Nocturnal Hypertension
2018; Lippincott Williams & Wilkins; Volume: 71; Issue: 6 Linguagem: Inglês
10.1161/hypertensionaha.118.10971
ISSN1524-4563
Autores Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 71, No. 6Nocturnal Hypertension Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBNocturnal HypertensionNew Technology and Evidence Kazuomi Kario Kazuomi KarioKazuomi Kario From the Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan (K.K.) Jichi Medical University Center of Excellence, Cardiovascular Research and Development (JCARD), Tochigi, Japan (K.K.) and Hypertension Cardiovascular Outcome Prevention and Evidence in Asia (HOPE Asia) Network, Tokyo, Japan (K.K.). Search for more papers by this author Originally published30 Apr 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.10971Hypertension. 2018;71:997–1009Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2018: Previous Version 1 The issues of hypertension paradox—more uncontrolled disease despite improved therapy—have received increased attention in the era of strict blood pressure (BP) control after SPRINT (Systolic Blood Pressure Intervention Trial) in 2015.1 The new direction in the management of hypertension is to pursue earlier and lower BP control throughout 24 hours.2 The new 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines propose that all the BPs measured during the awake period (clinic BP and home BP measured in the morning and evening) and daytime ambulatory BPs should be controlled to 110/65 mm Hg by the new 2017ACC/AHA guidelines; Table 1). Clinic and morning home BP of 20%; dipper: ≤20%, >10%; nondipper: ≤10%, >0%; riser: ≤0%.4,6–8 This classification is usually based on the ABPM data.Table 1. Definition and Associated Conditions of Nocturnal HypertensionDefinitionNocturnal hypertension Average of night-time BPs* ≥110/65 mm HgClinic BP-masked nocturnal hypertension Nocturnal hypertension with clinic BP <130/80 mm HgMorning BP-masked nocturnal hypertension Nocturnal hypertension with morning home BP <130/80 mm HgIsolated masked nocturnal hypertension Nocturnal hypertension with both clinic and morning home BPs <130/80 mm HgDeterminantsEnvironmental condition Summer (hot temperature)Behavioral factors High salt intake Reduced physical activity Poor sleep quality, nocturia Shift-workingRisk factor Aging Asians Obesity Stress Hypertension Diabetes mellitusSalt sensitivityAutonomic nervous dysfunction Orthostatic hypotensionSecondary hypertension Obstructive sleep apnea Endocrine disease (primary aldosteronism, renovascular hypertension, Cushing syndrome, pheochromocytoma) Chronic kidney diseaseDisease Heart failure CNS disease (stroke, cognitive dysfunction, depression) Restress leg syndromeBP indicates blood pressure; and CNS, central nervous system.*Night-time BPs measured from bedtime to rising (at least 3 readings/night and 2 days).Associated ConditionsThere are many conditions associated with nocturnal hypertension (Table 1). Advancing age, sedentary lifestyle, sleep and hot temperature, and risk factors all affect night-time BPs.6–8 Diabetes mellitus, CKD, and OSA are the 3 diseases most frequently associated with nocturnal hypertension. Age-related diseases frequently found in the elderly and poststroke patients, such as insomnia, cognitive dysfunction, frailty, slow walking speed, heart failure, and various diseases of secondary hypertension, are also closely associated with nocturnal uncontrolled hypertension. Asians are likely to have nocturnal hypertension because of their higher salt intake and higher salt sensitivity.29,30PathophysiologyMorning is generally considered a higher-risk period because the rupture of atherosclerotic plaques or arteriosclerotic bleeding can be triggered by a morning BP surge that is synergistically augmented by trigger conditions, such as cold, exercise, smoking, or work-site stress, resulting in morning onset of cardiovascular events (Figure 1).31,32In addition, a blunted morning BP surge is also reported to confer a risk of cardiovascular events.33 The high prevalence of the riser pattern in patients with blunted morning BP surges34 may account for the cardiovascular risk previously reported in such patients. Blunted or inverse BP reactivity in the morning is also partly associated with orthostatic hypotension, as well as the riser pattern of night-time BP, and it seems to be related to autonomic nervous dysfunction. Considering that exaggerated morning surge is associated with an extreme dipper pattern and orthostatic hypertension, both inverse and exaggerated extreme-edges of disrupted BP variability would be pathological.There are several pathogeneses of nocturnal hypertension (Figures 1 and 2). Advanced structural vascular disease (increased vascular resistance and arterial stiffness) and increase in salt sensitivity and high-salt diet