The Morning Blood Pressure Surge: Therapeutic Implications

Abstract

Adverse cardiovascular events such as myocardial infarction, stroke, arrhythmias, and sudden cardiac death are well known to follow a circadian pattern, peaking in the morning hours of 6 am to 12 pm. Many physiologic factors have been shown to follow a circadian pattern and together may create an environment that promotes intraluminal thrombi formation. Blood pressure follows this pattern with a “dip” at night and an increase on awakening. This morning surge may lead to hemodynamic forces that predispose patients to plaque rupture. The clinical impression of these known physiologic patterns associated with adverse cardiovascular events suggests that a strict treatment schedule targeting this phenomenon is needed. The goal of this review is to provide clinicians with an overview, allowing for informed decisions about chronotherapeutic formulations tailored to provide blood pressure control throughout the day and night.

The clinical management of hypertension and its associated adverse cardiovascular (CV) outcomes has consistently been at the forefront of prevention‐based care. Recently, our understanding of hypertension includes the complexities of fluctuations in blood pressure (BP). Part of this understanding has focused on the phenomenon known as the morning surge. In this review, we survey the quantification of the morning surge, its suspected causes, its associated clinical impacts and, finally, some suggestions for its management.

MEASURING THE MORNING SURGE

Multiple studies have used ambulatory BP monitoring (ABPM) to demonstrate that BP diurnally fluctuates. ¹ , ² It is accepted that most individuals experience a 10% to 20% nighttime “dip” in systolic and diastolic pressure. Staessen and colleagues ¹ characterized this pattern in an international database of hypertensive (n=2555) and normotensive (n=4765) patients using ABPM. The authors measured the nocturnal decrease as a ratio of nocturnal mean BP to day mean BP expressed as percentages.

Following this dip, a morning surge most commonly occurs between the hours of 6 am and 12 pm. There is a moderate and steady increase in BP before arousal, characterized by an increase in systolic BP (SBP) of approximately 3 mm Hg/h and in diastolic BP of 2 mm Hg/h. ³ At approximately 6 am, coincident with arousal, a spike in BP occurs. Kario and colleagues ⁴ calculated this morning surge by subtracting the mean SBP for the hour, including the lowest sleep BP, from the mean 2‐hour SBP after waking.

It is this morning surge that presents itself as a possible target for clinicians to control, particularly because there appears to be physiologic influences contributing to its origin or magnitude.

FACTORS INFLUENCING THE MORNING SURGE

Numerous physiologic and biochemical interactions may contribute to the BP surge seen in the early morning hours (Table). The most prominent is likely the sympathetic nervous system (SNS). Catecholamine levels closely follow the circadian BP pattern. ⁵ In a previous study in which doxazosin, an α‐blocking agent, was given at night to hypertensive patients, the peak effect was observed in the morning, likely due to this SNS pattern. ⁶

Table.

Factors that Influence the Morning Surge in Blood Pressure

Sympathetic nervous system

Renin‐angiotensin system

Increase in platelet aggregation

Plasminogen activator inhibition

Mechanical flow disturbances

Ubiquitin‐proteosome system

Oxidative stress (increased reactive oxygen species)

Plasma cortisol

Nitric oxide

Mental/physical activity

Tobacco/alcohol use

Sodium/caffeine/medication ingestion

Age (>70 y)

African American ethnicity

Day of week/season of year

Another contributor to the diurnal BP pattern is the renin‐angiotensin‐aldosterone system. Plasma renin decreases during the day with a nadir at approximately 4 pm. This is followed by a gradual overnight increase, peaking at 8 am. Plasma aldosterone follows a similar pattern, as does angiotensin II. Actual levels of these substances may show more complex variation throughout the day, although the trend of a gradual increase overnight is recognized. ⁷

Further evidence suggests that microvascular and molecular changes are related to the morning BP surge. Greater common carotid artery intima‐media thickness values, ⁸ increased reactive oxygen species formation by mononuclear cells, ⁹ and enhanced ubiquitin‐proteosome activity (associated with inflammatory‐induced plaque rupture) in atherosclerotic lesions ¹⁰ have all recently been shown to have an association with the BP rise.

A variety of other factors have also been suggested to contribute to the morning physiologic response, including age older than 70 years, ¹ African American ethnicity, ¹¹ mental/physical activity, ¹² tobacco/alcohol use, ¹³ , ¹⁴ sodium/caffeine/medication ingestion, ¹⁵ , ¹⁶ , ¹⁷ plasma cortisol levels, ¹² nitric oxide levels, ¹⁸ and even the day of the week or season of the year (Monday/winter). ¹⁹ , ²⁰

Although the definitive capacity in which the above factors may cause or contribute to the morning surge requires further investigation, it is clear that the morning surge may carry an increased risk for patients.

MORNING SURGE AS A RISK FACTOR FOR CV AND EXTRACARDIOVASCULAR DISEASE

Morning is the peak time for a variety of adverse CV events. Gosse and colleagues ²¹ analyzed the morning surge in 507 patients with untreated hypertension. They calculated a mean increase in SBP of 14 (SD ±15) mm Hg during the early morning and found that this rise was independently associated with an increased risk of CV complications.

