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1.  Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea 
NeuroImage : Clinical  2014;6:275-283.
Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during daytime wakefulness, leading to hypertension, but the underlying mechanisms are poorly understood. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI) of the brain we aimed to identify the central processes responsible for the sympathoexcitation. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted percutaneously into the common peroneal nerve in 17 OSA patients and 15 healthy controls lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. Fluctuations in BOLD signal intensity covaried with the intensity of the concurrently recorded bursts of MSNA. In both groups there was a positive correlation between MSNA and signal intensity in the left and right insulae, dorsolateral prefrontal cortex (dlPFC), dorsal precuneus, sensorimotor cortex and posterior temporal cortex, and the right mid-cingulate cortex and hypothalamus. In OSA the left and right dlPFC, medial PFC (mPFC), dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus showed augmented signal changes compared with controls, while the right hippocampus/parahippocampus signal intensity decreased in controls but did not change in the OSA subjects. In addition, there were significant increases in grey matter volume in the left mid-insula, the right insula, left and right primary motor cortices, left premotor cortex, left hippocampus and within the brainstem and cerebellum, and significant decreases in the mPFC, occipital lobe, right posterior cingulate cortex, left cerebellar cortex and the left and right amygdala in OSA, but there was no overlap between these structural changes and the functional changes in OSA. These data suggest that the elevated muscle vasoconstrictor drive in OSA may result from functional changes within these brain regions, which are known to be directly or indirectly involved in the modulation of sympathetic outflow via the brainstem. That there was no overlap in the structural and functional changes suggests that asphyxic damage due to repeated episodes of nocturnal obstructive apnoea is not the main cause of the sympathoexcitation.
•Obstructive sleep apnea increases muscle sympathetic nerve activity (MSNA).•fMRI was used to identify brain sites temporally coupled to the increase in MSNA.•Augmented BOLD signal intensity occurred in several cortical and subcortical sites.•The elevated MSNA in OSA may result from functional changes within these sites.
PMCID: PMC4215471  PMID: 25379440
fMRI; Microneurography; Muscle sympathetic nerve activity; Obstructive sleep apnoea
2.  Advantage of Recording Single-Unit Muscle Sympathetic Nerve Activity in Heart Failure 
Elevated sympathetic activation is a characteristic feature of heart failure (HF). Excessive sympathetic activation under resting conditions has been shown to increase from the early stages of the disease, and is related to prognosis. Direct recording of multiunit efferent muscle sympathetic nerve activity (MSNA) by microneurography is the best method for quantifying sympathetic nerve activity in humans. To date, this technique has been used to evaluate the actual central sympathetic outflow to the periphery in HF patients at rest and during exercise; however, because the firing occurrence of sympathetic activation is mainly synchronized by pulse pressure, multiunit MSNA, expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats), may have limitations for the quantification of sympathetic nerve activity. In HF, multiunit MSNA is near the maximum level, and cannot increase further than the heartbeat. Single-unit MSNA analysis in humans is technically demanding, but provides more detailed information regarding central sympathetic firing. Although a great deal is known about the response of multiunit MSNA to stress, little information is available regarding the responses of single-unit MSNA to physiological stress and disease. The purposes of this review are to describe the differences between multiunit and single-unit MSNA during stress and to discuss the advantages of single-unit MSNA recording in improving our understanding the pathology of increased sympathetic activity in HF.
PMCID: PMC3342584  PMID: 22563318
sympathetic nerve activity; heart failure; exercise; arrhythmia
3.  Change in Sympathetic Nerve Firing Pattern Associated with Dietary Weight Loss in the Metabolic Syndrome 
Sympathetic activation in subjects with the metabolic syndrome (MS) plays a role in the pathogenesis of cardiovascular disease development. Diet-induced weight loss decreases sympathetic outflow. However the mechanisms that account for sympathetic inhibition are not known. We sought to provide a detailed description of the sympathetic response to diet by analyzing the firing behavior of single-unit sympathetic nerve fibers. Fourteen subjects (57 ± 2 years, nine men, five females) fulfilling ATP III criteria for the MS underwent a 3-month low calorie diet. Metabolic profile, hemodynamic parameters, and multi-unit and single-unit muscle sympathetic nerve activity (MSNA, microneurography) were assessed prior to and at the end of the diet. Patients’ weight dropped from 96 ± 4 to 88 ± 3 kg (P < 0.001). This was associated with a decrease in systolic and diastolic blood pressure (−12 ± 3 and −5 ± 2 mmHg, P < 0.05), and in heart rate (−7 ± 2 bpm, P < 0.01) and an improvement in all metabolic parameters (fasting glucose: −0.302.1 ± 0.118 mmol/l, total cholesterol: −0.564 ± 0.164 mmol/l, triglycerides: −0.414 ± 0.137 mmol/l, P < 0.05). Multi-unit MSNA decreased from 68 ± 4 to 59 ± 5 bursts/100 heartbeats (P < 0.05). Single-unit MSNA indicated that the firing rate of individual vasoconstrictor fibers decreased from 59 ± 10 to 32 ± 4 spikes/100 heart beats (P < 0.05). The probability of firing decreased from 34 ± 5 to 23 ± 3% of heartbeats (P < 0.05), and the incidence of multiple firing decreased from 14 ± 4 to 6 ± 1% of heartbeats (P < 0.05). Cardiac and sympathetic baroreflex function were significantly improved (cardiac slope: 6.57 ± 0.69 to 9.57 ± 1.20 ms·mmHg−1; sympathetic slope: −3.86 ± 0.34 to −5.05 ± 0.47 bursts/100 heartbeats·mmHg−1, P < 0.05 for both). Hypocaloric diet decreased sympathetic activity and improved hemodynamic and metabolic parameters. The sympathoinhibition associated with weight loss involves marked changes, not only in the rate but also in the firing pattern of active vasoconstrictive fibers.
