Massimo Gallerani

Chronobiological aspects of acute cerebrovascular diseases

The study was aimed at further investigating the circadian and circannual patterns of stroke onset. Study design and type of participants: 977 strokes (475 in men and 502 in women) concerning 926 subjects (457 men and 469 women) admitted to Ferrara Hospital in two calendar years (1990–1991), were prospectively investigated. The strokes were classified as based on cerebral infarction (CI), transient ischemic attack (TIA) and cerebral hemorrhage (CH: subarachnoid and intracerebral hemorrhage). Two statistical models of analysis were used. The assessment of circadian and circannual periodicity was performed utilizing the single cosinor method. A separate analysis was performed after distribution of events into 6‐hour intervals, and chi‐square test for fit was applied to the number of observed versus expected cases. The majority of strokes occurred in the morning between 7 a.m. and noon (35% of cases) and the hypothesis of a uniform distribution of the time onset was rejected on the basis of the chi‐square for all subtypes of stroke. A circadian rhythm was found for CI and TIA with acrophase at the 11.56 and 12.41 respectively. Also a circannual periodicity was found for CI with a prevalent peak in October. The spectral analysis detected a circadian cycle for CH having a period of 4 h, and a circannual cycle for TIA with a period of 4 months. This study confirms that stroke is a high‐chronorisk disease, with specific circadian and circannual rhythms. This is very important for a better understanding and control of the underlying factors and in terms of prevention.

Chronobiological Patterns of Onset of Acute Cerebrovascular Diseases

There is a considerable amount of data indicating that several major unfavorable cerebrovascular events are not randomly distributed over time, but show a peculiar distribution along the day, the week, and the months of the year. The authors review the available evidence on the chronobiological (circadian, weekly, and seasonal) patterns of onset of acute cerebrovascular diseases and variations in their possible triggering mechanisms. The existence of a peculiar chronobiological pattern in the onset of acute cerebrovascular disease, characterized by both circadian (morning and evening occurrence), circaseptan (last and first days of the week), and circannual (especially in winter) is confirmed, although differences depending on biological (gender, age), pathological (diabetes, hypertension, smoke, alcohol), cultural, social, and environmental factors exist. A deeper knowledge of the underlying pathophysiologic mechanisms could provide more effective insights for both preventive strategies and optimization of therapeutic approach.

Circadian and Circannual Rhythmicity in the Occurrence of Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE Inconsistent data are available on the temporal pattern of onset of subarachnoid hemorrhage (SAH). We investigated the possible influence of vascular risk factors. METHODS Of a consecutive series of 217 cases of SAH, precise determination (within 30 minutes) of the time of symptom onset was possible in 199 (91.7%). Partial Fourier series with up to six harmonics were applied to hourly and monthly data, and the best-fitting curves for circadian and annual rhythmicity were calculated. The amplitude-MESOR (rhythm-adjusted mean over the time period analyzed) ratio was used as a measure of temporal variability. RESULTS In the total population, a significant circadian pattern of occurrence was demonstrated with major peaks in the morning (approximately 9 AM) and evening (approximately 9 PM) hours and a nocturnal trough (approximately 3 AM). Younger, male, and hypertensive subjects had lower amplitude-MESOR ratios; smokers had no significant rhythmicity. The annual pattern showed a 6-month periodicity with two major peaks in March and September and minor differences in the subgroups studied. CONCLUSIONS Our study indicates that the temporal distribution in onset of SAH may be influenced by variable combinations of environmental and vascular risk factors.

Serum cholesterol concentrations in parasuicide.

OBJECTIVE —To evaluate whether people who have committed parasuicide have low serum cholesterol concentrations. DESIGN —Results of blood tests in subjects admitted to hospital for parasuicide compared with those of a control group of non-suicidal subjects; comparison in subgroup of parasuicide subjects of two sets of blood test results (one set from admission for parasuicide and the other from admission for some other illness). SETTING —General hospital, Ferrara, Italy. SUBJECTS —331parasuicide subjects aged 44 (SD 21) years (109 with two sets of blood test results) and 331 controls. MAIN OUTCOME MEASURES —Serum cholesterol concentrations and possible association with parasuicide, considering sex, violence of method of parasuicide, and underlying psychiatric disorder. RESULTS —Lower serum cholesterol concentrations (4.96 (SD 1.16) mmol/l) were found in the parasuicide subjects than in the controls (5.43 (1.30); P < 0.001), regardless of sex and degree of violence of parasuicide method. Both men and women with two sets of blood test results had lower cholesterol concentrations after parasuicide. Linear regression analysis showed that the difference in cholesterol concentrations was significantly related to the length of time between the taking of the two sets of blood samples. CONCLUSION —The study showed low cholesterol concentrations after parasuicide. This finding agrees with previous studies, which suggest an association between low cholesterol concentration and suicide. Key messages Trials of cholesterol lowering have shown an increased mortality from violent deaths and suicide No studies of cholesterol concentrations in parasuicide subjects are available This study shows lower cholesterol concentrations in parasuicide subjects than in controls The association between low cholesterol concentration and parasuicide, however, does not allow definite conclusions to be drawn Further prospective trials are needed to focus on the possible effects of abrupt variation in cholesterol concentration on behaviour

