Nocturnal blood pressure surge in seconds is a new determinant of left ventricular mass index

Abstract Nocturnal blood pressure (BP) surge in seconds (sec‐surge), which is characterized as acute transient BP elevation over several tens of seconds, could be a predictor of target organ damage. However, it is not clear that the severity of sec‐surge is different between sec‐surges induced by sleep apnea (SA) (apnea/hypopnea detected by polysomnography (PSG) or oxygen desaturation) and those induced by non‐SA factors (rapid eye movement, micro arousal, etc.), and sec‐surge variables associate with left ventricular hypertrophy (LVH) independently of conventional BP variables. The authors assessed these points with 41 patients (mean age 63.2±12.6 years, 29% female) who underwent full PSG, beat‐by‐beat (BbB) BP, and cuff‐oscillometric BP measurement during the night. All patients were included for the analysis comparing sec‐surge severity between inducing factors (SA and non‐SA factors). There were no significant differences in the number of sec‐surges/night between SA‐related sec‐surges and non‐SA‐related sec‐surges (19.5±26.0 vs. 16.4±29.8 events/night). There were also no significant differences in the peak of sec‐surges, defined as the maximum systolic BPs (SBPs) in each sec‐surge, between SA‐related sec‐surges and non‐SA‐related sec‐surges (148.2±18.5 vs. 149.3±19.2 mm Hg). Furthermore, as a result of multiple regression analysis (n = 18), the peak of sec‐surge was significantly and strongly associated with the left ventricular mass index (standardized β = 0.62, p = .02), compared with the mean nocturnal SBPs measured by oscillometric method (β = −0.04, p = .87). This study suggests that peak of sec‐surge could be a better predictor of LVH compared to parameters derived from regular nocturnal oscillometric SBP.


INTRODUCTION
Management of nocturnal blood pressure (BP) is one of the important issue for preventing the progress of hypertensive target organ damage (TOD) and the onset of cardiovascular disease. [1][2][3] Recent studies have demonstrated that the nocturnal BP measured by ambulatory BP monitoring (ABPM) is a stronger predictor of cardiovascular events (CVE) than daytime BP. [4][5][6][7][8][9] Although ABPM has been the gold standard for assessing nocturnal BP, nocturnal BP measured by home BP monitoring (HBPM) also has high risk of future CVE [10][11][12][13][14] and correlates with TOD as with ABPM. 15 A new wrist-type nocturnal HBPM device that automatically measures BP in the supine position without reducing sleep quality has been developed, and it could be used to facilitate real-world sleeping studies. 16,17 In addition, the concern of an association between short-term BP variability (BPV) and cardiovascular disease has been growing. 18 Nocturnal BPV, defined as the standard deviation (SD) of nocturnal BP measured by ABPM, is associated with risks of CVE. 19 It is assumed that some pathological factors such as obstructive sleep apnea (SA), rapid eye movement (REM) sleep, and microarousal increase nocturnal BPV. [20][21][22] In particular, obstructive SA (OSA) has demonstrated a critical impact on nocturnal BP level and BPV. 23 We have developed an oxygen-triggered BP monitor and demonstrated that the maximum value of systolic BP (SBP) measured by the oxygentrigger function is higher than mean nocturnal SBP measured by the intermittent oscillometric method. [24][25][26][27][28] However, as this BP monitor is based on the oscillometric method, the peak of short-term BPV might be underestimated.
Consequently, we developed a continuous Beat-by-Beat (BbB) BP monitoring device using a tonometry method to detect the peak of the short-term BPV in detail 29 . Using this device, we have already observed "BP surge in seconds (sec-surge)", which characterized as an acute transient BP elevation over several tens of seconds in OSA patients. 2,30 We have developed the tools for studies on secsurges such as the device and an automatic sec-surge detection algorithm from BbB BP recordings overnight. 31,32 However, it is not clear whether the severity of sec-surge is different between sec-surges induced by SA (apnea/hypopnea detected by polysomnography (PSG) or oxygen desaturation) and those induced by non-SA factors (sympathetic nerve activity such as REM sleep, micro arousal), and the CVE risks of sec-surges.
Thus, this study aimed to assess the severity of the sec-surge between inducing factors and to assess the association between left ventricular hypertrophy (LVH) and sec-surge measured in a sleep laboratory setting.