PMCID: PMC3162210  PMID: 21904529
metabolic syndrome; sympathetic nervous system; autonomic function; diet
4.  Apnea-Induced Cortical BOLD-fMRI and Peripheral Sympathoneural Firing Response Patterns of Awake Healthy Humans 
PLoS ONE  2013;8(12):e82525.
End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35±4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29±6 (rest) to 49±6 (BH) and 47±6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.
PMCID: PMC3865029  PMID: 24358198
5.  Firing patterns of muscle sympathetic neurons during short-term use of continuous positive airway pressure in healthy subjects and in chronic heart failure patients 
The current study tested the hypothesis that modification in central hemodynamics during short-term continuous positive airway pressure (CPAP) application was accompanied by altered firing patterns of sympathetic nerve activity in CHF patients and healthy subjects.
Muscle sympathetic nerve activity (MSNA), hemodynamic and ventilatory parameters were obtained from 8 healthy middle aged subjects and 7 CHF patients. Action potentials (APs) were extracted from MSNA neurograms, quantified as AP frequency and classified into different sized clusters. While on CPAP at 10 cm H2O, multi-unit MSNA, AP frequency and mean burst area/min increased in healthy middle aged subjects (p < 0.05) whereas CPAP had no effect on these variables in CHF patients. In conclusion, the impact of CPAP on central hemodynamics in healthy individuals elicited a moderate activation of sympathetic neurons through increased AP firing frequency, whereas in CHF patients both hemodynamics and MSNA remained unaltered.
PMCID: PMC3919512  PMID: 23541507
Action potential detection; Microneurography; End-expiratory positive pressure; Human
6.  Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study 
PLoS Medicine  2014;11(2):e1001599.
Tetyana Kendzerska and colleagues explore the association between physiological measures of obstructive sleep apnea other than the apnea-hypopnea index and the risk of cardiovascular events.
Please see later in the article for the Editors' Summary
Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events.
Methods and Findings
A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence.
OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, particularly among middle-aged and elderly people. It is characterized by apnea—a brief interruption in breathing that lasts at least 10 seconds—and hypopnea—a decrease of more than 50% in the amplitude of breathing that lasts at least 10 seconds or clear but smaller decrease in amplitude associated with either oxygen desaturation or an arousal. Patients with OSA experience numerous episodes of apnea and hypopnea during the night; severe OSA is defined as having 30 or more episodes per hour (an apnea-hypopnea index [AHI] of >30). These breathing interruptions occur when relaxation of the upper airway muscles decreases the airflow, which lowers the amount of oxygen in the blood. As a result, affected individuals frequently wake from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air through a face mask into the airway to keep it open.
Why Was This Study Done?
OSA can be life-threatening. Most directly, daytime sleepiness can cause accidents, but OSA is also associated with an increased risk of developing cardiovascular disease (CVD, disease that affects the heart and the circulation). To date, studies that have investigated the association between OSA and the risk of myocardial infarction (heart attack), congestive heart failure, stroke, and other CVDs have used the AHI to diagnose and categorize the severity of OSA. However, by focussing on AHI, clinicians and researchers may be missing opportunities to improve their ability to predict which patients are at the highest risk of CVD. In this historical cohort study, the researchers investigate the association between other OSA-related variables (for example, blood oxygen saturation and sleep fragmentation) and the risk of cardiovascular events and all-cause mortality (death). A historical cohort study examines the medical records of groups of individuals who have different characteristics at baseline for the subsequent occurrence of specific outcomes.
What Did the Researchers Do and Find?
