Surges In Sympathetic Activity Research Articles

Surge of Sympathetic Activity during Hyperventilation at the End of Apnea for Patients with Obstructive Sleep Apnea.

Background and Objectives: The mechanisms connecting obstructive sleep apnea (OSA) and cardiovascular disease are multifactorial, involving intermittent hypoxia, hypercapnia, and sympathetic activation. The aim of this study was to explore the oscillations of sympathetic activity during the sleep apnea episodes throughout the entire night in patients with OSA. Materials and Methods: The participants received whole-night polysomnography (PSG), and electrocardiogram (EKG) data from the PSG were collected for heart rate variability (HRV) analysis. HRV measurements were conducted in the time and frequency domains. The root mean square of successive differences between normal heartbeats (RMSSD), which reflects parasympathetic activity, and the ratio of the absolute power of the low-frequency band (0.04-0.15 Hz) to the absolute power of the high-frequency band (0.015-0.4 Hz) (LF/HF ratio), which indicates sympathetic activity, were computed. Results: A total of 43 participants (35 men and 8 women) were included in the analysis. The mean age of the participants was 44.1 ± 11.3 years old, and the mean BMI was 28.6 ± 5.4 kg/m2. The sleep apnea episodes throughout the entire night in patients with OSA were selected randomly and occurred most frequently during the non-REM stages (39, 90.7%). The selected sleep apnea episodes typically exhibited multiple apneas, often interrupted by snoring respiration and followed by hyperventilation at the end of the episode (HE). Our findings indicate that the centers of the 5 min HRV window for the lowest and highest LF/HF ratios, at 111.8 ± 88.2 and 117.4 ± 88.6 min after sleep onset, respectively, showed a statistically significant difference (p < 0.001). Similarly, the ratios of the lowest and highest LF/HF, at 0.82 ± 0.56 and 3.53 ± 2.94, respectively, exhibited a statistically significant difference (p < 0.001). Conclusions: In the current study, the selected sleep apnea episodes throughout the entire night in patients with OSA occurred primarily during the non-REM stages. Additionally, we observed that sympathetic activity reached its peak in the window that includes hyperventilation at the end stage of apnea, potentially posing a cardiovascular risk. However, additional studies are needed to validate these results.

0982 Atrial fibrillation diagnosed from a home-based sleep study in a patient with REM behavior disorder

Abstract Introduction Atrial fibrillation (A-Fib) is the most common form of cardiac arrhythmia and is a major cause of stroke. Obstructive sleep apnea (OSA) is an established risk factor of A-Fib, but sleep disruption with frequent awakenings was recently identified as another risk factor, independent from OSA. Home sleep apnea test (HSAT) is widely used to diagnose OSA with low cost and short wait time, and HSAT that uses peripheral arterial tonometry (PAT) can reveal cardiac arrhythmia. Here we report a case of A-Fib detected by PAT-based HSAT in a patient with REM sleep disorder. Report of case(s) A 60-year-old man with hypertension, depression, anxiety, tobacco and alcohol use disorders presented to sleep clinic for frightening vivid dreams and violent dream enactments that gradually developed over the last two years. A diagnostic polysomnography study showed mild OSA, normal heart rhythm, and no epoch of REM sleep without atonia (RSWA). In the following four years, he used CPAP therapy, imagery rehearsal therapy, high-dose melatonin, doxepin and hydroxyzine. However, the frightening dreams and dream enactments persisted despite full adherence to CPAP. To reassess OSA, the patient took a PAT-based HSAT, which showed not only mild OSA, but one episode of irregularly irregular PAT-derived pulsation variations that lasted three hours and started and stopped abruptly. We therefore ordered longitudinal cardiac monitoring, which showed multiple asymptomatic episodes of A-Fib during nighttime. After treatments for A-Fib were started, a polysomnography study with effective CPAP titration showed one episode of A-Fib with rapid ventricular response that lasted 2.5 hours during non-REM sleep, and multiple epochs of RSWA. The diagnosis of REM sleep behavior disorder (RBD) was thus established. Conclusion We reported concurrent developments of RBD and asymptomatic paroxysmal A-Fib in a man in his early sixties. Our case suggests a potential association between RBD and A-Fib, which has not been studied but is conceivable, given that RBD causes frequent awakenings with surges of sympathetic activity. Our case also highlights the advantage of PAT in capturing not only OSA but cardiac arrhythmia. Clinical interpreters of PAT-based HSAT can seize the opportunity to diagnose A-Fib and prevent stroke. Support (if any)

