Circadian blood pressure: Clinical implications based on the pathophysiology of its variability

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1 & 27 International Society of Nephrology mini review Circadian blood pressure: Clinical implications based on the pathophysiology of its variability AJ Peixoto 1,2 and WB White 3 1 Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA; 2 Renal Section, VA Connecticut Healthcare System, West Haven, Connecticut, USA and 3 Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, USA The circadian blood pressure (BP) rhythm is associated with worsened cardiovascular outcomes in patients who have an excessive morning BP surge and in those who lack the normal nocturnal BP fall (non-dippers). There are multiple pathophysiologic mechanisms underlying abnormalities in circadian BP, most importantly abnormalities in sympathetic nervous system activity, salt and volume balance, and activation of the renin angiotensin system. Several of these factors can be modified by clinical interventions, either related to lifestyle changes and/or antihypertensive drug therapy. The timing of drug administration or specific drug delivery systems that lead to a greater effect at night and/or mitigate the early morning BP surge can correct abnormal circadian rhythms. Although these strategies have not yet been shown to alter clinical outcomes, it is reasonable to understand their biologic basis and take them into consideration when designing antihypertensive therapy. Kidney International (27) 71, doi:1.138/sj.ki.5213; published online 21 March 27 KEYWORDS: hypertension; blood pressure monitoring, ambulatory; circadian rhythm; antihypertensive agents; chronotherapy Correspondence: AJ Peixoto, Renal 111F, 95 Campbell Avenue, West Haven, Connecticut 6516, USA. aldo.peixoto@yale.edu Received 9 August 26; revised 28 November 26; accepted 5 December 26; published online 21 March 27 It has been known for over a century that systemic blood pressure (BP) has a daily variation characterized by substantial reductions during sleep. The circadian rhythm of BP was ultimately established by Millar-Craig et al. using continuous intra-arterial monitoring. 1 This seminal study showed that BP was highest mid-morning and then fell progressively throughout the rest of the day; in addition, the study showed that BP was lowest at night (nocturnal dip), but rose before awakening (morning surge). 1 These findings highlighted the importance of the circadian rhythm of BP with regard to the management of hypertension, a factor that had been acknowledged since the mid-196s. 2 Subsequent to the descriptive findings related to BP variability, investigators began to evaluate the physiological characteristics that produce the BP rise during the early morning and the substantial reductions in BP during sleep. Although it became clear that the timing and amplitude of the natural rhythm of BP is influenced by intrinsic factors, such as neurohormonal regulation, the effects of the extrinsic factors, such as physical activity and dietary sodium, are probably of greater significance. 3 Furthermore, behavioral influences, such as mental activity and emotional state, 4 and lifestyle factors, such as smoking cigarettes and drinking alcohol, can also affect the natural rhythm of BP. 3 Growing evidence indicates that excessive BP levels during the course of a circadian cycle may contribute to adverse cardiac outcomes, especially when examining the relationship between the morning peak in various cardiovascular (CV) events with the post-awakening morning surge in BP. The increased incidence of sudden death, non-fatal myocardial infarction, unstable angina and stroke in the morning indicates that a patient s physiological status may play an important role in the onset of CV events. 5 Hence, there is a need for 24-h control of BP to minimize this early morning increase in CV risk. CHARACTERISTICS OF THE CIRCADIAN FLUCTUATIONS IN BP THAT MAY LEAD TO HARM Early morning BP surge In the early morning, BP rises sharply in response to the natural activation of the sympathetic nervous system on morning arousal. 6 1 This early morning surge is also Kidney International (27) 71,