are the main causes of nocturnal hypertension, especially in patients with an increase in basal night-time BP (Figure 2). Based on the pressure-natriuresis, in patients with increased circulating volume, not only daytime but also night-time BP are elevated over 24 hours to excrete sodium from the kidneys.35,36 Salt sensitivity is increased by the renal dysfunction, the sympathetic hyperactivity, and the activation of the renin–angiotensin–aldosterone system. These processes are advanced in turn by aging, stress, obesity, diabetes mellitus, and sleep disorders (OSA and insomnia).Download figureDownload PowerPointFigure 2. Mechanism of the effects of nocturnal hypertension on cardiovascular risk. BP indicates blood pressure; LV, left ventricular; and MI, myocardial infarction.There are several heterogeneous pathophysiological mechanisms that account for the specific risk of nocturnal hypertension (Figure 2). First, sympathetic drive-induced night-time BP surges may trigger night-time onset of cardiovascular events (stroke, acute heart failure, coronary artery disease, etc; Figure 2) and may advance age-related organ damages (cognitive dysfunction, CKD). Night-time BP surge is triggered by specific triggers (OSA episode, arousal, rapid-eye-movement sleep, and nocturia) and is augmented by the impaired baroreflex by increased sympathetic tonus and vascular stiffness (Figure 1). The mechanism by which night-time BP surge confers cardiovascular risk seems to be similar to that by which morning BP surge does so.Second, nocturnal hypertension may be the final stage of hypertension in cases of advanced organ damage and pathological disease (Figure 2). During sleep, sympathetic activity is reduced compared with the morning and daytime periods. Thus, the night-time BP is less likely to be increased than BPs during other time periods. In the normal process of BP increase with age, the rise of morning BP comes first because of the higher sympathetic activity in the morning (which makes it easy to increase BP) while the rise in night-time BP comes last because of the lower sympathetic tonus in the night-time (which makes it more difficult to increase BP). Thus, when the night-time BP increases, it may express advanced structural changes of the large and small arteries (increase in arterial stiffness and vascular resistance) and increased circulating volume because of reduced ability of the kidneys to excrete sodium.Third, during sleep, the supine position increases venous return from the lower body to the heart, resulting in increased LV preload (Figure 2). The LV wall stress by the afterload of nocturnal hypertension is augmented by the night-time increase in LV preload (Law of Laplace). This night-time increase in LV wall stress would constitute a risk for night-time onset of heart failure. In addition, the increased circulating volume by the shift of interstitial fluid from the soft tissue of the lower body to the circulating volume also increases the LV preload. In addition, the simultaneous increase in night-time circulating volume and BP would synergistically worsen the renal function by increasing the intraglomerular pressure and hyperfiltration (Figure 2).Finally, the night-time is a blind-spot in terms of monitoring the current hypertensive drug, and thus the residual night-time risk may persist for a long time without the patient’s doctor noticing.Research and Development of Night-Time HBPM and Relevant FindingsABPM has historically been the gold standard for measuring night-time BP. However, self-measured HBPM was introduced to measure night-time BP during sleep.27,28,37–44 We recently developed an HBPM device that automatically measures night-time home BP (HBP) 20× with data memory (Medinote; Omron Healthcare Co, Ltd, Kyoto, Japan). The Jichi Medical University and Omron Healthcare Co, Ltd (Kyoto, Japan) have been conducting cutting-edge collaboration program projects in the SURGE (SUper ciRculation monitorinG with high TEchnology) R&D Center to develop a new HBPM system and a new index of clinically relevant BP profiles (Tables 2 and 3).Table 2. Research and Development of Night-Time Home Blood Pressure Monitoring Devices and Evidence (Jichi Medical University School of Medicine)YearSourceDeviceMajor Device FunctionICT-BasedValidationCompeting Device2010Kario et al38Medinote(HEM-5041; Omron Healthcare)Automatic BP monitoring during sleep with fixed intervals functionNot availableColeman et al53Watch BP Home N (microlife)2012Ishikawa et al272014Ishikawa et al392015Kario et al282017Kario et al41HEM-7252G-HP (Omron Healthcare)Automatic BP monitoring during sleep with fixed intervals function, timer function after going to bed and built-in third-generation mobile communication facilityAvailableTakahashi et al54Watch BP Home N (microlife)2018Fujiwara et al442006Shirasaki et al45Triggered