letter to the editor

Journal of Human Hypertension (2001) 15, 577–581  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh

LETTER TO THE EDITOR Alterations of blood pressure and heart rate circadian rhythmic structure in non-blind patients affected by retinitis pigmentosa Retinitis pigmentosa (RP) is a group of genetically transmitted diseases that are characterised by a progressive loss of photoreceptors, associated with night blindness, and a progressive restriction of peripheral and mid-peripheral visual field. Investigations demonstrated that totally blind persons, whose blindness depends on retinal lesions, can be subdivided into four categories, as far as the circadian biorhythms are concerned, ie, (1) normally synchronised to 24-h1; (2) abnormally synchronised to 24-h2; (3) ‘freerunning’ with a periodicity shorter or longer than 24-h3; (4) without a definite periodic pattern.4 Because of this, the present study is aimed at verifying the hypothesis that the patients affected by RP, who still maintain a certain visual function or light perception, can belong to one of these categories as far as the blood pressure (BP) and heart rate (HR) circadian rhythm (CR) is concerned. The demonstration that RP patients show a desynchronisation in BP and HR CR could be indicative for attempting rephasing them via extra-ocular techniques of exposure to bright light5 or melatonin administration.6 The study was performed in 10 patients (two men and eight women, ranging in age from 20 to 45 years) affected by RP, the variety genetically transmitted as a dominant autosomic disease, showing a different grade of severity in their retinopathy and visual loss, having at least a visual Correspondence: Dr Filippo Cruciani, Institute of Ophthalmology, Policlinico Umberto I, 00161 Rome, Italy. E-mail: c.balacco얀caspur.it Received 22 June 2000; revised and accepted 13 February 2001

acuity of 6/60 and a residual visual field of 5°, despite the impairment or extinction of the signal at the electroretinogram. These patients were well integrated with their family and social context. None complained of sleep disorders and other diseases, including arterial hypertension, depression and anxiety. They were excluded if they were taking any medication. The control group was constituted by 30 sedentary clinically healthy subjects (CHS, 15 men and 15 women, ranging in age from 20 to 45 years) whose general and ocular health status was established via clinical examination, including the ophthalmologic scrutiny and laboratory findings. All the participants volunteered with informed consent to the study. The investigation was performed in conformity to the principles outlined in the Declaration of Helsinki. Both the RP patients and CHS underwent a noninvasive ambulatory 24-h BP monitoring by means of the automated device (model 90202, SpaceLabs, Redmond, WA, USA), programmed to take readings at 30min intervals from an inflatable cuff attached to the upper nondominant arm. The recorder is able to measure the systolic (S) and diastolic (D) BP and HR via an oscillometric technique, storing the readings into a solid CMOS memory. Each individual SBP, DBP and HR series was estimated for the CR by means of the Single Cosinor method,7 validating the statistical significance of the nychtohemeral oscillation, and quantifying the parameters that characterise the 24-h oscillation, in terms of mesor (M, rhythmadjusted mean, acronym of mid-

line estimating statistic of rhythm), amplitude (A, oscillatory extent from mesor), and acrophase (␾, timing, in hours and minutes, of the oscillatory crest related to local midnight). The Single Cosinor method was used for investigating the circadian component of the oscillation (validation of the CR), knowing that the SBP, DBP and HR nychtohemeral variability is better fitted by a multiple component harmonic method, with at least two submultiple periodicities (ultradian components), in order to obtain the optimal variance by the regression.8,9 Therefore, each individual SBP, DBP and HR time series was further analysed, as recommended,8,9 via a threecomponent periodic regression analysis, fitting a cosine function with three harmonics having a period of 24-h, 12-h, and 8-h, respectively. Importantly, the second and third harmonic component, with a period of 12-h and 8-h, can be regarded as the expression of the synchronisation to the entraining agents that act during the diurnal part of the day, such as, occupational and social routines, meal timing schedule, motor-rest activity, etc. The individual rhythmometric estimates of the CHS were summarised by means of the Population-Mean Cosinor10 in order to obtain the reference mean estimates with their dispersion. Table 1 displays the rhythmometric estimates of SBP, DBP and HR CR in each RP patient by comparison with the reference mean estimates provided by the CHS. It is important to point out that among the investigated RP patients, two cases (nos 7 and 8) have lost the significant power of both the 24-h and 8-h periodic