2 m i n i r e v i e w AJ Peixoto and WB White: Clinical importance of circadian BP rhythm associated with other important hemodynamic and neurohormonal changes, such as increase in heart rate, vascular tone and blood viscosity, and decrease in vagal activity. 6,11 13 The activity of the sympathetic nervous system appears to be downregulated during the rapid eye movement period of sleep, whereas awakening selectively stimulates the sympathoadrenal branch of the sympathetic nervous system and increases epinephrine levels. 8 However, the increases in BP and heart rate are controlled by direct sympathetic neural input into the heart and vasculature in response to changes in activity and posture, rather than by an endogenous surge of plasma catecholamines. 9 LOSS OF THE NOCTURNAL DECLINE IN BP (NON-DIPPERS) The natural circadian rhythm of BP includes a nocturnal decrease of 1 2% in BP. However, in 25 35% of hypertensive patients a non-dipper pattern occurs. Non-dipping is arbitrarily defined as present when the night time BP reduction is less than 1% compared to the daytime pressure. This blunted nocturnal decrease occurs when the natural rhythm of BP is disrupted (for a variety of reasons), both in patients with essential hypertension and with secondary forms of hypertension. Clinical investigations in patients with hypertension have associated a blunted nocturnal BP decrease with increased adrenergic and decreased vagal activity during sleep In some patients, there is even a significant nocturnal increase in BP ( reverse dippers or risers ), a finding that is associated with substantial cardiac morbidity. 17 Less commonly, patients may display a larger than usual (42%) decline in BP during sleep compared with wakefulness; this profile of nocturnal BP has been closely associated with increased white matter ischemic lesions in the brain and an excessive morning BP surge. 18 At present, knowledge of the circadian profile of an individual patient (through ambulatory BP monitoring) aids in identifying increased risk. At this time, there are no data that show that modifying an abnormal circadian rhythm leads to improved outcomes. CLINICAL IMPLICATIONS OF THE CIRCADIAN VARIABILITY OF THE BP As noted above, the early morning BP surge period is associated with an increase in the incidence of CV events, including stroke and myocardial infarction Metaanalyses indicate that there is a 4% higher relative risk of acute myocardial infarction, a 29% increased risk of sudden cardiac death, and a 49% higher relative risk of stroke between 6 h and 12 h compared with the rest of the day. 2,21 This corresponds to approximately one in every 11 myocardial infarctions, one in every 15 sudden deaths, and one in every eight strokes being associated with the morning excess. The timing of onset of CV events strongly parallels the circadian rhythm of BP; however, only limited data directly link the two. In one of the more striking prospective analyses, Kario et al. demonstrated a 2.7-fold increase in clinical stroke risk in older patients with hypertension who were in the top decile of the morning BP surge (455 mm Hg). 22 After adjustments for age, antihypertensive drug use, and 24-h BP levels, each 1 mm Hg increase in the morning BP surge conferred a 24% increase in stroke risk (P ¼.4). At this time, no clinical trial has been devised to address the relationship between a reduction in the early morning BP and a possible reduction in CV events. Obstacles to doing this sort of trial include the enormous sample size required and the long period of follow-up that would be necessary. 23 In the CONVINCE trial, 23 it was estimated that in order to show differences in early morning CV events with two treatment strategies, more than 2 events during this period of time would be required in order to support this number of events, a patient population of 2 hypertensive patients would perhaps have to be followed for nearly a decade. Loss of the nocturnal decline in BP has been associated with increased risk of cardiac, kidney, and vascular target organ injury compared with patients whose decline in BP at night is normal, 24 and can be independent of the clinic and 24-h mean BP values. 25,26 Additionally, patients with hypertension who exhibit a nocturnal BP increase compared with daytime BP (risers) have the worst prognosis for stroke and cardiac events. 17,25 However, there is also some evidence that patients with marked nocturnal BP declines (extreme dippers) are at risk of lacunar strokes and silent myocardial ischemia. 18 Studies that have assessed the impact of elevated nocturnal BP on the kidney have found similar results to those analyses of cardiac and cerebrovascular target organ involvement (see review by Thompson and Pickering for more detailed information on ambulatory BP monitoring in kidney disease 26 ). Very early in the development of type 1 diabetes mellitus, Lurbe and co-workers showed that an increase in night time systolic BP may have a key role in the development of diabetic nephropathy. 