night-time blood pressure monitoring (TNP)Automatic BP monitoring during sleep with fixed intervals function and triggered BP function which initiates BP monitoring when oxygen saturation falls threshold or low heart rate period during the sleepNot availableViera et al55(not for addtional function but for HEM780REL itself)None2011Shirasaki et al462014Kario et al472017Kuwabara et al482018Kuwabara et al492014Kario et al47ICT-based TNP (ITNP)TNP with built-in third-generation mobile communication facility (nigh-by-night evaluation)AvailableNoneNone2015Kario et al502016Yoshida et al512016Kario10Wearable beat-by-beat surge BP monitoring (WSP)Wrist-type continuous BP monitoring based on the tonometry methodNot availableNoneNone2018Kario52BP indicates blood pressure; and ICT, information and communication technology.Night-Time HBPMWe developed the Medinote, a semiautomatic HBPM device that performs automatic, fixed-interval BP measurement during sleep and stores the data in memory.27,28,38,39 Using the Medinote, we initiated the J-HOP (Japan Morning Surge Home Blood Pressure) study, the first large nationwide night-time home BP cohort, and successfully measured night-time home BP 3× during sleep (at 2:00 am, 3:00 am, and 4:00 am) for 14 days in 2562 participants.28 The baseline data of this study demonstrated that the self-measurement of night-time BP at home is feasible27,28 and that there was no difference between the night-time home systolic BP levels at 2:00 am and 3:00 am while that at 4:00 am was slightly higher by 1.5 mm Hg (P<0.0001).28 The night-time HBP was almost comparable to night-time BP measured by ABPM27 and was significantly correlated with the urinary albumin/creatinine ratio, LV mass index, brachial-ankle pulse wave velocity, maximum carotid intima–media thickness, and plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitive cardiac troponin T levels, independently of clinic, morning, and evening home BPs.28 Even in those with well-controlled morning home systolic BP 120 mm Hg,28 and these patients had higher urinary albumin/creatinine ratio and NT-proBNP, indicating that a significant number of cases of masked home nocturnal hypertension remained as a hidden risk unrecognized by conventional HBPM. In addition, in our J-TOP (Japan Target Organ Protection) trial, we used night-time HBPM to assess the night-time BP in a clinical intervention trial for the first time.38,39 The reduction of night-time home BP was more closely associated with the regression of LV hypertrophy evaluated by cardiac echography than clinic BP,39 indicating that night-time home BP is a better indicator of good BP control during antihypertensive treatment. Thus, night-time HBPM could be a valuable method for assessing night-time BP, with accuracy comparable to ABPM in clinical practice.Night-Time Home BP TelemonitoringThe Medinote device has now advanced to a new information and communication technology (ICT)–based night-time home BP telemonitoring device, HEM-7252G-HP. This night-time home BP telemonitoring system directly sends night-time home BPs during the last sleep period at the time of the morning BP measurement from the patient’s home. Using this device, we have successfully conducted 2 clinical trials41,44 and confirmed that this night-time HBPM system could be made available for clinical practice.Trigger Night-Time HBPM (TNP)The second advance was the development of a TNP, which was based on the automated fixed interval measurement technique of Medinote with an added trigger function of hypoxia and heart rate monitored by pulse oximetry.2 There is currently no night-time BP monitoring device to evaluate the quality of nocturnal hypertension with different pathogenic pressor mechanisms. This double TNP thus adopts a brand new approach: it evaluates the pathogenic pressor mechanism of night-time BP by measuring BP only under specific conditions.2Hypoxia-Trigger FunctionIn the patients with OSA, repetitive OSA episodes produce hypoxia. When the desaturation falls below a set oxygen level as determined by continuous oxygen monitoring using pulse oximetry, the TNP automatically sends the signal to measure BP (hypoxia-trigger function).45,46,56 Thus, the TNP can detect the specific night-time BP surges triggered by hypoxic episodes and evaluate the effect of medication and device treatment on night-time BP profiles in patients with OSA.47–51,57,58 This feature is unique to TNP: neither the previous HBPM nor ABPM with fixed time-interval measurement can detect night-time BP surges specific to individual OSA episodes.50,51Heart Rate-Trigger FunctionWe also added a lowest heart rate-trigger function to TNP to detect the basal night-time BP when the sympathetic tonus and BP level and BP variability are at a minimum during slow wave sleep. The low heart rate-trigger function is an algorithm