Sex and Circadian Periodicity of Cardiovascular Diseases: Are Women Sufficiently Represented in Chronobiological Studies?

Women are often excluded/underrepresented in clinical trials; sometimes, the number of men/women participants or separate analysis by sex are not reported. A robust body of evidence demonstrated that several life-threatening acute cardiovascular diseases, for example, acute myocardial infarction, sudden cardiac death, cardiac arrest, rupture or dissection of aortic aneurysms, and stroke, exhibit a circadian periodicity with a morning peak. An analysis of 20 years of chronobiologic studies (44% of them, accounting for 85% of total cases, with separate analysis by sex) confirmed that morning hours are a critical time of onset of acute cardiovascular diseases in men and women.

Chronobiology of Takotsubo Syndrome and Myocardial Infarction: Analogies and Differences.

Several pathophysiologic factors, not harmful if taken alone, are capable of triggering unfavorable events when presenting together within the same temporal window (chronorisk), and the occurrence of many cardiovascular events is not evenly distributed in time. Both acute myocardial infarction and takotsubo syndrome seem to exhibit a temporal preference in their onset, characterized by variations according to time of day, day of the week, and month of the year, although with both analogies and differences.

Breaking heart: chronobiologic insights into takotsubo cardiomyopathy.

A considerable amount of evidence has shown that the major acute cardiovascular diseases, ie, myocardial infarction, sudden cardiac death, stroke, pulmonary embolism, and rupture or dissection of aortic aneurysms do not occur randomly in time, but exhibit specific temporal patterns in their onset, according to time of day, month or season, and day of the week. This contributes to the definition of "chronorisk", where several factors, not harmful if taken alone, are capable of triggering unfavorable events when presenting all together within the same temporal window. This article reviews the actual knowledge about time of onset of takotsubo cardiomyopathy.

Seasonal pattern of peptic ulcer hospitalizations: analysis of the hospital discharge data of the Emilia-Romagna region of Italy.

BACKGROUND: Previous studies have reported seasonal variation in peptic ulcer disease (PUD), but few large-scale, population-based studies have been conducted. METHODS: To verify whether a seasonal variation in cases of PUD (either complicated or not complicated) requiring acute hospitalization exists, we assessed the database of hospital admissions of the region Emilia Romagna (RER), Italy, obtained from the Center for Health Statistics, between January 1998 and December 2005. Admissions were categorized by sex, age (<65, 65-74, > or = 75 yrs), site of PUD lesion (stomach or duodenum), main complication (hemorrhage or perforation), and final outcome (intended as fatal outcome: in-hospital death; nonfatal outcome: patient discharged alive). Temporal patterns in PUD admissions were assessed in two ways, considering a) total counts per single month and season, and b) prevalence proportion, such as the monthly prevalence of PUD admissions divided by the monthly prevalence of total hospital admissions, to assess if the temporal patterns in the raw data might be the consequence of seasonal and annual variations in hospital admissions per se in the region. For statistical analysis, the chi2 test for goodness of fit and inferential chronobiologic method (Cosinor and partial Fourier series) were used. RESULTS: Of the total sample of PUD patients (26,848 [16,795 males, age 65 +/- 16 yrs; 10,053 females, age 72 +/- 15 yrs, p < 0.001)], 7,151 were < 65 yrs of age, 8,849 between 65 and 74 yrs of age, and 10,848 > or = 75 yrs of age. There were more cases of duodenal (DU). (89.8%) than gastric ulcer (GU) (3.6%), and there were 1,290 (4.8%) fatal events. Data by season showed a statistically difference with the lowest proportion of PUD hospital admissions in summer (23.3%) (p < 0.001), for total cases and rather all subgroups. Chronobiological analysis identified three major peaks of PUD hospitalizations (September-October, January-February, and April-May) for the whole sample (p = 0.035), and several subgroups, with nadir in July. Finally, analysis of the monthly prevalence proportions yielded a significant (p = 0.025) biphasic pattern with a main peak in August-September-October, and a secondary one in January-February. CONCLUSIONS: A seasonal variation in PUD hospitalization, characterized by three peaks of higher incidence (Autumn, Winter, and Spring) is observed. When data corrected by monthly admission proportions are analyzed, late summer-autumn and winter are confirmed as higher risk periods. The underlying pathophysiologic mechanisms are unknown, and need further studies. In subjects at higher risk, certain periods of the year could deserve an appropriate pharmacological protection to reduce the risk of PUD hospitalization.

Seasonal and weekly patterns of hospital admissions for nonfatal and fatal myocardial infarction.