Monitoring with wearable devices will clarify the association between indoor temperature and blood pressure.

The association of blood pressure and temperature is well known in seasonal observation, and low temperature in the winter season is often considered a cause of high blood pressure. The current evidence for short-term studies of temperature and blood pressure is based on the daily observation, however continuous monitoring with wearable devices will allow us to evaluate the rapid effect of cold temperature exposure on blood pressure. In a Japanese, prospective intervention study from 2014 to 2019 (the Smart Wellness Housing survey), approximately 90% of Japanese lived in cold houses (indoor temperature less than 18 °C). Importantly, the indoor temperature was associated with the increase of morning systolic blood pressure. We recently addressed the sympathetic nervous activation of individuals in both their houses and a highly insulated and airtight model house in the winter season using portable electrocardiography equipment. A few subjects showed a morning surge in sympathetic activity, which was more intense at their cold houses, which suggests the importance of the indoor environment in the management of early morning hypertension. In near future, real-time monitoring with wearable devices will provide important information for a better life-environment, leading to risk reduction of morning surge and cardiovascular events.

Morning surge in sympathetic nervous activity in the indoor environment during the cold winter season.

We addressed to the sympathetic nervous activation of the same people in both their houses and a highly insulated and airtight model house (model house) during the cold winter season. Eight subjects (4 males and 4 females) stayed two nights at each house and were continuously monitored for sympathetic nerve system by calculating LF (low frequency)/HF (high frequency) in the analysis of heart rate variability using a wearable electrocardiography equipment. The room temperatures were kept constant at 20 °C or more in model house, but much lower in their houses. In all subjects, the sleeping duration is longer in model house compared with that in the participants' houses. Four subjects showed a morning surge in sympathetic activity that were more intense at their houses. This morning surge in sympathetic activity in a residential setting suggests the importance of the indoor environment in the management of early morning hypertension.

A Wake-up Call for Human Immunodeficiency Virus (HIV) Providers: Obstructive Sleep Apnea in People Living With HIV.

Obstructive sleep apnea (OSA) is defined by repetitive collapse of the upper airway during sleep leading to transient hypoxemia and arousals from sleep. Surges in sympathetic activity, repeated oxygen desaturation, and sleep fragmentation can lead to cardiovascular (eg, myocardial infarction) and neurocognitive (eg, excessive daytime sleepiness) consequences. Emerging data suggest that OSA is common in people living with human immunodeficiency virus (PLWH) and that traditional risk factors for OSA, such as obesity, are not highly predictive of OSA in PLWH. Untreated OSA is associated with increased fatigue and levels of inflammation. Despite these data, most PLWH with OSA remain undiagnosed and untreated. Improved awareness of OSA among healthcare providers and greater use of OSA diagnostic approaches have the potential to substantially improve quality of life and outcomes in PLWH.

Chewing-induced hypertension in afferent baroreflex failure: a sympathetic response?

