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Evaluation of Sympathetic Activity in Hypertension
  JOHTN
MECHANISMS OF HYPERTENSION
Evaluation of Sympathetic Activity in Hypertension
1Poghni A Peri-Okonny, 2Wanpen Vongpatanasin
1Fellow, 2Professor
1Department of Internal Medicine, Hypertension SectionUniversity of Texas Southwestern Medical Center, DallasTexas, USA
2Department of Internal Medicine, Hypertension SectionCardiology Division, University of Texas Southwestern MedicalCenter, Dallas, Texas, USA
Correspondence: Wanpen Vongpatanasin, ProfessorDepartment of Internal Medicine, Hypertension SectionCardiology Division, University of Texas Southwestern MedicalCenter, Dallas, Texas, USA
Phone: +2146482103
e-mail:wanpen.vongpatanasin@utsouthwestern.edu
 
ABSTRACT
The sympathetic nervous system (SNS) plays a major role in thepathogenesis of hypertension and contributes to hypertensivetarget organ complications. Advances in technology overthe last three decades have improved the ability to measuresympathetic nerve activity (SNA), thus enabling investigatorsto probe the role of SNS in the development of cardiovasculardiseases. The most direct method of measuring SNA employsthe technique of microneurography, which involves recordingof postganglionic sympathetic action potential using asubcutaneous electrode inserted into the candidate nerve.This method allows assessment of sympathetic vasoconstrictordischarge to the peripheral circulation in hypertension andprovides prognostic information in patients with cardiovasculardiseases. However, application of microneurography andother methods of assessment of SNS activity, includingnorepinephrine spillover and imaging of SNS innervation, inroutine clinical practice is limited by availability of the techniqueand lack of normal reference range established from largepopulation-based data. Nevertheless, these measurementsprovide further insight into mechanisms of hypertension andeffectiveness of various interventions in modifying sympatheticregulation of blood pressure.
Keywords: Hypertension, Microneurography, Musclesympathetic nerve activity, Norepinephrine spillover, Renaldenervation, Sympathetic nerve activity.
How to cite this article: Peri-Okonny PA, Vongpatanasin W.Evaluation of Sympathetic Activity in Hypertension. HypertensJ 2016;2(2):60-64.
Source of support: Nil
Conflict of interest: None
 
 
INTRODUCTION

The sympathetic branch of the autonomic nervous systemplays an important role in regulating the function of differentorgans over a range of physiologic conditions.1 Thesympathetic nervous system (SNS) promotes hypertension by inducing direct vasoconstriction and indirectly viaactivation of the renin-aldosterone-angiotensin system(RAAS).2 In recent years, numerous device-based therapieshave been developed to tackle SNS to reduce bloodpressure (BP), particularly in patients with resistant hypertension.The effectiveness of these therapies is limited bylack of real-time assessment of sympathetic nerve activity(SNA) during the procedure to determine procedural success.This article provides a brief overview of the differentmodes of evaluating SNS activity that have been appliedin the study of hypertension.

  OVERVIEW OF THE SYMPATHETIC PATHWAY

Afferent signals emanate from visceral organs via theafferent autonomic pathway to the central nervous systemwhere signals are integrated and transmitted through theefferent pathway back to effector organs. Preganglionicefferent fibers have cell bodies in the brain and the intermediolateralhorn of the spinal cord at the T1-L2 or L3levels. The axon terminals of these neurons synapse in vertebralor paravertebral sympathetic ganglia with cell bodiesof postganglionic neurons which project to effector organs.Synapses in the sympathetic ganglion use acetylcholinewhile synapses of postganglion neurons use norepinephrine(NE), with the exception of postsympathetic neuronsto the sweat glands which use acetylcholine.

MODES OF SYMPATHETIC NERVE
ACTIVITY EVALUATION

Microneurography

Microneurography was initially developed by Hagbarthand Vallbo in Upsula, Sweden around 1965 to 1966.3 Sincethen, it has developed into a powerful investigationaltool for examining the SNA to muscular and cutaneousvascular beds, both in healthy and diseased states. Thetechnique involves externally mapping the course of asuperficial nerve (e.g., peroneal, popliteal, radial, andmedian) by transcutaneous stimulation to evoke motoror sensory effects. In the case of the commonly usedperoneal nerve, the nerve is accessed just under thefibular head with the subject in the supine or seatedposition. A 200 µm tungsten electrode is insertedsubcutaneously into the peripheral nerve fascicle todirectly record postganglionic efferent sympathetic nervebursts to the skeletal muscle or skin with a referenceelectrode positioned within 2 to 3 cm.4 The raw muscle sympathetic nerve activity (MSNA) signal is amplified,filtered, rectified, and integrated to produce a neurogram,as shown in Figure 1.

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Evaluation of Sympathetic Activity in Hypertension

Evaluation of Sympathetic Activity in Hypertension
Fig. 1: Representative neurogram

Microneurography provides direct and beat-to-beatmeasurement of central sympathetic outflow to skeletalmuscle or cutaneous circulation. Muscle sympatheticnerve activity recordings have a reliable intra-individualreproducibility over time, and nerve activity and patternobtained from different sites in the same individual arevery similar.5,6 The ability to quantitate muscle or skinnerve activity is also valuable.

