Circadian Variation in the Onset of Acute Critical Limb Ischemia

Thrombosis Research 92 (1998) 163–169

REGULAR ARTICLE

Circadian Variation in the Onset of Acute Critical Limb Ischemia Roberto Manfredini1, Massimo Gallerani4, Francesco Portaluppi1, Raffaella Salmi3, Paolo Zamboni2 and Carmelo Fersini1 1 First Institute of Internal Medicine and Hypertension Unit, Department of Clinical and Experimental Medicine and 2Institute of General Surgery, University of Ferrara; and 3Angiology Unit, 2nd General Medicine and 4Emergency Department, St Anna Hospital, Ferrara, Italy. (Received 5 May 1998 by Editor G.F. Gensini; revised/accepted 7 July 1998)

Abstract Research has identified a circadian rhythm for several acute thrombotic cardiovascular and cerebrovascular diseases. We investigated the possible existence of a circadian variation in the onset of acute critical limb ischemia. Out of a consecutive series of 198 cases, precise determination (within 30 minutes) of the time of symptom onset was possible in 156 (78.8%). Partial Fourier series were applied to hourly data and the best-fitting curves for circadian rhythmicity were calculated. Both in the total population and in subgroups by gender and location of ischemia, a highly significant circadian pattern of occurrence was demonstrated with peak in the morning (approximately 0800) and nocturnal minimum around midnight. This study is the first demonstration of the circadian pattern of acute arterial occlusion of the limbs, in agreement with several studies showing a circadian pattern to the time of onset of acute myocardial infarction and other unfavorable acute events related to thrombosis. This opens up the potential for therapeutic implications, suggesting the need to adjust the dose Abbreviations: MESOR, midline estimating statistic of rhythm; PT, prothrombin time; APTT, activated partial thromboplastin time; t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1. Corresponding author: Roberto Manfredini, Sezione di Medicina Interna I, Dipartimento di Medicina Clinicae Sperimentale, Universita` di Ferrara, via Savonarola 9, I-44100 Ferrara, Italy. Tel: 139 (532) 236817; Fax: 139 (532) 236816; E-mail: ,[email protected]..

of drugs based on the time of day. Further studies dealing with circadian variation in the efficacy of thrombolytic agents are so needed.  1998 Elsevier Science Ltd. Key Words: Circadian rhythm; Acute critical ischemia; Limbs

S

ince the first demonstration of a morning peak for acute myocardial infarction [1], there have been repeated reports of the circadian morning variability in the occurrence of acute cardiovascular and cerebrovascular events, e.g., myocardial ischemia [2], sudden cardiac death [3], pulmonary thromboembolism [4], and stroke [5,6]. On one hand, such acute events may be triggered or precipitated by a constellation of favoring factors, including increases in arterial blood pressure [7], catecholamines [8], heart rate [9], and vascular tone [10,11], hemodynamic changes [12], as well as physical activity [13,14], and mental stress [15]. On the other hand, a growing amount of evidence supports a role for a temporal relationship between acute cardiovascular events and morning variations in hemostatic variables [16]. Taken together, these findings suggest the need for pharmacologic protection of patients during the vulnerable periods and open up the potential for a temporized therapeutic approach to cardiovascular diseases [17]. Based on these considerations, we intended to investigate a possible temporal variability in the occurrence of acute critical limb ischemia.

0049-3848/98 $–see front matter  1998 Elsevier Science Ltd. Printed in the USA. All rights reserved. PII S0049-3848(98)00127-3

