Roberto Manfredini

Chronobiological Patterns of Acute Aortic Dissection

Background—Chronobiological rhythms have been shown to influence the occurrence of a variety of cardiovascular disorders. However, the effects of the time of the day, the day of the week, or monthly/seasonal changes on acute aortic dissection (AAD) have not been well studied. Methods and Results—Accordingly, we evaluated 957 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2000 (mean age 62±14 years, type A 61%). A &khgr;2 test for goodness of fit and partial Fourier analysis were used to evaluate nonuniformity and rhythmicity of AAD during circadian, weekly, and monthly periods. A significantly higher frequency of AAD occurred from 6:00 am to 12:00 noon compared with other time periods (12:00 noon to 6:00 pm, 6:00 pm to 12:00 midnight, and 12:00 midnight to 6:00 am;P <0.001 by &khgr;2 test). Fourier analysis showed a highly significant circadian variation (P <0.001) with a peak between 8:00 am and 9:00 am. Although no significant variation was found for the day of the week, the frequency of AAD was significantly higher during winter (P =0.008 versus other seasons by &khgr;2 test). Fourier analysis confirmed this monthly variation with a peak in January (P <0.001). Subgroup analysis identified a significant association for all subgroups with circadian rhythmicity. However, seasonal/monthly variations were observed only among patients aged <70 years, those with type B AAD, and those without hypertension or diabetes. Conclusions—Similar to other cardiovascular conditions, AAD exhibits significant circadian and seasonal/monthly variations. Our findings may have important implications for the prevention of AAD by tailoring treatment strategies to ensure maximal benefits during the vulnerable periods.

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 ≥ 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.

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 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.

2013 Ambulatory Blood Pressure Monitoring Recommendations for the Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other Hypertension-associated Risk, and Attainment of Therapeutic Goals

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as “masked normotensives” (elevated clinic BP but normal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “masked hypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of “normotensive” adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).

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.

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.

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 ones 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.

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