Abstract
The relationship between resting pulse rate (PR) and the occurrence of hypertension and cardiovascular (CV) mortality has been described in the general population. Few studies have examined the relationship between ambulatory PR, ambulatory blood pressure (BP), and target organ damage (TOD) in patients with chronic kidney disease (CKD). A total of 1509 patients with CKD were recruited in our hospital. Ambulatory blood pressure monitoring (ABPM) over a 24‐hours period was performed and referenced with clinical data in this cross‐sectional study. TOD was measured by estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), and carotid intima‐media thickness (cIMT). Univariate and multivariate analyses were used to evaluate the relationship between PR, BP, and TOD. The percentage of male patients was 58.3% with a mean age of 44.6 ± 16.2 years. Nocturnal PR rather than 24‐hours PR or daytime PR was an independent risk factor for clinical hypertension, 24‐hours hypertension, BP dipper state, poor renal function, and LVH. In addition, the authors found that nighttime PR >74 beats/min (bpm) group was independently associated with clinical hypertension, 24‐hours hypertension, day and night hypertension, nondipping BP, lower eGFR, and LVH when compared with nighttime PR <64 bpm group. Furthermore, 1:1 propensity score matching between PR ≤74 bpm group and PR >74 bpm group was performed. Multivariate analyses indicated nighttime PR >74 bpm remained independently associated with clinical hypertension, daytime and nighttime hypertension, and LVH. An increased nocturnal PR is associated with TOD, higher BP, and nondipping BP in patients with CKD.
Keywords: ambulatory blood pressure, chronic kidney disease, nocturnal pulse rate, target organ damage
1. INTRODUCTION
Chronic kidney disease (CKD) is a common disease worldwide. The estimated prevalence of CKD in China is 10.8%.1 CKD is strongly associated with an increased risk of cardiovascular (CV) mortality.2 It has been determined that hypertension is the most prevalent independent risk factor for the progression of renal failure and CV disease. It contributes to 45% of male deaths and 46% of female deaths in patients with CKD.3 Therefore, management of blood pressure (BP) to reduce the high risk of CV disease in patients with CKD could improve the prognosis of patients.
A large‐scale cohort study in children showed that elevated resting pulse rate (PR) increased the risk of hypertension.4 Elevated PR is strongly associated with high BP, and both variables are predictors of risk of chronic disease in adulthood.5 A previous study showed that in patients with CKD, elevated heart rate (HR) is also associated with increased risk of CV disease.6 Actually, most studies have emphasized resting HR and its prognostic significance for CV disease and the development of hypertension.7, 8, 9 However, HR/PR was not emphasized in any of the guidelines for treatment of hypertension and CV disease and there is still no consensus regarding an acceptable HR/PR One of the most important reasons for this discrepancy was that previous studies had utilized different methods to assess HR/PR, such as resting HR/PR, 24‐hours HR/PR, and daytime or nighttime HR/PR As a result, previous studies have shown low reproducibility and presented measurement bias. A few HR/PR readings taken in a clinical environment are likely poorly representative of the actual HR/PR levels leading to an underestimation of their real predictive power. HR/PR assessed out of the office in association with ambulatory BP is more representative of a participant's usual HR/PR and offers additional information about HR/PR circadian patterns, especially during the sleep period. HR during sleep is more stable and reproducible than HR during waking hours, which is subject to random fluctuations related to physical activities and occasional emotional triggers. Some studies also measured PR as an estimate of HR in normal and hypertensive patients.10, 11, 12, 13 After excluding patients with atrial fibrillation or serious severe ventricular arrhythmias which affected pulse, PR was usually equal or close to HR in this population. PR obtained from oscillometric devices has been shown to approximate the accuracy and reliability of measures obtained from the standard method.14 PR is a simple measurement that does not require special instruments and is convenient for the patients themselves to measure. However, there is no report on the association between nocturnal PR and PR, BP, or target organ damage (TOD) in patients with CKD. In the present study, therefore, we performed 24‐hours BP monitoring in patients with CKD and comprehensively examined the clinical correlation with nocturnal PR in patients with CKD.
2. MATERIALS AND METHODS
2.1. Study population
The study protocol was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat‐sen University (Guangdong, China). Written informed consent was obtained from patients before enrollment. Consecutive patients were recruited from the Third Affiliated Hospital of Sun Yat‐sen University from July 2010 to December 2017. Inclusion criteria were age ≥18 and <75 years and CKD. Exclusion criteria were as follows: acute changes in the estimated glomerular filtration rate (eGFR) >30% in the previous 3 months; dialysis; recipients of kidney transplant; atrial fibrillation or other arrhythmias (frequent ventricular premature beats or other serious ventricular arrhythmias; sick sinus syndrome); CV events in the previous 3 months; pregnancy; nightwork or shift‐work employment; taking prescription medications that could affect HR (decongestants, adrenergic agonists for glaucoma, digitalis, β‐blockers, and β‐agonist bronchodilators); intolerance to ambulatory blood pressure monitoring (ABPM); invalid ABPM data; PR <50 beats/minute (bpm) or >175 bpm.
A total of 1769 patients with CKD met the initial inclusion criteria from which 260 patients were excluded. Specifically excluded from our analytic sample were the following: 22 patients with eGFR >30% in the previous 3 months; 19 patients with PR greater than 175 bpm or lower than 50 bpm; 83 participants currently taking prescription medications that could affect HR (decongestants, adrenergic agonists for glaucoma, digitalis, β‐blockers, and β‐agonist bronchodilators); seven pregnant women; 61 participants with atrial fibrillation or other arrhythmias that affected PR; 40 patients intolerant to ABPM or who had invalid ABPM data; 8 patients with nightwork or shift‐work employment; and 20 patients with CV events in the previous 3 months. The total sample available for the normative analysis of PR was 1509. The distribution of renal diseases was as follows: 860 patients had chronic glomerulonephritis; 210 had diabetic nephropathy; 80 had hypertensive nephropathy; 21 had lupus nephritis; 153 had gouty nephropathy; and 185 patients had other causes of renal disease.
