Morning Surge in Blood Pressure: A Phenotype of Systemic Hemodynamic Atherothrombotic Syndrome

Cardiovascular events frequently occur in the morning, and blood pressure (BP) also exhibits circadian variation with a peak in the morning. We have previously demonstrated that exaggerated morning BP surge (MBPS), defined by ambulatory BP monitoring (ABPM), is a risk factor for future stroke in elderly hypertensives.1 Recent hypertension guidelines have documented the clinical relevance of MBPS, but have not yet made clear recommendations for antihypertensive treatments targeting MBPS. In this issue, Sheppard et al.2 provide a timely meta-analysis and demonstrate that MBPS is significantly associated with stroke risk. We have recently proposed a novel disease entity, systemic hemodynamic atherothrombotic syndrome (SHATS), which is characterized by the combination of hemodynamic stress and vascular disease and is a risk factor for cardiovascular events and organ damage (Figure 1).3,4 Exaggerated MBPS is one of the phenotypes of the BP variability in SHATS. In this editorial comment, I will address several lingering clinical questions in regard to MBPS from the viewpoint of this new disease entity. Concept of systemic hemodynamic atherothrombotic syndrome (SHATS)–acceleration of the risk of cardiovascular events and organ damage via a vicious cycle of hemodynamic stress and vascular disease. BP, blood pressure. *The phenotypes of BP variability of SHATS include morning BP surge, orthostatic BP dysregulation, nocturnal BP rise, and sleep apnea-triggered sleep BP surge. The novel contribution of SHATS is its synergistic consideration of various types of BP variability and hemodynamic stress in relation to vascular disease.3,4 SHATS is defined by both vascular (one or more clinical/subclinical vascular diseases) and BP components (one or more phenotypes of BP variability), although the precise definition and criteria of SHATS are not clearly established yet.3,4 Nonetheless, the concept underscores that clinicians should recognize the synergistic risk posed by exaggerated BP variability and vascular damage in clinical practice. Cardiovascular events are more likely to occur in patients with exaggerated MBPS than those with lower MBPS.1,2,5–7 Our prospective study showed for the first time that exaggerated MBPS defined by ABPM is associated with poor stroke prognosis in older hypertensives. After our patients were matched for age and 24-h BP, the relative risk of the MBPS group (top decile of MBPS >55 mmHg) vs. the non-surge group remained significant (2.7, P = 0.04).1 The risk posed by MBPS is likely to be independent of the 24-h BP level. Although the magnitude of MBPS is significantly correlated with the 24-h BP level,1,5 even in population-based studies including a large majority of normotensives, MBPS has been found to be an independent risk factor of cardiovascular events.6,7 The analysis of age- and sex-adjusted relative risk and 95% confidence intervals for the association between MBPS and incidence of cardiovascular events, after stratification according to hypertension classification, would expand the prognostic continuum of MBPS in clinical practice and could complement the risk stratification provided by current hypertension guidelines. A single ABPM may not be sufficient to characterize the MBPS profile and clinical prognosis in individual patients, due to the low reproducibility.8,9 The reproducibility of MBPS appears to be dependent on the number of BP readings that are averaged to define the pre- and post-rising BP. MBPS defined as the average over the first 2h after rising (morning BP) minus the average BP during sleep has been shown to provide the most reproducible results.8 However, by this definition an increase in the number of BP readings might increase the overlap with the dipping status of nocturnal BP. Thus, I first used a definition of dynamic sleep-trough MBPS based on the morning BP minus the least average over the 1h during sleep independently of nocturnal BP dipping.1,5 The pathophysiological effects of MBPS on cardiovascular events may be different from those of nocturnal BP dipping, since a recent study on treated elderly hypertensive demonstrated that exaggerated MBPS predicts stroke in dippers but not in nondippers.10 Because the magnitude of MBPS is significantly associated with the level of physical activity in the hours after arising,11 physical activity should be taken into account to assess the MBPS. The ABPM device equipped with an actigraph shows promise for increasing the reproducibility of MBPS by identifying the precise arising time,9 and for assessing the morning BP reactivity independently of physical activity (the slope of MBPS against physical activity), which may be a new biomarker of morning risk.5 In the linear model, a 10-mmHg increase in MBPS has been associated with an 11% increased risk of stroke.2 However, its association with cardiovascular risk may not be linear, since mild MBPS is physiological. Although there are numerous studies indicating the strong predictive ability of MBPS, a few studies have struck a discordant note. In a prospective study of hypertensives, blunted MBPS was an independent predictor of cardiovascular