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.
autonomic nervous system; muscle sympathetic nerve activity; cardiovascular; exercise; microneurography
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.
sympathetic nerve activity; heart failure; exercise; arrhythmia
We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.
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).
The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.
We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.
Static exercise in normal humans causes reflex increases in muscle sympathetic nerve activity (MSNA) that are closely coupled to the contraction-induced decrease in muscle cell pH, an index of glycogen degradation and glycolytic flux. To determine if sympathetic activation is attenuated when muscle glycogenolysis is blocked due to myophosphorylase deficiency (McArdle's disease), an inborn enzymatic defect localized to skeletal muscle, we now have performed microelectrode recordings of MSNA in four patients with McArdle's disease during static handgrip contraction. A level of static handgrip that more than doubled MSNA in normal humans had no effect on MSNA and caused an attenuated rise in blood pressure in the patients with myophosphorylase deficiency. In contrast, two nonexercise sympathetic stimuli, Valsalva's maneuver and cold pressor stimulation, evoked comparably large increases in MSNA in patients and normals. The principal new conclusion is that defective glycogen degradation in human skeletal muscle is associated with a specific reflex impairment in sympathetic activation during static exercise.
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.
Chronic heart failure; Sympathetic nervous system; Ventilation
The mechanisms by which blood pressure is maintained against the orthostatic stress caused by gravity's effect on the fluid distribution within the body are important issues in physiology, especially in humans who usually adopt an upright posture. Peripheral vasoconstriction and increased heart rate (HR) are major cardiovascular adjustments to orthostatic stress and comprise part of the reflex response elicited via the carotid sinus and aortic baroreceptors (arterial baroreflex: ABR) and cardiopulmonary stretch receptors (cardiopulmonary baroreflex). In a series of studies, we have been characterizing the ABR-mediated regulation of cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) while applying orthostatic stress in humans. We have found that under orthostatic stress, dynamic carotid baroreflex responses are modulated as exemplified by the increases in the MSNA, blood pressure, and HR responses elicited by carotid baroreflex unloading and the shorter period of MSNA suppression, comparable reduction and faster recovery of mean arterial blood pressure (MAP) and greater HR response to carotid baroreflex stimulation. Our results also show that ABR-mediated beat-to-beat control over burst incidence, burst strength and total MSNA is progressively modulated as orthostatic stress is increased until induction of syncope, and that the sensitivity of ABR control over the aforementioned MSNA variables is substantially reduced during the development of syncope. We suggest that in humans, the modulation of ABR function under orthostatic stress may be one of the mechanisms by which blood pressure is maintained and orthostatic hypotension limited, and impairment of ABR control over sympathetic vasomotor activity leads to the severe hypotension associated with orthostatic syncope.
sympathetic nervous system; lower body negative pressure; integrated circulatory regulation; blood pressure; peripheral reflexes
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.
chronic obstructive pulmonary disease; obstructive sleep apnea syndrome; overlap syndrome; sleep; cardiovascular disease
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.
Heart failure; Nervous system, sympathetic; Statin; Catecholamines; HRV
Objective: To clarify the characteristics of sympathetic vasomotor function in Parkinson's disease by sympathetic neurographic analysis.
Methods: Muscle sympathetic nerve activity (MSNA) was recorded using a microneurographic technique at rest and during head up tilt in 18 patients with idiopathic Parkinson's disease and 21 healthy controls.
Results: Heart rate and blood pressure at rest did not differ between index and control subjects. The increase in these variables and MSNA in response to tilting was slightly blunted in the Parkinson's group. Resting MSNA showed a negative correlation with age in patients with Parkinson's disease (p<0.05) and a positive correlation with age in controls (p<0.01). There was a negative correlation between duration of disease or disability levels and MSNA (p<0.01).
Conclusions: Sympathetic vasomotor function may be related to age and disease duration in Parkinson's disease.
Following tilt-induced syncope, blood pressure usually recovers rapidly after tilt back to the horizontal position. However, in some patients, hemodynamic recovery is delayed, a condition recently termed “prolonged post-faint hypotension” (PPFH). The mechanism is thought to be mediated by increased vagal outflow rather than exaggerated peripheral vasodilatation and sympathetic withdrawal. To date, no muscle sympathetic nerve activity (MSNA) recordings have been reported in this condition, so we aimed to confirm that neither vasodilatation nor MSNA withdrawal was responsible.
To retrospectively select patients with satisfactory recordings of continuous BP and MSNA during tilt-induced syncope. To compare hemodynamic and MSNA profiles in patients with PPFH to patients with normal recovery (NR) after tilt-back.
All patients were studied in Christchurch, New Zealand, between 1998 and 2008 using continuous arterial BP monitoring, and microneurographic recordings of MSNA from the right leg. Only patients with satisfactory BP and MSNA data throughout baseline, head-up tilt and presyncope were selected. Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were derived using Modelflow. After baseline measurements, patients were tilted to the head-up 60° position and given GTN spray if asymptomatic after 20 min. Following the onset of presyncope, patients were tilted slowly back to the horizontal. PPFH was defined as systolic BP <85 mmHg for at least 2 min after tilt-back. Measurements were averaged at baseline, early tilt, presyncope, early and late recovery. Within-group comparisons were made between baseline and all other time points. Between-group comparisons were made over all time points.
