Nocturnal BP dipping status

Different patterns of the circadian rhythm of BP can be determined using ambulatory BP monitoring (ABPM). Population‐based and clinical studies using ABPM have shown that nighttime BP is a better predictor of cardiovascular diseases than daytime BP [5, 6]. Nocturnal hypertension (where nighttime BP is high) and a non‐dipper/riser pattern (where nighttime BP is higher than daytime BP, even if office and 24‐hour BP readings are within the normal range) both increase the risk of target organ damage and subsequent cardiovascular events [7–10].

In healthy subjects, nighttime BP falls by 10–20% from daytime BP (normal dipper pattern). Patients with hypertension who do not have target organ damage also show the dipper pattern. However, those with organ damage tend to exhibit a non‐dipper pattern with diminished nighttime BP fall. Recent guidelines on the management of hypertension defined four different dipping patterns of nighttime BP: dipper, non‐dipper, riser, and extreme dipper based on the magnitude of the nighttime BP fall (Figure 1.3) [7, 8]. The terms “riser” and “extreme dipper” patterns describe the extremes on a continuum of circadian BP variability and represent the most pathologically relevant forms of disrupted circadian BP rhythm [11] .

Non‐dipper patterns of BP and pulse rate

O’Brien et al. first demonstrated that an abnormal, non‐dipping pattern of nighttime BP, with a <10% reduction in nocturnal BP compared with daytime BP, is associated with advanced organ damage [12] . The magnitude of the nighttime BP fall tends to diminish with advancing age. Shimada et al. first demonstrated that a non‐dipper pattern of nighttime BP in elderly patients with hypertension was associated with advanced silent cerebral disease (such as silent cerebral infarcts and deep white matter lesions) detected using brain magnetic resonance imaging (MRI) [13] .

Non‐dipping of the pulse rate pattern is also associated with poor cardiovascular prognosis, and synergistically increases the risk associated with a non‐dipper pattern of nighttime BP fall. In a prospective study of elderly patients with hypertension, those with a non‐dipper pulse rate pattern showed a increase in cardiovascular events compared with a dipping pattern, independent of BP. In addition, non‐dippers of both nighttime BP and nighttime pulse rate were found to have the worst cardiovascular prognosis, showing a synergistic 7.9‐fold increase in the risk of cardiovascular events compared to those with a dipping profile for both parameters (Figure 1.4) [14] .

Riser pattern of BP and cardiovascular disease risk

The “riser” pattern is defined as higher BP during nighttime vs. daytime BP (i.e. no nocturnal BP fall), and the term “extreme dippers” refers to patients with an exaggerated nighttime BP fall (≥20%) compared with the daytime BP reading [7] . Some authors use the term “reverse dipper” or “inverted dipper” instead of “risers,” but these refer to the same lack of nocturnal BP fall.

A study in elderly patients with hypertension was the first to demonstrate that both extreme forms of disrupted circadian BP pattern (i.e. riser and extreme dipper) were associated with advanced silent cerebral disease evaluated on brain MRI (Figure 1.5) and were significantly associated with the occurrence of stroke (Figure 1.6) [8] . In particular, the riser pattern appears to have a particularly poor prognosis with respect to stroke and cardiac events (Figure 1.7) [15] .

The multicenter, prospective, practitioner‐based, Japan Ambulatory Blood Pressure Monitoring Prospective (JAMP) study used the same ABPM device across all study centers to investigate the impact of nocturnal hypertension and nighttime BP dipping patterns on the occurrence of cardiovascular events, including heart failure (HF), in patients with hypertension (Figure 1.8) [16] . The results showed that both higher nighttime BP values and a riser pattern were significantly associated with the risk of developing atherosclerotic cardiovascular disease. The multivariable‐adjusted hazard ratio (HR) value for the risk of atherosclerotic cardiovascular disease associated with a 20 mmHg increase in nighttime systolic blood pressure (SBP) was 1.21 (95% confidence interval [CI] 1.03–1.41; p = 0.017) [16] .

A riser pattern has also been shown to significant increase the risk of cardiovascular disease events in very elderly patients (age ≥80 years) [17] . Even after adjustment for covariates and mean nighttime SBP, patients with a riser pattern of nighttime BP were at significantly higher risk of experiencing a cardiovascular event than those with a dipper pattern (HR 3.11; 95% CI 1.10–8.88) (Figure 1.9) [17] .