27 In contrast, patients were less likely to progress from normalbuminuria to microalbuminuria if their BP decreased during sleep. In a retrospective cohort study of patients with a wide range of renal function (average modification of diet in renal disease glomerular filtration rate 81 ml/min/m 2 in dippers, 76 ml/min/m 2 in non-dippers), those who were non-dippers had much faster loss of glomerular filtration rate over an average follow-up of 3.2 years ( ml/min/year versus for dippers, Po.1). 28 In a population of patients with chronic kidney disease and hypertension evaluated over 3 years, Timio et al. concluded that a non-dipping pattern of ambulatory BP was associated with a more rapid progression of renal insufficiency compared with patients lacking nocturnal hypertension. 29 In a similar, larger study of 217 men with chronic kidney disease followed over 3.5 years, Agarwal and Anderson found that one standard deviation increase (11.8 mm Hg) in sleep systolic BP increased the risk of death or dialysis by 26%. 3 Hence, these results have led to assumptions that high nocturnal BP and 856 Kidney International (27) 71,

3 AJ Peixoto and WB White: Clinical importance of circadian BP rhythm m i n i r e v i e w abnormal circadian BP could be a target for pharmacologic interventions. One important caveat in the interpretation of results from studies analyzing the relevance of the dipping phenomenon is the issue of its long-term reproducibility. Using the arbitrary cutoff of 1% decline in BP, studies in different populations have demonstrated reproducibility of dipping status on two separate monitoring periods between 57 and 91% In essential hypertensives, target organ damage (left ventricular hypertrophy, carotid intima thickness) is best predicted in patients with a reproducible profile. 31,35 Therefore, some of the associations between non-dipping and adverse end points may be weakened by the suboptimal reproducibility of the nocturnal decline in BP. EXTRINSIC FACTORS AFFECTING THE CIRCADIAN RHYTHM OF BP Effects of sleep quality and activity Physical activity is the major determinant of BP rise during the day. 36,37 The influence of sleep and wakefulness on BP is mediated through cyclic variations of the autonomic nervous system. 38,39 In the early morning, BP naturally rises sharply in response to activation of the sympathetic nervous system upon arousal. 3,6,8 Sleep deprivation increases sympathetic activity and may disrupt circadian rhythmicity. 4,41 Dietary influences on the circadian variation of BP The circadian BP rhythm, in particular the nocturnal decline in BP, can be affected by sodium intake in patients with hypertension. 42,43 In fact, Uzu et al. showed that a non-dipper nocturnal BP pattern can be converted to a dipper pattern in response to salt restriction in salt-sensitive patients with hypertension (Figure 1). 44 Conversely, the morning surge in BP may be enhanced by salt loading. 43 Normotensive subjects may differ in electrolyte handling and regulation during wakefulness, affecting the circadian rhythm of BP. 45,46 For example, following a period of a high potassium diet, a proportion of normotensive African-American adolescents switched from non-dipper status to dipper status, with a reversal in night time BP levels. 46 Animal studies have shown that the circadian pattern of expression of the sodium-hydrogen exchanger (NHE3) was directly controlled by the biological clock gene CLOCK:BMAL1 heterodimers, providing compelling evidence that central biological clock regulation may be directly involved in renal sodium handling. 47 Ernst et al. compared the antihypertensive efficacy of hydrochlorothiazide (HCTZ) and chlorthalidone on ambulatory BP in 3 patients with hypertension. 48 The change from baseline to week 8 in mean 24-h systolic ambulatory BP indicated a greater reduction with chlorthalidone 25 mg/day compared with HCTZ 5 mg/day. The greater reduction appeared to be primarily because of its effect on reducing night time mean systolic BP. The reduction in daytime mean systolic BP was not significantly different between treatment groups (Figure 2). Chlorthalidone has a much longer elimination half-life than HCTZ, which could help sustain a prolonged low level of diuresis, prevent the late period of anti-diuresis ( braking ), or have a more prominent and prolonged vasodilatory effect producing a lower mean night time BP. 49 INTRINSIC FACTORS AFFECTING THE CIRCADIAN RHYTHM OF BP Autonomic and sympathetic nervous activity Clinical studies of healthy subjects and patients with spinal injuries 5,51 support a direct role for the autonomic nervous system in the regulation of the circadian variability of BP. In these studies, BP increased independently of activity in neurologically intact patients with lower spinal cord injuries, but not in patients with sympathetic decentralization or higher spinal cord injuries. 