It is well known that hypertension is accompanied by a structural change in arteries of various size, from the small resistance artery to the large conduit artery. In this issue of the journal, Rizzoni et al. report an interesting study demonstrating that small artery remodeling is significantly correlated with a morning blood pressure (BP) surge in essential hypertension. In their study, small artery remodeling was directly assessed by the media thickness to lumen diameter ratio (M/L ratio) of the subcutaneous small artery. Based on previous reports, including their own study on the morning BP surge, it is time to join forces on morning hypertension in clinical practice [2,3]. In this editorial comment, I would like to stress the importance of the morning BP surge from a two-clinical points of view: (i) as a triggering risk factor in high-risk patients and (ii) as a possible indicator of prehypertension.
Morning blood pressure surge as a triggering factor
There is a diurnal variation of the onset time of cardiovascular events. Both clinical and silent cardiovascular events occur most frequently in the morning hours. The BP exhibits a similar diurnal variation, with a morning surge. In our previous prospective study in elderly patients with essential hypertension, an exaggerated morning BP surge was an independent risk factor for clinical stroke .
An exaggerated morning BP surge is one of the various surges in BP occurring in the ambulatory situation. Ambulatory BP variability is a possible risk for cardiovascular events; however, it is still controversial whether it is associated with cardiovascular risk independently of BP level . The 24-h ambulatory BP variability includes various behavior-induced BP changes and specific components of diurnal BP variation, which is a potential triggering risk for cardiovascular events in high-risk hypertensive patients. In addition to abnormal diurnal BP variation, such as marked nocturnal BP falls (extreme-dippers) and reverse diurnal BP variation patterns with higher sleep BP than awake BP (risers), these specific surge components may be more closely associated with hypertensive target organ damage, including small artery remodeling and subsequent cardiovascular events, than overall 24-h ambulatory BP variability . These phenotypes of ambulatory BP variability are partly associated with each other and with 24-h ambulatory BP variability. Abnormal diurnal BP variation is associated with other relatively shorter BP variability, such as orthostatic BP variability in elderly hypertensives . An exaggerated midnight surge at each sleep apnea episode was detected by hypoxia-triggered BP monitoring , and this surge may also contribute to cardiovascular events during sleep when cardiac sudden death occurs more frequently in patients with sleep apnea .
Ambulatory BP variability, including the morning BP surge, is more exaggerated in hypertensive patients than in normotensive patients . In addition to small artery remodeling, impaired baroreceptor sensitivity caused by large artery disease would amplify the BP surge, and baroreceptor sensitivity is decreased early in the morning . Recently, an exaggerated morning BP surge was reported to be associated with an increased inflammatory response and plaque instability in high-risk hypertensive patients with carotid artery disease [12,13]. Thus, the morning BP surge would be important as a triggering risk factor for cardiovascular events, particularly in high-risk hypertensive patients. Thus, in addition to strict BP control, antihypertensive therapy targeting the morning BP surge, along with plaque stabilizing strategies using statins, peroxisome proliferator-activated receptor-γ agonists and inhibitors of the renin–angiotensin system, could achieve a more beneficial effect for the prevention of cardiovascular disease in high-risk hypertensive patients .
Small artery disease and target organ damage
In previous prospective studies, the small artery M/L ratio was reported to be an independent predictor of cardiovascular events in hypertensive patients [15,16]. This ratio is reported to be associated with the reserve capacity of coronary blood flow in hypertensive patients. Small artery remodeling develops along with age and endothelial cell dysfunction before the development of hypertension, and it is accelerated with a higher BP level and metabolic risk factors such as diabetes . Previously, we found that an exaggerated morning BP surge is associated with silent cerebral infarcts detected by brain magnetic resonance imaging (MRI) independently of 24-h BP in elderly individuals . Silent cerebral infarcts are strong predictors of clinical stroke independently of 24-h BP level , particularly in conditions of increased atherosclerotic inflammatory reaction . Although it is not certain whether subcutaneous small artery remodeling and silent cerebral infarcts develop in parallel, silent cerebral infarcts usually are lacunar infarcts of the small cerebral artery. It is well known that sympathetic activity, particularly α-adrenergic activity, is increased in the morning and, in our previous study, silent cerebral infarcts were more closely associated with the morning BP surge related to α-adrenergic activity (defined as the reduction in morning BP surge by the α-blocker, doxazosin) than the overall morning BP surge.