2.2. Measurements
2.2.1. BP and PR measurements
Ambulatory 24‐hours BP and PR monitoring were performed using the oscillometric device TM‐2430 Monitor (A&D, Tokyo, Japan). The cuff was matched to the perimeter of the arm, and measurements of BP and PR were performed every 15 minutes in the daytime and every 30 minutes at night. Patients underwent 24‐hour ABPM using the TM‐2430 Monitor as previously reported.15, 16, 17 Before beginning ABPM, BP was measured according to standardized protocols, which has also been reported previously.15, 16, 17 All patients underwent standard supine 12‐lead electrocardiogram detection after the individual had rested in the supine position for 5 minutes.
2.2.2. Target organ assessment
Cardiac assessment
Cardiac structure was assessed as previously described.16 Briefly, left ventricular mass (LVM), systolic function, and diastolic function were assessed using 2D echocardiography. Linear measurements of end‐diastolic interventricular septal wall thickness (IVSd), end‐diastolic left ventricular internal dimension (LVIDd), and end‐diastolic posterior wall thickness (PWTd) were obtained from M‐mode tracings. LVM was calculated using the following formula18: LVM = (1.04 × (IVSd + LVIDd + PWTd)3 ‐ LVIDd3) × 0.8 + 0.6.
The left ventricular mass index (LVMI) was obtained by calculating the ratio of LVM to body surface area.19
Carotid ultrasonography
Carotid intima‐media thickness (cIMT) was assessed by two trained investigators before study commencement.16
Renal function
Serum concentrations of creatinine (Scr) were measured by an enzymatic method traceable to isotope dilution mass spectrometry. eGFR was calculated using the 2009 CKD‐EPI creatinine Equation.20
2.2.3. Collection of other data
We collected medical history including current medical treatments, demographic information, and laboratory data (hemoglobin, albumin, calcium, phosphorus, intact parathyroid hormone, serum fasting glucose, cholesterol, triglycerides, high‐density lipoprotein cholesterol [HDL‐C], low‐density lipoprotein cholesterol [LDL‐C], homocysteine, uric acid, SCr, and blood urea nitrogen [BUN]). Proteinuria was measured by immunoturbidimetry. All laboratory data were measured using a 7180 Biochemistry Auto‐analyzer (Hitachi, Tokyo, Japan).
2.3. Definitions
Patients with clinical systolic BP (SBP) ≥140 mm Hg and diastolic BP (DBP) ≥90 mm Hg were defined as having clinical hypertension. Ambulatory normotension was defined as 24‐hours SBP <130 and 24‐hours DBP <80 mm Hg; daytime SBP <135 and daytime DBP <85 mm Hg; and nighttime SBP <120 and nighttime DBP <70 mm Hg; all others were regarded as having ambulatory hypertension. ABPM daytime and nighttime were defined by time intervals according to the patients’ schedules, which were described previously.21 Nocturnal systolic hypertension was defined as nocturnal SBP ≥120 mmHg, and dipping was defined as a decline in nocturnal SBP >10%, whereas nondipping was defined as a decline in nocturnal SBP of ≤10%.22
CKD was defined according to KDIGO 2012 clinical practice guidelines.23
Diabetes mellitus (DM) was defined as the need for anti‐DM drugs or meeting the diagnostic criteria based on the Standards of Medical Care in Diabetes set by the American Diabetes Association.24
TOD was defined as previously reported.16 First, left ventricular hypertrophy (LVH) was diagnosed as LVMI >115 g/m2 (male) or >95 g/m2 (female). Second, with respect to large‐vessel disease, cIMT >1 mm was regarded as an abnormal value. Third, impaired renal function was defined as an eGFR <60 mL/min per 1.73 m2.
2.4. Statistical analysis
Descriptive statistics are presented as means ±standard deviation for continuous variables and as medians and interquartile range for nonparametric variables. Frequency and percentage were used for categorical variables. The differences between qualitative variables were assessed with the chi‐square test or Fisher's exact test. Comparisons of continuous variables between groups were evaluated by the Student t test, ANOVA, or nonparametric test (Kruskal‐Wallis H test for several independent samples and Mann‐Whitney U test for two independent samples). Binary logistic regression models (multivariate analysis) were performed using the presence of TOD (two categories), hypertension (two categories), and nondipping BP (two categories) as dependent variables, and 24‐hours PR, daytime PR, and nighttime PR as independent variables, analyzed separately (model 1) or together (model 2). Other adjusted variables included age, sex (male vs. female), diabetes mellitus (no = 0, yes = 1), current smoker (no = 0, yes = 1), alcohol intake (no = 0, yes = 1), RAS blockade (no = 0, yes = 1), calcium‐channel blocker (no = 0, yes = 1), α‐blocker (no = 0, yes = 1), hemoglobin, calcium, phosphate, LDL‐C, proteinuria, and eGFR. The entire study population was then divided into three groups according to night PR tertiles as an independent variable: tertile 1 (nighttime PR <64 bpm), tertile 2 (nighttime PR 64‐74 bpm), and tertile 3 (nighttime PR >75 bpm); parameters were compared between these three subgroups. Finally, we performed univariate and multivariate analyses using two models. Model 1 was the crude model. In model 2, we adjusted for age, sex (male vs. female), diabetes mellitus (no = 0, yes = 1), current smoker (no = 0, yes = 1), alcohol intake (no = 0, yes = 1), RAS blockade (no = 0, yes = 1), calcium‐channel blocker (no = 0, yes = 1), α‐blocker (no = 0, yes = 1), hemoglobin, calcium, phosphate, LDL‐C, proteinuria, and eGFR.
To reduce selection bias of potential confounding factors, propensity score‐matched analysis was performed with matched age and eGFR between nighttime PR ≤74 bpm group and nighttime PR ˃ 74 bpm group. One‐to‐one matching using nearest‐neighbor algorithm assuming independent observations and fixed weights was performed. A caliper width of 0.02 was ultimately used in subsequent analyses. Statistical method described above was used to compare these two groups.
