Undiagnosed sleep-disordered breathing among male nondippers with essential hypertension.

OBJECTIVE: A blunting of the nocturnal fall in arterial blood pressure is found in a minority of patients (nondippers) with essential hypertension. We tested whether sleep-disordered breathing (snoring and apnea or hypopnea) might explain such a finding for male patients, among whom its prevalence is much higher. SETTING AND PATIENTS: We studied 100 new cases of hypertension in men, observed consecutively by a local group of general practitioners and diagnosed essential hypertensives in a referral clinic. By using 24 h ambulatory blood pressure monitoring with a SpaceLabs 90207 device, 15 patients were classified initially nondippers (daytime ambulatory blood pressure > or = 136/87 mmHg; night-time decrease by < 10% of the daytime mean), but only 11 were confirmed to be nondippers by continuous blood pressure monitoring with a Finapres device. Ten dippers matched by age, body mass index and mean 24 h blood pressure were used as controls. MAIN OUTCOME MEASURES: Parameters of nocturnal polysomnography. RESULTS: During polysomnography, the nondippers exhibited a blunting of the sleep-related fall in blood pressure and an increased variability in blood pressure associated with sleep-disordered breathing (heavy snoring for all, with an apnea or hypopnea index > 10 in 10 cases). Six of the control patients breathed normally and four snored nonapneically. There was a normal fall in nocturnal blood pressure in all 10 cases. CONCLUSIONS: The nondipper condition appears to be associated with undiagnosed apneic snoring for an unselected population of previously untreated male subjects with a diagnosis of essential hypertension. Ambulatory blood pressure monitoring of such patients is of limited diagnostic value.

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.

Time-dependent effect of isradipine on the nocturnal hypertension in chronic renal failure.

Nocturnal hypertension is frequently observed in chronic renal failure and contributes to the risk of target organ damages. We assessed whether antihypertensive therapy may restore a nocturnal blood pressure (BP) fall in this condition. A sustained-release oral formulation (SRO) of isradipine was used, and the possible differences in the response to morning nu evening dosing were also investigated. Sixteen hypertensive patients with chronic renal failure due to parenchymal kidney disease were studied after 2 weeks of single-blind placebo runin. According to the double-blind, randomized, cross-over design, they received 5 mg isradipine SRO at 08:00, or at 20:00 for 4 weeks, separated by a single-blind placebo period of 2 weeks. A 24-h BP monitoring at 10-min intervals was carried out at the end of each treatment using a SpaceLabs 90207 instrument. Under placebo, blunt BP profiles were observed, whereas HR showed a mean nocturnal fall of 17.4%, which remained unaltered after isradipine. Both isradipine treatments were equally effective in reducing the mean 24-h BP levels. However, the evening regimen showed a more pronounced effect during the night. The mean nocturnal fall in systolic/diastolic BP represented 4.8/8.7% and 7.5/10.9% of the corresponding daytime mean after morning and evening dosing, respectively. Only the evening administration reset the normal synchronization of the 24-h BP and HR profiles. Our findings demonstrate that antihypertensive treatment may restore a nocturnal BP fall in renal patients. An evening regimen of isradipine SRO seems more apt than a morning regimen to obtain this therapeutic goal.

Endocrine mechanisms of blood pressure rhythms.

The temporal organization of blood pressure is mainly controlled by neuroendocrine mechanisms. The monoaminergic systems appear to integrate the major driving factors of temporal variability, but evidence also indicates a role of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, and endothelial systems as well as other vasoactive peptides. Although their hormonal secretions are typically episodic, the probability of secretory episodes is "gated" by mechanisms that are coupled either to sleep or to an endogenous pacemaker which usually is predominantly (though not only) circadian. Many hormones with established actions on the cardiovascular system (arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, CRF, ACTH, TRH, endogenous opioids, and prostaglandin E2) are also involved in sleep induction or arousal. Hence, physical, mental, and pathologic stimuli, which may drive activation or inhibition of these neuroendocrine effectors of biologic rhythmicity, may also interfere with the temporal blood pressure structure. On the other hand, the immediate adaptation of the exogenous components of blood pressure rhythms to the demands of the environment are modulated by the circadian-time-dependent responsiveness of the biologic oscillators and their neuroendocrine effectors. These notions may contribute to a better understanding of the pathophysiology and therapeutics of changes in blood pressure.

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.

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 variation in the onset of acute critical limb ischemia.

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 of drugs based on the time of day. Further studies dealing with circadian variation in the efficacy of thrombolytic agents are so needed.

Chronobiological aspects of pulmonary thromboembolism.

A growing body of evidence has recently accumulated suggesting that several unfavorable cardiovascular events, e.g., myocardial angina and infarction, sudden cardiac death, and stroke, present a specific temporal pattern in their occurrence. This has also been shown to be true for fatal pulmonary thromboembolism, with a high frequence peak in winter and in the morning hours. The authors report the circannual and circadian aspects of pulmonary thromboembolism, analysing both the temporal patterns of the underlying favouring or precipitating factors, and the possible therapeutic implications.

From a static to a dynamic concept of risk: the circadian epidemiology of cardiovascular events.