An indicator of prehypertension
The positive correlation between the morning BP surge and small artery remodeling found in the study of Rizzoni et al. indicated another important role of morning BP surge on the pathogenesis of hypertension. As well as a consequence of hypertension, small artery remodeling is also important as a leading cause of hypertension, which is a disease of increased peripheral resistance. Narrowing of the small arterioles has been hypothesized to contribute to the pathogenesis of hypertension, but the available prospective clinical data are scarce. There is no direct prospective study demonstrating that the M/L ratio of the subcutaneous small artery is a risk factor of hypertension. Smaller retinal arteriolar diameters were independently associated with incident hypertension in a population-based cohort, the Atherosclerosis Risk in Communities (ARIC) Study, suggesting that small artery remodeling is the preceding risk factor for hypertension . In the ARIC study, retinal arteriolar narrowing also was an independent risk factor of coronary heart disease in both men and women , and was significantly associated with silent cerebral infarcts detected by brain MRI .
As the morning surge is a physiological phenomenon, the significant association between a morning BP surge and small artery remodeling would begin in the earlier stage of the progression to hypertension from normotension (Fig. 1). As small artery remodeling is initiated from the earliest stage of hypertension , some subjects with an exaggerated morning surge, even when they are normotensive according to their clinical BP, may be considered as being in the stage of prehypertension. Thus, an exaggerated morning rise in BP may be one of the indicators of a prehypertensive status with advanced small artery remodeling. In future studies, the association between an exaggerated morning BP surge and small artery remodeling should be investigated directly.
Some of the other surges, such as orthostatic hypertension, physical and psychological stress-induced BP reactivity, and white-coat hypertension, etc. were reported to be a risk for developing hypertension [24–27], and probably may be accepted as a cardiovascular risk in the future . Although they are triggered by different specific pressor stimulations, these surges may partly be related to each other on the basis of sympathetic hyperactivity. In our previous study, orthostatic hypertension was associated with an increase in morning BP level . These ambulatory BP surges may be partly considered as indicating a prehypertensive status (Fig. 1).
The activation of various neurohumoral factors, including the sympathetic nervous system and the renin–angiotensin system, occurs in the morning. The morning surge triggered by these pressor stimulations could be augmented in the presence of small artery remodeling because of the limited capacity of vasodilation. In the morning, endothelial cell dysfunction is found even in healthy subjects, and this may partly augment the morning surge with small artery remodeling . Thus, the threshold of a BP surge by pressor stimuli may be lowest in the morning; in other words, the morning comprises a sensitive period for detecting a surge and variability in BP, which both reflect the vascular status. Indeed, ambulatory BP variability in response to physical activity (ambulatory BP reactivity)  and the time rate of BP variability are highest in the morning [31,32] and are associated with carotid intima–media thickness and left ventricular hypertrophy [31,33].
An exaggerated morning BP surge and BP variability in the morning may partly reflect the status of subclinical vascular disease and may also be sign of prehypertension, even when the average of BP levels is still in the normotensive range. The development of BP monitoring devices to detect the surge and variability in the morning reproducibly, as well as further prospective and interventional studies, are necessary to establish the clinical impact of a morning BP surge on target organ damage and cardiovascular events in normotensive subjects and hypertensive patients. Clinically, the detection and management of morning hypertension using self-measured home BP monitoring is likely to achieve greater beneficial target organ protection and the prevention of cardiovascular events.
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