All P‐values were two‐sided, and the level of the test (a) was set as 0.05. Data were analyzed using SPSS version 25.0 (IBM, Armonk, NY).
3. RESULT
3.1. Demographic and clinical characteristics and TOD according to different tertiles of nighttime pulse rate of the study population
A total of 1509 patients with CKD were included in this study. The mean age of the patients was 44.6 ± 16.2 years, and 58.3% were men. Among all patients, 17.6% had DM, 18.9% were current smokers, and 8.7% consumed alcohol.
The prevalence in tertile 1 of patients with CKD types 1, 2, 3, 4, and 5 was 37.7%, 17.8%, 15.7%, 9.1%, and 19.7%, respectively (patient numbers were 190, 89, 79, 46, and 99, respectively). Patients with CKD stage 1 had a higher prevalence in tertile 1 than patients with other renal dysfunctions (P < 0.05). The prevalence in tertile 2 of patients with CKD types 1, 2, 3, 4, and 5 was 25.5%, 12.7%, 15.7%, 10.2%, and 35.9%, respectively (patient numbers were 128, 64, 79, 51, and 181, respectively). Patients with CKD 5 had a higher prevalence in tertile two than patients with other CKD stages (P < 0.05). The prevalence in tertile 3 of patients with CKD types 1, 2, 3, 4, and 5 was 11.8%, 7.5%, 10.2%, 8.9%, and 61.6%, respectively (patient numbers were 59, 38, 51, 45, and 310, respectively). In tertile group 1, the prevalence of patients with CKD types 1 accounted for the greatest proportion and was much higher than the prevalence of patients with worse renal function (P < 0.001). In tertile group 2, the prevalence of patients with CKD types 5 accounted for the greatest proportion and was much higher than the prevalence of patients with CKD type 2 to type 4 (P < 0.001). In tertile group 3, the prevalence of patients with worse renal function accounted for the greatest proportion and was much higher than the prevalence of patients with better renal function (P < 0.001; Figure 1). The prevalence of nondipping BP, LVH, impaired renal function, and abnormal cIMT in patients in tertile 3 was higher than in patients from tertile 1 (P < 0.05). The prevalence of impaired renal function, LVH, and abnormal cIMT in patients from tertile 2 was higher than that in patients from tertile 1 (P < 0.05). Moreover, tertile 3 patients had a higher prevalence of nondipping BP, impaired renal function, and LVH (Figure 1).
Figure 1.
A, Comparison of the proportion of CKD stages in different nighttime pulse rate tertiles. *Comparison with stage 1 and stage 2 of CKD, P < 0.05; #comparison with stage 3 of CKD, P < 0.05. B, Comparison of the prevalence of target organ damage in tertiles of nighttime pulse rate. *Comparison with the tertile 1 group, P < 0.05; #comparison with the tertile 2 group, P < 0.05. (P‐value for multiple comparisons was corrected according to the Bonferroni method). CKD, chronic kidney disease; nondipping BP, no‐dipper blood pressure; LVH, Left ventricular hypertrophy; eGFR, estimated glomerular filtration rate; cIMT, carotid intima‐media thickness. Tertile 1: nighttime pulse rate <64 beats/min, tertile 2: nighttime pulse rate: 64 beats/min‐74 beats/min, tertile 3: nighttime pulse rate >74 beats/min
3.2. Baseline characteristics and comparisons among the three tertiles of nighttime average PR
The group of individuals with the highest nighttime PR (tertile 3) was significantly older, had more 24‐hours proteinuria, had higher values of Scr, BUN, and LVMI, had lower values of hemoglobin and eGFR, and had a higher proportion of DM, LVH, and eGFR <60 mL/min/1.73 m2 compared with tertile 1 patients (nighttime PR <64 bpm) and tertile 2 patients (nighttime PR 64‐74 bpm; Table 1). In addition, the group of tertile 3 patients had higher clinical BP, higher 24‐hours BP, and a higher rate of nocturnal BP decline than tertile 1 and 2 patients. The group of tertile 2 patients (nighttime PR 64‐74 bpm) was older, had higher values of Scr, BUN, and LVMI, had lower levels of hemoglobin and eGFR, and had a higher proportion of DM, LVH, and eGFR <60 mL/min/1.73 m2 compared with tertile 1 patients (nighttime PR <64 bpm). Tertile 2 patients also had higher clinical BP, higher 24‐hours BP, and a greater rate of nocturnal DBP decline than patients in tertile 1 (Table 1 and Table 2).
Table 1.