Stroke also occurs most often in the morning. Kario and colleagues ⁴ investigated the association between the morning BP surge and cerebrovascular disease in elderly hypertensive patients; they also quantified this surge, associating magnetic resonance imaging‐evident infarcts to specific surge magnitudes. The group with a morning BP surge of ≥55 mm Hg (n=53) had a higher prevalence of silent cerebral infarction (70% vs 48%; P<.002) and a higher incidence of stroke (19% vs 7.3%; P<.004) during an average 41‐month follow‐up period than did the group with lower BP surges (n=466). After controlling for age, sex, body mass index, and 24‐hour SBP, the relative risk of the morning BP surge group remained significant (relative risk, 2.2; P<0.04). Also evident in this morning surge group was that both ischemic and hemorrhagic strokes clustered within the times of 6 am to 12 pm. Thus, in older hypertensive patients, a greater morning BP surge is associated with more advanced cerebrovascular disease. ⁴

Kuwajima and colleagues ²² conducted an electrocardiographic (ECG) study using ABPM in elderly hypertensive patients to evaluate the relationship between hypertensive cardiac change and morning BP surge. The change in SBP level after rising from bed significantly correlated with the left ventricular mass index (r=0.51; P<.02) and the A/E ratio, which represents diastolic function (r=0.70; P<.01). In contrast, the change in SBP level before rising from bed was not correlated with any ECG parameters. Thus, the researchers concluded that the magnitude of the morning BP surge after arising is itself related to the severity of hypertensive target organ damage.

Myocardial infarction (MI) has a higher incidence in the morning. ²³ In the Thrombolysis in Myocardial Infarction Phase II (TIMI II) trial, ²⁴ Tofler and colleagues observed a 34% higher incidence of MI between 6 am and 12 pm. Cohen and associates ²⁵ performed a meta‐analysis that examined the proportion of morning events that are in excess of those expected in their sample and, more important, the proportion of all events that were attributable to the excess morning events in the population. In their analysis, the incidence rate of acute MI onset was 40% (relative risk, 1.38; 95% confidence interval, 1.37–1.40) higher between 6 am and 12 pm than throughout the rest of the day. Based on the meta‐analysis, 27.7% of morning infarctions, which account for 8.8% (95% confidence interval, 8.5%–9.0%) of all infarctions, are attributable to the morning excess.

There is an increase in platelet aggregability between 6 am and 9 pm. ²⁶ This, in addition to the inverse circadian pattern observed for tissue plasminogen activator activity, which helps to maintain fibrinolytic hemostasis, may lead to a hypercoagulable state. At the same time, the pressure surge may promote an environment of flow disturbances prone to plaque rupture. All of these effects in combination present an increased risk for patients with established CV disease.

While there is evidence that exogenous factors such as physical activity, mental status, and postural changes may play a role in ischemia in the morning, a circadian vulnerability for MI, independent of exogenous factors, is also evident from studies in coronary care environments. ²⁵ , ²⁶ Krantz and colleagues ²⁶ assessed the effects of exogenous activities at different times as well as the contribution of an endogenous circadian vulnerability to ischemia. Sixty‐three patients with stable coronary artery disease underwent ambulatory ECG monitoring and completed a structured diary that recorded physical and mental activities. During the morning, ischemic periods were more likely to occur with high levels of physical activity (P<.001). High levels of mental activity significantly triggered ischemia during the morning (P<.04) and evening (P<.04) but not in the afternoon. After corrections were performed, a circadian pattern was still observed (P<.001), with a peak at 6 am independent of simultaneously measured activities, hourly heart rates, and activity‐related heart rate changes. A significant increase in ischemia occurred immediately after awakening (P<.05), but activity‐adjusted increases in morning ischemia persisted (P<.05) for 2 hours afterward. Thus, the authors concluded that exogenous factors are most potent as triggers of ischemia and that the postural change after awakening also contributes to the morning increase in ischemia. There is also statistically significant evidence, however, for an endogenous circadian vulnerability that sustains the increase in ischemia on awakening. ²⁶ These phenomena may result from the increased oxygen demand of the myocardium, which is actively increasing cardiac output as a result of the morning BP surge.

The incidence of sudden cardiac death follows this same daily pattern. Many studies have investigated the incidence of sudden cardiac death in the morning. Thakur and colleagues ²⁷ specifically examined the effects of age, sex, and initial cardiac rhythm. In a retrospective analysis, they analyzed the records of 2250 consecutive adult patients with witnessed cardiac arrests who had undergone resuscitation in an urban paramedic system during a 5‐year period. A circadian pattern in the occurrence of sudden cardiac death was demonstrated, with a low occurrence rate between 12 am and 6 am and a 2.4‐fold increase between the rate at 6 am and that at 12 pm. This circadian pattern was not statistically different between men and women, between patients aged 18 to 70 years and patients older than 70 years, or between patients with various initial cardiac arrest rhythms (ventricular tachycardia or fibrillation, asystole, and electromechanical dissociation). This conclusion suggests a common pathophysiologic mechanism leading to sudden cardiac death that implicates circadian vulnerability.