However, microneurography only provides informationregarding central sympathetic discharge to theregional vasculature innervated by the superficial nervestudied, but not to other regional vascular beds, such asrenal or splanchnic circulation. This limits generalizabilityof SNA to the whole body due to regional variationin the control of SNA.1 Despite this major limitation,total body, cardiac, and renal norepinephrine spilloverpositively correlates with MSNA.7 Another limitationof microneurography is that burst amplitude is highlydependent on the position of the recording electroderelative to the active nerve fibers, making comparison ofburst amplitude between different individuals problematic.5 Microneurography also provides information on themuscle or skin nerve activity under laboratory conditionswith no information on ambulatory conditions. However,microneurography can be performed repeatedly in thesame human subjects over long-term duration of monthsor years, which allows assessment of pharmacologic ornon-pharmacologic intervention of the SNS.

Plasma Norepinephrine Measurement

Norepinephrine is the sympathetic postganglionicneurotransmitter, and measurement of this hormone has been used as a surrogate for SNA. Plasma NE is easy toobtain but has significant limitations.
 
Plasma NE concentration depends on the rate ofrelease of the neurotransmitter from sympathetic nervesas well as mechanisms related to neurotransmitterclearance from plasma.8 Plasma NE concentration may beelevated in the conditions associated with decreased NEreuptake in the postsynaptic sympathetic nerve terminals,such as the use of cocaine or tricyclic antidepressants, orreduced renal clearance in the presence of renal failure,which is independent of central sympathetic outflow.9-11Thus, without accounting for these factors, plasma NEserves as a poor marker for SNA. Furthermore, plasmaNE represents a small fraction of the total NE releasedfrom neurotransmitter terminals and does not take intoaccount the regional variation of SNS regulation.1 Finally,plasma NE concentration demonstrates suboptimalreproducibility, though this can be improved by obtainingthe average of multiple repeated measurements in thesupine position through a venous catheter that has beenplaced for at least 30 minutes.5

Norepinephrine Spillover

Steady-state infusion of small amounts of tritiatedNE permits the calculation of NE plasma clearanceand NE spillover rate. This method addresses some ofthe limitations of plasma NE concentration because itaccounts for NE clearance and has the ability to measuretotal body and organ-specific NE spillover using thefollowing equations;

Evaluation of Sympathetic Activity in Hypertension

where NEvenous and NEarterial are plasma venous andarterial norepinephrine concentrations respectively,T-NEextraction is the fractional extraction of tritiated norepinephrineacross the organ, PF is organ plasma flow,dpm is disintegrations per minute of T-NE, and pg ispicograms.12

Norepinephrine spillover does not directly measureNE release; thus it does not directly measure SNA. Therate of NE spillover is dependent on factors, such asreuptake at nerve terminals and into non-neural cells,o-methylation after reuptake into non-neural cells, anddiffusion into plasma. Changes in these factors may affectconclusions drawn from this NE spillover test. Measurementof organ NE spillover requires simultaneous arterial and venous cannulation and infusion of radiolabeled NE.Thus, it is used mainly in the research setting and notapplicable in clinical practice. Alteration in NE spilloverin each organ may vary depending on the condition studied.For example, renal NE spillover is elevated in obesewhen compared to lean individuals. In contrast, cardiacNE spillover is paradoxically suppressed in obese whencompared to lean individuals while the splanchnic NEspillover was comparable in lean and obese subjects. Thus,the regional NE spillover in one organ cannot be extrapolatedto other organs or to the whole body response.13
 
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Neuroimaging

Sympathetic activity has been investigated by neuroimagingtechniques that use radiolabeled sympatheticamines (e.g., [123I] metaiodobenzylguanidine/123 I-MIBG,6 [18F] fluorodopamine, [11C] - hydroxyephedrine) to imagesympathetic innervation of an organ. The heart hasbeen the most studied organ using sympathetic imagingand 123I-MIBG is the most utilized tracer. Washout of theinjected123I-MIBG or heart:mediastinum ratio of MIBGradioactivity are used as a surrogate for cardiac sympatheticactivity.5,14 Imaging techniques are limited bythe costs and limited availability. Furthermore, certaindrugs including cocaine, antidepressants, some antipsychoticdrugs, and reserpine were shown to interferewith MIBG uptake, thereby limiting its sensitivity andspecificity.15