Baseline characteristics of patients with CKD, stratified by tertiles of nighttime average PR
| Variables | Total (N = 1509) | Nighttime average pulse rate (bpm) | ||
|---|---|---|---|---|
| T1 <64 (n = 503) | T2 64‐74 (n = 503) | T3 >74 (n = 503) | ||
| Age (years) | 44.7 ± 16.1 | 41.9 ± 16.9 | 44.8 ± 15.4* | 47.2 ± 15.8** , # |
| Sex (M/F, %) | 58.3/41.7 | 62.3/37.7 | 55.8/44.2* | 56.9/43.1 |
| Current smoker, n (%) | 18.9% | 18.9% | 19.4% | 18.5% |
| Alcohol intake, n (%) | 8.9% | 7.5% | 9.4% | 9.7% |
| DM, n (%) | 18.7% | 11.0% | 17.5%* | 24.2%** , # |
| BMI (kg/m2) | 23.2 ± 3.9 | 23.2 ± 3.8 | 23.4 ± 4.1 | 23.0 ± 3.8 |
| Proteinuria (g/24 h) | 1.6 (0.5‐4.1) | 1.3 (0.4‐4.5) | 1.6 (0.5‐3.3) | 2.0 (0.8‐4.6)** , ## |
| Hemoglobin (G/L) | 111 ± 29 | 123 ± 25 | 113 ± 28** | 98 ± 28** , ## |
| Serum albumin (G/L) | 33.9 ± 8.1 | 33.7 ± 9.0 | 34.0 ± 7.8 | 33.1 ± 7.4 |
| Serum glucose (mmol/L) | 5.5 ± 2.1 | 4.9 ± 1.3 | 5.3 ± 2.2* | 5.5 ± 2.1** |
| CHOL (mg/dL) | 5.8 ± 3.9 | 6.1 ± 3.0 | 5.7 ± 5.5 | 5.5 ± 2.6 |
| LDL‐C (mmol/L) | 3.6 ± 2.1 | 3.9 ± 2.3 | 3.4 ± 1.8** | 3.5 ± 2.0** |
| Total calcium level (mmol/L) | 2.2 ± 0.2 | 2.2 ± 0.2 | 2.2 ± 0.2 | 2.1 ± 0.3** , ## |
| Phosphate level (mmol/L) | 1.5 ± 0.5 | 1.3 ± 0.3 | 1.4 ± 0.4 | 1.7 ± 0.6** , ## |
| iPTH (pg/mL) | 87.5 (39.6‐264.5) | 52.8 (31.1‐110.3) | 79.1 (40.6‐236.2)** | 174.5 (59.8‐397.0) ** , ## |
| Serum creatinine (mmol/L) | 179 (85‐611) | 107.4 (73.0‐239.5) | 165.1 (82.0‐540.5)** | 505.5 (146.0‐913.2) ** , ## |
| BUN (mmol/L) | 10.4 (5.7‐20.6) | 6.9 (4.9‐13.8) | 9.0 (5.5‐19.9)** | 17.5 (9.0‐26.7)** , ## |
| eGFR (mL/min/1.73 m2) | 33.0 (7.2‐88.9) | 70.7 (21.6‐107.0) | 36.8 (8.4‐91.6)** | 9.4 (4.7‐43.0)** , ## |
| eGFR <60 (mL/min/1.73 m2) | 48.5% | 28.8% | 46.1%** | 70.5%** , ## |
| LVMI (g/m2.7) | 51.4 ± 17.0 | 47.5 ± 16.4 | 50.0 ± 18.7* | 57.1 ± 18.1** , ## |
| LVH (%) | 54.2% | 41.7% | 53.2%** | 67.8% ** , ## |
| cIMT (cm) | 0.74 ± 0.26 | 0.70 ± 0.46 | 0.73 ± 0.28 | 0.76 ± 0.29 |
| Abnormal CIMT | 24.1% | 18.8% | 27.1% | 26.1% |
| RAS blockade | 871 (57.7%) | 318 (63.2%) | 305 (60.6%) | 248 (49.3%)** , ## |
| Calcium‐channel blocker | 498 (33.0%) | 111 (22.1%) | 156 (31.0%)** | 231 (45.9%)** , ## |
| α ‐blocker | 110 (7.3%) | 27 (5.4%) | 35 (7.0%) | 48 (9.5%)* |
BMI, body mass index; DM, diabetes mellitus; BUN, blood urea nitrogen; CHOL, total cholesterol; cIMT, carotid intima‐media thickness; eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone; LDL‐C, low‐density lipoprotein cholesterol; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; RAS blockade, renin‐angiotensin system blockade.
Indicates P < 0.05.
Indicates P < 0.01 when compared with tertile 1.
Indicates P < 0.05.
Indicates P < 0.01 when compared with tertile 2.
Table 2.
Differences in BP characteristics in Chinese patients with CKD, stratified by tertiles of nighttime PR
| Variables | Total (N = 1509) | Nighttime average pulse rate (bpm) | ||
|---|---|---|---|---|
| T1 <64 (n = 503) | T2 64‐74 (n = 503) | T3 >74 (n = 503) | ||
| Clinical SBP(mm Hg) | 145 ± 24 | 138 ± 22 | 146 ± 24** | 152 ± 24** , ## |
| Clinical DBP(mm Hg) | 87 ± 14 | 83 ± 13 | 88 ± 14** | 91 ± 15** , ## |
| Clinical hypertension, n (%) | 62.9% | 50.0% | 64.3%** | 74.2%** , ## |
| 24‐h SBP(mm Hg) | 135 ± 19 | 129 ± 17 | 134 ± 18** | 143 ± 19** , ## |
| 24‐h DBP(mm Hg) | 85 ± 11 | 76 ± 9 | 80 ± 11** | 85 ± 11** , ## |
| 24‐h hypertension | 64.3% | 51.0% | 63.0%** | 78.6%** , ## |
| Daytime SBP(mm Hg) | 136 ± 19 | 130 ± 17 | 135 ± 18** | 144 ± 19** , ## |
| Daytime DBP(mm Hg) | 81 ± 11 | 77 ± 9 | 81 ± 11** | 86 ± 11** , ## |
| Daytime hypertension | 54.8% | 38.3% | 53.8%** | 72.2%** , ## |
| Nighttime SBP(mm Hg) | 129 ± 23 | 121 ± 20 | 127 ± 22** | 138 ± 23** , ## |
| Nighttime DBP(mm Hg) | 76 ± 13 | 70 ± 11 | 75 ± 13** | 82 ± 13** , ## |
| Nighttime hypertension | 71.8% | 59.3% | 70%** | 85.8%** , ## |
| SBP nocturnal decline (%) | 6.3 (0.6‐11.2) | 7.8 (2.4‐12.0) | 6.9 (1.3‐11.8) | 4.4 (−2.2‐ 10.0)** , ## |
| DBP nocturnal decline (%) | 7.1 (1.3‐13.2) | 9.5 (4.1‐15.0) | 7.2 (1.6‐13.4)** | 4.1 (−1.8‐ 10.7)** , ## |
| Nondipping BP (%) | 59.3% | 52.3% | 56.7%* | 68.5%** , ## |
| Daytime pulse rate (bpm) | 78 ± 10 | 69.7 ± 6.5 | 77.3 ± 6.3** | 87.7 ± 8.1** , ## |
| Nighttime pulse rate (bpm) | 70 ± 12 | 58.2 ± 4.3 | 68.8 ± 2.8** | 83.1 ± 7.6** , ## |
| 24‐h pulse rate (bpm) | 77 ± 10 | 67.6 ± 5.8 | 75.7 ± 5.3** | 86.8 ± 7.6** , ## |
SBP, systolic blood pressure; DBP, diastolic blood pressure.