24‐HOUR BP CONTROL AND CHRONOTHERAPEUTIC TREATMENT STRATEGIES

Kuriyama and associates ²⁸ have examined the adequacy of BP control in the morning using ABPM. They showed that although routine office measurements may appear to control BP, this is not necessarily true in many patients with mild to moderate renal disease. They initiated additional antihypertensive therapy including calcium channel blockers (CCBs), diuretics, angiotensin receptor blockers, and α₁‐blockers and also showed that with an intensive treatment regimen, dosed to control BP in the morning, BP could be better controlled. They speculated that morbidity and prognosis in their patient population might be improved.

Controlling patients' BP throughout a 24‐hour period may be approached in 2 ways. Many physicians administer a once‐daily dose in the morning, although some fail to account for pharmacodynamic effects such as the half‐life of treatments, which vary extensively (Figure). Often, drugs with short half‐lives may have plasma concentration troughs coinciding with morning surges, leaving patients vulnerable. Doses of once‐daily drugs should be chosen for long elimination half‐lives with high trough‐to‐peak ratios, ensuring coverage during the morning surge. Alternatively, chronotherapeutic formulations that incorporate extended‐release, delayed‐onset, and bedtime dosing may be administered. These regimens are more effective in a highly compliant patient.

Figure.

Half‐lives of various blood pressure medications.

The role of β‐blockers in the early morning is intriguing because of the role of the SNS in the morning surge, which could potentially be addressed by this class of drug. These drugs have been associated with a decrease in CV events, ²³ although their BP control profile during this time period needs further investigation.

Because the renin‐angiotensin‐aldosterone system also has a physiologic influence over the morning surge, it may be a chronotherapeutic target. Even among treatments that affect this system, however, some may be more effective either because of a longer duration of effect or to a more effective action on target organs. In one example, an angiotensin II receptor blocker, telmisartan, performed statistically better than an angiotensin‐converting enzyme inhibitor, ramipril. ²⁹ Another example of this is seen in a trial with candesartan compared with lisinopril. ³⁰ A higher efficacy of one class of treatment over another should be taken into consideration by the clinician. Likewise, the clinician should also consider the duration of effect of some treatments within the same class. In another study of angiotensin II receptor blockers, telmisartan proved more effective than losartan and valsartan. ³¹ , ³²

Angiotensin II receptor blockers have also been shown to have a slight advantage when compared with CCBs. Chrysant and colleagues ³³ examined the efficacy of the angiotensin II receptor blocker olmesartan medoxomil compared with the CCB amlodipine besylate. In this trial, the angiotensin II receptor blocker was able to achieve a set goal of lowered BP when compared with the CCB in a more statistically significant number of patients. CCBs, however, should not be discounted for their efficacy, particularly in view of recent trial data. ³⁴ , ³⁵ Extended‐release forms of diltiazem and verapamil have shown efficacy during the morning. ³⁶ , ³⁷ In the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, ³⁸ a CCB‐based regimen was considered similar in efficacy to β‐blockers and diuretics alone. In this trial, coronary heart disease events were not decreased to a greater degree with the CCB compared with the other therapy, despite lower BP levels in the morning.

Finally, a recent study suggests that even one commonly prescribed drug may be more beneficial if administered at different times in the diurnal cycle. In a prospective, randomized, open‐label, blinded end point study (N=328), Hermida and colleagues ³⁹ determined that low‐dose aspirin given before bedtime was more effective in reducing BP as measured by ABPM than if administered on awakening in hypertensive patients (P<.001). The authors rationalize this effect with the circadian rhythms of certain markers of oxidative stress, such as 8‐hydroxydeoxyguanosine, malondialde‐hyde, or 9‐isoprostane.

Many of the available medications such as chlorthalidone (a diuretic), amlodipine (a CCB), and several angiotensin‐converting enzyme inhibitors as well as angiotensin receptor blockers reduce trough BP values 22 to 24 hours after the last dose and can be effective in reducing the surge effect. This is especially true when any of the above CCBs, angiotensin receptor blockers, or angiotensinconverting enzyme inhibitors are coupled with a diuretic. Moser and colleagues ⁴⁰ have published another review of the clinical implications of chronotropic therapy and whether it should be a major consideration in selecting a therapy.

CONCLUSIONS

Although research surrounding the morning surge may still be conflicting in some areas, it is clinically valuable to investigate the phenomena. This involves understanding schema by which the morning surge can be quantified, its possible physiologic causes, its deleterious effects, and possible methods of management. While many therapies exist, the clinician would benefit most from considering factors such as the half‐life of medications, the time of day at which the medications are administered, and the rate of compliance with the therapy. In addition, the clinician should be aware that certain classes of drugs may be more effective than others and that even within a class of treatments, efficacy may be limited by duration of effect or by other factors. With these in mind, appropriate chronotherapeutic measures can be developed that lower the morning surge and its associated risks of adverse cardiac events.