Circadian Clocks, Autonomic Rhythms And Blood Pressure Dipping

Blood pressure does not fluctuate in random fashion, but follows characteristic rhythmic patterns. A blood pressure rhythm of ∼0.1 Hz (about 6 cycles/minute) is easily recognizable when blood pressure is monitored continuously and was first independently recognized in the late 1800’s by Traube, Hering and Mayer. This pattern can be analyzed using spectral analysis of the low frequency range in the frequency domain. There is controversy about the genesis of this rhythm. Two theories have been proposed. The pacemaker theory suggests that the rhythm is generated from oscillators within the central nervous system, either located in discrete pacemaker neurons or originating in neuronal networks. Alternatively, this rhythm may result from a resonance phenomenon as the baroreflex inhibits sympathetic tone after every increase in blood pressure. There is some disagreement about the utility of using the power of the low frequency blood pressure variability as a measurement of sympathetic modulation of vascular tone. There is little doubt, however, that this rhythmic blood pressure fluctuation is mediated through efferent autonomic nerves because it is greatly reduced in patients with pure autonomic failure, and is abolished by blockade of autonomic ganglia neurotransmission ¹. It has been argued that rhythmic sympathetic discharge is beneficial because it provides a more effective mechanism to regulated cardiovascular tone ². In this regard, it is important to note that increasing the frequency of sympathetic activation much above ∼0.1 Hz would not translate into more effective neurovascular coupling, because of the relatively low frequency response of vascular contraction.

Blood pressure also fluctuates with a pattern that follows a circadian rhythm, with a peak in the early morning hours, and a trough during sleep. This rhythm originates in a “master oscillator” located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN receives input through the retinohypothalamic tract in the optical nerve. Circadian rhythms are generated within the SCN by the regulated expression of clock genes in discrete neuronal populations. Most of the 16,000 to 20,000 SCN neurons (and some cells that act as peripheral clocks) can independently generate a self-sustained circadian rhythm when grown in vitro, but molecular feedback loops and neuronal networks explain the expression of these genes in a circadian organized pattern (for review, see3). Furthermore, blood pressure is only one of many biological signals that follow a circadian pattern, but not all follow the same pattern with an early morning peak. The different timing of peak activity of these circadian rhythms appears to originate from distinct subpopulation of cells within the SCN.

The neuronal activity originating in the SCN translates into circadian rhythms either through hormones released from the hypothalamus, or through efferent neural pathways. The autonomic nervous system is increasingly recognized as an important pathway that mediates the circadian rhythm of glucose output by the liver ⁴, release of stem cell into the circulation from bone marrow ⁵, and other biological functions. The autonomic nervous system itself follows a circadian pattern, which is apparent when measuring sympathetic outflow directly ⁶ or through plasma catecholamines. It is not surprising, therefore, that the autonomic nervous system is the prime suspect in mediating the circadian variation in blood pressure.

Nocturnal dipping of blood pressure is part of this normal circadian pattern, and its absence (“non-dipping”) is more frequent in hypertensive patients, and is associated with more severe end-organ damage and increased risk of cardiovascular events. Several studies have examined the role of the autonomic nervous system in the non-dipping phenomenon. In this issue of Hypertension, Grassi et al. report that patients with hypertension and the most severe form of non-dipping, reverse dipping, had the highest level of early morning sympathetic activity, measured directly in the peroneal nerve (muscle sympathetic nerve activity, MSNA) ⁷. Furthermore, MSNA predicted the difference between nighttime and daytime blood pressure among all hypertensive patients (extreme dippers, dippers, non-dippers and reverse dippers). This study, therefore suggest that increased sympathetic activity, as seen in hypertension, is associated with non-dipping, presumably by failure of sympathetic activity to decrease during the night. This hypothesis was not directly tested in this study, as it is challenging to measure MSNA during the night without altering sleep. Other studies have shown that the normal nighttime decrease in sympathetic activity (assessed by urinary norepinephrine) ⁸ and increase in parasympathetic activity ⁹ are blunted in non-dippers. It is important to note, however, that patients with primary autonomic failure and very low sympathetic and parasympathetic activities also have a high incidence of non-dipping ¹⁰, suggesting that it is not the inability to inhibit sympathetic activity during the night, but the inability to modulate autonomic tone that is responsible for the non-dipping phenomenon.

Nonetheless, the finding by Grassi et al. that non-dippers have increased sympathetic activity is of importance. It raises the possibility that this mechanism, rather than non-dipping itself, contributes to the worsening in end-organ damage observed in these patients. It would be difficult to test this hypothesis using the careful recordings of sympathetic activity performed by Grassi et al. because of the large number of patients that would be required. Low frequency variability of blood pressure could offer an alternative method to estimate sympathetic activity, but it is limited by large interindividual variability.

It is possible that the increased sympathetic activity observed by Grassi et al. also contributes to the increased incidence of cardiovascular events, which are more frequent in the early morning hours, in non-dippers. An early morning increase in MSNA has not been documented in all studies, but its association with non-dipping, to our knowledge, has not been examined previously. On the other hand, an excessive early morning surge in blood pressure, defined as an exaggerated increase in post awake morning blood pressure compared to 2 hours preawake blood pressure, is also associated with increased cardiovascular events. This observation presents us with an apparent paradox. By definition, dippers would be more likely to have an early morning surge. Indeed, extreme dippers have been associated with increased cardiovascular events in some studies. One potential explanation for this apparent paradox is that both early morning surge and non-dipping are characterized by an exaggerated increase in sympathetic activity in the morning. This, however, remains hypothetical, and it would have been of interest if Grassi et al. had examined this possibility in their patient population.