The elevated cardiovascular risk associated with a riser pattern might be further increased when sleep duration is short. Data from a prospective study showed that a riser pattern and shorter sleep duration combined to synergistically increase cardiovascular risk in patients with hypertension; those with a riser pattern and short sleep duration had the worst cardiovascular prognosis (Figure 1.10) [18] .

Chronic kidney disease (CKD) is likely to be associated with nocturnal hypertension and the non‐dipper/riser pattern. The fall in nighttime BP is attenuated in parallel with decreases in the glomerular filtration rate and increases in urinary albumin excretion. Although CKD increases the risk of future cardiovascular events in both dippers and non‐dippers/risers, non‐dippers with CKD have the highest level of cardiovascular risk (Figure 1.11) [19] .

Riser pattern and HF

The JAMP study was one of the first to separately evaluate the risk of HF associated with nocturnal hypertension and disrupted circadian BP patterns [16] . Both higher nighttime BP values and a riser pattern were significantly associated with the risk of developing HF (multivariable adjusted HR: 2.45 [95% CI 1.34–4.48]; p = 0.004) (Figure 1.12). The relationship between a riser pattern and HF risk was independent of nighttime BP, and patients with a riser pattern was found to be at increased risk of developing HF even when 24‐hour SBP was well controlled (Figure 1.13) [16] . The risk of coronary artery disease and HF was highest in individuals with a riser pattern and higher nighttime SBP (Figure 1.12) [16] .

Additional data come from a follow‐up study of patients hospitalized with HF, which showed an association between a non‐dipper or riser pattern and a higher rate of cardiovascular events in HF patients who had preserved ejection fraction (HFpEF), but not in those with a reduced ejection fraction (HFrEF) (Figure 1.14) [20] . Furthermore, inpatients with HF who had a riser pattern of nighttime BP were more likely to have HFpEF than HFrEF (Figure 1.15) [21] .

Circadian BP pattern appears to be important even in normotensive community‐dwelling populations (24‐hour BP <125/80 mmHg), with non‐dippers and risers showed an increased frequency of concentric cardiac hypertrophy and higher plasma levels of atrial and B‐type natriuretic peptides (BNP) compared to individuals with a dipper profile (Table 1.1) [9] . These changes are precursors to the development of HF.

In addition, a pulse rate non‐dipper pattern was significantly associated with higher plasma BNP level, especially in those with a non‐dipping profile for both BP and pulse rate (Figure 1.16) [22] . A non‐dipper pulse rate profile combined with high N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels was associated with a substantial increase in cardiovascular risk in patients with cardiovascular risk factors undergoing ABPM (p = 0.002 vs. dipper pulse rate + high NT‐proBNP, and p < 0.001 vs. the other three groups) (Figure 1.17) [23] .

BNP levels have potential for use as a biomarker to assist in achieving perfect 24‐hour BP control. Even in patients receiving antihypertensive therapy who have well‐controlled office BP, the causes of an increase in wall stress (resulting in elevated BNP levels) should be examined because nocturnal hypertension and/or sleep apnea might be present (Figure 1.18) [24] . An increase in NT‐proBNP levels during antihypertensive treatment suggests an increase in left ventricular wall stress [25] because serum NT‐proBNP is a major determinant of left ventricular wall stress, especially during systole (Figure 1.19). Given that wall stress is determined by both cavity pressure and left ventricular cavity radius, an increase in serum NT‐proBNP level reflects an increase in preload (increased circulating volume) and afterload (SBP), and myocardial ischemia.

Riser pattern and brain damage

Elderly patients with hypertension, a non‐dipper or riser pattern, and high nighttime BP have been shown to have atrophy of the brain and insular cortex (Figures 1.20 and 1.21) [26, 27]. In addition, a non‐dipper pattern and nocturnal hypertension are significantly associated with cognitive dysfunction and slow walking speed in elderly subjects (Figure 1.22) [28] .

In patients with HF, a riser pattern was significantly associated with mild cognitive impairments [29] . A quantitative brain MRI study in patients with HF demonstrated that deep white matter lesions are in the presence of a riser pattern of nighttime BP (Figure 1.23) [30] .

Nocturnal hypertension

Nocturnal hypertension is diagnosed when the average of nighttime BP measurements is ≥120/70 mmHg. Patients with a non‐dipper or riser BP pattern are likely to have nocturnal hypertension.