What is the central question of this study? Our goal was to understand the autonomic responses to eating in patients with congenital afferent baroreflex failure, by documenting changes in blood pressure and heart rate with chewing, swallowing and stomach distension. What is the main finding and its importance? Patients born with lesions in the afferent baroreceptor pathways have an exaggerated pressor response to food intake. This appears to be a sympathetically mediated response, triggered by chewing, that occurs independently of swallowing or distension of the stomach. The chewing-induced pressor response may be useful as a counter-manoeuvre to prevent orthostatic hypotension in these patients. Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure resulting from baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and R-R intervals were measured continuously while chewing gum (n=15), eating (n=20) and distending the stomach by percutaneous endoscopic gastrostomy tube feeding (n=9). Responses were compared with those of normal control subjects (n=10) and of patients with efferent autonomic failure (n=10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked but transient pressor response (P<0.0001) and additional signs of sympathetic activation, including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in control subjects (P=0.0001), but was absent in patients with autonomic failure. In patients with FD, distending the stomach by percutaneous endoscopic gastrostomy tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure is exaggerated in patients with FD as a result of blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD.

Tight glycemic control in the management of diabetic patients: what has changed since the '90s in the clinical approach?

Tight glycemic control represents one of the major goals of the therapeutic management of diabetes mellitus. However, several clinical studies have reported that an intensive glucose-lowering treatment, especially when insulin or sulfonylureas are used, is associated with an increased risk of hypoglycemia and may exert negative effects on the cardiovascular risk. Hypoglycemia is the major side effect of antidiabetic therapy and it has also been associated with adverse cardiovascular events. The surge of sympathetic activity during hypoglycemic episodes may induce cardiac and cerebral ischemia and promote potentially fatal arrhythmias. In addition, hypoglycemic episodes have a negative effect on patient compliance to the antidiabetic treatment and consequently may worsen glycemic control, thus increasing the risk of micro- and macroangiopathic complications of diabetes. Therefore, in order to counteract the cardiovascular risk it is necessary achieving a good glycemic control through therapeutic strategies associated with a lower risk of hypoglycemia. Unlike treatment with sulfonylureas, glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors have been demonstrated to improve metabolic control without inducing hypoglycemia and, therefore, represent a new therapeutic option for type 2 diabetes, which offer the advantage of combining glucose-lowering activity with a low risk of hypoglycemia, thus providing a greater cardiovascular protection.

Therapeutic Strategies for Sleep Apnea in Hypertension and Heart Failure

Sleep-disordered breathing (SDB) causes hypoxemia, negative intrathoracic pressure, and frequent arousal, contributing to increased cardiovascular disease mortality and morbidity. Obstructive sleep apnea syndrome (OSAS) is linked to hypertension, ischemic heart disease, and cardiac arrhythmias. Successful continuous positive airway pressure (CPAP) treatment has a beneficial effect on hypertension and improves the survival rate of patients with cardiovascular disease. Thus, long-term compliance with CPAP treatment may result in substantial blood pressure reduction in patients with resistant hypertension suffering from OSAS. Central sleep apnea and Cheyne-Stokes respiration occur in 30–50% of patients with heart failure (HF). Intermittent hypoxemia, nocturnal surges in sympathetic activity, and increased left ventricular preload and afterload due to negative intrathoracic pressure all lead to impaired cardiac function and poor life prognosis. SDB-related HF has been considered the potential therapeutic target. CPAP, nocturnal O2 therapy, and adaptive servoventilation minimize the effects of sleep apnea, thereby improving cardiac function, prognosis, and quality of life. Early diagnosis and treatment of SDB will yield better therapeutic outcomes for hypertension and HF.

Molecular Mechanisms of Chronic Intermittent Hypoxia and Hypertension

Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension.

