From the Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain; and the Hypertension and Vascular Risk Unit, Hospital Clínico Universitario, Santiago de Compostela, Spain
Studies have shown that increased plasma fibrinogen levels are closely associated with a higher rate of cardiovascular events. Therefore, an increased fibrinogen level is considered a risk factor for acute myocardial infarction (MI) and stroke.1 In small samples of patients, primarily in elderly patients, plasma fibrinogen levels have also been shown to fluctuate with the seasons, with higher levels found during the winter.2-4 Some studies have also shown a seasonal variation in the incidence of onset of acute MI, with a peak during the coldest months.5 Separate studies, therefore, appear to show that the seasonal distribution of fibrinogen is related in time with the circannual fluctuation in coronary events.5 The diminished nocturnal decline in blood pressure (nondipping6) has also been shown to be related to end-organ damage and cardiovascular events.7-9
We studied the seasonal variation of plasma fibrinogen levels in a sample of hypertensive patients based on their circadian patterns of blood pressure fluctuations using 48-hour ambulatory blood pressure monitoring, taking into account the fact that fibrinogen is an independent risk factor for cardiovascular disease.
Patients and methods
Our study consisted of 1,006 sequential patients (482 men) who had been diagnosed with stage 1 or stage 2 essential hypertension and were evaluated for a span of 2.5 consecutive years. The mean age was 53.0 ± 13.4 years (range, 19 to 87 years). On enrollment into the study, 407 patients (40.5%) were not receiving therapy for their blood pressure. After overnight fasting, blood samples from an antecubital vein were taken between 8:00 am and
9:00 am the day ambulatory blood pressure monitoring began. Systolic and diastolic blood pressure measurements were taken for 48 consecutive hours. Between 7:00 am and 11:00 pm, measurements were taken every 20 minutes; at night, they were taken every 30 minutes. Patients were told to carry
out their normal activities and to follow a similar schedule on both days of monitoring. Patients were assessed during their customary daytime activities, which was between 8:00 am and 11:00 pm for most participants, and during sleep at night. They were given actigraphs to wear on their dominant wrists to assess physical activity every minute. The means for diurnal and nocturnal blood pressure were ascertained from the data from the actigraphs.
Based on the data collected over the 48 hours, participants were divided into two groups according to their nocturnal blood pressures: nondippers and dippers. Those with less than a 10% decline in sleep mean systolic blood pressure compared with the awake mean were categorized as nondippers (n = 513). The rest were considered dippers
(n = 493). A seasonal fluctuation in plasma fibrinogen levels was found for both nondippers and dippers using multiple components analysis of longitudinal time series,10 a method that can be used with nonsinusoidal-shaped time series consisting of values distributed at equal or unequal intervals. A nonparametric test designed to compare measurements from multiple component analysis was used to compare seasonal variations between dippers and nondippers.11
A marked circannual fluctuation in plasma fibrinogen levels was shown for the entire group of patients (P < .001), with a mean
fibrinogen level of 318 mg/dL, an extent of predictable change throughout the year (amplitude) of 40 mg/dL, and the time of peak value (orthophase) in February.
The seasonal variation in plasma fibrinogen levels was analyzed using a model that included comparison of elements with time periods of 6 and 12 months. We also compared the monthly means of plasma fibrinogen using analysis of variance (ANOVA) to additionally confirm the statistically sig-
nificant circannual distribution (P < .001). Nondippers and dippers were analyzed separately using the same model and time periods. Throughout the year, nondippers had a higher plasma fibrinogen level compared with dippers (P < .001, from the test for comparison of seasonal mean between both groups; figure). However, despite this difference, the pattern in seasonal variation was similar for both groups. The time of peak value, therefore, was comparable for nondippers and dippers. The greatest plasma fibrinogen levels occurred during the winter months, regardless of the degree of the nighttime drop in blood pressure. The extent of predictable change through out the year was also comparable for both groups, as shown by an analysis of rhythm parameters. The circannual variation was about 42 mg/dL for both nondippers and dippers (figure). After adjust-ing for possible confounding factors, such as sex, drinking alcohol, smoking, exercise, and antihypertensive medication, ANOVA test results showed that nondippers had a marked increase in plasma fibrinogen (P = .003).
Our study showed that hypertensive patients classified as both nondippers and dippers had a significant increase in plasma fibrinogen levels in February and had lower levels in September and October. This corroborates the findings of other studies that a seasonal variation in plasma fibrinogen levels exists, including two separate 1-year studies of elderly patients and a cross-sectional study of patients 55 years of age and older.4 In a study by Stout and Crawford, the predictable circannual variation in plasma fibrinogen levels was higher (71 mg/dL) than in our study (40 mg/dL).2 However, in studies by Woodhouse and colleagues3 and van der Bom and colleagues,4 the plasma fibrinogen levels were lower than in our study (13 mg/dL and 31 mg/dL, respectively). These disparities may be the result of environmental factors or differences in the study samples.