5 This sympathetic neural activity may contribute to the regulation of BP over the 24-h period. Additionally, higher resting measurements of sympathetic nerve activity were associated with greater daytime BP variability and a more marked nocturnal decline in BP in healthy normotensive subjects. 51 However, some investigators suggest that the existence of the non-dipper phenomenon MAP (mmhg) High sodium diet Low sodium diet 13 Non-sodium sensitive 13 Sodium sensitive MAP (mmhg) Daytime Night-time Daytime Night-time Figure 1 Sodium restriction shifts the circadian rhythm of BP from non-dipper to dipper in sodium-sensitive hypertension. Reproduced from Uzu et al. 44 MAP ¼ mean arterial pressure. Systolic BP (mmhg) HCTZ Chlorthalidone HCTZ : 7.4±1.7 HCTZ : 8.1±1.9 HCTZ : 6.4±1.7 Chlor : 12.4±1.8 Chlor : 11.4±2. Chlor : 13.5±1.9 P =.54 P =.23 P =.9 Week Week 8 Week Week 8 Week Week 8 24-h mean Daytime mean Night-time mean Figure 2 Mean 24-h, daytime, and night time ambulatory systolic BP with change from baseline after 8 weeks treatment with HCTZ 5 mg/day and chlorthalidone 25 mg/day in 3 patients with hypertension. Reproduced from Ernst et al. 48 Kidney International (27) 71,

4 m i n i r e v i e w AJ Peixoto and WB White: Clinical importance of circadian BP rhythm may not result from disruption of sympathetic neural activity, but from a corresponding decrease in parasympathetic function. 52 Renin angiotensin aldosterone system The renin angiotensin aldosterone system (RAAS), mainly via production of angiotensin II, is a key regulator of BP. The RAAS is activated in the early morning before arousal as a result of sympathetic neuronal activation. 53,54 In addition, both renin and aldosterone demonstrate significant circadian patterns in both normotensive and hypertensive individuals, 54 with peak values detected early morning then falling to their lowest point in late evening (Figure 3). A similar pattern has been observed for angiotensin II : 12: 16: 2: 24: 4: 8: 8: 12: 16: 2: 24: 4: 8: : 12: 16: 2: 24: 4: 8: 8: 12: 16: 2: 24: 4: 8: Figure 3 The 24-h profile of plasma renin activity and plasma aldosterone concentration in normotensive and hypertensive subjects (n ¼ 1 per group). Reproduced from Portaluppi et al. 54 PA ¼ plasma aldosterone; PRA ¼ plasma renin activity. PRA (ng/ml/h) PA (ng/dl) PRA (ng/ml/h) PA (ng/dl) UTILIZATION OF THE PATHOPHYSIOLOGY OF THE CIRCADIAN VARIABILITY OF BP FOR THE TREATMENT OF HYPERTENSION The available evidence reported above demonstrates two distinct findings. First, the early morning surge in hypertension, clearly associated with increases in stroke events in older patients with hypertension, is mediated in part by the sympathetic nervous system and through the RAAS. Second, the pathophysiology leading to a loss of decline in nocturnal BP is probably mediated RAAS activation and volume excess. Therefore, these findings allow us to examine the potential for blockade of the systems leading to these abnormal profiles in circadian BP. On a more pragmatic level, the pharmacodynamics of antihypertensive drugs must play a role in these considerations, as control of nocturnal BP and BP during the early morning period will require that agents either have a reasonably long half-life or be administered twice daily. Modification of the timing of drug administration can alter the circadian BP profile. In fact, modification of the time of drug administration for many of the antihypertensive agents may affect the extent of 24-h BP control and modify the circadian rhythm, including the conversion from a nondipper to dipper profile. 55,56 These effects are most uniform with blockers of the RAAS, which typically will have a substantial effect on nocturnal BP when administered at night whereas also maintaining adequate control during the daytime (Table 1). 56 Drugs with long duration of action may be particularly useful to this purpose. White et al. evaluated the effects of telmisartan alone and in combination with HCTZ on 24-h BP, including the early morning period. 