Study design and patients
In total, 48 outpatients were recruited for this study at the Washiya Hospital, Tochigi, Japan, from July, 2017 to February, 2019. Patients who met at least one of the following criteria were temporarily registered: (1) hypertensive patients, and (2) patients who had subjective symptoms of sleep apnea syndrome. Next, patients whose mean nocturnal SBP was ≥120 mm Hg, measured by ABPM or using a home BP monitor measuring BP automatically and intermittently, before 1 month of formal registration for the study were enrolled in this study.

Development of beat-by-beat BP monitoring device
In the present study, overnight BbB BP was recorded by using the BbB BP monitoring device, based on the tonometry method 34 we recently developed. Figure 1(A) shows a block diagram of the device. Pulse wave signals were obtained by 46 sensors in the "tonometry sensor unit 35 " (the appearance is shown in Figure 1(B)) directly placed on the skin above a radial artery, and were transmitted to the processor. Meanwhile, BP for calibration was measured when the "cuff-oscillometric BP measurement unit" received a triggering signal from the "calibration control" function in the processor. The timing of calibration was automatically judged by the function when contact between the tonometry sensor and the skin was significantly changed due to body motion.
Once the processor received BP for calibration, the "calculation of calibrated BbB BP" function transforms an amplitude of pulse wave were maintained as (a). By selecting the active sensor automatically at each moment, the device could continuously monitor BbB BP without BP calibration, even though the contact between the tonometry sensor and the skin was slightly changed. F I G U R E 2 Definition of nocturnal blood pressure surge in seconds (sec-surge) variables. BbB indicates beat-by-beat; SBP, systolic blood pressure; and DBP, diastolic blood pressure

Definition of oscillometric BP variables
The office BP of the study patients was measured when they were recruited into this study. Conventional nocturnal BPs were measured using the arm-cuff-oscillometric BP monitor (HEM-7220; Omron Healthcare Co., Ltd), which measures both intermittent BPs (30 min intervals) and oxygen-triggered BPs. Oxygen-triggered BPs were measured when the oxygen saturation (continuously monitored by pulse oximetry) falls below a variable threshold. [24][25][26][27] For further details of the definition of oscillometric BP variables, see Expanded Methods in the data supplement.

Definition of nocturnal beat-by-beat blood pressure surge in seconds (sec-surge)
The sec-surges were detected from overnight BbB BP recordings by an automatic sec-surge detection algorithm 32  We defined the sec-surge feature as shown in Figure 2. All sec-surge variables were calculated from the BbB SBPs between the start and end points of sec-surges (duration of sec-surge). The peak, start, and end point of the sec-surge were detected by the above-mentioned algorithm. The threshold of the amplitude of sec-surge (difference between the peak SBP and the start SBP) was ≥20 mm Hg. The peak point was detected as the local maximum of BbB SBPs by using a sliding window. The start point was detected as the final point during stable BbB SBPs in backward-searching ranges set before the peak point. The end point was detected as the point that SBP decreased by 75% of the amplitude of sec-surge. We defined the duration from start to peak as upward duration and from peak to end as downward duration. The  Non-REM2, % 57.1 ± 11.7 64.1 ± 9.0 52.1 ± 10.9 * 60.7 ± 11.9 SWS, % 6.1 ± 7.5 6.8 ± 7.7 5.7 ± 7.5 6.7 ± 7.1 Data are expressed as mean ± SD or frequency and percentage. Abbreviations: AHI, apnea hypopnea index; SpO2, oxygen saturation; REM, rapid eye movement; SWS, slow wave sleep. *P < 0.05 versus patients with non-severe obstructive sleep apnea (AHI < 30) using t-test.
percentile of BbB SBP (instead of the maximum value) to avoid noises.
The mean and maximum value of cuff-oscillometric BPs used for BbB BP calibration (it was different from the abovementioned conventional nocturnal BP variables) were also calculated.