OBJECTIVE: This retrospective study, based on the database of hospital admissions of the region Emilia-Romagna [RER], Italy, was aimed to confirm the existence of a seasonal or weekly pattern of hospital admission of acute myocardial infarction (AMI) and to verify possible differences between nonfatal or fatal cases. METHODS: The study included all cases of patients with AMI hospitalized between 1998 and 2006. Day of admission was categorized, respectively, into four 3-month intervals, into twelve 1-month intervals, and into seven 1-day intervals for statistical analysis, performed by chi(2) test goodness of fit and partial Fourier series on total cases, males, females, and nonfatal and fatal cases. RESULTS: The database included 64 191 cases of AMI (62.9% males, 12.3% fatal). Acute myocardial infarction was most frequent in winter and least in summer (P < .0001). The highest number of cases was recorded in January and the lowest in July (P < .0001). Chronobiologic analysis showed winter peaks for total cases (January, P = .035), females (December, P = .009), and fatal cases (January, P < .001). Acute myocardial infarction was most frequent on Monday and least on Sunday (P < .0001). Comparing observed vs expected events, there was a significantly higher frequency of cases on weekdays and reduced on weekends, for total (P < .0001), nonfatal (P < .0001), and fatal cases (P = .0001). CONCLUSIONS: This study confirms a significantly higher frequency of AMI admissions in winter and on a Monday. No difference in the frequency of nonfatal vs fatal events, depending of patients' admissions on weekdays or weekends, was found.

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 chi(2) 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 > or = 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 chi(2)=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; > or = 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.

Massive thrombosis of brachiocephalic veins and superior vena cava syndrome in a patient with non-small cell lung cancer treated with the epidermal growth factor receptor inhibitor erlotinib.

The superior vena cava (SVC) syndrome occurs when obstruction of this vessel interrupts venous return of blood from the head, upper extremities and thorax to the right atrium. Most cases of SVC syndrome result from neoplasia, especially from lung cancer, but other non-cancer-associated causes may include fibrosis caused by radiotherapy, collagen-vascular diseases, arteriovenous shunts or thrombosis as a complication of use of central venous catheters or devices. We report here the case of a 60-year-old woman with non-small cell lung cancer who was treated, after three lines of chemotherapy, with the epidermal growth factor receptor inhibitor erlotinib and subsequently presented to the hospital with abrupt onset of syncope, shortness of breath and cyanosis (face, neck and trunk). A CT scan of the chest demonstrated a massive thrombosis of both brachiocephalic veins and the SVC. The patient was treated with the systemic thrombolytic agent urokinase, with resolution of the clinical picture and no bleeding complications. The possible pathogenetic causes of thrombosis of the brachiocephalic veins and SVC syndrome in this case are discussed. It is possible that acute thrombosis may be associated with erlotinib use, even if it is likely that cancer may be the main cause of the thrombotic complication.

Marital Status, Cardiovascular Diseases, and Cardiovascular Risk Factors: A Review of the Evidence.

BACKGROUND: There is evidence showing that marital status (MS) and marital disruption (i.e., separation, divorce, and being widowed) are associated with poor physical health outcomes, including for all-cause mortality. We checked for the available evidence on the association between MS and cardiovascular (CV) diseases, outcomes, and CV risk factors. METHODS: A search across the PubMed database of all articles, including the term "marital status" in their title, was performed. All articles were then manually checked for the presence of the following terms or topic: CV diseases, acute myocardial infarction, acute coronary syndrome, coronary artery disease, cardiac arrest, heart failure, heart diseases, and CV mortality. Moreover, other search terms were: CV risk factors, hypertension, cholesterol, obesity, smoking, alcohol, fitness and/or physical activity, and health. Systematic reviews, meta-analyses, controlled trials, cohort studies, and case-control studies were potentially considered pertinent for inclusion. Case reports, comments, discussion letters, abstracts of scientific conferences, articles in other than English language, and conference abstracts or proceedings were excluded. RESULTS: In total, 817 references containing the title words "marital status" were found. After elimination of articles dealing with other topics, 70 records were considered pertinent. Twenty-two were eliminated for several reasons, such as old articles, no abstract, full text unavailable, other than English language, comments, and letters. Out of the remaining 48 articles, 13 were suitable for the discussion, and 35 (accounting for 1,245,967 subjects) were included in this study. CONCLUSIONS: Most studies showed better outcomes for married persons, and men who were single generally had the poorest results. Moreover, being married was associated with lower risk factors and better health status, even in the presence of many confounding effects.

[Circadian rhythms and cardiovascular diseases: clinical perspectives]. / Ritmi circadiani e patologia cardiovascolare: prospettive cliniche.

Chronobiology is a branch of biomedical sciences devoted to the study of biological rhythms. Biological rhythms exist at any level of living organisms and, according to their cycle length, may be divided into: a) circadian rhythms (period of approximately 24 hours), b) ultradian rhythms (period shorter than 24 hours), c) infradian rhythms (period longer than 24 hours). The cardiovascular system is organized according to an oscillatory pattern, and most cardiovascular functions exhibit circadian changes. Most evidence suggests that occurrence of cardiovascular events is not evenly distributed in time, but shows peculiar temporal patterns varying with time of the day, day of the week, and month of the year. These patterns coincide with the temporal variation in the (a) pathophysiological mechanisms that trigger cardiovascular events, and (b) physiological changes in the body rhythms. We will here briefly review the temporal aspects in occurrence of myocardial ischemia and infarction, as well as underlying triggering factors and possible applications in therapy.

Chronotype, gender and general health.

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.