Serious Cardiovascular Outcomes in Diabetes

Hypoglycemia is a well-recognized side effect of glucose-lowering therapies in patients with diabetes mellitus. The incidence of mild self-reported hypoglycemic episodes in patients with type 1 diabetes mellitus is approximately 30 episodes per patient per year, whereas the incidence of severe hypoglycemic episodes (ie, those that require third-party assistance) may be as high as 3.2 episodes per patient per year.1,–,3 Hypoglycemic episodes occur much less frequently in patients with type 2 diabetes mellitus, in whom the incidence of mild and severe hypoglycemic episodes is 2 to 10 per patient per year and 0.1 to 0.7 per patient per year, respectively.2 When patients are alerted to the occurrence of a hypoglycemic episode by symptoms such as tremor, diaphoresis, tachycardia, malaise, hunger, and anxiety, they can abort these episodes by consuming carbohydrates. However, if hypoglycemic episodes occur rapidly or are unrecognized and untreated, the resulting neuroglycopenia may cause confusion, seizures, accidents, angina, and, rarely, death or permanent cognitive impairment.3,4 Patients who experience frequent episodes of hypoglycemia are especially at risk of having unrecognized hypoglycemic episodes (and their sequelae), because their counterregulatory response to hypoglycemia becomes blunted. Indeed, the rare occurrence of sudden death during sleep in young patients with type 1 diabetes mellitus (the so-called dead-in-bed syndrome) has been attributed to hypoglycemia, although this cause is seldom proven.5,–,7 It is well known that hypoglycemic episodes are associated with a surge of sympathetic activity and a release of catecholamines.8,–,10 These observations have supported the suggestion that the tachycardia and the rise in blood pressure observed during a hypoglycemic episode might destabilize an atherosclerotic plaque.11 These hemodynamic changes, the increased myocardial work, and hypoglycemia-induced increases in platelet aggregation, platelet activity,12,–, …

Circadian changes in autonomic function in conscious rats with heart failure: Effects of amiodarone on sympathetic surge

Cardiovascular events are characterized by circadian periodicity with a peak prevalence during the awakening period, which suggests a morning surge in sympathetic activity. We developed an experimental system to determine circadian changes in heart rate (HR), blood pressure (BP), locomotor activity (Loc), respiratory rate and autonomic function in conscious, unrestrained rats. The effects of amiodarone on circadian variation of these variables were determined in rats with myocardial infarction and subsequent congestive heart failure (CHF). We continuously recorded BP, HR and Loc for 24 h in rats with CHF ( n = 16) or after a sham operation (Sham; n = 7). To determine circadian changes in sympathovagal balance, digitized BP and HR data throughout 24 h were analyzed based on maximum entropy. The study was repeated after 3 weeks of oral amiodarone (50 mg/kg/day) or saline administration. Baseline HR, mean BP, and Loc were higher in the dark period than in the light period (all p < 0.05) in both CHF and Sham rats, which is consistent with the circadian periodicity of nocturnal animals. Low-frequency components of diastolic BP variability (LFdp), an index of sympathetic tone, were significantly higher during the awakening period (16:00–20:00) than during the sleeping period (08:00–14:00), a finding analogous to the sympathetic morning surge in men. Amiodarone suppressed this transient increase in LFdp power during the awakening period. Our experimental system could detect sympathetic surge in conscious rats. Amiodarone suppressed the sympathetic surge, which could explain, at least in part, beneficial effects of amiodarone in patients with CHF.

Obstructive sleep apnoea – an update

Obstructive sleep apnoea (OSA) is a common disorder characterized by the repetitive complete or partial collapse of the upper airway during sleep. It results in intermittent hypoxaemia and hypercapnia, cortical arousals and surges of sympathetic activity. The occurrence of OSA has also been linked to serious long-term adverse health consequences; such as hypertension, metabolic dysfunction, cardiovascular disease, neurocognitive deficits and motor vehicle accidents. There have been several advances in the field of particular clinical importance: (i) the development of portable monitoring as part of a simplified clinical algorithm for the diagnosis of OSA in selected patients; (ii) growing awareness of the cardio-metabolic health consequences of OSA and (iii) emerging evidence to support a range of non-continuous positive airway pressure (CPAP) treatment modalities, such as oral appliances.