Indicates P < 0.05.
Indicates P < 0.01 when compared with tertile 1.
Indicates P < 0.05.
Indicates P < 0.01 when compared with tertile 2.
3.3. Regression analysis of the relationship between hypertension, TOD, and the different tertiles of nighttime average PR
By multivariate regression analysis (Table 3, model 1), higher PR was independently associated with clinical and 24‐hours hypertension and eGFR <60 mL/min/1.73 m2, with the exception of daytime average PR, which showed no association with nighttime hypertension. Only nighttime PR was associated with nondipping BP and LVH. PR was not independently associated with cIMT. In model 2, in which the significant PR associations in model 1 were added to the multivariate regression analysis, we found that nighttime PR was independently related to clinical hypertension and 24‐hours hypertension, LVH, and lower eGFR. The 24‐hours average PR was only related to lower eGFR (Table 3).
Table 3.
Multivariate logistic regression analysis: relationship between clinical hypertension, 24‐h hypertension, dipper BP, eGFR <60 mL/min/1.73 m2, LVH and cIMT with average PR in patients with CKD
| Variables | Multivariate regression analysis OR(95% CI) | |
|---|---|---|
| Model 1 | Model 2 | |
| Clinical BP (1 = normal BP, 2 = hypertension) | ||
| 24‐h average pulse rate (per bpm) | 1.019 (1.006‐1.032)* | 0.840 (0.642‐1.100) |
| Daytime average pulse rate (per bpm) | 1.018 (1.005‐1.030)* | 1.154 (0.923‐1.444) |
| Nighttime average pulse rate (per bpm) | 1.020 (1.008‐1.032)** | 1.021 (1.009‐1.033)** |
| 24‐h BP (1 = normal BP, 2 = hypertension) | ||
| 24‐h average pulse rate (per bpm) | 1.022 (1.008‐1.036)* | 0.881 (0.664‐1.169) |
| Daytime average pulse rate (per bpm) | 1.019 (1.006‐1.033)* | 1.099 (0.869‐1.390) |
| Nighttime average pulse rate (per bpm) | 1.025 (1.013‐1.038)** | 1.027 (1.014‐1.040)** |
| Daytime BP (1 = normal BP, 2 = hypertension) | ||
| 24‐h average pulse rate (per bpm) | 1.031 (1.017‐1.046)** | 0.962 (0.733‐1.263) |
| Daytime average pulse rate (per bpm) | 1.029 (1.015‐1.044)** | 1.024 (0.817‐1.282) |
| Nighttime average pulse rate (per bpm) | 1.033 (1.020‐1.047)** | 1.033 (1.019‐1.047)** |
| Nighttime BP (1 = normal BP, 2 = hypertension) | ||
| 24‐h average pulse rate (per bpm) | 1.017 (1.001‐1.033)* | 0.835 (0.619‐1.126) |
| Daytime average pulse rate (per bpm) | 1.015 (1.000‐1.030) | ‐ |
| Nighttime average pulse rate (per bpm) | 1.024 (1.009‐1.039)** | 1.050 (1.017‐1.084)** |
| Dipper state (1 = dipper BP, 2 = nondipping BP) | ||
| 24‐h average pulse rate (per bpm) | 0.997 (0.985 ‐ 1.009) | ‐ |
| Daytime average pulse rate (per bpm) | 0.994 (0.983 −1.006) | ‐ |
| Nighttime average pulse rate (per bpm) | 1.013 (1.002‐1.024)* | 1.013 (1.002‐1.024)* |
| Dependent variable: eGFR by EPI formula (1 = eGFR ≥60 mL/min/1.73 m2; 2 = eGFR <60 mL/min/1.73 m2) | ||
| 24‐h average pulse rate (per bpm) | 1.033 (1.013‐1.053)** | 0.935 (0.913‐0.957)** |
| Daytime average pulse rate (per bpm) | 1.027 (1.008‐1.046)** | 0.904 (0.673‐1.125) |
| Nighttime average pulse rate (per bpm) | 1.051 (1.032‐1.071)** | 1.132 (1.107‐1.158)** |
| Dependent variable: LVH (1 = no LVH; 2 = LVH) | ||
| 24‐h average pulse rate (per bpm) | 0.996 (0.977‐1.016) | ‐ |
| Daytime average pulse rate (per bpm) | 0.991 (0.971‐1.012) | ‐ |
| Nighttime average pulse rate (per bpm) | 1.044 (1.009‐1.080)* | 1.044 (1.009‐1.080)* |
| Dependent variable: cIMT (1 = cIMT≤1 mm; 2 = cIMT >1 mm) | ||
| 24‐h average pulse rate (per bpm) | 0.987 (0.963‐1.011) | ‐ |
| Daytime average pulse rate (per bpm) | 0.986 (0.962‐1.010) | ‐ |
| Nighttime average pulse rate (per bpm) | 0.992 (0.969‐1.015) | ‐ |
CI: confidence interval. ‐Pulse rate with no significant associations in model 1 was not included in model 2.
Model 1: Multivariate logistic regression analysis for the relationship between clinical hypertension, 24‐h hypertension, dipper BP, eGFR <60 mL/min/1.73 m2, LVH, abnormal cIMT, and daytime, nighttime, and 24‐h average PR, respectively. Variables for simple regression analysis of hypertension include age, sex (female = 0, male = 1), diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, and eGFR. Variables for simple regression analysis of dipper state include age, sex, diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, eGFR, and 24‐h hypertension. Variables for simple regression analysis of LVH and abnormal cIMT include age, sex, diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, eGFR, 24‐h SBP, and 24‐h DBP. Variables for simple regression analysis of eGFR include diabetes mellitus, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, 24‐h SBP, and 24‐h DBP. Model 2: All above variables and PRs with significant associations in model 1 were added to the multiple regression analysis.