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SBP DBP HR

SBP DBP HR

SBP DBP HR

SBP DBP HR

SBP DBP HR

SBP DBP HR

SBP DBP HR SBP DBP HR

SBP DBP HR

2

3

4

5

6

7

8

10

9

SBP DBP HR

Variables

1

RP patients (No.)

Single Cosinor Method

126±1.52 75±1.29 96±1.27

120±1.94 66±2.29 79±2.66 109±1.67 68±1.16 97±1.44

129±2.15 73±2.06 80±1.86

110±1.20 66±1.17 79±2.18

114±1.81 70±1.49 84±1.59

115±1.67 72±1.43 80±1.33

102±1.24 63±1.22 68±1.13

109±0.92 66±0.82 85±1.17

110±1.37 67±1.12 79±1.41

Mesor ±s.e.m. Amplitude 1 ±s.e.m. 21±1.96 18±1.60 14±2.01 8±1.30 9±1.16 11±1.65 8±1.74 6±1.76 6±1.60 8±2.35 7±2.03 10±1.88 14±2.72 13±2.25 17±2.39 13±1.73 11±1.69 17±3.10 7±3.19 5±2.86 6±2.75 2±2.79 5±3.42 14±3.99 12±2.34 9±1.62 12±2.02 15±2.12 15±1.81 13±1.77

P1

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 =0.003 =0.005 =0.007 =0.007 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 =0.103 =0.220 =0.085 =0.785 =0.425 =0.002 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

24-h period

16:28±00:33 16:36±00:28 16:48±00:32

— — 16:44±00:55 15:16±00:44 14:29±00:42 15:16±00:39

— — —

14:32±00:29 14:25±00:33 16:31±00:42

14:53±00:40 13:40±00:34 14:36±00:29

17:04±01:09 16:16±01:09 13:32±00:45

14:43±00:50 13:12±01:00 14:12±01:05

15:11±00:39 14:47±00:30 15:34±00:34

13:49±0021 13:42±00:20 13:53±00:33

Acrophase 1 ±s.e.m.

=0.106 =0.150 =0.020

=0.001 ⬍0.001 =0.315 =0.699 =0.792 =0.497

=0.018 =0.002 ⬍0.001

=0.743 =0.128 =0.301

=0.005 =0.061 =0.176

=0.001 =0.005 =0.005

=0.002 =0.001 =0.073

=0.205 =0.143 =0.096

=0.713 =0.785 =0.258

P2

7±3.07 6±2.86 7±2.49

8±2.03 10±2.37 7±4.12 3±3.01 1±2.13 3±2.65

9±2.90 10±2.57 10±2.26

2.01±2.68 4.65±2.32 6.20±3.96

11±3.02 7±2.81 7±3.47

8±2.13 7±1.89 7±1.99

7±1.87 7±1.71 4±1.71

3±1.67 3±1.70 5±2.22

3±3.67 2±319 5±2.82

Amplitude 2 ±s.e.m

12-h period

Rhythmometric estimates

— — 16:19±01:14

15:56±01:07 17:19±01:04 — — — —

17:43±01:15 17:41±00:60 14:45±00:52

— — —

15:23±01:06 — —

16:01±01:06 15:57±01:14 15:42±01:14

14:29±01:01 14:03±00:58 —

— — —

— — —

Acrophase 2 ±s.e.m

=0.531 =0.331 =0.403

=0.510 =0.197 =0.796 =0.038 =0.003 =0.244

=0.238 =0.588 =0.220

=0.382 =0.695 =0.518

=0.792 =0.428 =0.686

=0.467 =0.241 =0.866

=0.229 =0.317 =0.149

=0.376 =0.306 =0.129

=0.957 =0.971 =0.128

P3

4±3.09 4±2.90 3±2.52

3±2.57 6±3.01 3±4.42 7±2.82 7±1.89 5±2.65

5±3.06 3±2.91 5±2.86

3.65±2.63 2.00±2.35 4.58±3.94

2±3.50 4±2.93 3±3.51

3±2.58 4±2.17 1±2.39

4±2.02 3±1.89 3±1.70

2±1.71 3±1.73 5±2.25

1±3.68 1±3.16 6±2.74

Amplitude 3 ±s.e.m

8-h period

Continued

— — —

— — — 14:07±01:26 12:44±01:03 —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