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1. Subjects and Methods Ferrara is a town in northern Italy with approximately 150,000 inhabitants with a distribution of age, sex, and socioeconomic status similar to that of Italy as a whole. The population is almost exclusively white. The only available hospital in this community is St Anna Hospital, which also serves as the sole teaching center for the School of Medicine. For geographic (other hospitals with acute care facilities are not available for approximately 40 miles) and practical reasons (there is one transport service for all out-of-hospital emergencies, with vehicles strategically distributed throughout the territory and average time of arrival at the Emergency Department <15 minutes from the time the call is received) and because the excellent standard of care of the local medical facilities, there is very little, if any, loss of cases because of admission in other hospitals. House calls are performed by general practitioners during the daytime hours (8 AM to 8 PM) and by physicians of a specific section of the Emergency Department during nocturnal hours and holidays at no charge for the patient. Thus, the Emergency Department has a total flow of 57,000 patient visits per year. Between January 1990 and December 1996, a consecutive series of 198 cases of acute critical limb ischemia were observed in the St Anna Hospital of Ferrara, Italy. Precise determination (within 30 minutes, witnessed) of the time of symptom onset was possible in 156 (78.8%). The remaining cases were excluded from the analysis. The diagnosis of arterial occlusion was always confirmed by either physical examination, ecodoppler ultrasonography, angiography, surgical intervention, or autopsy. Presence or history of concomitant diseases and/ or risk factors was always assessed on the basis of clinical records. The precise clock hour of symptom onset was categorized into 24 1-hour increments (e.g., 0600 to 0659 hours reported as 0600 hours). Analysis of rhythmicity was performed by applying partial Fourier series with up to 6 harmonics to hourly data, using the Chronolab software on an Apple Macintosh computer [18]. The program permits, among all the possible combinations of the periods chosen by the user, the selection of the harmonic or the combination of harmonics that best explains the variance of data. The percentage of rhythms (percentage of overall variability of data

about the arithmetic mean attributable to the fitted rhythmic function) and the probability value resulting from the F statistic used to test the hypothesis of zero amplitude were chosen to be reported in the results as representative parameters of goodness of fit and statistical significance of each fitted function, respectively. The program calculates the midline estimating statistic of rhythm (MESOR, the rhythm-adjusted mean over the time period analyzed) and the amplitude (half the distance between the absolute maximum and minimum of the function) of the best-fitting curve. By division of the two values, the amplitude-MESOR ratio is then calculated and used as a quantitative measure of temporal variability. The program also calculates peak and through times of the fitted curve (times of occurrence of the absolute maximum and minimum) and the acrophase of each single harmonic (peak time of rhythmic change).

2. Results The characteristics of study population are reported in Table 1. An older age was observed in the female as compared with the male subgroup. In Table 2, the concomitant diseases and risk factors of the study population are reported. Paroxysmal atrial fibrillation was significantly more present in the female as compared with the male subgroup. On the other hand, the male subgroup showed an increased incidence of other diseases, e.g., malignancy, coronary artery disease, aortic or femoropoliteal aneurysm, and previous aorto-femoral bypass. Frequency of both hypertension and diabetes did not show significant differences among groups. The circadian onset distribution of acute critical limb ischemia in the total population showed a pattern (Fig. 1) with maximal occurrence in the morning hours (approximately 0800 hours) and minimal occurrence at night (approximately 2400 hours). This pattern was reflected by the best fitting curve (Fig. 1) calculated at rhythm analysis, which resulted of two significant components of 24- and 12-hour periods, respectively (Table 3). The same hourly pattern was found also after separate analysis of upper- and lower-limb ischemia. No differences were detected in hypertensive or normotensive patients who showed a similar pattern.

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Table 1. Characteristics of study population Subjects Total Males Females Considered sample Total Males Females Upper limbs Lower limbs a

n

%

Mean age6SD

198 84 114

100.0 42.4 57.6

76.9611.5 72.4610.2 80.2611.6a

156 62 94 29 127

100.0 39.8 60.2 18.6 81.4

77.4611.3 72.7612.0 80.569.8a 82.6610.3 76.3611.3b

extensively investigated, showing a higher incidence during the early morning hours and a secondary peak after lunch [21–23]. Since atrial fibrillation may cause acute embolization, the temporal pattern of its paroxysmal form may contribute also to the circadian distribution of acute critical limb ischemia. Apart from these considerations, it is possible that the morning thrombophilic status may play an important role. Many factors contribute to the delicate balance existing between coagulation and fibrinolysis. Moreover, in addition to basal levels, the activity of several of the factors involved in such balance varies in a circadian pattern and in response to external stressors.

p,0.0001 versus the mean age of the preceding group. b p50.005 versus the mean age of the preceding group.