Indicates P < 0.05.
Indicates P < 0.01.
In unadjusted regression analyses, compared to patients with nighttime PR <64 bpm, nighttime PR of 64‐74 bpm was associated with hypertension and LVH, while nighttime PR >74 bpm was associated with hypertension, lower eGFR, LVH, and nondipping BP. We then examined PR associations after adjusting for age, sex, DM, current smoking status, alcohol intake, BMI, hemoglobin, albumin, calcium, phosphate, serum fasting glucose, cholesterol, triglycerides, HDL‐C, LDL‐C, uric acid, proteinuria, and eGFR. Nighttime PR >74 bpm remained independently associated with hypertension, lower eGFR, LVH, and nondipping BP, while nighttime PR 64‐74 bpm was independently associated with only clinical and 24‐hours hypertension and lower eGFR (Table 4).
Table 4.
Univariate and multivariate logistic regression analyses: relationship between clinical hypertension, 24‐h hypertension, nondipping BP, eGFR <60 mL/min/1.73 m2, and LVH with different tertiles of average PR in patients with CKD
| Variables | Univariate regression analysis multivariate regression analysis | |
|---|---|---|
| OR (95% CI) | OR (95% CI) | |
| Clinical BP (1 = normal BP, 2 = hypertension) | ||
| T1 | Reference | Reference |
| T2 | 1.798 (1.392‐2.323)** | 1.393 (1.051‐1.848)** |
| T3 | 2.882 (2.199‐3.775)** | 1.787 (1.310‐2.438)** |
| 24‐h BP (1 = normal BP, 2 = hypertension) | ||
| T1 | Reference | Reference |
| T2 | 1.637 (1.271‐2.107)** | 1.467 (1.070‐2.009)* |
| T3 | 3.527 (2.673‐4.653)** | 2.706 (1.902‐3.849)** |
| Daytime BP (1 = normal BP, 2 = hypertension) | ||
| T1 | Reference | Reference |
| T2 | 1.877 (1.459‐2.415)** | 1.545 (1.118‐2.136)** |
| T3 | 4.191 (3.210‐5.473)** | 2.764 (1.925‐3.969)** |
| Nighttime BP (1 = normal BP, 2 = hypertension) | ||
| T1 | Reference | Reference |
| T2 | 1.604 (1.234‐2.084)** | 1.151 (0.823‐1.611) |
| T3 | 4.145 (3.044‐5.644)** | 1.799 (1.192‐2.761)** |
| Dipper state (1 = dipper BP, 2 = nondipping BP) | ||
| T1 | Reference | Reference |
| T2 | 1.235 (0.963‐1.585) | 1.022 (0.780‐1.338) |
| T3 | 2.039 (1.575‐2.640)** | 1.315 (1.002‐1.788)* |
| Dependent variable: eGFR by EPI formula (1 = eGFR ≥60 mL/min/1.73 m2; 2 = eGFR <60 mL/min/1.73 m2) | ||
| T1 | Reference | Reference |
| T2 | 2.115 (1.620 −2.762)** | 1.563 (1.056‐2.315)* |
| T3 | 5.915 (4.474‐7.822)** | 2.451 (1.575‐3.704)** |
| Dependent variable: LVH (1 = no LVH; 2 = LVH) | ||
| T1 | Reference | Reference |
| T2 | 1.532 (1.026‐2.287)** | 1.302 (0.822‐2.061) |
| T3 | 3.904 (2.685‐5.678)** | 2.267 (1.363‐3.770)** |
Variables for multivariate regression analysis of hypertension include age, sex, diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker (no = 0, yes = 1), α‐blocker (no = 0, yes = 1), hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, and eGFR. Variables for multivariate regression analysis of dipper state include age, sex, diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, eGFR, and 24‐h hypertension. Variables for multivariate regression analysis of LVH and abnormal cIMT include age, sex, diabetes mellitus, current smoker, alcohol intake, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, eGFR, 24‐h SBP, and 24‐h DBP. Variables for multivariate regression analysis of eGFR include diabetes mellitus, RAS blockade, calcium‐channel blocker, α‐blocker, hemoglobin, LDL‐C, calcium, phosphate, iPTH, 24‐h proteinuria, 24‐h SBP, and 24‐h DBP.
Indicates P < 0.05.
Indicates P < 0.01.
3.4. Propensity score‐matched analysis
Consistent with the above results, the group of individuals with the nighttime PR >74 bpm was significantly older, had higher values of phosphate and iPTH, had lower values of hemoglobin, and had a higher proportion of DM, proteinuria >3 g/24 h, and eGFR <60 mL/min/1.73 m2 compared with PR ≤74 bpm (Table 5). After 1:1 propensity score matching, a total of 966 matched patients, 483 in each group, were produced. There were no significant differences in age and the proportion of eGFR <60 mL/min/1.73 m2 (Table 5). PR ≤74 bpm group had a lower incidence of clinical hypertension, 24‐hypertension, daytime and nighttime hypertension, nondipping BP, and LVH than nighttime PR >74 bpm group (Table 6). After adjustment for diabetes mellitus, HGB, proteinuria, calcium, phosphate, iPTH, proteinuria >3 g/24 h, and calcium‐channel blocker, nighttime PR >74 bpm was still significantly associated with clinical hypertension, daytime and nighttime hypertension, and LVH (Table 6).
Table 5.