Acrophase 3 ±s.e.m

Table 1 Rhythmic biometry of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) monitored over a day–night period in non-blind patients affected by retinitis pigmentosa (RP) as compared to clinically healthy subjects (CHS)

Letter to the editor

106±0.94

64±0.84

73±1.53

SBP

DBP

HR

Mesor ±s.e.m.

8.97 (7.33;10.63) 8.83 (7.55;10.15) 10.56 (8.23;12.90)

⬍0.001 ⬍0.001 14:44 (14:00;15:20)

14:20 (15:36;14:56)

14:52 (14:04;15:36)

⬍0.001

⬍0.001

⬍0.001

P2

4.30 (2.96;5.66)

3.90 (2.41;5.47)

4.61 (3.30;5.95)

Amplitude 2 (95%CL)

Acrophase 1 (95%CL)

Amplitude 1 (95%CL)

⬍0.001

P1

12-h period

24-h period

Rhythmometric estimates

15:04 (13:52;14:08)

16:20 (14:12;16:44)

15:44 (14:48;16:24)

Acrophase 2 (95%CL)

⬍0.001

⬍0.001

⬍0.001

P3

2.85 (1.97;3.88)

2.75 (1.68;3.82)

2.78 (1.89;3.75)

Amplitude 3 (95%CL)

8-h period

11:28 (09:12;13:16)

09:56 (08:08;11:48)

10:20 (08:24;12:40)

Acrophase 3 (95%CL)

Values rounded to the nearest unit; Mesor and amplitude given in mm Hg for SBP and DBP, in bpm for HR; acrophase given in h:min; s.e.m., standard error of the mean; 95%CL, 95% confidence limits.

Reference values by CHS

Variables

Population Mean Cosinor Method

Table 1 Continued


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components which contribute to the SBP, DBP and CR, resulting, thus, ‘free-running’ with a period of 12-h; three cases have lost the significant power, respectively, of the second periodic component (no. 9), and, of the third periodic component (nos 3 and 4), showing an imperfect synchronisation to 24-h; the remaining five cases (nos 1, 2, 5, 6 and 10) have partially or totally lost the significant power of both the second and third periodic components, appearing, thus, synchronised to 24-h without the ultradian modulation which contributes to the diurnal-nocturnal asymmetry of the BP and HR circadian oscillation. The retina is a phototransductive organ which conveys the light stimulus to the suprachiasmatic nuclei, a hypothalamic structure which is involved, as a master clock, in entraining the BP and HR CR.11,12 Accordingly, the hypothesis was formulated that the patients affected by RP should be in some way disturbed in their BP and HR CR, because of the gradual abolition of the photic stimulus caused by the degeneration of the retina. The present study has confirmed such a hypothesis, revealing that two RP cases were effectively lacking the BP CR. It must be stressed that the circadian fluctuation of human BP and HR is not sustained by a single periodic component with a 24h period, in that it results from the intermodulation of at least two other ultradian cyclic components, having the period of 12-h and 8-h, respectively.8,9 This means that the ultradian components represent the influence of the entraining agents, which are active during the diurnal part of the day. Vice versa, the 24-h periodic component maximally reflects the entraining influence of the day–night cycle. In discussing the results of the present study, it is mandatory to take into account the multifrequency structure which sustain the BP and HR CR in healthy humans. In fact, looking at the RP