The researchers used administrative data (including hospitalization records and physicians' claims for services supplied to patients) to follow up adults referred for suspected OSA who underwent diagnostic polysomnography (a sleep study) at a single Canadian hospital between 1994 and 2010. A database of the polysomnography results provided information on OSA-related variables for all the study participants. Over an average follow-up of about 6 years, 11.5% of the 10,149 participants were hospitalized for a myocardial infarction, stroke, or congestive heart failure, underwent a revascularization procedure (an intervention that restores the blood supply to an organ or tissue after CVD has blocked a blood vessel), or had died from any cause. After adjusting for multiple established risk factors for CVD such as smoking and age in Cox regression models (a statistical approach that examines associations between patient variables and outcomes), several OSA-related variables (but not AHI) were significant predictors of CVD. The strongest OSA-related predictor of cardiovascular events or all-cause mortality was total sleep time spent with oxygen saturation below 90%, which increased the risk of a cardiovascular event or death by 50%. Other statistically significant OSA-related predictors (predictors that were unlikely to be associated with the outcome through chance) of cardiovascular events or death included total sleep time, number of awakenings, frequency of periodic leg movements, heart rate, and daytime sleepiness.
What Do These Findings Mean?
These findings indicate that OSA-related factors other than AHI are important predictors of the composite outcome of a cardiovascular event or all-cause mortality. Indeed, although AHI was significantly associated with the researchers' composite outcome in an analysis that did not consider other established risk factors for CVD (“confounders”), the association became non-significant after controlling for potential confounders. The accuracy of these findings, which need to be confirmed in other settings, is likely to be limited by the lack of information available about the use of CPAP by study participants and by the lack of adjustment for some important confounders. Importantly, however, these findings suggest that OSA-related factors other than AHI should be considered as predictors of CVD in future studies and in clinical practice.
Additional Information
Please access these websites via the online version of this summary at
The US National Heart Lung and Blood Institute has information (including several videos) about obstructive sleep apnea (in English and Spanish), sleep studies, heart disease, and other cardiovascular diseases (some information in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about sleep apnea and about cardiovascular disease
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and health-care professionals, including personal stories about the condition
The MedlinePlus encyclopedia has pages on obstructive sleep apnea and on polysomnography; MedlinePlus provides links to further information and advice about obstructive sleep apnea, heart diseases, and vascular diseases (in English and Spanish)
PMCID: PMC3913558  PMID: 24503600
7.  Sympathetic nerve activity in stress-induced cardiomyopathy 
Clinical Autonomic Research  2012;22(6):259-264.
To evaluate directly recorded efferent sympathetic nerve traffic in patients with stress-induced cardiomyopathy (SIC).
SIC is a syndrome affecting mostly postmenopausal women following severe emotional stress. Though the precise pathophysiology is not well understood, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis.
Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24–48 h) and 7 in the recovery phase (1–6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA %). One of the twelve patients in this study was on beta blockade treatment due to a different illness, at time of onset of SIC. All patients were investigated with ongoing medication.
MSNA was lower in patients with SIC as compared to matched controls, but did not differ between the acute and recovery phase of SIC. RMBA %, blood pressure and heart rate did not differ between the groups.
MSNA is shown to be lower in patients with SIC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of SIC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase, may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients.
PMCID: PMC3501184  PMID: 22492095
Sympathetic nervous system; Cardiomyopathy; Stress; Women
8.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
9.  Muscle sympathetic nerve activity and ventilation during exercise in subjects with and without chronic heart failure 
Changes within skeletal muscle, including augmentation of its capacity to elicit reflex increases in both efferent muscle sympathetic nerve activity (MSNA) and ventilation during work, contribute significantly to exercise intolerance in heart failure (HF). Previously, we demonstrated that peak oxygen uptake (pVO2) in HF relates inversely to MSNA at rest and during exercise.
To test the hypothesis that there is an independent positive relationship between resting MSNA and the ratio of ventilation to carbon dioxide output during exercise (VE/VCO2) that is augmented in HF.
MSNA at rest and VE/VCO2 during stationary cycling were measured in 30 patients (27 men) with HF (mean ± SD ejection fraction 20±6%) and in 31 age-matched controls (29 men).
MSNA was higher in HF patients than in controls (51.5±14.3 bursts/min versus 33.0±11.1 bursts/min; P<0.0001). The VE/VCO2 slope was also higher in HF patients than in controls (33.7±5.7 versus 26.0±3.5; P<0.0001), whereas pVO2 was lower in HF patients than in controls (18.6±6.6 versus 31.4±8.4 mL/kg/min; P<0.0001). There were significant relationships between MSNA and VE/VCO2 in both HF (r=0.50; P=0.005) and control subjects (r=0.36; P=0.046). The slope of this regression equation was steeper in HF (0.20 versus 0.11 × MSNA; P=0.001). An analysis of covariance for main effects, including age and pVO2, identified a significant independent relationship between MSNA burst frequency and VE/VCO2 (P=0.013) that differed between HF and controls (P<0.01).