3. Discussion

3.1. Coagulation

The main result of this study is the demonstration of the existence of a circadian pattern of onset for acute critical limb ischemia. To our knowledge, this is the first report in the literature of such a circadian pattern, whereas a well-known morning peak has been previously reported for myocardial [1] and cerebral thrombosis [5]. For acute cardiovascular accidents, a possible triggering role of factors that rise in the morning hours (e.g., vasoconstrictor effect of catecholamines [19], serum cortisol [20], and morning arterial blood pressure [7]) may be postulated. In our sample, paroxysmal atrial fibrillation was present in approximately 50% of the total population, but in the female group, the percentage was significantly higher (69%). The daily pattern of paroxysmal atrial fibrillation has been

A circadian variation in several parameters was found, identifying a pro-coagulative tendency in the morning [24]. In particular, a morning peak was shown for fibrinogen and factor VIII [25], in concomitance with shortened prothrombin time (PT) and activated partial thromboplastin time (APTT). Moreover, a morning peak of platelet aggregability has been reported both in healthy subjects [26] and in patients suffering from atherosclerotic diseases [27]. However, after the first report of a morning increase in in vitro platelet aggregability [28], the same authors found that platelet aggregability was not particularly related to the time of day but to assumption of an upright posture and to activity [29]. Clinical indirect evi-

Table 2. Characteristics of study population: Concomitant diseases and risk factors Total (%) Subjects Diseases Hypertension Paroxysmal atrial fibrillation Diabetes Malignancy Valvulopathy Previous aorto-femoral by-pass Coronary artery disease Arterial aneurysmc Miscellaneousd a

156 (100) 88 84 19 12 6 8 6 6 8

(56.4) (53.8) (12.1) (7.7) (3.8) (5.1) (3.8) (3.8) (5.1)

Males (%)

Females (%)

62 (39.8)

94 (60.2)

37 19 5 8 2 6 5 5 3

51 65 14 4 4 2 1 1 5

(59.6) (30.6) (8.0) (12.9) (3.2) (9.6) (8.0) (8.0) (4.8)

(54.2) (69.1)a (14.9) (4.2)b (4.2) (2.1)b (1.1)b (1.1)b (5.3)

p,0.001 versus the percentage of the preceding group. b p50.05 versus the percentage of the preceding group. c aortic or femoro-popliteal aneurysm. d severe chronic obstructive bronchitis, thyroid disease, rheumatoid arthritis, Crohn’s disease, severe acute renal failure.

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3.3. Possible Implications

Fig. 1. Circadian distribution in the study population of acute arterial embolism of the limbs (n5156). Histograms represent total events occurring in each hour of the day. Superimposed is the best-fitting curve at rhythm analysis with partial Fourier series. The parameters of the curve are given in Table 3 under “Total cases.”

dence of the circadian variation in platelet aggregability is provided by the Physicians’ Health Study [30], in which the reduction in the incidence of myocardial infarction in patients assuming aspirin (47% on average) was found to be 59.3% for the morning events, compared with a decrease of 34.1% in the infarctions occurring during the remaining hours of the day.

3.2. Fibrinolysis Fibrinolysis shows wide oscillations during the day [31]. Opposite circadian patterns, characterized by lower tissue-type plasminogen activator (t-PA) and higher plasminogen activator inhibitor-1 (PAI-1) levels, with variations ranging up to 250%, have been reported [32]. In fact, a higher incidence of ischemic myocardial events occurs in the hours in which the highest PAI levels are found [33,34]. Other studies showed that subjects with coronary artery disease have a peculiar circadian variation of fibrinolysis, characterized by peaks of PAI and absence of peaks of t-PA [35,36].