Heart Rate and Heart Rate Spectral Analysis

Elevation in heart rate could be the consequence ofsympathetic activation or vagal withdrawal.16 Powerspectral analysis of heart rate variability was thoughtto provide more specific information regarding vagal vssympathetic control of the heart rate. A power spectrumof very low (∼0.03 Hz), low (∼0.05-0.15 Hz), and high(∼0.3-0.4 Hz) frequency oscillations is constructedby Fourier transformation of instantaneous heart rate(converted from ECG-derived RR intervals).17 The areaunder the low-frequency (LF) oscillation was thoughtto represent cardiac sympathetic activity while the areaunder the high-frequency (HF) oscillation representsparasympathetic activity. However, this dichotomyhas been called into question18 as autonomic blockingstudies showed that the HF power was also increasedby beta adrenergic receptor (AR) blocker propranololand reduced by intranasal cocaine, which was not shownto have an impact on the vagal tone in humans.19,20Furthermore, results from multiple studies have shownthat LF spectral oscillations were not a measure of cardiacsympathetic activity, but rather a measure of baroreflexfunction.18
 
SYMPATHETIC NERVE ACTIVITY
AND HYPERTENSION


Using the technique of microneurography and othercomplementary techniques, researchers have observedsympathetic overactivity in pre-hypertensive individuals,suggesting the role of SNS in the pathogenesis ofhypertension.21 Individuals with essential hypertensiondisplay high sympathetic nerve traffic when comparedto normal controls across young, middle, and elderlyage groups.1 Plasma NE, cardiac, and renal NE spilloverwere also shown to be elevated in hypertensive individualscompared to age-matched controls.1,10,22 Sympatheticnerve activity as measured by microneurography is alsoincreased in secondary forms of hypertension, includingprimary aldosteronism and renovascular hypertension,which was reversed after specific treatment to eliminatesecondary causes (adrenalectomy for unilateral aldosteroneproducing adenoma and percutaneous renal interventionin renovascular hypertension).23,24 Total body NEspillover was also increased in patients with renovascularhypertension compared to age-matched controls.25 Sympatheticnerve activity and BP also increased in individualswith renal failure, which improved after renal transplantation,suggesting the role of renal disease in inducingsympathetic overactivation.26-28 Sympathetic innervationto the kidneys is potentially more important than SNSinfluence to other organs in BP regulation via increasingrenal sodium absorption in the renal tubules via alphaAR, renin release through beta AR, and renal vasoconstrictionthrough alpha AR mechanism. As a result, renalsympathetic denervation has been developed to reduce BPin patients with resistant hypertension. The procedureswere designed to ablate both efferent nerve terminals andafferent nerve ending, which may, in turn, reduce overallcentral sympathetic discharge to other organs. However,recent studies failed to show reduction in MSNA29,30 asassessed by microneurography or cardiac sympatheticactivity measured by 123I-MIBG after renal denervation.31

In addition to renal disease, previous studies havedemonstrated increased SNA in individuals with type 2diabetes mellitus, related to the sympathoexcitatoryeffects of insulin. Diabetic patients with hypertensiondisplay higher MSNA compared with hypertensivepatients without diabetes.32 Similarly, higher levels ofSNA have been observed in patients with both metabolicsyndrome and hypertension when compared to patientswith hypertension alone without metabolic syndrome.33Individuals with obstructive sleep apnea (OSA) exhibitincreased SNA34 related to chronic intermittent hypoxiacausing activation of chemoreflex. Human studieshave also demonstrated a strong association betweenOSA and hypertension, with a recent study showing a direct correlation between OSA severity and increase inMSNA in normotensive individuals.35,36 Functional brainimaging studies have shown that compared to controls,individuals with OSA have decreased signal intensitychanges and increased gray matter concentration inbrainstem regions important for SNA regulation, suchas the rostral ventrolateral medulla, ventral mid-brain,dorsolateral pons, and medullary raphe. Furthermore,these changes were not only directly correlated withincrease in MSNA but were reversed with chroniccontinuous positive airway pressure (CPAP) treatmentwith sustained improvement of mid-brain functionalmagnetic resonance imaging (fMRI) changes and SNAat 12 months.37 Thus, chronic intermittent hypoxiain OSA may predispose to anatomic and functionalchanges resulting in increase in sympathetic outflowfrom the brainstem center which can be amelioratedwith CPAP. This increase in SNA seen in OSA is likely tobe important in the recognition of OSA as an importantsecondary cause of hypertension and an important causeof uncontrolled or resistant hypertension.38,39

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Evaluation of Sympathetic Activity in Hypertension

Excessive activation of SNS is not only implicatedin the pathogenesis of hypertension, but also in thepathogenesis of hypertensive target organ complications.Patients with left ventricular hypertrophy (LVH) possesshigher levels of SNA compared to hypertensive patientswithout LVH.40,41 Increased SNS activity has been linkedto increased mortality in patients with congestive heartfailure, renal failure, stroke, and chronic obstructivepulmonary disease,42-45 which may explain increasedcardiovascular events in hypertensive patients with LVH.

CONCLUSION

Different methods used in evaluating SNA have shownthat SNA is increased in various types of human hypertension.There is currently no ideal method for obtainingan instantaneous snapshot of the complex systemicregional regulation of SNA. Microneurography and NEspillover are the most direct methods for assessing SNA,though these methods are not used beyond the investigationalsetting or in highly specialized centers. Giventhe regional regulation of the SNS and the limitations ofthe different methods of evaluating SNA, the use of complimentarymethods may provide a more comprehensiveassessment of SNA in humans.

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