The magnitude of resting sympathetic activity correlates positively with the VE/VCO2 slope. Augmentation of this relationship in HF patients is consistent with the concept that enhanced mechanoreceptor reflex activity exaggerates their ventilatory response to exercise.
PMCID: PMC2644031  PMID: 18401467
Chronic heart failure; Sympathetic nervous system; Ventilation
10.  Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans 
Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus, we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to ~34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P < 0.005) and mean arterial blood pressure (P < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P = 0.11) or mean arterial blood pressure (P = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI, and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.
PMCID: PMC3531047  PMID: 18441194
prostaglandins; exercise; nervous system; sympathetic; mechanoreceptor
11.  Limb congestion and sympathoexcitation during exercise. Implications for congestive heart failure. 
Journal of Clinical Investigation  1993;92(5):2353-2359.
During static exercise, heart failure (HF) subjects activate the sympathetic nervous system differently than normal controls. HF causes metaboreceptor desensitization with either enhanced mechanoreceptor activity or central command. In this report, we examined whether increased muscle interstitial pressure, as seen in HF, augments other neural systems. We measured muscle sympathetic nerve activity (MSNA; peroneal nerve) in 10 normals during static exercise (40% maximal voluntary grip) and posthandgrip circulatory arrest (PHG-CA). This was repeated after venous congestion (VC; cuff inflation to 90 mmHg). VC increased forearm volume (plethysmography) by 4.7%. MSNA responses to exercise were greater after VC (150.5 +/- 41.8 vs. 317.3 +/- 69.9 arbitrary units; P < 0.01). However, MSNA responses during PHG-CA were not affected by VC, and 31P nuclear magnetic resonance (n = 5) demonstrated no effect of VC on pH or H2PO4-. Similar effects of VC on MSNA were noted after ischemic exercise (n = 7), excluding flow alterations as the explantation. VC probably sensitized mechanically sensitive afferents since MSNA during involuntary biceps contractions increased after VC (n = 6), and skin sympathetic nerve responses during handgrip, an index of central command, were not increased by VC (n = 6).
PMCID: PMC288417  PMID: 8227351
12.  Sympathoinhibitory effect of statins in chronic heart failure 
Clinical Autonomic Research  2009;20(2):73-78.
Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients.
Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations.
During discontinuation of statin therapy, MSNA was significantly increased (73 ± 4 vs. 56 ± 5 and 52 ± 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 ± 3 burst/min without statin vs. 32 ± 3 and 28 ± 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 ± 0.04 without statin vs. 0.29 ± 0.04 and 0.22 ± 0.04 during statin, p < 0.05; total normalized MSNA 15.70 ± 2.78 without statin, vs. 9.28 ± 1.41 and 6.56 ± 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected.
Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA.
PMCID: PMC2858805  PMID: 19960360
Heart failure; Nervous system, sympathetic; Statin; Catecholamines; HRV
13.  Effect of Acute Ozone Induced Airway Inflammation on Human Sympathetic Nerve Traffic: A Randomized, Placebo Controlled, Crossover Study 
PLoS ONE  2011;6(4):e18737.
Ozone concentrations in ambient air are related to cardiopulmonary perturbations in the aging population. Increased central sympathetic nerve activity induced by local airway inflammation may be one possible mechanism.
Methodology/Principal Findings
To elucidate this issue further, we performed a randomized, double-blind, cross-over study, including 14 healthy subjects (3 females, age 22–47 years), who underwent a 3 h exposure with intermittent exercise to either ozone (250 ppb) or clean air. Induced sputum was collected 3 h after exposure. Nineteen to 22 hours after exposure, we recorded ECG, finger blood pressure, brachial blood pressure, respiration, cardiac output, and muscle sympathetic nerve activity (MSNA) at rest, during deep breathing, maximum-inspiratory breath hold, and a Valsalva maneuver. While the ozone exposure induced the expected airway inflammation, as indicated by a significant increase in sputum neutrophils, we did not detect a significant estimated treatment effect adjusted for period on cardiovascular measurements. Resting heart rate (clean air: 59±2, ozone 60±2 bpm), blood pressure (clean air: 121±3/71±2 mmHg; ozone: 121±2/71±2 mmHg), cardiac output (clean air: 7.42±0.29 mmHg; ozone: 7.98±0.60 l/min), and plasma norepinephrine levels (clean air: 213±21 pg/ml; ozone: 202±16 pg/ml), were similar on both study days. No difference of resting MSNA was observed between ozone and air exposure (air: 23±2, ozone: 23±2 bursts/min). Maximum MSNA obtained at the end of apnea (air: 44±4, ozone: 48±4 bursts/min) and during the phase II of the Valsalva maneuver (air: 64±5, ozone: 57±6 bursts/min) was similar.
