Nocturnal Blood Pressure Surge Behind Morning Surge in Obstructive Sleep Apnea Syndrome: Another Phenotype of Systemic Hemodynamic Atherothrombotic Syndrome

It is well-known that cardiovascular events occur more frequently in the morning, with blood pressure (BP) levels shown to increase during the period from night to early morning.1 In recent years, clinical research using ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM) has clarified that morning BP and BP surge are more closely related to cardiovascular risk than clinic BP.2-5 In this issue of The Journal of Clinical Hypertension, Cho and colleagues6 demonstrated that morning BP surge was significantly increased in patients with obstructive sleep apnea syndrome (OSAS). There are several factors associated with morning BP surge and morning hypertension. Morning BP surge is increased by various factors, including aging, hypertension, high-normal normotension, diabetes, inflammation, alcohol intake, smoking, physical stress, and psychological stress.5 As the underlying mechanism of these pressor factors, diurnal variation and activation of neurohumoral factors that regulate the vascular tonus and cardiac output, such as renin-angiotensin system and sympathetic nervous activity, potentially in relation to central and peripheral clock genes, have been conserved to be involved in diurnal BP variation and morning BP surge. In addition, nocturnal hypoxia or poor sleep quality would augment morning BP surge. Even in children with OSAS without any early vascular damage, morning BP surge has been shown to be augmented.7 The tonic sympathetic nervous activation, frequently triggered by hypoxic episodes throughout the sleep period, in the morning would augment morning BP reactivity through impaired baroreceptor sensitivity. Cardiovascular events more frequently occur during sleep in OSAS patients when compared with non-OSAS patients,8, 9 suggesting that risks that trigger cardiovascular events remain significant during sleep in OSAS patients. OSAS is known as one of the leading causes of nondipper/riser pattern of nocturnal BP and nocturnal hypertension, which are significantly associated with increased risk of cardiovascular disease.10 In addition to nocturnal hypertension, increased nocturnal BP variability is one characteristic of nocturnal hypertension in OSAS patients.10 Episodic apnea episodes induce hypoxia and sympathetic nervous activation and reduce baroreceptor sensitivity, resulting in increased nocturnal BP surge and nocturnal BP variability.11 Previously, only ABPM was available to assess nocturnal BP during sleep. Recently, we developed a new HBPM device with timer and memory that could measure nocturnal BP at fixed intervals and store BP data (Medinote, Omron Healthcare Co, Ltd, Kyoto, Japan).12 This HBPM device has been used in the Japan Morning Surge-Home Blood Pressure (J-HOP) study, a prospective study on outpatients with one or more risk factor.13, 14 In the J-HOP study, we demonstrated that nocturnal BP measured by HBPM (the average of nocturnal BPs at 2 am, 3 am, and 4 am) was significantly associated with measures of organ damage (eg, left ventricular hypertrophy, carotid intima-media thickness, pulse wave velocity, and albuminuria)14 and their association was greater than that measured by ABPM.15 However, neither conventional ABPM nor HBPM have been able to detect nocturnal BP surge specific to each apnea episode in OSAS patients. We recently developed an information technology–based trigger nocturnal HBPM system (ITNP) with oxygen and heart rate triggers and a 3G web system (ITNP1, Figure S1; Jichi Medical University, Tochigi, Omron Healthcare Co, Ltd, Kyoto, Japan) that can detect specific nocturnal BP surges triggered by hypoxic apnea episodes.1, 12, 16, 17 The ITNP is based on the automated fixed interval measurement technique with an added hypoxia trigger function that initiates BP measurement when oxygen desaturation falls below the variable threshold continuously monitored by pulse oximetry. This system can detect repeated and day-to-day variability in morning and nocturnal BP and the nocturnal BP surges associated with sleep apnea episodes, the degree of which can be affected by daily environmental changes. Using this ITNP, we have started the prospective Sleep Pressure and Disordered Breathing in Resistant Hypertension and Cardiovascular Disease (SPREAD) study, a registry to evaluate the clinical implications of nocturnal BP and nocturnal BP surges in high-risk patients with resistant hypertension, cardiovascular disease, and/or OSAS. One-day polysomnography in patients under alcohol-prohibited conditions in the hospital may underestimate the severity of sleep apneas and may miss those with moderate OSAS. The repeated assessment of OSAS using ITNP in the real-world setting increase the sensitivity of the detection of OSAS and OSAS-related nocturnal hypertension and BP surge. Figure 1 demonstrates exaggerated morning BP surge in a 76-year-old woman with OSAS. The conventional ABPM detected exaggerated morning BP surge, but the average of nocturnal BPs measured intermittently at 30-minute interval was considered normotensive at <120/70 mm Hg. The ITNP evaluation performed on three different nights detected severe hypoxic episodes <50% of blood oxygen saturation and exaggerated hypoxia-related nocturnal BP surge reaching around ≥160 mm Hg at the time of the apnea episodes (Figure 2). These hypoxia-induced nocturnal BP surges may trigger sleep-onset cardiovascular events in OSAS patients. Treatment with continuous positive airway pressure (CPAP) often eliminates the nocturnal BP surge in patients with OSAS.10 Bedtime dosing of doxazosin has been shown to significantly reduce nocturnal BP surge and basal nocturnal BP in patients with OSAS, while the cluster of hypoxic episodes are comparable between baseline and after treatment.10 In our recent study of ITNP, the bedtime dosing of nifedipine and carvedilol significantly reduced all measures of nocturnal BP,17 while the nocturnal BP-lowering effect was different between the two drugs. Compared with nifedipine, carvedilol reduced peak nocturnal BP, while it significantly but less extensively reduced basal BP, resulting in significant suppression of hypoxia-induced nocturnal BP surge.17 We recently proposed a novel disease entity, the systemic hemodynamic atherothrombotic syndrome (SHATS), which is characterized by a vicious cycle between hemodynamic stress and vascular disease and is a risk factor for cardiovascular events and organ damage.12, 18-20 The novel contribution of SHATS is its synergistic consideration of various types of BP variability and hemodynamic stress from very short-term (beat-by-beat) to long-term (yearly) in relation to vascular disease.12, 18-20 OSAS is one of the major leading diseases that exhibits SHATS,12, 20 because hypoxia and sympathetic activation result in vascular disease and BP variability (Figure 3). OSAS-related morning BP surge can be detected by ABPM and partly by HBPM, while the best BP monitoring of OSAS-related nocturnal BP surge is with ITNP. OSAS increases BP variability such as morning surge and nocturnal surge in relation to vascular disease, resulting in SHATS. Repeated home nocturnal BP monitoring with hypoxia trigger function contributes to the detection of high-risk OSAS with nocturnal hypertension and/or nocturnal BP surge and assesses the quality of BP control during CPAP and/or antihypertensive treatment in OSAS patients. Strict BP control throughout 24 hours including nocturnal BP and hypoxia-induced BP peak would effectively suppress the development of organ damage and cardiovascular events in OSAS patients. The ITNP system is a valuable contribution in achieving this goal. Dr Kario received a research grant from Teijin and honoraria from Omron and A&D. 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