that sends the command to measure BP when the lowest heart rate persists for a significant time period.Definition of Trigger Night-Time BP ParametersThe hypoxia-peak night-time BP is defined as the maximum systolic BP measured by the hypoxia-trigger function, and OSA-induced night-time BP surge is defined as the hypoxia-peak systolic BP minus the average of the 2 BPs measured by fixed interval measurement before and after the peak systolic BP measured by hypoxia-trigger function (Figure 3A).47 The basal BP is defined as the lowest BP measured by low heart rate-trigger function. Nocturnal hypertension exhibits similar average night-time BPs although possibly by a different mechanism: peak night-time BPs measured by a hypoxia trigger might be attributed to sympathetic overdrive58 while the basal night-time BP would be determined by the circulating volume and structural vascular disease with the least sympathetic tonus.Download figureDownload PowerPointFigure 3. Night-time blood pressure (BP) profile detected by trigger night-time home BP monitoring (TNP) and wearable beat-by-beat surge blood pressure monitoring (WSP). A, Detection and definition of night-time BP profile by TNP. B, Sleep apnea–induced night-time BP surges detected by WSP (top), and effect of bedtime dosing of a β-blocker on the night-time surge BP. Middle, BPs detected by TNP; Bootom, BPs monitored by WSP. In a 50-y-old normotensive women with obstructive sleep apnea, the WSP-Trigger successfully detected the highest peak of night-time BP surge 1 d before (day 1: baseline) and on the day of night-time dosing of carvedilol 20 mg (day 2: carvedilol-added). Carvedilol therapy decreased the Surge Index (BP surges/h) from 17.2/h to 7.4/h. The peak of surge was also decreased from 178 to 133 mm Hg by the oscillometric method triggered by hypoxia (middle), and from184 to 137 mm Hg by the continuous beat-by-beat method (bottom). SBP indicates systolic BP.Reproducibility of Night-Time BP ParametersWe evaluated the distribution and reproducibility of night-time BP parameters obtained from TNP compared with those of fixed-interval night-time BP parameters for 2 consecutive nights in 147 patients with OSA.48 The mean and distribution (SD) of the hypoxia-peak systolic BP were much greater than those of the mean night-time systolic BP, by 25.4 mm Hg (mean±SD: 148.8±20.5 versus 123.4±14.2 mm Hg; P<0.001). The repeatability coefficient (expressed as %MV; the percentage of 4 times the SD of the average of the repeat measurements) of hypoxia-peak systolic BP between night 1 and night 2 was comparable to that of mean night-time systolic BP (43% versus 32%), indicating that hypoxia-peak night-time BP was much higher than mean night-time BP, and as reproducible as mean night-time BP. Among the patients with nocturnal hypertension (mean night-time systolic BP ≥120 mm Hg), ≈50% have reached hypoxia peak systolic BP ≥160 mm Hg. Among polysomnography-derived sleep parameters (apnea-hypopnea index, arousal index, percentage of hypoxia [Spo2<90%] of the total sleep), the most potent determinant of this hypoxia-peak and surge in night-time BP was the lowest oxygen saturation (lowest Spo2).SPREAD StudyUsing the TNP, we are now conducting a prospective study of SPREAD (Sleep Pressure and Disordered Breathing in Resistant Hypertension and Cardiovascular Disease); this study will provide the first TNP registry and will use this data to evaluate the clinical implications of night-time BP and night-time BP surges in high-risk patients with resistant hypertension and cardiovascular disease.2,10 This ongoing SPREAD study includes the case of a 36-year-old man in whom TNP-detected exaggerated hypoxia-triggered night-time BP surges. He actually developed the sleep-onset of ischemic and hemorrhagic stroke 3×.51 Moreover, in a 74-year-old woman with OSA, even when the mean night-time BP measured by ABPM with fixed 30-minute intervals was normotensive <120/70 mm Hg, TNP determined that the repetitive exaggerated hypoxia peak systolic BP reached ≥160 mm Hg for systolic BP.50ICT-Based TNP (ITNP) System for Night-by-Night EvaluationFinally, we have recently developed the ITNP system, a cloud-computing–based composite management and analysis system for the data sent from the BP device in the patient’s home.2,47 The most important benefit of the ITNP is the repeated assessments at home. One-day polysomnography under alcohol-prohibited conditions in hospitals may underestimate the severity of OSA and related risk. The evaluation of OSA using ITNP in a real-life setting increases the sensitivity to detect OSA-related night-time BP surge.2 The repeated assessments enable the detection of day-by-day variabilities in night-time BP profiles, which can be affected by the daily OSA severity and sleep quality during sleep, as well as by daily behavioral changes (salt