Our study suggests that acute ozone-induced airway inflammation does not increase resting sympathetic nerve traffic in healthy subjects, an observation that is relevant for environmental health. However, we can not exclude that chronic airway inflammation may contribute to sympathetic activation.
PMCID: PMC3073001  PMID: 21494635
Blood pressure  2013;22(3):183-187.
High-normal blood pressure (BP) increases the risk of cardiovascular (CV) disease. The mechanisms underlying this increased risk are not clear. Sympathetic activation appears to be a potential mechanism linking high-normal BP to CV disease. This study examined whether high-normal BP compared to optimal BP is linked to sympathoexcitation at rest and/or during laboratory stressors.
Heart rate (HR), BP and muscle sympathetic nerve activity (MSNA) were obtained at rest and during stress tests (sustained hand grip and mental stress) in 18 subjects (15 males and 3 females) with high-normal BP (systolic BP of 130 to 139 mm Hg, diastolic BP of 85 to 89 mm Hg, or both) and in 12 subjects (10 males and 2 females) with optimal BP (<120/80 mm Hg) matched for age (34±3 years in both groups) and body mass index (25±2 kg/m2 in both groups).
Despite the higher resting BP levels, MSNA was higher in subjects with high-normal BP than in the optimal BP group (26±3 vs 18±2 bursts/min, P<0.05). During sustained hand grip, MSNA increased by 37±14% in high-normal BP group compared with an increase of 49±15% in optimal BP group (P=0.55). Changes during mental stress were 50±28% and 37±12%, respectively (P=0.73). There were no significant differences in SBP responses to handgrip and mental stress between the high-normal and optimal BP groups. Baseline HR and chronotropic responses to stress tests were comparable between the two groups.
In comparison to optimal BP, high-normal BP is associated with increased resting MSNA, but normal neural and circulatory responses to stress tests. These findings suggest that tonic activation of the sympathetic nervous system may precede overt arterial hypertensionand contribute to an excess risk of CV disease in subjects with high-normal BP.
PMCID: PMC3951917  PMID: 23356493
heart rate; high-normal blood pressure; hypertension; laboratory stressors; sympathetic nerve activity
15.  Arterial Pressure Lowering Effect of Chronic Atenolol Therapy in Hypertension and Vasoconstrictor Sympathetic Drive 
Hypertension  2004;44(4):454-458.
Although the β1-adrenergic blocking agent atenolol is an established antihypertensive therapy, its effect on peripheral sympathetic vasoconstrictor drive has remained controversial. In patients with hypertension, atenolol therapy has been reported to either increase or have no effect on peripheral vascular resistance, despite other reports showing no change or a decrease in peripheral sympathetic drive. This study was designed, in patients with untreated essential hypertension (EHT), to quantify changes in simultaneously measured peroneal muscle sympathetic nerve activity (MSNA) and calf vascular resistance (CVR) accompanying atenolol therapy. MSNA was quantified as the mean frequency of single units (s-MSNA) and as multiunit bursts (MSNA bursts) using the technique of microneurography, and CVR was measured using a standard plethysmographic technique. Firstly, by comparing two age- and body weight-matched groups, each of 14 patients with hypertension, we found that the group on atenolol therapy (treated-HT) had similar MSNA values counted over the same number of cardiac beats and similar CVR levels (at least P>0.40) to the group without therapy (untreated-HT). Secondly, we examined 10 EHT patients before and after 8±0.4 weeks of oral atenolol therapy (HT-A) in comparison to seven control patients with hypertension and no treatment (HT-C) who were examined over a similar period of time. We found that the measures of MSNA and CVR did not significantly change in both groups. We conclude that the arterial pressure lowering effect of atenolol was not related to significant changes in central vasoconstrictor sympathetic drive to the periphery.
PMCID: PMC3925819  PMID: 15326085
antihypertensive therapy; sympathetic nervous system; hypertension, essential; vascular resistance
16.  Acute cyclooxygenase inhibition does not alter muscle sympathetic nerve activity or forearm vasodilator responsiveness in lean and obese adults 
Physiological Reports  2014;2(7):e12079.
Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity (MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers (C‐reactive protein [CRP] and Interleukin‐6 [IL‐6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control (CON) and after 800 mg ibuprofen (IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL‐6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL‐6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group.
Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation. However, an acute dose of the cyclooxygenase inhibitor ibuprofen did not alter blood pressure or muscle sympathetic nerve activity in lean and obese humans.
PMCID: PMC4187568  PMID: 25347862
Autonomic nervous system; blood pressure; forearm blood flow; inflammation
17.  Association of chronic obstructive pulmonary disease and obstructive sleep apnea consequences 
Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two diseases that often coexist within an individual. This coexistence is known as overlap syndrome and is the result of chance rather than a pathophysiological link. Although there are claims of a very high incidence of OSAS in COPD patients, recent studies report that it is similar to the general population. Overlap patients present sleep-disordered breathing associated to upper and lower airway obstruction and a reduction in respiratory drive. These patients present unique characteristics, which set them apart from either COPD or OSAS patients. COPD and OSAS are independent risk factors for cardiovascular events and their coexistence in overlap syndrome probably increases this risk. The mechanisms underlying cardiovascular risk are still unclear, but may involve systemic inflammation, endothelial dysfunction, and tonic elevation of sympathetic neural activity. The treatment of choice for overlap syndrome in stable patients is CPAP with supplemental oxygen for correction of upper airway obstructive episodes and hypoxemia during sleep.
PMCID: PMC2650593  PMID: 19281082
chronic obstructive pulmonary disease; obstructive sleep apnea syndrome; overlap syndrome; sleep; cardiovascular disease
18.  Postural Change Alters Autonomic Responses to Breath-Holding 
Clinical Autonomic Research  2009;20(2):65-72.
We used breath-holding during inspiration as a model to study the effect of pulmonary stretch on sympathetic nerve activity. Twelve healthy subjects (7 females, 5 males; 19–27 yrs) were tested while they performed an inspiratory breath-hold, both supine and during a 60° head-up tilt (HUT 60). Heart rate (HR), mean arterial blood pressure (MAP), respiration, muscle sympathetic nerve activity (MSNA), oxygen saturation (SaO2) and end tidal carbon dioxide (ETCO2) were recorded. Cardiac output (CO) and total peripheral resistance (TPR) were calculated. While breath-holding, ETCO2 increased significantly from 41±2 to 60±2 Torr during supine (p<0.05) and 38±2 Torr to 58±2 during HUT60 (p<0.05); SaO2 decreased from 98±1.5% to 95±1.4% supine, and from 97±1.5% to 94±1.7% during HUT60 (p=NS). MSNA showed three distinctive phases - a quiescent phase due to pulmonary stretch associated with decreased MAP, HR, CO and TPR; a second phase of baroreflex-mediated elevated MSNA which was associated with recovery of MAP and HR only during HUT60; CO and peripheral resistance returned to baseline while supine and HUT60; a third phase of further increased MSNA activity related to hypercapnia and associated with increased TPR. Breath-holding results in initial reductions of MSNA, MAP and HR by the pulmonary stretch reflex followed by increased sympathetic activity related to the arterial baroreflex and chemoreflex.
PMCID: PMC3378244  PMID: 20012144
Breath-holding; orthostatic stress; muscle sympathetic nerve activity; baroreflex; chemoreflex
19.  Obstructive sleep apnea is associated with higher healthcare utilization in elderly patients 
Annals of Thoracic Medicine  2014;9(2):92-98.
Obstructive sleep apnea (OSA) is an important cause of morbidity in the elderly population. Limited data are available regarding the healthcare utilization and predisposing conditions related to OSA in the elderly. Our aim was to evaluate the healthcare utilization and the conditions associated with new and chronic diagnosis of OSA in a large cohort of elderly patients in the Veterans Health Administration (VHA).
This retrospective cohort study used inpatient and outpatient VHA data to identify the individuals diagnosed with OSA using ICD-9 codes during the fiscal years 2003-2005. Primary outcomes were emergency department (ED) visits and hospitalizations. Multivariable logistic regression analysis was performed to identify the demographic and clinical characteristics associated with new and chronic diagnosis of OSA.
Of 1,867,876 elderly veterans having 2 years of care, 82,178 (4.4%) were diagnosed with OSA. Individuals with OSA were younger and more likely to have chronic diseases than those without OSA. Individuals with chronic OSA were more likely to have diagnoses of congestive heart failure (CHF), pulmonary circulation disorders, COPD, and obesity and less likely to have diagnoses of hypertension, osteoarthritis, and stroke than individuals with newly diagnosed OSA. The proportion of patients with new OSA diagnosis who required at least one ED visit was higher than the proportion of chronic OSA and no OSA patients (37%, 32%, and 15%, respectively; P-value <0.05). The proportion of new OSA patients who required at least one hospitalization was also higher than the proportion of chronic OSA and no OSA patients (24%, 17%, and 7%, respectively; P-value <0.05).