In prospective studies, nocturnal hypertension was associated with an increased risk of cardiovascular events, both stroke and coronary artery disease. This risk increased in parallel with increasing daytime and nighttime BP readings, but only the increase in nighttime BP was significantly associated with elevated ten‐year risk of cardiovascular events, particularly in medicated patients (Figure 1.24) [6] . However, these findings were based only on baseline BP meaning that any change in medication would be based on office BP, which relates more closely to daytime BP rather than nighttime BP. Therefore, elevated nighttime BP is likely to persist during long‐term follow‐up. This highlights the fact that antihypertensive therapy guided by office BP measurements may not reduce the risk of nocturnal hypertension.

The risk of cardiovascular events in the ABP‐International registry showed a synergistic relationship between nighttime SBP and nighttime pulse rate (Figure 1.25) [31] . Another study in well‐medicated patients with congestive HF and uncontrolled nocturnal hypertension showed that a nighttime/sleep SBP >120 mmHg) was associated with a significant increase in stroke risk during follow‐up (Figure 1.26) [32] . Nighttime SBP in particular appeared to be an important risk factor for HF compared with other cardiovascular events (Figure 1.27) [16] .

The negative impact of nocturnal hypertension is greater in patients with hypertension and diabetes than in those with hypertension without diabetes. In a prospective study, the increase in cardiovascular risk associated with nocturnal hypertension (nighttime SBP >135 mmHg) vs. nocturnal normotension (nighttime SBP <120 mmHg) was 10.8 times in patients with diabetes compared with 2.7 times in those without diabetes (Figure 1.28) [33] .

In treated patients with hypertension who have well‐controlled home BP, the presence of uncontrolled nocturnal hypertension (nighttime SBP ≥120 mmHg on ABPM) attenuated effects of antihypertensive therapy on the urinary albumin‐creatinine ratio (UACR) and BNP compared to patients with well‐controlled home and nighttime BP (both p < 0.001) (Figure 1.29) [25] . Isolated and masked nocturnal hypertension are also significant risk factors for target organ damage, which in turn increases cardiovascular risk [34–36]. For example, patients with isolated nocturnal hypertension show greater arterial stiffness than those with ambulatory normotension, as assessed using peripheral and central augmentation index, the ambulatory arterial stiffness index, and brachial‐ankle pulse wave velocity (PWV).

Taken together, the above data indicate that controlling nighttime BP during sleep, as well as morning and evening home BP levels, is essential to reduce target organ damage in patients receiving antihypertensive therapy.

Associated Conditions and Mechanisms of Nocturnal Hypertension

Risk factors for nocturnal hypertension include aging, orthostatic hypotension, diabetes, and Asian ethnicity, while nocturnal hypertension is common in patients with conditions such as CKD or obstructive sleep apnea. In addition, secondary hypertension and diseases with an increase in sympathetic nervous activity or renin‐angiotensin system activity increase circulating volume, resulting in nocturnal hypertension (Table 1.2) [37] .

With respect to circadian BP patterns, increased circulating volume, autonomic nervous dysfunction, poor sleep quality, and structural vascular disease are the major mechanisms of nocturnal hypertension in individuals with a non‐dipper or riser pattern of nighttime BP (Figure 1.30) [38] . Increased circulating volume may have a compensatory effect and increase nighttime BP as well as daytime BP by excreting sodium from the kidney based on Guyton’s theory of the pressure–natriuresis relationship, resulting in nocturnal hypertension of the non‐dipper/riser type [39] . Thus, conditions that increase sympathetic nervous activity, and renin–angiotensin–aldosterone system‐associated increases in circulating volume due to reduced sodium excretion, result in a non‐dipper/riser pattern of nighttime BP. Activation of neurohumoral factors due to orthostatic hypotension during the daytime may persist during sleep when an individual is in the supine position. Poor sleep quality (such as that associated with obstructive sleep apnea), insomnia, anxiety, and depression (Figure 1.31) [40] , and shift work can all contribute to nocturnal hypertension.

Environmental factors	Salt sensitivity
Summer (hot temperature)
Behavioral factors  High salt intake  Reduced physical activity  Poor sleep quality  Nocturia  Shift‐working	Secondary hypertension  Endocrine disease (primary aldosteronism, renovascular hypertension, Cushing syndrome, pheochromocytoma)  Chronic kidney disease (CKD)  Obstructive sleep apnoea syndrome (OSAS)
Risk factors
Aging
Hypertension	Disease
Orthostatic hypotension	Heart failure
Diabetes	Stroke
Asian ethnicity	Cognitive dysfunction

Mechanism of cardiovascular risk of nocturnal hypertension

The specific increase in cardiovascular risk associated with nocturnal hypertension can be accounted for by several heterogeneous pathophysiological mechanisms (Figure 1.32). First, nighttime BP surges driven by increased sympathetic activity could trigger nocturnal cardiovascular events and potentiate age‐related target organ damage (Figure 1.32). These surges in nighttime BP have a number of potential triggers (including an episode of obstructive sleep apnea, arousals, rapid‐eye‐movement sleep, and nocturia) and are augmented by an impaired baroreflex secondary to increased sympathetic tone and vascular stiffness.