Patients with PPFH (7 males, age 46 ± 5 years, n = 8) and with NR (8 males, age 47 ± 6 years, n = 8) were selected. Presyncope was provoked by GTN in 4/8 patients in each group. In both groups, MAP remained below baseline during early and late recovery: PPFH 84 ± 5 versus 51 ± 5 and 64 ± 5 mmHg (p = 0.001, p = 0.001); NR 104 ± 5 versus 83 ± 5 and 93 ± 5 mmHg (p = 0.001, p = 0.03). However, MAP and HR were lower in the PPFH group (p = 0.004, p = 0.023). During early recovery, CO remained below baseline only in the PPFH group (p = 0.001), whereas TPR remained constant in both groups. In both groups, all MSNA indices tended to remain above baseline levels during early and late recovery. PPFH 25 ± 2 increased to 31 ± 6 and 29 ± 4 bursts/min (p = 0.09, 0.02); NR 23 ± 3 increased to 33 ± 3 and 34 ± 3 bursts/min (p = 0.06, 0.01).
PPFH does not appear to be mediated by exaggerated vasodilatation or sympathetic withdrawal. Delayed recovery of cardiac output by increased vagal outflow is a more likely mechanism.
Prolonged post faint hypotension (PPFH); Muscle sympathetic nerve activity (MSNA); Total peripheral resistance (TPR); Cardiac output (CO); Sympathetic withdrawal; Vagal outflow
Hemorrhage remains a major cause of mortality following traumatic injury in both military and civilian settings. Lower body negative pressure (LBNP) has been used as an experimental model to study the compensatory phase of hemorrhage in conscious humans, as it elicits central hypovolemia like that induced by hemorrhage. One physiological compensatory mechanism that changes during the course of central hypovolemia induced by both LBNP and hemorrhage is a baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA), as assessed with microneurography. The purpose of this review is to describe recent results obtained using microneurography in our laboratory as well as those of others that have revealed new insights into mechanisms underlying compensatory increases in MSNA during progressive reductions in central blood volume and how MSNA is altered at the point of hemodynamic decompensation. We will also review recent work that has compared direct MSNA recordings with non-invasive surrogates of MSNA to determine the appropriateness of using such surrogates in assessing the clinical status of hemorrhaging patients.
hemorrhage; sympathetic activity; MSNA; baroreflex function; central hypovolemia; LBNP
The menstrual cycle has been reported to alter mean arterial pressure (MAP), but not muscle sympathetic nerve activity (MSNA), during vestibular activation. Specifically, MAP responses to head-down rotation (HDR) are augmented during the midluteal (ML) phase compared to the early follicular (EF) phase in young, eumenorrheic women. The purpose of the present study was to determine if the menstrual cycle influences vestibular-mediated changes in limb blood flow. MSNA, MAP, heart rate, and limb blood flow responses to HDR were measured in 12 healthy women. Resting MSNA, MAP, heart rate, forearm blood flow and calf blood flow were not altered by the menstrual cycle. HDR elicited similar increases in MSNA during the EF (Δ3 ± 1 bursts/min; P < 0.05) and ML (Δ2 ± 1 bursts/min; P < 0.05) phase, but only increased MAP during the ML phase (Δ4 ± 2 mmHg; P < 0.05). HDR did not change heart rate during either the EF or ML phase. HDR elicited similar increases in calf vascular resistance during the EF (Δ6 ± 2 mmHg/mL/100mL/min; P < 0.05) and ML (Δ7 ± 2 mmHg/mL/100mL/min; P < 0.05) phases of the menstrual cycle. In contrast, HDR increased forearm vascular resistance during the ML phase (Δ4 ± 2 mmHg/mL/100mL/min; P<0.05), but not the EF phase (Δ0 ± 2 mmHg/mL/100mL/min). These findings suggest an increased transduction of sympathetic nerve activity into forearm vascular resistance during the ML phase, and reveal the first recorded divergent vascular response to vestibular excitation in human limbs.