Differential effects of waking from non-rapid eye movement versus rapid eye movement sleep on cardiovascular activity

The occurrence of cardiovascular events increases in the morning, and while the mechanism responsible is yet to be determined, possible contributors include surges in sympathetic activity and concurrent rises in blood pressure (BP). This study tested the hypothesis that the increase in sympathetic dominance and the surge in BP were greater when waking spontaneously from Stage 2 sleep compared with waking from rapid eye movement (REM) sleep. Twenty healthy young adults had overnight polysomnography, including electrocardiogram measurements. Spectral analysis of heart rate variability (HRV) was conducted on 2-min blocks of stable data selected from the last 30 min of sleep and during 30 min of resting wakefulness (supine) immediately following sleep. Outputs included absolute low frequency (LF) and high frequency (HF) power, the LF/HF ratio, heart rate (HR) and BP. To investigate the effect of waking from Stage 2 or REM sleep on HRV and BP responses, two-way analyses of variance (anovas) (Stage 2 versus REM) with repeated measures (sleep versus morning wakefulness) were performed. It was found that waking from Stage 2 sleep was associated with significant increases in HR (P = 0.002) and BP (P < 0.001), as well as a tendency towards an increase in the LF/HF ratio (P = 0.08), whereas measurements during REM sleep and subsequent wakefulness were similar (P > 0.05). The greater increase in BP and HR when waking from Stage 2 sleep compared with REM sleep suggests that in vulnerable populations, waking from Stage 2 sleep could be an adjunct risk factor of cardiovascular events during the morning period.

Clinical and Functional Correlates of Platelet Cyclic GMP in Essential Hypertensives

Platelets play a central role in atherothrombosis, which is responsible of major cardiovascular complications in human hypertension. Nitric oxide (NO) inhibits platelet aggregation via the second messenger cyclic guanosine monophosphate (cGMP). In essential hypertensives (EHs), we examined the relationship between platelet cGMP and clinical, hemodynamic, humoral variables as well as the responses to aggregating agents. In untreated EHs (male/female 106/43, age 44.4 +/- 1.1 years, smokers yes/no 38/111), blood pressure (BP), heart rate (HR), and stroke volume (SV) (impedance cardiography) were assessed after supine rest and venous blood was sampled for platelet cGMP (radioimmunoassay on acid extracts of washed platelets), plasma cGMP, atrial natriuretic peptide (ANP), renin activity, aldosterone and platelet aggregation to epinephrine (EPI, 5 micromol/l), and adenosine diphosphate (ADP) (4 micromol/l) (optical aggregometry on platelet-rich plasma (PRP)). Platelet cGMP (7.0 +/- 0.3 pmol/10(9) cells, mean +/- s.e.m.) was lower in males and smokers than in their counterparts (P < 0.01 for both). Among the variables tested, platelet cGMP was related to number of cigarettes (-0.21), high-density lipoprotein cholesterol (HDLc) (r = 0.32), aldosterone (r = -0.21), and hemoglobin (-0.16); in a multivariate analysis that also included sex, HDLc was the best predictor of platelet cGMP. The aggregating response to EPI (r = -0.28), but not to ADP (r = -0.07, ns), was inversely related to platelet cGMP levels. cGMP in resting platelets of EHs is positively predicted by HDLc and is inversely related to the aggregating response to EPI. It is suggested that a defect of the platelet NO/cGMP system could identify uncomplicated EHs at higher risk of thrombotic events during surges of sympathetic activity.