A 67% higher risk of death from ischemic heart disease was shown when plasma fibrinogen levels increased above one standard deviation (59 mg/dL) in 5 years of follow-up in the Northwick Park Heart Study.12 Based on this finding and using the seasonal predictable variation shown in our study, our subjects would have a 45% increased risk of ischemic heart disease during the coldest months. These figures show how the circannual variation in plasma fibrinogen levels can have a
significant influence on death rates from cardiovascular disease, although projection of results between studies must be done carefully.
In addition to showing a relationship between circannual fluctuation and many other parameters related to risk of cardiovascular disease, other studies have found that seasonal fluctuation of plasma fibrinogen levels is associated with yearly variation in the incidence of mortality from coronary artery disease and of onset of acute MI.5 Further research is needed to reveal the mechanisms involved. Activation of the acute phase response due to respiratory infections, which are more common in winter, may be one cause, as suggested by Woodhouse and colleagues.3 There is no evidence to implicate infections as a cause of the circannual fluctuation in fibrinogen, however, as shown by studies on interleukin-6, soluble P-selectin, factor VII, C-reactive protein, plasminogen activator inhibitor, and white blood cell count.13
Our study is the first to show that nondipper hypertensive patients have a marked increase in plasma fibrinogen levels throughout the year compared with dipper hypertensive patients. This study also confirms the results of other studies showing the seasonal variation of high amplitude that characterizes plasma fibrinogen. Nondipper hypertensive patients are at much greater risk of having a stroke compared with dippers, as shown by O’Brien and colleagues, although the reasons for this are not understood.6 In another study, the number of adverse events was increased threefold for nondippers compared with dippers over a follow-up of 3.2 years.7 In the Systolic Hypertension in Elderly in Europe (Syst-Eur) trial, nondippers were shown to have a higher rate of MI and stroke than dippers in a subsample of 808 patients receiving ambulatory blood pressure monitoring.8 In another study, hypertensive patients with a decrease in the nocturnal blood pressure drop of 5% had a 31% higher risk of mortality from cardio-
vascular disease after a follow-up of 9.2 years.9 Furthermore, dipper hypertensive and nondipper normotensive subjects had a comparable relative hazard of cardiovascular mortality (2.37 for dippers and 2.16 for nondippers).9 This shows that risk of cardiovascular events is affected by abnormal circadian blood pressure variability, not just increased blood pressure, and the treatment of patients who lack a nocturnal decline in blood pressure is extremely important.9
In our study, we used ambulatory blood pressure monitoring for 48 hours, compared with the more common 24-hour assessment. Although less practical, 48-hour monitoring provides better data regarding blood pressure fluctuations, diagnosis of disease, and assessment of response to medication.14 Studies of 24-hour blood pressure monitoring have shown that this period of time may not be long enough to correctly evaluate circadian patterns. A marked reduction in the diurnal mean of blood pressure was shown on the second day of monitoring in patients who were undergoing ambulatory blood pressure monitoring for the first time. During the first 4 hours of monitoring, systolic blood pressure increased an average of 7 mm Hg and diastolic blood pressure increased an average of 5 mm Hg. This effect persisted for at least the first 9 hours of measurement.15 Thirty-five percent of patients who were classified as dippers on the first day of measurement became nondippers on the second day because of the decrease in blood pressure during diurnal activity but not during nocturnal resting hours.15 This blood pressure monitoring effect, which occurs in studies based on
24-hour ambulatory monitoring, explains why categorizing patients based on their dipping status has not been reproducible and why the percentage of nondippers in many studies has been underestimated.
Our study showed that there was a marked increase in plasma fibrinogen levels during the colder months of the year in nondipper and dipper hypertensive patients. In addition, nondipper hypertensive patients had increased plasma fibrinogen levels throughout the year compared with dipper hypertensive patients. These findings may support other studies that have correlated an increase in the occurrence of cardiovascular events with a lack of nocturnal decline in blood pressure and may also support the finding that the seasonal variation in plasma fi-brinogen levels is associated with the yearly variation in the incidence of mortality from coronary artery disease and onset of acute MI. This study highlights the importance of the need to identify patients with altered circadian blood pressure patterns, especially nondipper hypertensive patients, and to provide appropriate treatment. n