Relationships of the Circadian Rhythms of Thrombotic, Ischemic, Hemorrhagic, and Arrhythmic Events to Blood Pressure Rhythms

Convincing evidence has recently accumulated that several unfavorable cardiovascular events show a well defined pattern in their occurrence throughout the day. Myocardial angina and infarction, sudden cardiac death, arrhythmias, fatal pulmonary thromboembolism, and ischemic and hemorrhagic cerebrovascular accidents occur more frequently in the morning, after awaking, until noon. Diurnal variations in multiple biologic functions, such as assumption of an upright posture associated with increased platelet aggregability, changes in blood clotting, fibrinolysis, and vascular tone and resistance, may be potentially active triggering factors. Moreover, variations in sympathetic tone, catecholamine secretion, and blood pressure have to be considered. The role of triggering factors and their relationships with blood pressure patterns is discussed in view of an optimized pharmacologic treatment.

Out-of-hospital sudden death referring to an emergency department☆

Over an 11-year period, autopsies were performed on 957 of 1038 nontraumatic deaths in the Emergency Department of the Central Hospital in Ferrara, Italy. Of these 957 cases, 732 (76.5%) met criteria for sudden death. In 100 (14%) of these cases, the death could be attributed to pulmonary embolism (55 cases), stroke (17), or rupture of aortic aneurysm (28). Acute myocardial infarction accounted for 403 (55%) of all sudden deaths. Severe coronary artery disease was found in 340 (84%) of these 403 deaths, with plaque fissuring or thrombi in 189 or 151 cases, respectively. Among the 229 sudden deaths for whom no immediate cause could be determined (31% of the total population), all had evidence of heart disease: 147 individuals had severe coronary artery disease, with plaque fissuring or thrombi found in 72 or 43, respectively. The remaining cases with no immediate cause of death had evidence of a cardiomyopathy (61) or valvular disease (21). We conclude that acute myocardial infarction accounts for the majority of cases of nontraumatic sudden death in our Emergency Department. Altogether, 84% of these patients had severe coronary artery disease. In approximately one-third of cases for whom no immediate cause of sudden death could be determined, all had evidence of heart disease, and about two-thirds had severe coronary artery disease.

Seasonal variation in occurrence of pulmonary embolism: analysis of the database of the Emilia-Romagna region, Italy.

Seasonal variation in the occurrence of cardiovascular and cerebrovascular events, including pulmonary embolism (PE), has been reported; however, recent large‐scale, population‐based studies conducted in the United States did not confirm such seasonality. The aim of this large‐scale population study was to determine whether a temporal pattern in the occurrence of PE exists. The analysis considered all consecutive cases of PE in the database of all hospital admissions of the Emilia Romagna region in Italy at the Center for Health Statistics between January 1998 and December 2005. PE cases were first grouped according to season of occurrence, and the data were analyzed by the χ2 test for goodness of fit. Then, inferential chronobiologic (cosinor and partial Fourier) analysis was applied to monthly data, and the best‐fitting curve for the annual variation was derived. The total sample consisted of 19,245 patients (8,143 male, mean age 71.6±14.1 yrs; 11,102 female, mean age 76.1±13.7 yrs). Of these, 2,484 were <65 yrs, 5,443 were between 65 and 74, and 11,318 were ≥75 yrs. There were 4,486 (23.3%) fatal‐case outcomes. PE occurred least frequently in spring (n=4,442 or 23.1%) and most frequent in winter (n=5,236 or 27.2%, goodness of fit χ2=75.75, p<0.001). Similar results were obtained for subgroups formed by gender, age, fatal/non‐fatal outcome, presence/absence of major underlying co‐morbid conditions, and specific risk factors. Inferential chronobiological analysis identified a significant annual pattern in PE, with the peak between November and December for the total sample of cases (p<0.001), males (p<0.001), females (p=0.002), fatal and non‐fatal cases (p<0.001 for both), and subgroups formed by age (<65 yrs, p=0.012; 65–74 yrs, p<0.001; ≥75 yrs, p=0.012). This pattern was independent of the presence/absence of hypertension (p=0.003 and p<0.001, respectively), pulmonary disease (p<0.001 and p<0.001, respectively), stroke (p<0.001 and p=0.004, respectively), neoplasms (p=0.005 and p=0.001, respectively), heart failure (p=0.022 and p<0.001, respectively), and deep vein thrombosis (p=0.002 and p<0.001, respectively). However, only a non‐statistically significant trend was found for subgroups formed by cases of diabetes mellitus, infections, renal failure, and trauma.