Syndromes d’apnées du sommeil et pathologie cardiovasculaire

Sleep-disordered breathing is very common and is associated with an increased risk of cardiovascular disease, cardiac arrhythmia and stroke. There are two types of sleep apnea: obstructive and central. The objective of this review is to provide a broad perspective of the pathophysiological and clinical aspects of the two types of apnea and to discuss their cardiovascular adverse effects. The diagnosis of sleep apnea syndrome is based on polysomnography, and severity is measured with an apnea-hypopnea index that counts the total number of apneas per hour of sleep. Recent large epidemiologic studies have shown that sleep apnea affects about 16% of men and 5% of women between 30 and 65 years of age. Obstructive sleep apnea is characterized by abnormal collapse of the pharyngeal airway during sleep, snoring, vigorous inspiratory efforts causing frequent arousal, and excessive daytime drowsiness. Central sleep apnea with Cheyne-Stokes respiration is a form of periodic breathing with frequent periods of hyperventilation, and carries a poor prognosis in patients with heart failure. Obstructive apnea can also have substantial health consequences. Although the exact mechanism linking sleep apnea with cardiovascular disease is unknown, there is evidence that obstructive apnea is associated with a group of proinflammatory and prothrombic factors that are also important in the development of atherosclerosis. Nocturnal and daytime sympathetic activity is elevated after sleep apnea. Autonomic abnormalities include an increased resting heart rate, decreased cardiac rhythm activity, and increased blood pressure variability. Obstructive apnea is associated with endothelial dysfunction, increased C-reactive protein and cytokine expression, elevated fibrinogen levels and decreased fibrinolytic activity. Enhanced platelet activity and aggregation, leukocyte adhesion and accumulation of endothelial cells are common in both obstructive apnea and atherosclerosis. Surges in sympathetic activity, blood pressure, ventricular wall tension and afterload adversely affect ventricular function. Many studies have shown that patients with obstructive apnea have an increased incidence of daytime hypertension, and this syndrome is recognized as an independent risk factor for hypertension. Obstructive apnea is associated with myocardial ischemia (silent or symptomatic), acute coronary events, stroke and transient ischemic attacks, cardiac arrhythmia, pulmonary hypertension and heart failure. Central sleep apnea is frequent in severe heart failure. Most heart failure patients with pulmonary congestion chronically hyperventilate because of stimulation of vagal irritant receptors and central and peripheral chemosensitivity. When PaCO2 falls below the threshold required to stimulate breathing, the central drive to respiratory muscles and air inflow ceases and central apnea ensues. Apnea, hypoxia, CO2 retention and arousals provoke elevated sympathetic activity, increased afterload and elevated left ventricular transmural pressure, and promote the progression of heart failure. Tentative relationships have been identified between central apnea and markers of inflammation, oxidative stress and endothelial dysfunction. Recent mid-terms trials showed that nocturnal use of positive airway pressure in patients with the two types of apnea alleviates symptoms, reduces sympathetic activity, improves ventricular function and quality of life, and reduces daytime drowsiness. More studies are needed to understand the mechanisms underlying the relationship between sleep apnea and cardiovascular disease, but clinicians should be aware of this link and should attempt to identify patients with these syndromes.

Could vaccinations prevent myocardial infarction?

