Raffaella Salmi

Circadian Variation in Stroke Onset: Identical Temporal Pattern in Ischemic and Hemorrhagic Events

Stroke is the culmination of a heterogeneous group of cerebrovascular diseases that is manifested as ischemia or hemorrhage of one or more blood vessels of the brain. The occurrence of many acute cardiovascular events—such as myocardial infarction, sudden cardiac death, pulmonary embolism, critical limb ischemia, and aortic aneurysm rupture—exhibits prominent 24 h patterning, with a major morning peak and secondary early evening peak. The incidence of stroke exhibits the same 24 h pattern. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical double‐peak 24 h pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulative balance, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important. Clinical medicine has been most concerned with the prevention of stroke in the morning, when population‐based studies show it is of greatest risk during the 24 h; however, improved protection of at‐risk patients against stroke in the early evening, the second most vulnerable time of cerebrovascular accidents, has received relatively little attention thus far.

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.

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).

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.

Seasonal Variation in Onset of Pulmonary Embolism is Independent of Patients' Underlying Risk Comorbid Conditions

As for many cardiovascular events, pulmonary embolism (PE) is not randomly distributed over time, but shows rhythmic patterns. The purpose of this study was to investigate whether such temporal pattern of occurrence varied in subgroups of patients according to different risk comorbid conditions. All cases of PE observed at the Hospital of Ferrara, Italy, from 1998 to 2001, were considered. After determination of the day of onset, the population was grouped by gender and the most common underlying risk comorbid conditions, e.g., deep vein thrombosis (DVT), neoplasms, cardiomyopathies, traumas/surgical operations, diabetes mellitus, pulmonary diseases, hypertension, cerebrovascular diseases, heart failure, hematologic diseases. For statistical analysis, chi-square test for goodness of fit and partial Fourier series were used. A total of 784 cases (mean age 71 ± 14 years) were included. Frequency of onset was higher in winter for total population (p=0.002), men (p=0.004), DVT (p=0.001), pulmonary disease (p=0.008), cardiomyopathies (p=0.011), and major traumas/surgical operations (p=0.049). Chronobiologic analysis identified a winter peak for total population (p=0.008), men (p<O.OOl), DVT (p=0.006), pulmonary diseases (p=0.017), and hypertension (p=0.026). This study confirms the winter peak of PE and provides evidence that it is not influenced by the underlying clinical conditions, but probably by endogenous variations.

Interventional treatment of venous thromboembolism: A review

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease after coronary artery disease and cerebrovascular disease and is responsible for significant morbidity and mortality in the general population. Full dose anticoagulation is the standard therapy for VTE, both for the acute and the long-term phase. The latest guidelines of the American College of Chest Physicians recommend treatment with a full-dose of unfractioned heparin (UFH), low-molecular-weight-heparin (LMWH), fondaparinux, vitamin K antagonist (VKA) or thrombolysis for most patients with objectively confirmed VTE. Catheter-guided thrombolysis and trombosuction are interventional approaches that should be used only in selected populations; interruption of the inferior vena cava (IVC) with a filter can be performed to prevent life-threatening PE in patients with VTE and contraindications to anticoagulant treatment, bleeding complications during antithrombotic treatment, or VTE recurrences despite optimal anticoagulation. In this review we summarize the currently available literature regarding interventional approaches for VTE treatment (vena cava filters, catheter-guided thrombolysis, thrombosuction) and we discuss current evidences on their efficacy and safety. Moreover, the appropriate indications for their use in daily clinical practice are reviewed.

Cricadian rhythms and the heart: Implications for chronotherapy of cardiovascular diseases

Clinical Pharmacology and Therapeutics (1994) 56, 244–247; doi:10.1038/clpt.1994.133

Chronotype, gender and general health.

ABSTRACT Background: Light–dark alternation has always been the strongest external circadian “zeitgeber” for humans. Due to its growing technological preference, our society is quickly transforming toward a progressive “eveningness” (E), with consequences on personal circadian preference (chronotype), depending on gender as well. The aim of this study was to review the available evidence of possible relationships between chronotype and gender, with relevance on disturbances that could negatively impact general health, including daily life aspects. Methods: Electronic searches of the published literature were performed in the databases MEDLINE and Web of Science, by using the Medical Subject Heading (MeSH), when available, or other specific keywords. Results: Results were grouped into four general areas, i.e. (a) “General and Cardiovascular Issues”, (b) “Psychological and Psychopathological Issues”, (c) “Sleep and Sleep-Related Issues” and (d) “School and School-Related Issues”. (a) E is associated with unhealthy and dietary habits, smoking and alcohol drinking (in younger subjects) and, in adults, with diabetes and metabolic syndrome; (b) E is associated with impulsivity and anger, depression, anxiety disorders and nightmares (especially in women), risk taking behavior, use of alcohol, coffee and stimulants, psychopathology and personality traits; (c) E has been associated, especially in young subjects, with later bedtime and wake-up time, irregular sleep–wake schedule, subjective poor sleep, school performance and motivation, health-related quality of life; (d) E was associated with lowest mood and lower overall grade point average (especially for women). Conclusions: Eveningness may impact general health, either physical or mental, sleep, school results and achievements, especially in younger age and in women. The role of family support is crucial, and parents should be deeply informed that abuse of technological devices during night hours may lead to the immature adjustment function of children’s endogenous circadian pacemakers.

Twenty-Four-Hour Patterns in Occurrence and Pathophysiology of Acute Cardiovascular Events and Ischemic Heart Disease

The scientific literature clearly establishes the occurrence of cardiovascular (CV) accidents and myocardial ischemic episodes is unevenly distributed during the 24 h. Such temporal patterns result from corresponding temporal variation in pathophysiologic mechanisms and cyclic environmental triggers that elicit the onset of clinical events. Moreover, both the pharmacokinetics and pharmacodynamics of many, though not all, CV medications have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. Twenty-four-hour rhythmic organization of CV functions is such that defense mechanisms against acute events are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent evening (in diurnally active persons), to aggressive mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables, such as blood pressure (BP), heart rate (HR), rate pressure product (systolic BP × HR, surrogate measure of myocardial oxygen demand), sympathetic activation, and plasma levels of endogenous vasoconstricting substances, are aligned together at the same circadian time, the risk of acute events becomes significantly elevated such that even relatively minor and usually harmless physical and mental stress and environmental phenomena can precipitate dramatic life-threatening clinical manifestations. Hence, the delivery of CV medications needs to be synchronized in time, i.e., circadian time, in proportion to need as determined by established temporal patterns in risk of CV events, and in a manner that averts or minimizes undesired side effects. (Author correspondence: prf@unife.it)