Muscle sympathetic nerve activity; autonomic activity; arterial blood pressure; head-down rotation; estrogen
Mental stress (MS) and changes in posture can both be associated with cardiovascular dysfunction. The purpose of this study was to determine neurovascular responses to MS in the supine and upright postures. MS was elicited in 17 subjects (26 ± 1 y) by 5 min of mental arithmetic. Doppler ultrasound was used to measure peak blood velocity in the renal (RBFV) and superior mesenteric arteries (SMBFV). Leg blood flow (LBF) was measured using Doppler ultrasound and forearm blood flow (FBF) was measured using plethysmography. Microneurography was used to measure muscle sympathetic nerve activity (MSNA; n = 5) in the leg. At rest, heart rate and MSNA were significantly greater whereas LBF, FBF, RBFV, and SMBFV and their respective conductances were significantly less in the upright compared to supine posture. MS elicited similar increases in mean arterial pressure (~12 mmHg) and heart rate (~17 beats/min) regardless of posture. MS in both postures elicited a decrease in RBFV, SMBFV, and their conductances and an increase in LBF, FBF, and their conductances. Changes in blood flow were blunted in the upright posture in all vascular beds examined, but the pattern of the vascular response was the same as the supine posture. MS did not elicit changes in MSNA in either the supine or upright posture (~ Δ 2 ± 2 bursts/min and ~ Δ 1 ± 2 bursts/min, respectively). In conclusion, the augmented sympathetic activity of the upright posture does not alter heart rate, mean arterial pressure, or MSNA responses to MS. MS elicits a divergent vascular response in the visceral and peripheral vasculature. These results indicate that although the upright posture attenuates vascular responses to MS, the pattern of neurovascular responses does not differ between postures.
visceral blood flow; sympathetic; orthostatic; vascular conductance; renal; forearm
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.
prostaglandins; exercise; nervous system; sympathetic; mechanoreceptor
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.
obstructive sleep apnea; hypertension; chronic intermittent hypoxia; sympathoexcitation; systems biology
Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals.
Methods and Results
In 10 healthy normotensive subjects (3 f/7 m), (age 37±11 yrs), (BMI 24±3 kg/m2) direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA) were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT) technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index), was within the normal range (1,9–3,3) and MSNA was as expected for age and gender (13–44 burst/minute). RH-PAT index was inversely related to MSNA (r = −0.8, p = 0.005). RH-PAT index and MSNA were reciprocally related to time (h/week) spent on physical activity (p = 0.005 and p = 0.006 respectively) and platelet concentration (PLT) (p = 0.02 and p = 0.004 respectively).
Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular health.
Obstructive sleep apnea (OSA) is increasingly being recognized as a major health burden with strong focus on the associated cardiovascular risk. Studies from the last two decades have provided strong evidence for a causal role of OSA in the development of systemic hypertension. The acute physiological changes that occur during apnea promote nocturnal hypertension and may lead to the development of sustained daytime hypertension via the pathways of sympathetic activation, inflammation, oxidative stress, and endothelial dysfunction. This review will focus on the acute hemodynamic disturbances and associated intermittent hypoxia that characterize OSA and the potential pathophysiological mechanisms responsible for the development of hypertension in OSA. In addition the epidemiology of OSA and hypertension, as well as the role of treatment of OSA, in improving blood pressure control will be examined.
obstructive sleep apnea; hypertension; intermittent hypoxia; ambulatory blood pressure; sympathetic activation
Aging effects on sleep are important to consider for the practicing pulmonologist due to the increase in prevalence of major respiratory disorders as well as the normal changes that occur in sleep patterns with aging. Typically, aging is associated with decreases in the amount of slow wave sleep and increases in stage 1 and 2 non–rapid eye movement sleep, often attributed to an increased number of spontaneous arousals that occur in the elderly. Elderly individuals tend to go to sleep earlier in the evening and wake earlier due to a phase advance in their normal circadian sleep cycle. Furthermore the development of sleep-related respiratory disorders such as obstructive sleep apnea (OSA) and central sleep apnea or Cheyne-Stokes respiration (CSA-CSR) associated with congestive heart failure (CHF) occur with increasing prevalence in the elderly. The development of such disorders is often of major concern because they are associated with systemic hypertension and cardiovascular disease, metabolic disorders such as diabetes, and impaired neurocognition. The present review reflects the current understanding of the normal changes in sleep patterns and sleep needs with advancing age, in addition to the effect that aging has on the predisposition to and consequences of OSA and CSA-CSR associated with CHF.
Aging; sleep patterns; sleep apnea; congestive heart failure
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.
metabolic syndrome; sympathetic nervous system; autonomic function; diet
Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96 +/- 25% (n = 6, P < 0.01) and MABP by 12 +/- 3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 microgram/ml forearm per min) blocked the increase in MSNA (92 +/- 15% vs. 28 +/- 6%, n = 7, P < 0.01) and MABP (38 +/- 6 vs. 27 +/- 4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans.
The majority of patients with obstructive sleep apnea (OSA) suffer from hypertension as a complication of both the metabolic syndrome and OSA. In animal studies, intermittent hypoxia that simulates changes seen in OSA leads to chemoreceptor and chromaffin cell stimulation of sympathetic nerve activity, endothelial damage and impaired blood pressure modulation. Human studies reveal activation of sympathetic nerves, endothelial damage and exaggerated pressor responses to sympathetic neurotransmitters and endothelin. Although treatment of the OSA normalizes sympathetic nerve responses, it only lowers blood pressure modestly. Agents that block the consequences of sympathetic over activity, such as β1 blockers and angiotensin antagonists have effectively lowered blood pressure. Diuretics have been less successful. Treatment of hypertensive patients with OSA usually requires consideration of both increased sympathetic nerve activity and the metabolic syndrome.
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.
Sympathetic nervous system; Cardiomyopathy; Stress; Women