patients only in terms of the 24-h harmonic component, one could affirm that the majority of these cases, not yet blind, have no perturbation in their BP and HR CR. This is demonstrated by the finding that the power of the 24-h harmonic component shows a statistical significance in eight of the 10 RP patients (80%), confirming that the synchronisation to 24-h is not a phenomenon which can be regarded as casual. However, looking at the RP patients in terms of statistical significance for the second and third periodic component, one can easily detect that all the eight cases with a preserved synchronisation to 24-h, show a demodulation of at least one ultradian harmonic component. Such a finding suggests that the RP patients with a certain residual grade of visual acuity, show a defective synchronisation to the entraining agents which act during the diurnal part of the day. In other words, this means that the RP patients with a preserved light perception can be enclosed into a ‘fifth category’, in addition to the ones described in the outset. They can be classified as showing a desynchronisation to the environmental ultradian entraining agents which act during the time of the day in which human beings are not sleeping. Importantly, the loss of the ultradian components in BP and HR 24-h variability in RP patients could induce us to take into alternative consideration other extraocular techniques of synchronisation. With respect to this, it has been reported that the exposure to bright light applied to the skin behind the knee (popliteal illumination) can entrain the circadian rhythm of melatonin and body temperature, two major markers of circadian synchronisation.13 An entrainment could also be achieved by administring melatonin as it has been suggested in blind people.6

P Cugini1 F Cruciani2 R De Rosa1 AM Pellegrino1 S Fontana1 S Coda1 GP De Francesco1 A Mastromatteo2 B Antonelli2 EM Vingolo2 F Regine2 1 Department of Clinical Sciences and 2Institute of Ophthalmology University of Rome ‘La Sapienza’ Rome, Italy References 1 Martens H, Endlich H, Hildebrandt G, Moog R. Sleep/wake distribution in blind subjects with and without sleep complaints. Sleep Res 1990; 19: 398 (Abstract). 2 Nakagawa H, Sack RL, Lewy AJ. Sleep propensity free-runs with the temperature, melatonin and cortisol rhythms in a totally blind person. Sleep 1992; 15: 330–336. 3 Orth DN, Besser GM, King PH, Nicholson WE. Free-running circadian plasma cortisol rhythm in a blind human subject. Clin Endocrinol (Oxf) 1979; 10: 603–617. 4 Miles LM, Raynal DM, Wilson MA. Blind man living in normal society has circadian rhythms of 24.9-hours. Science 1977; 198: 421– 423. 5 Von Schantz M, Provencio I, Foster RG. Recent developments in circadian photoreception: more than meets the eye. Invest Ophthal Vis Res 2000; 41: 1605–1607. 6 Sack RL, Brandes RW, Kendall AR, Lewy AY. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000; 343: 1070–1077. 7 Halberg F et al. Autorhythmometry: procedures for physiologic selfmeasurements and their analysis. Physiol Teacher 1972; 1: 1–11. 8 Germano` G, Damiani S, Pecchioli V. Once-daily administration of captopril plus hydrochlorothiazide in patients with essential hypertension. Curr Ther Res 1990; 47: 940–951. 9 Mattes A, Witte K, Hohmann W, Lemmer B. PHARMFIT – a non-linear fitting program for pharmacology. Chronobiol Internat 1991; 8: 460– 476. 10 Halberg F, Tong YL, Johnson EA. Circadian system phase: an aspect of temporal morphology-procedures and illustrative examples. In: Von Mayersbach H (ed). The Cellular Aspects of Biorhythms. Springer-Verlag: Berlin, 1967, pp 20– 48. 11 Penev PD, Stoynev AG, Ikonomov OC, Halberg F. Murine circadian blood pressure and heart rate variation after lesioning of suprachiasmatic nuclei. Chronobiologia 1991; 18: 119–120.


12 Sano H et al. Effects of suprachiasmatic lesions on circadian rhythms of blood pressure, heart rate and loco-

motor activity in the rat. Japan Circ J 1995; 59: 565–573. 13 Campbell SS, Murphy PJ. Extraocular

circadian phototransduction in humans: Science 1998; 279: 396–399.

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letter to the editor - Nature

letter to the editor - Nature

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