Kosin Medical Journal 2020;35:89-100. https://doi.org/10.7180/kmj.2020.35.2.89

Effects of White-coat on Heart Rate Recovery and Response during Exercise Test

Sol Jin 1, Jung Ho Heo 2, Bong Jun Kim 2

1Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea 2Department of Cardiology, Kosin University College of Medicine, Busan, Korea

Objectives : White-coat hypertension is defined as high blood pressure (BP) on clinical assessment but normal BP elsewhere or on ambulatory measurement. Autonomic dysfunction may be one of the mechanisms causing white-coat hypertension. Slowed heart rate recovery and excessive BP response during exercise test are associated with autonomic dysfunction. The purpose of this study was to determine the association between white-coat hypertension and abnormal autonomic nervous system response. Methods : We assessed 295 patients stratified into three groups via 24hr ambulatory BP monitoring, following 2017 ACC/AHA guidelines : normal BP group, white-coat hypertension group, and a hypertension group. We analyzed medical history, blood test, echocardiography, 24hr ambulatory BP monitoring, and exercise test data. Results : There was no difference in basement characteristics and echocardiography among the groups. Blunted heart rate recovery of each group showed a significant difference. Control group had 0% blunted heart rate recovery, but 33.3% in white coat group and 27.6% in true hypertension group ( P < 0.001). Also, in the control group, 4.5% showed excessive BP response, but 31.5% in the white coat hypertension group and 29.3% in the true hypertension group ( P < 0.001). Ex - cessive BP response during the exercise test or blunted heart rate recovery, which is an indicator of autonomic nervous system abnormality, was more common in the hypertensive group and white-coat hypertension group than in the normal BP group. Conclusions : These results confirmed that white-coat hypertension has an autonomic nervous system risk. Therefore, white-coat hypertension can be a future cardiovascular risk factor.

Key Words : Autonomic dysfunction, Exercise test, White-coat hypertension

Hypertension is one of the most common dis - , which accounts for several eases that affects about 30% of the population deaths in Korean adults. 2 over the age of 30 years in Korea. 1 The preven - Patients with normal blood pressure (BP) dur - tion, diagnosis, and management of hyperten - ing rest may occasionally stop testing their BP sion is very important because it is closely level due to excessive elevation in systolic BP related to cerebrovascular disease and cardio - (SBP) during exercise testing. One of the under -

Corresponding Author : Jung Ho Heo, Department of Cardiology, Kosin University College of Medicine, 262, Receive d: Apr . 03, 2020 Gamcheon-ro, Seo-gu, Busan 49267, Korea Revise d: May. 28, 2020 Tel: +82-51-990-6460 Fax: +82-51-990-3049 E-mail: [email protected] Accepted : Ju n. 26, 2020

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lying mechanisms of the hypertensive response trol study. We retrospectively reviewed 295 pa - to exercise is the increase in the sympathetic re - tients who underwent Treadmill test and 24-hour sponse. 3 Increased sympathetic activity is known ambulatory BP monitoring (ABPM) between to be one of the mechanisms underlying the ex - January 2008 and February 2015. Inclusion cri - aggerated BP response to exercise (EBPR). 4 teria were: 18–80 years of age, normal renal EBPR is associated with a higher rate of hyper - function, and for women to be on a regular men - tension than normal, and is associated with in - strual cycle. Exclusion criteria were: any sys - creased cardiovascular mortality. 5 The risk of temic disease such as significant liver disease, hypertension can be confirmed through the exer - neurologic disorders or malignant disease, or cise test. 6 In addition, exercise capacity and heart . rate recovery (HRR) were significant predictive Patients were classified according to the ABPM, factors of the relative risk of death. 7 Measure - following diagnostic criteria suggested by the ment of HRR is a simple non-invasive procedure 2017 ACC/AHA guidelines. 13 Hypertension analyzing the autonomic nervous dysfunction. 8,9 group was meeting one or more of these criteria; An earlier study showed that a blunted HRR, a 24-hour mean of 125/75 mmHg or above, day - which is defined as a decrease in heart rate (HR) time (awake) mean of 130/80 mmHg or above or of less than 12 beats/min from peak exercise to Nighttime (asleep) mean of 110/65 mmHg or 1 min into recovery, is a powerful predictor of above. White coat hypertension is defined as overall mortality. 7,10 having elevated clinic blood pressure, at or above White-coat hypertension is defined as high BP on threshold for hypertension without elevated out- clinical assessment but normal BP elsewhere or on of-office blood pressure, below threshold for hy - ambulatory measurement. In this case, ambulatory pertension. Patients not included in the two BP monitoring and home BP monitoring are rec - groups were classified as normotensive control. ommended. 11 Autonomic dysfunction may be one After all, patients were classified as 174 patients of mechanisms causing white-coat hypertension. 12 with true hypertension, 54 patients with white- Its association with HRR and EBPR in white-coat coat hypertension, and 67 normotensive controls hypertension patients has not been well studied. were included. We aimed to investigate the association between Demographic characteristics recorded at the HRR and EBPR in patients with white-coat hy - first visit included age, sex, height, weight, cur - pertension. rent medications, smoking history, and other co - morbidities. Blood was drawn for the measurement of total serum , high- MATERIALS AND METHODS density lipoprotein (HDL), low-density lipopro - tein (LDL) cholesterol, triglycerides, blood This is a cross-sectional, single center, case con - glucose, creatinine, uric acid, and high sensitivity

