Many hypertensive patients display an exaggerated increase in blood pressure (BP) levels in the morning, referred to as the morning BP surge, a phenomenon that is known to increase the risk of cardiovascular events [1–5]. Indeed, a number of studies have shown that the onset of acute events, including sudden death, myocardial infarction and stroke peak in the first 4–6 h after awakening [6,7]. The pathogenesis of the morning surge is not well known and understanding the mechanisms responsible for this abnormal increase in BP, particularly in hypertensive patients, might be of help for identifying new therapeutic strategies. Two main definitions of the morning surge in BP are currently used in the literature [8,9]. One is called the ‘sleep-through morning surge’ and is defined as the difference between the morning pressure during the first 2 h after awakening and the average of the lowest nighttime BP. The second definition is the ‘preawakening morning surge’ and is calculated as the difference between the morning BP during the first 2 h after awakening and the BP during the first 2 h before awakening. The level of the morning BP surge at which the risk appears to become excessive is not well known. Kario et al. in their seminal description of the impact of the morning BP surge on stroke events used the 55 mmHg threshold level (top decile of sleep-through morning surge). In the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome that analyzed 5645 people from eight countries, the top decile for the two definitions of morning BP surge was 37 and 28 mmHg, respectively . Using both definitions, the authors suggested that a systolic morning BP surge less than 20 mmHg is unlikely to be associated with increased risk. In a study by Marfella et al., the morning BP surge was defined as a rise in SBP of at least 50 mmHg (90% percentile of normotensive patients) and/or DBP of at least 22 mmHg during the early morning (0600–1000 h), compared with the mean BP during the night. According to Suzuki et al., there are even two types of morning surge, the mechanisms of which may differ. The BP rise occurring immediately after waking up is more common in older hypertensive individuals, and is probably related to augmented arousal response in BP, whereas the morning surge beginning gradually during sleep is more common in younger hypertensive individuals and is characterized by reaching basal BP earlier at night.
Several studies performed in the past decade have found significant relations among the early morning BP surge and target-organ damage in hypertension. Kuwajima et al. reported a significant association between the increase in SBP after arising from bed and left ventricular mass index. Gosse et al. found that left ventricular mass index and wall thickness were better correlated with the SBP on arising than with office BP. Similar results were found by Marfella et al., who found that morning BP surge was significantly positively correlated with left ventricular posterior wall thickness and left ventricular internal diastolic diameter. Some authors have found significant relations of the early morning BP surge also with vascular disease  or white matter lesions of the brain [10,17]. In a group of individuals with exaggerated morning BP surge, Marfella et al. observed that increased sympathetic activity in the morning led to prolonged QTc dispersion, a harbinger of ventricular arrhythmias and sudden death. Prospective studies in Japan and Europe have demonstrated a longitudinal association of the early morning BP surge with cardiovascular events. In older hypertensive individuals, Kario et al. showed that a higher morning BP surge was a main predictor of stroke risk independently of the nocturnal BP decline. In this study, for each 10-mmHg increase in the morning BP surge, the risk of stroke increased by 22%. In the Ohasama study, an exaggerated early morning BP surge was associated with the development of hemorrhagic stroke . These results are consistent with those obtained in a French population in which a higher cardiovascular morbidity and mortality rate was observed in the patients with the highest morning BP surge compared with those in the lowest morning BP surge group . In a recent analysis of the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome, the morning BP surge was associated with a 30–45% increase in hazard for cardiovascular events . Some studies, however, failed to confirm morning surge as an independent predictor of cardiovascular events. This is the case for the evidence collected in the general population sample of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study in which morning BP surge displayed a significant relationship with cardiovascular events only when the data were unadjusted for potential confounders, such as age and the cyclic and noncyclic components of BP variability .
The reason why the morning BP surge is associated with cardiovascular morbidity and mortality may depend on the direct hemodynamic effect of the BP peak on the arterial wall as well as on the effects of the associated neurohumoral activation. Repeated peaks of pressure may favor the development of vascular remodeling through increased mechanical pressure and shear stress [1,2]. In addition, the morning BP surge also seems to have a role in the progression of atherosclerosis. Marfella et al. demonstrated that exaggerated morning surge in BP was significantly associated with vulnerable plaques and stressed the importance of oxidative stress and activation of the ubiquitin–proteasome system as the mechanism of morning BP surge-related plaque instability. In addition, hypertensive patients with exaggerated morning BP surge were found to have higher levels of systemic inflammatory markers, such as high-sensitive C-reactive protein and interleukin-6, than those without surge.