A growing body of evidence substantiates that the occurrence of cardiovascular events in unevenly distributed in time, especially during the 24 h. These temporal patterns are indicative of temporal variation in the (1) pathophysiological mechanisms that trigger cardiovascular events and (2) physiological status of the cardiovascular system, which combine to give rise to 24 h and other periodicities in the susceptibility to disease. The classic assumption of epidemiologic studies is constancy (or homeostasis) in one's risk to disease during the 24 h, as well as other, time domains. However, we propose a new concept, that of chronorisk since it takes into account the temporal variability in the pathophysiological mechanisms and their reciprocal temporal interactions that lead to day-night and other time-dependent patterns in cardiovascular events. This chronobiological approach, which is expected to contribute new insight into the prognostic and therapeutic assessment of cardiovascular events, is worthy of broader application in cardiovascular and other fields of medicine and warrants further investigation.

Circadian variation in onset of acute cardiogenic pulmonary edema is independent of patients' features and underlying pathophysiological causes.

BACKGROUND: The present study aimed to confirm the existence of a circadian pattern in the onset of acute pulmonary edema (APE) and to verify whether sex, age, preexisting diseases, and clinical causes determining the event may influence it. SUBJECTS AND METHODS: The study considered all consecutive cases of APE observed at the St. Anna General Hospital of Ferrara, Italy, during a 7-year period from January 1, 1992, to December 31, 1998. The sample population was divided into subgroups by sex, age (<75 and > or =75 years), presence or absence of diabetes and hypertension, clinical causes determining the event (i.e., acute myocardial infarction (AMI), pulmonary embolism, arrhythmias). The most important associated or concomitant diseases were also considered (i.e., coronary heart disease and angina, previous myocardial infarction, chronic cardiac failure, dilatative cardiopathy, chronic atrial fibrillation, valvular disease, chronic obstructive pulmonary disease, chronic cor pulmonale, malignancy, chronic renal failure). Time of symptom onset of each event was recorded accurately, then tabulated into 24 increments of 1h (e.g., 06:00 to 06:59 was reported as 6 A.M.). For statistical chronobiological analysis, partial Fourier series were used. RESULTS: During the 7-year period, 1321 consecutive cases of APE in 1014 different subjects were observed. The majority of events occurred at night, and statistical analysis showed a 24h rhythmicity both in the total sample population and in all considered subgroups, with the only exception being patients with pulmonary embolism and arrhythmias, for which the small number of cases made the study of rhythms in APE impossible. CONCLUSIONS: The nighttime preference in the occurrence of APE appears to be quite independent of all demographic features or underlying pathophysiological causes.

Circadian variation in the occurrence of paroxysmal supraventricular tachycardia in clinically healthy subjects.

The purpose of this study was to assess prospectively the circadian distribution of spontaneous paroxysmal supraventricular tachycardia (PSVT) in drug-free subjects with no previous history or symptoms and signs of concomitant heart or lung disease. Of 112,424 presumably diurnally active patients admitted to the Emergency Department of a city hospital during a 2-year period (1990-1991), a total of 185 patients were screened with these characteristics. Time of symptom onset was exactly recordable in 177 (75 men and 102 women). Analysis of variance documented a higher incidence in the morning-afternoon hours. Cosinor analysis, although not a perfect method for the time series analysis, verified circadian rhythmicity with afternoon peak times. Our findings suggest that a circadian pattern in intrinsic electrical instability of the heart conduction system exists irrespective of the circadian fluctuations in the pathophysiologic mechanisms of the cardiovascular or lung diseases most frequently associated with PSVT itself.

Fatal pulmonary embolism in hospitalized patients: evidence for a winter peak.

This study was intended to determine whether there are circa-annual variations in the incidence of fatal pulmonary embolism for hospitalized patients. Patients (152), admitted into both the medical and surgical departments of St. Anna Hospital of Ferrara, Italy, during an 8-year period (1983-1990) and who died in hospital as a result of pulmonary embolism, were considered. The day and month of death were registered, and analysed by inferential statistics (single cosinor). A circa-annual variation, with a statistically significant peak in late January (P = 0.002), was found for the total sample. After stratification by sex, this winter peak was confirmed only for women (P = 0.006).

Circadian variation in the time of onset of acute gastrointestinal bleeding.

The increased attention to biologic rhythms and clinical manifestations of several diseases has recently led to the identification of "chronorisks" for certain pathologic events. To evaluate whether a temporal pattern exists for acute gastrointestinal bleeding, 369 consecutive patients with acute gastrointestinal bleeding observed at the emergency department (ED) of S. Anna Hospital of Ferrara, Italy, during a 3-year period (1988-1990) were studied. On presentation to the ED, 287 patients had upper gastrointestinal tract bleeding (UGB), and 82 patients had lower gastrointestinal tract bleeding (LGB). In 270 cases of UGB and in 75 cases of LGB, the hour of symptom onset was known and the data were analyzed for the number of observed versus expected events during the four 6-hour intervals of a day. The majority of events occurred in the morning (32.2% of UGB and 42.7% of LGB). Cosinor analysis yielded a circadian rhythmicity with a peak in the late morning to early afternoon for both UGB and LGB independent of sex and site of bleeding.

Chronoepidemiology in human diseases.

Current knowledges about time-dependent variations in onset of several acute medical diseases are briefly reviewed. Moreover, temporal variation in relative risk factors are also discussed. Any clue to the increased likelihood of a given event can heighten suspicion and shorten time of effective action. The predictability of a certain event, due to the periodicity of cyclic changes, can be of a practical interest in everyday medical practice.

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: 331 parasuicide 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.