Baseline characteristics between PR ≤74 bpm and PR ˃74 bpm in the entire study population and in the matched population
| Variables | Overall population (n = 1506) | Propensity‐matched population (n = 483) | ||||
|---|---|---|---|---|---|---|
|
PR ≤74 bpm (N = 1006) |
PR ˃74 bpm (N = 503) |
P‐value |
PR ≤74 bpm (N = 483) |
PR ˃74 bpm (N = 483) |
P‐value | |
| Age (years) | 43.3 ± 16.2 | 47.2 ± 15.8 | <0.001 | 47.3 ± 15.7 | 47.4 ± 15.8 | 0.884 |
| Sex (M/F, %) | 59.1/40.9 | 56.9/43.1 | 0.396 | 58.6/41.4 | 56.9/43.1 | 0.648 |
| Current smoker, n (%) | 19.2% | 18.5% | 0.745 | 22.2% | 20.4% | 0.529 |
| Alcohol intake, n (%) | 8.5% | 9.7% | 0.444 | 8.1% | 10.9% | 0.153 |
| DM, n (%) | 14.3% | 24.2% | <0.001 | 18.2% | 26.3% | 0.010 |
| BMI (kg/m2) | 23.3 ± 3.9 | 23.0 ± 3.8 | 0.121 | 23.1 ± 3.6 | 23.0 ± 3.8 | 0.766 |
| Proteinuria >3 g/24 h | 29.2% | 38.0% | <0.001 | 26.3% | 39.3% | <0.001 |
| eGFR <60 (mL/min/1.73 m2) | 37.5% | 70.5% | <0.001 | 68.5% | 70.4% | 0.575 |
| Hemoglobin (G/L) | 118 ± 27 | 98 ± 28 | <0.001 | 106 ± 27 | 98 ± 28 | <0.001 |
| LDL‐C (mmol/L) | 3.7 ± 2.1 | 3.5 ± 2.0 | 0.126 | 3.4 ± 1.8 | 3.5 ± 2.0 | 0.677 |
| Total calcium level (mmol/L) | 2.2 ± 0.2 | 2.1 ± 0.3 | <0.001 | 2.2 ± 0.2 | 2.1 ± 0.3 | <0.001 |
| Phosphate level (mmol/L) | 1.4 ± 0.4 | 1.7 ± 0.6 | <0.001 | 1.5 ± 0.5 | 1.7 ± 0.6 | <0.001 |
| iPTH (pg/mL) | 63.5 (35.4‐176.3) | 174.5 (59.8‐397.0) | <0.001 | 127.8 (58.0‐294.5) | 174.4 (59.8‐397.0) | 0.013 |
| RAS blockade | 623 (61.9%) | 248 (49.3%) | <0.001 | 267 (55.3%) | 243 (50.3%) | 0.138 |
| Calcium‐channel blocker | 267 (26.5%) | 231 (45.9%) | <0.001 | 182 (37.7%) | 220 (45.5%) | 0.016 |
| α‐blocker | 62 (6.1%) | 48 (9.5%) | 0.188 | 35 (7.2%) | 44 (9.1%) | 0.348 |
BMI, body mass index; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; LDL‐C, low‐density lipoprotein cholesterol; iPTH, intact parathyroid hormone; RAS blockade, renin‐angiotensin system blockade.
Table 6.
Univariate and multivariate logistic regression analyses: relationship between clinical hypertension, 24‐h hypertension, nondipping BP, eGFR <60 mL/min/1.73 m2, LVH, and nighttime PR in the propensity score‐matched cohort
| Variables |
PR ≤74 bpm (N = 483) |
PR ˃74 bpm (N = 483) |
Unadjusted HR (95% CI) | Adjusted HR (95% CI) |
|---|---|---|---|---|
| Clinical hypertension | 316 (65.4%) | 357 (73.9%) | 1.215 (1.069‐1.238)** | 1.258 (1.011‐1.844)* |
| 24‐h hypertension | 334 (69.2%) | 381 (78.9%) | 1.267 (1.114‐1.442)** | 1.563 (1.137‐2.148)** |
| Daytime hypertension | 280 (60.0%) | 351 (72.7%) | 1.366 (1.208‐1.544)** | 1.579 (1.117‐2.130)** |
| Nighttime hypertension | 377 (78.1%) | 415 (85.9%) | 1.280 (1.13‐1.472)** | 1.512 (1.029‐2.220)* |
| Nondipping BP | 285 (59.0%) | 327 (68.3%) | 1.395 (1.073‐1.813)* | 1.294 (0.965‐1.737) |
| LVH | 293 (60.7%) | 328 (67.9%) | 1.226 (1.034‐1.454)* | 1.452 (1.006‐2.096)* |
LVH: left ventricular hypertrophy.
Adjustment for diabetes mellitus, calcium‐channel blocker, hemoglobin, calcium, phosphate, iPTH, proteinuria >3 g/24 h, and 24‐h hypertension were additional adjusted in LVH.
Indicates P < 0.05.
Indicates P < 0.01.
4. DISCUSSION
In the present cross‐sectional study with patients with CKD, we investigated the role of nighttime PR in BP and TOD. We found that 24‐hours average PR, daytime average PR, and nighttime PR were all correlated with BP and TOD, while only nighttime PR was an independent risk factor for clinical BP, 24‐hours BP, BP dipping state, poor renal function, and LVH. In addition, by further analysis we found that in tertile 2 patients (nighttime PR 64‐74 bpm), nocturnal PR was independently associated with clinical and 24‐hours hypertension and lower eGFR (eGFR <60 mL/min/1.73 m2) when compared with tertile 1 patients (nighttime PR <64 bpm), while in tertile 3 patients (nighttime PR >74 bpm), nocturnal PR was independently associated with clinical hypertension, 24‐hours hypertension, day and night hypertension, nondipping BP, and lower eGFR (eGFR <60 mL/min/1.73 m2). After 1:1 propensity score matching, nighttime PR >74 bpm remained independently associated with clinical hypertension, daytime and nighttime hypertension, and LVH. All these results suggest that nighttime PR, rather than 24‐hours average PR or daytime average PR, was better associated with hypertension, nondipping BP, and TOD in patients with CKD. We therefore conclude that in the present study, among the ambulatory HR measurements, nighttime PR showed a better predictive value than daytime HR.