Patients with OSA had a higher incidence of healthcare utilization compared to patients without OSA. New OSA patients had a higher rate of healthcare utilization in the year of diagnosis compared to chronic patients and patients without OSA. Early OSA recognition may reduce healthcare utilization in these patients.
PMCID: PMC4005168  PMID: 24791172
Elderly; emergency department visit; healthcare utilization; hospitalization; obstructive sleep apnea
20.  Abnormal Sympathetic Reactivity to the Cold Pressor Test in Overweight Humans 
American Journal of Hypertension  2012;25(12):1236-1241.
Overweight individuals (body mass index (BMI) 25–29.9 kg/m2) are at higher risk for developing cardiovascular disease and hypertension when compared with lean individuals of normal weight (BMI 18.5–24.9 kg/m2). The purpose of this study was to test the hypothesis that exaggerated sympathetic nervous system responses to stressors may be one potential mechanism that predisposes overweight individuals to developing hypertension.
We compared heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) using microneurography, in normotensive overweight individuals compared with age-matched lean controls, at baseline and during two sympathoexcitatory maneuvers: cold pressor test (CPT), and static handgrip exercise (SHG 30%).
During CPT, MSNA increased in both groups, but the magnitude of MSNA response was significantly greater (P = 0.03) in overweight (+18.1 ± 2.8 bursts/min) compared with lean controls (+10.8 ± 1.2 bursts/min). MSNA response to SHG at 30% maximum voluntary contraction (MVC) was similar between the two groups. There were no significant differences in systolic (SBP) or diastolic BP (DBP) responses or HR responses between the two groups during either maneuver.
Normotensive overweight individuals have an exaggerated MSNA response to the CPT. Augmented sympathetic reactivity to cold stress may contribute to increased risk of hypertension in overweight individuals.
PMCID: PMC3577042  PMID: 22895452
blood pressure; hypertension; overweight; physiological stress response; sympathetic nervous system
21.  The Role of the Cyclooxygenase Products in Evoking Sympathetic Activation in Exercise 
Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied; in part because of systemic effects of pharmacologic agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and post exercise muscle ischemia (PEMI) before and after local infusion of 6 mg ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n=10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to ~33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Δ502±111; post ketorolac: Δ348±62%, P=0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P=0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip, and suggest that prostaglandins contribute to the exercise pressor reflex.
PMCID: PMC2559802  PMID: 17604332
prostaglandins; exercise; nervous system; sympathetic; regional blood flow
22.  Enhanced muscle pump during mild dynamic leg exercise inhibits sympathetic vasomotor outflow 
Physiological Reports  2014;2(7):e12070.
Muscle sympathetic nerve activity (MSNA) is not increased during leg cycling at light and mild intensities, despite activation of central command and the exercise pressor reflex. We determined whether increasing central blood volume and loading the cardiopulmonary baroreceptors modulate sympathetic vasomotor outflow during leg cycling. To this end, we changed the pedaling frequency to enhance skeletal muscle pump. Subjects performed two leg cycle exercises at differential pedal rates of 60 and 80 rpm (60EX and 80EX trials) for two conditions (with and without MSNA measurement). In each trial, subjects completed leg cycling with a differential workload to maintain constant oxygen consumption (VO2). MSNA was recorded via microneurography at the right median nerve of the elbow. Without MSNA measurement, thoracic impedance, stroke volume (SV), and cardiac output (CO) were measured non‐invasively using impedance cardiography. Heart rate and VO2 during exercise did not differ between the 60EX and 80EX trials. Changes in thoracic impedance, SV, and CO during the 80EX trial were greater than during the 60EX trial. MSNA during the 60EX trial was unchanged compared with that at rest (25.8 ± 3.1 [rest] to 28.3 ± 3.4 [exercise] bursts/min), whereas a significant decrease in MSNA was observed during the 80EX trial (25.8 ± 2.8 [rest] to 19.7 ± 2.0 [exercise] bursts/min). These results suggest that a muscle pump‐induced increase in central blood volume, and thereby loading of cardiopulmonary baroreceptors, could inhibit sympathetic vasomotor outflow during mild dynamic leg exercise, despite activation of central command and the exercise pressor reflex.
Muscle sympathetic nerve activity during leg cycling was reduced when central blood volume was manipulated by increasing the pedaling frequency. This result suggest that sympathetic vasomotor outflow is strongly affected by loading of cardiopulmonary baroreceptors at light and mild dynamic leg exercise to maintain arterial blood pressure.
PMCID: PMC4187562  PMID: 25347854
cardiopulmonary baroreceptors; dynamic leg exercise; sympathetic activity
23.  Caffeine Enhances Heart Rate Variability in Middle-Aged Healthy, But Not Heart Failure Subjects 
Journal of Caffeine Research  2012;2(2):77-82.