and alcohol intake at dinner, bedtime, sleep time, awakening time, nocturia, etc),2 and environmental factors (temperature, illumination, atmospheric pressure in the bedroom, etc).Evaluation of CPAP TherapyContinuous positive airway pressure (CPAP) treatment nearly eliminates TNP-detected night-time BP surge in patients with OSA.2,56 However, the cardiovascular protection and BP-lowering effect of CPAP are not perfect, and a significant number of OSA patients on CPAP develop cardiovascular events.59 The 2017 AHA/ACC guidelines described that in adults with hypertension and OSA, the effectiveness of CPAP to reduce BP has not been well established, and thus CPAP was classified only as a class IIb recommendation.3 Another report suggested that adherence to CPAP may be the key to its effectiveness.60ITNP can evaluate the adherence and efficacy of CPAP on a day-by-day basis.2 Even in patients with OSA on nightly CPAP therapy, the CPAP mask may not be properly positioned on the face, or the pressure of CPAP may be insufficient because of poor conditions, such as upper tract infection and allergic rhinitis. Nonetheless, effective CPAP was shown to reduce the mean night-time systolic BP by 8 mm Hg in a patient on CPAP. This reduction was markedly greater by 42 mm Hg when evaluated by hypoxia-peak night-time systolic BP.2Wearable Beat-by-Beat Continuous Surge BP Monitoring (WSP)Wearable noninvasive beat-by-beat BP monitoring has long been a dream of doctors who manage hypertension. Omron Healthcare Co, Ltd, recently publicized a prototype of a wearable wrist-type of tonometry BP monitor that capitalizes on advances in automatically controlled technology. This prototype has 2 tonometry sensor plates, and the angle of the arrayed sensor plate to cover the radial artery is automatically adjusted to obtain effective applanation. We are currently testing the clinical utility of this device and improving it in collaboration with Omron with the goal of developing a more accurate, WSP device, which could measure the absolute values of the maximum peaks of beat-by-beat pressure.2,10,52 Using our current prototype of the WSP device, we successfully monitored beat-by-beat BP continuously during sleep while simultaneously performing polysomnography. In our recent study, this device demonstrated that the night-time BP level and variability were significantly lower in stage 2 and stage 3 sleep, and higher during stage 1 sleep, rapid-eye-movement sleep, and the waking (by nocturnal behaviors, such as nocturia, drinking water, etc) period.2 This device successfully detected the 3 night-time BP surges triggered by rapid-eye-movement sleep, arousal (unconscious microarousals), and OSA episodes (Figure 3B).2,52 Nonetheless, WSP has limitations because of weaknesses of the tonometry BP monitoring device: (1) the position of the sensor to cover the artery is strict, and (2) artifacts because of movement of the wrist, which disturb effective applanation, are frequent.10Finally, we developed an approach using the WSP combined with the trigger function technique to measure the accurate absolute BP value (WSP-Trigger). The peak of systolic BP surge detected by the WSP-Trigger was always higher than the hypoxia-triggered BP surge detected by trigger TNP using the oscillometric method (Figure 3B).2 These peaks of hypoxia-triggered night-time BP detected by WSP-Trigger and by TNP were diminished by sympatholytics (Figure 3B).We developed the WSP-Trigger because earlier detection of mild OSA and associated night-time BP surge is critically important because OSA is mostly diagnosed in a rather advanced stage of the disease and therapy may incompletely reverse organ damage (remodeling, lung function, and so on).3 However, it is not certain that the initiation of additional drug therapy and use of novel technologies, such as WSP-Trigger, will finally lead to zero cardiovascular events. TNP may underestimate the risk of OSA because in treated patients with OSA, there might be remaining hypopnea and apnea episodes without a clear trigger of hypoxia. Even by the combination therapy of CPAP and medication, the risk of OSA might remain significant. Extensive research will be needed to validate the quantity and quality of the night-time BP-lowering effects of CPAP and antihypertensive drugs of different classes.Management of Nocturnal HypertensionThe 2017 AHA/ACC guidelines for the management of hypertension recommend a goal of <110/65 mm Hg for night-time BP control.3 In clinical practice, the morning home BP-guided titration of antihypertensive drugs is the first step to achieve perfect 24-hour BP control, which consists of 3 components: lowering 24-hour BP; maintaining a normal circadian rhythm (dipper-type); and suppressing exaggerated BP variability, especially fo
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