90 Effects of white-coat hypertension on HRR and EBPR

C-reactive protein (Hs-CRP). Body mass index with standard deviation (SD). (BMI) was calculated as the ratio of weight in kilograms to height in square meters. This study - Treadmill test was approved by the Kosin University Interna - All patients underwent symptom-limited exer - tional Review Board. cise stress testing (GE CASE T2100; GE Med - ical Systems, Milwaukee, WI, USA) according - BP measurement and 24-h ambulatory BP to the protocol by Bruce et al.. 14 BP was meas - monitoring ured using an automated BP monitor (Suntech Office BP measurements were performed twice Tango; Suntech Medical, Morrisville, NC, USA) at 5-min intervals using a mercury sphygmo - throughout the treadmill test using the same arm manometer. Noninvasive 24-h ABPM was per - as was used to measure the resting BP. Twelve- formed on each patient’s non-dominant arm lead electrocardiography was monitored contin - using an automatic oscillometric device (TONO - uously and printed at a paper speed of 25 mm/s; PORT V, PAR Medizintechnik, Berlin, Germany) measurements of HR and BP were recorded at on a normal working day. Patients were asked to the end of each 3-min stage at peak exercise and at refrain from performing fast exercises. All sub - 1-min and 2-min intervals throughout recovery. jects were instructed to rest or sleep between Treadmill test was continued until the partici - 10:00 PM and 7:00 AM (nighttime) and continue pants felt intolerable fatigue or their HR ex - their usual activities between 7:00 AM and 10:00 ceeded 95% of estimated maximal HR (220 bpm, PM (daytime). The accuracy of the device was age). The total exercise time was also recorded. checked against the standard auscultatory EBPR was defined as the peak exercise SBP of method of measuring BP to ensure that the dif - ≥ 210 mmHg in men and ≥ 190 mmHg in ference in BP measurements between methods women. 15 Functional capacity was estimated in did not exceed 5 mmHg. The device was set to metabolic equivalents (METs) on the basis of obtain BP readings at 20-min intervals during the speed and grade of the treadmill. 16 During the re - daytime and at 40-min intervals during the night - covery phase, the subjects continued to walk for time. Only 24-h recordings that included at least 60s at a speed of 1.5 mph, and then they sat down 80% successful recordings were accepted as for 3min with continued monitoring of BP, HR, valid. Each ABPM dataset was first automati - and heart rhythm. HRR was defined as peak cally scanned to remove artifactual readings ac - heart rate minus heart rate after a 1-min recovery; cording to preselected editing criteria. The abnormal HRR was defined as ≤ 12 beats/min. 17 following ABPM parameters were evaluated: 24- h mean SBP and diastolic BP (DBP) levels, day - - Echocardiographic measurement time mean SBP and DBP levels, nighttime mean Standard 2-dimensional echocardiography was SBP and DBP levels, and BP variability assessed performed on all subjects lying in the left lateral