Seasonal Variation in Onset of Myocardial Infarction—A 7‐year single‐center study in Italy

Like many other serious acute cardiovascular and cerebrovascular events, acute myocardial infarction (AMI) shows seasonal variation, being most frequent in the winter. We sought to investigate whether age, gender, and hypertension influence this pattern. We studied 4014 (2259 male and 1755 female) consecutive patients with AMI presenting to St. Anna Hospital of Ferrara, Italy between January 1998 and December 2004. Some 1131 (28.2%) of the AMI occurred in persons <65 yrs of age, and 2883 (71.8%) in those ≥65 yrs of age. AMI was over‐represented in males (82% in the <65 yr group vs. 56.6% in the ≥65 yr group (χ2=13.99; p<0.001). Hypertension had been previously documented in 964 (24%) of the cases. There were 691 (17.2%) fatal case outcomes; fatal outcomes were significantly higher among the 3054 normotensive (n=614 or 20.1%) than the 964 hypertensive cases (n=77 or 8%; χ2=74.94, p<0.001). AMIs were most frequent in the winter (n=1076 or 26.8% of all the events) and least in the summer (n=924 or 23.0% of all the events; χ2=12.36, p=0.007). The greatest number of AMIs occurred in December (n=379 or 9.44%), and the lowest number in September (n=293 or 7.3%; χ2=11.1, p=0.001). Inferential chronobiological (Cosinor) analysis identified a significant annual pattern in AMI in those ≥65 yrs of age, with a peak between December and February—January for the total sample (p<0.005), January for the sample of males (p=0.014), February for fatal infarctions (p=0.017), and December for non‐fatal infarctions (p=0.006). No such temporal variations were detected in any of these categories in those <65 yrs of age. The annual pattern in AMI was also verified by Cosinor analysis in the following hypertensive subgroups: hypertensive males (n=552: January, p=0.014), non‐fatal infarctions in hypertensive patients (n=887: January, p=0.018), and elderly normotensives (n=1556: November, p=0.007).

Acute intracerebral haemorrhage : circadian and circannual patterns of onset

Hypothesis of the circannual and circadian variation in onset of intracerebral haemorrhage (CH) was verified, by means of single cosinor method and chi‐square test for goodness of fit, in 161 consecutive patients (94 men and 67 women) admitted into the Institute of Neurosurgery of Ferrara Hospital, Italy, over 9 years. The majority of CH occurred in the morning between 06.00 AM and 12.00 noon (36.7% of cases, p<0.001); when considering the specific anatomical sites, typical supratentorial haemorrhages showed a similar pattern (37.4%, p= 0.01). A similar morning behavior was found when considering subgroups by sex (men 36.2%, women 37.3%), age ≥60 years (42.5%), no presence of hypertension (39.7%), no presence of diabetes mellitus (33.3%) and non‐smokers (30.4%). The results by cosinor analysis yielded a circadian rhythmicity both for total sample and, for the mens subgroup, with a morning peak at 11.44 and 11.25, respectively. For women, however, spectral analysis found a significant ultradian cycle, having a period of 12 h (p = 0.01). A circannual periodicity, with a prevalent peak in February, was found for total sample and males subgroups, too. The results of this study confirm that intracerebral haemorrhages present a characteristic circadian and circannual pattern in onset.

Seasonal variation in the occurrence of nontraumatic rupture of thoracic aorta

Research has identified circadian and seasonal patterns for several acute cardiovascular diseases. In order to investigate the possible existence of a seasonal variation in the onset of acute nontraumatic ruptures of thoracic aorta, this study considered all patients referred to the emergency department of St Anna Hospital of Ferrara, Italy, from January 1985 to December 1996. In the considered period, 85 patients (52 males, 33 females) of nontraumatic ruptures of thoracic aorta were observed. Cosinor analysis and partial Fourier series with up to 4 harmonics were applied to monthly data, and the best-fitting curves for circannual rhythmicity were calculated. A higher winter occurrence with a significant peak in January was found for the total population and the male subgroup. Although the underlying factors are not fully known, such patterns strictly resemble that of arterial blood pressure. Emergency doctors can put to practical use the recognition of a clearly identified chronorisk for aortic rupture, increasing alertness, and providing the most effective antihypertensive protection at the specific vulnerable periods.