In chronic heart failure (CHF) due to left ventricular dysfunction, diminished heart rate variability (HRV) is an independent predictor of poor prognosis. Caffeine has been shown to increase HRV in young healthy subjects. Such an increase may be of potential benefit to patients with CHF.
We hypothesized that intravenous infusion of caffeine would increase HRV in CHF, and in age-matched healthy control subjects.
On two separate days, 11 patients (1F) with CHF (age=51.3±4.6 years; left ventricular ejection fraction=18.6±2.7%; mean±standard error) and 10 healthy control subjects (age=48.0±4.0) according to a double-blind randomization design, received either saline or caffeine (4 mg/kg) infusion. We assessed HRV over 7 minutes of supine rest (fast Fourier Transform analysis) to determine total spectral power as well as its high-frequency (HF) (0.15–0.50 Hz) and low-frequency (LF) (0.05–0.15 Hz) components, and recorded muscle sympathetic nerve activity (MSNA) directly from the peroneal nerve (microneurography).
In healthy control subjects, compared with saline, caffeine reduced both heart rate and sympathetic nerve traffic (p≤0.003) and increased the ratio of HF/total power (p≤0.05). Baseline LF power and the ratio LF/HF were significantly lower in CHF compared with controls (p=0.02), but caffeine had no effect on any element of HRV.
Caffeine increases cardiac vagal heart rate modulation and reduces MSNA in middle-aged healthy subjects, but not in those with CHF.
PMCID: PMC3621323  PMID: 24761268
Hypertension  2012;60(3):842-848.
Neural control of blood pressure (BP) has been reported to differ between young blacks and whites. We hypothesized that elderly blacks have enhanced sympathetic neural responses during orthostasis compared with elderly whites. Muscle sympathetic nerve activity (MSNA), arm-cuff BP, and heart rate (HR) were recorded continuously, and cardiac output (Qc), stroke volume (SV) and total peripheral resistance (TPR) were measured intermittently during supine and 5-min 60° upright tilt in 10 blacks [65 (4; SD) yrs (4 women)] and 20 whites [68 (6) yrs (8 women)]. We found that MSNA burst frequency was similar between blacks and whites in the supine position [44 (10) vs 42 (7) bursts/min] and during upright tilt [59 (11) vs 60 (9) bursts/min; P=0.846 for race, <0.001 for posture, and =0.622 for interaction]. However, upright total MSNA was smaller in blacks than whites [162 (39) vs 243 (112)%; P=0.003]. Systolic BP, HR, Qc and SV were not different between groups. Diastolic BP was similar in the supine position, increased in all subjects during tilting; upright diastolic BP was greater in blacks than whites [80 (10) vs 71 (7) mmHg; P=0.008]. TPR did not differ between blacks and whites in the supine position or during upright tilt (P=0.354 for race, <0.001 for posture, =0.825 for interaction). Thus, elderly blacks have a blunted sympathetic neural responsiveness but enhanced pressor response to orthostasis compared to elderly whites, which may be attributable to an augmented sympathetic vascular transduction and/or non-adrenergic vasoconstrictor mechanisms (i.e., angiotensin II or the venoarteriolar response).
PMCID: PMC3889472  PMID: 22777937
Muscle sympathetic nerve activity; sympathetic vascular transduction; aging; race; vasoconstriction
25.  Increases in muscle sympathetic nerve activity, heart rate, respiration, and skin blood flow during passive viewing of exercise 
The cardiovascular and respiratory effects of exercise have been widely studied, as have the autonomic effects of imagined and observed exercise. However, the effects of observed exercise in the first person have not been documented, nor have direct recordings of muscle sympathetic nerve activity (MSNA) been obtained during observed or imagined exercise. The aim of the current study was to measure blood pressure, heart rate, respiration, skin blood flow, sweat release, and MSNA (via microelectrodes inserted into the common peroneal nerve), during observation of exercise from the first person point of view. It was hypothesized that the moving stimuli would produce robust compensatory increases in the above-mentioned parameters as effectively as those generated by mental imagery and—to a lesser extent—actual exercise. Nine subjects watched a first-person running video, allowing them to view the action from the perspective of the runner rather than viewing someone else perform the exercise. On average, statistically significant increases from baseline during the running phase were seen in heart rate, respiratory rate, skin blood flow, and burst amplitude of MSNA. These results suggest that observation of exercise in the first person is a strong enough stimulus to evoke “physiologically appropriate” autonomic responses that have a purely psychogenic origin.
PMCID: PMC3678085  PMID: 23781170
autonomic nervous system; muscle sympathetic nerve activity; cardiovascular; exercise; microneurography

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