RESULTS
The clinical characteristics of the study patients are shown in Table 1. In the analysis of the difference in sec-surge severity between sec-surges induced by SA (apnea or hypopnea) and those induced by non-SA A typical case of sec-surges is shown in Figure S4. Three sec-surges were induced repeatedly, and the peak of sec-surge reached almost 200 mm Hg from the baseline of 150 mm Hg. The distribution of the number of sec-surges per patient is shown in Figure S5. In the analysis of associations between sec-surges and LVH, the mean ± SD of LVMI in 18 patients who had LVM data was 68.9 ± 13.2 g/m 2 , and nonsevere LVH.

Comparison of sec-surge features between inducing factors
There was no significant difference in the peak of sec-surges between SA-related sec-surges and non-SA-related sec-surges in the whole sleep period (148.2±18.5 vs. 149.3±19.2 mm Hg) and each sleep stage (Table 2). Similarly, there were no significant differences in the num-

Association between nocturnal BP variables and LVH
The BP measurements and correlations between LVMI and each BP variable were shown in Table 4. The mean nocturnal SBP measured using the oscillometric method and the mean nocturnal BbB SBP were almost comparable, and were distributed around the threshold for sleep SBP (120 mm Hg). 36,37 The mean of the oscillometric SBP for BbB BP calibration, the maximum of that, and the mean of nocturnal BbB SBP were significantly and strongly correlated with LVMI (r = 0.614,  Table S1. Although the peak of sec-surge strongly correlated with the mean of nocturnal BbB SBPs (r = 0.916, p < .01, n = 41), there was no multicollinearity between the peak of sec-surge and other conventional BP variables.

DISCUSSION
This study was the first to assess the nocturnal sec-surge quantitatively using a BbB BP monitoring device based on the tonometry method in TA B L E 4 Simple Pearson's correlations between LVMI and blood pressure variables in study patients for analyzing the association between sec-surges and LVH (n = 18) Data are expressed as mean ± SD. Abbreviations: LVMI, left ventricular mass index; sec-surge, surge blood pressure in seconds; SBP, systolic blood pressure; DBP, diastolic blood pressure; SD, standard deviation; CV, coefficient of variation. a Oxygen desaturation was not detected by an oxygen-triggered BP monitor in six patients. b Each sec-surge variable was taken as an average of sec-surges during the night.