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decubitus position using a 3.5-MHz transducer From January 2008 to February 2015, 295 pa - (Philips iE33, Philips Medical Systems, Bothell, tients were enrolled in this study. Patients were WA, USA) and the echocardiography examiners divided into control, white-coat hypertension, and were blinded to patient information. Measure - true hypertension groups. ments of thickness of the interventricular septum At baseline, compared to the normotensive con - and posterior wall, diameter of the left ventricle trol group, the white-coat hypertension group (LV) cavity, and the LV mass index (LVMI) were showed higher BMI, SBP, and DBP. BMI was performed according to criteria outlined by the lowest in the control group at 23.2 kg/m2 and American Society of Echocardiography. 18 Pulsed highest at 24.9 kg/m 2 in the true hypertension wave Doppler of transmitral LV inflow was per - group ( P = 0.001). SBP/DBP was lowest in the formed in the apical four-chamber view with the control group and highest in the white-coat group sample volume placed at the level of the mitral (P < 0.001). There was no difference in age, sex, valve tips; doppler variables were analyzed dur - heart rate, current smoking, diabetes, and dyslipi - ing three consecutive beats. The following meas - demia among the groups (Table 1). urements of global LV diastolic function were There was no statistically significant difference determined: peak early (E) and late (A) diastolic in medical history with regard to aspirin, RAS mitral flow velocity, E/A ratio, and early (Ea) di - blocker, calcium channel blocker, diuretics, beta astolic mitral annular velocity. blocker, and statin intake.

- Statistical analysis 2. Laboratory test Statistical analyses were performed using the com - In laboratory data, uric acid, eGFR, Hs-CRP, mercially available computer program SPSS 18.0 WBC, and Platelet levels were similar between for Windows (IBM, Chicago, IL, USA). Data are the groups. Mean total cholesterol, LDL choles - presented as mean ± standard deviation for contin - terol, HDL cholesterol, and triglycerides were the uous variables and percentage (%) if the data are cat - highest in the true hypertension group, but the dif - egorical. The Mann–Whitney U test was used for ference was not significant. continuous variables and the Chi-square test was used for categorical data. The normality of data was 3. 24-h ambulatory HR & BP monitoring tested using the Kolmogorov–Smirnov test. For all 24-h ambulatory BP monitoring was done. As a tests, the significance level was set to P < 0.05. result, 24-h heart rate and daytime and night time heart rate were higher in the true hypertensive group than in the control and white hypertensive RESULTS groups ( P = 0.001). Additionally, the 24-hour sys - tolic blood pressure/diastolic blood pressure was 1. Characteristics & Medical history 142/91 in the true hypertension group, but 119/75

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Table 1. Baseline characteristics

SBP : systolic blood pressure, DBP : diastolic blood pressure, RAS : renin angiotensin system, CCB : calcium channel blocker

and 122/75 in the control and white-coat hyper - and compared according to hypertension type. tension groups respectively. This represents a sig - Ejection fraction (EF), diastolic left ventricular nificant difference in BP ( P < 0.001). Day time internal dimension (LVIDd), systolic left ventric - SBP, DBP, SBP-SD, DBP-SD, MBP, and MBP-SD ular internal dimension (LVIDs), left atrium (LA) showed meaningful differences between control, diameter, LA volume, E velocity, A velocity, and white-coat hypertension, and true hypertension E/Ea shows no significant difference. The white- groups. All results were highest in the true hyper - coat hypertension and true hypertension groups tension group, and the same appeared in the night have significantly higher epicardial thickness time ( P < 0.001) (Table 2). value, and the left ventricle posterior wall diam - eter on echocardiography was thicker in the true 4. Echocardiography hypertension group than in the control and white Echocardiography was performed on all patients hypertensive groups ( P < 0.001).

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Table 2. Clinicopathogenic features of papillary thyroid carcinomas patients analyzed in this study

All values are presented as the mean ± SD. hr : hour, HR : heart rate, SD : standard deviation, SBP : systolic blood pressure, DBP : diastolic blood pressure

5. Exercise test heart rate, QT, and QTC. However, HRR was sig - Compared to the normotensive group, there is nificantly lower in the white-coat hypertension no difference in exercise time, rest heart rate, max and true hypertension groups when compared to

94 Effects of white-coat hypertension on HRR and EBPR the normotensive group ( P < 0.001). HRR be - In conclusion, the white-coat hypertension tween groups showed a significant difference. group and the true hypertension group showed The control group had 0 blunted HRR, but 33.3% significantly low HRR and higher prevalence of (18 patients) in the white-coat group and 27.6% blunted HRR (Fig. 1). (48 patients) in the true hypertension group. This shows that the prevalence of blunted HRR was significantly higher in the white-coat hyperten - DISCUSSION sion and true hypertension groups than the nor - motensive group (Table 3) . The main finding of our study is that the param - In the control group, 4.5% (3 patients) showed eter related with the nervous system responses to EBPR, but 31.5% (17 patients) in the white-coat exercise such as HRR and EBPR are signifi - hypertension group and 29.3% (51 patients) in cantly different in the white-coat hypertension the true hypertension group showed EBPR. The group from the normotensive group. These ab - white-coat hypertension group showed the high - normal responses are similar to that of the true est percentage of EBPR among all the groups. hypertension group. These results could repre -

