Endothelial dysfunction (evaluated by FMD) and arterial stiffness (evaluated by baPWV) are independent predictors of hypertension and are increasingly associated with age-related physiological alterations (Citation31,Citation32). Therefore, to minimize the risk of bias associated with age in this study, we stratified patients depending on their age. We further analyzed the relationship between the percentage of nocturnal SBP decline and baPWV/FMD. The results showed that nocturnal SBP decline was significantly associated with decreased FMD in patients aged <65 years. Besides, the relationship between elevated baPWV and the percentage of nocturnal SBP decline remained statistically significant regardless of age. This indicates that in middle-aged hypertension patients, nocturnal hypertension impairs both endothelial function and arterial stiffness, which is more prominent in older patients. These findings are consistent with our previous study showing that vascular dysfunction is more strongly associated with subclinical target organ damage in younger hypertensive patients (Citation33).
Decreased vascular function and blunted nocturnal BP decline are associated with increased age (Citation34,Citation35). The cause may be at an early age; elevated blood pressure causes central arterial strain to reduce and impairment of endothelial function. However, with increasing age, hemodynamics also changes (Citation36–38). These changes result in mechanical alterations dramatically increasing arterial stiffness (Citation36–38). Similar studies have shown a significant association between endothelial dysfunction, acute ST-segment elevation MI, and hypertension in young adults (Citation39,Citation40). Compared with younger patients with endothelial injuries, aging per se is a promoter of arterial stiffness. Wu et al (Citation41). conducted a large-scale community-based longitudinal study and found that baPWV level mediated the positive association between aging and BP level. In contrast, the Bogalusa Heart Study (Citation42) reported that elevated BP preceded increased large-artery stiffness during young adulthood. Our results indicated that nocturnal blood pressure is associated with arterial stiffness regardless of age.
Study limitations
This study has several limitations. First, the single-center retrospective design limited the cause-and-effect relationship between nocturnal BP decline and baPWV/FMD in essential hypertension. Second, the study did not include a normotensive group, and there was a difference in the comorbidities of DM and stable angina among the three groups. Therefore, we could not determine the impact of the circadian rhythm of BP alone on vascular function. Third, most of the hypertensive patients were receiving antihypertensive treatment, which might affect their circadian rhythm of BP and vascular function. Four, the AUC values of ROC analysis were very low, but the relationship between baPWV/FMD and BP circadian rhythms was not affected. Finally, it should be noted that we utilized data from the hospitalized individuals; therefore, patients did not record their bedtime or wake time individually.
Conclusion
In conclusion, we found solid independent associations between high baPWV and decreased FMD and abnormal BP circadian rhythms in essential hypertension. Also, our study identified that the nocturnal drop in SBP was independently associated with endothelial dysfunction and arterial stiffness in middle-aged hypertension patients and only with arterial stiffness in old-aged hypertension patients. Furthermore, our data appears highly clinically relevant, which is essential to monitor vascular function in abnormal blood pressure rhythms in middle-aged hypertensive patients, which may allow early interventions on vascular damage and prevent clinical events.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.
Additional information
Funding
References
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