Second, nocturnal hypertension may represent the final stage of hypertension in individuals with target organ damage and other comorbidities (Figure 1.32). Sympathetic activity during sleep is lower than that in the morning and daytime periods, meaning that nighttime BP is less likely to increase than BP at other times of the day. In general, BP increases with age; morning BP increases first due to the higher level of sympathetic activity in the morning, while nighttime BP is the last to increase because sympathetic tone is lower at night. This means that increases in night‐time BP probably indicate advanced structural changes in the large and small arteries (i.e. increased arterial stiffness and vascular resistance) and increased circulating volume because the ability of the kidneys to excrete sodium is reduced.

Third, the supine position during sleep results in increased venous return from the lower body to the heart, which increases left ventricular (LV) preload (Figure 1.32). LV wall stress secondary to the increase in afterload associated with nocturnal hypertension is augmented by the nighttime increase in LV preload (Law of Laplace). Increased LV wall stress is a risk factor for nocturnal‐onset HF. Furthermore, LV preload is also increased by a shift of interstitial fluid from the soft tissue of the lower body into the circulating volume. The simultaneous increase in nighttime circulating volume and nighttime BP could combine to worsen renal function by increasing intraglomerular pressure and hyperfiltration (Figure 1.32).

Finally, morning dosing of existing antihypertensive agents may not provide sufficient BP‐lowering coverage through the nighttime period, despite reductions in daytime BP. This means that nocturnal hypertension could go undetected if not specifically assessed.

Extreme dipping

Extreme dippers with nighttime BP fall of ≥ 20% also show increased cardiovascular risk, including advanced silent cerebral disease detected by brain MRI (Figure 1.33) [7] . A typical case of extreme dipping is shown in (Figure 1.34) [41] . In addition, the prospective JMS‐ABPM study wave 1 showed that elderly patients with hypertension who had an extreme dipper pattern were at increased risk of future clinical stroke events (Figure 1.6) [8] . Results from the JAMP study are consistent, showing that patients with an extreme dipper pattern were at high risk of experiencing a stroke event (Figure 1.35) [16] . This relationship was due to an increase in stroke risk in extreme dipper patients with well‐controlled 24‐hour BP, whereas the risk of stroke was not significantly increased in extreme dipper patients for whom 24‐hour BP was uncontrolled (Figure 1.36) [16] . In a meta‐analysis of data from 17 312 hypertensive patients from three continents, the Ambulatory Blood pressure Collaboration in patients with hypertension (ABC‐H) study found that an extreme dipper pattern was only significantly associated with cardiovascular events in patients with hypertension not receiving antihypertensive medication (Figure 1.37) [42] . Furthermore, the relationship between extreme dipping and cardiovascular events appears to be modified by patient age, being greatest in those aged 70–79 and, especially, ≥80 years (Figure 1.38) [43] .

The increase in cardiovascular risk associated with extreme dipping can be predicted by the target organ damage documented in these patients. In the CARDIA study of young normotensive subjects, extreme dippers, non‐dippers, and risers (based on baseline ABPM) went on to develop more advanced coronary calcification over the next ≥10 years. Even after controlling for baseline covariates, the risk of having coronary calcium was at least four times greater in both extreme dippers and non‐dippers/risers compared with normal dippers (Figure 1.39) [44] . Extreme dippers have also been shown to have deep white matter lesions on brain MRI [45] , reduced cerebral blood flow [46] , and increased PWV [47] .

The pathophysiology of extreme dipping not well understood. Baroreflex failure caused by increased daytime sympathetic activity in patients with increased arterial stiffness is one possible pathophysiological mechanism (Figure 1.40) [41] . Furthermore, increases in the plasma vasopressin level following head‐up tilting have been shown to be significantly greater in extreme dippers than in dippers, which might counteract lower circulating blood volume in extreme dippers [48] . Extreme dipping is also associated with other phenotypes of BP variability, increasing the risk of organ damage and cardiovascular events.