Given the detrimental effect of an exaggerated morning surge on the cardiovascular system, it is important to unveil the mechanisms responsible for this hemodynamic phenomenon. According to most authors [1,2,22–24], the sympathetic nervous system is a key regulator of the morning BP surge and a sudden activation of the sympathetic nervous system, particularly the α-adrenergic component, is thought to be the primary mediator of the morning rise in BP. A significant rise both in epinephrine and norepinephrine has been found to be responsible for the morning increase in BP in normal individuals [25,26].
In this issue of the Journal of Hypertension, Hering et al. investigated the relationship between the morning BP surge and sympathetic activity through microneurographic assessment of sympathetic nerve traffic to blood vessels. Muscle sympathetic nerve activity (MSNA) was measured during undisturbed supine rest in 68 untreated hypertensive patients. In a multivariate analysis, taking into consideration age, BMI and sex, they found that MSNA was independently related to both daytime (P = 0.006) and night-time heart rate (P = 0.02), but not to the morning surge of BP, either calculated as the difference between the morning BP and the preawake BP or the morning BP minus mean BP during the 1 h that included the lowest sleep BP. They concluded that sympathetic neural mechanisms are unlikely to contribute to the morning BP surge in recently diagnosed essential hypertensive patients. According to Hering et al. the lack of relationship between the morning surge and MSNA in their study might be attributed to the relatively small average preawakening SBP morning surge present in their group (19 mmHg) compared with previous reports. In the study by Li et al., only a morning BP surge exceeding 37.0 mmHg at least was a significant and independent predictor of mortality and cardiovascular events. In the prospective clinical study by Kario et al., a BP surge of at least 55.0 mmHg was an independent risk factor involved in stroke events in elderly hypertensive individuals. However, the lack of correlation between morning hemodynamics and MSNA measured in resting conditions may not be surprising. As the authors themselves point out, patients were studied in the supine position using direct measurements of MSNA from the peroneal nerve during daytime and not upon awakening. For obvious technical reasons, measurement of MSNA was not available during sleep (very few are the studies performed so far recording MSNA during sleep) and, thus, direct calculation of the change in sympathetic nervous system activity from night to day was not possible. The results obtained by Marfella et al. with spectral analysis of heart rate variability in two groups of hypertensive individuals, one with exaggerated BP morning surge and one with normal BP rise, may reconcile the apparently conflicting results of the study by Hering et al. with those by other investigators. In keeping with the results by Hering et al., Marfella et al. found no significant differences between the two morning surge groups for the low-frequency/high-frequency power ratio (LF/HF), an indirect index of sympathetic activity, during the daytime or the nighttime period (Fig. 1) . However, the morning LF/HF ratio was significantly higher in the individuals with exaggerated morning surge than in the rest of the group. In addition, a relative decrease in the high-frequency component and a significant increase in LF/HF ratio was observed in the individuals with exaggerated BP surge during the morning period. Also, diurnal and nocturnal plasma catecholamine concentrations, other well recognized markers of sympathetic activity, did not differ according to the amplitude of the morning surge . However, in the individuals with large morning BP surge, both urinary epinephrine and norepinephrine outputs during the morning period were significantly greater than that in individuals with normal BP rise. These data confirm that autonomic nervous system activity measured in steady-state basal conditions may be normal in patients with increased BP morning surge. However, the greater morning increase in LF/HF ratio and urinary catecholamine levels observed in people with morning BP peaks indicate that sympathetic reactivity is a key determinant of the morning rise in BP. According to Kario et al., an exaggerated morning BP surge may be present in extreme dippers that may be closely associated with morning sympathetic activation. These authors found that 24% of extreme dippers had an exaggerated morning BP surge, which was accompanied by orthostatic increases in BP and plasma norepinephrine levels that were selectively abolished by an α-adrenergic blocker.
On the basis of the background information provided by the experimental studies discussed above, it is reasonable to hypothesize that the α-adrenergic vasoconstrictor response of small resistance vessels, and a progressive remodeling of the small vessels with time, would contribute to the BP rise upon awakening chiefly in predisposed individuals. Risk factors for a profile of excessive early morning hypertension include excessive alcohol use and tobacco consumption, older age, longer sleep times and later awakening times [1,2]. Data by Modesti et al. showed that cold weather was significantly associated with increased morning BP surge in elderly individuals, which may partly account for the increased number of cardiovascular events observed in the morning during the winter season.