The demonstration of a circadian variability in the onset of acute arterial occlusion deserves a certain attention due to the possibility of practical applications in the everyday medical practice. On one hand, it has been shown that patients suffering from acute myocardial infarction in the morning have a worse prognosis compared with subjects presenting their infarction at other times of the day [37]. On the other hand, a circadian pattern has also been found in the effectiveness of anticoagulant drugs. It has been shown that a continuous intravenous infusion of heparin may result in a greater anticoagulant effect at night than in the daytime [38,39]. Moreover, thrombolytic therapy recently has been demonstrated to have a circadian pattern of efficacy, as assessed by the ability to provide coronary patency rapidly. A circadian fluctuation (with a morning increase) in the resistance to thrombolysis was shown for both intravenous urokinase [40] and rt-PA [41]. Onset of acute myocardial infarction and resistance to thrombolysis have similar circadian variations with early morning and late evening peaks, independent of type of thrombolytic agent [42].

4. Conclusions The main result of this study is the first demonstration of a circadian pattern of acute critical limb ischemia, with a striking morning peak independent of gender and location of ischemia. It could be argued that the morning peak that we found could be overestimated due to possible late manifestation of a significant number of nocturnal events. This objection may also be made to the results of studies on coronary and cerebral ischemias, which detected circadian patterns quite similar to those found in this study. However, a recent meta-analysis of the studies on this topic published from 1985 to 1996 confirmed the morning excess of myocardial infarction and sudden cardiac death [43]. The increase in heart rate occurring during the second part of the night in relation to REM sleep and the night peak of paroxysmal atrial fibrillation (when present) may both act as starting factors of a process that becomes clinicallly manifested later in the morning.

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Table 3. Twenty-four-hour rhythmicity in the onset of acute arterial embolism of the limbs Period (h) Total Cases (n5156) 24 12 24 and 12 Males (n562) 24 12 24 and 12 Females (n594) 24 12 24 and 12 Upper limbs (n529) 24 12 24 and 12 Lower limbs (n5127) 24 12 24 and 12 Hypertension (n588) 24 12 24 and 12 No hypertension (n568) 24 12 24 and 12

Percentage of rhythm

p

49.6 17.3 66.9

,0.001 0.018 ,0.001

39.9 7.8 47.7

0.004 0.283 0.009

34.4 19.5 53.8

0.004 0.032 0.003

34.9 22.7 57.6

0.003 0.015 0.001

39.0 10.4 49.5

0.001 0.173 0.006

60.9 9.0 69.9

,0.001 0.083 ,0.001

21.1 23.7 44.8

0.045 0.032 0.014

In our opinion, this study may open up the potential for therapeutic implications, suggesting the need to adjust the dose of drugs based on the time of day, as already put forward for other cardiovascular medications [17]. The efficacy of the thrombolytic therapy of coronary arteries has already been shown to have a clear circadian pattern. An international consensus document [44] has recently given the guidelines for a correct, useful, and safe utilization of thrombolytic agents in the management of peripheral arterial occlusion of the lower limbs. Our findings suggest that tailoring the thrombolytic therapy according to time of the day may be advantageous also in this clinical condition. Considering costs and risks of thrombolytic drugs, further studies dealing with the circadian variation in the efficacy and possible resistance to various thrombolytic agents are warranted in the arterial occlusion of the limbs.

Amplitude/ MESOR ratio

Acrophase (hours:minutes)

95% Confidence limits of acrophase (hours:minutes)

0.86

9:54 8:09 Peak time58:40

8:24/11:24 6.54/8:22 Trough time50:56

0.90

9:30 7:26 Peak time58:12

7:24/11:36 2/2 Trough time523:56

0.86

10:16 8:29 Peak time58:56

8:08/12:24 7:08/9:50 Trough time51:32

0.94

9:39 8:35 Peak time58:48

7:44/11:40 7:24/9:46 Trough time51:32

0.72

10:01 7:51 Peak time58:32

7:56/12:08 2/2 Trough time50:36

0.85

9:41 8:22 Peak time58:52

8:24/10:56 2/2 Trough time50:24

0.82

10:29 7:50 Peak time58:20

7:28/13:32 6:28/9:12 Trough time51:16

Partially supported by grants from the Italian Ministry of University and Scientific and Technological Research. We thank Mrs. Maria Cecilia Barbi, librarian of the First Institute of Internal Medicine, for her helpful collaboration. This study was presented at the International Congress on Chronobiology, Paris, France, September 7–11, 1997.

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