Only a few studies have reported on the relationship between PR or BP and CV disease.4, 5, 25, 26 Beddhu et al6 classified patients with CKD into four groups according to resting HR and compared their survival rates. In a multivariate Cox model adjusted for demographics, comorbidity, hemoglobin, and physical activity, these authors found that compared to the 60‐74 bpm group, the hazard ratios of CV composites in the <60, 75 ‐ 89, and ≥90 bpm groups were associated with increased mortality and possible CV events. To our knowledge, our study is the first to investigate the association between nighttime PR, BP, and TOD in a population with CKD.
The better predictive power of nighttime HR compared with daytime HR or 24‐hours HR found in the present study parallels our previous data on ambulatory BP, which showed a stronger association of nighttime BP than daytime or 24‐hours BP with TOD and prognosis in patients with CKD. 16, 17 Our findings are also in keeping with previous data showing that high nighttime HR measured by ambulatory BP monitoring devices but not daytime HR was associated with increased non‐CV mortality in the Japanese general population.12 This study also suggested that the lowest tertile (nighttime PR <64 bpm) was associated with lower BP and less TOD compared with the highest tertile (nighttime PR ≥74 bpm) in patients with CKD. In a (RHR) prospective Kailuan cohort study, the highest rest HR quartile (RHR ≥78 bpm) had a 16% greater risk of hypertension compared to the lowest quartile (RHR ≤66 bpm).27 Another cross‐sectional study showed that elevated nocturnal HR ≥65 bpm obtained from an ABPM registry was associated with the presence of TOD in hypertensive patients.13 Our study is highly consistent with these previous studies.
The exact mechanism underlying the above associations has not been fully elucidated. A direct link between elevated HR and CV disease may involve hemodynamic stress, which causes atherosclerotic lesions and may be an underlying factor in CV events.28 Another possible reason is that elevated HR decreases diastolic time in each heart cycle, which may influence cardiac oxygenation and nourishment.9 Furthermore, elevated HR increases cardiac output and therefore increases BP. Elevated HR also may represent sympathetic overactivation.29 Previous study used standard deviation of normal‐to‐normal RR intervals (SDNN) of HRV as a measure of cardiac sympathetic overdrive.30, 31 CKD resulted in sympathetic overactivation (reduced HRV).30 Sympathetic overactivation increases vasoconstriction of resistance vessels through adrenergic stimulation, resulting in increased BP.32 Chronic elevated HR causes sustained pulsatile stress on the arterial wall, leading to increased arterial stiffening and hypertension.9 Finally, sympathetic overactivation leads to increased insulin resistance via adrenergic stimulation resulting in a cascade of CV risk factors, atherosclerosis, and elevated BP.32
Office HR is correlated with the hemodynamic reaction elicited by the doctor's visit reflecting sympathetic nervous system reactivity and is thus poorly representative of the basal HR33 Persistent sympathetic overactivity may be better represented by an elevated sleeping HR than by office HR34 HR during sleep is more representative of the overall hemodynamic load on the arteries and the heart. Thus, a high sleeping HR would better reflect cumulative arterial injury from mechanical stress on the arterial wall. In the present study, we found strong correlations of nighttime HR with BP, which may be explained by a high sympathetic tone underlying elevated HR High sleep HR may also reflect episodes of sleep apnea that are associated with an increase in sympathetic drive.35
The main strength of our study has been to clarify the relationship between 24‐hours PR, daytime PR, nocturnal PR, TOD, and BP. The European Society of Hypertension guidelines of 2013 have recommended measuring RHR when CV risk in hypertensive patients and patients with high‐normal BP is assessed.36 Our results strengthen this recommendation and show that elevated nighttime PR plays a role in predicting arterial hypertension and TOD. Potential limitations of our study should also be mentioned. First, because we did not use actigraphy, the values of awake/sleep BP and PR may not have been entirely precise. Therefore, prospective studies from different populations are necessary to describe more accurately the longitudinal relationship between resting PR, arterial hypertension, and TOD. Second, we excluded patients with atrial fibrillation, frequent ventricular premature beats, and other serious ventricular arrhythmias. PR measured by oscillometric device is still not as accurate as HR measured by electrocardiogram in patients with CKD. However, in contrast to the electrocardiogram, recording of pulse wave requires only single sensor, which allows for development of devices that can be used every day in daily life. Furthermore, PR measured by oscillometric device is widely used in local practice and has been employed in large epidemiological surveys, based on the recommendations from experts.37 Third, although we excluded some patients who take some medications may affect PR, the diurnal pattern of PR and BP might have been affected by other antihypertensive medications. However, we obtained the same results after adjusted the patients taking RAS blockade, calcium‐channel blocker, or α‐blocker. Finally, the cross‐sectional design in this study was unable to determine a causal relationship between PR and BP levels and TOD. Therefore, further multicenter, larger‐sample follow‐up studies are necessary to explore the relationship between nighttime PR and BP level and TOD.
In summary, our findings demonstrated that nighttime PR but not the 24‐hours or daytime rate was associated with an increase in BP and TOD in patients with CKD. We should therefore pay special attention to nighttime PR, which should be maintained at less than 75 bpm or even below 64 bpm in patients with CKD as standard clinical practice. Nighttime PR should be routinely examined in all patients with CKD.
CONFLICT OF INTEREST
No conflict of interests, financial or otherwise, are declared by the authors.
ACKNOWLEDGMENTS
We would like to thank all patients and their families for participating in this study.
Zhang J, Wen R, Yin J, et al. Nocturnal pulse rate correlated with ambulatory blood pressure and target organ damage in patients with chronic kidney disease. J Clin Hypertens. 2019;21:77–87. 10.1111/jch.13438
Jun Zhang and Ruowei Wen contributed equally to this work.
Funding information
This work was supported by “the project of cultivating young teachers in Sun Yat‐sen University” (No. 17kypy56).
Contributor Information
Hui Peng, Email: pengh@mail.sysu.edu.cn.
Cheng Wang, Email: wt770716@163.com.
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