events.12 Similarly, a study of patients referred for ABPM showed that an increased MBPS was significantly associated with decreased mortality, especially in nondippers.13 Thus, both extremes—i.e., the absence (or a negative value) of MBPS, and exaggerated MBPS may be pathological, resulting in nonlinear J-shaped (or U-shaped) associations with specific thresholds between MBPS and cardiovascular events.5 Thus, the identification of pathological thresholds of MBPS is clinically important. In high-risk patients, advanced vulnerable plaque may be the first target. MBPS triggers plaque rupture by mechanical stress of BP and shear stress from exaggerated variability of blood flow, resulting in the onset of cardiovascular events. The small arteries branching rectangularly from large arteries may be an appropriate second target.3 These vessels are the so-called “strain vessels” that are anatomically exposed to high pressure and that must maintain strong vascular tone in order to provide large pressure gradients from the parent vessels to the capillaries.14 These vascular structures are found in the cerebral perforating arteries, renal juxtamedullary afferent arterioles, and retinal and coronary arteries.14 Cerebral hemorrhage and infarction occur most frequently in the regions of the small perforating arteries. In fact, in elderly hypertensives, silent cerebral infarcts, particularly when occurring as multiple silent cerebral infarcts, is more frequently detected by brain magnetic resonance imaging in the exaggerated MBPS group than in the normal MBPS group.1 In addition, cerebral hemorrhage was observed more frequently in the exaggerated MBPS group than the normal MBPS group.6 Large artery disease will augment the impact of exaggerated MBPS on atherosclerotic and small artery-related cardiovascular events. An increase in large artery stiffness decreases the attenuation of pulse to transmit to the peripheral arteries.15 In particular, exaggerated MBPS and BP variability constitute risks for branch atheromatous disease, which frequently occurs in the proximal lesions of perforating cerebral arteries such as the lenticulostriate arteries and paramedian pontine arteries. The branch atheromatous diseases are known to be associated with metabolic risk factors for advanced atherosclerotic large artery disease.16 The focal pressure on the proximal portion of the strain vessel is higher in those with increased stiffness of the large artery. Exaggerated MBPS, specifically potentiated by neurohumoral activation in the morning, is the phenotype of BP variability of SHATS. SHATS is characterized by an increase in BP variability and clinically detected by one of the specific surges, which may partly be associated with each other. In fact, MBPS is associated with other phenotypes such as orthostatic hypertension (a 15 –20 mmHg increase in systolic BP by standing), increase in the SD of daytime ambulatory BPs, and circadian BP variation, especially with extreme-dipping of nocturnal BP (a nocturnal systolic BP fall >20%).4,5,17,18 Although it remains unclear whether MBPS provides information beyond the overall BP variability indices (independent effect),19 with the use of antihypertensive agents that target the underlying pathophysiological mechanisms related to MBPS—e.g., bedtime dosing of sympatholytic agents and drugs blocking the renin angiotensin system—the control of morning hypertension might become a clinically feasible and potentially important therapeutic target. Increases in BP variability, central pressure, and impaired baroreceptor sensitivity are the three BP measures of SHATS, and are closely related.4 The overall underlying mechanism of SHATS may include impaired neural and vascular components of baroreflex due to increased central sympathetic activity and decreased carotid dispensability, respectively. In addition, small artery remodeling as well as large artery disease may contribute to increases in BP variability.3,4 Arterial stiffness and pressure wave reflections are two important components of pulsatile hemodynamics. The measurements of ambulatory BP, including MBPS, can reflect pulsatile hemodynamics through the influences of arterial stiffness and wave reflections. In other words, these BP measures are the presentations (or epiphenomena) of the alterations of the arterial pulsatile hemodynamics. The degree of central and peripheral neurohumoral activation and their related cardiovascular reactivity in each specific condition may determine the different phenotypes of BP variability. There is growing evidence that increased BP variability poses a risk of cardiovascular disease.20 There is insufficient evidence to determine whether pharmacological targeting of MBPS can cause regression of organ damage and prevention of cardiovascular consequences. However, evidence that MBPS is independently associated with stroke should, in addition to lowering average BP, encourage the search for means to mute both the morning surge, and its deleterious consequences. Potential therapeutic strategies to achieve these goals include timing of medication dosing, renal denervation, or baroreceptor sensitization,3 as well as improved organ protection. The author declared no conflict of interest.