In a recent report, Naghavi and coworkers 1 determined the frequency of antecedent influenza vaccination in 218 of their patients with coronary heart disease during the months of October 1997 through March 1998. Among 109 patients who experienced an acute myocardial infarction (AMI) in that period, the percentage who had been vaccinated in that current season was 47% versus 71% among 109 patients with coronary heart disease without AMI (odds ratio 0.33, 95% confidence interval 0.13 to 0.82, p 0.017). They suggested that vaccination against influenza might reduce the risk of AMI. The public health implications, if their observation is correct, are tremendous. Although the idea that vaccination could beneficially impact on AMI is novel and seemingly unfounded, there is a surprising amount of observational evidence to support the hypothesis. Disruption of the so-called “vulnerable plaque” with resultant intravascular thrombosis often leads to unstable coronary syndromes and most ischemic strokes. Plaque disruption and intraluminal thrombosis is not a random event. Purported triggers of plaque disruption have been reported in nearly 50% of patients with AMI. Plaque disruption is most likely caused by surges in sympathetic activity with a sudden increase in blood pressure, pulse rate, heart contraction, and coronary blood flow. Thrombosis then occurs on plaques when the systemic thrombotic tendency is high, as with platelet hyperaggregability or hypercoagulability, or thrombus may abnormally persist because of impaired fibrinolysis. It was first observed in the 1920s that acute vascular events occur more frequently in winter months. Since then, similar observations have been made in several temperate but geographically diverse areas. In 300,000 deaths from the Canadian Mortality Database, the incidence of fatal AMI and ischemic stroke was increased 19% and 20%, respectively, in January compared with the trough in September. A total of 259,891 cases of AMI from the Second National Registry of Myocardial Infarction, which occurred between July 1, 1994, and July 31, 1996, were analyzed by season. The incidence of AMI was 53% greater in winter than in summer, with case fatality rates following a similar seasonal pattern. Conversely, in a subtropical region with no seasonal temperature extremes, no seasonal variation of the incidence of AMI was observed. The winter peaks in AMI mortality have been correlated with temperature and shown to be greater among those with less personal protection from temperature extremes. Whereas no mechanism has been elucidated, many physiologic and biochemical changes associated with plaque disruption and intravascular thrombosis are known to correlate with temperature or season. Sympathetic tone, blood pressure, myocardial oxygen consumption, red blood cell count, hematocrit, platelet count, blood viscosity, and white blood cell count are all increased in winter. Cholesterol, antitrypsin, thromboglobulin, plasma cortisol, and C-reactive protein also increase in winter. Components of the clotting system show winter elevations including fibrinogen, factor VII activity, and platelet factor 4, while the fibinolytic system concurrently reaches a seasonal trough. Could the seasonal changes observed in both AMI incidence and relevant biochemical factors be due to seasonal infections? Systemic infection produces changes similar to those observed in cold weather. The link between infection and inflammation on the one hand and the immune response and coagulation on the other hand is phylogenetically ancient. Systemic infection results in elevations in blood pressure, white blood cell count, total and low-density lipoprotein cholesterol, tumor necrosis factor, interleukin-1, C-reactive protein, and fibrinogen. These changes certainly could either precipitate plaque disruption or predispose to intravascular thrombosis. In 1981, Pesonen and Siitonen were the first to call attention to an association between respiratory infections and AMI. This was followed in the United States by a matched case-control study, which showed an odds ratio of 2.1 for antecedent upper respiratory symptoms among patients with AMI. In a nested case-control study of 1,922 cases and 7,649 matched controls, significantly more cases (2.8%) than controls (0.9%) recalled having an acute respiratory tract infection in the 10 days before their index AMI (odds ratio 3.6, 95% confidence interval 2.2 to 5.7). In a database of 2,264 persons with AMI, 19% reported a flu-like illness or infection in the week preceding their AMI. To avoid recall bias, a nested case-control study of 3,172 male farmers used office records of visits to confirm that those with recurrent or chronic upper respiratory infections were at increased From the Division of Cardiovascular Disease, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, Kansas. Manuscript received October 9, 2001; revised manuscript received and accepted November 21, 2001. Address for reprints: David Meyers, MD, MPH, Division of Cardiovascular Disease, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160-7378. E-mail: dmeyers@ kumc.edu.

Early morning surge in blood pressure.

Early-morning blood pressure is generally viewed as an important therapeutic target, for two reasons. First, for antihypertensive agents taken once daily in the morning, the timing of the trough plasma drug level, and thereby the lowest pharmacodynamic effect, often coincides with the early morning rise in blood pressure and heart rate. Evidence has been accumulated to suggest that blood pressure control throughout the 24 h period may be necessary to gain complete benefit from antihypertensive medication. In fact, in a longitudinal study, the regression of cardiac hypertrophy in patients with hypertension was more accurately predicted by treatment-induced changes in average 24 h ambulatory blood pressure than by clinic or home-monitored blood pressure readings. The other reason for the importance of morning blood pressure is that cardiovascular risk is heightened at this time of day. A morning surge in sympathetic activity alters haemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. At the same time as this risk of plaque rupture is greatest, circadian variations in haemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting the formation of intraluminal thrombi. We recently showed that, in older hypertensives, a greater morning blood pressure surge, mediated at least in part by an exaggerated alpha-sympathetic activity, is associated with more advanced silent cerebrovascular disease as well as a higher future incidence of stroke. The early morning surge in blood pressure could become a new therapeutic target for preventing target-organ damage and subsequent cardiovascular events in hypertension. Of greatest interest is the potential benefit of a chronotherapeutic approach, involving, for example, long-acting chronoformulations, which has not yet been extensively studied.