BP variables
patients with OSA. The high BP value caused by sec-surge was missed by conventional cuff-oscillometric intermittent measurement (peak of sec-surge measured by BbB BP monitoring device was 148.2 mm Hg and mean of nocturnal SBP measured by cuff-oscillometric BP device was 127.2 mm Hg). Moreover, our results showed that the peak of secsurge was significantly and strongly associated with LVMI compared with the mean or SD of nocturnal SBP. Furthermore, no significant difference in the severity of sec-surge was found between sec-surges induced by SA (apnea or hypopnea) and those induced by non-SA factors (sympathetic nerve activity). These findings imply that the peak of sec-surge is a better predictor of LVH than conventional BP parameters regardless of inducing factors of sec-surges. Assessing sec-surges could be important for nocturnal BP management.
The peak of sec-surge was ≥ 20 mm Hg higher than the mean of nocturnal SBP measured using the conventional oscillometric method.
The intermittent BP measurement was insufficient to assess the risk of BP elevation. Whereas, the hypoxia-peak SBP (the maximum value of SBP in the night measured by the oxygen-triggered function) was 147.6 mm Hg and comparable with the peak of sec-surge detected using the BbB BP monitor. However, the oxygen-triggered BP monitor does not always detect the peak of BP elevation 38 because the BP monitor takes three BP measurements based on the cuff-oscillometric method at 15-second intervals after the pulse oximeter senses oxygen desaturation. 25 Almeneessier and coworkers have assessed and estimated BbB BPs from pulse transit time (PTT) using electrocardiography (ECG) and finger photoplethysmography in each section before, during, and after OSA events in a sleep setting. 39 The estimated SBP increased by ∼4 mm Hg in non-REM and ∼7 mm Hg in REM after OSA events compared with SBP before OSA events. Although this increase may indicate the amplitude of sec-surge (peak SBP-start SBP) in this study, it might be underestimated compared with that (25.8 mm Hg) calculated from calibrated BbB SBPs. The accuracy of the estimated SBP and DBP using PTT is affected by arterial elasticity and preejection period (the time interval between QRS on ECG and the beginning of ventricular ejection). 30,40 Especially, PTT calculated at a finger might affect the property of the artery more. Moreover, although we identified the peak and start points of sec-surges using the algorithm 32 for calculating the amplitude, they did not detect them accurately. At present, the method for assessing the peak of sec-surge overnight is only using the BbB BP measurement method based on the tonometry technology and the automatic sec-surge detection algorithm.
The peak of sec-surge was strongly associated with LVMI independently of conventional mean nocturnal SBP measured using the oscillometric method every 30 min in the present study. To the best of our knowledge, no study has demonstrated the association between LVH and sec-surges. Palatini and coworkers have demonstrated that general nocturnal BPV, defined as the SD of BP measured by ABPM every 15 or 30 min, is associated with the risk of CVEs using 7112 hypertensive patients in a prospective study. 19 In this study, the contribution to LVMI was stronger in the peak of sec-surges than the SD of nocturnal SBPs. In addition, no correlations were found between sec-surge variables and SD, CV, and ARV of nocturnal SBPs measured using the cuff-oscillometric method (Table S1). We are now proposing the "res-onance hypothesis of BPV 31 ". BPV is induced in different time phases (yearly, seasonal, day-by-day, diurnal, and BbB is significantly associated with LVMI (r = 0.18; p < .001; n = 2563) in outpatients with one or more cardiovascular risks enrolled at multiple centers. 44 The strength of the association between LVMI and the mean nocturnal SBP in this study conform to the results of the J-HOP study.
Furthermore, our results showed that the hypoxia-peak SBP measured using an oxygen-triggered BP monitor was significantly associated with LVMI (r = 0.602; p = .038; n = 12). However, the BP monitor only detects the sec-surges induced by SA, and oxygen desaturation was actually not detected by the BP monitor in six out of 18 patients.
Surprisingly, no significant differences in the severity of secsurges (number, peak, and amplitude) were found between SA-related sec-surges induced by apnea/hypopnea or oxygen desaturation and non-SA-related sec-surges induced by sympathetic nerve activity in patients with OSA. It is known that baroreceptor reflex sensitivity is depressed in patients with OSA. 45 It is assumed that frequent non-SA-related sec-surges were induced by sympathetic nerve acti- (JENTOW-7700, Nihon Colin, Japan) was −0.3 ± 4.7 mm Hg in SBP, and 0.7 ± 3.4 mm Hg in DBP, respectively. 29 The study has been conducted in a controlled laboratory setting and evaluated BbB BPs measured in both stable state and BP elevation state induced by the Valsalva maneuver. In the present sleep setting study, although biological BP changing or pressure signal reduction due to contact state changing between the sensor and skin might be occurred, our BP monitoring device can be recalibrated for robust measurement when BP significantly changing from the previous calibration BP.

CONCLUSIONS AND PERSPECTIVES
The peak of sec-surge measured using the BbB BP monitoring device was strongly associated with LVH and was better predictor of LVH than conventional nocturnal BP variables. Furthermore, there were no significant differences in the peak, amplitude, and number of secsurges between sec-surges induced by SA (apnea or hypopnea) and