Table 3. Parameters of the exercise test

METs : metabolic equivalents, HRR : heart rate recovery, BP : blood pressure, EBPR : exagerated blood pressure response

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sent another pathomechanism of white-coat hy - increased risk ( P < 0.001). The risk for fatal car - pertension. diovascular events was increased even more, the The prognostic impact of white-coat hyperten - incidence being 4.0% and 1.2% in the white-coat sion is still a matter of debate and controversy. 19 hypertension and normotensive groups, respec - Accumulating evidence focusing on the associa - tively. tion of white-coat hypertension with subclinical There are many studies on the identification of target organ damage and, more importantly, in - the mechanism of white-coat hypertension, but cident suggests that the these are not clear. The current study investigates risk is intermediate between normotension and whether individuals with white-coat hyperten - sustained hypertension. Pierdomenico et al. 20 sion have abnormal autonomic-cardiac regula - stated that the white-coat hypertension group did tion or impaired vascular function, similar to that not differ significantly from the normotensive observed in sustained or persistent hypertension. group in terms of risk of a cardiovascular event, Sustained hypertension is associated with sym - but because the white-coat hypertension group pathetic predominance or diminished parasym - patients have much greater rate of antihyperten - pathetic nervous system influences on heart rate, sive treatment at follow up than the normotensive or both. 3, 24 Such “autonomic dysregulation” may group, the results are not conclusive. The risk of be related to hypertension by increasing cardiac cardiovascular event in white-coat hypertension output, vascular resistance, and salt retention. was shown in a study by Verdecchia et al. 21 to Parasympathetic and sympathetic cardiac nerv - be dependent on baseline value of BP on ABPM. ous system functions can be quantified noninva - In this study, data identified that the incidence of sively through spectral analysis of variability in cardiovascular events tends to increase consis - heart rate. 25 Generally, an increase in HR during tently above the daytime BP cut-off value of exercise occurs as a result of combined sympathetic 130/80 mmHg. Similarly, as per the International activation and parasympathetic with drawal. 26 In Database of Home BP in relation to Cardiovas - contrast, parasympathetic rea ctivation is the prin - cular Outcomes (IDHOCO), among the un - cipal determinant of decreased HR during early treated subjects, cardiovascular risk was recovery. Given the prognostic significance of significantly higher in the white-coat hyperten - diminished parasympathetic tone at rest, post-ex - sion group than in the normotensive group. 22 Fur - ercise HRR measurement is a noninvasive pro - thermore, a meta-analysis of 14 studies with cedure that can be used to assess parasympathetic 29,100 participants performed by Briasoulis et activation. 27 HRR is simple to calculate using the al.. 23 showed that the incidence of overall cardio - data obtained from standard exercise tests; more - vascular events was 6.0% in the white-coat hy - over, because it does not require 24-h Holter pertension subjects when compared to 4.0% in monitoring or baro-reflex sensitivity testing, the normotensive subjects, thus meaning a 73% HRR may be valuable for assessing the risk in

96 Effects of white-coat hypertension on HRR and EBPR

Fig. 1. The percentage of blunted heart rate recovery and exaggerated blood pressure response to exercise ac - cording to blood pressure pattern.

routine clinical practice, including exercise test. creased and abnormal endothe - EBPR is also related with the risk of future hy - lial function, is associated with increased exer - pertension and cardiovascular mortality. 28 We ob - cise BP response. 30 Among the parameters of BP served that the white-coat hypertension group response, exercise BP response is an important had a higher prevalence of EBPR, suggesting marker of cardiovascular risk that is associated that white-coat hypertension might present due with cardiovascular mortality. In particular, to the pathomechanism of impaired vascular re - EBPR is a significant predictor of cardiovascular sponse. A recent study by Androulakis el al. events and for new onset of resting hypertension. showed that the white-coat hypertension group This study has several limitations. First, this is presented with worse endothelial function, more a retrospective study. Second, the cross-sectional pronounced arterial stiffness, and LVH. 29 BP re - study design eliminated our ability to determine flects the changes in cardiac output during exer - causal relationships. Third, this study was per - cise or recovery that can lead to changes in SBP. formed at a single center, and relatively small Cardiovascular reactivity to both isometric and number of subjects. So it is possible that biases dynamic exercise has been shown to be one of existed with respect to patient referral and popu - the most important markers for predicting hyper - lation sampling. In order to overcome this limi - tension. Impaired vascular function, including in - tation, it is thought that additional large

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