Several other mechanisms have been postulated to explain the morning BP surge. Different functional alterations of the circulation can variably combine in individual patients and account for the heterogeneous pathophysiological mechanisms of the morning rise in BP. The renin–angiotensin–aldosterone system (RAAS) is also activated in the morning and could contribute to the high BP reactivity in the morning [1,2]. In addition to circulating factors, it was shown that tissue RAAS also exhibits diurnal variation, possibly in relation to a clock gene . Reduced endothelial function could contribute to the exaggerated increases in vascular resistance and peaks of pressure during the morning hours [31,32]. Even in healthy individuals, flow-mediated dilatation of the brachial artery was reduced in the early morning when compared with other periods of the day , and the degree of attenuation in endothelial function in the morning in healthy normal individuals was very similar to the attenuation of brachial artery reactivity found in high-risk patients . Marques et al. recently studied the genes responsible for exaggerated circadian variation of BP in the Schlager hypertensive mouse, a model that exhibits a similar morning BP surge as seen in human essential hypertension. These authors identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in the expression of hormones implicated in the regulation of BP such as vasopressin, oxytocin and thyrotropin-releasing hormone. In summary, several potential causes of exaggerated morning BP surge have been described in hypertension, suggesting different, and variously concurrent, pathogenetic mechanisms in individual patients, which can account for the described heterogeneous pathophysiological features of this hemodynamic phenomenon. These mechanisms may variously involve a transient increase in neurohumoral vasoconstrictor activity and a background of increased susceptibility to vasoconstrictor agents.
Although the morning BP surge may be seen as a physiological phenomenon in the hypertensive patients, it is an independent risk factor for the development of atherosclerosis and target-organ damage and a potential trigger of cardiovascular events. Thus, in addition to strict BP control, it seems reasonable to consider targeting this time of day with appropriate antihypertensive drug therapy. As suggested by some investigators , α-adrenergic blockade at bedtime may be an effective means to reduce the morning BP rise in patients with uncontrolled ‘morning hypertension.’ Also, renin–angiotensin-blocking agents that maintain pharmacodynamic effects into the early morning period may be of help in individuals with exaggerated rise in morning BP . These two classes of drugs would favorably act on the two main mechanisms that regulate BP during this period of the day. Future research should appropriately focus on the effect of a therapy targeting BP and heart rate in the early morning to evaluate whether reduction of the morning surge will reduce cardiovascular morbidity and mortality.
Conflicts of interest
There are no conflicts of interest.
1. Kario K. Morning surge in blood pressure and cardiovascular risk: evidence and perspectives. Hypertension
2. White WB. The risk of waking-up: impact of the morning surge in blood pressure. Hypertension
3. Eguchi K, Matsui Y, Shibasaki S, Hoshide S, Kabutoya T, Ishikawa J, et al. Japan Morning Surge-1 (JMS-1) Study GroupControlling evening BP as well as morning BP is important in hypertensive patients with prediabetes/diabetes: the JMS-1 study. Am J Hypertens
4. Turin TC, Kita Y, Rumana N, Takashima N, Ichikawa M, Sugihara H, et al. Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990–2003. Eur J Neurol
5. Amici A, Cicconetti P, Sagrafoli C, Baratta A, Passador P, Pecci T, et al. Exaggerated morning blood pressure surge and cardiovascular events. A 5-year longitudinal study in normotensive and well controlled hypertensive elderly. Arch Gerontol Geriatr
6. White WB. Clinical assessment of early morning blood pressure in patients with hypertension. Prev Cardiol
7. Muller JE, Ludmer P, Willich SN, Tofler GH, Aylmer G, Klangos I, et al. Circadian variation in the frequency of sudden cardiac death. Circulation
8. Stergiou GS, Mastorantonakis SE, Roussias LG. Morning blood pressure surge: the reliability of different definitions. Hypertens Res
9. Wizner B, Dechering DG, Thijs L, Atkins N, Fagard R, O’Brien E, et al. Short-term and long-term repeatability of the morning blood pressure in older patients with isolated systolic hypertension. J Hypertens
10. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular diseases in elderly hypertensives: a prospective study. Circulation
11. Li Y, Thijs L, Hansen TW, Kikuya M, Boggia J, Richart T, et al. for the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes InvestigatorsPrognostic value of the morning blood pressure surge in 5645 subjects from 8 populations. Hypertension
12. Marfella R, Gualdiero P, Siniscalchi M, Carusone C, Verza M, Marzano S, et al. Morning blood pressure peak, QT intervals, and sympathetic activity in hypertensive patients. Hypertension
13. Suzuki Y, Kuwajima I, Mitani K, Miyao M, Uno A, Matsushita S, et al. The relation between blood pressure variation and daily physical activity in early morning surge in blood pressure [in Japanese]. Nihon Ronen Igakkai Zasshi
14. Kuwajima I, Mitani K, Miyao M, Suzuki Y, Kuramoto K, Ozawa T. Cardiac implications of the morning surge in blood pressure in elderly hypertensive patients: relation to arising time. Am J Hypertens
15. Gosse P, Ansoborlo P, Lemetayer P, Clementy J. Left ventricular mass is better correlated with arising blood pressure than with office or occasional blood pressure. Am J Hypertens
16. Marfella R, Siniscalchi M, Nappo F, Gualdiero P, Esposito K, Sasso FC, et al. Regression of carotid atherosclerosis by control of morning blood pressure peak in newly diagnosed hypertensive patients. Am J Hypertens
17. Murakami S, Otsuka K, Kubo Y, Shinagawa M, Yamanaka T, Ohkawa S, et al. Repeated ambulatory monitoring reveals a Monday morning surge in blood pressure in a community dwelling population. Am J Hypertens
18. Metoki H, Ohkubo T, Kikuya M, Asayama K, Obara T, Hashimoto J, et al. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the Ohasama Study. Hypertension
19. Gosse P, Lasserre R, Minifie C, Lemetayer P, Clementy J. Blood pressure surge on rising. J Hypertens
20. Bombelli M, Polo Friz H, Primitz L, Toso E, Ganz F, Buzzi S, et al.
Relationship of morning blood pressure surge with cardiovascular events and total mortality in a general population. J Hypertens
21. Marfella R, Siniscalchi M, Portoghese M, Di Filippo C, Ferraraccio F, Schiattarella C, et al. Morning blood pressure surge as a destabilizing factor of atherosclerotic plaque: role of ubiquitin-proteasome activity. Hypertension
22. Grassi G, Bombelli M, Seravalle G, Dell’Oro R, Quarti-Trevano F. Diurnal blood pressure variation and sympathetic activity. Hypertens Res
23. Palatini P, Julius S. The role of cardiac autonomic function in hypertension and cardiovascular disease. Curr Hypertens Rep
24. Kaplan NM. Morning surge in blood pressure. Circulation
25. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl J Med
26. Dodt C, Breckling U, Derad I, Fehm HL, Born J. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension
27. Hering D, Kucharska W, Kara T, Somers VK, Narkiewicz K. Resting sympathetic outflow does not predict the morning blood pressure surge in hypertension. J Hypertens
28. Kario K, Pickering TG, Hoshide S, Eguchi K, Ishikawa J, Morinari M, et al. Morning blood pressure surge and hypertensive cerebrovascular disease: role of the alpha adrenergic sympathetic nervous system. Am J Hypertens
29. Modesti PA, Morabito M, Bertolozzi I, Massetti L, Panci G, Lumachi C, et al. Weather related changes in 24-h blood pressure profile: effects of age and implications for hypertension management. Hypertension
30. Naito Y, Tsujino T, Fujioka Y, Ohyanagi M, Iwasaki T. Augmented diurnal variations of the cardiac renin-angiotensin system in hypertensive rats. Hypertension
31. Otto ME, Svatikova A, Barretto RB, Santos S, Hoffmann M, Khandheria B, et al. Early morning attenuation of endothelial function in healthy humans. Circulation
32. Kario K. Morning surge and variability in blood pressure: a new therapeutic target? Hypertension
33. Marques FZ, Campain AE, Davern PJ, Yang YH, Head GA, Morris BJ. Genes influencing circadian differences in blood pressure in hypertensive mice. PLoS One
34. Matsui Y, Eguchi K, Shibasaki S, Ishikawa J, Hoshide S, Pickering TG, et al. Effect of doxazosin on the left ventricular structure and function in morning hypertensive patients: the Japan Morning Surge 1 Study. J Hypertens
35. White WB, Weber MA, Davidai G, Neutel JM, Bakris GL, Giles T. Ambulatory blood pressure monitoring in the primary care setting: assessment of therapy on the circadian variation of blood pressure from the MICCAT-2 Trial. Blood Press Monit