57 Patients with hypertension received telmisartan 4 mg/day; if BP remained uncontrolled after 2 weeks, the dose was increased to 8 mg/ day; if BP was still uncontrolled after a further 4 weeks, HCTZ 12.5 mg was added and continued for a final 4-week period. Twenty-four hour ambulatory BP monitoring was performed at baseline and the end of the treatment period in 1628 patients. Telmisartan alone and in combination with HCTZ produced significant reductions in both daytime and night time mean BP. The effects of telmisartan were sustained over the entire dosing period, reflective of its long duration of action. As most analyses have shown that renin activity begins to rise during the night and peaks in the morning period, another pharmacologic approach to consider in the treatment of nocturnal and early morning hypertension would be a long-acting direct renin inhibitor. Stanton et al. have provided data supporting the notion that aliskiren, a direct renin inhibitor with a plasma half-life of approximately 4 h might provide efficacy in patients with abnormal circadian BP variability, particularly in the high-risk populations discussed herein. 58 In addition, Mitchell et al. reported an analysis of ambulatory BP monitoring in 216 patients with hypertension who were randomized to 8 weeks treatment with aliskiren 15, 3, or 6 mg once daily or placebo (Abstract: Mitchell J, Oh B, Herron J, Chung J, Khan M, Satlin A. Once-daily aliskiren provides effective, smooth 24-h BP control in patients with hypertension. J Clin Hypertens 26; 8 (Suppl A): P-29). Aliskiren significantly reduced mean 24-h ambulatory BP compared with placebo at all dosages. Consistent with its long half-life, effective BP lowering was maintained throughout the 24-h dosing period, Table 1 Nocturnal blood pressure is reduced to a greater extent with evening (22) versus morning (8) dosing of quinapril 2 mg, without loss of daytime efficacy Placebo run-in Quinapril 2 mg once daily Morning dosing (8) Evening dosing (22) Daytime SBP (mm Hg) Daytime DBP (mm Hg) Night time SBP (mm Hg) ** Night time DBP (mm Hg) * Heart rate (beats/min) DBP, diastolic blood pressure; SBP, systolic blood pressure. Data from Palatini et al. 56 *Po.5, **Po.1 versus morning administration. 858 Kidney International (27) 71,

5 AJ Peixoto and WB White: Clinical importance of circadian BP rhythm m i n i r e v i e w persisting overnight and throughout the high-risk period in the early hours of the morning. Of note is that, despite the potential benefits of conversion of a non-dipping pattern to a dipping pattern, there does remain the possibility that excessive BP reduction at night might be associated with orthostatic hypotension or excessive hypotension during sleep in certain individuals, particularly the elderly. Thus, in the ideal situation, changes in drug administration time should be followed by repeat ambulatory BP monitoring to assess the effects of therapy and rule out an excessive BP fall during the night. 59 A limitation to this approach, however, is the limited coverage provided by some of the third-party payers for ambulatory BP monitoring (in the United States). In perspective, it is important to recognize the importance of adequate BP control over the entire 24-h period, particularly the early morning hours. Several of the pathophysiological systems responsible for the circadian BP variability, especially salt balance and the RAAS, can be modulated by appropriate, long-acting therapy, and such interventions may result in improved clinical outcomes. The confirmation that correcting abnormal circadian rhythms results in clinical benefit will require clinical trials that specifically test this hypothesis, such as studies wherein patients are randomized to different drug-dosing schedules with efficacy confirmed by sequential ambulatory BP monitoring, and relevant outcomes assessed. These outcomes could be initially comprised of surrogate measures, such as changes in left ventricular mass, carotid intima-media thickness, ischemic cerebral lesions, or proteinuria. If safety is ascertained and probable benefit is suggested, larger studies with conventional CV or renal end points would then be justified. ACKNOWLEDGMENTS We thank Mr Neil Marmont for his editorial assistance. REFERENCES 1. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood-pressure. Lancet 1978; 1: Cranston WI. Diurnal variations in plasma volume in normal and hypertensive subjects. Am Heart J 1964; 68: Pickering TG, James GD. Determinants and consequences of the diurnal rhythm of blood pressure. Am J Hypertens 1993; 6: 166S 169S. 4. James GD, Pickering TG. The influence of behavioral factors on the daily variation of blood pressure. Am J Hypertens 1993; 6: 17S 173S. 5. Muller JE, Kaufmann PG, Luepker RV et al. Mechanisms precipitating acute cardiac events. Circulation 1997; 96: Linsell CR, Lightman SL, Mullen PE et al. Circadian rhythms of epinephrine and norepinephrine in man. J Clin Endocrinol Metab 1985; 6: Furlan R, Guzzetti S, Crivellaro W et al. 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