IMPAIRED MODULATION OF CIRCADIAN RHYTHMS IN PATIENTS WITH DIABETES MELLITUS: A RISK FACTOR FOR CARDIAC THROMBOTIC EVENTS?

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day–night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic–thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109–121, 2001)

OBSTRUCTIVE SLEEP APNOEA CAUSES TRANSIENT AND SUSTAINED SYSTEMIC HYPERTENSION

SUMMARYApnoea with associated fall in arterial oxygen tension results in increased blood pressure and a striking surge in sympathetic activity, which can be measured as high catecholamine levels or increase in muscle sympathetic nerve activity. Following the termination of apnoea with resumption of breathing, sympathetic nerve activity decreases and blood pressure returns to lower values. Sympathetic mediated alternations in peripheral vascular resistance best explain these findings. Hypertension during wakefulness in untreated patients with apnoea is also associated with high sympathetic nervous system activity. Nasal continuous positive airway pressure (CPAP) has been shown to lower blood pressure in some hypertensive obstructive sleep apnoea (OSA) patients. Recently, previously untreated OSA patients exhibiting awake sympathetic hyperexcitation demonstrated striking attentuation of the response following initiation of effective CRAP therapy. Accordingly, the common problem of systemic hypertension found in untreated OSA appears to be mediated by sympathetic excitation and responds to effective CRAP therapy.

Role of inflammation and metalloproteinases in plaque disruption and thrombosis.

Numerous pathological, clinical, angiographic and angioscopic studies have demonstrated that acute coronary syndromes (unstable angina, acute myocardial infarction and ischemic sudden death) are most frequently the consequence of plaque disruption (plaque rupture or superficial plaque erosion) and consequent coronary thrombosis. Several serial angiographic studies have demonstrated that nearly 60-70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques. Coronary plaque disruption appears to be a function of both the composition of the plaque (plaque vulnerability ) as well as extrinsic triggers that may precipitate plaque disruption in a vulnerable plaque. Vulnerability for plaque disruption appears to be largely determined by the size of the lipid-rich atheromatous core, the thickness of the fibrous cap covering the core, and the presence of ongoing inflammation within and underneath the cap. Inflammatory cells may play a critical role in plaque disruption through the elaboration of matrix degrading metalloproteinases or MMPs (collagenases, gelatinases, stromelysins and matrilysin) and by inhibition of function and survival of matrix-synthesizing smooth muscle cells. Inflammatory cells may also play a critical role in triggering thrombosis following plaque disruption through the tissue factor pathway. In addition, stresses resulting from hemodynamic and mechanical forces may precipitate plaque disruption, particularly at points where the fibrous cap is weakest, such as at its shoulders. The degree of thrombosis following plaque disruption is determined by the thrombogenicity of the disrupted plaque, disturbed local rheology and systemic thrombotic-thrombolytic milieu. Surges in sympathetic activity provoked by sudden vigorous exercise, emotional stress -- including anger, or cold weather, may also trigger plaque disruption. These observations have led to the concept of plaque stabilization as a new clinical strategy for the prevention of acute coronary syndromes. Plaque stabilization can be achieved through pharmacologic and lifestyle-modifying interventions that reduce vulnerability to plaque disruption by altering plaque composition and/or inflammatory activity within the plaque.