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 > or =65 yrs of age. AMI was over-represented in males (82% in the <65 yr group vs. 56.6% in the > or =65 yr group (chi2=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%; chi2=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; chi2=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%; chi2=11.1, p=0.001). Inferential chronobiological (Cosinor) analysis identified a significant annual pattern in AMI in those > or =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).

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.

The crucial factor of hospital readmissions: a retrospective cohort study of patients evaluated in the emergency department and admitted to the department of medicine of a general hospital in Italy.

BACKGROUND: Early hospital readmissions, defined as rehospitalization within 30 days from a previous discharge, represent an economic and social burden for public health management. As data about early readmission in Italy are scarce, we aimed to relate the phenomenon of 30-day readmission to factors identified at the time of emergency department (ED) visits in subjects admitted to medical wards of a general hospital in Italy. METHODS: We performed a retrospective 30-month observational study, evaluating all patients admitted to the Department of Medicine of the Hospital of Ferrara, Italy. Our study compared early and late readmission: patients were evaluated on the basis of the ED admission diagnosis and classified differently on the basis of a concordant or discordant readmission diagnosis in respect to the diagnosis of a first hospitalization. RESULTS: Out of 13,237 patients admitted during the study period, 3,631 (27.4%) were readmitted; of those, 656 were 30-day rehospitalizations (5% of total admissions). Early rehospitalization occurred 12 days (median) later than previous discharge. The most frequent causes of rehospitalization were cardiovascular disease (CVD) in 29.3% and pulmonary disease (PD) in 29.7% of cases. Patients admitted with the same diagnosis were younger, had lower length of stay (LOS) and higher prevalence of CVD, PD and cancer. Age, CVD and PD were independently associated with 30-day readmission with concordant diagnosis and kidney disease with 30-day rehospitalization with a discordant diagnosis. CONCLUSIONS: Comorbid patients are at higher risk for 30-day readmission. Reduction of LOS, especially in elderly subjects, could increase early rehospitalization rates.

Takotsubo cardiomyopathy and acute infectious diseases: a mini-review of case reports.

Takotsubo cardiomyopathy (TTC), also defined as "stress cardiomyopathy," is characterized by a systolic dysfunction localized in the apical and medial left ventricles. Takotsubo cardiomyopathy is more prevalent in females and it is usually related to an event triggered by physical or emotional stress. We systematically explored PubMed and Embase medical information source to identify case reports showing association between infection and TTC. For each kind of infection, we collected a set of data, including pathogen, site of infection, clinical outcome, patient age and sex, and author and year of publication. We found 26 articles dealing with 27 case reports (74% women). The mean age was 61.4 ± 13.7 years and bacterial infections were more frequent (n = 23, 85.2%). In 14 cases, there was a culture-based definition of the bacterial strain: gram+ in 8 cases (57.1%) and gram- in 6 cases (42.9%). Clinical outcome was always favorable.

Seasonal variation in the onset of acute pancreatitis.

AIM: A circannual variation in the onset of several acute diseases, mostly dealing with cardiovascular system, has been reported. The present study was to verify the possible existence of a seasonal variability in the onset of acute pancreatitis. METHODS: All patients consecutively admitted to the Hospital of Ferrara, Italy, between January 1998 to December 2002, whose discharge diagnosis was acute pancreatitis, were considered. According to the time of admission, cases were categorized into twelve 1-mo intervals and in four periods by season. chi (2) test for goodness of fit and partial Fourier series were used for statistical analysis. RESULTS: During the study period, 549 cases of acute pancreatitis were observed. A significant peak of higher incidence was found in March-May, both for total population, males and subgroups with and without cholelithiasis or alcoholism. Fourier analysis showed the existence of a circannual rhythmic pattern with its main peak in March (95% C.L.: February-April, P = 0.005), and a secondary one in September. Death occurred more frequently in December-February, compared to the other periods (P = 0.029), and chronobiologic analysis yielded a seasonal peak in November-December (P<0.001). CONCLUSION: This study shows the existence of a circannual variation in the onset of acute pancreatitis, with a significantly higher frequency of events in the spring, especially for patients with cholelithiasis or alcoholism. Moreover, events occurring during the colder months seem to be characterized by a higher mortality rate.

Thromboangiitis obliterans (Buerger disease) in a female mild smoker treated with spinal cord stimulation.

The authors report the case of a 42-year-old female mild smoker admitted to the Hospital of Ferrara for the onset of asymptomatic necrotic ulcerations localized to the second, third, and fourth toes of left foot. Physical examination showed asphygmia of inferior limb distal peripheral pulses, with localized extremity marbleized and cyanotic skin at the level of the left foot, where necrotic ulcers were present at the second, third, and fourth toes. Doppler ultrasonography and angiography revealed a severe obliterating arteriopathy of bilateral distal arterial circulation. Both blood chemistry panel (including autoimmune and hypercoagulable profile) and diagnostic examination findings were normal. Thus, the patient met several criteria to be diagnosed with Buerger disease. After an attempt at medical therapy with the intravenous administration of the prostaglandin-analogue iloprost, given the young age and the lack of viable distal target vessels for bypass grafting, a spinal cord stimulator was implanted. More than 2 years later, the patient has a normal life.